**Nutrition in CKD**

**Chapter 8**

**Provisional chapter**

**The Roles of Indoxyl Sulphate and p-Cresyl Sulphate in**

Indoxyl sulphate (IS) and p-cresyl sulphate (PCS) are products of proteolytic bacterial fermentation by gut microbiota. They accumulate in the sera of patients with chronic kidney disease (CKD) and have been associated with CKD progression and cardiovascular and all-cause mortality. Therapeutic strategies for lowering IS and PCS include increased clearance (enhanced dialysis), gastrointestinal sequestration (oral adsorbents), reduced synthesis (dietary protein restriction, dietary fibre augmentation and pre-, pro- or synbiotics), antioxidants and organic anion transporter modulators. This review will discuss the roles of IS and PCS as therapeutic targets and examine the clinical evidence for different treatment options and their effects on CKD and cardiovascular disease risk. We will include our group's research with pre-, pro- and synbiotic interventions to mitigate serum uraemic

**Keywords:** indoxyl sulphate, p-cresyl sulphate, uraemic toxins, chronic kidney disease,

The reciprocal relationship observed between gut microbiota and chronic kidney disease (CKD) has led to the recent recognition of the 'gut-kidney axis'. Patients with CKD, including those with end-stage kidney disease (ESKD), often experience impaired uraemic toxin clearance, salt and water retention, dietary restrictions, anorexia, dysgeusia and malnutrition,

**The Roles of Indoxyl Sulphate and p-Cresyl Sulphate** 

**in Patients with Chronic Kidney Disease: A Review of** 

DOI: 10.5772/intechopen.69325

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

**Patients with Chronic Kidney Disease: A Review of**

**Therapeutic Options**

**Therapeutic Options**

Melissa Nataatmadja, Yeoungjee Cho, Katrina Campbell and David W. Johnson

Melissa Nataatmadja, Yeoungjee Cho, Katrina Campbell and David W. Johnson

http://dx.doi.org/10.5772/intechopen.69325

**Abstract**

gut microbiome

**1. Introduction**

Additional information is available at the end of the chapter

toxin accumulation and modify cardiovascular and renal risk.

Additional information is available at the end of the chapter

**Provisional chapter**

## **The Roles of Indoxyl Sulphate and p-Cresyl Sulphate in Patients with Chronic Kidney Disease: A Review of Therapeutic Options The Roles of Indoxyl Sulphate and p-Cresyl Sulphate in Patients with Chronic Kidney Disease: A Review of Therapeutic Options**

DOI: 10.5772/intechopen.69325

Melissa Nataatmadja, Yeoungjee Cho, Katrina Campbell and David W. Johnson Melissa Nataatmadja, Yeoungjee Cho, Katrina Campbell and David W. Johnson

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.69325

#### **Abstract**

Indoxyl sulphate (IS) and p-cresyl sulphate (PCS) are products of proteolytic bacterial fermentation by gut microbiota. They accumulate in the sera of patients with chronic kidney disease (CKD) and have been associated with CKD progression and cardiovascular and all-cause mortality. Therapeutic strategies for lowering IS and PCS include increased clearance (enhanced dialysis), gastrointestinal sequestration (oral adsorbents), reduced synthesis (dietary protein restriction, dietary fibre augmentation and pre-, pro- or synbiotics), antioxidants and organic anion transporter modulators. This review will discuss the roles of IS and PCS as therapeutic targets and examine the clinical evidence for different treatment options and their effects on CKD and cardiovascular disease risk. We will include our group's research with pre-, pro- and synbiotic interventions to mitigate serum uraemic toxin accumulation and modify cardiovascular and renal risk.

**Keywords:** indoxyl sulphate, p-cresyl sulphate, uraemic toxins, chronic kidney disease, gut microbiome

## **1. Introduction**

The reciprocal relationship observed between gut microbiota and chronic kidney disease (CKD) has led to the recent recognition of the 'gut-kidney axis'. Patients with CKD, including those with end-stage kidney disease (ESKD), often experience impaired uraemic toxin clearance, salt and water retention, dietary restrictions, anorexia, dysgeusia and malnutrition,

which in turn leads to quantitative and qualitative alterations in gut microbiome composition (gut dysbiosis). Further effects include gut wall oedema, intestinal barrier impairment, translocation of bacteria and endotoxins across the intestinal wall and resultant systemic inflammation [1–3]. Gut dysbiosis may in turn lead to the production of various toxins and metabolites that contribute to uraemic toxicity, cardiovascular disease and progressive kidney scarring and failure [4–6]. The central role of the gut microbiome in kidney health therefore makes it an appealing therapeutic target in patients with CKD [7, 8].

**3. Serum IS and PCS levels are associated with adverse renal, metabolic** 

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183

Elevation of serum IS and PCS levels in patients with CKD is associated with CKD progression [17]. The mechanisms underpinning the adverse renal effects of IS and PCS are thought to be at least partly mediated by the production of reactive oxygen species, which in turn activate the nuclear factor kappa B pathway (NFκB) (**Figure 1**) [18]. *In vitro* studies have demonstrated that pro-inflammatory cytokine release and plasminogen activator inhibitor-1 upregulation via the NFκB pathway subsequently led to inhibition of cell proliferation and induction of renal tubulointerstitial fibrosis [4, 5]. These observations have been similarly replicated in animal models, whereby oral administration of IS [6, 19] and PCS [20] caused renal function impairment, glomerular sclerosis and tubulointerstitial fibrosis. IS and PCS have also been shown both *in vitro* and *in vivo* to activate the intrarenal renin-angiotensinaldosterone system and promote renal tubular epithelial-to-mesenchymal transition, possi-

In a prospective, observational study of 268 patients with varying stages of CKD, Wu and colleagues demonstrated a significant association between higher IS (hazard ratio [HR] 1.06, 95% confidence interval [CI] 1.04–1.09, p < 0.001) and PCS levels (HR 1.09, 95% CI 1.06–1.13, p < 0.001) and CKD progression, defined as greater than 50% reduction in estimated glomerular filtration rate (eGFR) or progression to ESKD [17]. Serum PCS and IS remained independently associated with CKD progression after adjustment for patient demographic characteristics (age, gender, diabetes mellitus, p < 0.001) or baseline renal function (p < 0.001). Additionally, IS and PCS levels at baseline were significantly higher in those patients who died during follow-up (serum PCS 12.07 [<1–42.06] mg/L vs. 4.1 (<1–36.24) mg/L in survivors, p = 0.002; serum IS 4.78 [0.7–12.54] mg/L vs. 2.07 [<0.225–53.58] mg/dL, p = 0.05). Elevated serum total PCS was also found to be significantly associated with all-cause mortality on univariable analysis (HR 1.10, 95% CI 1.05–1.15, p < 0.001) and remained a predictor of mortality independent of other risk factors on multivariable analysis adjusted for patient demographic characteristics, baseline renal function and biomarkers including highly sensitive C-reactive protein [17].

Elevated PCS has been associated with insulin resistance and may therefore predispose to the metabolic syndrome and its complications. In mouse models, the administration of PCS for 4 weeks has been observed to induce hyperglycaemia, insulin resistance, hypercholesterolaemia and fat redistribution to muscle and liver, similar to the metabolic derangements observed in CKD [22] (**Figure 1**). These metabolic effects appeared to be ameliorated by uraemic toxin-reducing therapy, as the use of the prebiotic agent, arabino-xylo-oligosaccharide, reduced serum PCS concentration and improved glucose tolerance, insulin resistance, dyslipidaemia and ectopic fat distribution in uraemic, subtotal nephrectomised mice [22].

bly via increased expression of transforming growth factor-β and Snail [21].

**and cardiovascular effects**

**3.1. Renal effects**

**3.2. Metabolic effects**

Two key nephrovascular toxins produced by proteolytic bacterial fermentation in the gut are indoxyl sulphate (IS) and p-cresyl sulphate (PCS). IS is produced by tryptophan metabolism facilitated by *Escherichia coli* and *Clostridium sporogenes*, while PCS is generated by break down of tyrosine and phenylalanine by intestinal anaerobes, such as *Clostridium difficile, Faecalibacterium prausnitzii, Subdoligranulum* and selected strains within the *Bifidobacterium* and *Lactobacillus genus* [8]. IS and PCS are both solely produced by the gut microbiota [9–12] and accumulate in the serum of patients with CKD due to both increased intestinal production and reduced glomerular filtration and proximal tubular secretion [12–14]. Elevated serum levels of IS and PCS have been reported to be associated with CKD progression [13] and increased risks of cardiovascular events and all-cause mortality [15].

Although IS and PCS levels can be lowered with various therapeutic modalities, how this impacts on the risks of mortality and cardiovascular outcomes remains unclear. This review will discuss the roles of IS and PCS as therapeutic targets and examine the clinical evidence for different treatment options and their effects on CKD and cardiovascular disease risk.

## **2. Serum IS and PCS levels are elevated in CKD**

Serum IS and PCS levels have been demonstrated to be elevated in patients with CKD, where IS levels may be more than 50 times and PCS levels more than 15 times the levels of those found in healthy people [12, 14]. Our group has demonstrated that IS and PCS levels are significantly elevated in patients with early-stage CKD compared with control subjects. These levels were seen to be progressively more elevated with advancing severity of CKD [13]. Increased circulating levels of IS and PCS have also been observed in living kidney donors, which were sustained at 2 years post-surgery [16]. Levels of IS and PCS appear to be most elevated in ESKD and are not effectively removed by haemodialysis [14]. In a sample of 45 haemodialysis patients, Itoh et al. observed IS and PCS levels were markedly elevated (2.99 ± 0.18 mg/dL and 3.71 ± 0.28 mg/dL, respectively) compared with the healthy subjects (0.05 ± 0.01 mg/dL and 0.22 ± 0.99 mg/dL, respectively), and these levels were only lowered by approximately 30% post-dialysis (2.02 ± 0.12 mg/dL and 2.60 ± 0.21 mg/dL, respectively). This degree of elevation and inefficient removal warrants exploration of the potential impact of these toxins in CKD.

## **3. Serum IS and PCS levels are associated with adverse renal, metabolic and cardiovascular effects**

## **3.1. Renal effects**

which in turn leads to quantitative and qualitative alterations in gut microbiome composition (gut dysbiosis). Further effects include gut wall oedema, intestinal barrier impairment, translocation of bacteria and endotoxins across the intestinal wall and resultant systemic inflammation [1–3]. Gut dysbiosis may in turn lead to the production of various toxins and metabolites that contribute to uraemic toxicity, cardiovascular disease and progressive kidney scarring and failure [4–6]. The central role of the gut microbiome in kidney health therefore makes it

Two key nephrovascular toxins produced by proteolytic bacterial fermentation in the gut are indoxyl sulphate (IS) and p-cresyl sulphate (PCS). IS is produced by tryptophan metabolism facilitated by *Escherichia coli* and *Clostridium sporogenes*, while PCS is generated by break down of tyrosine and phenylalanine by intestinal anaerobes, such as *Clostridium difficile, Faecalibacterium prausnitzii, Subdoligranulum* and selected strains within the *Bifidobacterium* and *Lactobacillus genus* [8]. IS and PCS are both solely produced by the gut microbiota [9–12] and accumulate in the serum of patients with CKD due to both increased intestinal production and reduced glomerular filtration and proximal tubular secretion [12–14]. Elevated serum levels of IS and PCS have been reported to be associated with CKD progression [13] and increased risks of cardiovascular events and all-cause

Although IS and PCS levels can be lowered with various therapeutic modalities, how this impacts on the risks of mortality and cardiovascular outcomes remains unclear. This review will discuss the roles of IS and PCS as therapeutic targets and examine the clinical evidence for different treatment options and their effects on CKD and cardiovascular

Serum IS and PCS levels have been demonstrated to be elevated in patients with CKD, where IS levels may be more than 50 times and PCS levels more than 15 times the levels of those found in healthy people [12, 14]. Our group has demonstrated that IS and PCS levels are significantly elevated in patients with early-stage CKD compared with control subjects. These levels were seen to be progressively more elevated with advancing severity of CKD [13]. Increased circulating levels of IS and PCS have also been observed in living kidney donors, which were sustained at 2 years post-surgery [16]. Levels of IS and PCS appear to be most elevated in ESKD and are not effectively removed by haemodialysis [14]. In a sample of 45 haemodialysis patients, Itoh et al. observed IS and PCS levels were markedly elevated (2.99 ± 0.18 mg/dL and 3.71 ± 0.28 mg/dL, respectively) compared with the healthy subjects (0.05 ± 0.01 mg/dL and 0.22 ± 0.99 mg/dL, respectively), and these levels were only lowered by approximately 30% post-dialysis (2.02 ± 0.12 mg/dL and 2.60 ± 0.21 mg/dL, respectively). This degree of elevation and inefficient removal warrants exploration of the potential impact

an appealing therapeutic target in patients with CKD [7, 8].

182 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

**2. Serum IS and PCS levels are elevated in CKD**

mortality [15].

disease risk.

of these toxins in CKD.

Elevation of serum IS and PCS levels in patients with CKD is associated with CKD progression [17]. The mechanisms underpinning the adverse renal effects of IS and PCS are thought to be at least partly mediated by the production of reactive oxygen species, which in turn activate the nuclear factor kappa B pathway (NFκB) (**Figure 1**) [18]. *In vitro* studies have demonstrated that pro-inflammatory cytokine release and plasminogen activator inhibitor-1 upregulation via the NFκB pathway subsequently led to inhibition of cell proliferation and induction of renal tubulointerstitial fibrosis [4, 5]. These observations have been similarly replicated in animal models, whereby oral administration of IS [6, 19] and PCS [20] caused renal function impairment, glomerular sclerosis and tubulointerstitial fibrosis. IS and PCS have also been shown both *in vitro* and *in vivo* to activate the intrarenal renin-angiotensinaldosterone system and promote renal tubular epithelial-to-mesenchymal transition, possibly via increased expression of transforming growth factor-β and Snail [21].

In a prospective, observational study of 268 patients with varying stages of CKD, Wu and colleagues demonstrated a significant association between higher IS (hazard ratio [HR] 1.06, 95% confidence interval [CI] 1.04–1.09, p < 0.001) and PCS levels (HR 1.09, 95% CI 1.06–1.13, p < 0.001) and CKD progression, defined as greater than 50% reduction in estimated glomerular filtration rate (eGFR) or progression to ESKD [17]. Serum PCS and IS remained independently associated with CKD progression after adjustment for patient demographic characteristics (age, gender, diabetes mellitus, p < 0.001) or baseline renal function (p < 0.001). Additionally, IS and PCS levels at baseline were significantly higher in those patients who died during follow-up (serum PCS 12.07 [<1–42.06] mg/L vs. 4.1 (<1–36.24) mg/L in survivors, p = 0.002; serum IS 4.78 [0.7–12.54] mg/L vs. 2.07 [<0.225–53.58] mg/dL, p = 0.05). Elevated serum total PCS was also found to be significantly associated with all-cause mortality on univariable analysis (HR 1.10, 95% CI 1.05–1.15, p < 0.001) and remained a predictor of mortality independent of other risk factors on multivariable analysis adjusted for patient demographic characteristics, baseline renal function and biomarkers including highly sensitive C-reactive protein [17].

#### **3.2. Metabolic effects**

Elevated PCS has been associated with insulin resistance and may therefore predispose to the metabolic syndrome and its complications. In mouse models, the administration of PCS for 4 weeks has been observed to induce hyperglycaemia, insulin resistance, hypercholesterolaemia and fat redistribution to muscle and liver, similar to the metabolic derangements observed in CKD [22] (**Figure 1**). These metabolic effects appeared to be ameliorated by uraemic toxin-reducing therapy, as the use of the prebiotic agent, arabino-xylo-oligosaccharide, reduced serum PCS concentration and improved glucose tolerance, insulin resistance, dyslipidaemia and ectopic fat distribution in uraemic, subtotal nephrectomised mice [22].

with aortic calcification measured by multislice spiral computed tomography [24]. Likewise, total and free PCS levels have been linked with vascular disease [25]. Not surprisingly, elevated serum levels of both toxins have been reported to be predictors of cardiovascular events and mortality. Higher serum IS levels independently predicted overall mortality (HR 2.47, 95% CI 1.62–3.77), but not CV mortality, in 139 patients with stage 2–5 CKD participating in a study performed by the European Uraemic Toxin Work Group (EUTox) [24]. Similar results were reported in a prospective, observational cohort study of 521 US incident haemodialysis patients whereby serum IS concentrations above the median value of 1.6 mg/dL were independently associated with all-cause mortality (HR 1.30, 95% CI 1.01–1.69) after adjustment for age, sex, race, comorbidity score, baseline serum albumin, obesity and serum creatinine [26]. Elevated free PCS concentration has also been demonstrated to be an independent predictor of cardiovascular events [27, 28] and overall cardiovascular mortality [25] in CKD patients,

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185

A meta-analysis by Lin and colleagues of 11 observational studies involving 1572 patients with stages 1–5 CKD followed for 0.83 to 5 years found that all-cause mortality was significantly associated with both free PCS (pooled odds ratio [OR] 1.16, 95% CI 1.03–1.30, p = 0.013) and free IS levels (pooled OR 1.10, 95% CI 1.03–1.17, p = 0.03) [15]. However, there was a moderate

IS, respectively. Furthermore, there was a concern about publication bias based on an asymmetrical funnel plot and significant Egger's test (p = 0.005). Following subsequent adjustment for the effect of publication bias, the adjusted point estimate of the OR reduced from 1.16 to 1.03 (95% CI 0.93–1.16), thereby raising concern about exaggeration of the observed effect size in the primary analysis. The study also reported a significantly increased risk of cardiovascular events with elevated levels of free PCS (pooled OR 1.28, 95% CI 1.10–1.50, p = 0.002),

Furthermore, there was evidence of publication bias, such that when analysis was repeated using Duval and Tweedie's trim-and-fill method, the estimate was no longer statistically sig-

Given the numerous deleterious, multi-system effects that have been associated with elevated serum IS and PCS concentrations, much interest has been generated in developing therapeutic options to reduce the levels of these nephrovascular toxins with the aim of improving clinical outcomes in patients with CKD. Potential therapeutic strategies to reduce IS and PCS levels in patients with CKD may involve reducing gut synthesis, gastrointestinal sequestra-

Since increased dietary protein load can result in heightened generation of uraemic toxins by the gut microbiota, prescription of very low-protein diets has experienced a resurgence of interest. Marzocco and colleagues performed a post-hoc analysis of a very low vs. low-protein

**4. Therapeutic opportunities for reducing serum IS and PCS levels**

tion, reduced proximal tubular retention and increased dialytic clearance (**Table 1**).

although this result was again limited by a high level of heterogeneity (I2

nificant with an adjusted OR of 1.10 (95% CI 0.93–1.27).

values of 71.5% (p = 0.004), and 74.2% (p = 0.004) for PCS and

= 80.7%, p < 0.001).

including those ESKD receiving dialysis.

level of heterogeneity with I2

**4.1. Reduced gut synthesis**

**Figure 1.** Mechanisms and potential effects of indoxyl sulphate (IS) and p-cresyl sulphate (PCS) on renal, metabolic and cardiovascular outcomes.

#### **3.3. Cardiovascular effects and mortality**

IS has been demonstrated to cause concentration-dependent vascular smooth muscle cell proliferation [23] and aortic calcification with aortic wall thickening in rats [6]. This appears to apply similarly to humans, such that elevated serum IS levels have been shown to be associated with aortic calcification measured by multislice spiral computed tomography [24]. Likewise, total and free PCS levels have been linked with vascular disease [25]. Not surprisingly, elevated serum levels of both toxins have been reported to be predictors of cardiovascular events and mortality. Higher serum IS levels independently predicted overall mortality (HR 2.47, 95% CI 1.62–3.77), but not CV mortality, in 139 patients with stage 2–5 CKD participating in a study performed by the European Uraemic Toxin Work Group (EUTox) [24]. Similar results were reported in a prospective, observational cohort study of 521 US incident haemodialysis patients whereby serum IS concentrations above the median value of 1.6 mg/dL were independently associated with all-cause mortality (HR 1.30, 95% CI 1.01–1.69) after adjustment for age, sex, race, comorbidity score, baseline serum albumin, obesity and serum creatinine [26]. Elevated free PCS concentration has also been demonstrated to be an independent predictor of cardiovascular events [27, 28] and overall cardiovascular mortality [25] in CKD patients, including those ESKD receiving dialysis.

A meta-analysis by Lin and colleagues of 11 observational studies involving 1572 patients with stages 1–5 CKD followed for 0.83 to 5 years found that all-cause mortality was significantly associated with both free PCS (pooled odds ratio [OR] 1.16, 95% CI 1.03–1.30, p = 0.013) and free IS levels (pooled OR 1.10, 95% CI 1.03–1.17, p = 0.03) [15]. However, there was a moderate level of heterogeneity with I2 values of 71.5% (p = 0.004), and 74.2% (p = 0.004) for PCS and IS, respectively. Furthermore, there was a concern about publication bias based on an asymmetrical funnel plot and significant Egger's test (p = 0.005). Following subsequent adjustment for the effect of publication bias, the adjusted point estimate of the OR reduced from 1.16 to 1.03 (95% CI 0.93–1.16), thereby raising concern about exaggeration of the observed effect size in the primary analysis. The study also reported a significantly increased risk of cardiovascular events with elevated levels of free PCS (pooled OR 1.28, 95% CI 1.10–1.50, p = 0.002), although this result was again limited by a high level of heterogeneity (I2 = 80.7%, p < 0.001). Furthermore, there was evidence of publication bias, such that when analysis was repeated using Duval and Tweedie's trim-and-fill method, the estimate was no longer statistically significant with an adjusted OR of 1.10 (95% CI 0.93–1.27).

## **4. Therapeutic opportunities for reducing serum IS and PCS levels**

Given the numerous deleterious, multi-system effects that have been associated with elevated serum IS and PCS concentrations, much interest has been generated in developing therapeutic options to reduce the levels of these nephrovascular toxins with the aim of improving clinical outcomes in patients with CKD. Potential therapeutic strategies to reduce IS and PCS levels in patients with CKD may involve reducing gut synthesis, gastrointestinal sequestration, reduced proximal tubular retention and increased dialytic clearance (**Table 1**).

## **4.1. Reduced gut synthesis**

**3.3. Cardiovascular effects and mortality**

184 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

cardiovascular outcomes.

IS has been demonstrated to cause concentration-dependent vascular smooth muscle cell proliferation [23] and aortic calcification with aortic wall thickening in rats [6]. This appears to apply similarly to humans, such that elevated serum IS levels have been shown to be associated

**Figure 1.** Mechanisms and potential effects of indoxyl sulphate (IS) and p-cresyl sulphate (PCS) on renal, metabolic and

Since increased dietary protein load can result in heightened generation of uraemic toxins by the gut microbiota, prescription of very low-protein diets has experienced a resurgence of interest. Marzocco and colleagues performed a post-hoc analysis of a very low vs. low-protein


Probiotics and prebiotics represent another strategy for reducing uraemic toxin synthesis. Preparations of lactic-acid bacteria, simulating a probiotic, have been shown to decrease serum IS concentrations by 30% and also reverse aerobic bacterial overgrowth [35]. Their use has been demonstrated to result in a significant decrease in urinary PCS and an increase in faecal bifidobacteria [36]. Synbiotics, which represent a combination of pre- and probiotics, have similarly been demonstrated to reduce serum IS and PCS levels in CKD and haemodialysis patients [37–39]. More recently, the use of synbiotics for reducing uraemic toxin levels has been evaluated in the SYNbiotics Easing Renal failure by improving Gut microbiologY (SYNERGY) trial [40, 41]. In this single-centre, double-blind, placebo-controlled, cross-over trial, 37 pre-dialysis patients with stage 4 or 5 CKD were randomized to receive either synbiotic supplements or placebo for 6 weeks, followed by a 4-week wash-out period, followed by treatment with the alternative therapy for a further 6 weeks. Thirty-one participants completed both treatments. Although the study failed to demonstrate a significant change in total serum IS levels (−2 mmol/L, 95% CI −5 to 1 mmol/L, p = 0.12), the change in serum PCS levels did reach a level of statistical significance, with a 13% reduction in the treatment group (−14 mmol/L, 95% CI −27 to −2 mmol/L, p = 0.03). Furthermore, after excluding the 10 participants who had received antibiotic therapy during the trial, which is known to affect the balance of bacterial species in the gut [8, 42], the changes in serum levels with synbiotic therapy for both total IS (−5 mmol/L, 95% CI −8 to −1 mmol/L, p = 0.03) and PCS (−25 mmol/L, 95% CI −38 to −12 mmol/L, p = 0.001) were significant. The changes in free IS and PCS levels were also significant amongst antibiotic-free completers. Synbiotic therapy additionally had an effect on the stool microbiome, with significantly increased abundance of *Bifidobacterium* spp. (3.2%, p = 0.003) and *Lachnospiraceae* (2.1%, p = 0.01) and decreased abundance of *Ruminococcaceae* (4.3%, p = 0.01). Interestingly, albuminuria was observed to significantly increase with synbiotic therapy, which contradicted the reports of a beneficial effect on proteinuria from animal studies using other uraemic toxin-lowering therapies, such as AST-120 [43, 44]. Due to the short duration and small participant numbers of synbiotic trials to date, the effects of treatment on patient-level clinical outcomes remain

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Lastly, the use of acarbose for lowering serum levels of gut-derived uraemic toxins has been investigated. Acarbose, an alpha-glucosidase inhibitor, causes increased delivery of undigested carbohydrate to the colon, which may drive gut bacterial fermentation towards a saccharolytic pathway and away from proteolytic fermentation and toxin production. In a pilot pre-test/post-test study involving nine healthy volunteers, Evanepoel et al. demonstrated that treatment with oral acarbose 300 mg per day for 3 weeks resulted in significant reductions in both serum p-cresol concentration (1.14–1.11 mg/L, p = 0.047) and urinary excretion of p-cresol (29.93–10.54 mg/day, p = 0.03), suggesting reduced colonic generation of p-cresol, the

IS and PCS absorption from the gut may also be prevented by the use of oral intestinal adsorbents, such as AST-120 (Kremezin), which bind uraemic toxins and their precursors thereby sequestering them in the gut and allowing them to be excreted via the faeces. Oral administration of AST-120 has been shown to result in a dose-dependent decrease in serum IS and PCS

precursor of PCS [45]. Further studies confirming this finding are required.

unknown [2].

**4.2. Gastrointestinal sequestration**

**Table 1.** Potential therapeutic interventions targeting indoxyl sulphate (IS) and p-cresyl sulphate (PCS).

diet cross-over study [29]. Thirty-two patients with a creatinine clearance between 20 and 55 ml/min were included and randomized to receive either a very low-protein diet (VLPD; 0.3 g/ kg/day) or a low-protein diet (LPD; 0.6 g/kg/day) in the first week, then switched to the other in the second week. There was no wash-out period. The authors found that patients treated with a VLPD experienced a significant 36% reduction in serum IS levels compared with those treated with a LPD (7.12 ± 3.89 μM during VLPD vs. 11.1 ± 6.6 μM during LPD, p < 0.0001). Although a meta-analysis has identified reduction in the occurrence of renal death with a lowprotein intake in CKD patients, the overall value of these diets remains a subject of debate, given that the risks of malnutrition may present a greater danger [30–32]. Furthermore, poor compliance is also likely to be an issue, as participants often did not meet dietary targets even with the intensive support provided within a trial setting.

There is newer evidence to suggest that dietary fibre may in fact be more important than dietary protein intake in terms of managing uraemic toxin levels. A single-centre, cross-sectional study of 40 patients with CKD measured baseline total and free serum IS and PCS levels and correlated this with dietary factors including dietary fibre, protein and protein-fibre index [10]. In this study, dietary fibre was found to be inversely associated with free and total serum PCS (r = −0.42 and r = −0.44, both p < 0.01) whereas dietary protein was not (r= −0.14, p = 0.38). Protein-fibre index was significantly associated with both total PCS (r = 0.43, p = 0.005) and total IS (r = 0.40, p = 0.012) levels. Increased dietary fibre as an intervention has been shown to result in significantly reduced free plasma IS in haemodialysis patients [33]. Moreover, a prospective cohort study of 390 Swedish men between the age of 70 and 71 years found an association between protein-fibre intake ratio and cardiovascular events (adjusted HR 1.33, 95% CI 1.08–1.64). These findings suggest that dietary intervention focusing on protein-fibre ratio has the potential to influence clinical outcomes [34], mediated via uraemic toxin production.

Probiotics and prebiotics represent another strategy for reducing uraemic toxin synthesis. Preparations of lactic-acid bacteria, simulating a probiotic, have been shown to decrease serum IS concentrations by 30% and also reverse aerobic bacterial overgrowth [35]. Their use has been demonstrated to result in a significant decrease in urinary PCS and an increase in faecal bifidobacteria [36]. Synbiotics, which represent a combination of pre- and probiotics, have similarly been demonstrated to reduce serum IS and PCS levels in CKD and haemodialysis patients [37–39]. More recently, the use of synbiotics for reducing uraemic toxin levels has been evaluated in the SYNbiotics Easing Renal failure by improving Gut microbiologY (SYNERGY) trial [40, 41]. In this single-centre, double-blind, placebo-controlled, cross-over trial, 37 pre-dialysis patients with stage 4 or 5 CKD were randomized to receive either synbiotic supplements or placebo for 6 weeks, followed by a 4-week wash-out period, followed by treatment with the alternative therapy for a further 6 weeks. Thirty-one participants completed both treatments. Although the study failed to demonstrate a significant change in total serum IS levels (−2 mmol/L, 95% CI −5 to 1 mmol/L, p = 0.12), the change in serum PCS levels did reach a level of statistical significance, with a 13% reduction in the treatment group (−14 mmol/L, 95% CI −27 to −2 mmol/L, p = 0.03). Furthermore, after excluding the 10 participants who had received antibiotic therapy during the trial, which is known to affect the balance of bacterial species in the gut [8, 42], the changes in serum levels with synbiotic therapy for both total IS (−5 mmol/L, 95% CI −8 to −1 mmol/L, p = 0.03) and PCS (−25 mmol/L, 95% CI −38 to −12 mmol/L, p = 0.001) were significant. The changes in free IS and PCS levels were also significant amongst antibiotic-free completers. Synbiotic therapy additionally had an effect on the stool microbiome, with significantly increased abundance of *Bifidobacterium* spp. (3.2%, p = 0.003) and *Lachnospiraceae* (2.1%, p = 0.01) and decreased abundance of *Ruminococcaceae* (4.3%, p = 0.01). Interestingly, albuminuria was observed to significantly increase with synbiotic therapy, which contradicted the reports of a beneficial effect on proteinuria from animal studies using other uraemic toxin-lowering therapies, such as AST-120 [43, 44]. Due to the short duration and small participant numbers of synbiotic trials to date, the effects of treatment on patient-level clinical outcomes remain unknown [2].

Lastly, the use of acarbose for lowering serum levels of gut-derived uraemic toxins has been investigated. Acarbose, an alpha-glucosidase inhibitor, causes increased delivery of undigested carbohydrate to the colon, which may drive gut bacterial fermentation towards a saccharolytic pathway and away from proteolytic fermentation and toxin production. In a pilot pre-test/post-test study involving nine healthy volunteers, Evanepoel et al. demonstrated that treatment with oral acarbose 300 mg per day for 3 weeks resulted in significant reductions in both serum p-cresol concentration (1.14–1.11 mg/L, p = 0.047) and urinary excretion of p-cresol (29.93–10.54 mg/day, p = 0.03), suggesting reduced colonic generation of p-cresol, the precursor of PCS [45]. Further studies confirming this finding are required.

#### **4.2. Gastrointestinal sequestration**

diet cross-over study [29]. Thirty-two patients with a creatinine clearance between 20 and 55 ml/min were included and randomized to receive either a very low-protein diet (VLPD; 0.3 g/ kg/day) or a low-protein diet (LPD; 0.6 g/kg/day) in the first week, then switched to the other in the second week. There was no wash-out period. The authors found that patients treated with a VLPD experienced a significant 36% reduction in serum IS levels compared with those treated with a LPD (7.12 ± 3.89 μM during VLPD vs. 11.1 ± 6.6 μM during LPD, p < 0.0001). Although a meta-analysis has identified reduction in the occurrence of renal death with a lowprotein intake in CKD patients, the overall value of these diets remains a subject of debate, given that the risks of malnutrition may present a greater danger [30–32]. Furthermore, poor compliance is also likely to be an issue, as participants often did not meet dietary targets even

**Strategy Intervention Outcome**

186 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

Increased dialytic clearance Extended dialysis (long dialysis,

^OAT: organic anion transporters

Reduced gut synthesis Very low-protein diet [29] Reduced serum IS levels

Gastrointestinal sequestration AST-120 (Kremezin) [51–56] Reduced renal disease progression

Reduced proximal tubular retention OAT^ modulators [11, 58, 61] Reduced proximal tubular uptake

short daily dialysis) [65, 66]

Super-flux cellulose triacetate

membranes [69]

**Table 1.** Potential therapeutic interventions targeting indoxyl sulphate (IS) and p-cresyl sulphate (PCS).

Dietary fibre [10, 33, 34] Reduced serum IS and PCS levels Pre-, pro- and synbiotics [35–41] Reduced IS and PCS levels

Ai Xi Te [54] Reduced renal disease progression Niaoduqing granules [54] Reduced renal disease progression

Haemodiafiltration [67, 68] Reduced serum IS and PCS levels

Nanoporous monolith dialysis [70] Reduced serum IS and PCS levels

of IS

No clear benefit

Reduced serum IS levels

There is newer evidence to suggest that dietary fibre may in fact be more important than dietary protein intake in terms of managing uraemic toxin levels. A single-centre, cross-sectional study of 40 patients with CKD measured baseline total and free serum IS and PCS levels and correlated this with dietary factors including dietary fibre, protein and protein-fibre index [10]. In this study, dietary fibre was found to be inversely associated with free and total serum PCS (r = −0.42 and r = −0.44, both p < 0.01) whereas dietary protein was not (r= −0.14, p = 0.38). Protein-fibre index was significantly associated with both total PCS (r = 0.43, p = 0.005) and total IS (r = 0.40, p = 0.012) levels. Increased dietary fibre as an intervention has been shown to result in significantly reduced free plasma IS in haemodialysis patients [33]. Moreover, a prospective cohort study of 390 Swedish men between the age of 70 and 71 years found an association between protein-fibre intake ratio and cardiovascular events (adjusted HR 1.33, 95% CI 1.08–1.64). These findings suggest that dietary intervention focusing on protein-fibre ratio has the potential to influence clinical outcomes [34], mediated via uraemic toxin production.

with the intensive support provided within a trial setting.

IS and PCS absorption from the gut may also be prevented by the use of oral intestinal adsorbents, such as AST-120 (Kremezin), which bind uraemic toxins and their precursors thereby sequestering them in the gut and allowing them to be excreted via the faeces. Oral administration of AST-120 has been shown to result in a dose-dependent decrease in serum IS and PCS in both human [46–48] and animal studies [19, 49], and its use is associated with slower progression of renal dysfunction [44, 50] and reduction of proteinuria [43, 44] in animal models of CKD. It has also been demonstrated to slow progression of renal dysfunction in early non-randomized and randomized studies in pre-dialysis patients [51–53]. In a subsequent Cochrane systematic review and meta-analysis of eight randomized controlled trials (RCTs) of AST-120 plus routine care compared with routine care alone in patients with stages 1–5 (non-dialysis) CKD, Wu et al. [54] reported that AST-120 treatment resulted in a significant reduction in the rate of decline in creatinine clearance (2 studies, 486 participants; standardized mean difference [SMD] 0.39, 95% CI 0.21–0.57; I<sup>2</sup> = 0%), but did not significantly affect reciprocal serum creatinine slope over time (2 studies, 76 participants; mean difference [MD] 0.07 dL/mg/month, 95% CI −0.12 to 0.26; I<sup>2</sup> = 69%), doubling of serum creatinine concentration (1 study, 460 participants; relative risk [RR] 0.55, 95% CI 0.19 to 1.62), ESKD incidence (3 studies, 504 participants; RR 0.70, 95% CI 0.15–3.35; I<sup>2</sup> = 11%) or all-cause mortality (1 study, 460 participants; RR 0.70, 95% CI 0.19–1.62). In three separate placebo-controlled RCTs, AST-120 treatment did not significantly affect changes in serum creatinine, slope of reciprocal serum creatinine over time or creatinine clearance [54].

OAT, particularly OAT1 and OAT3, and are excreted into the tubular lumen by luminal OATs [58, 59]. Using cultured kidney tubule cells (LLC-PK1) and rat kidney slices, Deguchi et al. demonstrated that p-aminohippurate (OAT1 inhibitor), pravastatin (OAT3 inhibitor) and benzylpenicillin (OAT3 inhibitor) inhibited the renal tubular uptake of indoxyl sulphate to comparable extents [60]. In a 5/6-nephrectomized rat model of CKD, Enomoto et al. demonstrated that administration of IS resulted in IS accumulation in proximal tubule cells expressing OAT1 and OAT3, and was associated with more rapid CKD progression, as measured by creatinine clearance [58]. Furthermore, addition of IS to cultured rat proximal tubule (S2) cells reduced their viability, although this nephrotoxicity was abrogated by administration of the OAT1 inhibitor, probenecid [58]. Thus, OAT inhibitors, such as probenecid and statins, might be a potential strategy for preventing proximal tubule cell accumulation of IS and ensuing nephrotoxicity and CKD progression. In addition, as OATs are expressed widely throughout the body, these transporters may play a role in uraemic toxin-induced pathology in various organs. For example, Liu and colleagues demonstrated that administration of 10 µM IS to cultured Sprague-Dawley cardiac myocytes and fibroblasts stimulated myocyte hypertrophy and collagen synthesis, which was abrogated by probenecid (OAT1 antagonist) and cilastatin

The Roles of Indoxyl Sulphate and p-Cresyl Sulphate in Patients with Chronic Kidney Disease:...

http://dx.doi.org/10.5772/intechopen.69325

189

Therapeutic manipulation of efflux transporters, such as OAT polypeptide 4C1 (SCLO4C1), may also lead to enhanced excretion of uraemic retention solutes into the urine [62]. For example, Toyohara et al. demonstrated that overexpression of SLCO4C1 in rat kidney decreased plasma levels of uraemic toxins and reduced inflammation, hypertension and cardiomegaly [11]. Moreover, renal clearance of uraemic toxins was also increased by pravastatin, which is

The activities of multidrug resistance protein (MRP) 4 and BRCP efflux transporters have also been demonstrated to be downregulated by PCS *in vitro* [63] and may be potential therapeutic

IS and PCS are highly (>90%) protein bound and are therefore not easily removed with conventional haemodialysis and peritoneal dialysis [14, 59, 64]. Long dialysis, short daily dialysis and high-flux haemodialysis have been investigated as potential methods of improving clear-

In contrast to conventional haemodialysis, which mainly depends on diffusion to clear solutes, haemodiafiltration combines convection and diffusion, which is potentially very useful in facilitating removal of larger molecules, such as protein-bound solutes. Haemodiafiltration has been shown in prospective cross-over studies to be superior to high-flux haemodialysis in removing IS and PCS [67, 68]. In this respect, the effectiveness of pre- and post-dilution haemodiafiltration was comparable [67, 68]. The mechanism for the improved clearance of protein-bound solutes is not well understood but seemed to be dependent on a combination of both diffusion and convection since haemofiltration (which does not involve diffusion) reduced the serum levels

ance of protein-bound molecules, but have failed to show clear benefit [59, 65, 66].

of protein-bound solutes but not to the same extent as haemodiafiltration [67].

(OAT3 antagonist) [61].

**4.4. Increased dialytic clearance**

targets.

known to upregulate proximal tubular SLCO4C1 [11].

In the following year, the Evaluating Prevention of Progression in CKD (EPPIC)-1 and EPPIC-2 trials [55] reported on the effects of AST-120 (9 g/day) or placebo on CKD progression in 2035 patients with non-dialysis-dependent CKD treated at 239 sites in 13 countries. No significant difference was observed in time to primary end point (composite of doubling of serum creatinine, dialysis initiation and kidney transplantation) between treatment arms (pooled analysis HR 0.97, 95% CI 0.83–1.12, p = 0.64). Furthermore, the treatment group did not experience any difference in proteinuria or quality of life compared with the placebo group. Similarly, a subsequent prospective, open-label, randomized controlled trial of 579 patients with stage 3 or 4 CKD from 11 Korean centres reported that oral administration of AST (6 g/day of AST-120 in 3 divided daily doses) did not significantly affect time to the primary composite outcome of doubling of serum creatinine, eGFR decrease >50%, or initiation of renal replacement therapy (HR 1.12, 95% CI 0.85–1.48) [56]. There was no significant difference in change in serum IS levels over time between the intervention and control group (p = 0.29). The treatment also did not result in a significant difference in mortality, health-related quality of life or serious adverse effects.

A Cochrane systematic review of alternative oral adsorbents, Ai Xi Te and Niaoduqing granules, reported positive effects on CKD progression, but were limited by small samples sizes and poor methodologic quality with unclear or high risks of bias [54].

## **4.3. Reduced proximal tubular retention**

Renal proximal tubular cells contain multiple transporters that perform basolateral uptake or luminal excretion of various substances, including uraemic toxins. Such transporters include the organic anion transporters (OAT)1, OAT3 and OATP4C1, as well as the organic cation transporter (OCT)2, the multidrug and toxin extrusion proteins (MATEs), the breast cancer resistance protein (BCRP) and the adenosine triphosphate (ATP)-binding cassette transporter family [57]. Anionic substances, such as IS, enter renal proximal tubule cells via basolateral OAT, particularly OAT1 and OAT3, and are excreted into the tubular lumen by luminal OATs [58, 59]. Using cultured kidney tubule cells (LLC-PK1) and rat kidney slices, Deguchi et al. demonstrated that p-aminohippurate (OAT1 inhibitor), pravastatin (OAT3 inhibitor) and benzylpenicillin (OAT3 inhibitor) inhibited the renal tubular uptake of indoxyl sulphate to comparable extents [60]. In a 5/6-nephrectomized rat model of CKD, Enomoto et al. demonstrated that administration of IS resulted in IS accumulation in proximal tubule cells expressing OAT1 and OAT3, and was associated with more rapid CKD progression, as measured by creatinine clearance [58]. Furthermore, addition of IS to cultured rat proximal tubule (S2) cells reduced their viability, although this nephrotoxicity was abrogated by administration of the OAT1 inhibitor, probenecid [58]. Thus, OAT inhibitors, such as probenecid and statins, might be a potential strategy for preventing proximal tubule cell accumulation of IS and ensuing nephrotoxicity and CKD progression. In addition, as OATs are expressed widely throughout the body, these transporters may play a role in uraemic toxin-induced pathology in various organs. For example, Liu and colleagues demonstrated that administration of 10 µM IS to cultured Sprague-Dawley cardiac myocytes and fibroblasts stimulated myocyte hypertrophy and collagen synthesis, which was abrogated by probenecid (OAT1 antagonist) and cilastatin (OAT3 antagonist) [61].

Therapeutic manipulation of efflux transporters, such as OAT polypeptide 4C1 (SCLO4C1), may also lead to enhanced excretion of uraemic retention solutes into the urine [62]. For example, Toyohara et al. demonstrated that overexpression of SLCO4C1 in rat kidney decreased plasma levels of uraemic toxins and reduced inflammation, hypertension and cardiomegaly [11]. Moreover, renal clearance of uraemic toxins was also increased by pravastatin, which is known to upregulate proximal tubular SLCO4C1 [11].

The activities of multidrug resistance protein (MRP) 4 and BRCP efflux transporters have also been demonstrated to be downregulated by PCS *in vitro* [63] and may be potential therapeutic targets.

## **4.4. Increased dialytic clearance**

in both human [46–48] and animal studies [19, 49], and its use is associated with slower progression of renal dysfunction [44, 50] and reduction of proteinuria [43, 44] in animal models of CKD. It has also been demonstrated to slow progression of renal dysfunction in early non-randomized and randomized studies in pre-dialysis patients [51–53]. In a subsequent Cochrane systematic review and meta-analysis of eight randomized controlled trials (RCTs) of AST-120 plus routine care compared with routine care alone in patients with stages 1–5 (non-dialysis) CKD, Wu et al. [54] reported that AST-120 treatment resulted in a significant reduction in the rate of decline in creatinine clearance (2 studies, 486 participants; standardized mean differ-

creatinine slope over time (2 studies, 76 participants; mean difference [MD] 0.07 dL/mg/month,

pants; relative risk [RR] 0.55, 95% CI 0.19 to 1.62), ESKD incidence (3 studies, 504 participants;

95% CI 0.19–1.62). In three separate placebo-controlled RCTs, AST-120 treatment did not significantly affect changes in serum creatinine, slope of reciprocal serum creatinine over time or

In the following year, the Evaluating Prevention of Progression in CKD (EPPIC)-1 and EPPIC-2 trials [55] reported on the effects of AST-120 (9 g/day) or placebo on CKD progression in 2035 patients with non-dialysis-dependent CKD treated at 239 sites in 13 countries. No significant difference was observed in time to primary end point (composite of doubling of serum creatinine, dialysis initiation and kidney transplantation) between treatment arms (pooled analysis HR 0.97, 95% CI 0.83–1.12, p = 0.64). Furthermore, the treatment group did not experience any difference in proteinuria or quality of life compared with the placebo group. Similarly, a subsequent prospective, open-label, randomized controlled trial of 579 patients with stage 3 or 4 CKD from 11 Korean centres reported that oral administration of AST (6 g/day of AST-120 in 3 divided daily doses) did not significantly affect time to the primary composite outcome of doubling of serum creatinine, eGFR decrease >50%, or initiation of renal replacement therapy (HR 1.12, 95% CI 0.85–1.48) [56]. There was no significant difference in change in serum IS levels over time between the intervention and control group (p = 0.29). The treatment also did not result in a significant difference in mortality, health-related quality of life or serious

A Cochrane systematic review of alternative oral adsorbents, Ai Xi Te and Niaoduqing granules, reported positive effects on CKD progression, but were limited by small samples sizes

Renal proximal tubular cells contain multiple transporters that perform basolateral uptake or luminal excretion of various substances, including uraemic toxins. Such transporters include the organic anion transporters (OAT)1, OAT3 and OATP4C1, as well as the organic cation transporter (OCT)2, the multidrug and toxin extrusion proteins (MATEs), the breast cancer resistance protein (BCRP) and the adenosine triphosphate (ATP)-binding cassette transporter family [57]. Anionic substances, such as IS, enter renal proximal tubule cells via basolateral

and poor methodologic quality with unclear or high risks of bias [54].

**4.3. Reduced proximal tubular retention**

= 0%), but did not significantly affect reciprocal serum

= 69%), doubling of serum creatinine concentration (1 study, 460 partici-

= 11%) or all-cause mortality (1 study, 460 participants; RR 0.70,

ence [SMD] 0.39, 95% CI 0.21–0.57; I<sup>2</sup>

188 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

95% CI −0.12 to 0.26; I<sup>2</sup>

RR 0.70, 95% CI 0.15–3.35; I<sup>2</sup>

creatinine clearance [54].

adverse effects.

IS and PCS are highly (>90%) protein bound and are therefore not easily removed with conventional haemodialysis and peritoneal dialysis [14, 59, 64]. Long dialysis, short daily dialysis and high-flux haemodialysis have been investigated as potential methods of improving clearance of protein-bound molecules, but have failed to show clear benefit [59, 65, 66].

In contrast to conventional haemodialysis, which mainly depends on diffusion to clear solutes, haemodiafiltration combines convection and diffusion, which is potentially very useful in facilitating removal of larger molecules, such as protein-bound solutes. Haemodiafiltration has been shown in prospective cross-over studies to be superior to high-flux haemodialysis in removing IS and PCS [67, 68]. In this respect, the effectiveness of pre- and post-dilution haemodiafiltration was comparable [67, 68]. The mechanism for the improved clearance of protein-bound solutes is not well understood but seemed to be dependent on a combination of both diffusion and convection since haemofiltration (which does not involve diffusion) reduced the serum levels of protein-bound solutes but not to the same extent as haemodiafiltration [67].

The use of super-flux cellulose triacetate membranes has also been evaluated and found to be superior to low-flux haemodialysis with respect to removing IS and most proteinbound compounds, although this might be at least partly explained by an increase in removal of albumin [69]. Similarly, dialysis with the use of a nanoporous carbon monolith (pores 2–100 nm) was able to almost completely remove IS and PCS, whereas the use of a microporous monolith (<2 mm) resulted in only partial removal, and standard high-flux haemodialysis resulted in insignificant removal [70]. A potential issue with enhanced dialysis of toxins is the rebound release of further toxins from tissues, which is observed with water-based solutes. However, Martinez and colleagues demonstrated that the rebound movement of PCS and protein solutes in the first 30 minutes post-dialysis appeared to be negligible [71].

**Author details**

**References**

C1110-C1117

PMID: 26965149

Melissa Nataatmadja<sup>1</sup>

Brisbane, Queensland, Australia

Nephrology. 2016;**11**(2):199-201

, Yeoungjee Cho1,2,3, Katrina Campbell1,3 and David W. Johnson1,2,3\*

The Roles of Indoxyl Sulphate and p-Cresyl Sulphate in Patients with Chronic Kidney Disease:...

http://dx.doi.org/10.5772/intechopen.69325

191

1 Department of Nephrology, Princess Alexandra Hospital, Brisbane, Queensland, Australia 2 Australasian Kidney Trials Network, School of Medicine, University of Queensland,

[1] Mafra D, Barros AF, Fouque D. Dietary protein metabolism by gut microbiota and its consequences for chronic kidney disease patients. Future Microbiology. 2013;**8**(10):1317-1323

[2] Vaziri ND. Effect of synbiotic therapy on Gut-Derived uremic toxins and the intestinal microbiome in patients with CKD. Clinical Journal of the American Society of

[3] Vaziri ND, Yuan J, Rahimi A, Ni Z, Said H, Subramanian VS. Disintegration of colonic epithelial tight junction in uremia: A likely cause of CKD-associated inflammation.

[4] Shimizu H, Bolati D, Adijiang A, Enomoto A, Nishijima F, Dateki M, Niwa T. Senescence and dysfunction of proximal tubular cells are associated with activated p53 expression by indoxyl sulfate. American Journal of Physiology Cell Physiology. 2010;**299**(5):

[5] Shimizu H, Bolati D, Adijiang A, Muteliefu G, Enomoto A, Nishijima F, Dateki M, Niwa T. NF-kappaB plays an important role in indoxyl sulfate-induced cellular senescence, fibrotic gene expression, and inhibition of proliferation in proximal tubular cells.

[6] Adijiang A, Goto S, Uramoto S, Nishijima F, Niwa T. Indoxyl sulphate promotes aortic calcification with expression of osteoblast-specific proteins in hypertensive rats.

[7] Evenepoel P, Meijers BK, Bammens BR, Verbeke K. Uremic toxins originating from colonic microbial metabolism. Kidney International Supplements. 2009;**76**(114):S12-S19

[8] Briskey D, Tucker P, Johnson DW, Coombes JS. The role of the gastrointestinal tract and microbiota on uremic toxins and chronic kidney disease development. Clin Exp Nephrol. 2017 Feb;**21**(1):7-15. DOI: 10.1007/s10157-016-1255-y. pub 2016 Mar 10. Review.

American journal of physiology Cell Physiology. 2011;**301**(5):C1201-C1212

\*Address all correspondence to: david.johnson2@health.qld.gov.au

3 Translational Research Institute, Brisbane, Queensland, Australia

Nephrology Dialysis Transplantation. 2012;**27**(7):2686-2693

Nephrology Dialysis Transplantation. 2008;**23**(6):1892-1901

Eloot and colleagues utilised kinetic modelling to try to determine optimal dialysis parameters to facilitate protein-bound solute removal, and found that regardless of longer or more frequent dialysis, increased volume of blood processing per week was required to increase clearance [72].

In a cross-over study of 14 patients, high-clearance dialysis (high dialysate flow rate and large dialyzer) resulted in significantly greater PCS and IS clearance compared with lowclearance dialysis (PCS 23 ± 4 ml/min vs. 12 ± 3 ml/min, p < 0.001; IS 30 ± 5 ml/min vs. 17 ± 4 ml/min, p < 0.001). However, there was no significant change in serum PCS levels with high-clearance dialysis although there was a significant decrease in IS levels [73]. The authors suggested that this lack of reduction in serum PCS levels may be due to concurrent PCS generation, and thus treatment to suppress PCS production would be required in order to achieve significant reductions in serum PCS.

## **5. Summary and future directions**

In summary, IS and PCS are products of bacterial metabolism within the gut. Serum IS and PCS levels are increased in patients with CKD and have been associated with CKD progression, vascular disease acceleration, adverse metabolic profile and poorer cardiovascular and overall mortality. There are several methods of lowering serum IS and PCS levels, including reduced intestinal bacterial production through dietary modification of protein and/or fibre intake or pre-, pro- and synbiotic use, gastrointestinal sequestration through oral adsorbent use, reduced cellular uptake of IS through OAT inhibition, and increased clearance through enhanced dialysis. Though these treatments have been shown in some studies to successfully reduce IS and PCS levels in sera and/or cells, it is less clear whether this translates into meaningful and sustained improvements in clinical outcomes. The studies conducted to date have been limited by small patient numbers, relatively short follow-up duration and poor methodologic quality. Given the biological plausibility and clinical importance of the adverse health outcomes thought to be mediated by these toxins, further high-quality studies are needed to evaluate the short- and long-term effects of IS and PCS lowering treatments on patient-level clinical outcomes.

## **Author details**

The use of super-flux cellulose triacetate membranes has also been evaluated and found to be superior to low-flux haemodialysis with respect to removing IS and most proteinbound compounds, although this might be at least partly explained by an increase in removal of albumin [69]. Similarly, dialysis with the use of a nanoporous carbon monolith (pores 2–100 nm) was able to almost completely remove IS and PCS, whereas the use of a microporous monolith (<2 mm) resulted in only partial removal, and standard high-flux haemodialysis resulted in insignificant removal [70]. A potential issue with enhanced dialysis of toxins is the rebound release of further toxins from tissues, which is observed with water-based solutes. However, Martinez and colleagues demonstrated that the rebound movement of PCS and protein solutes in the first 30 minutes post-dialysis appeared to be

Eloot and colleagues utilised kinetic modelling to try to determine optimal dialysis parameters to facilitate protein-bound solute removal, and found that regardless of longer or more frequent dialysis, increased volume of blood processing per week was required to increase clearance

In a cross-over study of 14 patients, high-clearance dialysis (high dialysate flow rate and large dialyzer) resulted in significantly greater PCS and IS clearance compared with lowclearance dialysis (PCS 23 ± 4 ml/min vs. 12 ± 3 ml/min, p < 0.001; IS 30 ± 5 ml/min vs. 17 ± 4 ml/min, p < 0.001). However, there was no significant change in serum PCS levels with high-clearance dialysis although there was a significant decrease in IS levels [73]. The authors suggested that this lack of reduction in serum PCS levels may be due to concurrent PCS generation, and thus treatment to suppress PCS production would be required in order

In summary, IS and PCS are products of bacterial metabolism within the gut. Serum IS and PCS levels are increased in patients with CKD and have been associated with CKD progression, vascular disease acceleration, adverse metabolic profile and poorer cardiovascular and overall mortality. There are several methods of lowering serum IS and PCS levels, including reduced intestinal bacterial production through dietary modification of protein and/or fibre intake or pre-, pro- and synbiotic use, gastrointestinal sequestration through oral adsorbent use, reduced cellular uptake of IS through OAT inhibition, and increased clearance through enhanced dialysis. Though these treatments have been shown in some studies to successfully reduce IS and PCS levels in sera and/or cells, it is less clear whether this translates into meaningful and sustained improvements in clinical outcomes. The studies conducted to date have been limited by small patient numbers, relatively short follow-up duration and poor methodologic quality. Given the biological plausibility and clinical importance of the adverse health outcomes thought to be mediated by these toxins, further high-quality studies are needed to evaluate the short- and long-term effects of IS and PCS lowering treatments on patient-level

negligible [71].

clinical outcomes.

to achieve significant reductions in serum PCS.

190 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

**5. Summary and future directions**

[72].

Melissa Nataatmadja<sup>1</sup> , Yeoungjee Cho1,2,3, Katrina Campbell1,3 and David W. Johnson1,2,3\*

\*Address all correspondence to: david.johnson2@health.qld.gov.au

1 Department of Nephrology, Princess Alexandra Hospital, Brisbane, Queensland, Australia

2 Australasian Kidney Trials Network, School of Medicine, University of Queensland, Brisbane, Queensland, Australia

3 Translational Research Institute, Brisbane, Queensland, Australia

## **References**


[9] Meijers BK Evenepoel P. The gut-kidney axis: Indoxyl sulfate, p-cresyl sulfate and CKD progression. Nephrology Dialysis Transplantation. 2011;**26**(3):759-761

[20] Watanabe H, Miyamoto Y, Honda D, Tanaka H, Wu Q, Endo M, Noguchi T, Kadowaki D, Ishima Y, Kotani S, Nakajima M, Kataoka K, Kim-Mitsuyama S, Tanaka M, Fukagawa M, Otagiri M, Maruyama T. p-Cresyl sulfate causes renal tubular cell damage by inducing oxidative stress by activation of NADPH oxidase. Kidney International. 2013;**83**(4):582-592

The Roles of Indoxyl Sulphate and p-Cresyl Sulphate in Patients with Chronic Kidney Disease:...

http://dx.doi.org/10.5772/intechopen.69325

193

[21] Sun CY, Chang SC, Wu MS. Uremic toxins induce kidney fibrosis by activating intrarenal renin-angiotensin-aldosterone system associated epithelial-to-mesenchymal transi-

[22] Koppe L, Pillon NJ, Vella RE, Croze ML, Pelletier CC, Chambert S, Massy Z, Glorieux G, Vanholder R, Dugenet Y, Soula HA, Fouque D, Soulage CO. p-Cresyl sulfate promotes insulin resistance associated with CKD. Journal of the American Society of Nephrology.

[23] Yamamoto H, Tsuruoka S, Ioka T, Ando H, Ito C, Akimoto T, Fujimura A, Asano Y, Kusano E. Indoxyl sulfate stimulates proliferation of rat vascular smooth muscle cells.

[24] Barreto FC, Barreto DV, Liabeuf S, Meert N, Glorieux G, Temmar M, Choukroun G, Vanholder R, Massy ZA. Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clinical Journal of the American Society of

[25] Liabeuf S, Barreto DV, Barreto FC, Meert N, Glorieux G, Schepers E, Temmar M, Choukroun G, Vanholder R, Massy ZA. Free p-cresylsulphate is a predictor of mortality in patients at different stages of chronic kidney disease. Nephrology Dialysis

[26] Melamed ML, Plantinga L, Shafi T, Parekh R, Meyer TW, Hostetter TH, Coresh J, Powe NR. Retained organic solutes, patient characteristics and all-cause and cardiovascular mortality in hemodialysis: Results from the retained organic solutes and clinical out-

[27] Meijers BK, Claes K, Bammens B, de Loor H, Viaene L, Verbeke K, Kuypers D, Vanrenterghem Y, Evenepoel P. p-Cresol and cardiovascular risk in mild-to-moderate kidney disease. Clinical Journal of the American Society of Nephrology. 2010;**5**(7):1182-1189

[28] Bammens B, Evenepoel P, Keuleers H, Verbeke K, Vanrenterghem Y. Free serum concentrations of the protein-bound retention solute p-cresol predict mortality in hemodialysis

[29] Marzocco S, Dal Piaz F, Di Micco L, Torraca S, Sirico ML, Tartaglia D, Autore G, Di Iorio B. Very low protein diet reduces indoxyl sulfate levels in chronic kidney disease. Blood

[30] Fouque D, Laville M. Low protein diets for chronic kidney disease in non diabetic adults. Cochrane Database Syst Rev. 2009 Jul 8;(3):CD001892. DOI: 10.1002/14651858.CD001892.

[31] Johnson DW. Dietary protein restriction as a treatment for slowing chronic kidney dis-

ease progression: The case against. Nephrology (Carlton). 2006;**11**(1):58-62

comes (ROSCO) investigators. BMC Nephrology. 2013;**14**:134

patients. Kidney International. 2006;**69**(6):1081-1087

tion. PLoS One. 2012;**7**(3):e34026

Kidney International. 2006;**69**(10):1780-1785

Nephrology. 2009;**4**(10):1551-1558

Transplantation. 2010;**25**(4):1183-1191

Purification. 2013;**35**(1-3):196-201

pub3. Review. PMID: 19588328

2013;**24**(1):88-99


[20] Watanabe H, Miyamoto Y, Honda D, Tanaka H, Wu Q, Endo M, Noguchi T, Kadowaki D, Ishima Y, Kotani S, Nakajima M, Kataoka K, Kim-Mitsuyama S, Tanaka M, Fukagawa M, Otagiri M, Maruyama T. p-Cresyl sulfate causes renal tubular cell damage by inducing oxidative stress by activation of NADPH oxidase. Kidney International. 2013;**83**(4):582-592

[9] Meijers BK Evenepoel P. The gut-kidney axis: Indoxyl sulfate, p-cresyl sulfate and CKD

[10] Rossi M, Johnson DW, Xu H, Carrero JJ, Pascoe E, French C, Campbell KL. Dietary protein-fiber ratio associates with circulating levels of indoxyl sulfate and p-cresyl sulfate in chronic kidney disease patients. Nutrition, Metabolism & Cardiovascular Diseases.

[11] Toyohara T, Suzuki T, Morimoto R, Akiyama Y, Souma T, Shiwaku HO, Takeuchi Y, Mishima E, Abe M, Tanemoto M, Masuda S, Kawano H, Maemura K, Nakayama M, Sato H, Mikkaichi T, Yamaguchi H, Fukui S, Fukumoto Y, Shimokawa H, Inui K, Terasaki T, Goto J, Ito S, Hishinuma T, Rubera I, Tauc M, Fujii-Kuriyama Y, Yabuuchi H, Moriyama Y, Soga T, Abe T. SLCO4C1 transporter eliminates uremic toxins and attenuates hypertension and renal inflammation. Journal of the American Society of Nephrology.

[12] Vanholder R, De Smet R, Glorieux G, Argiles A, Baurmeister U, Brunet P, Clark W, Cohen G, De Deyn PP, Deppisch R, Descamps-Latscha B, Henle T, Jorres A, Lemke HD, Massy ZA, Passlick-Deetjen J, Rodriguez M, Stegmayr B, Stenvinkel P, Tetta C, Wanner C, Zidek W. Review on uremic toxins: Classification, concentration, and interindividual

[13] Rossi M, Campbell K, Johnson D, Stanton T, Pascoe E, Hawley C, Dimeski G, McWhinney B, Ungerer J, Isbel N. Uraemic toxins and cardiovascular disease across the chronic kidney disease spectrum: An observational study. Nutrition, Metabolism & Cardiovascular

[14] Itoh Y, Ezawa A, Kikuchi K, Tsuruta Y, Niwa T. Protein-bound uremic toxins in hemodialysis patients measured by liquid chromatography/tandem mass spectrometry and their effects on endothelial ROS production. Analytical and Bioanalytical Chemistry.

[15] Lin CJ, Wu V, Wu PC, Wu CJ. Meta-Analysis of the associations of p-Cresyl Sulfate (PCS) and indoxyl sulfate (IS) with cardiovascular events and All-Cause mortality in patients

[16] Rossi M, Campbell KL, Johnson DW, Stanton T, Haluska BA, Hawley CM, Dimeski G, McWhinney BC, Ungerer JP, Kaisar OM, Isbel NM. Uremic toxin development in living

[17] Wu IW, Hsu KH, Lee CC, Sun CY, Hsu HJ, Tsai CJ, Tzen CY, Wang YC, Lin CY, Wu MS. p-Cresyl sulphate and indoxyl sulphate predict progression of chronic kidney disease.

[18] Motojima M, Hosokawa A, Yamato H, Muraki T, Yoshioka T. Uremic toxins of organic anions up-regulate PAI-1 expression by induction of NF-kappaB and free radical in

[19] Niwa T, Ise M. Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis. Journal of Laboratory and Clinical Medicine 1994;**124**(1):96-104

kidney donors: A longitudinal study. Transplantation. 2014;**97**(5):548-554

variability. Kidney International. 2003;**63**(5):1934-1943

with chronic renal failure. PLoS One. 2015;**10**(7):e0132589

Nephrology Dialysis Transplantation. 2011;**26**(3):938-947

proximal tubular cells. Kidney International. 2003;**63**(5):1671-1680

progression. Nephrology Dialysis Transplantation. 2011;**26**(3):759-761

192 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

2015;**25**(9):860-865

2009;**20**(12):2546-2555

Diseases. 2014;**24**(9):1035-1042

2012;**403**(7):1841-1850


[32] Johnson DW, Atai E, Chan M, Phoon RK, Scott C, Toussaint ND, Turner GL, Usherwood T, Wiggins KJ. KHA-CARI guideline: Early chronic kidney disease: Detection, prevention and management. Nephrology (Carlton). 2013;**18**(5):340-350

clindamycin results in sustained susceptibility to Clostridium difficile-induced colitis.

The Roles of Indoxyl Sulphate and p-Cresyl Sulphate in Patients with Chronic Kidney Disease:...

http://dx.doi.org/10.5772/intechopen.69325

195

[43] Okada K, Takahashi S, Nagura Y, Hatano M, Shimamura T. Early morphological changes of tubules in rats with chronic renal failure. Nihon Jinzo Gakkai Shi. 1992;**34**(1):65-70

[44] Horike K, Usami T, Kamiya Y, Kamiya T, Yoshida A, Itoh S, Yamato H, Ise M, Kimura G. Oral carbonaceous absorbent modifies renal function of renal ablation model without affecting plasma renin-angiotensin system or protein intake. Clinical and Experimental

[45] Evenepoel P, Bammens B, Verbeke K, Vanrenterghem Y. Acarbose treatment lowers generation and serum concentrations of the protein-bound solute p-cresol: A pilot study.

[46] Schulman G, Agarwal R, Acharya M, Berl T, Blumenthal S, Kopyt N. A multicenter, randomized, double-blind, placebo-controlled, dose-ranging study of AST-120 (Kremezin) in patients with moderate to severe CKD. American Journal of Kidney Diseases.

[47] Wu IW, Hsu KH, Sun CY, Tsai CJ, Wu MS, Lee CC. Oral adsorbent AST-120 potentiates the effect of erythropoietin-stimulating agents on Stage 5 chronic kidney disease patients: A randomized crossover study. Nephrology, Dialysis, Transplantation.

[48] Yamamoto S, Kazama JJ, Omori K, Matsuo K, Takahashi Y, Kawamura K, Matsuto T, Watanabe H, Maruyama T, Narita I. Continuous reduction of Protein-Bound uraemic toxins with improved oxidative stress by using the oral charcoal adsorbent AST-120 in

[49] Kikuchi K, Itoh Y, Tateoka R, Ezawa A, Murakami K, Niwa T. Metabolomic search for uremic toxins as indicators of the effect of an oral sorbent AST-120 by liquid chromatography/tandem mass spectrometry. Journal of Chromatography B. 2010;**878**(29):2997-3002

[50] Miyazaki T, Aoyama I, Ise M, Seo H, Niwa T. An oral sorbent reduces overload of indoxyl sulphate and gene expression of TGF-beta1 in uraemic rat kidneys. Nephrology,

[51] Takahashi N, Kawaguchi T, Suzuki T. Therapeutic effects of long-term administration of an oral adsorbent in patients with chronic renal failure: Two-year study. International

[52] Sanaka T, Akizawa T, Koide K, Koshikawa S. Protective effect of an oral adsorbent on renal function in chronic renal failure: Determinants of its efficacy in diabetic nephropa-

[53] Shoji T, Wada A, Inoue K, Hayashi D, Tomida K, Furumatsu Y, Kaneko T, Okada N, Fukuhara Y, Imai E, Tsubakihara Y. Prospective randomized study evaluating the efficacy of the spherical adsorptive carbon AST-120 in chronic kidney disease patients with moderate decrease in renal function. Nephron Clinical Practice. 2007;**105**(3):c99-c107

haemodialysis patients. Scientific Reports. 2015;**5**:14381

Dialysis, Transplantation. 2000;**15**(11):1773-1781

thy. Therapeutic Apheresis and Dialysis. 2004;**8**(3):232-240

Journal of Urology. 2005;**12**(1):7-11

Infection and Immunity. 2012;**80**(1):62-73

Kidney International. 2006;**70**(1):192-198

Nephrology. 2003;**7**(2):120-124

2006;**47**(4):565-577

2014;**29**(9):1719-1727


clindamycin results in sustained susceptibility to Clostridium difficile-induced colitis. Infection and Immunity. 2012;**80**(1):62-73

[43] Okada K, Takahashi S, Nagura Y, Hatano M, Shimamura T. Early morphological changes of tubules in rats with chronic renal failure. Nihon Jinzo Gakkai Shi. 1992;**34**(1):65-70

[32] Johnson DW, Atai E, Chan M, Phoon RK, Scott C, Toussaint ND, Turner GL, Usherwood T, Wiggins KJ. KHA-CARI guideline: Early chronic kidney disease: Detection, preven-

[33] Sirich TL, Plummer NS, Gardner CD, Hostetter TH, Meyer TW. Effect of increasing dietary fiber on plasma levels of colon-derived solutes in hemodialysis patients. Clinical

[34] Xu H, Rossi M, Campbell KL, Sencion GL, Arnlov J, Cederholm T, Sjogren P, Riserus U, Lindholm B, Carrero JJ. Excess protein intake relative to fiber and cardiovascular events in elderly men with chronic kidney disease. Nutrition, Metabolism & Cardiovascular

[35] Hida M, Aiba Y, Sawamura S, Suzuki N, Satoh T, Koga Y. Inhibition of the accumulation of uremic toxins in the blood and their precursors in the feces after oral administration of Lebenin, a lactic acid bacteria preparation, to uremic patients undergoing hemodialysis.

[36] Francois IE, Lescroart O, Veraverbeke WS, Marzorati M, Possemiers S, Evenepoel P, Hamer H, Houben E, Windey K, Welling GW, Delcour JA, Courtin CM, Verbeke K, Broekaert WF. Effects of a wheat bran extract containing arabinoxylan oligosaccharides on gastrointestinal health parameters in healthy adult human volunteers: A doubleblind, randomised, placebo-controlled, cross-over trial. British Journal of Nutrition.

[37] Nakabayashi I, Nakamura M, Kawakami K, Ohta T, Kato I, Uchida K, Yoshida M. Effects of synbiotic treatment on serum level of p-cresol in haemodialysis patients: A prelimi-

[38] Guida B, Germano R, Trio R, Russo D, Memoli B, Grumetto L, Barbato F, Cataldi M. Effect of short-term synbiotic treatment on plasma p-cresol levels in patients with chronic renal failure: A randomized clinical trial. Nutrition, Metabolism & Cardiovascular Diseases.

[39] Rossi M, Klein K, Johnson DW, Campbell KL. Pre-, pro-, and synbiotics: Do they have a role in reducing uremic toxins? A systematic review and meta-analysis. International

[40] Rossi M, Johnson DW, Morrison M, Pascoe E, Coombes JS, Forbes JM, McWhinney BC, Ungerer JP, Dimeski G, Campbell KL. SYNbiotics easing renal failure by improving gut microbiologY (SYNERGY): A protocol of placebo-controlled randomised cross-over

[41] Rossi M, Johnson DW, Morrison M, Pascoe EM, Coombes JS, Forbes JM, Szeto CC, McWhinney BC, Ungerer JP, Campbell KL. Synbiotics easing renal failure by improving gut microbiology (SYNERGY): A randomized trial. Clinical Journal of the American

[42] Buffie CG, Jarchum I, Equinda M, Lipuma L, Gobourne A, Viale A, Ubeda C, Xavier J, Pamer EG. Profound alterations of intestinal microbiota following a single dose of

nary study. Nephrology, Dialysis, Transplantation. 2011;**26**(3):1094-1048

tion and management. Nephrology (Carlton). 2013;**18**(5):340-350

194 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

Journal of the American Society of Nephrology. 2014;**9**(9):1603-1610

Diseases. 2016;**26**(7):597-602

Nephron. 1996;**74**(2):349-355

2012;**108**(12):2229-2242

2014;**24**(9):1043-1049

Journal of Nephrology. 2012;**2012**:673631

trial. BMC Nephrology. 2014;**15**:106

Society of Nephrology. 2016;**11**(2):223-231


[54] Wu HM, Sun HJ, Wang F, Yang M, Dong BR, Liu GJ. Oral adsorbents for preventing or delaying the progression of chronic kidney disease. Cochrane Database Syst Rev. 2014 Oct 15;(10):CD007861. DOI: 10.1002/14651858.CD007861.pub2. Review. PMID: 25317905

[66] Basile C, Libutti P, Di Turo AL, Casino FG, Vernaglione L, Tundo S, Maselli P, De Nicolo EV, Ceci E, Teutonico A, Lomonte C. Removal of uraemic retention solutes in standard bicarbonate haemodialysis and long-hour slow-flow bicarbonate haemodialysis.

The Roles of Indoxyl Sulphate and p-Cresyl Sulphate in Patients with Chronic Kidney Disease:...

http://dx.doi.org/10.5772/intechopen.69325

197

[67] Meert N, Eloot S, Schepers E, Lemke HD, Dhondt A, Glorieux G, Van Landschoot M, Waterloos MA, Vanholder R. Comparison of removal capacity of two consecutive generations of high-flux dialysers during different treatment modalities. Nephrology,

[68] Meert N, Eloot S, Waterloos MA, Van Landschoot M, Dhondt A, Glorieux G, Ledebo I, Vanholder R. Effective removal of protein-bound uraemic solutes by different convective strategies: A prospective trial. Nephrology, Dialysis, Transplantation. 2009;**24**(2):562-570

[69] De Smet R, Dhondt A, Eloot S, Galli F, Waterloos MA, Vanholder R. Effect of the super-flux cellulose triacetate dialyser membrane on the removal of non-proteinbound and protein-bound uraemic solutes. Nephrology, Dialysis, Transplantation.

[70] Sandeman SR, Howell CA, Phillips GJ, Zheng Y, Standen G, Pletzenauer R, Davenport A, Basnayake K, Boyd O, Holt S, Mikhalovsky SV. An adsorbent monolith device to augment the removal of uraemic toxins during haemodialysis. Journal of Materials Science:

[71] Martinez AW, Recht NS, Hostetter TH, Meyer TW. Removal of P-cresol sulfate by hemodialysis. Journal of the American Society of Nephrology. 2005;**16**(11):3430-3436

[72] Eloot S, Schneditz D, Cornelis T, Van Biesen W, Glorieux G, Dhondt A, Kooman J, Vanholder R. Protein-Bound uremic toxin profiling as a tool to optimize hemodialysis.

[73] Camacho O, Rosales MC, Shafi T, Fullman J, Plummer NS, Meyer TW, Sirich TL. Effect of a sustained difference in hemodialytic clearance on the plasma levels of p-cresol sulfate

and indoxyl sulfate. Nephrology, Dialysis, Transplantation. 2016;**31**(8):1335-1341

Nephrology, Dialysis, Transplantation. 2011;**26**(4):1296-1303

Dialysis, Transplantation. 2011;**26**(8):2624-2630

Materials in Medicine. 2014;**25**(6):1589-1597

PLoS One. 2016;**11**(1):e0147159

2007;**22**(7):2006-2012


[66] Basile C, Libutti P, Di Turo AL, Casino FG, Vernaglione L, Tundo S, Maselli P, De Nicolo EV, Ceci E, Teutonico A, Lomonte C. Removal of uraemic retention solutes in standard bicarbonate haemodialysis and long-hour slow-flow bicarbonate haemodialysis. Nephrology, Dialysis, Transplantation. 2011;**26**(4):1296-1303

[54] Wu HM, Sun HJ, Wang F, Yang M, Dong BR, Liu GJ. Oral adsorbents for preventing or delaying the progression of chronic kidney disease. Cochrane Database Syst Rev. 2014 Oct 15;(10):CD007861. DOI: 10.1002/14651858.CD007861.pub2. Review. PMID: 25317905

[55] Schulman G, Berl T, Beck GJ, Remuzzi G, Ritz E, Arita K, Kato A, Shimizu M. Randomized Placebo-Controlled EPPIC trials of AST-120 in CKD. Journal of the American Society of

[56] Cha RH, Kang SW, Park CW, Cha DR, Na KY, Kim SG, Yoon SA, Han SY, Chang JH, Park SK, Lim CS, Kim YS. A Randomized, controlled trial of oral intestinal sorbent AST-120 on renal function deterioration in patients with advanced renal dysfunction. Clinical

[57] Masereeuw R, Mutsaers HA, Toyohara T, Abe T, Jhawar S, Sweet DH, Lowenstein J. The kidney and uremic toxin removal: Glomerulus or tubule? Seminars in Nephrology.

[58] Enomoto A, Takeda M, Tojo A, Sekine T, Cha SH, Khamdang S, Takayama F, Aoyama I, Nakamura S, Endou H, Niwa T. Role of organic anion transporters in the tubular transport of indoxyl sulfate and the induction of its nephrotoxicity. Journal of the American

[59] Neirynck N, Glorieux G, Schepers E, Pletinck A, Dhondt A, Vanholder R. Review of protein-bound toxins, possibility for blood purification therapy. Blood Purification,

[60] Deguchi T, Kusuhara H, Takadate A, Endou H, Otagiri M, Sugiyama Y. Characterization of uremic toxin transport by organic anion transporters in the kidney. Kidney

[61] Liu S, Wang BH, Kompa AR, Lekawanvijit S, Krum H. Antagonists of organic anion transporters 1 and 3 ameliorate adverse cardiac remodelling induced by uremic toxin

[62] Glorieux G, Tattersall J. Uraemic toxins and new methods to control their accumulation: Game changers for the concept of dialysis adequacy. Clinical Kidney Journal.

[63] Mutsaers HA, Caetano-Pinto P, Seegers AE, Dankers AC, van den Broek PH, Wetzels JF, van den Brand JA, van den Heuvel LP, Hoenderop JG, Wilmer MJ, Masereeuw R. Proximal tubular efflux transporters involved in renal excretion of p-cresyl sulfate and p-cresyl glucuronide: Implications for chronic kidney disease pathophysiology.

[64] Viaene L, Annaert P, de Loor H, Poesen R, Evenepoel P, Meijers B. Albumin is the main plasma binding protein for indoxyl sulfate and p-cresyl sulfate. Biopharmaceutics &

[65] Fagugli RM, De Smet R, Buoncristiani U, Lameire N, Vanholder R. Behavior of nonprotein-bound and protein-bound uremic solutes during daily hemodialysis. American

indoxyl sulfate. International Journal of Cardiology. 2012;**158**(3):457-458

Journal of the American Society of Nephrology. 2016;**11**(4):559-567

Nephrology. 2015;**26**(7):1732-1746

196 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

Society of Nephrology. 2002;**13**(7):1711-1720

2014;**34**(2):191-208

2013;**35**(Suppl 1):45-50

2015;**8**(4):353-362

International. 2004;**65**(1):162-174

Toxicology In Vitro. 2015;**29**(7):1868-1877

Journal of Kidney Diseases. 2002;**40**(2):339-347

Drug Disposition. 2013;**34**(3):165-175


**Chapter 9**

**Provisional chapter**

**Role of Organochlorine Pesticides in Chronic Kidney**

Chronic kidney disease (CKD) contributes to a significant burden on the healthcare system and economy worldwide. In the last two decades, a new form of CKD: chronic kidney disease of unknown etiology (CKDu) in which the disease is not attributed to known causes has emerged as a major health issue in different geographical areas over the world mainly from farming community and has become a global concern today. Despite intense and numerous research works dedicated to CKDu, very little is known with certainty regarding its etiology and the pathophysiology behind its development. Recent evidences are emerging in favor of possible role of agrochemicals and pesticides in the pathogenesis of CKDu. Organochlorine pesticides (OCPs) due to their longer halflife and lipophilic nature persist long in the environment and are known to be biomagnified through food chain. Some study reports by the authors and a few others constitute the important body of evidences depicting the association between chronic exposures to OCPs and occurrence of CKDu through environmental contamination in farming as well

as non-farming communities in different geographical areas around the globe.

**Keywords:** chronic kidney disease, organochlorine pesticides, end stage renal disease,

**Role of Organochlorine Pesticides in Chronic Kidney** 

DOI: 10.5772/intechopen.71196

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

Chronic kidney disease (CKD) refers to a gradual and progressive decline of renal function as a result of damage to renal microstructure due to various causes ultimately leading to

**Diseases of Unknown Etiology**

**Diseases of Unknown Etiology**

Pawan Kuman Kare, Om Prakash Kalra and

Pawan Kuman Kare, Om Prakash Kalra and

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

Rishila Ghosh, Manushi Siddharth,

Rishila Ghosh, Manushi Siddharth,

http://dx.doi.org/10.5772/intechopen.71196

Ashok Kumar Tripathi

**Abstract**

eGFR, CKDu

**1.1. Overview**

**1. Chronic kidney disease (CKD)**

Ashok Kumar Tripathi

**Provisional chapter**

## **Role of Organochlorine Pesticides in Chronic Kidney Diseases of Unknown Etiology Diseases of Unknown Etiology**

**Role of Organochlorine Pesticides in Chronic Kidney** 

DOI: 10.5772/intechopen.71196

Rishila Ghosh, Manushi Siddharth, Pawan Kuman Kare, Om Prakash Kalra and Ashok Kumar Tripathi Pawan Kuman Kare, Om Prakash Kalra and Ashok Kumar Tripathi Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.71196

Rishila Ghosh, Manushi Siddharth,

#### **Abstract**

Chronic kidney disease (CKD) contributes to a significant burden on the healthcare system and economy worldwide. In the last two decades, a new form of CKD: chronic kidney disease of unknown etiology (CKDu) in which the disease is not attributed to known causes has emerged as a major health issue in different geographical areas over the world mainly from farming community and has become a global concern today. Despite intense and numerous research works dedicated to CKDu, very little is known with certainty regarding its etiology and the pathophysiology behind its development. Recent evidences are emerging in favor of possible role of agrochemicals and pesticides in the pathogenesis of CKDu. Organochlorine pesticides (OCPs) due to their longer halflife and lipophilic nature persist long in the environment and are known to be biomagnified through food chain. Some study reports by the authors and a few others constitute the important body of evidences depicting the association between chronic exposures to OCPs and occurrence of CKDu through environmental contamination in farming as well as non-farming communities in different geographical areas around the globe.

**Keywords:** chronic kidney disease, organochlorine pesticides, end stage renal disease, eGFR, CKDu

## **1. Chronic kidney disease (CKD)**

#### **1.1. Overview**

Chronic kidney disease (CKD) refers to a gradual and progressive decline of renal function as a result of damage to renal microstructure due to various causes ultimately leading to

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

end-stage renal disease (ESRD). Most, but not all forms of CKD are irreversible and progressive [1]. The progression of the disease is often silent to start with, but gradually over a period of time the disease reaches a stage in which due to increased renal damage and kidney dysfunction renal replacement therapy (RRT) in the form of dialysis or renal transplant becomes necessary to sustain life. Currently, 10% of the global population regardless of ethnic origin are affected by CKD and it has become a major burden on the healthcare system worldwide [2]. Globally, CKD is the 12th most common cause of death and 17th cause of disability [3]. It is estimated that nearly 1,00,000 new patients of end-stage renal disease (ESRD) enters RRT programs annually in India [4]. Worldwide, over two million people are on renal replacement therapy but this figure nearly represents 10% of those who need it [5]. With this alarming number, CKD has emerged as a global epidemic. The adverse outcomes like cardiovascular disease (CVD) and premature death are universal [6].

#### **1.2. Definition and classification**

Keeping in mind the global impact of CKD, a simple definition and classification was necessary for international development, dissemination, and implementation of clinical practice guideline. One such initiative was undertaken by KDIGO (Kidney Disease: Improving Global Outcomes) through one of the series of International Controversies Conferences in which, by the consensus of a large number of nephrologists worldwide, the definition and classification of CKD devised by KDOQI (Kidney Disease Outcomes Quality Initiative) was accepted with a minor modification (**Table 1**).

**1.3. Etiology**

**Stages GFR Common features**

2 60–90\* ↑ Parathyroid hormone, ↓ renal calcium reabsorption

anorexia, and bone pain 5 <15 Renal failure: severe uremic symptoms

urine (e.g., proteinuria) tests or imaging studies.

**Table 2.** Stages of chronic kidney disease.

3 30–59 Left ventricular hypertrophy, anemia secondary to erythropoietin deficiency

4 15–29 ↑ Serum triglycerides, hyperphosphatemia, hyperkalemia, metabolic acidosis, fatigue, nausea,

Role of Organochlorine Pesticides in Chronic Kidney Diseases of Unknown Etiology

http://dx.doi.org/10.5772/intechopen.71196

201

↑: increase; ↓: decrease. Adapted from: Lopez-Novoa et al. [1].\*CKD is defined as either GFR < 60 mL/min/1.73m2 for 3 months or a GFR above those values in the presence of evidence of kidney damage such as abnormalities in blood or

1 ≥90\* –

ease (0.8%), and graft failure (0.3%) [11] (**Figure 1**).

16%

13.80% 12.90% 11.70%

**Figure 1.** Etiological spectrum of Indian CKD patients of chronic kidney disease of unknown etiology (CKDu).

7%

3.40% 2.60% 0.80% 0.30%

31.30%

0.00% 5.00% 10.00% 15.00% 20.00% 25.00% 30.00% 35.00%

Some decades ago, the leading cause of CKD was glomerulonephritis secondary to infection. Introduction of antibiotics and improved sanitary practice have changed the scenario; presently, the most common causes of CKD in adults are diabetes and hypertension in the developed world [8]. The leading causes of CKD in USA according to the 2012 US Renal Data System Annual Data Report are diabetes (49.1%), hypertension (28%), and glomerulonephritis (4.7%) [9]. As a fact, about 50% of ESRD patients in USA are diabetic and about 50–60% of all patients with CKD are hypertensive [10]. According to the CKD Registry of India, the most common cause of CKD in Indian population is diabetes (31%) followed by CKD of undetermined etiology (16%) followed by chronic glomerulonephritis (14%) and hypertensive nephrosclerosis (13%) with almost equal frequency. Other less common causes were: interstitial nephritis (7%), chronic obstructive uropathy (3.4%), miscellaneous (11.7), renovascular dis-

The National Kidney Foundation (NFK) of the United States of America classified the progression of CKD in five stages depending on the extent of renal dysfunction symptomatology and therapeutic guidelines (**Table 2**).

The term chronic renal failure applies to the reduction of significant number of functional nephron and typically corresponds to CKD stage 3–5. For obvious reason, the late stage 4 and stage 5 pose a large social, human, and economic burden. The term ESRD represents a stage in which the accumulation of toxic substances, fluid, and electrolytes which are excreted otherwise by normal kidneys produces significant clinical symptoms and even cause death unless removed from the body by renal replacement therapy in the form of kidney transplant or regular dialysis. In most of the cases but not all, patients of CKD with stage 3 or 4 progress to ESRD at a rate of 1.5% per year, whereas patients with stage 1 or 2 progress to more advanced stages approximately 0.5% per year [7].

Abnormalities in imaging tests

GFR < 60 mL/min/1.73m<sup>2</sup> for ≥3 months, with or without kidney damage

Adapted from: Levey et al. [6].

**Table 1.** Criteria for chronic kidney disease (CKD).

Kidney damage for ≥3 months, as defined by structural or functional abnormalities of the kidney, with or without

decreased glomerular filtration rate (GFR), that can lead to decreased GFR, manifested by either:

Pathologic abnormalities; or

Markers of kidney damage, including abnormalities in the composition of the blood or urine; or


↑: increase; ↓: decrease. Adapted from: Lopez-Novoa et al. [1].\*CKD is defined as either GFR < 60 mL/min/1.73m2 for 3 months or a GFR above those values in the presence of evidence of kidney damage such as abnormalities in blood or urine (e.g., proteinuria) tests or imaging studies.

**Table 2.** Stages of chronic kidney disease.

#### **1.3. Etiology**

end-stage renal disease (ESRD). Most, but not all forms of CKD are irreversible and progressive [1]. The progression of the disease is often silent to start with, but gradually over a period of time the disease reaches a stage in which due to increased renal damage and kidney dysfunction renal replacement therapy (RRT) in the form of dialysis or renal transplant becomes necessary to sustain life. Currently, 10% of the global population regardless of ethnic origin are affected by CKD and it has become a major burden on the healthcare system worldwide [2]. Globally, CKD is the 12th most common cause of death and 17th cause of disability [3]. It is estimated that nearly 1,00,000 new patients of end-stage renal disease (ESRD) enters RRT programs annually in India [4]. Worldwide, over two million people are on renal replacement therapy but this figure nearly represents 10% of those who need it [5]. With this alarming number, CKD has emerged as a global epidemic. The adverse outcomes like cardiovascular disease (CVD) and premature death are universal [6].

Keeping in mind the global impact of CKD, a simple definition and classification was necessary for international development, dissemination, and implementation of clinical practice guideline. One such initiative was undertaken by KDIGO (Kidney Disease: Improving Global Outcomes) through one of the series of International Controversies Conferences in which, by the consensus of a large number of nephrologists worldwide, the definition and classification of CKD devised by KDOQI (Kidney Disease Outcomes Quality Initiative) was accepted with a minor modification (**Table 1**). The National Kidney Foundation (NFK) of the United States of America classified the progression of CKD in five stages depending on the extent of renal dysfunction symptomatology

The term chronic renal failure applies to the reduction of significant number of functional nephron and typically corresponds to CKD stage 3–5. For obvious reason, the late stage 4 and stage 5 pose a large social, human, and economic burden. The term ESRD represents a stage in which the accumulation of toxic substances, fluid, and electrolytes which are excreted otherwise by normal kidneys produces significant clinical symptoms and even cause death unless removed from the body by renal replacement therapy in the form of kidney transplant or regular dialysis. In most of the cases but not all, patients of CKD with stage 3 or 4 progress to ESRD at a rate of 1.5% per year, whereas patients with stage 1 or 2 progress to more advanced

Kidney damage for ≥3 months, as defined by structural or functional abnormalities of the kidney, with or without

decreased glomerular filtration rate (GFR), that can lead to decreased GFR, manifested by either:

Markers of kidney damage, including abnormalities in the composition of the blood or urine; or

for ≥3 months, with or without kidney damage

**1.2. Definition and classification**

200 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

and therapeutic guidelines (**Table 2**).

stages approximately 0.5% per year [7].

**Table 1.** Criteria for chronic kidney disease (CKD).

Pathologic abnormalities; or

Abnormalities in imaging tests

Adapted from: Levey et al. [6].

GFR < 60 mL/min/1.73m<sup>2</sup>

Some decades ago, the leading cause of CKD was glomerulonephritis secondary to infection. Introduction of antibiotics and improved sanitary practice have changed the scenario; presently, the most common causes of CKD in adults are diabetes and hypertension in the developed world [8]. The leading causes of CKD in USA according to the 2012 US Renal Data System Annual Data Report are diabetes (49.1%), hypertension (28%), and glomerulonephritis (4.7%) [9]. As a fact, about 50% of ESRD patients in USA are diabetic and about 50–60% of all patients with CKD are hypertensive [10]. According to the CKD Registry of India, the most common cause of CKD in Indian population is diabetes (31%) followed by CKD of undetermined etiology (16%) followed by chronic glomerulonephritis (14%) and hypertensive nephrosclerosis (13%) with almost equal frequency. Other less common causes were: interstitial nephritis (7%), chronic obstructive uropathy (3.4%), miscellaneous (11.7), renovascular disease (0.8%), and graft failure (0.3%) [11] (**Figure 1**).

**Figure 1.** Etiological spectrum of Indian CKD patients of chronic kidney disease of unknown etiology (CKDu).

## **2. Chronic kidney disease of unknown etiology (CKDu)**

## **2.1. Overview**

In the mid of 1990s, a new form of CKD was identified among the rice paddy farmers of North Central Province (NCP) of Sri Lanka. This form of CKD is otherwise known as chronic kidney disease of unknown etiology (CKDu) [12]. Over the last two decades, similar kind of cases in significant number was reported from other farming areas of Sri Lanka and different parts of the world including Central America, among immigrants in UK from South-east Asia and India. Different terms have been used to describe CKDu in literature: chronic kidney disease of uncertain origin; chronic kidney disease of unknown origin; agrochemical nephropathy, etc. [13]. In some cases, it is named after the region or country of its origin: Central American nephropathy [14]; Salvadoran agricultural nephropathy; Mesoamerican endemic nephropathy (MeN); chronic tubulo-interstitial kidney disease of Central America; Udhanam endemic nephropathy (India); Sri Lankan agricultural nephropathy; or chronic interstitial nephritis in agricultural communities (CINAC) [15].

The prevalence of ESRD in Egypt's El Minia Governorate has increased from 250 to 367 per million populations from 2002 to 2007. The etiology is unknown in 27% patients [20, 21]. A case control study among ESRD patients from this area has shown association with rural residence, unsafe drinking water, family history of CKD, pesticide exposure, and medicinal plant use [21]. The authors concluded that the disease may be attributed to environmental factors.

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According to the report of the CKD Registry of India, of 52,273 CKD patients during 2006– 2010, chronic kidney disease of unknown etiology was found in 16% of the CKD patients and was estimated to be the second leading cause only after diabetes mellitus. In this study, CKDu was more frequent in young low income patients and is clinically characterized by no or mild hypertension or proteinuria. Since there are few symptoms, disease is usually diagnosed at

Another study from the Udhanam coastal region of Andhra Pradesh, India revealed prevalence of proteinuria to be 15.3% (54/354) in an agricultural community primarily involved in the cultivation of coconut, jackfruit, rice, and cashew with a higher prevalence in men compared to women (20% vs. 12% respectively). The prevalence of reduced GFR among males and females was 67 and 57%, respectively. The total prevalence of reduced GFR was 61% combining both males and females. Younger population showed mild to moderate proteinuria and renal histopathology studies revealed chronic tubulointerstitial nephritis. The authors suspected environmental exposure to toxic agents as the most likely cause [22]. In a recent publication by Jayasumana et al., the authors mentioned about an epidemic of CKD, not associated with the traditional risk factors from a few coastal areas of the same geographical region of Andhra Pradesh [12]. According to them, more than 4000 cases have already been diagnosed among paddy and coconut farmers of this area. The source of this information is through a personal communication with Dr. Gangadhar, Nephrologist, Nizam's Institute of Medical Sciences, Hyderabad, India [13]. No significant data of CKDu particularly among CKD patients in general population of urban or rural area are available so far.

The clinical profile of CKDu patients from different geographical regions has striking similarities. Due to the slower rate of progression, majority of the affected individuals are asymptomatic for long time particularly during the early course of the disease [23]. The urine sediment shows no significant abnormalities in the markers of renal damage. Proteinuria is rare and moderate if present and can be described as "tubular" since β2 microglobulin and other tubular markers are found to be elevated in urine [24]. In the year of 2009, Ministry of Health of Sri Lanka developed the criteria for case definition of CKDu. According to these criteria, chronic kidney disease is considered to be of unknown etiology if there is: (1) no past history of, or current treatment for diabetes mellitus or chronic or severe hypertension, snake bites, urological disease of known etiology or glomerulonephritis; (2) normal glycosylated hemoglobin level (HbA1<sup>C</sup> < 6.5%); and (3) blood pressure < 160/100 mm Hg untreated or <140/90 mm Hg on up to two antihyperten-

**2.3. Indian scenario**

an advanced stage [11].

sive drugs [25].

**2.4. CKDu: clinical profile and case definition**

## **2.2. Global impact and epidemiological pattern**

Since the first case was reported, it has become the most alarming public health issue of Sri Lanka with more than 60,000 patients and more than 20,000 deaths annually. Hospital records show a steady increase of CKDu from the year 2000 to 2015 [12]. According to the NCP (North Central Province) statistics, the cause is unknown for 2809 (70.2%) of the newly diagnosed cases of CKD and only 15.7 and 9.6% cases were diagnosed to have hypertension and diabetes, respectively. The male to female ratio was 2.6:1 showing a male preponderance. The majority of patients of CKD with undetermined etiology were in stage 4 (40%) at presentation [16].

In Central America, increasing number of CKD patients and CKD-specific mortality has been observed over the last 20 years particularly in Nicaragua and El Salvador. In the farming community of El Salvador, CKD is the fifth leading cause of death in adults. Women, men, adolescents and children, all who live in these farming communities are affected, irrespective of whether they are involved in agricultural activity or not. In Nicaragua, another endemic area for CKDu in Central America, the studies showed positive association between CKD and agricultural work, exposure to pesticides, dehydration, hypertension, drinking of *lija* (homemade liquor), and a family history of CKD [17]. Another endemic country in Central America is Costa Rica where the disease appeared in agricultural workers who work for long hours in sugarcane plantations. Clinical presentation and histopathology were consistent with chronic interstitial nephritis. The authors suspected work environment related factors to be associated with the disease [18]. A recent cross-sectional study conducted in 2009–2011 in females in agricultural communities of El Salvador, shows the prevalence of CKDu in women of these communities to be 6.7%. The key factors behind CKDu in women are probably chronic exposure to toxic agents and environmental toxins [19].

The prevalence of ESRD in Egypt's El Minia Governorate has increased from 250 to 367 per million populations from 2002 to 2007. The etiology is unknown in 27% patients [20, 21]. A case control study among ESRD patients from this area has shown association with rural residence, unsafe drinking water, family history of CKD, pesticide exposure, and medicinal plant use [21]. The authors concluded that the disease may be attributed to environmental factors.

## **2.3. Indian scenario**

**2. Chronic kidney disease of unknown etiology (CKDu)**

202 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

In the mid of 1990s, a new form of CKD was identified among the rice paddy farmers of North Central Province (NCP) of Sri Lanka. This form of CKD is otherwise known as chronic kidney disease of unknown etiology (CKDu) [12]. Over the last two decades, similar kind of cases in significant number was reported from other farming areas of Sri Lanka and different parts of the world including Central America, among immigrants in UK from South-east Asia and India. Different terms have been used to describe CKDu in literature: chronic kidney disease of uncertain origin; chronic kidney disease of unknown origin; agrochemical nephropathy, etc. [13]. In some cases, it is named after the region or country of its origin: Central American nephropathy [14]; Salvadoran agricultural nephropathy; Mesoamerican endemic nephropathy (MeN); chronic tubulo-interstitial kidney disease of Central America; Udhanam endemic nephropathy (India); Sri Lankan agricultural nephropathy; or chronic interstitial nephritis in

Since the first case was reported, it has become the most alarming public health issue of Sri Lanka with more than 60,000 patients and more than 20,000 deaths annually. Hospital records show a steady increase of CKDu from the year 2000 to 2015 [12]. According to the NCP (North Central Province) statistics, the cause is unknown for 2809 (70.2%) of the newly diagnosed cases of CKD and only 15.7 and 9.6% cases were diagnosed to have hypertension and diabetes, respectively. The male to female ratio was 2.6:1 showing a male preponderance. The majority of patients of CKD with undetermined etiology were in stage 4 (40%) at

In Central America, increasing number of CKD patients and CKD-specific mortality has been observed over the last 20 years particularly in Nicaragua and El Salvador. In the farming community of El Salvador, CKD is the fifth leading cause of death in adults. Women, men, adolescents and children, all who live in these farming communities are affected, irrespective of whether they are involved in agricultural activity or not. In Nicaragua, another endemic area for CKDu in Central America, the studies showed positive association between CKD and agricultural work, exposure to pesticides, dehydration, hypertension, drinking of *lija* (homemade liquor), and a family history of CKD [17]. Another endemic country in Central America is Costa Rica where the disease appeared in agricultural workers who work for long hours in sugarcane plantations. Clinical presentation and histopathology were consistent with chronic interstitial nephritis. The authors suspected work environment related factors to be associated with the disease [18]. A recent cross-sectional study conducted in 2009–2011 in females in agricultural communities of El Salvador, shows the prevalence of CKDu in women of these communities to be 6.7%. The key factors behind CKDu in women are probably chronic exposure to toxic agents and environmental

**2.1. Overview**

presentation [16].

toxins [19].

agricultural communities (CINAC) [15].

**2.2. Global impact and epidemiological pattern**

According to the report of the CKD Registry of India, of 52,273 CKD patients during 2006– 2010, chronic kidney disease of unknown etiology was found in 16% of the CKD patients and was estimated to be the second leading cause only after diabetes mellitus. In this study, CKDu was more frequent in young low income patients and is clinically characterized by no or mild hypertension or proteinuria. Since there are few symptoms, disease is usually diagnosed at an advanced stage [11].

Another study from the Udhanam coastal region of Andhra Pradesh, India revealed prevalence of proteinuria to be 15.3% (54/354) in an agricultural community primarily involved in the cultivation of coconut, jackfruit, rice, and cashew with a higher prevalence in men compared to women (20% vs. 12% respectively). The prevalence of reduced GFR among males and females was 67 and 57%, respectively. The total prevalence of reduced GFR was 61% combining both males and females. Younger population showed mild to moderate proteinuria and renal histopathology studies revealed chronic tubulointerstitial nephritis. The authors suspected environmental exposure to toxic agents as the most likely cause [22]. In a recent publication by Jayasumana et al., the authors mentioned about an epidemic of CKD, not associated with the traditional risk factors from a few coastal areas of the same geographical region of Andhra Pradesh [12]. According to them, more than 4000 cases have already been diagnosed among paddy and coconut farmers of this area. The source of this information is through a personal communication with Dr. Gangadhar, Nephrologist, Nizam's Institute of Medical Sciences, Hyderabad, India [13]. No significant data of CKDu particularly among CKD patients in general population of urban or rural area are available so far.

## **2.4. CKDu: clinical profile and case definition**

The clinical profile of CKDu patients from different geographical regions has striking similarities. Due to the slower rate of progression, majority of the affected individuals are asymptomatic for long time particularly during the early course of the disease [23]. The urine sediment shows no significant abnormalities in the markers of renal damage. Proteinuria is rare and moderate if present and can be described as "tubular" since β2 microglobulin and other tubular markers are found to be elevated in urine [24]. In the year of 2009, Ministry of Health of Sri Lanka developed the criteria for case definition of CKDu. According to these criteria, chronic kidney disease is considered to be of unknown etiology if there is: (1) no past history of, or current treatment for diabetes mellitus or chronic or severe hypertension, snake bites, urological disease of known etiology or glomerulonephritis; (2) normal glycosylated hemoglobin level (HbA1<sup>C</sup> < 6.5%); and (3) blood pressure < 160/100 mm Hg untreated or <140/90 mm Hg on up to two antihypertensive drugs [25].

#### **2.5. CKDu: histopathological pattern**

The morphological pattern of CKDu is described as chronic tubulo-interstitial nephritis, from two of the important endemic geographical areas: Sri Lanka and El Salvador [26, 27]. The prominent findings are interstitial fibrosis and tubular atrophy with or without inflammatory monocyte infiltration. In a retrospective study of 251 renal biopsies from patients in Sri Lanka, histopathological features of the first four stages of CKDu have been described [28]. The predominant feature of stage 1 disease is mild to moderate interstitial fibrosis without the evidence of interstitial inflammation in most of the cases. Glomerulosclerosis was absent in 62.3% of the specimens. Stage 2 CKD specimens show moderate interstitial fibrosis with or without mild interstitial inflammation. Features of Stage 3 CKD had moderate to severe interstitial fibrosis, moderate inflammation, tubular atrophy, and glomerulosclerosis. In a recent study from El Salvador, more severe tubular atrophy and less glomerular lesion were found among patients of CKDu involved in sugarcane farming along with more mononuclear inflammatory infiltration when compared to non-agricultural workers [29].

Available literatures on CKDu mostly show prevalence of this disease from agricultural communities of low socio-economic strata. But there is increasing concern among scientists that the health hazards of agrochemicals are no longer limited to the agricultural communities. Due to extensive and widespread contamination of food, water, soil, air, flora and fauna by environmental pollutants like OCPs, general populations not involved in agriculture and

Role of Organochlorine Pesticides in Chronic Kidney Diseases of Unknown Etiology

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205

Agrochemicals are chemicals such as inorganic fertilizers, liming agents and acidifying agents, pesticides, plant hormones or phytohormones, and plant growth agents used to improve the production of crops. The obvious benefit of using agrochemicals is the improved production of quality and quantity of vegetables, fruits, and crops, but not without a toll. Widespread and uncontrolled use of these chemicals for long time caused extensive contamination of the environment and thus caused significant adverse effect on the ecosystem and the health of the

A pesticide is a substance or mixture of substances used to kill a pest. It may be a chemical substance, biological agents (such as virus or bacteria), antimicrobial, disinfectant or device used against any pest [39]. The Food and Agriculture Association (FAO) of the United Nations has defined the term pesticide as "any substance or mixtures of substances intended for preventing, destroying or controlling any pest, including vectors of human or animal disease, unwanted species of plants or animals causing harm during or otherwise interfering with the production, processing, storage, transport, or marketing of food, agricultural commodities, wood and wood product or animal feedstuffs, or substances which can be administered to animals for the control of insects, arachnids or other pests in or on their bodies." Pesticides include variety of different compounds such as insecticides, ovicides, larvicides, adulticides, herbicides, fungicides, rodenticides, etc. [40]. The use of pesticides was of great help in increasing the yield of crops in agriculture and in public health programmes for controlling vector-borne diseases. On the other hand, due to their potential toxicity to human and animals, it has become a global concern for environmental pollution and health hazard. More than 98% of sprayed pesticides and 95% of herbicides reach a destination other than their targeted species including air, water, soil, food, and non-targeted living species. Some of them are persistent organic pollutants (POPs) and contribute to significant soil contamination. In this way, they have become an integral part of the ecosystem and environment, and as they are meant for destruction of some particular species, they leave a devastating effect on other non-targeted species as well as humans leading to a

Organochlorine pesticides have a long history of indiscriminate and uncontrolled use for about five decades for both agricultural and sanitary purposes. Some of the OCPs which have

been banned or restricted in the last two decades in India are shown in **Table 3**.

populations from non-rural area are also exposed to these toxic chemicals as well.

living organisms as well as humans.

potential hazard to their health [39].

**3.1. Organochlorine pesticides (OCPs)**

**3. Pesticides**

#### **2.6. CKDu: probable etiological factors**

Most of the available literature points toward the exposure to environmental contaminants and agrochemicals as possible etiological factors. The countries and regions where CKDu has clustered, followed age-old practice of traditional agriculture for centuries prior to the introduction of biotechnologically produced high yield seeds, chemical fertilizers, and pesticides as a part of "green revolution" in the 1960s [30]. Interestingly, it was only after the green revolution that a high prevalence of CKD cases was reported from rural agricultural communities from the endemic areas all over the world, suggesting that a factor related to the changed agricultural practice could be a trigger to this disease [31]. Recently, evidence implicating agrochemicals, particularly fertilizers emerged in Sri Lanka, where CKDu patients were found to have higher urinary excretion of cadmium having a dose-dependent association with CKDu severity [32]. Other risk factors identified for CKDu are being a farmer, handling pesticides, drinking well water, having taken herbal or Ayurvedic medicines, etc. [33]. In a recent study, Jayasumana et al. [13] proposed a well-researched theory of renal tubular damage by heavy metals which absorbed into the body as a lattice structure formed by chelation of metal ions with glyphosate, a widely used herbicides by the farmers of the endemic area. This theory, though attractive has yet to be proven by bench research and many academic chemists do not support this view. The high prevalence of CKD in the villages located downstream [34], and among consumers of water from shallow wells [16, 35] strongly indicates the possibility of entry of toxins through contaminated drinking water [13]. Genetic susceptibility is another possible risk factor according to some studies [36].

The etiology of CKDu in Central America appears to be multifactorial. Two main hypotheses have emerged. One identifies the trigger as exposure to agrochemicals and pesticides either due to exposure during agricultural activity or through contaminated physical environment, water, and food. Occurrence of extra-renal manifestations in CKDu patients suggests generalized toxicity affecting different organ systems with renal damage being a part of systemic pathology. The second hypothesis is the effect of heat stress compounded with strenuous labor and insufficient fluid intake triggering repeated episodes of subclinical acute renal injury that could lead to chronic kidney disease [37, 38].

Available literatures on CKDu mostly show prevalence of this disease from agricultural communities of low socio-economic strata. But there is increasing concern among scientists that the health hazards of agrochemicals are no longer limited to the agricultural communities. Due to extensive and widespread contamination of food, water, soil, air, flora and fauna by environmental pollutants like OCPs, general populations not involved in agriculture and populations from non-rural area are also exposed to these toxic chemicals as well.

Agrochemicals are chemicals such as inorganic fertilizers, liming agents and acidifying agents, pesticides, plant hormones or phytohormones, and plant growth agents used to improve the production of crops. The obvious benefit of using agrochemicals is the improved production of quality and quantity of vegetables, fruits, and crops, but not without a toll. Widespread and uncontrolled use of these chemicals for long time caused extensive contamination of the environment and thus caused significant adverse effect on the ecosystem and the health of the living organisms as well as humans.

## **3. Pesticides**

**2.5. CKDu: histopathological pattern**

204 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

**2.6. CKDu: probable etiological factors**

injury that could lead to chronic kidney disease [37, 38].

The morphological pattern of CKDu is described as chronic tubulo-interstitial nephritis, from two of the important endemic geographical areas: Sri Lanka and El Salvador [26, 27]. The prominent findings are interstitial fibrosis and tubular atrophy with or without inflammatory monocyte infiltration. In a retrospective study of 251 renal biopsies from patients in Sri Lanka, histopathological features of the first four stages of CKDu have been described [28]. The predominant feature of stage 1 disease is mild to moderate interstitial fibrosis without the evidence of interstitial inflammation in most of the cases. Glomerulosclerosis was absent in 62.3% of the specimens. Stage 2 CKD specimens show moderate interstitial fibrosis with or without mild interstitial inflammation. Features of Stage 3 CKD had moderate to severe interstitial fibrosis, moderate inflammation, tubular atrophy, and glomerulosclerosis. In a recent study from El Salvador, more severe tubular atrophy and less glomerular lesion were found among patients of CKDu involved in sugarcane farming along with more mononuclear

Most of the available literature points toward the exposure to environmental contaminants and agrochemicals as possible etiological factors. The countries and regions where CKDu has clustered, followed age-old practice of traditional agriculture for centuries prior to the introduction of biotechnologically produced high yield seeds, chemical fertilizers, and pesticides as a part of "green revolution" in the 1960s [30]. Interestingly, it was only after the green revolution that a high prevalence of CKD cases was reported from rural agricultural communities from the endemic areas all over the world, suggesting that a factor related to the changed agricultural practice could be a trigger to this disease [31]. Recently, evidence implicating agrochemicals, particularly fertilizers emerged in Sri Lanka, where CKDu patients were found to have higher urinary excretion of cadmium having a dose-dependent association with CKDu severity [32]. Other risk factors identified for CKDu are being a farmer, handling pesticides, drinking well water, having taken herbal or Ayurvedic medicines, etc. [33]. In a recent study, Jayasumana et al. [13] proposed a well-researched theory of renal tubular damage by heavy metals which absorbed into the body as a lattice structure formed by chelation of metal ions with glyphosate, a widely used herbicides by the farmers of the endemic area. This theory, though attractive has yet to be proven by bench research and many academic chemists do not support this view. The high prevalence of CKD in the villages located downstream [34], and among consumers of water from shallow wells [16, 35] strongly indicates the possibility of entry of toxins through contaminated drinking water [13]. Genetic susceptibility is another possible risk factor according to some studies [36]. The etiology of CKDu in Central America appears to be multifactorial. Two main hypotheses have emerged. One identifies the trigger as exposure to agrochemicals and pesticides either due to exposure during agricultural activity or through contaminated physical environment, water, and food. Occurrence of extra-renal manifestations in CKDu patients suggests generalized toxicity affecting different organ systems with renal damage being a part of systemic pathology. The second hypothesis is the effect of heat stress compounded with strenuous labor and insufficient fluid intake triggering repeated episodes of subclinical acute renal

inflammatory infiltration when compared to non-agricultural workers [29].

A pesticide is a substance or mixture of substances used to kill a pest. It may be a chemical substance, biological agents (such as virus or bacteria), antimicrobial, disinfectant or device used against any pest [39]. The Food and Agriculture Association (FAO) of the United Nations has defined the term pesticide as "any substance or mixtures of substances intended for preventing, destroying or controlling any pest, including vectors of human or animal disease, unwanted species of plants or animals causing harm during or otherwise interfering with the production, processing, storage, transport, or marketing of food, agricultural commodities, wood and wood product or animal feedstuffs, or substances which can be administered to animals for the control of insects, arachnids or other pests in or on their bodies." Pesticides include variety of different compounds such as insecticides, ovicides, larvicides, adulticides, herbicides, fungicides, rodenticides, etc. [40]. The use of pesticides was of great help in increasing the yield of crops in agriculture and in public health programmes for controlling vector-borne diseases. On the other hand, due to their potential toxicity to human and animals, it has become a global concern for environmental pollution and health hazard. More than 98% of sprayed pesticides and 95% of herbicides reach a destination other than their targeted species including air, water, soil, food, and non-targeted living species. Some of them are persistent organic pollutants (POPs) and contribute to significant soil contamination. In this way, they have become an integral part of the ecosystem and environment, and as they are meant for destruction of some particular species, they leave a devastating effect on other non-targeted species as well as humans leading to a potential hazard to their health [39].

## **3.1. Organochlorine pesticides (OCPs)**

Organochlorine pesticides have a long history of indiscriminate and uncontrolled use for about five decades for both agricultural and sanitary purposes. Some of the OCPs which have been banned or restricted in the last two decades in India are shown in **Table 3**.

Others which are in main use include lindane, endosulfan, dicofol, methoxychlor, and pentachlorophenol [39]. Organochlorine pesticides (OCPs), due to their chemical stability and extremely resistant nature to degradation, persist for long in the environment (**Table 4**).

**3.2. Exposure to OCPs**

milk samples [54].

sionals from Pakistan [58].

**3.3. Detectable blood levels of OCPs in general population**

Exposure to organochlorine pesticides may occur by direct exposure through handling or spraying during agricultural activity particularly by inadequately educated farmers, without proper protective gears, by using some personal care products like lice shampoo or indirectly through contaminated food and water. Organochlorine pesticides are carried long distance via atmospheric and oceanic currents from the site of its manufacture or use and build up in the fatty tissues of animals [46]. Many studies have linked OCP exposure with consumption of contaminated animal products, mostly meat, fish, and marine mammals [47, 48]. Fetuses and children may get exposed to pesticides *in utero* as well as through breast milk [49]. Even after replacement of organochlorine pesticides by organophosphate, consumer products such as edible crops, fruits, and milk show substantial levels of organochlorine pesticides residue. In a multicentric study, residues of OCPs, especially DDT and HCH have been detected in humans and in environment [50]. Before the imposition of ban, endosulfan was in extensive use in agricultural practice and this led to its occurrence in a variety of food items in India [51]. High levels of DDT and HCH have been reported in human blood, fat, and milk samples in India [52, 53]. A recent study from Punjab, India has shown p,p′-DDE as the major contaminant detected in human breast

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Detectable blood levels of organochlorine pesticides (OCPs) such as DDT, DDE, HCH, endosulfan, and aldrin have been reported from different parts of the worlds like Spain, Canada, Mexico, Egypt, Pakistan and different parts of India in agro professional as well as in the non-agro professional general population. In a recent published report from Mexico, p,p′-DDE was detected in 100% of the blood samples of the participants. p,p′- DDT was detected in 41.3% of samples. β-HCH was present in 48.6% of samples and o,p′-DDT was found in only 3.3% of the samples analyzed [55]. Published data on the level of OCPs from the blood samples of general population from different parts of India have shown the presence of a number of OCPs. The OCPs levels ranged from 2.92 to 4.52 parts per billion (ppb) for α-HCH, 1.93–10.05 ppb for β-HCH, 1.69–5.33 ppb for γ-HCH, 0.03–3.32 ppb for aldrin, 1.97–2.77 ppb for dieldrin, 0.01–2.21 ppb for α-endosulfan, 1.18–1.49 ppb for β-endosulfan, 0.045–1.62 ppb for p,p′-DDT, and 2.18–4.26 ppb for p,p′- DDE [56]. High serum concentration of BHC and DDE (range: 0.006–0.130 ppm for BHC and 0.002–0.033 ppm for DDE) were detected in agro and non-agro professionals in and around Madurai, India [50]. A recent publication from Punjab, India, revealed the presence of p,p′-DDE, p,p′-DDD, o,p′-DDE, and β-endosulfan at mean levels of 15.26, 2.71, 5.62, and 4.02 ng/ml, respectively, from the blood samples of the study subjects. Though statistically non-significant (p > 0.05), higher levels of total DDT residues were detected in non-vegetarians [54]. Higher blood levels of DDT have also have been reported earlier [57]. High blood levels of endosulfan (with highest mean concentration of 0.30 mg/kg) was detected along with other organophosphate and p,p′-DDT from agro and non-agro profes-

These compounds are mainly found associated with organic matter in soil and in animal tissue due to their strong lipophilic property. They bioaccumulate in the adipose tissue of animals as well as humans and even get biomagnified through food chain [41]. Increased level of different OCP residues has been detected in different human samples such as placenta, blood, semen, amniotic fluid, breast milk, etc. [42–45]. Some of the notable examples are: dichlorodiphenyltrichloroethane (DDT) and its analogues (such as methoxychlor), dicofol, aldrin, endrin, heptachlor, endosulfan, chlordane, dieldrin, lindane, mirex, etc. [39].


**Table 3.** Current status of organochlorine pesticides in India.


**Table 4.** Environmental half-life of organochlorines.

#### **3.2. Exposure to OCPs**

Others which are in main use include lindane, endosulfan, dicofol, methoxychlor, and pentachlorophenol [39]. Organochlorine pesticides (OCPs), due to their chemical stability and extremely resistant nature to degradation, persist for long in the environment (**Table 4**).

These compounds are mainly found associated with organic matter in soil and in animal tissue due to their strong lipophilic property. They bioaccumulate in the adipose tissue of animals as well as humans and even get biomagnified through food chain [41]. Increased level of different OCP residues has been detected in different human samples such as placenta, blood, semen, amniotic fluid, breast milk, etc. [42–45]. Some of the notable examples are: dichlorodiphenyltrichloroethane (DDT) and its analogues (such as methoxychlor), dicofol, aldrin,

Complete ban 2003

endrin, heptachlor, endosulfan, chlordane, dieldrin, lindane, mirex, etc. [39].

**Compounds Status in India Year** Aldrin Banned 1996 Chlordane Banned 1996 DDT Restricted use 1980 Dieldrin Restricted use 1990

Endrin Banned 1990 HCH Banned 1997 Heptachlor Banned 1996

**Organochlorine pesticides Half-life in soil** α-HCH 2–8 years β-HCH 1–7 years γ-HCH 1.2–6.5 years Aldrin 0.3–3.0 years Dieldrin 2.5–8.0 years α-Endosulfan 35–67 days β-Endosulfan 104–265 days p,p′-DDT 2.8–10.0 years p,p′-DDE 1–15 years

Adapted from: Agrawal and Sharma [39] and Free Wikipedia, the free encyclopedia [49].

**Table 4.** Environmental half-life of organochlorines.

Adapted from: Free Wikipedia, the free encyclopedia.

**Table 3.** Current status of organochlorine pesticides in India.

206 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

Exposure to organochlorine pesticides may occur by direct exposure through handling or spraying during agricultural activity particularly by inadequately educated farmers, without proper protective gears, by using some personal care products like lice shampoo or indirectly through contaminated food and water. Organochlorine pesticides are carried long distance via atmospheric and oceanic currents from the site of its manufacture or use and build up in the fatty tissues of animals [46]. Many studies have linked OCP exposure with consumption of contaminated animal products, mostly meat, fish, and marine mammals [47, 48]. Fetuses and children may get exposed to pesticides *in utero* as well as through breast milk [49]. Even after replacement of organochlorine pesticides by organophosphate, consumer products such as edible crops, fruits, and milk show substantial levels of organochlorine pesticides residue. In a multicentric study, residues of OCPs, especially DDT and HCH have been detected in humans and in environment [50]. Before the imposition of ban, endosulfan was in extensive use in agricultural practice and this led to its occurrence in a variety of food items in India [51]. High levels of DDT and HCH have been reported in human blood, fat, and milk samples in India [52, 53]. A recent study from Punjab, India has shown p,p′-DDE as the major contaminant detected in human breast milk samples [54].

#### **3.3. Detectable blood levels of OCPs in general population**

Detectable blood levels of organochlorine pesticides (OCPs) such as DDT, DDE, HCH, endosulfan, and aldrin have been reported from different parts of the worlds like Spain, Canada, Mexico, Egypt, Pakistan and different parts of India in agro professional as well as in the non-agro professional general population. In a recent published report from Mexico, p,p′-DDE was detected in 100% of the blood samples of the participants. p,p′- DDT was detected in 41.3% of samples. β-HCH was present in 48.6% of samples and o,p′-DDT was found in only 3.3% of the samples analyzed [55]. Published data on the level of OCPs from the blood samples of general population from different parts of India have shown the presence of a number of OCPs. The OCPs levels ranged from 2.92 to 4.52 parts per billion (ppb) for α-HCH, 1.93–10.05 ppb for β-HCH, 1.69–5.33 ppb for γ-HCH, 0.03–3.32 ppb for aldrin, 1.97–2.77 ppb for dieldrin, 0.01–2.21 ppb for α-endosulfan, 1.18–1.49 ppb for β-endosulfan, 0.045–1.62 ppb for p,p′-DDT, and 2.18–4.26 ppb for p,p′- DDE [56]. High serum concentration of BHC and DDE (range: 0.006–0.130 ppm for BHC and 0.002–0.033 ppm for DDE) were detected in agro and non-agro professionals in and around Madurai, India [50]. A recent publication from Punjab, India, revealed the presence of p,p′-DDE, p,p′-DDD, o,p′-DDE, and β-endosulfan at mean levels of 15.26, 2.71, 5.62, and 4.02 ng/ml, respectively, from the blood samples of the study subjects. Though statistically non-significant (p > 0.05), higher levels of total DDT residues were detected in non-vegetarians [54]. Higher blood levels of DDT have also have been reported earlier [57]. High blood levels of endosulfan (with highest mean concentration of 0.30 mg/kg) was detected along with other organophosphate and p,p′-DDT from agro and non-agro professionals from Pakistan [58].

#### **3.4. Association of blood OCPs levels and pathological conditions**

Cumulative data from all over the world have linked a number of pathological conditions with detectable or high blood levels of OCPs such as metabolic syndrome, hypercholesterolemia, insulin resistance, preterm labor, urogenital and breast cancer, diabetes mellitus, etc. In a recent report from Thailand, the total amount of serum p,p′-DDE concentration was found to have significant correlation with plasma glucose levels [59]. Another study from Egypt has shown significant positive association of only heptachlor residue and blood glucose level among the OCPs studied [60]. A recent study from Northern Benin, West Africa has shown consistently higher serum levels of four OCPs namely p,p′-DDE, p,p′-DDT, β-HCH, and trans-nonachlor in diabetic subjects compared to non-diabetic controls [61]. In a recent publication, β-HCH and aldrin has been shown to be significantly and positively associated with the risk of having metabolic syndrome [62]. Another report from this Institute has shown significant positive association of higher blood levels of α-HCH, β-HCH, p,p′-DDE, and o′,p′-DDD from mothers of preterm birth cases as compared to term controls [63]. A significant association of high blood levels of BHC and its isomers, dieldrin, heptachlor, DDT and its metabolites have been shown with the occurrence of reproductive tract cancer among women from Jaipur, India [64]. Another report from U.S. has shown that serum concentration of β-HCH, trans-nonachlor, and dieldrin has significant association with risk for prostate cancer [65].

**Acknowledgements**

**Author details**

Ashok Kumar Tripathi<sup>1</sup>

Rishila Ghosh<sup>1</sup>

**References**

The author acknowledges Dr. Debashis Adhikary for his generous help in editing the draft

, Pawan Kuman Kare<sup>1</sup>

1 Department of Biochemistry, Environmental Biochemistry and Immunology Laboratory, University College of Medical Sciences (University of Delhi) and G.T.B. Hospital, Delhi, India

2 Multidisciplinary Research Unit, University College of Medical Sciences (University of

3 Department of Medicine, University College of Medical Sciences (University of Delhi) and

[1] Lopez-Novoa JM, Rodriguez-Pena AB, Ortiz A, Martinez-Salgado C, Lopez Hernandez FJ. Etiopathology of chronic tubular, glomerular and renovascular nephropathies: Clinical

[2] World Kidney Day: Chronic Kidney Disease. 2015; http://www.worldkidneyday.org/

[3] Prabahar MR, Chandrasekaran V, Soundararajan P. Epidemic of chronic kidney disease in India—What can be done? Saudi Journal of Kidney Diseases and Transplantation.

[4] Kher V. End stage renal disease in developing countries. Kidney International. 2002;

[5] Couser WG, Rrmuzzi G, Mendis S, Tonelli M. The contribution of chronic kidney disease to the global burden of major noncommunicable diseases. Kidney International.

[6] Levey AS, Eckardt KU, Tsukamoto Y, Levin A, Coresh J, Rossert J, et al. Definition and classification of chronic kidney disease: Improving global outcomes (KDIGO). Kidney

[7] Hsu CY, Vittinghoff E, Lin F, Shlipak MG. The incidence of end-stage renal disease in increasing faster than the prevalence of chronic renal insufficiency. Annals of Internal

implications. Journal of Translational Medicine. 2011;**1479**:9-13

, Om Prakash Kalra<sup>3</sup>

Role of Organochlorine Pesticides in Chronic Kidney Diseases of Unknown Etiology

and

http://dx.doi.org/10.5772/intechopen.71196

209

and providing important suggestions which made this endeavor a success.

, Manushi Siddharth<sup>2</sup>

\*Address all correspondence to: aktripathiucms@gmail.com

\*

Delhi) and G.T.B. Hospital, Delhi, India

faqs/chronic-kidney-disease/

2008;**19**:847-853

2011;**12**:1258-1270

International. 2005;**67**:2089-2100

Medicine. 2004;**2**:95-101

**62**:350-362

G.T.B. Hospital, Delhi, India

## **4. OCPs exposure and CKDu**

Literatures are scarce about the role of OCPs in CKDu. A recent study from the same laboratory has reported significant negative correlation of eGFR of patients of CKD of unknown etiology with blood levels of γ-HCH (p < 0.05), total HCH (p < 0.05), aldrin (p < 0.05), and total pesticides (p < 0.05). The authors also observed a tendency to accumulate pesticides by the CKD patients with decreasing eGFR. They also demonstrated a significant association of total pesticide load with increased oxidative stress in CKD patients [56]. In a previous study by the same authors from the same laboratory showed that the increased OCP levels in CKD patients were partially dependent on GSTM1/GSTT1 polymorphism and particularly GSTM1 (−)/GSTT1 (−) genotype was more vulnerable in this regard [66]. Earlier, Rutten et al. has shown the significant higher levels of HCB and p,p′-DDE in the serum of dialysed and nondialysed uremic patients than in controls [67].

Epidemiological studies from the endemic areas strongly suggest the role of agrochemicals and pesticides in the development of CKDu. The detectable blood levels of these persistent organic pollutants in the general population worldwide confirms chronic exposure of humans to these toxins which are known to have significant and diverse adverse effect on different organ systems including kidney. In view of the available literatures till date, it seems to be plausible that chronic exposure to OCPs have a crucial role in the development and progression of CKDu although precise underlying mechanisms and evidence-based effective preventive and therapeutic strategies remains an unmet goal till date. Future research works with improved study design should focus on this important issue and fresh body of evidences is expected to emerge more and more in the days ahead.

## **Acknowledgements**

**3.4. Association of blood OCPs levels and pathological conditions**

208 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

prostate cancer [65].

**4. OCPs exposure and CKDu**

dialysed uremic patients than in controls [67].

expected to emerge more and more in the days ahead.

Cumulative data from all over the world have linked a number of pathological conditions with detectable or high blood levels of OCPs such as metabolic syndrome, hypercholesterolemia, insulin resistance, preterm labor, urogenital and breast cancer, diabetes mellitus, etc. In a recent report from Thailand, the total amount of serum p,p′-DDE concentration was found to have significant correlation with plasma glucose levels [59]. Another study from Egypt has shown significant positive association of only heptachlor residue and blood glucose level among the OCPs studied [60]. A recent study from Northern Benin, West Africa has shown consistently higher serum levels of four OCPs namely p,p′-DDE, p,p′-DDT, β-HCH, and trans-nonachlor in diabetic subjects compared to non-diabetic controls [61]. In a recent publication, β-HCH and aldrin has been shown to be significantly and positively associated with the risk of having metabolic syndrome [62]. Another report from this Institute has shown significant positive association of higher blood levels of α-HCH, β-HCH, p,p′-DDE, and o′,p′-DDD from mothers of preterm birth cases as compared to term controls [63]. A significant association of high blood levels of BHC and its isomers, dieldrin, heptachlor, DDT and its metabolites have been shown with the occurrence of reproductive tract cancer among women from Jaipur, India [64]. Another report from U.S. has shown that serum concentration of β-HCH, trans-nonachlor, and dieldrin has significant association with risk for

Literatures are scarce about the role of OCPs in CKDu. A recent study from the same laboratory has reported significant negative correlation of eGFR of patients of CKD of unknown etiology with blood levels of γ-HCH (p < 0.05), total HCH (p < 0.05), aldrin (p < 0.05), and total pesticides (p < 0.05). The authors also observed a tendency to accumulate pesticides by the CKD patients with decreasing eGFR. They also demonstrated a significant association of total pesticide load with increased oxidative stress in CKD patients [56]. In a previous study by the same authors from the same laboratory showed that the increased OCP levels in CKD patients were partially dependent on GSTM1/GSTT1 polymorphism and particularly GSTM1 (−)/GSTT1 (−) genotype was more vulnerable in this regard [66]. Earlier, Rutten et al. has shown the significant higher levels of HCB and p,p′-DDE in the serum of dialysed and non-

Epidemiological studies from the endemic areas strongly suggest the role of agrochemicals and pesticides in the development of CKDu. The detectable blood levels of these persistent organic pollutants in the general population worldwide confirms chronic exposure of humans to these toxins which are known to have significant and diverse adverse effect on different organ systems including kidney. In view of the available literatures till date, it seems to be plausible that chronic exposure to OCPs have a crucial role in the development and progression of CKDu although precise underlying mechanisms and evidence-based effective preventive and therapeutic strategies remains an unmet goal till date. Future research works with improved study design should focus on this important issue and fresh body of evidences is The author acknowledges Dr. Debashis Adhikary for his generous help in editing the draft and providing important suggestions which made this endeavor a success.

## **Author details**

Rishila Ghosh<sup>1</sup> , Manushi Siddharth<sup>2</sup> , Pawan Kuman Kare<sup>1</sup> , Om Prakash Kalra<sup>3</sup> and Ashok Kumar Tripathi<sup>1</sup> \*

\*Address all correspondence to: aktripathiucms@gmail.com

1 Department of Biochemistry, Environmental Biochemistry and Immunology Laboratory, University College of Medical Sciences (University of Delhi) and G.T.B. Hospital, Delhi, India

2 Multidisciplinary Research Unit, University College of Medical Sciences (University of Delhi) and G.T.B. Hospital, Delhi, India

3 Department of Medicine, University College of Medical Sciences (University of Delhi) and G.T.B. Hospital, Delhi, India

## **References**


[8] Molitch ME, DeFrozo RA, Franz MJ, Keane WF, Mogensen CE, Parving HH, et al. Nephropathy in diabetes. Diabetes Care. 2004;**7**:S79-S83

[20] Kamell EG, El-Minshawy O. Environmental factors incriminated in the development of end stage renal disease in El-Mina Governorate, Upper Egypt. International Journal of

Role of Organochlorine Pesticides in Chronic Kidney Diseases of Unknown Etiology

http://dx.doi.org/10.5772/intechopen.71196

211

[21] El-Minshawy O. End stage renal disease in the El-Mina governorate, Upper Ezypt: An epidemiological study. Saudi Journal of Kidney Diseases and Transplantation. 2011;**5**:

[22] Machiraju RS, Yaradi K, Gowrishankar S, Edwards KL, Attaluri S, Miller F, et al. Epidemiology of Udhanam endemic nephrology. Journal of the American Society of

[23] Athuraliya NT, Abeysekera TD, Amerasinghe PH, Kumarasiri R, Bandara P, Karunaratne U, et al. Uncertain etiologies of proteinuric-chronic kidney disease in rural Sri Lanka.

[24] Noiri C, Shimizu T, Takayanagi K. Clinical significance of fractional magnesium excretion (FEMg) as a predictor of interstitial nephropathy and its correlation with conven-

[25] Ministry of Health. Chronic Kidney Disease of Unknown Etiology; Circular no 01-10/2009.

[26] Nanayakkara S, Komiya T, Ratnatunga N. Tubulointerstitial damage as the major pathological lesion in endemic chronic kidney disease among farmers in North Central Province of Sri Lanka. Environmental Health and Preventive Medicine. 2012;**17**:213-221

[27] Lopez-Marin L, Chavez Y, Garcia XA, Flores WM, Garcia YM, Herrera R. Histopathology of chronic kidney disease of unknown etiology in Salvadoran agricultural communities.

[28] Wijetunge S, Ratnatunga NV, Abeysekera TD. Endemic chronic kidney disease of unknown etiology in Sri Lanka: Correlation of pathology with clinical stages. Indian

[29] Lopez-Marin L, Chavez Y, Garcia XA. Histopathology of chronic kidney disease of unknown etiology in Salvadoran agricultural communities. MEDICC Review. 2014;**16**:49-54

[30] Pimentel D. Green revolution agriculture and chemical hazards. Science of the Total

[31] Wimalawansa SA, Wimalawansa SJ. Impact of changing agricultural practices on human health: Chronic kidney disease of multi-factorial origin in Sri Lanka. Journal of

[32] Jayatilake N, Mendis S, Maheepala P, Mehta FR. CKDu National Research Project Team. Chronic kidney disease of uncertain aetiology: Prevalence and causative factors in a

[33] Wanigasuriya KP, Peiris-John RJ, Wickremasinghe R. Chronic renal failure in North Central Province of Sri Lanka: An environmentally induced disease. Transactions of the

Royal Society of Tropical Medicine and Hygiene. 2007;**101**:1013-1017

tional parameters. Clinical and Experimental Nephrology. 2015;**19**:1071-1078

Nephrology and Urology. 2010;**3**:431-437

Kidney International. 2011;**11**:1212-1221

Colombo, Sri Lanka: Ministry of Health; 2009

MEDICC Review. 2014;**16**:49-54

Environment. 1996;**188**:S86-S98

Agricultural Research. 2014;**3**:110-234

developing country. BMC Nephrology 2013;**14**:1-13

Journal of Nephrology. 2015;**25**:274-280

1048-1054

Nephrology. 2009;**643A**:20


[20] Kamell EG, El-Minshawy O. Environmental factors incriminated in the development of end stage renal disease in El-Mina Governorate, Upper Egypt. International Journal of Nephrology and Urology. 2010;**3**:431-437

[8] Molitch ME, DeFrozo RA, Franz MJ, Keane WF, Mogensen CE, Parving HH, et al.

[9] Collins AJ, Foley RN, Chavers B. US Renal Data System 2013 Annual Data Report.

[10] U.S. Renal Data System, USRDS. 2009 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases;

[11] Rajapurkar MM, John GT, Kirpalani AL, Abraham G, Agarwal SK, Almeida AF, et al. What do we know about chronic kidney disease in India: First report of the Indian CKD

[12] Jayasumana MA, Paranagama PA, Dahanayake KS, Wijewardena KC, Amarasinghe MD, Fonseka SI. Possible link of chronic arsenic toxicity to chronic kidney disease of unknown

[13] Jayasumana C, Orantes C, Herrera R, Almaguer M, Lopez L, Silva LC, et al. Chronic interstitial nephritis in agricultural communities: A worldwide epidemic with social, occupational and environmental determinants. Nephrology, Dialysis, Transplantation.

[14] Ministry of Public Health and Social Assistance of El Salvador, Pan American Health Organization. Asociación de Nefrología e Hipertensión Arterial de El Salvador. Recomendaciones del Primer Taller de Salud Renal al Ministerio de Salud y Asistencia Social de El Salvador [Internet]. San Salvador: Ministry of Public Health and Social Assistance of El Salvador; 2010 [cited 2013 Oct 21]. Available from: http://nefrologiaelsalvador.com/wp-content/uploads/2013/05/DECLARACION-TALLER-SALUD-

[15] Almaguer M, Herrera R. Chronic kidney disease of unknown etiology in agricultural

[16] Jayasekara KB, Dissanayake DM, Sivakanesan R. Epidemiology of chronic kidney disease, with special emphasis on chronic kidney disease of uncertain etiology, in north

[17] Brooks D. Final Scoping Study Report. Epidemiology of Chronic Kidney Disease in Nicaragua [Internet]. Boston: Boston University School of Public Health; 2009. Available from: http://www.cao-ombudsman.org/cases/documentlinks/documents/03H\_BU\_FINAL\_

[18] Cerdas. Chronic kidney disease in Costa Rica. Kidney International. Supplement. 2005;**97**:

[19] Navarro CMO, Valdes RH, Lopez MA, Calero DJ, de Morales JF, Ascencio NPA et al. Epidemiological characteristics of chronic kidney disease of non-traditional causes in woman of agricultural communities of El Salvador. Clinical Nephrology. 2015;**83**:S24-S31

central region of Sri Lanka. Journal of Epidemiology. 2015;**25**:275-280

etiology in Sri Lanka. Journal of Natural Science Research. 2013;**3**:64-73

Nephropathy in diabetes. Diabetes Care. 2004;**7**:S79-S83

American Journal of Kidney Diseases. 2014;**63**:A1-A7

registry? BMC Nephrology. 2012;**13**:1-10

210 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

2009

2016;**0**:1-8

S31-S33

RENAL-160310.doc Spanish

communities. MEDICC Review. 2014;**16**:9-15

report\_scope study CRI\_18.Dec.2009.pdf


[34] Jayasekara JM, Dissanayake DM, Adhikari SB. Geographical distribution of chronic kidney disease of unknown origin in north central region of Sri Lanka. Ceylon Medical Journal. 2013;**58**:6-10

[47] Mwevura H, Othman OC, Mehe GL. Organochlorine pesticide residues in edible biota from the coastal area of Dares Salaam city. Journal of Marine Science. 2002;**1**:91-96 [48] Fitzgerald E, Hwang SA, Deres DA, Bush B, Cook K, Worswick P. The association between local fish consumption and DDE, mirex, and HCB concentrations in the breast milk of Mohawk women at Akwesanse. Journal of Exposure Analysis and Environmental

Role of Organochlorine Pesticides in Chronic Kidney Diseases of Unknown Etiology

http://dx.doi.org/10.5772/intechopen.71196

213

[49] Jurewicz J, Hanke W. Prenatal and childhood exposure to pesticides and neurobehavioral development: Review of epidemiological studies. International Journal of Occupational

[50] Subhramanium K, Solomon J. Organochlorine pesticides BHC and DDE in human blood in and around Madurai, India. Indian Journal of Clinical Biochemistry. 2006;**2**:169-172

[51] Thakur JS, Rao BT, Rajwanshi A, Parwana HK, Kumar R. Epidemiological study of high cancer among rural agricultural community of Punjab in northern India. Environmental

[52] Chatterjee SK, Kashyap SK, Gupta SK. Pesticide Pollution Due to Chlorinated Insecticides Especially DDT in the Environment of Man and Other Livestock in the Country. Report

[53] Raha P, Agarwal NR, Samanta S. Organochlorine pesticide residues in mother milk. In: Agnihotri NP, Walia S, Gajbhiya VT, editors. Green Pesticides, Crop Protection and

[54] Bedi JS, Gill JPS, Kaur P, Sharma A, Aulakh RS. Evaluation of pesticide residues in

[55] Waliszewski SM, Caba M, Herrero-Mercado M, Saldariaga-Norena H, Meza E, et al. Organochlorine pesticide residue levels in blood serum of inhabitants from Veracruz,

[56] Siddharth M, Datta SK, Bansal S, Mustafa M, Banerjee BD, Kalra OP, et al. Study on organochlorine pesticide levels in chronic kidney disease patients: Association with estimated glomerular filtration rate and oxidative stress. Journal of Biochemical and

[57] Kumar A, Baroth A, Soni I, Bhatnagar P, John PJ. Organochlorine pesticide residues in milk and blood of women from Anupgarh, Rajasthan, India. Environmental Monitoring

[58] Latif Y, Sherazi STH, Bhanger MI, Nizamani S. Evaluation of pesticide residues in human blood samples of agro professionals and non-agro professionals. American Journal of

[59] Teeyapant P, Ramchiun S, Polputpisatkul D, Uttawichai C, Parnmen S. Serum concentrations of organochlorine pesticides p,p′-DDE in adult Thai residents with background

levels of exposure. The Journal of Toxicological Sciences. 2014;**39**:121-127

human blood samples from Punjab (India). Veterinary World. 2015;**8**:66-71

Mexico. Environmental Health and Monitoring. 2012;**184**:5613-5621

of a DST Project. Ahmedabad: National Institute of Occupational Health; 1980

Safety Evaluation. Society of Pesticide Science; 1999. p. 231-234

Epidemiology. 2001;**11**:381-388

Medicine and Environmental Health. 2008;**2**:121-132

Research and Public Health. 2008;**5**:399-407

Molecular Toxicology. 2012;**26**:241-247

Analytical Chemistry. 2012;**3**:587-595

and Assessment. 2006;**116**:1-7


[47] Mwevura H, Othman OC, Mehe GL. Organochlorine pesticide residues in edible biota from the coastal area of Dares Salaam city. Journal of Marine Science. 2002;**1**:91-96

[34] Jayasekara JM, Dissanayake DM, Adhikari SB. Geographical distribution of chronic kidney disease of unknown origin in north central region of Sri Lanka. Ceylon Medical

[35] Meharg AA, Norton G, Deacon C. Variation in rice cadmium related to human exposure.

[36] Nanayakkara S, Senevirathna S, Abeysekera T. An integrative study of the genetic, social and environmental determinants of chronic kidney disease characterized by tubulointerstitial damages in the north central region of Sri Lanka. Journal of Occupational

[37] Peraza S, Wesseling C, Aragon A, Leiva R, Garcia RA, Torres C, et al. Decreased kidney function among agricultural workers in El Salvador. American Journal of Kidney

[38] Herrera R, Orantes CM, Almaguer M, Alfonso P, Bayarre HD, Leiva IM, et al. Clinical characteristics of chronic kidney disease of non-traditional causes in Salvadoran farming

[39] Agrawal A, Sharma B. Pesticides induced oxidative stress in mammalian systems.

[40] Ellenhorn MJ, Schonwald S, Ordog G, Wasserberger J. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. Maryland: Williams & Wilkins; 1997.

[41] Siddiqui MK, Srivastava S, Srivastava SP, Mehrotra PK, Mathur N. Persistent chlorinated pesticides and intra-uterine foetal growth retardation: A possible association.

International Archives of Occupational and Environmental Health. 2003;**76**:75-80 [42] Pant N, Mathur N, Banerjee AK, Srivastava SP, Saxena DK. Correlation of chlorinated pesticides concentration in semen with seminal vesicle and prostatic markers.

[43] Devanathan G, Subramanian A, Someya M, Sudaryanto A, Isobe T. Persistent organochlorines in human breast milk from major metropolitan cities in India. Environmental

[44] Sharma E, Mustafa M, Pathak R, Guleria K, Ahmed RS. A case control study of gene environmental interaction in fetal growth restriction with special reference to organochlorine pesticides. European Journal of Obstetrics & Gynaecology and Reproductive

[45] Dewan P, Jain V, Gupta P, Banerjee BD. Organochlorine pesticide residues in maternal blood, cord blood, placenta and breast milk and their relation to birth size. Chemosphere.

[46] Bentzen TW, Follman EH, Amstrup SC, York GS, Woller MJ, Muir DCG, et al. Dietary biomagnification of organochlorine contaminants in Alaskan polar bears. Canadian

Environmental Science and Technology. 2013;**47**:5613-5618

212 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

Journal. 2013;**58**:6-10

Health. 2014;**56**:28-38

Diseases. 2012;**4**:531-540

p. 1614-1663

communities. MEDICC Review. 2014;**2**:39-48

Reproductive Toxicology. 2004;**19**:209-214

Pollution. 2009;**157**:148-154

Biology. 2012;**161**:163-169

Journal of Zoology. 2008;**3**:177-191

2013;**90**:1704-1710

International Journal of Biomedical Research. 2010;**3**:90-104


[60] Sharaf NE, Amer NM, Ibrahim KS, El-Tahlawy EM, Abdelgelil KS. Pesticides usage in agriculture among rural women in Egypt: Association between serum organo-chlorine pesticide residues and occurrence of diabetes. World Journal of Medical Sciences. 2013;**1**:8-15

**Chapter 10**

**Provisional chapter**

**Nutritional Status Disorders in Chronic Kidney Disease:**

Despite the significant achievements in the management of chronic kidney disease (CKD) patients, the mortality rate of these patients still remains high. Nutritional status disorders (NSD) are considered now as one of the prognostic risk factors not only for dialysis but also for predialysis CKD stages. Since the publication of KDIGO 2012 guidelines for CKD patient's management, there has been some significant advancement in our understanding of main NSD mechanisms in CKD, including different nosological group patients (first, in diabetic and systemic diseases patients). At the same time, there is still an urgent need for randomized trials for better-informed decisions and future optimization of CKD patients' care. This chapter provides the current data on all aspects of NSD in CKD: etiology, diagnosis, prevention, and treatment approaches, as well as on risk factors of NSD at predialysis stages and in chronic hemodialysis patients. Considerable attention was devoted to the diagnosis and differential diagnosis of NSD in CKD patients. It was determined that the overall strategy for dietary treatment contributed to improving the life quality of patients and slowing down of CKD progression. The review is written based on the published results of clinical studies performed on the position of evidence-

**Nutritional Status Disorders in Chronic Kidney Disease:** 

DOI: 10.5772/intechopen.69297

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

**Keywords:** chronic kidney disease, nutrition status disorders, protein energy wasting,

**Practical Aspects (Systematic Review)**

**Practical Aspects (Systematic Review)**

Lidia V. Lysenko (Kozlovskaya), Yuriy S. Milovanov,

Marina V. Taranova, Svetlana Y. Milovanova, Marina V. Lebedeva and Aigul Zh. Usubalieva

Svetlana Y. Milovanova, Marina V. Lebedeva

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

Ludmila Y. Milovanova, Victor V. Fomin,

Yuriy S. Milovanov, Nikolay A. Mukhin, Vasiliy V. Kozlov, Marina V. Taranova,

Ludmila Y. Milovanova, Victor V. Fomin,

Nikolay A. Mukhin, Vasiliy V. Kozlov,

Lidia V. Lysenko (Kozlovskaya),

and Aigul Zh. Usubalieva

**Abstract**

based medicine.

Klotho

http://dx.doi.org/10.5772/intechopen.69297


**Provisional chapter**

## **Nutritional Status Disorders in Chronic Kidney Disease: Practical Aspects (Systematic Review) Practical Aspects (Systematic Review)**

**Nutritional Status Disorders in Chronic Kidney Disease:** 

DOI: 10.5772/intechopen.69297

Ludmila Y. Milovanova, Victor V. Fomin, Lidia V. Lysenko (Kozlovskaya), Yuriy S. Milovanov, Nikolay A. Mukhin, Vasiliy V. Kozlov, Marina V. Taranova, Svetlana Y. Milovanova, Marina V. Lebedeva and Aigul Zh. Usubalieva Lidia V. Lysenko (Kozlovskaya), Yuriy S. Milovanov, Nikolay A. Mukhin, Vasiliy V. Kozlov, Marina V. Taranova, Svetlana Y. Milovanova, Marina V. Lebedeva and Aigul Zh. Usubalieva

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

Ludmila Y. Milovanova, Victor V. Fomin,

http://dx.doi.org/10.5772/intechopen.69297

#### **Abstract**

[60] Sharaf NE, Amer NM, Ibrahim KS, El-Tahlawy EM, Abdelgelil KS. Pesticides usage in agriculture among rural women in Egypt: Association between serum organo-chlorine pesticide residues and occurrence of diabetes. World Journal of Medical Sciences.

[61] Azandjeme CS, Bouchard M, Francois D, Houinato D, Delisle H. Serum concentrations of organochlorine pesticides associated with diabetes and obesity in northern Benin (West Africa). Journal of Environmental and Occupational Sciences. 2014;**3**:121-129 [62] Tomar LR, Agarwal MP, Avasthi R, Tyagi V, Mustafa MD, Banerjee BD. Serum organochlorine pesticide levels in patients with metabolic syndrome. Indian Journal of

[63] Md M, Garg N, Banerjee BD, Sharma T, Tyagi V, Dar SA, et al. Inflammatory-mediated pathway in association with organochlorine pesticides levels in the etiology of idio-

[64] Mathur V, John PJ, Soni I, Bhatnagar P. Blood levels of organochlorine pesticide residues and risk of reproductive tract cancer among women from Jaipur, India. Advances in

[65] Xu X, Dailey AB, Talbott EO, Iiacqua VA, Kearney G, Asal NR. Associations of serum concentrations of organochlorine pesticides with breast cancer and prostate cancer in

[66] Siddarth M, Datta SK, Mustafa MD, Ahmed RS, Banerjee BD, Kalra OP, Tripathi AK. Increased level of organochlorine pesticides in chronic kidney disease patients of unknown etiology: Role of GSTM1/GSTT1 polymorphism. Chemosphere. 2014;**96**(1-7)

[67] Rutten GA, Schoots AC, Vanholder R, Desmet R, Ringoir SM, Cramers CA.Hexachlorobenzene and 1,1-di(4-chlorophenyl)-2,2-dichloroethene in serum of uremic patients and healthy persons: Determination by capillary gas chromatography an electron capture detection.

Endocrinology and Metabolism. 2013;**17**:S342-S344

214 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

Experimental Medicine and Biology. 2008;**617**:387-394

Nephron. 1988;**48**:217-221

pathic preterm birth. Reproductive Toxicology. 2015;**57**:111-120

U.S. adults. Environmental Health Perspectives. 2010;**118**:60-66

2013;**1**:8-15

Despite the significant achievements in the management of chronic kidney disease (CKD) patients, the mortality rate of these patients still remains high. Nutritional status disorders (NSD) are considered now as one of the prognostic risk factors not only for dialysis but also for predialysis CKD stages. Since the publication of KDIGO 2012 guidelines for CKD patient's management, there has been some significant advancement in our understanding of main NSD mechanisms in CKD, including different nosological group patients (first, in diabetic and systemic diseases patients). At the same time, there is still an urgent need for randomized trials for better-informed decisions and future optimization of CKD patients' care. This chapter provides the current data on all aspects of NSD in CKD: etiology, diagnosis, prevention, and treatment approaches, as well as on risk factors of NSD at predialysis stages and in chronic hemodialysis patients. Considerable attention was devoted to the diagnosis and differential diagnosis of NSD in CKD patients. It was determined that the overall strategy for dietary treatment contributed to improving the life quality of patients and slowing down of CKD progression. The review is written based on the published results of clinical studies performed on the position of evidencebased medicine.

**Keywords:** chronic kidney disease, nutrition status disorders, protein energy wasting, Klotho

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **1. Introduction**

One of the actual problems of nephrology is to improve quality of life and overall survival of patients with chronic kidney disease (CKD), the prevalence of which is steadily growing throughout the world. Therefore, the retardation of CKD progression and prevention of its complications, as well as the delay of renal replacement therapy (RRT) onset, are the primary medical and social-economical goal [1–3].

The review was written based on the published results of clinical studies performed on the position of evidence-based medicine. It is intended not only for nephrologists but also for

Nutritional Status Disorders in Chronic Kidney Disease: Practical Aspects (Systematic Review)

http://dx.doi.org/10.5772/intechopen.69297

217

Literature searches were made of 10 major databases among which were PubMed, Medline, Embase, Cochrane Library, CINAHL, and e-library. The search was carried out to find all articles relevant to CKD and Nutrition Status Disorders. This search encompassed original

• Research should include at least 20 patients in each group. The minimum mean duration

articles, systematic reviews, and meta-analyses. There was no language restriction.

Articles should be full-text. Brief publications and abstracts were not included:

• The article has the detailed research protocol for assessing its quality.

**3. Nutritional status disorders in chronic kidney disease patients**

CKD patients with a glomerular filtration rate (GFR) of 44–30 ml/min/1.73m2

The International Society of Renal Nutrition and Metabolism (ISRNM) [14] recommended the term "Protein-energy wasting (PEW)" to describe the state of decreased body stores of protein and energy in CKD patients and proposed a common nomenclature and diagnostic criteria

PEW was traditionally considered for a long time as the problem of patients who receive RRT. Meanwhile, the results of epidemiological studies conducted for recent years have convincingly demonstrated that nutritional status disorders appear to be revealed much earlier, before dialysis treatment starting, from stages 3B–4 CKD, and impact on prognosis of patients on dialysis [1, 2, 12, 13, 15]. The incidence of PEW depends on the stage of CKD (**Table 1**): among

in 4.2% of cases in average, whereas in CKD patients with GFR of 29-15 ml/min/1.73m2

21.3%, and almost all patients with end-stage of CKD have PEW [1, 2, 7, 13, 15, 16].

, PEW is detected

in

• Patients examination must meet KDIGO 2012 guidelines.

internists, cardiologists, and endocrinologists.

**2.1. Agreed criteria for article inclusion in the review**

of a study was 6 months.

• Randomized controlled trials.

• Retrospective nonrandomized trials.

for these alterations in the context of CKD.

**3.1. Prevalence PEW in CKD**

• Analyzed literature over past 15 years.

**2. Methods**

The rate of renal failure progression depends on a range of factors, and among them, nutritional status disorders (NSD) have the important prognostic value [2, 3]. Early detection of NSD requires a further in-depth examination of a patient to identify the potential cause (or causes) of NSD. NSD develops 2.5 times more often in patients with systemic disease that is caused by both the underlying disease activity (increased levels of inflammatory cytokines) and duration of corticosteroid therapy in addition to the general CKD risk factors [4]. NSD at predialysis CKD stages is found mainly to occur in diabetes mellitus, in patients with severe anemia (hemoglobin <100 g/l) or with high proteinuria (more than 2.5 g/day), as well as in patients who eat low-calorie nutrition (less than 30 kcal/kg/day) [1, 2, 5].

Low-protein diet (LPD) is considered now as more optimal for CKD patients. LPD, reducing glomerular hypertension, favors decreasing proteinuria as well as hemodynamic damage of renal glomeruli and thus contributing to a slowdown of CKD progression [2, 6, 7]. The influence of LPD on CKD progression is more expressed in case of diabetic nephropathy (DN). The annual rate of glomerular filtration rate (GFR) decline in patients who follow LPD and slow down by 1.5–2 times compared with standard diet, and outcome to the end-stage of CKD is observed less often almost by three times [5, 7]. Renal protective effects of LPD are connected with its hemodynamic and metabolic abilities. The adjustment of protein and phosphorus contents in the diet in accordance with patient's residual renal function contributes to reducing hemodynamic load to the residual nephrons, in addition to the decreasing of uremic intoxication. As a result, the glomerular hypertrophy process as well as the renin-angiotensin-aldosterone system (RAAS) activation decreases, intraglomerular autoregulation normalizes, and intraglomerular and systemic hypertension reduces. LPD also partially corrects such unfavorable uremic, metabolic, and endocrine complications, such as hypoalbuminemia, dyslipidemia, anemia, hyperphosphatemia with parathyroid glands hyperplasia, and thereby it helps to reduce the risk of uremic hyperparathyroidism, vascular calcification, and atherosclerosis [2, 8, 9]. LPD in combination with ketoanalogs of essential amino acids enhances also antihypertensive and antiproteinuric effects of angiotensin receptor blockers (ARB), corrective action of erythropoietins in anemia, effects of synthetic vitamin D analogs and calcimimetics on hyperparathyroidism symptoms, and hypolipidemic effect of statins [4, 10, 11].

It was found that the mortality rate of dialysis patients is inversely related to the amount of protein intake (protein quota), body mass index, and serum albumin [1, 12].

Improvement of the approaches to the early diagnosis, treatment, and prevention of NSD in CKD patients is an important strategy to reduce cardiovascular (CV) and overall mortality, to increase quality of life, as well as to reduce the cost of hospital and RRT treatment [1, 13].

The review was written based on the published results of clinical studies performed on the position of evidence-based medicine. It is intended not only for nephrologists but also for internists, cardiologists, and endocrinologists.

## **2. Methods**

**1. Introduction**

medical and social-economical goal [1–3].

216 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

hypolipidemic effect of statins [4, 10, 11].

low-calorie nutrition (less than 30 kcal/kg/day) [1, 2, 5].

One of the actual problems of nephrology is to improve quality of life and overall survival of patients with chronic kidney disease (CKD), the prevalence of which is steadily growing throughout the world. Therefore, the retardation of CKD progression and prevention of its complications, as well as the delay of renal replacement therapy (RRT) onset, are the primary

The rate of renal failure progression depends on a range of factors, and among them, nutritional status disorders (NSD) have the important prognostic value [2, 3]. Early detection of NSD requires a further in-depth examination of a patient to identify the potential cause (or causes) of NSD. NSD develops 2.5 times more often in patients with systemic disease that is caused by both the underlying disease activity (increased levels of inflammatory cytokines) and duration of corticosteroid therapy in addition to the general CKD risk factors [4]. NSD at predialysis CKD stages is found mainly to occur in diabetes mellitus, in patients with severe anemia (hemoglobin <100 g/l) or with high proteinuria (more than 2.5 g/day), as well as in patients who eat

Low-protein diet (LPD) is considered now as more optimal for CKD patients. LPD, reducing glomerular hypertension, favors decreasing proteinuria as well as hemodynamic damage of renal glomeruli and thus contributing to a slowdown of CKD progression [2, 6, 7]. The influence of LPD on CKD progression is more expressed in case of diabetic nephropathy (DN). The annual rate of glomerular filtration rate (GFR) decline in patients who follow LPD and slow down by 1.5–2 times compared with standard diet, and outcome to the end-stage of CKD is observed less often almost by three times [5, 7]. Renal protective effects of LPD are connected with its hemodynamic and metabolic abilities. The adjustment of protein and phosphorus contents in the diet in accordance with patient's residual renal function contributes to reducing hemodynamic load to the residual nephrons, in addition to the decreasing of uremic intoxication. As a result, the glomerular hypertrophy process as well as the renin-angiotensin-aldosterone system (RAAS) activation decreases, intraglomerular autoregulation normalizes, and intraglomerular and systemic hypertension reduces. LPD also partially corrects such unfavorable uremic, metabolic, and endocrine complications, such as hypoalbuminemia, dyslipidemia, anemia, hyperphosphatemia with parathyroid glands hyperplasia, and thereby it helps to reduce the risk of uremic hyperparathyroidism, vascular calcification, and atherosclerosis [2, 8, 9]. LPD in combination with ketoanalogs of essential amino acids enhances also antihypertensive and antiproteinuric effects of angiotensin receptor blockers (ARB), corrective action of erythropoietins in anemia, effects of synthetic vitamin D analogs and calcimimetics on hyperparathyroidism symptoms, and

It was found that the mortality rate of dialysis patients is inversely related to the amount of

Improvement of the approaches to the early diagnosis, treatment, and prevention of NSD in CKD patients is an important strategy to reduce cardiovascular (CV) and overall mortality, to increase quality of life, as well as to reduce the cost of hospital and RRT treatment [1, 13].

protein intake (protein quota), body mass index, and serum albumin [1, 12].

Literature searches were made of 10 major databases among which were PubMed, Medline, Embase, Cochrane Library, CINAHL, and e-library. The search was carried out to find all articles relevant to CKD and Nutrition Status Disorders. This search encompassed original articles, systematic reviews, and meta-analyses. There was no language restriction.

## **2.1. Agreed criteria for article inclusion in the review**

Articles should be full-text. Brief publications and abstracts were not included:


## **3. Nutritional status disorders in chronic kidney disease patients**

The International Society of Renal Nutrition and Metabolism (ISRNM) [14] recommended the term "Protein-energy wasting (PEW)" to describe the state of decreased body stores of protein and energy in CKD patients and proposed a common nomenclature and diagnostic criteria for these alterations in the context of CKD.

## **3.1. Prevalence PEW in CKD**

PEW was traditionally considered for a long time as the problem of patients who receive RRT. Meanwhile, the results of epidemiological studies conducted for recent years have convincingly demonstrated that nutritional status disorders appear to be revealed much earlier, before dialysis treatment starting, from stages 3B–4 CKD, and impact on prognosis of patients on dialysis [1, 2, 12, 13, 15]. The incidence of PEW depends on the stage of CKD (**Table 1**): among CKD patients with a glomerular filtration rate (GFR) of 44–30 ml/min/1.73m2 , PEW is detected in 4.2% of cases in average, whereas in CKD patients with GFR of 29-15 ml/min/1.73m2 in 21.3%, and almost all patients with end-stage of CKD have PEW [1, 2, 7, 13, 15, 16].


alanine through the transamination way is reversibly converted to pyruvate oxaloacetate, which are subsequently directly included in the carbohydrate metabolism. An inverse relationship was found between the leptin concentration and the nutritional status (NS) parameters and a direct

Nutritional Status Disorders in Chronic Kidney Disease: Practical Aspects (Systematic Review)

http://dx.doi.org/10.5772/intechopen.69297

219

Proteins (and consequently, amino acids as products of their hydrolysis) are directly involved in the biosynthesis of a number of hormones and other biologically active compounds that regulate metabolic processes in the body. With insufficient intake of protein from food, the protein from its own pool disintegrate into free amino acids, which ensure the synthesis of the necessary cytoplasmic fractions of protein, enzymes, hormones, and other biologically active compounds [16, 18].

PEW in CKD can also be exacerbated by eating mostly plant proteins of low biological value and low-calorie diet. This increases the insulin secretion, which inhibits lipolysis and mobilization of skeletal muscle proteins. These disturbances lead to that the levels of amino acids in the blood drop the levels of amino acids in the blood drop, the synthesis of albumin and other proteins decreases, leading to hypoalbuminemia. The adaptation mechanism includes hormonal changes. These changes help mobilize free fatty acids from adipose tissue and amino acids from the muscles. Gluconeogenesis and oxidation of amino acids provide the energy that is necessary for the organism-sustaining processes, as a result, protein synthesis is inhibited, metabolism is slowed down, and muscle mass and body fat stores decrease [1, 6, 9].

An important role in the development of PEW is assigned to cytokines and chemokines, which begin to accumulate in the blood of patients as the stage of CKD progresses. Cytokines, suppressing appetite, cause loss of body weight [13, 18]. Patients with CKD, stages 4–5, are prone to negative nitrogen balance and hypercatabolism due to anorexia, inhibition of protein

In acute and chronic infections or immune inflammations, there are effects of tumor necrosis factor α (TNF α), interleukin 2 and 6 (IL-2 and IL-6), etc., which also contribute to the develop-

At the same time, in chronic renal failure patients who ignore the use of protein restricted diet and consume protein in the amounts greater than recommended for their stage of CKD, progressively increased levels of glycation products are observed, which trigger a complex cascade of reactions involving the generation of active forms of oxygen. Amino acids, proteins, carbohydrates, and lipids (primarily unsaturated fatty acids both free and in the composition of phospholipids) are subjected to reactions of free radical oxidation involving reactive oxygen species [1, 16]. Acidosis, induced by uncontrolled protein intake, leads to suppression of amino acid synthesis, increases their decarboxylation in muscles, and reduces albumin synthesis [17].

In clinical practice in the predialysis patient population, PEW is divided into three degrees: mild, moderate, and severe [1, 14, 21]. The degree of PEW is established by determining the ratio of body weight/recommended body weight × 100%. A decreased ratio down to 80% means a mild degree of nutritional disorder, a decrease from 80–70%—moderate, and less

and amino acid synthesis, and the deficiency of vitamins and microelements [1, 16].

ment of hypoalbuminemia and worsen the prognosis [1, 20].

**3.3. Classification**

than 70%—severe nutrition disorder.

relationship with the leptin of the C-reactive protein (CRP) [19].

GFR: glomerular filtration rate, is calculated by CKD-EPI creatinine equation (2009); PEW: protein-energy wasting; and RRT: renal replacement therapy.

**Table 1.** Incidence of PEW depending on CKD stage.

At the predialysis stages, PEW is typical for patients with DN because of insulin deficiency or insulin resistance, accelerating protein catabolism, as well as due to a high incidence of infectious complications, diabetic neuropathy of gastrointestinal tract with malabsorption, [1, 5, 15, 17]; for patients with systemic diseases; high proteinuria (more than 2.5 g/day); severe anemia (hemoglobin <100 g/L); for those who receive prolonged corticosteroid therapy (more than 6 months); for patients who eat low-calorie foods (less than 30 kcal/kg/day) [1, 2, 4, 15].

#### **3.2. Etiology and pathogenesis**

In contrast to the end products of fat and carbohydrate metabolism (CO2 and H2 O) that are excreted through the lungs and skin, the products of protein metabolism can be excreted only by kidneys [7, 16].

Qualitative protein food composition is very important because the absence or deficiency of at least one of any essential amino acid (EAA) may be a limiting factor for protein biosynthesis in the body. Even when the dietary intake provides all amino acids, the body may suffer from a protein deficiency if the absorption of any amino acid decreases in the intestine, or when it breaks up more than usual under the influence of gut microbiota. In these cases, limited protein synthesis will occur or the body will compensate for the lack of amino acid required for protein biosynthesis by breaking down its own proteins [9, 18]. Changes in protein metabolism in uremia are closely related to amino acid metabolism disturbance. Due to a decrease in the metabolically active mass of the kidneys, the deficiency of the enzymes synthesized in the kidneys, which are necessary for the formation of amino acids, develops [9, 13]. Decrease in plasma concentration of EAA can also be largely due to acidosis [15, 17].

The degree of protein and amino acids assimilation from food also depends on the quantitative and qualitative composition of carbohydrates and lipids. Experimental and clinical data indicate that a diet with insufficient fat and low-calorie diet contribute to the increased oxidation of amino acids, intensified degradation, and, partly, even protein synthesis [7, 18]. Protein metabolism, in turn, is closely integrated with the exchange of carbohydrates, lipids, and nucleic acids through amino acids or α-ketoacids (α-ketoglutarate, oxaloacetate, and pyruvate). Thus, aspartic acid or alanine through the transamination way is reversibly converted to pyruvate oxaloacetate, which are subsequently directly included in the carbohydrate metabolism. An inverse relationship was found between the leptin concentration and the nutritional status (NS) parameters and a direct relationship with the leptin of the C-reactive protein (CRP) [19].

Proteins (and consequently, amino acids as products of their hydrolysis) are directly involved in the biosynthesis of a number of hormones and other biologically active compounds that regulate metabolic processes in the body. With insufficient intake of protein from food, the protein from its own pool disintegrate into free amino acids, which ensure the synthesis of the necessary cytoplasmic fractions of protein, enzymes, hormones, and other biologically active compounds [16, 18].

PEW in CKD can also be exacerbated by eating mostly plant proteins of low biological value and low-calorie diet. This increases the insulin secretion, which inhibits lipolysis and mobilization of skeletal muscle proteins. These disturbances lead to that the levels of amino acids in the blood drop the levels of amino acids in the blood drop, the synthesis of albumin and other proteins decreases, leading to hypoalbuminemia. The adaptation mechanism includes hormonal changes. These changes help mobilize free fatty acids from adipose tissue and amino acids from the muscles. Gluconeogenesis and oxidation of amino acids provide the energy that is necessary for the organism-sustaining processes, as a result, protein synthesis is inhibited, metabolism is slowed down, and muscle mass and body fat stores decrease [1, 6, 9].

An important role in the development of PEW is assigned to cytokines and chemokines, which begin to accumulate in the blood of patients as the stage of CKD progresses. Cytokines, suppressing appetite, cause loss of body weight [13, 18]. Patients with CKD, stages 4–5, are prone to negative nitrogen balance and hypercatabolism due to anorexia, inhibition of protein and amino acid synthesis, and the deficiency of vitamins and microelements [1, 16].

In acute and chronic infections or immune inflammations, there are effects of tumor necrosis factor α (TNF α), interleukin 2 and 6 (IL-2 and IL-6), etc., which also contribute to the development of hypoalbuminemia and worsen the prognosis [1, 20].

At the same time, in chronic renal failure patients who ignore the use of protein restricted diet and consume protein in the amounts greater than recommended for their stage of CKD, progressively increased levels of glycation products are observed, which trigger a complex cascade of reactions involving the generation of active forms of oxygen. Amino acids, proteins, carbohydrates, and lipids (primarily unsaturated fatty acids both free and in the composition of phospholipids) are subjected to reactions of free radical oxidation involving reactive oxygen species [1, 16]. Acidosis, induced by uncontrolled protein intake, leads to suppression of amino acid synthesis, increases their decarboxylation in muscles, and reduces albumin synthesis [17].

## **3.3. Classification**

At the predialysis stages, PEW is typical for patients with DN because of insulin deficiency or insulin resistance, accelerating protein catabolism, as well as due to a high incidence of infectious complications, diabetic neuropathy of gastrointestinal tract with malabsorption, [1, 5, 15, 17]; for patients with systemic diseases; high proteinuria (more than 2.5 g/day); severe anemia (hemoglobin <100 g/L); for those who receive prolonged corticosteroid therapy (more than 6 months);

GFR: glomerular filtration rate, is calculated by CKD-EPI creatinine equation (2009); PEW: protein-energy wasting; and

**CKD stage Description GFR, ml/min/1.73 m2 Incidence of PEW**

1 Kidney damage with normal or increased GFR ≥90 No 2 Kidney damage with mildly decreased GFR 89–60 No

3a Mild-to-moderate decrease in GFR 59–45 No 3b Moderate-to-severe decrease in GFR 44–30 4.2% 4 Severely decreased GFR 29–15 21.3% 5 End-stage of renal failure <15 or RRT onset 74.5%

3 59–30

218 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

excreted through the lungs and skin, the products of protein metabolism can be excreted only

Qualitative protein food composition is very important because the absence or deficiency of at least one of any essential amino acid (EAA) may be a limiting factor for protein biosynthesis in the body. Even when the dietary intake provides all amino acids, the body may suffer from a protein deficiency if the absorption of any amino acid decreases in the intestine, or when it breaks up more than usual under the influence of gut microbiota. In these cases, limited protein synthesis will occur or the body will compensate for the lack of amino acid required for protein biosynthesis by breaking down its own proteins [9, 18]. Changes in protein metabolism in uremia are closely related to amino acid metabolism disturbance. Due to a decrease in the metabolically active mass of the kidneys, the deficiency of the enzymes synthesized in the kidneys, which are necessary for the formation of amino acids, develops [9, 13]. Decrease in

The degree of protein and amino acids assimilation from food also depends on the quantitative and qualitative composition of carbohydrates and lipids. Experimental and clinical data indicate that a diet with insufficient fat and low-calorie diet contribute to the increased oxidation of amino acids, intensified degradation, and, partly, even protein synthesis [7, 18]. Protein metabolism, in turn, is closely integrated with the exchange of carbohydrates, lipids, and nucleic acids through amino acids or α-ketoacids (α-ketoglutarate, oxaloacetate, and pyruvate). Thus, aspartic acid or

and H2

O) that are

for patients who eat low-calorie foods (less than 30 kcal/kg/day) [1, 2, 4, 15].

In contrast to the end products of fat and carbohydrate metabolism (CO2

plasma concentration of EAA can also be largely due to acidosis [15, 17].

**3.2. Etiology and pathogenesis**

RRT: renal replacement therapy.

**Table 1.** Incidence of PEW depending on CKD stage.

by kidneys [7, 16].

In clinical practice in the predialysis patient population, PEW is divided into three degrees: mild, moderate, and severe [1, 14, 21]. The degree of PEW is established by determining the ratio of body weight/recommended body weight × 100%. A decreased ratio down to 80% means a mild degree of nutritional disorder, a decrease from 80–70%—moderate, and less than 70%—severe nutrition disorder.

## **3.4. Clinical presentation**

Complaints depending on the underlying pathology that caused signs of PEW: a weight loss over the past 6 months, poor appetite, in case of severe PEW—refusal to eat, vomiting, nausea, bloating, diarrhea, constipation, abdominal pain, edema, cramps, cough, shortness of breath, prolonged fever, anxiety, dry skin, hair loss, deformation of the nails, and weakness.

*3.4.1.2. Severe PEW*

**3.5. Diagnosis**

last stage of CKD [1, 7, 21, 22].

skin (sm) = (*d*<sup>1</sup> + *d*<sup>2</sup> + *d*<sup>3</sup> + *d*<sup>4</sup>

with CKD once every 3 months.

the shoulder blade; d<sup>4</sup>

*3.5.1. Anthropometric methods of assessment*

height of a person measured in meters and squared.

)/8, where *d*<sup>1</sup>

Anthropometric criteria of PEW are BMI <18.5 kg/m2

fat reserves, and SMV is an indicator of the peripheral protein pool.

where *M* is the weight (kg), *P* is height (sm), and *K* is a constant equal to 1.3.

It is accompanied by more pronounced changes in clinical and laboratory parameters. Physical examination reveals the intercostal depression, atrophy of the temporal muscles, and muscles of the extremities. Subcutaneous fat tissue is atrophied or absent. Apathy, rapid fatigue, and a feel-

Nutritional Status Disorders in Chronic Kidney Disease: Practical Aspects (Systematic Review)

deficiency of trace elements (iron, zinc, copper, and selenium), calcium, arginine and l-carnitine are added symptoms; and signs of oxidative stress, aggravating renal anemia, cardiomyopathy, myopathy, encephalopathy, and hypertension also accompany. There may be atrophy of intes-

Diagnostic challenges with PEW arise from a variety of causes and also because the body weight of patients changes a little due to sodium and water retention and decrease only at the

Anthropometric methods include determination of body mass index and evaluation of muscle and fat mass of the body [1, 14, 21]. The body mass index (BMI) (Quetelet index, kg/m2

calculated by the formula: BMI = *M*/*L*2, where *M* is the body weight in kilograms and *L* is the

Measurement of the SFFT by a caliper at 4 points (subscapular region, above the biceps, triceps, and iliac crest) allows to calculate the proportion of fat component as a percentage of the total body weight, which is 15–16% in healthy men and 25% in women. If the SFFT is reduced by more than 10% from the normal value, it indicates a predominant *energy insufficiency* [1, 14, 22]. The amount of fat in the body (fat mass) can be calculated by the formula: *D* = *d* × *S* × *K*, where *D* is fat mass (kg); *d* is the average thickness of the subcutaneous fat layer together with the

is above the triceps; d2

About the muscle mass, it can be indirectly judged by the formula: SMV (sm) = SC (sm) – 0.314 × SFFT (mm), where SMV is the shoulder muscles volume; SC is shoulder circumference at midshoulder level; and SFFT is the skin-fat fold thickness above the triceps at the point of shoulder circumference measurement. Deficiency of SMV, exceeding 10%, is typical for *protein deficiency*. For dialysis PEW, a combination of muscle deficiency with a decreased volume of adipose tissue is typical. Assessment of anthropometric parameters should be performed in all patients

<13 mm; SMV in men <23 cm, in women <21 cm. At the same time, SFFT is a reflection of body

is on the abdomen; *S* is the surface of the body = *M*0.425 × *P*0.725 × 71.84 × 10−4,

is above the biceps; d<sup>3</sup>

; SFFT in men <9.5 mm, in women

and B12, and PP);

221

http://dx.doi.org/10.5772/intechopen.69297

) is

is above

ing of cold are often symptoms of hypovitaminosis (vitamins B, C, folic acid, D<sup>3</sup>

tinal villi and increased growth of microflora in the small intestine.

Medical history allows to identify the *kidney disease*, which has led to the development of PEW.

## *3.4.1. Physical examination*

Assessment of nutritional status is carried out on a four- or seven-point scale. A seven-point scale evaluation is considered more reliable [14, 21, 22].

The following basic criteria are important:


Familiarity with the anamnesis and physical examination reveals the **clinical picture of PEW** [1, 13, 14, 21]:


## *3.4.1.1. Mild-to-moderate PEW*

Symptoms of nutritional disorders are characterized by a decrease in the body weight (by 3–5% per month) and a progressive decrease in appetite with the development of anorexia. The thickness of the skin-fat fold (SFFT) above the triceps muscle of the shoulder as well as a muscular mass in the shoulder region is reduced. The blood levels of albumin, prealbumin, transferrin, and triiodothyronine (T3) decrease. Lymphopenia and impaired glucose tolerance may develop.

## *3.4.1.2. Severe PEW*

**3.4. Clinical presentation**

*3.4.1. Physical examination*

[1, 13, 14, 21]:

ronine (T<sup>3</sup>

• Reduced subcutaneous tissue.

*3.4.1.1. Mild-to-moderate PEW*

glucose tolerance may develop.

scale evaluation is considered more reliable [14, 21, 22].

220 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

diary; the presence of symptoms of gastrointestinal dysfunction.

and iliac crest) and the shoulder circumference in the middle third.

• Possible apathy, fast fatigue, decreased taste, and slowing of peristalsis.

• Subjective assessment (according to seven-point scale) ≤ 5 points.

The following basic criteria are important:

Complaints depending on the underlying pathology that caused signs of PEW: a weight loss over the past 6 months, poor appetite, in case of severe PEW—refusal to eat, vomiting, nausea, bloating, diarrhea, constipation, abdominal pain, edema, cramps, cough, shortness of breath,

Medical history allows to identify the *kidney disease*, which has led to the development of PEW.

Assessment of nutritional status is carried out on a four- or seven-point scale. A seven-point

• The dynamics of the patient's weight since the last examination (usually for 6 months).

• The protein quota intake and calorie content of food calculated according to a 3-day food

• The status of the patient's fat and muscle mass bases on a visual examination (shoulder line, the contouring of clavicles, shoulder blades, and ribs) and palpation (the thickness of the fat fold above the biceps and triceps, muscular mass of the triceps, and muscles between the thumb and index finger). To objectify the data, the caliper can be used to measure the fat fold thickness in several places (subscapular region, above the biceps, triceps,

Familiarity with the anamnesis and physical examination reveals the **clinical picture of PEW**

• Decrease in the body weight by 10% over the last 6 months and shorter period; poor appetite.

• Basal metabolic rate and body temperature are lowered due to decreased levels of triiodothy-

Symptoms of nutritional disorders are characterized by a decrease in the body weight (by 3–5% per month) and a progressive decrease in appetite with the development of anorexia. The thickness of the skin-fat fold (SFFT) above the triceps muscle of the shoulder as well as a muscular mass in the shoulder region is reduced. The blood levels of albumin, prealbumin, transferrin, and triiodothyronine (T3) decrease. Lymphopenia and impaired

) below 3.5 pg/ml and loss of the heat-insulating function of the subcutaneous tissue.

prolonged fever, anxiety, dry skin, hair loss, deformation of the nails, and weakness.

It is accompanied by more pronounced changes in clinical and laboratory parameters. Physical examination reveals the intercostal depression, atrophy of the temporal muscles, and muscles of the extremities. Subcutaneous fat tissue is atrophied or absent. Apathy, rapid fatigue, and a feeling of cold are often symptoms of hypovitaminosis (vitamins B, C, folic acid, D<sup>3</sup> and B12, and PP); deficiency of trace elements (iron, zinc, copper, and selenium), calcium, arginine and l-carnitine are added symptoms; and signs of oxidative stress, aggravating renal anemia, cardiomyopathy, myopathy, encephalopathy, and hypertension also accompany. There may be atrophy of intestinal villi and increased growth of microflora in the small intestine.

## **3.5. Diagnosis**

Diagnostic challenges with PEW arise from a variety of causes and also because the body weight of patients changes a little due to sodium and water retention and decrease only at the last stage of CKD [1, 7, 21, 22].

## *3.5.1. Anthropometric methods of assessment*

Anthropometric methods include determination of body mass index and evaluation of muscle and fat mass of the body [1, 14, 21]. The body mass index (BMI) (Quetelet index, kg/m2 ) is calculated by the formula: BMI = *M*/*L*2, where *M* is the body weight in kilograms and *L* is the height of a person measured in meters and squared.

Measurement of the SFFT by a caliper at 4 points (subscapular region, above the biceps, triceps, and iliac crest) allows to calculate the proportion of fat component as a percentage of the total body weight, which is 15–16% in healthy men and 25% in women. If the SFFT is reduced by more than 10% from the normal value, it indicates a predominant *energy insufficiency* [1, 14, 22].

The amount of fat in the body (fat mass) can be calculated by the formula: *D* = *d* × *S* × *K*, where *D* is fat mass (kg); *d* is the average thickness of the subcutaneous fat layer together with the skin (sm) = (*d*<sup>1</sup> + *d*<sup>2</sup> + *d*<sup>3</sup> + *d*<sup>4</sup> )/8, where *d*<sup>1</sup> is above the triceps; d2 is above the biceps; d<sup>3</sup> is above the shoulder blade; d<sup>4</sup> is on the abdomen; *S* is the surface of the body = *M*0.425 × *P*0.725 × 71.84 × 10−4, where *M* is the weight (kg), *P* is height (sm), and *K* is a constant equal to 1.3.

About the muscle mass, it can be indirectly judged by the formula: SMV (sm) = SC (sm) – 0.314 × SFFT (mm), where SMV is the shoulder muscles volume; SC is shoulder circumference at midshoulder level; and SFFT is the skin-fat fold thickness above the triceps at the point of shoulder circumference measurement. Deficiency of SMV, exceeding 10%, is typical for *protein deficiency*.

For dialysis PEW, a combination of muscle deficiency with a decreased volume of adipose tissue is typical. Assessment of anthropometric parameters should be performed in all patients with CKD once every 3 months.

Anthropometric criteria of PEW are BMI <18.5 kg/m2 ; SFFT in men <9.5 mm, in women <13 mm; SMV in men <23 cm, in women <21 cm. At the same time, SFFT is a reflection of body fat reserves, and SMV is an indicator of the peripheral protein pool.

#### *3.5.2. Laboratory diagnostics*

For the diagnose of impairments in the synthesis of visceral proteins, the determination of the content of albumin, transferrin, and lymphocytes number in the blood, as well as of the level and spectrum of essential amino acids, is used [1, 14, 21]. The serum albumin level only is insufficient for the decision about NS in CKD patients, since its level depends on the intravascular volume and the half-life period of albumin is approximately 21 days [14]. Therefore, a decrease in the albumin serum level is a relatively a late marker of PEW. It should be taken into account that the decrease in serum albumin level may be due to the other causes, in addition to PEW. Infections, injuries, and surgical interventions, associated with blood and plasma loses; a high level of proteinuria; and disturbances of the proteinsynthetic function of the liver can cause a rapid and significant decrease in serum albumin level [14]. On the other hand, prolonged and persistent decrease in serum albumin level regardless of its cause always leads to PEW in CKD patients [1, 14]. Hypoalbuminemia is closely associated with an increase in concomitant diseases, hospitalizations, and the mortality rate of CKD patients [1, 3, 20, 23].

distribution of fluid in the body [22, 24]. Complex instrumental methods for analyzing NS of the body (neutron activation analysis, two-photon X-ray absorptiometry, etc.) are not widely

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223

Bioimpedansometry measures the volume of the total fluid and the proportion of extracellular and cellular fluids separately, allows to establish a nonfat body mass and a "dry weight," and thus contributes to the selection of an effective mode of HD and ultrafiltration as well as

DEXA is a noninvasive method for assessing the condition of the three main body components (fatty tissue, muscle mass, bone mass, and bone mineral density). The state of hyperhydration of dialysis patients practically does not affect the accuracy of DEXA. The principle of the DEXA method is the scanning of a body in a rectilinear section with the help of two beams of photons emitted by an X-ray source. Different tissues (fat, muscle, and bone) absorb X-rays in varying degrees. The composition of the body is calculated from the ratio of the natural

Fresenius Medical Care (Germany) company has developed a device that allows to determine the individual fluid balance and body composition of the patient—the Body Composition Monitor (BCM). The BCM can be used in patients with CKD, regardless of patient's treatment. The measurement is based on the bioimpedance spectroscopy technology, which allows to calculate the volume of body water (total, intra-, and extracellular), as well as muscle and fat mass of the body (**Table 2**). Since the total body water (TBW) index is equivalent to the urea volume distribution (V), it is not necessary to spend working time for calculating urea kinetic modeling and calculating TBW based on anthropometric parameters. Indicator V can be used

In addition to the anthropometric (BMI, SFFT, and SMV) and laboratory (albumin, transferrin, and absolute number of lymphocytes) indicators of NS, the evaluation of protein

> 40–59 60–79

> 40–59 60–79

> 40–59 60–80

> 40–59 60–80

12.9 ± 0.65 (19.9–8.0) 18.1 ± 0.41(21.9–11.0) 20.7 ± 0.66 (24.9–13.0)

29.1 ± 0.44 (32.9–21.0) 26.4 ± 0.51 (33.9–2.30) 27.8 ± 0.35 (35.9–24.0)

35.4 ± 0.75 (39.3–33.3) 37.1 ± 0.85 (39.1–31.1) 34.6 ± 0.31 (38.9–32.9)

26.2 ± 0.45 (30.3–24.3) 27.1 ± 0.65 (30.1–24.1) 27.3 ± 0.55 (29.9–23.9)

**Parameter Gender Age Normal range** BMI, kg/m2 19.5 ± 0.33 (23–18.4)

F 20–39

F 18–39

available due to high cost.

the value of the protein quota.

to calculate the dose of dialysis [22].

Body fat mass, % M 20–39

Body muscles mass, % M 18–39

BMI: body mass index; M: male; F: female; and BIA: bioimpedance analysis.

**Table 2.** Normal range of nutritional status parameters according to BIA.

logarithms of the absorbed and unabsorbed beams [14, 22].

The association of hypoalbuminemia with inflammatory process may be established using the ratio of the levels of albumin and C-reactive protein in serum [1, 4, 13, 14].

An important diagnostic marker of PEW is also a low serum level of transferrin in the blood and is representative of the fraction of beta-globulin; its decrease is observed at an earlier stage of protein metabolism disturbance than changes in albumin levels (lifetime of transferrin is 7–8 days). However, the concentration of transferrin may increase the iron deficiency usually accompanying PEW, which should be taken into account in determining the severity of PEW [1, 14, 21].

More accurate markers of the visceral protein pool status are both short-lived transport proteins—prealbumin (lifespan is 2 days) and retino-binding protein (lifespan is 10–12 h). The prealbumin level below 0.3 g/l is associated with an increased risk of death and correlates with other indicators of PEW [13, 14, 16]. Their content in serum decreases earlier in the case of protein deficiency in the diet, although it can quickly decrease due to intercurrent diseases [14].

The degree of PEW correlates with the content of lymphocytes in blood [14, 15]. Therefore, the absolute number of lymphocytes in the blood can be used to judge the severity of PEW in patients with CKD: absolute number of lymphocytes = % of lymphocytes × number of white blood cells/100.

The laboratory signs of PEW are serum albumin <35 g/l; serum transferrin <180 mg/dl; and absolute number of blood lymphocytes <1800

The study of serum protein counts and the absolute number of lymphocytes should be carried out once every 3 months, and if necessary—once every 1.5 months [1, 14].

#### *3.5.3. Instrumental diagnostics*

From the instrumental methods for the main body components assessing, the method of 2-hour bioimpedanceometry is most often used in practical work in connection with the ability to quantitatively determine not only fatty tissue and muscle mass of the body but also the distribution of fluid in the body [22, 24]. Complex instrumental methods for analyzing NS of the body (neutron activation analysis, two-photon X-ray absorptiometry, etc.) are not widely available due to high cost.

*3.5.2. Laboratory diagnostics*

222 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

ity rate of CKD patients [1, 3, 20, 23].

blood cells/100.

*3.5.3. Instrumental diagnostics*

absolute number of blood lymphocytes <1800

For the diagnose of impairments in the synthesis of visceral proteins, the determination of the content of albumin, transferrin, and lymphocytes number in the blood, as well as of the level and spectrum of essential amino acids, is used [1, 14, 21]. The serum albumin level only is insufficient for the decision about NS in CKD patients, since its level depends on the intravascular volume and the half-life period of albumin is approximately 21 days [14]. Therefore, a decrease in the albumin serum level is a relatively a late marker of PEW. It should be taken into account that the decrease in serum albumin level may be due to the other causes, in addition to PEW. Infections, injuries, and surgical interventions, associated with blood and plasma loses; a high level of proteinuria; and disturbances of the proteinsynthetic function of the liver can cause a rapid and significant decrease in serum albumin level [14]. On the other hand, prolonged and persistent decrease in serum albumin level regardless of its cause always leads to PEW in CKD patients [1, 14]. Hypoalbuminemia is closely associated with an increase in concomitant diseases, hospitalizations, and the mortal-

The association of hypoalbuminemia with inflammatory process may be established using

An important diagnostic marker of PEW is also a low serum level of transferrin in the blood and is representative of the fraction of beta-globulin; its decrease is observed at an earlier stage of protein metabolism disturbance than changes in albumin levels (lifetime of transferrin is 7–8 days). However, the concentration of transferrin may increase the iron deficiency usually accompanying PEW, which should be taken into account in determining the severity of PEW [1, 14, 21]. More accurate markers of the visceral protein pool status are both short-lived transport proteins—prealbumin (lifespan is 2 days) and retino-binding protein (lifespan is 10–12 h). The prealbumin level below 0.3 g/l is associated with an increased risk of death and correlates with other indicators of PEW [13, 14, 16]. Their content in serum decreases earlier in the case of protein deficiency in the diet, although it can quickly decrease due to intercurrent diseases [14]. The degree of PEW correlates with the content of lymphocytes in blood [14, 15]. Therefore, the absolute number of lymphocytes in the blood can be used to judge the severity of PEW in patients with CKD: absolute number of lymphocytes = % of lymphocytes × number of white

The laboratory signs of PEW are serum albumin <35 g/l; serum transferrin <180 mg/dl; and

The study of serum protein counts and the absolute number of lymphocytes should be carried

From the instrumental methods for the main body components assessing, the method of 2-hour bioimpedanceometry is most often used in practical work in connection with the ability to quantitatively determine not only fatty tissue and muscle mass of the body but also the

out once every 3 months, and if necessary—once every 1.5 months [1, 14].

the ratio of the levels of albumin and C-reactive protein in serum [1, 4, 13, 14].

Bioimpedansometry measures the volume of the total fluid and the proportion of extracellular and cellular fluids separately, allows to establish a nonfat body mass and a "dry weight," and thus contributes to the selection of an effective mode of HD and ultrafiltration as well as the value of the protein quota.

DEXA is a noninvasive method for assessing the condition of the three main body components (fatty tissue, muscle mass, bone mass, and bone mineral density). The state of hyperhydration of dialysis patients practically does not affect the accuracy of DEXA. The principle of the DEXA method is the scanning of a body in a rectilinear section with the help of two beams of photons emitted by an X-ray source. Different tissues (fat, muscle, and bone) absorb X-rays in varying degrees. The composition of the body is calculated from the ratio of the natural logarithms of the absorbed and unabsorbed beams [14, 22].

Fresenius Medical Care (Germany) company has developed a device that allows to determine the individual fluid balance and body composition of the patient—the Body Composition Monitor (BCM). The BCM can be used in patients with CKD, regardless of patient's treatment. The measurement is based on the bioimpedance spectroscopy technology, which allows to calculate the volume of body water (total, intra-, and extracellular), as well as muscle and fat mass of the body (**Table 2**). Since the total body water (TBW) index is equivalent to the urea volume distribution (V), it is not necessary to spend working time for calculating urea kinetic modeling and calculating TBW based on anthropometric parameters. Indicator V can be used to calculate the dose of dialysis [22].

In addition to the anthropometric (BMI, SFFT, and SMV) and laboratory (albumin, transferrin, and absolute number of lymphocytes) indicators of NS, the evaluation of protein


BMI: body mass index; M: male; F: female; and BIA: bioimpedance analysis.

**Table 2.** Normal range of nutritional status parameters according to BIA.

intake and calorie content of food assessed according to a three-day food diary is needed [22, 25].

allow to slow the progression of renal failure and eliminates PEW [1, 4]. However, it should be borne in mind that the long-term (more than 6 months) use of CS in CKD patients in predialysis stages can enhance hypercatabolism, promote the development or aggravation of an existing PEW, and therefore careful and regular monitoring of anthropometric indices and

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225

LPD with a protein content of 0.6 g/kg body weight/day should be carefully balanced both in essential amino acid contents and in calories (at least 34 kcal/kg of ideal body weight/day). This requirement must be strictly observed in patients with 4–5 stages of CKD with digestive disorders due to uremia and also in patients with stages 3–4 of CKD in systemic diseases with persistent disease activity, long-term treatment with GS [1]. When making a 7-day menu, it is allowed to substitute products for their protein and carbohydrate equivalents, and to replace a portion of the animal protein (0.1 g/kg body weight/day or more) with a high-purity soy-

It is promising to use highly purified soy protein SUPRO-760 (DuPont Protein Technologies USA) [1, 13, 14]. Protein "SUPRO" is a protein of high quality, fully digested by the body (adjusted amino acid coefficient of protein digestion—1.0). It is prescribed as an additive to food at the rate of 0.2–0.3 g soy protein per kg body weight per day [1, 14]. When compiling a diet that includes the soy protein SUPRO-760, the total amount of protein in the diet should not exceed 0.7 g/kg of body weight/day, whereas the total caloric value should not be less than 30 kcal/kg body weight/day for patients with 3B-5 stages of CKD [1, 14]. In patients who are committed to the use of predominantly vegetable protein, as well as in patients with

tein in a traditional LPD (0.6 g/kg body weight/day) may be replaced with highly purified soy protein [1, 13, 14]. In most of CKD 4–5 stages, patients with anorexia, when using such diet, dyspeptic phenomena decreased, blood urea nitrogen level decreased, acidosis corrected,

In the clinical practice of recent years, high-energy nutrient mixtures that are balanced by the essential amino acids content such as Fresubin Renal, manufactured by Fresenius Kabi, Germany, etc., is introduced in the diet of CKD patients to treat the NSD. These specialized mixtures are made on the basis of CKD patients' requirements in protein, fat, carbohydrate,

In the predialysis period of CKD, the use of a low-protein mixture (3 g protein/100 ml) Suplena (Abbott Nutrition, USA), with a minimum amount of potassium, sodium, and phosphorus balanced with a vitamin-mineral complex, is also promising for prevention and treatment of

The using of EAA and their α-KA (Ketosteril, Fresenius Kabi ) in the LPD allows to maintain the protein balance [1, 6, 10]. EAA and KA are important components of LPD, which prevents the development of PEW, and enhance the beneficial effects of LPD [7, 13]. Ketoanalogues, in contrast to the matched their amino acids, do not contain a nitrogen group; by capturing endogenous nitrogen they are converted into amino acids in the body, and they contribute to the disintegration of urea. The ready-pharmaceutical complex of all EAA and KA in the optimal ratio (ketosteril) provides the need of CKD patients in essential amino

PEW. The energy value of one package of a liquid mixture (237 ml) is 474 kcal [14].

), half the daily amount of animal origin pro-

serum albumin level is required for these patients [1, 13, 14].

bean protein (equivalent amount) in the LPD [1, 14, 21, 26].

anorexia (usually with eGFR <25 ml/min, 1.73 m2

and energy and also enriched with vitamins and minerals.

and the general condition improved [19].

Integrated assessment of nutritional status can be performed also using the malnutrition inflammation score (MIS) scale. It allows to analyze anthropometric data (BMI, dry weight dynamics, body fat, and muscle mass), gastrointestinal symptoms, dialysis time, laboratory data (albumin and blood transferrin), hospitalization rates, and the risk of lethality on dialysis [14, 22].

All patients with an identified PEW should be given anthropometric measurements (or bioelectrical impedance analysis), a clinical and biochemical blood test, and a general urinalysis at least one time per 1.5 months, an analysis of protein intake and calorie content on a 3-day food diary for at least one time in 3 months [1, 15, 21].

## **3.6. Differential diagnosis**

PEW should be differentiated with a malabsorption syndrome, given a number of common manifestations (progressive decrease in BMI and blood albumin). In contrast to malabsorption, chronic diarrhea with steatorrhea and creatoria is not typical for PEW; while there is pronounced increase in serum CRP and TNF-α, calcification of the arteries [1, 14, 20] is found [1, 14, 20].

According to the WHO, the diagnostic sign of PEW is a decrease in the mental and physical performance of patients, identified as a decrease in the quality of life when determining the psychosomatic status according to the standard questionnaires of Kidney Disease Quality of life short form (KDQOL-SF) [1].

## **3.7. Prognosis**

Disorders of nutritional status are of great prognostic importance, since they significantly impact on the survival and level of rehabilitation of these patients. According to a single-site study [23], the mortality rate during the first year on dialysis therapy was 1% in patients with a serum albumin level > 38 g/l at the moment of admission to HD treatment, and 30% for patients in whom the serum albumin did not exceed 30 g/l.

## **3.8. Possibilities for PEW correction in CKD: goals and approaches**

In CKD patients at the predialysis stage with PEW, the main goal of the treatment is to eliminate the factors contributing to the progression of nutritional disorders and to achieve the stabilization of renal failure [1, 14, 21]. The main aim of the diet is to inhibit glomerular hypertrophy and intraglomerular hypertension, to reduce the traffic load to tubules, to decrease cytokines and uremic toxins production: (TGF-β, ATII, oxygen radicals, TIMP (tissue inhibitor matrix metalloproteinases), indoxyl sulfate, guanidine, phosphates, oxalic acid, NO, etc.)

In most patients with CKD and systemic disease (systemic lupus erythematosus, and systemic vasculitis) with persistent disease activity, therapy (correction of the diet and hypertension, suppression of disease activity by glucocorticosteroids (GS) and/or cytostatics) can allow to slow the progression of renal failure and eliminates PEW [1, 4]. However, it should be borne in mind that the long-term (more than 6 months) use of CS in CKD patients in predialysis stages can enhance hypercatabolism, promote the development or aggravation of an existing PEW, and therefore careful and regular monitoring of anthropometric indices and serum albumin level is required for these patients [1, 13, 14].

intake and calorie content of food assessed according to a three-day food diary is needed

Integrated assessment of nutritional status can be performed also using the malnutrition inflammation score (MIS) scale. It allows to analyze anthropometric data (BMI, dry weight dynamics, body fat, and muscle mass), gastrointestinal symptoms, dialysis time, laboratory data (albumin and blood transferrin), hospitalization rates, and the risk of lethality on

All patients with an identified PEW should be given anthropometric measurements (or bioelectrical impedance analysis), a clinical and biochemical blood test, and a general urinalysis at least one time per 1.5 months, an analysis of protein intake and calorie content on a 3-day

PEW should be differentiated with a malabsorption syndrome, given a number of common manifestations (progressive decrease in BMI and blood albumin). In contrast to malabsorption, chronic diarrhea with steatorrhea and creatoria is not typical for PEW; while there is pronounced increase in serum CRP and TNF-α, calcification of the arteries [1, 14, 20] is found

According to the WHO, the diagnostic sign of PEW is a decrease in the mental and physical performance of patients, identified as a decrease in the quality of life when determining the psychosomatic status according to the standard questionnaires of Kidney Disease Quality of

Disorders of nutritional status are of great prognostic importance, since they significantly impact on the survival and level of rehabilitation of these patients. According to a single-site study [23], the mortality rate during the first year on dialysis therapy was 1% in patients with a serum albumin level > 38 g/l at the moment of admission to HD treatment, and 30% for

In CKD patients at the predialysis stage with PEW, the main goal of the treatment is to eliminate the factors contributing to the progression of nutritional disorders and to achieve the stabilization of renal failure [1, 14, 21]. The main aim of the diet is to inhibit glomerular hypertrophy and intraglomerular hypertension, to reduce the traffic load to tubules, to decrease cytokines and uremic toxins production: (TGF-β, ATII, oxygen radicals, TIMP (tissue inhibitor matrix metalloproteinases), indoxyl sulfate, guanidine, phosphates, oxalic acid, NO, etc.)

In most patients with CKD and systemic disease (systemic lupus erythematosus, and systemic vasculitis) with persistent disease activity, therapy (correction of the diet and hypertension, suppression of disease activity by glucocorticosteroids (GS) and/or cytostatics) can

food diary for at least one time in 3 months [1, 15, 21].

224 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

patients in whom the serum albumin did not exceed 30 g/l.

**3.8. Possibilities for PEW correction in CKD: goals and approaches**

[22, 25].

dialysis [14, 22].

[1, 14, 20].

**3.7. Prognosis**

**3.6. Differential diagnosis**

life short form (KDQOL-SF) [1].

LPD with a protein content of 0.6 g/kg body weight/day should be carefully balanced both in essential amino acid contents and in calories (at least 34 kcal/kg of ideal body weight/day). This requirement must be strictly observed in patients with 4–5 stages of CKD with digestive disorders due to uremia and also in patients with stages 3–4 of CKD in systemic diseases with persistent disease activity, long-term treatment with GS [1]. When making a 7-day menu, it is allowed to substitute products for their protein and carbohydrate equivalents, and to replace a portion of the animal protein (0.1 g/kg body weight/day or more) with a high-purity soybean protein (equivalent amount) in the LPD [1, 14, 21, 26].

It is promising to use highly purified soy protein SUPRO-760 (DuPont Protein Technologies USA) [1, 13, 14]. Protein "SUPRO" is a protein of high quality, fully digested by the body (adjusted amino acid coefficient of protein digestion—1.0). It is prescribed as an additive to food at the rate of 0.2–0.3 g soy protein per kg body weight per day [1, 14]. When compiling a diet that includes the soy protein SUPRO-760, the total amount of protein in the diet should not exceed 0.7 g/kg of body weight/day, whereas the total caloric value should not be less than 30 kcal/kg body weight/day for patients with 3B-5 stages of CKD [1, 14]. In patients who are committed to the use of predominantly vegetable protein, as well as in patients with anorexia (usually with eGFR <25 ml/min, 1.73 m2 ), half the daily amount of animal origin protein in a traditional LPD (0.6 g/kg body weight/day) may be replaced with highly purified soy protein [1, 13, 14]. In most of CKD 4–5 stages, patients with anorexia, when using such diet, dyspeptic phenomena decreased, blood urea nitrogen level decreased, acidosis corrected, and the general condition improved [19].

In the clinical practice of recent years, high-energy nutrient mixtures that are balanced by the essential amino acids content such as Fresubin Renal, manufactured by Fresenius Kabi, Germany, etc., is introduced in the diet of CKD patients to treat the NSD. These specialized mixtures are made on the basis of CKD patients' requirements in protein, fat, carbohydrate, and energy and also enriched with vitamins and minerals.

In the predialysis period of CKD, the use of a low-protein mixture (3 g protein/100 ml) Suplena (Abbott Nutrition, USA), with a minimum amount of potassium, sodium, and phosphorus balanced with a vitamin-mineral complex, is also promising for prevention and treatment of PEW. The energy value of one package of a liquid mixture (237 ml) is 474 kcal [14].

The using of EAA and their α-KA (Ketosteril, Fresenius Kabi ) in the LPD allows to maintain the protein balance [1, 6, 10]. EAA and KA are important components of LPD, which prevents the development of PEW, and enhance the beneficial effects of LPD [7, 13]. Ketoanalogues, in contrast to the matched their amino acids, do not contain a nitrogen group; by capturing endogenous nitrogen they are converted into amino acids in the body, and they contribute to the disintegration of urea. The ready-pharmaceutical complex of all EAA and KA in the optimal ratio (ketosteril) provides the need of CKD patients in essential amino acids with minimal nitrogen administration, correcting amino acid metabolism, and accelerating urea metabolism, reduces the risk of protein hypercatabolism, and negative nitrogen balance when applied diet with protein restriction. This reduces the insulin resistance, uremic dyslipidemia (hypertriglyceridemia), oxidative stress (formation of an active form of oxygen, RO—reactive oxygen). The need of EAA and KA addition to LPD is determined by the CKD stage (**Table 3**) [1, 14].

decrease in the preglomerular vasodilation (due to the restriction of protein intake) and postglomerular vasoconstriction (caused by RAAS inhibition), leading to a decrease in intraglomerular hyperfiltration, the main determinant of the tubulointerstitial fibrosis progression [1]. In addition, RAAS blockers in combination with a LPD may affect the maintenance of Klotho products

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The cardionephroprotective role of ketoacids and LPD was demonstrated in the experiment after subtotal nephrectomy. There was a decrease in proteinuria, arterial hypertension, and slowing down of left ventricular hypertrophy formation [14]. The retardation of CKD progression is associated with a lesser effect of EAA and KA on intra-glomerular hypertension, as well as with its ability as an additional source of calcium to correct hyperphosphatemia and slow the formation of uremic hyperparathyroidism. LPD in combination with EAA and KA enhances the following positive effects: antihypertensive and antiproteinuric effects of RAAS blockers, the corrective effect of erythropoietin preparations on anemia and of synthetic analogs of vitamin D, calcimi-

metics on hyperparathyroidism, and also the hypolipidemic effect of statins [1, 13, 14]

At the same time, CKD patients, with combined administration of EAA and active metabolites of vitamin D, due to a possible risk of hypercalcemia should stop taking vitamin D. If hypercalcemia persists, then it is necessary to reduce the dose of EAA to normalize the plasma concentration of calcium [1]. In recent years, the effect of ketosteril on the risk of vascular cal-

The addition of soy protein in the diet of patients with 3B-5 stages of CKD may also contribute to an antihypertensive effect. According to our data, patients with CKD 3B-5 stages who added soy protein to food achieved more effective correction of hypertension than patients who used milk protein as a food additive [4]. The antihypertensive effect of soy protein is due to the isoflavone in it, genistein (an estrogen of plant origin) that has an anti-inflammatory effect and a protective effect on the vascular endothelium (8 mg of isoflavone is contained in 1 g of soy protein). Soy protein contains more than animal protein, arginine (7.6% vs. 3.7%) the precursor of NO and glycine (4.2% vs. 1.8%), which inhibit the stress hormone adrenalin

All patients with PEW to reduce the rate of protein catabolism (PCR) should consume at least

At the same time, in prescribing the caloric content of the diet, in addition to taking into account the age, sex, general condition of the patient, and pathogenetic features of the disease, it is necessary to take into consideration the general regimen of the patient. In persons who comply with bed rest, energy expenditure will be significantly less than that of patients on a general regime. Therefore, the total calorie content of food cannot be the same for all patients [25].

The use of new drug groups, in particular, endothelin-1 receptor agonists, which have an antiproteinuric effect, agents that inhibit fibrogenesis and inflammation such as pyrophenidone and bardoxolone, as well as an inhibitor of aminoguanidine proteins glycation, are discussed [22]. Based on the available literature data, the correction of NSD, especially early, even at the predialysis stage not only improves the quality of life of patients but also contributes to slowing

as a cardionephroprotective factor [27, 28]

cification has not been confirmed [29].

and contribute to vasodilation [19, 30].

35 kcal/kg of body weight/day [1, 25].

The use of EAA and KA allows to limit protein intake to the required minimum amount to enhance the positive effects of LPD and at the same time to prevent the development of PEW [6, 11]. With the use of ketoacids, even very low protein intake (up to 0.3 g/kg/day) can be achieved without increasing the risk of PEW developing [1]. In patients who were observed in predialysis stages of CKD who used LPD and received EAA and KA for at least 12 months, there was a significantly lower incidence of NSD and a slower decline in GFR per year than in patients who did not limit the protein content in the diet [4].

In patients with 3B-5 stages of CKD, attachment of PEW can contribute to the development or aggravation of existing arterial hypertension because of decreased synthesis of nitric oxide (NO) due to arginine deficiency. Arginine deficiency in uremia is due to insufficient intake of amino acids with food, as well as a decrease in the formation of arginine from citrulline [16, 18]. CKD patients with PEW need antihypertensive therapy more than other patients. In CKD, ACE inhibitors and ARB have an antihypertensive effect comparable to the effect of calcium channel blockers (CCB), but ACE inhibitors and ARB are more likely, than CCB, have a nephroprotective effect, slowing the progression of renal failure, especially with persistent proteinuria [27]. A "strict" LPD in combination with ACE inhibitors (with predominantly hepatic way of elimination) or ARB in patients with stage 3B-4 CKD and persistent proteinuria more than 1 g/day have a joint effect on proteinuria reduction. The antiproteinuric effect is provided by two components: a


GFR: glomerular filtration rate is calculated by CKD-EPI creatinine equation; EAA: essential amino acids; and KA: ketoanalogs of amino acids.

**Table 3.** Essential ketoanalogs and amino acids requirement depending on the diet protein restriction and CKD stage (KDIGO guidelines, 2012).

decrease in the preglomerular vasodilation (due to the restriction of protein intake) and postglomerular vasoconstriction (caused by RAAS inhibition), leading to a decrease in intraglomerular hyperfiltration, the main determinant of the tubulointerstitial fibrosis progression [1]. In addition, RAAS blockers in combination with a LPD may affect the maintenance of Klotho products as a cardionephroprotective factor [27, 28]

acids with minimal nitrogen administration, correcting amino acid metabolism, and accelerating urea metabolism, reduces the risk of protein hypercatabolism, and negative nitrogen balance when applied diet with protein restriction. This reduces the insulin resistance, uremic dyslipidemia (hypertriglyceridemia), oxidative stress (formation of an active form of oxygen, RO—reactive oxygen). The need of EAA and KA addition to LPD is determined by

The use of EAA and KA allows to limit protein intake to the required minimum amount to enhance the positive effects of LPD and at the same time to prevent the development of PEW [6, 11]. With the use of ketoacids, even very low protein intake (up to 0.3 g/kg/day) can be achieved without increasing the risk of PEW developing [1]. In patients who were observed in predialysis stages of CKD who used LPD and received EAA and KA for at least 12 months, there was a significantly lower incidence of NSD and a slower decline in GFR per year than in

In patients with 3B-5 stages of CKD, attachment of PEW can contribute to the development or aggravation of existing arterial hypertension because of decreased synthesis of nitric oxide (NO) due to arginine deficiency. Arginine deficiency in uremia is due to insufficient intake of amino acids with food, as well as a decrease in the formation of arginine from citrulline [16, 18]. CKD patients with PEW need antihypertensive therapy more than other patients. In CKD, ACE inhibitors and ARB have an antihypertensive effect comparable to the effect of calcium channel blockers (CCB), but ACE inhibitors and ARB are more likely, than CCB, have a nephroprotective effect, slowing the progression of renal failure, especially with persistent proteinuria [27]. A "strict" LPD in combination with ACE inhibitors (with predominantly hepatic way of elimination) or ARB in patients with stage 3B-4 CKD and persistent proteinuria more than 1 g/day have a joint effect on proteinuria reduction. The antiproteinuric effect is provided by two components: a

**) Daily protein intake (g** 

**day)**

0.8 0.6/0.7

2. 0.3–0.4

GFR: glomerular filtration rate is calculated by CKD-EPI creatinine equation; EAA: essential amino acids; and KA:

**Table 3.** Essential ketoanalogs and amino acids requirement depending on the diet protein restriction and CKD stage

**1.** 0.6 2. 0.3–0.4

1 ≥90 0.8 Not required 2 60–89 0.8 Not required

**protein/kg body weight/**

**EAA и КA**

Not required

1 tablet/5 kg of body weight/day

1 tablet/5 kg of body weight/day 1 tablet/5 kg of body weight/day

1 tablet/5 kg of body weight/day 1 tablet/5 kg of body weight/day

the CKD stage (**Table 3**) [1, 14].

**CKD stage GFR (ml/min/1.73 m2**

30–59 30–44

5 >10 to <15

ketoanalogs of amino acids.

(KDIGO guidelines, 2012).

4 15–29 **1.** 0.6

(predialysis)

3A 3B

patients who did not limit the protein content in the diet [4].

226 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

The cardionephroprotective role of ketoacids and LPD was demonstrated in the experiment after subtotal nephrectomy. There was a decrease in proteinuria, arterial hypertension, and slowing down of left ventricular hypertrophy formation [14]. The retardation of CKD progression is associated with a lesser effect of EAA and KA on intra-glomerular hypertension, as well as with its ability as an additional source of calcium to correct hyperphosphatemia and slow the formation of uremic hyperparathyroidism. LPD in combination with EAA and KA enhances the following positive effects: antihypertensive and antiproteinuric effects of RAAS blockers, the corrective effect of erythropoietin preparations on anemia and of synthetic analogs of vitamin D, calcimimetics on hyperparathyroidism, and also the hypolipidemic effect of statins [1, 13, 14]

At the same time, CKD patients, with combined administration of EAA and active metabolites of vitamin D, due to a possible risk of hypercalcemia should stop taking vitamin D. If hypercalcemia persists, then it is necessary to reduce the dose of EAA to normalize the plasma concentration of calcium [1]. In recent years, the effect of ketosteril on the risk of vascular calcification has not been confirmed [29].

The addition of soy protein in the diet of patients with 3B-5 stages of CKD may also contribute to an antihypertensive effect. According to our data, patients with CKD 3B-5 stages who added soy protein to food achieved more effective correction of hypertension than patients who used milk protein as a food additive [4]. The antihypertensive effect of soy protein is due to the isoflavone in it, genistein (an estrogen of plant origin) that has an anti-inflammatory effect and a protective effect on the vascular endothelium (8 mg of isoflavone is contained in 1 g of soy protein). Soy protein contains more than animal protein, arginine (7.6% vs. 3.7%) the precursor of NO and glycine (4.2% vs. 1.8%), which inhibit the stress hormone adrenalin and contribute to vasodilation [19, 30].

All patients with PEW to reduce the rate of protein catabolism (PCR) should consume at least 35 kcal/kg of body weight/day [1, 25].

At the same time, in prescribing the caloric content of the diet, in addition to taking into account the age, sex, general condition of the patient, and pathogenetic features of the disease, it is necessary to take into consideration the general regimen of the patient. In persons who comply with bed rest, energy expenditure will be significantly less than that of patients on a general regime. Therefore, the total calorie content of food cannot be the same for all patients [25].

The use of new drug groups, in particular, endothelin-1 receptor agonists, which have an antiproteinuric effect, agents that inhibit fibrogenesis and inflammation such as pyrophenidone and bardoxolone, as well as an inhibitor of aminoguanidine proteins glycation, are discussed [22].

Based on the available literature data, the correction of NSD, especially early, even at the predialysis stage not only improves the quality of life of patients but also contributes to slowing the progression of CKD and CVE, to prevent PEW at the stage of regular HD [12]. Thus, the correction of NSD becomes an important and obligatory part in the treatment of patients with CKD [1, 14]

pork, smoked products, meat and fish canned food, beans (green peas, beans, French beans, and lentils), cocoa, chocolate, nuts, strong tea and coffee, grapes, raisins, and grape wines [1, 14].

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If oxalic acid is impaired (oxaluria, oxalate kidney stones, and oxalosis), in addition to restrictions for patients with elevated uric acid, the consumption of sorrel, spinach, rhubarb, and

Contraindications to the administration of LPD in CKD are mainly related to patients with

Long-term compliance with LPD is difficult due to anorexia as well as the tendency of CKD patients to protein hypercatabolism. The methods that affect anorexia and hypercatabolism in CKD include correction of metabolic acidosis (calcium carbonate, and α-ketoanalogs of EAA), deficiency of iron and erythropoietin, elimination of hyperleptinemia (eicosapentaenoic acid),

Treatment with calcium carbonate in the background of protein-intake restriction increases the level of plasma bicarbonate and reduces the protein catabolic rate (PCR) from 1.2 to 1.0 g/day. As a result, protein's catabolism and anorexia that are typical for acidosis are reduced, neutral or positive nitrogen balance is maintained, and parathyroid gland activation is partially

EAA and KA are important components of LPD, which help to prevent the development of PEW, correct acidosis, and enhance the beneficial effects of LPD [7, 13]. The need of EAA and

The absorption of α-keto acids in the gastrointestinal tract is quick, and their conversion to essential amino acids averages from 30% for valine and up to 70% for phenylalanine. The number of α-keto acids involved in conversion to essential amino acids is inversely proportional

> form) • Severe anemia • Noncompliance • Anorexia

LPD: low-protein diet; GFR: glomerular filtration rate; BMI: body mass index; CKD: chronic kidney disease.

• Decompensate diabetes mellitus • Severe hypercatabolism

• Bacterial infection (acute, exacerbation of chronic

• Psychopathy, mental disorders, encephalopathy

and hyperparathyroidism (calcitriol, paricalcitol, and cinacalcet) [1, 13, 14, 21].

peppers should also be limited [1, 14, 16].

**3.10. Pharmacological support for tolerance to a LPD**

KA supplementation to LPD is determined by the CKD stage.

**Absolute contradiction Relative contradiction**

• 5 CKD stage with GFR < 10 ml/min and decompensate metabolic acidosis, uremic polyneuropathy, or

)

uncontrolled hypertension • Cachexia (BMI < 18 kg/m2

• Severe nephrotic syndrome • Intolerance to dietary restrictions

• Rapidly progressive glomerulonephritis

**Table 4.** Contraindication to LPD in CKD.

late 5 stage of CKD (**Table 4**).

inhibited [14].

#### **3.9. Prophylaxis and dispensary observation**

All patients with CKD are advised to consult a dietician, as well as to train in educational programs concerning the need to restrict protein, phosphorus, potassium, and salt in the diet. Primary prevention of NSD in patients with CKD traditionally is the restriction of protein in the diet adequately to the reducing degree of GFR. So if at 2–3A stages of CKD with GFR >45 ml/min/1.73m2 , the recommended daily protein intake is 0.8 g protein/kg/day, then with GFR 44-30 ml/min/1.73m2 , its intake is limited to 0.7–0.6 g/kg body weight/day and 0.6–0.3 g/kg body weight/day when GFR 29-15 ml/min/1.73m2 [1, 14]. In CKD patients with proteinuria > 3 g/day, the total amount of protein in the daily ration is increased by 1 g protein/g of proteinuria [1, 14, 21, 22].

In a diet with a protein restriction of 0.6 g/ kg body weight, at least 60% should be a protein of animal origin as the most valuable in the content of EAA. Plant protein has a lower biological value, since it does not contain the whole composition of EAA. The exception is the soy protein, which is close to the protein of animal origin in the spectrum of EAA [1, 18, 19, 30].

In a "strict" LPD—0.3 g protein/kg/day—the whole protein could be of plant origin but it is a mandatory requirement to combine this diet with EAA and their α- keto-analogues [6, 11]. However, a strict LPD (but not lower than 0.3 g/kg/day) is permissible only if there are technical and organizational facilities for regular monitoring of nutritional status, and it should be combined with the mandatory intake of EAA and KA.

To ensure that the LPD (0.6–0.3 g protein/kg/day) did not lead to catabolism of the body's own proteins, patients, along with the addition of EAA, should consume at least 35 kcal/kg/day, and only in a background of large amounts of protein (0.8–0.7 g/kg/day) the consumption of 30 kcal/kg/day is sufficient. [25]. High energy value of food should be provided by carbohydrates and fats. [14, 25].

Nutritional value of fats is determined by the presence of fatty unsaturated acids (linoleic and linolenic) in their composition, which are not synthesized by the body, but come from food. The ratio of vegetable oils and animal fats in the diet should be 1:3. Vegetable oil (e.g., sunflower, soybean, corn, and cotton) should be present in the daily diet of the patient [14, 22].

The energy value of food is calculated on the basis of the percentage content of carbohydrates, fats, and proteins in it, and the coefficient of their biological value. The coefficient of biological energy value for carbohydrates is 4 kcal/g, for fats is 9 kcal/g, and for protein is 4 kcal/g. Combining the energy value of the protein, fat, and carbohydrates contained in the products, the caloric value of the entire diet may be calculated [14, 25].

Patients with a purine metabolism disorders (hyperuricemia and hyperuricosuria) should exclude rich broths, by-products—liver, kidneys, heart, tongues, as well as pates, sausages, veal, pork, smoked products, meat and fish canned food, beans (green peas, beans, French beans, and lentils), cocoa, chocolate, nuts, strong tea and coffee, grapes, raisins, and grape wines [1, 14].

If oxalic acid is impaired (oxaluria, oxalate kidney stones, and oxalosis), in addition to restrictions for patients with elevated uric acid, the consumption of sorrel, spinach, rhubarb, and peppers should also be limited [1, 14, 16].

Contraindications to the administration of LPD in CKD are mainly related to patients with late 5 stage of CKD (**Table 4**).

## **3.10. Pharmacological support for tolerance to a LPD**

the progression of CKD and CVE, to prevent PEW at the stage of regular HD [12]. Thus, the correction of NSD becomes an important and obligatory part in the treatment of patients with

All patients with CKD are advised to consult a dietician, as well as to train in educational programs concerning the need to restrict protein, phosphorus, potassium, and salt in the diet. Primary prevention of NSD in patients with CKD traditionally is the restriction of protein in the diet adequately to the reducing degree of GFR. So if at 2–3A stages of CKD with

proteinuria > 3 g/day, the total amount of protein in the daily ration is increased by 1 g

In a diet with a protein restriction of 0.6 g/ kg body weight, at least 60% should be a protein of animal origin as the most valuable in the content of EAA. Plant protein has a lower biological value, since it does not contain the whole composition of EAA. The exception is the soy protein, which is close to the protein of animal origin in the spectrum of EAA [1, 18, 19, 30]. In a "strict" LPD—0.3 g protein/kg/day—the whole protein could be of plant origin but it is a mandatory requirement to combine this diet with EAA and their α- keto-analogues [6, 11]. However, a strict LPD (but not lower than 0.3 g/kg/day) is permissible only if there are technical and organizational facilities for regular monitoring of nutritional status, and it should be

To ensure that the LPD (0.6–0.3 g protein/kg/day) did not lead to catabolism of the body's own proteins, patients, along with the addition of EAA, should consume at least 35 kcal/kg/day, and only in a background of large amounts of protein (0.8–0.7 g/kg/day) the consumption of 30 kcal/kg/day is sufficient. [25]. High energy value of food should be provided by carbohy-

Nutritional value of fats is determined by the presence of fatty unsaturated acids (linoleic and linolenic) in their composition, which are not synthesized by the body, but come from food. The ratio of vegetable oils and animal fats in the diet should be 1:3. Vegetable oil (e.g., sunflower, soybean, corn, and cotton) should be present in the daily diet of the patient [14, 22]. The energy value of food is calculated on the basis of the percentage content of carbohydrates, fats, and proteins in it, and the coefficient of their biological value. The coefficient of biological energy value for carbohydrates is 4 kcal/g, for fats is 9 kcal/g, and for protein is 4 kcal/g. Combining the energy value of the protein, fat, and carbohydrates contained in the products,

Patients with a purine metabolism disorders (hyperuricemia and hyperuricosuria) should exclude rich broths, by-products—liver, kidneys, heart, tongues, as well as pates, sausages, veal,

, the recommended daily protein intake is 0.8 g protein/kg/day, then

, its intake is limited to 0.7–0.6 g/kg body weight/day and

[1, 14]. In CKD patients with

CKD [1, 14]

GFR >45 ml/min/1.73m2

drates and fats. [14, 25].

with GFR 44-30 ml/min/1.73m2

protein/g of proteinuria [1, 14, 21, 22].

**3.9. Prophylaxis and dispensary observation**

228 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

0.6–0.3 g/kg body weight/day when GFR 29-15 ml/min/1.73m2

combined with the mandatory intake of EAA and KA.

the caloric value of the entire diet may be calculated [14, 25].

Long-term compliance with LPD is difficult due to anorexia as well as the tendency of CKD patients to protein hypercatabolism. The methods that affect anorexia and hypercatabolism in CKD include correction of metabolic acidosis (calcium carbonate, and α-ketoanalogs of EAA), deficiency of iron and erythropoietin, elimination of hyperleptinemia (eicosapentaenoic acid), and hyperparathyroidism (calcitriol, paricalcitol, and cinacalcet) [1, 13, 14, 21].

Treatment with calcium carbonate in the background of protein-intake restriction increases the level of plasma bicarbonate and reduces the protein catabolic rate (PCR) from 1.2 to 1.0 g/day. As a result, protein's catabolism and anorexia that are typical for acidosis are reduced, neutral or positive nitrogen balance is maintained, and parathyroid gland activation is partially inhibited [14].

EAA and KA are important components of LPD, which help to prevent the development of PEW, correct acidosis, and enhance the beneficial effects of LPD [7, 13]. The need of EAA and KA supplementation to LPD is determined by the CKD stage.

The absorption of α-keto acids in the gastrointestinal tract is quick, and their conversion to essential amino acids averages from 30% for valine and up to 70% for phenylalanine. The number of α-keto acids involved in conversion to essential amino acids is inversely proportional


LPD: low-protein diet; GFR: glomerular filtration rate; BMI: body mass index; CKD: chronic kidney disease.

**Table 4.** Contraindication to LPD in CKD.

to the daily protein quota in food and directly depends on the caloric content of the diet. Some α-keto acids, e.g., ketoisoleucine, in uremia suppress protein degradation in muscles, allowing to maintain a neutral nitrogen balance in conditions of renal failure in the background of protein restriction [25].

### **3.11. Consumption of potassium, sodium, and phosphorus in CKD: water regime**

At 3B stage CKD daily intake of potassium, phosphorus in the diet should not exceed 3000 mg and 700 mg, respectively, at the 4th stage CKD—potassium intake should be reduced by half. LPD allows to reduce the consumption of phosphorus—when consuming 0.6 g/kg protein, patients receive 500–800 mg of phosphorus a day, and when the protein quota is limited to 0.3 g/kg—250 mg of phosphorus. In case of hyperphosphatemia, it should be limited to a fish (no more than 1 time per week), as well as cereals (except rice) and other foods rich in phosphorus. As an alternative to cereals, artificial sago can be used [1, 14, 26].

In order to correct hyperkalemia, it is recommended to limit the use of dried apricots, figs, bananas, apricots, peaches, and nectarines [1, 14].

Restriction of salt intake (no more than 5 g/day) increases the antiproteinuric effectiveness of RAAS inhibitors. Exceptions include patients with increased sodium excretion in tubular lesions [26].

Most patients with CKD should be recommended a consumption of at least 2 liters of fluid/day and up to 3 liters of fluid/day in hot weather, especially when purine metabolism is disordered, oxalic acid turnover disturbances, urolithiasis, and a tendency to urinary infection [1, 14, 26]

With nephrotic syndrome, as well as in the terminal stage of CKD with a GFR value of less than 15 ml/min, when the patient cannot form more than 1 l urine/day, the fluid intake is corrected by diuresis (300–500 ml to be added to the amount of excreted urine from the previous day) [1].

The effect of LPD directly depends on the correct compliance by patients with the prescribed restriction of the amount of protein in the diet (0.8–0, 6–0.3 g/kg body weight/day), depending on the stage of CKD, the ratio of animal and vegetable proteins in it, and also on high caloric

TGF-β: transforming growth factor β; AII: angiotensin II; RO: reactive oxygen; TIMP: tissue inhibitor matrix metalloproteinases; NO: nitrogen oxygen; PTH: parathyroid hormone; and GFR: glomerular filtration rate is calculated

Decrease in level of uremic toxins, azotemia,

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Decrease in proteinuria, correction of hypertension,

Slowing down of atherosclerosis progression, decrease in risk of cardiovascular complications and mortality

Suppression of hyperparathyroidism, vascular calcification, improvement of anemia, and decrease in

slowing down of glomerulosclerosis and tubulointerstitial fibrosis, and GRF stabilization

hyperuricemia

protein catabolism; hypoalbuminemia; amino acids metabolism

Nutritional Status Disorders in Chronic Kidney Disease: Practical Aspects (Systematic Review)

erythropoietin doses

According to the re-analysis of the MDRD multicentre study (Modification of diet in renal disease), in the background of LPD in patients with GFR more than 25 ml/min, the rate of CKD progression decreased by approximately 10%, and with GFR less than 25 ml/min, it was

The results of the research indicate that "strict" LPD (0.3 g/kg/day of vegetable protein) and the use of a complex of EAA and KA (ketosteril 1 table/5 kg of body weight per day) in patients with stage 4 CKD provide a more effective reduction of uremia symptoms and provide an extension of the predialysis period than conventional LPD (0.6 g protein/kg/day) [6, 11]. Strengthening of the nephroprotective role of LPD by combining it with α-ketoanalogs of amino acids is associated with a lesser effect it has on intra-glomerular hypertension, as well as with their ability as an additional source of calcium to inhibit hyperphosphatemia and slow the formation of uremic hyperparathyroidism [1, 11]. LPD in combination with EAA and KA enhances the antihypertensive and antiproteinuric effects of RAAS blockers, the corrective effect of erythropoietin preparations on the anemia, the effects of synthetic analogs of vitamin D and calcimimetics on

manifestations of hyperparathyroidism, and the hypolipidemic effect of statins [10].

an average of 30% for every 0.2 g/kg of protein excluded from the diet [1].

intake (30–35 kcal/kg body weight/day) [1, 14, 21].

**Table 5.** Mechanisms of action and clinical effects of low-protein diet (LPD).

**Mechanisms of action Clinical effect**

Correction of metabolic acidosis Correction of nutrition status:

Protein restriction to the level, adapted to residual renal

Decrease in serum phosphate and PTH levels, increase

Inhibition of glomerular hypertrophy and intraglomerular hypertension, decrease in tubular transport overload, suppression of cytokines and uremic toxins synthesis: TGF-β, AII and RO, TIMP, indoxyl sulfate, guanidine, phosphate, oxalic acid, NO

Partial correction of dyslipidemia: • of hypercholesteremia; • of hypertriglyceridemia; • decrease in insulin resistance

by CKD EPI creatinine equation.

function

in calcitriol

## **3.12. Nephroprotective effect of LPD**

The nephroprotective effect of LPD is associated with its hemodynamic and metabolic effects. The dietary load of protein and phosphorus, according to the possibilities of the residual function of the kidneys of the patient, in addition to reducing uremic intoxication and lowering the level of urea, creatinine, and uric acid in the blood, reduces the hemodynamic load on the residual nephrons, which slows the progress of glomerular hypertrophy, as well as activation of RAAS, normalizes intraglomerular autoregulation, and reduces intra-glomerular and systemic arterial hypertension [1, 14]. The LPD partially corrects such unfavorable uremic metabolic and endocrine disorders, as hypoalbuminemia, dyslipidemia, insulinoresistance, hyperphosphatemia with parathyroid gland hyperplasia, and anemia, and thereby reduces the risk of uremic hyperparathyroidism, vascular calcification, and atherosclerosis (**Table 5**) [7, 20, 26].

The effect of LPD on CKD advancing is more pronounced in cases of DN. In the background of LPD, the annual incidence of GFR declines by 1.5–2 times, and the outcome in the terminal stage of CKD is observed almost three times less frequently than in the standard diet [5, 7].


TGF-β: transforming growth factor β; AII: angiotensin II; RO: reactive oxygen; TIMP: tissue inhibitor matrix metalloproteinases; NO: nitrogen oxygen; PTH: parathyroid hormone; and GFR: glomerular filtration rate is calculated by CKD EPI creatinine equation.

**Table 5.** Mechanisms of action and clinical effects of low-protein diet (LPD).

to the daily protein quota in food and directly depends on the caloric content of the diet. Some α-keto acids, e.g., ketoisoleucine, in uremia suppress protein degradation in muscles, allowing to maintain a neutral nitrogen balance in conditions of renal failure in the background of

At 3B stage CKD daily intake of potassium, phosphorus in the diet should not exceed 3000 mg and 700 mg, respectively, at the 4th stage CKD—potassium intake should be reduced by half. LPD allows to reduce the consumption of phosphorus—when consuming 0.6 g/kg protein, patients receive 500–800 mg of phosphorus a day, and when the protein quota is limited to 0.3 g/kg—250 mg of phosphorus. In case of hyperphosphatemia, it should be limited to a fish (no more than 1 time per week), as well as cereals (except rice) and other foods rich in phos-

In order to correct hyperkalemia, it is recommended to limit the use of dried apricots, figs,

Restriction of salt intake (no more than 5 g/day) increases the antiproteinuric effectiveness of RAAS inhibitors. Exceptions include patients with increased sodium excretion in tubular

Most patients with CKD should be recommended a consumption of at least 2 liters of fluid/day and up to 3 liters of fluid/day in hot weather, especially when purine metabolism is disordered, oxalic acid turnover disturbances, urolithiasis, and a tendency to urinary

With nephrotic syndrome, as well as in the terminal stage of CKD with a GFR value of less than 15 ml/min, when the patient cannot form more than 1 l urine/day, the fluid intake is corrected by diuresis (300–500 ml to be added to the amount of excreted urine from the previous day) [1].

The nephroprotective effect of LPD is associated with its hemodynamic and metabolic effects. The dietary load of protein and phosphorus, according to the possibilities of the residual function of the kidneys of the patient, in addition to reducing uremic intoxication and lowering the level of urea, creatinine, and uric acid in the blood, reduces the hemodynamic load on the residual nephrons, which slows the progress of glomerular hypertrophy, as well as activation of RAAS, normalizes intraglomerular autoregulation, and reduces intra-glomerular and systemic arterial hypertension [1, 14]. The LPD partially corrects such unfavorable uremic metabolic and endocrine disorders, as hypoalbuminemia, dyslipidemia, insulinoresistance, hyperphosphatemia with parathyroid gland hyperplasia, and anemia, and thereby reduces the risk of uremic hyperparathyroidism, vascular calcification, and atherosclerosis (**Table 5**) [7, 20, 26]. The effect of LPD on CKD advancing is more pronounced in cases of DN. In the background of LPD, the annual incidence of GFR declines by 1.5–2 times, and the outcome in the terminal stage of CKD is observed almost three times less frequently than in the standard diet [5, 7].

**3.11. Consumption of potassium, sodium, and phosphorus in CKD: water regime**

phorus. As an alternative to cereals, artificial sago can be used [1, 14, 26].

bananas, apricots, peaches, and nectarines [1, 14].

230 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

protein restriction [25].

lesions [26].

infection [1, 14, 26]

**3.12. Nephroprotective effect of LPD**

The effect of LPD directly depends on the correct compliance by patients with the prescribed restriction of the amount of protein in the diet (0.8–0, 6–0.3 g/kg body weight/day), depending on the stage of CKD, the ratio of animal and vegetable proteins in it, and also on high caloric intake (30–35 kcal/kg body weight/day) [1, 14, 21].

According to the re-analysis of the MDRD multicentre study (Modification of diet in renal disease), in the background of LPD in patients with GFR more than 25 ml/min, the rate of CKD progression decreased by approximately 10%, and with GFR less than 25 ml/min, it was an average of 30% for every 0.2 g/kg of protein excluded from the diet [1].

The results of the research indicate that "strict" LPD (0.3 g/kg/day of vegetable protein) and the use of a complex of EAA and KA (ketosteril 1 table/5 kg of body weight per day) in patients with stage 4 CKD provide a more effective reduction of uremia symptoms and provide an extension of the predialysis period than conventional LPD (0.6 g protein/kg/day) [6, 11]. Strengthening of the nephroprotective role of LPD by combining it with α-ketoanalogs of amino acids is associated with a lesser effect it has on intra-glomerular hypertension, as well as with their ability as an additional source of calcium to inhibit hyperphosphatemia and slow the formation of uremic hyperparathyroidism [1, 11]. LPD in combination with EAA and KA enhances the antihypertensive and antiproteinuric effects of RAAS blockers, the corrective effect of erythropoietin preparations on the anemia, the effects of synthetic analogs of vitamin D and calcimimetics on manifestations of hyperparathyroidism, and the hypolipidemic effect of statins [10].

The replacing of a portion of the animal protein (0.1–0.2 g/kg/day) in the LPD (0.6 g protein/ kg body weight/day) with a highly purified soy protein (an equivalent amount) contributed to retardation of CKD progression [4]. Soy protein is less able than animal protein (meat, fish, milk, etc.) to increase hyperperfusion and hyperfiltration in remnant nephrons [30]. The results of studies on the model of unilateral ureteral obstruction in rats receiving LPD demonstrated a decrease in the expression of the nuclear factor of Kappa B transcription (NFkB), the most important mediator of activation of many proinflammatory and profibrotic cytokines and TGF-β-key as a profibrotic factor in the renal tissue [28, 30]. LPD with an addition of soy protein to the diet reduces tubulointerstitial fibrosis also due to suppression of tyrosine protein kinase as a powerful sclerosis stimulant [30]. Currently, the possibility of LPD influence to maintain the serum level of klotho protein, as an established strong early cardio and nephroprotective factor, is being actively studied [29].

## **4. Conclusion**

Thus, the restriction of daily food protein intake to 0.3–0.6 g/kg/day prevents accumulation of toxic products, retards, and delays terminal renal failure. Replacing a portion of the animal protein in a LPD by an equivalent amount of highly purified soy protein enhances the nephroprotective effect of a LPD and favors more pronounced slowdown of CKD progression. The use of keto-analogues of essential amino acids with LPD at predialysis stage of CKD allows preserving CKD patients from nutrition status disorders and contributes to slow down of CKD complications. Control of nutrition status in CKD should be carried out regularly. A comprehensive assessment of NS in CKD patients can be quickly performed using bioimpedance analysis.

## **Acknowledgements**

This work was supported by Russian Science Foundation (grant No. 14-15-00947 2014).

**Author details**

**References**

Marina V. Lebedeva and Aigul Zh. Usubalieva

\*Address all correspondence to: ludm.milovanova@gmail.com

CVC Cardiovascular complications

Nutritional Status Disorders in Chronic Kidney Disease: Practical Aspects (Systematic Review)

http://dx.doi.org/10.5772/intechopen.69297

233

CVE cardiovascular events DN diabetic nephropathy EAA essential amino acids EPO erythropoietins

FGF-23 fibroblast growth factor GFR Glomerular Filtration Rate GS glucocorticosteroids HD Regular Hemodialysis KA Keto-analogues

LVH left ventricular hypertrophy

NSD nutritional status disorders PTH parathyroid hormone PCR protein catabolism rate

PEW protein-energy wasting RRT renal replacement therapy SFFT thickness of the skin-fal fold SMV Shoulder muscles volume

TBW total body water

RAAS renin angiotensin aldosterone system

LPD low protein diet NS nutritional status

Ludmila Y. Milovanova\*, Victor V. Fomin, Lidia V. Lysenko (Kozlovskaya), Yuriy S. Milovanov,

[1] KDIGO. Clinical Practice Guideline for the evaluation and management of chronic kidney disease. Journal of the International Society of Nephrology. 2013;**3**(Suppl. 1):1-136

Nikolay A. Mukhin, Vasiliy V. Kozlov, Marina V. Taranova, Svetlana Y. Milovanova,

I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation

## **Abbreviations**



## **Author details**

The replacing of a portion of the animal protein (0.1–0.2 g/kg/day) in the LPD (0.6 g protein/ kg body weight/day) with a highly purified soy protein (an equivalent amount) contributed to retardation of CKD progression [4]. Soy protein is less able than animal protein (meat, fish, milk, etc.) to increase hyperperfusion and hyperfiltration in remnant nephrons [30]. The results of studies on the model of unilateral ureteral obstruction in rats receiving LPD demonstrated a decrease in the expression of the nuclear factor of Kappa B transcription (NFkB), the most important mediator of activation of many proinflammatory and profibrotic cytokines and TGF-β-key as a profibrotic factor in the renal tissue [28, 30]. LPD with an addition of soy protein to the diet reduces tubulointerstitial fibrosis also due to suppression of tyrosine protein kinase as a powerful sclerosis stimulant [30]. Currently, the possibility of LPD influence to maintain the serum level of klotho protein, as an established

232 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

strong early cardio and nephroprotective factor, is being actively studied [29].

Thus, the restriction of daily food protein intake to 0.3–0.6 g/kg/day prevents accumulation of toxic products, retards, and delays terminal renal failure. Replacing a portion of the animal protein in a LPD by an equivalent amount of highly purified soy protein enhances the nephroprotective effect of a LPD and favors more pronounced slowdown of CKD progression. The use of keto-analogues of essential amino acids with LPD at predialysis stage of CKD allows preserving CKD patients from nutrition status disorders and contributes to slow down of CKD complications. Control of nutrition status in CKD should be carried out regularly. A comprehensive assessment of NS in CKD patients can be quickly performed using bioimpedance analysis.

This work was supported by Russian Science Foundation (grant No. 14-15-00947 2014).

ACE Angiotensin converting enzyme ARB Angiotensin receptor blockers BCM Body Composition Monitor

BMI Body mass index CKD Chronic Kidney Disease CRP C-reactive protein CRF Chronic Renal Failure

CV cardiovascular

**4. Conclusion**

**Acknowledgements**

**Abbreviations**

Ludmila Y. Milovanova\*, Victor V. Fomin, Lidia V. Lysenko (Kozlovskaya), Yuriy S. Milovanov, Nikolay A. Mukhin, Vasiliy V. Kozlov, Marina V. Taranova, Svetlana Y. Milovanova, Marina V. Lebedeva and Aigul Zh. Usubalieva

\*Address all correspondence to: ludm.milovanova@gmail.com

I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation

## **References**

[1] KDIGO. Clinical Practice Guideline for the evaluation and management of chronic kidney disease. Journal of the International Society of Nephrology. 2013;**3**(Suppl. 1):1-136

[2] Bellizzi V, Cupisti A, Locatelli F, et al., on behalf of the "Conservative Treatment of CKD" study group of the Italian Society of Nephrology. Low-protein diets for chronic kidney disease patients: The Italian experience. BMC Nephrology. 2016;**17**:77. DOI: 10.1186/ s12882-016-0280-0

[13] Yoshitsugu Obi, Hemn Qader, Csaba P. Latest consensus and update on protein energywasting in chronic kidney disease. Current Opinion in Clinical Nutrition and Metabolic

Nutritional Status Disorders in Chronic Kidney Disease: Practical Aspects (Systematic Review)

http://dx.doi.org/10.5772/intechopen.69297

235

[14] Fouque D, Kalantar-Zadeh K, Kopple J, et al. A proposed nomenclature and diagnostic criteria for protein-energy wasting in acute and chronic kidney disease. Kidney

[15] Hyun YY, Lee KB, Han SH, et al. Nutritional status in adults with predialysis chronic kidney disease: KNOW-CKD Study. Journal of Korean Medical Science. 2017;**32**(2):257-

[16] Fouque D, Pelletier S, Mafra D, et al. Nutrition and chronic kidney disease. Kidney

[17] Franch HA, Raissi S, Wang X, et al. Acidosis impairs insulin receptor substrate-1-associated phosphoinositide 3-kinase signaling in muscle cells: Consequences on proteolysis. American Journal of Physiology. Renal Physiology. 2004;**287**:700-706. DOI: 10.1152/

[18] Carrero JJ, Stenvinkel P, Cuppari L, et al. Etiology of the protein-energy wasting syndrome in chronic kidney disease: A consensus statement from the International Society of Renal Nutrition and Metabolism (ISRNM). Journal of Renal Nutrition. 2013;**23**:77-90.

[19] Zoccali C, Malamaci F. Adiponectin and leptin in chronic kidney disease: Causal factors or mere risk markers? Journal of Renal Nutrition. 2011;**21**(1):87-91. DOI: 10.1053/j.

[20] Mutsert R, Grootendorst DC, Axelsson J, et al, NECOSAD Study Group. Excess mortality due to interaction between protein-energy wasting, inflammation and cardiovascular disease in chronic dialysis patients. Nephrology, Dialysis, Transplantation. 2008;**23**:2957-

[21] Kovesdy CP, Kopple JD, Kalantar-Zadeh K. Management of protein-energy wasting in non-dialysis-dependent chronic kidney disease: Reconciling low protein intake with nutritional therapy. American Journal of Clinical Nutrition. 2013;**97**:1163-1177. DOI:

[22] Dumler F. Body composition modifications in patients under low protein diets. Journal

[23] Pupim LB, Caglar K, Hakim RM, et al. Uremic malnutrition is a predictor of death independent of inflammatory status. Kidney International. 2004;**66**:2054-2060. DOI: 10.

[24] Wilson FP, Xie D, Anderson AH, et al. Urinary creatinine excretion, bioelectrical impedance analysis, and clinical outcomes in patients with CKD: The CRIC study. Clinical

of Renal Nutrition. 2011;**21**(1):76-81. DOI: 10.1053/j.jrn.2010.10.005

Care. 2015;**18**(3):254-262. DOI: 10.1097/MCO.0000000000000171

International. 2011;**80**:348-357. DOI: 10.3346/jkms.2017.32.2.257

International. 2008;**73**:391-398. DOI: 10.1038/sj.ki.5002585

263. DOI: 10.3346/jkms.2017.32.2.257

ajprenal.00440.2003

jrn.2010.10.014

DOI: 10.1053/j.jrn.2013.01.001

2964. DOI: 10.1093/ndt/gfn167

10.3945/ajcn.112.036418

1111/j.1523-1755.2004.00978.x


[13] Yoshitsugu Obi, Hemn Qader, Csaba P. Latest consensus and update on protein energywasting in chronic kidney disease. Current Opinion in Clinical Nutrition and Metabolic Care. 2015;**18**(3):254-262. DOI: 10.1097/MCO.0000000000000171

[2] Bellizzi V, Cupisti A, Locatelli F, et al., on behalf of the "Conservative Treatment of CKD" study group of the Italian Society of Nephrology. Low-protein diets for chronic kidney disease patients: The Italian experience. BMC Nephrology. 2016;**17**:77. DOI: 10.1186/

[3] Bonanni A, Mannucci I, Verzola D, et al. Protein-energy wasting and mortality in chronic kidney disease. International Journal of Environmental Research and Public Health.

[4] Milovanov YS, Milovanova LY, Mikhailov AA, et al. Influence of diet balanced with essential amino acids and keto acids analogs and high-nutrient blend on the progression of renal failure in patients in the pre-dialysis stage of chronic kidney disease caused by systemic autoimmune diseases. International Journal of BioMedicine. 2013;**3**(3):184-187.

[5] Firouzi S, Barakatun-Nisak MY, Nor Azmi K. Nutritional status, glycemic control and its associated risk factors among a sample of type 2 diabetic individuals, a pilot study. Journal of Research in Medical Sciences. 2015;**20**(1):40-46. DOI: https://www.ncbi.nlm.

[6] Bellizzi V. Long-term outcome of patients following a very low protein diet supplemented with keto/amino acids during the pre-dialysis period. Journal of Renal Nutrition.

[7] Chauvean P, Aparicio MR. Benefits in nutritional interventions in patients with CKD stage 3-4. Journal of Renal Nutrition. 2011;**21**(1):20-22. DOI: 10.1053/j.jrn.2010.11.005

[8] Mitch WE, Remuzzi G. Diets for patients with chronic kidney disease, should we recon-

[9] D'Alessandro C, Piccoli GB, Calella P, et al. "Dietaly": Practical issues for the nutritional management of CKD patients in Italy. BMC Nephrology. 2016;**17**:102-104. DOI: 10.1186/

[10] Aparicio M, Bellizzi V, Chauveau X, et al. Protein-restricted diets plus keto|amino acids – A valid therapeutic approach for chronic kidney disease patients. Journal of Renal

[11] Garneata L. Ketoanalog-supplementted very low protein diet in pre-dialysis chronic kidney disease it really work? The Romanian experience. Journal of Renal Nutrition.

[12] Caria S, Cupisti A, Sau G, et al. The incremental treatment of ESRD: A low-protein diet combined with weekly hemodialysis may be beneficial for selected patients. BMC

sider? BMC Nephrology. 2016;**17**:80-86. DOI: 10.1186/s12882-016-0283-x

Nutrition. 2012;**22**(25):1-21. DOI: 10.1053/j:jrn.2011.09.005

Nephrology. 2014;**15**:172. DOI: 10.1186/1471-2369-15-172

2012;**22**(2):9-10 DOI: 10.1053/j.jrn.2013.01.030

s12882-016-0280-0

2011;**8**(5):1631-1654. DOI: 10.3390/ijerph8051631

234 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

DOI: http://www.ijbm.org/articles/Article3\_3\_CR7.pdf

nih.gov/pmc/articles/PMC4354064/

2012;**22**(2):7-8. DOI: 10.1093/ndt/gfu251

s12882-016-0296-5


Journal of the American Society of Nephrology. 2014;**9**:2095-2103. DOI: 10.2215/CJN. 03790414

**Section 4**

**Genetic Aspects in CKD**


## **Genetic Aspects in CKD**

Journal of the American Society of Nephrology. 2014;**9**:2095-2103. DOI: 10.2215/CJN.

[25] Avesani CM, Kamimura MA, Cupari L. Energy expenditure in chronic kidney disease patients. Journal of Renal Nutrition. 2011;**21**(1):27-30. DOI: 10.1053/j.jrn.2010.10.013

[26] Turner JM, et al. Treatment of chronic kidney disease. Kidney International - International

[27] Karalliedde J, Maltese G, Hill B, et al. Effect of renin-angiotensin system blockade on soluble Klotho in patients with type 2 diabetes, systolic hypertension, and albuminuria. Clinical Journal of the American Society of Nephrology. 2013;**8**(11):1899-1905. DOI:

[28] Adijiang A, Shimizu H, Higuchi Y, et al. Indoxil sulfate reduces klotho expression and promotes senescence in the kidneys of hypertensive rats. Journal of Renal Nutrition.

[29] Milovanova L, Kozevnikova E, Milovanov Y, et al. Influence of essential amino acids ketoanalogs and protein restriction diet on morphogenetic proteins (FGF-23 and Klotho) in CKD patients". Materials of 53rd ERA-EDTA Congress, 21-24 May 2016 Vienna DOI: 10.3252/pso.eu.53era.2016 341\_SP https://www.postersessiononline.eu/173580348\_eu/

[30] McGraw NJ, Krul ES, Grunz-Borgmann E, et al. Soy-based renoprotection. World

Journal of Nephrology. 2016;**5**(3):233-257. DOI: 10.5527/wjn.v5.i3.233

Society of Nephrology. 2012;**81**(4):351-362. DOI:10.1038/ki.2011.380

2011;**21**(1):105-109. DOI: 10.1053/j.jrn.2010.10.020

236 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

congresos/53era/aula/-SP\_341\_53era.pdf

03790414

10.2215/CJN.02700313

**Chapter 11**

**Provisional chapter**

**Discovery of Single Nucleotide Polymorphism in**

**Polycystic Kidney Disease among South Indian** 

**Discovery of Single Nucleotide Polymorphism in** 

DOI: 10.5772/intechopen.71201

The kidneys serve an essential regulatory role in most of the animals, including vertebrates and some invertebrates. They are important in the urinary system and also serve homeostatic functions like regulation of electrolytes, maintenance of acid-base balance and regulation of blood pressure (via maintaining salt and water balance). They also serve as natural filter of the blood and remove wastes that are diverted to the urinary bladder. By producing urine, the kidneys excrete wastes such as urea and ammonia. The kidneys are responsible for reabsorption of water, glucose, amino acids and trace elements. They also produce hormones including calcitriol, renin and erythropoietin. The kidney is approximately 11–14 cm long, 6 cm wide and 4 cm thick. Each adult kidney weighs between 125 and 170 g in males and between 115 and 155 g in females. The left kidney is typically slightly larger than the right kidney. Each kidney is made up of about

**Keywords:** polycystic kidney disease, renal failure, single nucleotide polymorphism,

The kidneys play an essential regulatory role in animals and are responsible for reabsorption of water, glucose, amino acids and trace elements. They also produce hormones including calcitriol, renin and erythropoietin. The kidney is approximately 11–14 cm long, 6 cm wide and 4 cm thick. Each adult kidney weighs between 125 and 170 g in males and between 115 and 155 g in females. The left kidney is typically slightly larger than the right kidney [1] **(Figure 1).** Each kidney is made up of about 1 million microprocessor units called nephrons.

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

**Polycystic Kidney Disease among South Indian**

**(Madurai) Population**

**(Madurai) Population**

http://dx.doi.org/10.5772/intechopen.71201

**Abstract**

**1. Introduction**

Pandiaraj Veeramuthumari and William Isabel

1 million microprocessor units called nephrons.

polymerase chain reaction, disease complications

Pandiaraj Veeramuthumari and William Isabel

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

**Provisional chapter**

## **Discovery of Single Nucleotide Polymorphism in Polycystic Kidney Disease among South Indian (Madurai) Population Polycystic Kidney Disease among South Indian (Madurai) Population**

**Discovery of Single Nucleotide Polymorphism in** 

DOI: 10.5772/intechopen.71201

Pandiaraj Veeramuthumari and William Isabel Pandiaraj Veeramuthumari and William Isabel Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.71201

#### **Abstract**

The kidneys serve an essential regulatory role in most of the animals, including vertebrates and some invertebrates. They are important in the urinary system and also serve homeostatic functions like regulation of electrolytes, maintenance of acid-base balance and regulation of blood pressure (via maintaining salt and water balance). They also serve as natural filter of the blood and remove wastes that are diverted to the urinary bladder. By producing urine, the kidneys excrete wastes such as urea and ammonia. The kidneys are responsible for reabsorption of water, glucose, amino acids and trace elements. They also produce hormones including calcitriol, renin and erythropoietin. The kidney is approximately 11–14 cm long, 6 cm wide and 4 cm thick. Each adult kidney weighs between 125 and 170 g in males and between 115 and 155 g in females. The left kidney is typically slightly larger than the right kidney. Each kidney is made up of about 1 million microprocessor units called nephrons.

**Keywords:** polycystic kidney disease, renal failure, single nucleotide polymorphism, polymerase chain reaction, disease complications

## **1. Introduction**

The kidneys play an essential regulatory role in animals and are responsible for reabsorption of water, glucose, amino acids and trace elements. They also produce hormones including calcitriol, renin and erythropoietin. The kidney is approximately 11–14 cm long, 6 cm wide and 4 cm thick. Each adult kidney weighs between 125 and 170 g in males and between 115 and 155 g in females. The left kidney is typically slightly larger than the right kidney [1] **(Figure 1).** Each kidney is made up of about 1 million microprocessor units called nephrons.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*1.1.2.1. Polycystic kidney disease (PKD)*

*1.1.3. Acquired kidney diseases*

**2. Renal failure**

**2.1. Acute renal failure**

are:

**2.2. Stage 5 chronic kidney diseases**

Epithelial cell polarity is vitally important for correct function of different tubule segments [3]. Cell polarity defects have been linked to a number of hereditary kidney diseases including polycystic kidney diseases (PKDs) characterized by the accumulation of fluid-filled cysts in the cortex and medulla [7–10]. There are two types of PKDs. They are autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) [10].

Discovery of Single Nucleotide Polymorphism in Polycystic Kidney Disease among South Indian…

http://dx.doi.org/10.5772/intechopen.71201

241

These diseases are numerous and are generally known as nephritis (inflammation of the kidney). The most common type of nephritis is glomerulonephritis and has many causes. The acquired kidney diseases are renal agenesis, multicystic dysplastic kidney, renal dysplasia, diabetic nephropathy, glomerulonephritis, hydronephrosis, interstitial nephritis, kidney stones, kidney tumors: Wilms tumor and renal cell carcinoma, lupus nephritis, minimal

In renal failure, the kidneys lose their normal function due to various factors including infections, autoimmune diseases, diabetes and other endocrine disorders, cancer, and toxic chemicals [11]. Genetic variability on the development of renal failure is becoming clearer and emphasizes the need to elucidate the genetic basis for renal diseases and associated complications. Studies on genetic variability in renal failure would lead to better understanding of different phenotypes observed in polycystic kidney disease and would enable us to determine

Acute kidney injury (AKI), previously called acute renal failure (ARF), is a rapid loss of kidney function due to low blood volume from any cause, exposure to substances harmful to the kidney and obstruction of the urinary tract [12, 13]. Elevated blood urea nitrogen and creatinine or inability of the kidneys to produce sufficient amounts of urine is noted in these patients.

Stage 5 CKD is often called **end stage renal disease (ESRD).** The symptoms of Stage 5 CKD

• The patients develop hypertension or congestive heart failure due to fluid overload and production of vasoactive hormones created by the kidney via the RAS (renin-angiotensin system).

change disease (MCD), nephrotic syndrome, pyelonephritis and renal failure.

whether a patient is genetically predisposed to such complications.

• Increase in serum creatinine or protein in the urine are observed.

The nephron is the basic structural and functional unit of a kidney [3]. Each nephron has an initial filtering component composed of a glomerulus and Bowman's capsule, which is connected to a long convoluted tubule lined by transporting epithelia.

Sodium chloride, potassium and glucose are filtered and reabsorbed along with water in the nephron back into the bloodstream. This maintains a correct balance of trace element within the blood, which assists in blood pressure regulation and normal levels of blood sugars. Hence, the kidneys are found to play a crucial role in regulating the amount of water and chemicals (electrolytes) in the body such as sodium, potassium and phosphorus [4].

#### **1.1. Different types of kidney diseases**

Usually both the kidneys are affected by various forms of diseases and then the waste products and excess fluid build up, causing severe swelling and symptoms of uremia (kidney failure). They are congenital kidney disease, hereditary kidney disorders and acquired kidney diseases.

#### *1.1.1. Congenital disease*

It involves malformation of the genitourinary tract, usually leading to some type of obstruction that subsequently produces infection and/or destruction of kidney tissue, which may eventually progress to chronic kidney failure. For example, horseshoe kidney, also known as *ren arcuatus* (in Latin), renal fusion or super kidney, is a congenital disorder affecting about 1 in 500 people [5, 6].

#### *1.1.2. Hereditary disorders*

Hereditary diseases are Alport's syndrome or hereditary nephritis, primary hyperoxaluria, cystinuria and polycystic kidney disease (PKD). The chapter found that polycystic kidney disease is more common among the population.

## *1.1.2.1. Polycystic kidney disease (PKD)*

Epithelial cell polarity is vitally important for correct function of different tubule segments [3]. Cell polarity defects have been linked to a number of hereditary kidney diseases including polycystic kidney diseases (PKDs) characterized by the accumulation of fluid-filled cysts in the cortex and medulla [7–10]. There are two types of PKDs. They are autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) [10].

## *1.1.3. Acquired kidney diseases*

These diseases are numerous and are generally known as nephritis (inflammation of the kidney). The most common type of nephritis is glomerulonephritis and has many causes. The acquired kidney diseases are renal agenesis, multicystic dysplastic kidney, renal dysplasia, diabetic nephropathy, glomerulonephritis, hydronephrosis, interstitial nephritis, kidney stones, kidney tumors: Wilms tumor and renal cell carcinoma, lupus nephritis, minimal change disease (MCD), nephrotic syndrome, pyelonephritis and renal failure.

## **2. Renal failure**

The nephron is the basic structural and functional unit of a kidney [3]. Each nephron has an initial filtering component composed of a glomerulus and Bowman's capsule, which is con-

**Figure 1.** Structure and location of kidney. Source: [2] (http://www.sugarbp.org/kidneystucture\_diabetes.htm).

Sodium chloride, potassium and glucose are filtered and reabsorbed along with water in the nephron back into the bloodstream. This maintains a correct balance of trace element within the blood, which assists in blood pressure regulation and normal levels of blood sugars. Hence, the kidneys are found to play a crucial role in regulating the amount of water and

Usually both the kidneys are affected by various forms of diseases and then the waste products and excess fluid build up, causing severe swelling and symptoms of uremia (kidney failure). They are congenital kidney disease, hereditary kidney disorders and acquired kidney

It involves malformation of the genitourinary tract, usually leading to some type of obstruction that subsequently produces infection and/or destruction of kidney tissue, which may eventually progress to chronic kidney failure. For example, horseshoe kidney, also known as *ren arcuatus* (in Latin), renal fusion or super kidney, is a congenital disorder affecting about

Hereditary diseases are Alport's syndrome or hereditary nephritis, primary hyperoxaluria, cystinuria and polycystic kidney disease (PKD). The chapter found that polycystic kidney

chemicals (electrolytes) in the body such as sodium, potassium and phosphorus [4].

nected to a long convoluted tubule lined by transporting epithelia.

240 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

**1.1. Different types of kidney diseases**

diseases.

*1.1.1. Congenital disease*

1 in 500 people [5, 6].

*1.1.2. Hereditary disorders*

disease is more common among the population.

In renal failure, the kidneys lose their normal function due to various factors including infections, autoimmune diseases, diabetes and other endocrine disorders, cancer, and toxic chemicals [11]. Genetic variability on the development of renal failure is becoming clearer and emphasizes the need to elucidate the genetic basis for renal diseases and associated complications. Studies on genetic variability in renal failure would lead to better understanding of different phenotypes observed in polycystic kidney disease and would enable us to determine whether a patient is genetically predisposed to such complications.

## **2.1. Acute renal failure**

Acute kidney injury (AKI), previously called acute renal failure (ARF), is a rapid loss of kidney function due to low blood volume from any cause, exposure to substances harmful to the kidney and obstruction of the urinary tract [12, 13]. Elevated blood urea nitrogen and creatinine or inability of the kidneys to produce sufficient amounts of urine is noted in these patients.

#### **2.2. Stage 5 chronic kidney diseases**

Stage 5 CKD is often called **end stage renal disease (ESRD).** The symptoms of Stage 5 CKD are:


People with chronic kidney disease (hyperlipidemia) suffer from accelerated atherosclerosis and are likely to develop cardiovascular disease than the general population [16].

## **3. Polycystic kidney disease (PKD)**

There are two forms of **PKD:**


#### **3.1. Autosomal dominant polycystic kidney disease (ADPKD)**

Autosomal dominant polycystic kidney disease occurs worldwide and in all races. ADPKD is one of the most commonly inherited conditions in humans with an incidence of 1:500 to 1:1000 [17, 18]. It is genetically heterogeneous with two genes identified: PKD1 (16p13.3) and PKD2 (4q21) [9, 19, 20].

#### **3.2. Autosomal recessive polycystic kidney disease (ARPKD)**

ARPKD is uncommon and occurs primarily in neonates and children. The gene responsible for ARPKD (*PKHD1*) has recently been identified on chromosome 6. Fibrocystin is defective in ARPKD [21, 22]. The occurrence of ADPKD is most common when compared to ARPKD and the mean age of onset is between 30 and 40 years. Both men and women are equally affected [23]. Hence the present study is also focused on PKD1 and PKD2 gene polymorphism in autosomal dominant polycystic kidney disease subjects and control subjects among South Indian population.

in adults. ADPKD is a genetically heterogeneous condition [39], which is caused by mutations in one of the three genes: PKD1 on chromosome 16 accounts for 85% of cases, whereas PKD2 on chromosome 4 accounts for 15% and mutations in the PKD3 gene are rare [40]. Hence the present study is focused on PKD1 and PKD2 genes in patients with ADPKD among South

**Author and year Gene Population Mutation**

Sumathy [24] PKD1 Indian PKD1 C-T or G-A, SSCP Nair et al. [25] ACE, Nellore, Andhra Pradesh I/D polymorphism Elumalai et al. [26] eNOS, VNTR South Indian a/b polymorphism

Veeramuthumari and Isabel [27]\* PKD1 South Indian (Madurai) Ala/Val (C/T) polymorphism Veeramuthumari et al. [28]\* PKD2 South Indian (Madurai) Arg/Pro (G/C) polymorphism

> C-T substitution, deletion, nonsense mutation, frameshift, missense, splice mutation

http://dx.doi.org/10.5772/intechopen.71201

243

Cyprus Mutation in exon 24, mutation in exon 1

Discovery of Single Nucleotide Polymorphism in Polycystic Kidney Disease among South Indian…

Slovenia Frameshift/missense mutation; nonsense mutation

PKD1 has been mapped to the short arm of the 16th (16p13.3) chromosome, which encodes a protein called polycystin-1. The PKD1 gene is very large in size, consisting of 46 exons distributed over 52 kb of genomic DNA [41]. The gene encodes a 14.1-kb mRNA transcript to be translated into a protein composed of 4302 amino acids transcript with an open reading frame (ORF) of 12,909 bp [42] (**Figure 2**). The PKD2 gene maps to chromosome 4q21–23 (**Figure 3**). The PKD2 gene encodes a protein, polycystin-2, which is composed of 968 amino acids [45]. The interaction of polycystin-1 and polycystin-2 in renal tubules promotes normal

Indian (Madurai) population.

\*

Current study.

Koptides et al. [30] PKD1 &

**3.4. Chromosomal location of PKD1 and PKD2 gene**

**Table 1.** National reports of PKD1 and PKD2 gene polymorphism.

Hateboer et al. [29] PKD2 Spain, Netherlands, UK,

PKD2

PKD1 & PKD2

**Author and Year Gene Population Mutation**

Bulgaria, Australia

Son et al. [31] PKD1 Devis, USA CT transversion (SNP)

Lee et al. [32] PKD1 Taiwan C → A transversion

Galeano et al. [33] PKD1 Belgium SNP

**Table 2.** International reports of PKD1 and PKD2 gene polymorphism.

PKD1 & 2 US Mutation

development and function of the kidneys [46].

**Tables 1** and **2** show polymorphism study in PKD1 and PKD2 gene among various populations on both national and international level.

#### **3.3. Pathogenesis and genetics of polycystic kidney disease (PKD)**

Abnormalities in gene expression, cell polarity, fluid secretion, apoptosis and extracellular matrix have also been described in PKD [17, 34–36]. ADPKD is one of the most common Mendelian disorders in humans [37, 38] and the most frequent genetic cause of renal failure


**Table 1.** National reports of PKD1 and PKD2 gene polymorphism.

• Urea accumulates, leading to azotemia and ultimately uremia. Urea is excreted by sweating and crystallizes on skin ("uremic frost") (http://en.wikipedia.org/wiki/Chronic\_kid-

• Later this progresses to secondary hyperparathyroidism, renal osteodystrophy and vascu-

• Metabolic acidosis, due to accumulation of sulfates, phosphates, uric acid, etc., leads to excitability of cardiac and neuronal membranes by promoting hyperkalemia [15].

People with chronic kidney disease (hyperlipidemia) suffer from accelerated atherosclerosis

Autosomal dominant polycystic kidney disease occurs worldwide and in all races. ADPKD is one of the most commonly inherited conditions in humans with an incidence of 1:500 to 1:1000 [17, 18]. It is genetically heterogeneous with two genes identified: PKD1 (16p13.3) and

ARPKD is uncommon and occurs primarily in neonates and children. The gene responsible for ARPKD (*PKHD1*) has recently been identified on chromosome 6. Fibrocystin is defective in ARPKD [21, 22]. The occurrence of ADPKD is most common when compared to ARPKD and the mean age of onset is between 30 and 40 years. Both men and women are equally affected [23]. Hence the present study is also focused on PKD1 and PKD2 gene polymorphism in autosomal dominant polycystic kidney disease subjects and control subjects among South

**Tables 1** and **2** show polymorphism study in PKD1 and PKD2 gene among various popula-

Abnormalities in gene expression, cell polarity, fluid secretion, apoptosis and extracellular matrix have also been described in PKD [17, 34–36]. ADPKD is one of the most common Mendelian disorders in humans [37, 38] and the most frequent genetic cause of renal failure

and are likely to develop cardiovascular disease than the general population [16].

ney\_disease; "Chronic Kidney Disease". medscape.) [14].

(i) Autosomal dominant polycystic kidney disease (ADPKD) (ii) Autosomal recessive polycystic kidney disease (ARPKD)

**3.1. Autosomal dominant polycystic kidney disease (ADPKD)**

**3.2. Autosomal recessive polycystic kidney disease (ARPKD)**

**3.3. Pathogenesis and genetics of polycystic kidney disease (PKD)**

tions on both national and international level.

lar calcification that further impair cardiac function.

242 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

**3. Polycystic kidney disease (PKD)**

There are two forms of **PKD:**

PKD2 (4q21) [9, 19, 20].

Indian population.


**Table 2.** International reports of PKD1 and PKD2 gene polymorphism.

in adults. ADPKD is a genetically heterogeneous condition [39], which is caused by mutations in one of the three genes: PKD1 on chromosome 16 accounts for 85% of cases, whereas PKD2 on chromosome 4 accounts for 15% and mutations in the PKD3 gene are rare [40]. Hence the present study is focused on PKD1 and PKD2 genes in patients with ADPKD among South Indian (Madurai) population.

#### **3.4. Chromosomal location of PKD1 and PKD2 gene**

PKD1 has been mapped to the short arm of the 16th (16p13.3) chromosome, which encodes a protein called polycystin-1. The PKD1 gene is very large in size, consisting of 46 exons distributed over 52 kb of genomic DNA [41]. The gene encodes a 14.1-kb mRNA transcript to be translated into a protein composed of 4302 amino acids transcript with an open reading frame (ORF) of 12,909 bp [42] (**Figure 2**). The PKD2 gene maps to chromosome 4q21–23 (**Figure 3**). The PKD2 gene encodes a protein, polycystin-2, which is composed of 968 amino acids [45]. The interaction of polycystin-1 and polycystin-2 in renal tubules promotes normal development and function of the kidneys [46].

polycystin-1 is expressed in all nephron segments, with the possible exception of the thin limbs but absent from glomeruli. Several studies have shown that the polycystin-2 channel conducts divalent cations including calcium and that this activity can be stimulated by

Discovery of Single Nucleotide Polymorphism in Polycystic Kidney Disease among South Indian…

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245

The protein encoded by the *PKHD1* gene has been named polyductin or fibrocystin and is composed of 4074 amino acids [22]. Polyductin/fibrocystin is predicted to be a membrane protein consisting of a large extracellular domain, a single transmembrane segment and a short carboxyl-terminal tail. Polyductin is a novel protein, although it has some similarities to

Cysts will form in these patient's kidneys and several studies suggest that the cells that line these cysts will have lost both functional copies of a polycystin gene [50, 51]. Defects in the genes encoding PC1 or PC2 lead to aberrant gene transcription, cell proliferation and ion secretion, which in turn result in the formation of fluid-filled cysts. These cysts lead to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with

Common complications associated with ADPKD are hypertension, hematuria, urinary tract infection, renal calculi, cardiac valve abnormalities, diabetes, hernia of the anterior abdominal wall and cerebral berry aneurysms [29, 53]. Hematuria is the presence of red blood cells (RBCs) in the urine. In microscopic hematuria, the urine appears normal to the naked eye, but examination with a microscope shows a high number of RBCs [54]. Diabetic nephropathy (*neuropatia diabetica*) also known as Kimmelstiel-Wilson syndrome, or nodular diabetic glomerulosclerosis [55] and intercapillary glomerulonephritis, is a progressive kidney disease. Anterior abdominal wall hernias, also known as ventral hernias, are involved in the protrusion of part of the peritoneal sac through a defect in the muscle layers of the anterior abdominal wall [56]. A cerebral or brain aneurysm is a cerebrovascular disorder in which weakness in the wall of a

cerebral artery or vein causes a localized dilation or ballooning of the blood vessel [57].

calcium on the cytosolic side.

other proteins in the database.

**3.5. Mechanism of cyst formation**

reduced functional capacity (**Figure 4**).

**3.6. ADPKD-associated common complications**

**Figure 4.** Cyst formation in nephron, kidney and at cellular level [52].

*3.4.3. Fibrocystin/polyductin*

**Figure 2.** Chromosomal location of PKD1 gene. Source: [43] http://ghr.nlm.nih.gov/gene/PKD1.

**Figure 3.** Chromosomal location of PKD2 gene. Source: [44] http://ghr.nlm.nih.gov/gene/PKD2.

#### *3.4.1. Polycystin-1*

The PKD1 gene codes for polycystin-1 (PC-1) and plays a vital role in cell-cell and cell-matrix interaction [41]. Thus, a defect in polycystin-1 leads to the alteration in the differentiation of epithelial cells and abnormal phenotypic expression of autosomal dominant polycystic kidney disease (ADPKD). The proteins encoded by the PKD1 and PKD2 genes define a new family. The polycystins play an important role in a variety of biological processes including fertilization, ion transduction and mechanosensation. Polycystin-1 is an integral membrane protein, which is predicted to contain an array of distinct protein motifs, including two leucine-rich repeats flanked by cystine-rich domains. Many of these motifs are involved in protein-protein or protein-carbohydrate interaction, which raises the possibility of polycystin-1, as a receptor for a yet unidentified ligand. The carboxyl terminus of polycystin-1 is located in cytoplasm and contains coil-coil domains and mediates the protein-protein interaction as well as several potential sites of phosphorylation. Polycystin-1 is expressed in many tissues, including the kidney, brain, heart, bone and muscles [47]. Foggensteiner et al. [48] have reported that several studies have identified polycystin-1 in the plasma membrane of tubular epithelial cells, in the distal nephron and in the collecting duct. The defect of polycystin-1 might lead to alteration in differentiation of epithelial cells and abnormal phenotypic expression of ADPKD [49].

#### *3.4.2. Polycystin-2*

Polycystin-2 is also widely expressed in many tissues, particularly the kidney, heart, ovary, testis, vascular smooth muscle and small intestine [47]. In the kidney, polycystin-2 like polycystin-1 is expressed in all nephron segments, with the possible exception of the thin limbs but absent from glomeruli. Several studies have shown that the polycystin-2 channel conducts divalent cations including calcium and that this activity can be stimulated by calcium on the cytosolic side.

## *3.4.3. Fibrocystin/polyductin*

**Figure 2.** Chromosomal location of PKD1 gene. Source: [43] http://ghr.nlm.nih.gov/gene/PKD1.

244 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

**Figure 3.** Chromosomal location of PKD2 gene. Source: [44] http://ghr.nlm.nih.gov/gene/PKD2.

The PKD1 gene codes for polycystin-1 (PC-1) and plays a vital role in cell-cell and cell-matrix interaction [41]. Thus, a defect in polycystin-1 leads to the alteration in the differentiation of epithelial cells and abnormal phenotypic expression of autosomal dominant polycystic kidney disease (ADPKD). The proteins encoded by the PKD1 and PKD2 genes define a new family. The polycystins play an important role in a variety of biological processes including fertilization, ion transduction and mechanosensation. Polycystin-1 is an integral membrane protein, which is predicted to contain an array of distinct protein motifs, including two leucine-rich repeats flanked by cystine-rich domains. Many of these motifs are involved in protein-protein or protein-carbohydrate interaction, which raises the possibility of polycystin-1, as a receptor for a yet unidentified ligand. The carboxyl terminus of polycystin-1 is located in cytoplasm and contains coil-coil domains and mediates the protein-protein interaction as well as several potential sites of phosphorylation. Polycystin-1 is expressed in many tissues, including the kidney, brain, heart, bone and muscles [47]. Foggensteiner et al. [48] have reported that several studies have identified polycystin-1 in the plasma membrane of tubular epithelial cells, in the distal nephron and in the collecting duct. The defect of polycystin-1 might lead to alteration in differentiation of epithelial cells and abnormal phenotypic expression of ADPKD [49].

Polycystin-2 is also widely expressed in many tissues, particularly the kidney, heart, ovary, testis, vascular smooth muscle and small intestine [47]. In the kidney, polycystin-2 like

*3.4.1. Polycystin-1*

*3.4.2. Polycystin-2*

The protein encoded by the *PKHD1* gene has been named polyductin or fibrocystin and is composed of 4074 amino acids [22]. Polyductin/fibrocystin is predicted to be a membrane protein consisting of a large extracellular domain, a single transmembrane segment and a short carboxyl-terminal tail. Polyductin is a novel protein, although it has some similarities to other proteins in the database.

### **3.5. Mechanism of cyst formation**

Cysts will form in these patient's kidneys and several studies suggest that the cells that line these cysts will have lost both functional copies of a polycystin gene [50, 51]. Defects in the genes encoding PC1 or PC2 lead to aberrant gene transcription, cell proliferation and ion secretion, which in turn result in the formation of fluid-filled cysts. These cysts lead to the displacement of the normal renal parenchyma and the formation of a cyst-filled kidney with reduced functional capacity (**Figure 4**).

## **3.6. ADPKD-associated common complications**

Common complications associated with ADPKD are hypertension, hematuria, urinary tract infection, renal calculi, cardiac valve abnormalities, diabetes, hernia of the anterior abdominal wall and cerebral berry aneurysms [29, 53]. Hematuria is the presence of red blood cells (RBCs) in the urine. In microscopic hematuria, the urine appears normal to the naked eye, but examination with a microscope shows a high number of RBCs [54]. Diabetic nephropathy (*neuropatia diabetica*) also known as Kimmelstiel-Wilson syndrome, or nodular diabetic glomerulosclerosis [55] and intercapillary glomerulonephritis, is a progressive kidney disease. Anterior abdominal wall hernias, also known as ventral hernias, are involved in the protrusion of part of the peritoneal sac through a defect in the muscle layers of the anterior abdominal wall [56]. A cerebral or brain aneurysm is a cerebrovascular disorder in which weakness in the wall of a cerebral artery or vein causes a localized dilation or ballooning of the blood vessel [57].

**Figure 4.** Cyst formation in nephron, kidney and at cellular level [52].

Clinically, PKD is characterized by progressive formation and enlargement of cysts leading to end-stage renal disease (ESRD) in late middle age. Overall, ADPKD accounts for approximately 5–10% of ESRD [58]. Hypertension occurs in 50–75% of patients prior to renal insufficiency and it is thought to accelerate the decline in renal function [59, 60]. Systemic hypertension is also very common, occurring in more than 75% of patients. Increased blood pressure (BP) has been attributed to activation of the renin-angiotensin system, but a primary defect in blood vessels may also exist [61].

**4. Methodology to be followed for the discovery of single nucleotide** 

Discovery of Single Nucleotide Polymorphism in Polycystic Kidney Disease among South Indian…

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247

**Reagents required:** phosphate buffer saline (PBS), red blood cell (RBC) lysis buffer, cell lysis

**Procedure:** the blood samples were thawed at room temperature and 300 μl of blood was transferred to centrifuge tubes. Equal volume of PBS was added to it and incubated for 20 min and centrifuged at 3000 rpm for 5 min. The supernatant was removed and the pellet was resuspended in 900 μl of RBC lysis buffer and mixed thoroughly. This was centrifuged at 3000 rpm for 5 min and the supernatant was discarded. To the pellet 600 μl of ice-cold cell, lysis buffer was added and mixed well, and then 200 μl of ammonium acetate was added to the mixture to precipitate the proteins and centrifuged at 3000 rpm for 7 min. The supernatant was separated and 1000 μl of isopropanol was added and the tube was inverted till the DNA was precipitated and centrifuged at 7000 rpm for 2 min. The precipitated genomic DNA was washed with 600 μl of 70% ethanol and allowed to air dry. The DNA was resuspended in TE

**Electrophoretic analysis of genomic DNA:** the isolated DNA was confirmed by 0.7% agarose

**Reagents required:** Tris-boric acid EDTA buffer (TBE), gel loading dye, ethidium bromide

**Equipment required:** electrophoresis tank, power pack, voltage (100 V), gel documentation

**Principle:** electrophoresis refers to the separation of macromolecules of different size by application of a constant electric field (100 V) onto the DNA fragments placed in a matrix of polymerized agarose. As the DNA molecule is negatively charged and travels toward the anode, it is loaded at the cathode end. The speed of migration of the fragments has an inverse relation with the size of DNA. The separated fragments are visualized by staining the gels with an intercalating dye (ethidium bromide), which fluoresces under UV light. Acrylamide gels are used for separation of small fragments of DNA (5–500 bp). Agarose gels can resolve DNA fragments varying in size from 200 bp to about 50 kb depending upon the concentration

**Procedure:** electrophoresis tank was filled with the 1× TBE buffer and the gel was immersed into the tank containing the buffer. Agarose gel (0.7%) was prepared with ethidium bromide and the gel was allowed to run for 1 hour at 80–100 V as pulse voltage. 20 μl of DNA sample was loaded with loading dye (bromophenol blue) in the wells. When bromophenol blue dye reached three fourth of the gel length, the power was shut down, and DNA bands were

observed using gel documentation apparatus and photographed.

buffer (CLB), ammonium acetate, isopropyl alcohol, 70% ethanol, TE buffer

**polymorphism in polycystic kidney disease**

**Genomic DNA preparation:** [68, 69].

buffer and stored at −20°C.

gel electrophoresis [68, 69].

apparatus, UV-transilluminator.

of agarose in the gel.

(ETBR).

#### **3.7. Method of diagnosis and screening**

Nowadays, ADPKD is studied by ultrasound, CT or MRI with multiple cysts that are generally visible that increase in size and number with age [62]. ADPKD is typically diagnosed in adults by the detection of bilaterally enlarged polycystic kidneys using transabdominal ultrasound scanning. The diagnosis of ADPKD is established primarily by imaging studies of the kidney [53]. For diagnosis of ADPKD, computer tomography (CT) has been used effectively, which has also revealed multiple cysts in kidneys and left ovary and aneurysm in the brain [53].

## *3.7.1. Treatment*

When renal function, measured by glomerular filtration rate, is persistently poor, dialysis and kidney transplantation could be done. Cotran et al. [63] have stated that a common symptom of kidney stones is a sharp pain in the medial/lateral segments of the lower back. Approximately 50% of afflicted individuals have been shown to develop end-stage renal disease requiring dialysis or kidney transplantation before the age of 60 [8].

#### *3.7.2. Trends in potential therapies and clinical trials*

Until now, therapy for ADPKD has been directed toward limiting its complications. Cardiovascular complications, related to hypertension, are a major cause of morbidity and mortality. A major problem in therapeutic interventions in ADPKD is that this is a very slowly evolving condition, and GFR is well maintained until relatively late in the course of the disease at the age of 40. Better understanding of signaling pathways and cellular changes associated with ADPKD has suggested possible therapies to directly inhibit the development or growth of cysts, some of which are now being tested in clinical trials [64]. A stable somatostatin analogue, octreotide, has been shown to be effective at limiting progression in liver and kidney cystic disease in a rat model of PKD [65].

Advanced-stage ADPKD patients frequently receive a renal transplant without removal of the affected cystic kidneys, without side effects. Rapamycin is often used to prevent transplant rejection. The absence of polycystin permits excessive kinase activity in the mTOR pathway and the development of renal cysts [66]. Patients treated with rapamycin have been reported to show a statistically significant reduction in native polycystic kidney size over a period of 24 months compared with patients treated with other antirejection drugs. Other targets for therapy include triptolide, a compound derived from a traditional Chinese herbal therapy, which blocks glycosyl ceramide synthesis [67].

## **4. Methodology to be followed for the discovery of single nucleotide polymorphism in polycystic kidney disease**

## **Genomic DNA preparation:** [68, 69].

Clinically, PKD is characterized by progressive formation and enlargement of cysts leading to end-stage renal disease (ESRD) in late middle age. Overall, ADPKD accounts for approximately 5–10% of ESRD [58]. Hypertension occurs in 50–75% of patients prior to renal insufficiency and it is thought to accelerate the decline in renal function [59, 60]. Systemic hypertension is also very common, occurring in more than 75% of patients. Increased blood pressure (BP) has been attributed to activation of the renin-angiotensin system, but a primary

Nowadays, ADPKD is studied by ultrasound, CT or MRI with multiple cysts that are generally visible that increase in size and number with age [62]. ADPKD is typically diagnosed in adults by the detection of bilaterally enlarged polycystic kidneys using transabdominal ultrasound scanning. The diagnosis of ADPKD is established primarily by imaging studies of the kidney [53]. For diagnosis of ADPKD, computer tomography (CT) has been used effectively, which has also

When renal function, measured by glomerular filtration rate, is persistently poor, dialysis and kidney transplantation could be done. Cotran et al. [63] have stated that a common symptom of kidney stones is a sharp pain in the medial/lateral segments of the lower back. Approximately 50% of afflicted individuals have been shown to develop end-stage renal dis-

Until now, therapy for ADPKD has been directed toward limiting its complications. Cardiovascular complications, related to hypertension, are a major cause of morbidity and mortality. A major problem in therapeutic interventions in ADPKD is that this is a very slowly evolving condition, and GFR is well maintained until relatively late in the course of the disease at the age of 40. Better understanding of signaling pathways and cellular changes associated with ADPKD has suggested possible therapies to directly inhibit the development or growth of cysts, some of which are now being tested in clinical trials [64]. A stable somatostatin analogue, octreotide, has been shown to be effective at limiting progression in liver and kidney cystic disease in a rat model of PKD [65]. Advanced-stage ADPKD patients frequently receive a renal transplant without removal of the affected cystic kidneys, without side effects. Rapamycin is often used to prevent transplant rejection. The absence of polycystin permits excessive kinase activity in the mTOR pathway and the development of renal cysts [66]. Patients treated with rapamycin have been reported to show a statistically significant reduction in native polycystic kidney size over a period of 24 months compared with patients treated with other antirejection drugs. Other targets for therapy include triptolide, a compound derived from a traditional Chinese herbal therapy,

revealed multiple cysts in kidneys and left ovary and aneurysm in the brain [53].

ease requiring dialysis or kidney transplantation before the age of 60 [8].

*3.7.2. Trends in potential therapies and clinical trials*

which blocks glycosyl ceramide synthesis [67].

defect in blood vessels may also exist [61].

246 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

**3.7. Method of diagnosis and screening**

*3.7.1. Treatment*

**Reagents required:** phosphate buffer saline (PBS), red blood cell (RBC) lysis buffer, cell lysis buffer (CLB), ammonium acetate, isopropyl alcohol, 70% ethanol, TE buffer

**Procedure:** the blood samples were thawed at room temperature and 300 μl of blood was transferred to centrifuge tubes. Equal volume of PBS was added to it and incubated for 20 min and centrifuged at 3000 rpm for 5 min. The supernatant was removed and the pellet was resuspended in 900 μl of RBC lysis buffer and mixed thoroughly. This was centrifuged at 3000 rpm for 5 min and the supernatant was discarded. To the pellet 600 μl of ice-cold cell, lysis buffer was added and mixed well, and then 200 μl of ammonium acetate was added to the mixture to precipitate the proteins and centrifuged at 3000 rpm for 7 min. The supernatant was separated and 1000 μl of isopropanol was added and the tube was inverted till the DNA was precipitated and centrifuged at 7000 rpm for 2 min. The precipitated genomic DNA was washed with 600 μl of 70% ethanol and allowed to air dry. The DNA was resuspended in TE buffer and stored at −20°C.

**Electrophoretic analysis of genomic DNA:** the isolated DNA was confirmed by 0.7% agarose gel electrophoresis [68, 69].

**Reagents required:** Tris-boric acid EDTA buffer (TBE), gel loading dye, ethidium bromide (ETBR).

**Equipment required:** electrophoresis tank, power pack, voltage (100 V), gel documentation apparatus, UV-transilluminator.

**Principle:** electrophoresis refers to the separation of macromolecules of different size by application of a constant electric field (100 V) onto the DNA fragments placed in a matrix of polymerized agarose. As the DNA molecule is negatively charged and travels toward the anode, it is loaded at the cathode end. The speed of migration of the fragments has an inverse relation with the size of DNA. The separated fragments are visualized by staining the gels with an intercalating dye (ethidium bromide), which fluoresces under UV light. Acrylamide gels are used for separation of small fragments of DNA (5–500 bp). Agarose gels can resolve DNA fragments varying in size from 200 bp to about 50 kb depending upon the concentration of agarose in the gel.

**Procedure:** electrophoresis tank was filled with the 1× TBE buffer and the gel was immersed into the tank containing the buffer. Agarose gel (0.7%) was prepared with ethidium bromide and the gel was allowed to run for 1 hour at 80–100 V as pulse voltage. 20 μl of DNA sample was loaded with loading dye (bromophenol blue) in the wells. When bromophenol blue dye reached three fourth of the gel length, the power was shut down, and DNA bands were observed using gel documentation apparatus and photographed.

## **4.1. Genetic analysis**

## *4.1.1. Polymerase chain reaction (PCR) for PKD1 gene (C/T polymorphism)*

Amplification of isolated DNA using the following primers 5′-AGCTGTACGCCCTCACTGG-3′ (forward) and 5′-GTGACAGGTGCCAGGACTC-3′-(reverse). PCR was performed using genomic DNA (50 ng), *Taq* polymerase (1 U), dNTPs (10 mM) and each primers (10 μM) [37, 69, 70].

**PCR condition used:**

at 37o

gel [69–71]).

**Statistical analysis:**

• Pearson Chi-square (χ<sup>2</sup>

product was subjected to RFLP analysis.

*4.1.2.1. Restriction fragment length polymorphism (RFLP)*

C for 2 hours and inactivated by incubation at 65o

Initial denaturation 94°C 5 min Denaturation 94°C 30 s

Extension 72°C 30 s Final extension 72°C 7 min

Annealing 61°C 30 s 35 cycles

sequenced by automated sequencer (Chromous Biotech, Chennai).

**Source:** *E. coli* strain that carries the cloned *BanII* gene from *Bacillus aneurinolyticus*.

**Restriction site for** *BanII***:** 5′ G RGCY↓ C 3′

organisms could be determined by applying simple algebraic expression.

The PCR product (279 bp) is confirmed by 1.8% of agarose gel electrophoresis. The amplified

Discovery of Single Nucleotide Polymorphism in Polycystic Kidney Disease among South Indian…

Amplified product is digested with restriction enzyme *BanII*, incubated the reaction mixture

sequence if "C" was at position 28. The digested segments were confirmed by 1.2% agarose

**Sequencing:** PKD1 gene (C/T) and PKD2 gene (G/C) single nucleotide polymorphism was

**Allelic frequency calculation:** allelic frequency was calculated by using *Hardy-Weinberg Equilibrium*. The phenotype and genotypic frequencies in sexually reproducing, diploid

p + q = 1 (1)

) test was performed to find the statistical significance of genotypes

5′ C↑YCGR G 5′

where p is the frequency of dominant allele and q is the frequency of recessive allele.

and the gene frequency between the control group and ADPKD patients.

• Heterozygosity was calculated for the control subject and PKD patients.

• Odds ratio (OR) was calculated for allelic frequency.

C for 20 min. The enzyme cuts the

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249

## **PCR condition used**:


The PCR product (298 bp) was confirmed by 1.8% of agarose gel electrophoresis. The amplified product was subjected to RFLP analysis.

#### *4.1.1.1. Restriction fragment length polymorphism (RFLP)*

Amplified PCR product is digested with restriction enzyme *AvaII*, incubated the reaction mixture at 37°C for 3 hours and inactivated by incubation at 64°C for 15 min. The enzyme cuts the sequence if "T" was at position 4058. The digested fragments (298, 225 and 73bp) were confirmed by 1.2% agarose gel [37, 69, 70].

#### **Restriction fragment length polymorphism (RFLP)**


#### *4.1.2. Polymerase chain reaction (PCR) for PKD2 gene (G/C polymorphism)*

**A**mplification of PKD2 gene using the following primers 5′-CGCGCCGGACGCCAGTGACC-3′ (forward) and 5′-GCCGGCCGTTCTGGTTCGT-3′ (reverse). PCR was performed using genomic DNA (50ng), *Taq p*olymerase (1U) and dNTPs (10mM) [69, 71].

#### **PCR condition used:**

**4.1. Genetic analysis**

**PCR condition used**:

fied product was subjected to RFLP analysis.

confirmed by 1.2% agarose gel [37, 69, 70].

*4.1.1.1. Restriction fragment length polymorphism (RFLP)*

**Restriction fragment length polymorphism (RFLP)**

**Source:** *E. coli* strain that carries the *AvaII* gene from *Anabaena variabilis*

*4.1.2. Polymerase chain reaction (PCR) for PKD2 gene (G/C polymorphism)*

**Restriction site for** *AvaII* 5′….G↓GWCG ….3′

genomic DNA (50ng), *Taq p*olymerase (1U) and dNTPs (10mM) [69, 71].

[37, 69, 70].

*4.1.1. Polymerase chain reaction (PCR) for PKD1 gene (C/T polymorphism)*

248 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

Initial denaturation 94°C 5 min Denaturation 94°C 30 s

Extension 72°C 30 s Final extension 72°C 7 min

Annealing 61°C 30 s 35 cycles

Amplification of isolated DNA using the following primers 5′-AGCTGTACGCCCTCACTGG-3′ (forward) and 5′-GTGACAGGTGCCAGGACTC-3′-(reverse). PCR was performed using genomic DNA (50 ng), *Taq* polymerase (1 U), dNTPs (10 mM) and each primers (10 μM)

The PCR product (298 bp) was confirmed by 1.8% of agarose gel electrophoresis. The ampli-

Amplified PCR product is digested with restriction enzyme *AvaII*, incubated the reaction mixture at 37°C for 3 hours and inactivated by incubation at 64°C for 15 min. The enzyme cuts the sequence if "T" was at position 4058. The digested fragments (298, 225 and 73bp) were

**A**mplification of PKD2 gene using the following primers 5′-CGCGCCGGACGCCAGTGACC-3′ (forward) and 5′-GCCGGCCGTTCTGGTTCGT-3′ (reverse). PCR was performed using

3′….CCWG↑G….5′


The PCR product (279 bp) is confirmed by 1.8% of agarose gel electrophoresis. The amplified product was subjected to RFLP analysis.

#### *4.1.2.1. Restriction fragment length polymorphism (RFLP)*

Amplified product is digested with restriction enzyme *BanII*, incubated the reaction mixture at 37o C for 2 hours and inactivated by incubation at 65o C for 20 min. The enzyme cuts the sequence if "C" was at position 28. The digested segments were confirmed by 1.2% agarose gel [69–71]).


**Sequencing:** PKD1 gene (C/T) and PKD2 gene (G/C) single nucleotide polymorphism was sequenced by automated sequencer (Chromous Biotech, Chennai).

**Allelic frequency calculation:** allelic frequency was calculated by using *Hardy-Weinberg Equilibrium*. The phenotype and genotypic frequencies in sexually reproducing, diploid organisms could be determined by applying simple algebraic expression.

$$\mathbf{p} \star \mathbf{q} = \mathbf{1} \tag{1}$$

where p is the frequency of dominant allele and q is the frequency of recessive allele.

#### **Statistical analysis:**


## **5. Identifications of single nucleotide and polymorphisms and discussions**

## **5.1. Genetic analysis**

ADPKD is one of the most common genetic diseases in humans, affecting all ethnic groups with a prevalence of 1 in 500 to 1000 individuals [9, 18, 19, 72]. The disease is characterized by the progressive formation and enlargement of fluid-filled cysts in both kidneys due to mutations in PKD1 (85%), PKD2 (15%) and PKD3 (rare) that leads to renal failure [73]. Cyst development involves impairments in a wide range of cellular processes including increased proliferation of the renal epithelial cells, fluid transport defects, alterations in tubular basement membrane, altered cell polarity and increased apoptosis [9, 74].

Genomic DNA was isolated from frozen blood of control and ADPKD patients; it was confirmed by agarose gel electrophoresis (0.7%). After confirming the presence of genomic DNA, most of the prepared gDNA of the 260/280 ratio was found to be 1.8 or 1.9; in a few subjects, the DNA showed 2.0, which might be RNA or protein contamination. To avoid that, RNase, protease was added. Then, it was confirmed and used for PCRanalysis.

## *5.1.1. Analysis of C/T polymorphism in PKD1 gene*

Prepared gDNA when subjected to polymerase chain reaction (PCR), 298bp fragment was obtained. The amplified PCR product was subjected to RFLP analysis using *AvaII* enzyme. When "T" allele was present at position 4058, 225bp and 73bp (homozygous mutant -TT), heterozygous mutant (CT) 298bp, 225bp and 73bp was obtained, and for homozygous normal allele (CC), 298bp fragments were identified **(Figure 5).** The PCR and RLFP products were detected and confirmed by 1.2% agarose gel electrophoresis.

frequent disorder among Caucasian population with an estimated incidence of approximately 1:100. It has been shown to be characterized by genetic heterogeneity and three genes have

**Figure 5.** Confirmation of PKD 1 gene polymorphism using 1.2% agarose gel electrophoresis. T/T: homozygous mutant

Discovery of Single Nucleotide Polymorphism in Polycystic Kidney Disease among South Indian…

http://dx.doi.org/10.5772/intechopen.71201

251

The study found that the identification of DNA variation at nucleotide position at 12173 of PKD1 gene and C or T allele variation in the second position of amino acid codon at 4058 of polycystin-1 observed in 44 Japanese subjects, leading to suggest that these polymorphic alleles would be useful for linkage analysis only in specific ethnic groups [41]. It has been also reported that the PKD2 gene provides instructions for making a protein called polycystin-2, which is found in the kidneys before birth and in many adult tissues. It is also stated that the polycystin could be regulated by a larger and somewhat similar protein called polycystin-1, which is encoded by

Prepared gDNA was subjected to polymerase chain reaction (PCR) and 279bp fragment was amplified. The amplified PCR product is digested with the enzyme *Ban II*. The enzyme acts on the "C" variation but not on the "G" variation. If a "C" allele was present at position 83, 170bp and 109bp were obtained. If it was a homozygous mutant (CC), 170bp and 109bp; heterozygous mutant (GC), 279bp, 170bp and 109bp and homozygous normal (GG), 279bp fragments were identified**.** One such variation was at position 83 of PKD2, which was occupied by either G or C at exon 1. Hence, the amino acid residue was changed from arginine

The study also found that *BSP12861* restriction enzyme *also* acts on the "C" variation. This enzyme was added to 10 ADPKD patients of amplified PKD2 gene product (279bp). The

been implicated in its pathogenesis called PKD1, PKD2 and PKD3 [76, 77].

(225, 73 bp); C/T: heterozygous mutant (298bp, 225bp, 73bp) ; C/C: homozygous normal (298bp).

PKD1 gene [78].

to proline.

*5.2.1. Analysis of G/C polymorphism in PKD2 gene*

## **5.2. Genotype and allelic frequency analysis of PKD1 (C/T) gene**

The study group comprised 300 ADPKD patients and an equal number of age- and sexmatched control group. Among them, the C/C genotype was observed in 131 (43.67%) control group and in 58 (19.33%) ADPKD patients; C/T genotype in 82 (27.33%) control group and in 99 (33%) ADPKD patients; T/T genotype was found in 87 (29%) control group and in 143 (47.67%) ADPKD patients. The allelic frequency was calculated by using *Hardy-Weinberg equation* (*p + q = 1*) and the study group showed the mutant "T" allele frequency (0.642) to be significantly higher in ADPKD patients than in the control group (0.425) and the normal "C" allele frequency was observed to be significantly decreased in ADPKD patients (0.358) than in the control group (0.575). The significant difference (P < 0.05, 9.488, *χ<sup>2</sup>* calculated value = 14.048) (**Table 3**) was noted both in genotype and in allelic frequency between the ADPKD patients and control group among South Indian (Madurai) population by using chi-square (*χ<sup>2</sup>* ) test. This work, which coincides with the work done by Constantinides [70] among Caucasian and Japanese population, also has revealed the association of C/T4058 polymorphism with ADPKD. The PKD1 gene is responsible for causing autosomal dominant polycystic kidney disease and it has been recently cloned and sequenced [75]. ADPKD is reported to be a very Discovery of Single Nucleotide Polymorphism in Polycystic Kidney Disease among South Indian… http://dx.doi.org/10.5772/intechopen.71201 251

**Figure 5.** Confirmation of PKD 1 gene polymorphism using 1.2% agarose gel electrophoresis. T/T: homozygous mutant (225, 73 bp); C/T: heterozygous mutant (298bp, 225bp, 73bp) ; C/C: homozygous normal (298bp).

frequent disorder among Caucasian population with an estimated incidence of approximately 1:100. It has been shown to be characterized by genetic heterogeneity and three genes have been implicated in its pathogenesis called PKD1, PKD2 and PKD3 [76, 77].

The study found that the identification of DNA variation at nucleotide position at 12173 of PKD1 gene and C or T allele variation in the second position of amino acid codon at 4058 of polycystin-1 observed in 44 Japanese subjects, leading to suggest that these polymorphic alleles would be useful for linkage analysis only in specific ethnic groups [41]. It has been also reported that the PKD2 gene provides instructions for making a protein called polycystin-2, which is found in the kidneys before birth and in many adult tissues. It is also stated that the polycystin could be regulated by a larger and somewhat similar protein called polycystin-1, which is encoded by PKD1 gene [78].

## *5.2.1. Analysis of G/C polymorphism in PKD2 gene*

**5. Identifications of single nucleotide and polymorphisms and** 

250 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

ment membrane, altered cell polarity and increased apoptosis [9, 74].

ase was added. Then, it was confirmed and used for PCRanalysis.

detected and confirmed by 1.2% agarose gel electrophoresis.

**5.2. Genotype and allelic frequency analysis of PKD1 (C/T) gene**

control group (0.575). The significant difference (P < 0.05, 9.488, *χ<sup>2</sup>*

*5.1.1. Analysis of C/T polymorphism in PKD1 gene*

ADPKD is one of the most common genetic diseases in humans, affecting all ethnic groups with a prevalence of 1 in 500 to 1000 individuals [9, 18, 19, 72]. The disease is characterized by the progressive formation and enlargement of fluid-filled cysts in both kidneys due to mutations in PKD1 (85%), PKD2 (15%) and PKD3 (rare) that leads to renal failure [73]. Cyst development involves impairments in a wide range of cellular processes including increased proliferation of the renal epithelial cells, fluid transport defects, alterations in tubular base-

Genomic DNA was isolated from frozen blood of control and ADPKD patients; it was confirmed by agarose gel electrophoresis (0.7%). After confirming the presence of genomic DNA, most of the prepared gDNA of the 260/280 ratio was found to be 1.8 or 1.9; in a few subjects, the DNA showed 2.0, which might be RNA or protein contamination. To avoid that, RNase, prote-

Prepared gDNA when subjected to polymerase chain reaction (PCR), 298bp fragment was obtained. The amplified PCR product was subjected to RFLP analysis using *AvaII* enzyme. When "T" allele was present at position 4058, 225bp and 73bp (homozygous mutant -TT), heterozygous mutant (CT) 298bp, 225bp and 73bp was obtained, and for homozygous normal allele (CC), 298bp fragments were identified **(Figure 5).** The PCR and RLFP products were

The study group comprised 300 ADPKD patients and an equal number of age- and sexmatched control group. Among them, the C/C genotype was observed in 131 (43.67%) control group and in 58 (19.33%) ADPKD patients; C/T genotype in 82 (27.33%) control group and in 99 (33%) ADPKD patients; T/T genotype was found in 87 (29%) control group and in 143 (47.67%) ADPKD patients. The allelic frequency was calculated by using *Hardy-Weinberg equation* (*p + q = 1*) and the study group showed the mutant "T" allele frequency (0.642) to be significantly higher in ADPKD patients than in the control group (0.425) and the normal "C" allele frequency was observed to be significantly decreased in ADPKD patients (0.358) than in the

(**Table 3**) was noted both in genotype and in allelic frequency between the ADPKD patients and control group among South Indian (Madurai) population by using chi-square (*χ<sup>2</sup>*

This work, which coincides with the work done by Constantinides [70] among Caucasian and Japanese population, also has revealed the association of C/T4058 polymorphism with ADPKD. The PKD1 gene is responsible for causing autosomal dominant polycystic kidney disease and it has been recently cloned and sequenced [75]. ADPKD is reported to be a very

calculated value = 14.048)

) test.

**discussions**

**5.1. Genetic analysis**

Prepared gDNA was subjected to polymerase chain reaction (PCR) and 279bp fragment was amplified. The amplified PCR product is digested with the enzyme *Ban II*. The enzyme acts on the "C" variation but not on the "G" variation. If a "C" allele was present at position 83, 170bp and 109bp were obtained. If it was a homozygous mutant (CC), 170bp and 109bp; heterozygous mutant (GC), 279bp, 170bp and 109bp and homozygous normal (GG), 279bp fragments were identified**.** One such variation was at position 83 of PKD2, which was occupied by either G or C at exon 1. Hence, the amino acid residue was changed from arginine to proline.

The study also found that *BSP12861* restriction enzyme *also* acts on the "C" variation. This enzyme was added to 10 ADPKD patients of amplified PKD2 gene product (279bp). The results showed to be like *Ban II* restriction digestion gene products. If a "C" allele was present at position 83, 170bp and 109bp were obtained. If it was homozygous mutant (CC), 170bp and 109bp; heterozygous mutant (GC), 279bp, 170bp and 109bp and homozygous normal (GG), 279bp fragments were identified **(Figure 6).** The study was supported by the work of Koptides et al., [30]. Koptides et al. demonstrated that both G/C transversion mutation and six 'Cs" insertion mutation in exon 1 of the PKD2 gene of three separate cysts. This mutation is expected to cause a translation frameshift, leading to the incorporation of 20 novel amino acids before a new stop codon is encountered.

#### **5.3. Genotype and allelic frequency analysis of PKD2 (G/C) gene**

The G/G genotype was observed in 137 (45.67%) control group and in 55 (18.33%) ADPKD patients, G/C genotype in 84 (28%) control group and in 93 (31%) ADPKD patients and C/C genotype in 79 (26.33%) control group and in 152 (50.67%) ADPKD patients. The allelic frequency was calculated by using *Hardy-Weinberg equation* (*p + q* = 1) and the study group showed the mutant "C" allele frequency (0.662) to be significantly higher in ADPKD patients than in the control group (0.403) and the normal "G" allele frequency to be significantly decreased in ADPKD patients (0.338) than in the control group (0.597). Significant difference (P < 0.005, 14.860, *χ<sup>2</sup>* calculated value = 20.451) (**Table 4**) was noted in genotype and allelic frequency between the ADPKD patients. G/C polymorphism at position 83 in exon 1 of PKD2 gene among South Indian (Madurai) population with ADPKD revealed the "CC" and "GC" genotype and the frequency of "C" allele was found to be significantly higher in the ADPKD patients compared to the control group. The study has revealed higher frequency of "C" allele and lower frequency of "G" allele in ADPKD patients. These results coincide with the work of Koptides et al., [30], who identified a polymorphism at position 83, which was occupied by either G or C encoding either arginine or proline (R28P).

**5.4. PKD1 (C/T) and PKD2 (G/C) SNP sequencing**

79 (26.33%) 84 (28%) 137

87 (29%) 82 (27.33%) 131

143 (47.67%) 99 (33%) 58

T/T: homozygous mutant; /T: heterozygous mutant; C/C: homozygous normal.

152 (50.67%) 93 (31%) 55

C/C: homozygous mutant; G/C: heterozygous mutant; G/G–homozygous normal.

**PKD1 (C/T) – Ala/Val. 4058 in Exon 45:**

A. 5′-AAG CTG TAC G**C**C CTC ACT GG-3′—Wild type Allele

B. 5′-CG CGC C**G**G ACG CCA CTG ACC-3′—Wild type Allele

5′-CG CGC C**C**G ACG CCA CTG ACC-3′—Mutant Allele

5′-AAG CTG TAC G**T**C CTC ACT GG-3′—Mutant Allele

Control group **N** = **300**

Control group **N** = **300**

ADPKD patients **N** = **300**

ADPKD patients **N** = **300**

Ala

Val

Arg

Pro

South Indian (Madurai) population.

South Indian (Madurai) population.

**PKD2 (G/C) – Arg/Pro.28 in Exon 1**

sequencing the PCR amplified gene products of PKD1 and PKD2.

The PKD1 (C/T) and PKD2 (G/C) single nucleotide polymorphism was also confirmed by

Underlined sequence denotes change in allele leads to new amino acid formation, which is known to be polymorphism.

**Table 4.** Comparison of genotype and allelic frequency of PKD2 gene in control group and ADPKD patients among

**Genotype Allele frequency** *χ***<sup>2</sup>**

**Genotype Allele frequency** *χ***<sup>2</sup>**

Discovery of Single Nucleotide Polymorphism in Polycystic Kidney Disease among South Indian…

(43.67%)

(19.33%)

**Table 3.** Comparison of genotype and allelic frequency of PKD1 gene in control group and ADPKD patients among

**T/T C/T C/C T C**

**C/C G/C G/G C G**

(45.67%)

(18.33%)

 **value** *p* **value**

 **value** *p* **value**

253

http://dx.doi.org/10.5772/intechopen.71201

0.403 0.662 20.79 *P* < 0.005, 14.860

0.425 0.575 14.16 P < 0.05 9.488

0.642 0.358 13.93

0.597 0.338 20.10

**Figure 6.** Confirmation of PKD 2 gene polymorphism using 1.2% agarose gel electrophoresis. C/C: homozygous mutant (170 bp, 109 bp); G/C: heterozygous mutant (279 bp, 170, 109); G/G: homozygous normal (279 bp); Lane 1: ladder (100 bp).


**Table 3.** Comparison of genotype and allelic frequency of PKD1 gene in control group and ADPKD patients among South Indian (Madurai) population.


**Table 4.** Comparison of genotype and allelic frequency of PKD2 gene in control group and ADPKD patients among South Indian (Madurai) population.

#### **5.4. PKD1 (C/T) and PKD2 (G/C) SNP sequencing**

The PKD1 (C/T) and PKD2 (G/C) single nucleotide polymorphism was also confirmed by sequencing the PCR amplified gene products of PKD1 and PKD2.

### **PKD1 (C/T) – Ala/Val. 4058 in Exon 45:**

Ala A. 5′-AAG CTG TAC G**C**C CTC ACT GG-3′—Wild type Allele Val 5′-AAG CTG TAC G**T**C CTC ACT GG-3′—Mutant Allele

#### **PKD2 (G/C) – Arg/Pro.28 in Exon 1**

Arg

results showed to be like *Ban II* restriction digestion gene products. If a "C" allele was present at position 83, 170bp and 109bp were obtained. If it was homozygous mutant (CC), 170bp and 109bp; heterozygous mutant (GC), 279bp, 170bp and 109bp and homozygous normal (GG), 279bp fragments were identified **(Figure 6).** The study was supported by the work of Koptides et al., [30]. Koptides et al. demonstrated that both G/C transversion mutation and six 'Cs" insertion mutation in exon 1 of the PKD2 gene of three separate cysts. This mutation is expected to cause a translation frameshift, leading to the incorporation of 20 novel amino

The G/G genotype was observed in 137 (45.67%) control group and in 55 (18.33%) ADPKD patients, G/C genotype in 84 (28%) control group and in 93 (31%) ADPKD patients and C/C genotype in 79 (26.33%) control group and in 152 (50.67%) ADPKD patients. The allelic frequency was calculated by using *Hardy-Weinberg equation* (*p + q* = 1) and the study group showed the mutant "C" allele frequency (0.662) to be significantly higher in ADPKD patients than in the control group (0.403) and the normal "G" allele frequency to be significantly decreased in ADPKD patients (0.338) than in the control group (0.597). Significant difference

frequency between the ADPKD patients. G/C polymorphism at position 83 in exon 1 of PKD2 gene among South Indian (Madurai) population with ADPKD revealed the "CC" and "GC" genotype and the frequency of "C" allele was found to be significantly higher in the ADPKD patients compared to the control group. The study has revealed higher frequency of "C" allele and lower frequency of "G" allele in ADPKD patients. These results coincide with the work of Koptides et al., [30], who identified a polymorphism at position 83, which was occupied by

**Figure 6.** Confirmation of PKD 2 gene polymorphism using 1.2% agarose gel electrophoresis. C/C: homozygous mutant (170 bp, 109 bp); G/C: heterozygous mutant (279 bp, 170, 109); G/G: homozygous normal (279 bp); Lane 1: ladder (100 bp).

calculated value = 20.451) (**Table 4**) was noted in genotype and allelic

acids before a new stop codon is encountered.

252 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

(P < 0.005, 14.860, *χ<sup>2</sup>*

**5.3. Genotype and allelic frequency analysis of PKD2 (G/C) gene**

either G or C encoding either arginine or proline (R28P).

B. 5′-CG CGC C**G**G ACG CCA CTG ACC-3′—Wild type Allele

Pro

5′-CG CGC C**C**G ACG CCA CTG ACC-3′—Mutant Allele

Underlined sequence denotes change in allele leads to new amino acid formation, which is known to be polymorphism.

The study coincides with the work of Constantinides et al. [70], Watnick et al. [79] and Koptides et al., [30] in Caucasians, Greek-Cypriot populations. The present study reveals that these mutation/polymorphism leads to evolution of new alleles and formation of new amino acids among South Indian population.

[6] Oktem H, Gozil R, Calguner E, et al. Morphometric study of a horseshoe kidney. Medical

Discovery of Single Nucleotide Polymorphism in Polycystic Kidney Disease among South Indian…

http://dx.doi.org/10.5772/intechopen.71201

255

[7] Grantham JJ. Polycystic kidney disease: From the bedside to the gene and back. Current

[8] Harris PC, Torres VE. Autosomal dominant polycystic kidney disease. GeneReviews.

[9] Igarashi P, Somlo S. Genetics and pathogenesis of polycystic kidney disease. Journal of

[10] Khonsari RH, Ohazama A, Raouf R, Kawasaki M, Kawasaki K, Porntaveetus T, Ghafoor S, Hammond P, Suttie M, Odri GA, Sandford RN, Wood JN, Sharpe PT. Multiple postnatal craniofacial anomalies are characterized by conditional loss ofpolycystic kidney disease 2

[11] Liao M-T, Sung C-C, Hung K-C, C-C W, Lo L, K-C L. Insulin resistance in patients with

[12] Longo D, Fauci A, Kasper D, Hauser S, Jameson J, Loscalzo J. Harrison's Principles of

[13] Webb S, Dobb G. ARF, ATN or AKI? It's now acute kidney injury. Anaesthesia and

[14] Available from: http://en.wikipedia.org/wiki/Chronic\_kidney\_disease; "Chronic Kidney

[15] Bacchetta J, Sea JL, Chun RF, Lisse TS. FGF23 inhibits extra-renal synthesis of 1,25-dihydroxyvitamin D in human monocytes. Journal of Bone and Mineral Research. 2012;

[16] Chauhan V, Vaid M. Dyslipidemia in chronic kidney disease: Managing a high-risk com-

[17] Grantham JJ, Calvet PJ. Polycystein-2, the protein mutated in autosomal dominant polycystic kidney disease (ADPKD), is a Ca2+–Permeable nonselective cation chennel. Proceedings of the National Academy of Sciences of the United States of America. 2001;

[18] Persu A, Stoenoiu T, Messiaen S. Modifier effect of ENOS in autosomal dominant poly-

[19] Hoefele J, Mayer K, Scholz M, Klein HG. Novel PKD1 and PKD2 mutations in autosomal dominant polycystic kidney disease (ADPKD). Nephrology, Dialysis, Transplantation.

[20] Ravind D, Walker R, Gibson R, Forrest S, Richerd R, Friend K, Sheffied L, Kincaid-Smith A, Danks D. Phenotype and genotypes heterogenicity in autosomal dominant polycystic

cystic kidney disease. Human Molecular Genetics. 2002;**11**:229-241

chronic kidney disease. Journal of Biomedicine & Biotechnology. 2012:1-5

Principles and Practice. 2008;**17**(1):80-83

2006;**4**:326-329

Opinion in Nephrology and Hypertension. 2003;**10**:533-542

the American Society of Nephrology. 2002;**13**:2384-2398

(Pkd2). Human Molecular Genetics. 2013;**22**:1873-1885

Internal Medicine. 18th ed. McGraw-Hill Professional; 2011

bination. Postgraduate Medicine. 2009;**121**(6):54-61

kidney disease. Lancet. 1992;**340**:1330-1333

Intensive Care. 2007;**35**(6):843-844

Disease". Medscape

**28**(1):46-55

**98**(3):790-792

2011;**26**:2181-2188

## **6. Conclusion**

Polymorphic DNA markers could be used for presymptomatic and prenatal diagnosis of ADPKD. Breuning et al. [80] and Balcells and Criach [81] recommended that prenatal diagnosis of PKD by chorionic villi sampling and linkage phase of the DNA markers has been established by haplotyping the index family. This testing offers the chance of performing prenatal or preimplantation testing in families with severe cases of the disease. Hence the current study suggests that genetic testing is very important in determining the severity and progression of the disease and could possibly be treated with effective drug and delay the end-stage renal disease (ESRD). Further research of this study is on DNA based on drug design using bioinformatics databases that might help the physicians in providing better treatment for polycystic kidney disease patients.

## **Author details**

Pandiaraj Veeramuthumari1 \* and William Isabel2

\*Address all correspondence to: muthusdream@gmail.com

1 Department of Zoology, V.V. Vanniaperumal College for Women, Virudhunagar, Tamil Nadu, India

2 Lady Doak College (affiliated by Madurai Kamaraj University), Madurai, India

## **References**


[6] Oktem H, Gozil R, Calguner E, et al. Morphometric study of a horseshoe kidney. Medical Principles and Practice. 2008;**17**(1):80-83

The study coincides with the work of Constantinides et al. [70], Watnick et al. [79] and Koptides et al., [30] in Caucasians, Greek-Cypriot populations. The present study reveals that these mutation/polymorphism leads to evolution of new alleles and formation of new amino

Polymorphic DNA markers could be used for presymptomatic and prenatal diagnosis of ADPKD. Breuning et al. [80] and Balcells and Criach [81] recommended that prenatal diagnosis of PKD by chorionic villi sampling and linkage phase of the DNA markers has been established by haplotyping the index family. This testing offers the chance of performing prenatal or preimplantation testing in families with severe cases of the disease. Hence the current study suggests that genetic testing is very important in determining the severity and progression of the disease and could possibly be treated with effective drug and delay the end-stage renal disease (ESRD). Further research of this study is on DNA based on drug design using bioinformatics databases that might help the physicians in providing better treatment for

\* and William Isabel2

1 Department of Zoology, V.V. Vanniaperumal College for Women, Virudhunagar,

2 Lady Doak College (affiliated by Madurai Kamaraj University), Madurai, India

[2] Available from: http://www.sugarbp.org/kidneystucture\_diabetes.htm

A case report of a rare entity. Grand Rounds. 2010;**10**:46-50

[1] Glodny B, Unterholzner V, Taferner B. Normal kidney size and its influencing factors–A 64-slice MDCT study of 1.040 asymptomatic patients. BMC Urology. 2009;**9**:13-19

[3] Kriz W, Kaissing B. Structural and Functional Organization of the Kidney. Academic

[4] Jameson JL, Loscalzo J. Harrison's Nephrology and Acid-Base Disorders. 17th ed. McGraw-

[5] de Hoog JP, Murray S, Chou W. Horseshoe kidney and primary renal carcinoid tumour:

\*Address all correspondence to: muthusdream@gmail.com

acids among South Indian population.

254 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

polycystic kidney disease patients.

**6. Conclusion**

**Author details**

Tamil Nadu, India

**References**

Pandiaraj Veeramuthumari1

Press; 2008. p. 479-564

Hill Professional; 2010. p. 3


[21] Onuchic LF, Furu L, Nagasawa Y. PKHD1, the polycystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple immunoglobulin-like plexintranscription-factor domains and parallel beta-helix 1 repeats. American Journal of Human Genetics. 2002;**70**:1305-1317

[33] Galeano CH, Cortes AC, Fernansez A, Soler A, Franco-Herrera N, Makunde G, Vanderleyden J, Blair MW. Gene-based single nucleotide polymorphism markers for genetic and associa-

Discovery of Single Nucleotide Polymorphism in Polycystic Kidney Disease among South Indian…

http://dx.doi.org/10.5772/intechopen.71201

257

[34] Grantham JJ, Cook LT, Torres VE, Bost JE, Chapman AB, Harris PC, Guay-Woodford LM, Bae KT, Grantham J, Cook L, Wetzel L, et al. Evidence of extraordinary growth in the progressive enlargement of renal cysts. Clinical Journal of the American Society of Nephrology.

[35] Murcia NS, Richards WG, Yoder BK, Mucenski ML, Dunlap JR, Woychik RP. The Oak Ridge Polycystic Kidney (orpk) disease gene is required for left-right axis determination.

[36] Wilson PD. Epithelial cell polarity and disease. The American Journal of Physiology.

[37] Pei Y, Wang K, Kasenda M, Paterson AD, Chan G, Liang Y, Roscoe J, Brissenden J, Hefferton D, Parfrey P, Somlo S, George Hyslop P. A spectrum of mutation in polycystic kidney disease-2 (PKD2) genes from eight Canadian kindred. Journal of the American

[38] Tazon-Vega Mireia V. Study of candidate genes affecting the progression of renal disease in autosomal dominant polycystic kidney disease type 1. Nephrology, Dialysis,

[39] Torra R, Viribay M, Tellaria D, Badenas C, Watson M, Harris P, Darnell A, San Millan JL. Seven novel mutations of the PKD2 gene families with autosomal dominant polycyctic

[40] Koptides M, Hadjimichael C, Koupepidou P, Pierides A, Constantinou Deltas C. Germinal and somatic mutations in the PKD2 gene of renal cysts in abnormal dominant polycystic

[41] Hughes J, Ward CJ, Peral B, Aspinwall R, Clark K, San MJ, Gamble V, Harris PC. The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell rec-

[42] Bogdanova N, Markoff A, Gerke V, McCluskey M, Horst J, Dworniczak B. Homologues to the first gene for autosomal dominant polycystic kidney disease are pseudogenes.

[45] Torres VE, Harris PC. Autosomal dominant polycystic kidney disease: The last 3 years.

[46] Charron A, Nakamura S, Bacallao R, Wandinger-Ness A. Compermised cytoarchitecture and polarised trafficking in autosomal dominant polycystic kidney disease cells. The

tion mapping in common bean. BMC Genetics. 2012;**13**(48):1-11

2010;**5**(5):889-896

1997;**272**:434-442

Development. 1999;**127**:2347-2355

Society of Nephrology. 1998;**9**:1853-1860

kidney disease. Kidney International. 1999;**56**:28-33

ognition domains. Nature Genetics. 1995;**10**:151-160

[43] Avialable from: http://ghr.nlm.nih.gov/gene/PKD1 [44] Available from: http://ghr.nlm.nih.gov/gene/PKD2

Kidney International. 2009;**76**:149-168

Journal of Cell Biology. 2000;**149**:111-124

kidney disease. Human Molecular Genetics. 1999;**8**(3):509-513

Transplantation. 2007;**22**:1567-1577

Genomics. 2002;**74**:333-341


[33] Galeano CH, Cortes AC, Fernansez A, Soler A, Franco-Herrera N, Makunde G, Vanderleyden J, Blair MW. Gene-based single nucleotide polymorphism markers for genetic and association mapping in common bean. BMC Genetics. 2012;**13**(48):1-11

[21] Onuchic LF, Furu L, Nagasawa Y. PKHD1, the polycystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple immunoglobulin-like plexintranscription-factor domains and parallel beta-helix 1 repeats. American Journal of

[22] Ward C, Hogan M, Rossetti S, Walker D, Sneddon T, Wang X, Kubly V, Cunningham J, Bacallao R, Ishibashi M, Milliner D, Torres V, Harris P. The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein. Nature Genetics.

[23] Ahmad S, Choi R, Roberts Q, Simpson B, Wallace J. Polycystic kidney disease: The cyst-

[24] Sumathy VJH.Pathogenetic and molecular study of human polycystic kidney population. International Journal of Engineering and Innovative Technology (IJEIT). 2013;**3**(3):20-27

[25] Nair S, Kolla PK, Desai M, Mohan PR, Ramalingam K, Aruna R. Angiotensin-converting enzyme gene polymorphism in autosomal dominant polycystic kidney disease. NJCA.

[26] Elumalai R, Periasamy S, Ramanathan G, Lakkakula BVKS. Role of endothelial nitric oxide synthase VNTR (intron 4 a/b) polymorphism on the progression of renal disease in autosomal dominant polycystic kidney disease. Journal of Renal Injury Prevention.

[27] Veeramuthumari P, Isabel W. Identification of C/T genetic marker in autosomal dominant polycystic kidney disease among South Indian population (Madurai). International

[28] Veeramuthumari P, Srividhya K, Isabel W. Evaluation of PKD2 gene (G/C) polymorphism in patients with autosomal dominant polycystic kidney disease among South

[29] Hateboer N, Veldhusen B, Peters D, Breuning MH, Dijk MA, Afzal AR, Jeffery S, Saggar AK, Torra R, Dimitrakov D, Matinez I, Sanz S, Krawczak M, Ravine D. Location of mutations within the PKD2 gene influences clinical outcome. Kidney International. 2000;**57**:

[30] Koptides M, Mean R, Demetriou K, Pierides A, Deltas CC. Genetic evidence for a transheterozygous model for cystogenesis in autosomal dominant polycystic kidney disease.

[31] Son D, Kojima I, Inagi R, Matsumoto M, Fujita T, Nangaku M. Chronic hypoxia aggravates injury via suppression of Cu/Zn-SOD: A proteomic analysis. American Journal of

[32] Lee Y-J, Chen H-Y, Wong M-L, Hsu W-L, C-M O, Wong M-L. Diagnosis of feline polycystic kidney disease by a combination of ultrasonographic examination and PKD1 gene

Indians (Madurai). Journal of Drug Discovery and Therapeutics. 2013;**1**(5):37-41

Journal of Pharma and Bio Sciences. 2013;**2**(6):628-639

Human Molecular Genetics. 2000;**9**:447-452

Physiology. Renal Physiology. 2008;**294**:F62-F72

analysis. Veterinary Record. 2010;**167**:614-617

ematic destruction of renal function. Eukaryon Editor's Corner. 2009. p. 5

Human Genetics. 2002;**70**:1305-1317

256 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

2002;**30**:259-269

2014;**3**(2):57-63

2014;**3**(3):69-73

1444-1451


[47] Geng L, Segal Pavlova A, Barros EJ, Lohing C, Lu W, Nigam SK, Frischauf AM, Reeders ST, Zhou J. Distribution and developmentally regulated expression of murine polycystine. The American Journal of Physiology. 1997;**272**:451-459

[62] Grantham JJ, Chapman AB, Torres VE. Volume progression in autosomal dominant polycystic kidney disease: The major factor determining clinical outcomes. Clinical

Discovery of Single Nucleotide Polymorphism in Polycystic Kidney Disease among South Indian…

http://dx.doi.org/10.5772/intechopen.71201

259

[63] Cotran RS, Vinay K, Nelson F, Stanley L, Abbas K. Robbins and Cotran Pathologic Basis

[64] Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, Perrone RD, Krasa HB, Ouyang J, Czerwiec FS, For the TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. The New

[65] Masyuk TV, Masyuk AI, Torre VE, et al. Octreotide inhibits hepatic cystogenesis in a rodent model of polycystic liver disease by reducing cholangiocyte adenosine 3′,5′-cyclic

[66] Shillingford JM, Murcia NS, Larson CH, Low SH, Hedgepeth R, Brown N, Flask CA, Novick AC, Goldfarb DA, Kramer-Zucker A, Walz G, Piontek KB, Germino GG, Weimbs T. The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proceedings of the National Academy of Sciences.

[67] Natoli TA, Smith LA, Rogers KA, Wang B, Komarnitsky B, Budman Y, Belenky A, Bukanov NO, Dackowski WR, Husson H. Inhibition of glucosylceramide accumulation results in effective blockade of polycystic kidney disease in mouse models. Nature

[68] Sambrooke J, Russel DW. Molecular Cloning, A Laboratory Manual. 3rd ed. New York:

[69] Veeramuthumari P, Isabel W, Kannan K. A study on the level of T3, T4, TSH and the association of A/G polymorphism with CTLA-4 gene in Graves' hyperthyroidism among South Indian population. Indian Journal of Clinical Biochemistry. 2011;**26**(1):66-69

[70] Constantinides R, Xenophontos S, Neophytou P, Nomura S, Pierides A, Constantinou C. New amino acid polymorphism, Ala/Val4058, in exon 45 of the polycystic kidney disease

[71] Reynolds D, Hayashi T, Cai YQ, Veldhuisen B, Watnick T, Lens X, Mochizuki T, Qian F, Maeda Y, Li L, Fossdal R, Coto E, GQ W, Breuning M, Germino G, Peters D, Somlo S.Aberrant splicing in the PKD2 gene as a cause of polycystic kidney disease. Journal of the American

[72] Hogan MC, Masyuk TV, Page LJ, Kubly VJ, Bergstralh EJ, Li X, Kim B, King BF, Glockner J, Holmes DR III, Rossetti S, Harris PC, Nicholas F, La Russo NF, Torres VE. Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and

liver disease. Journal of the American Society of Nephrology. 2010;**21**:1052-1061

Cold Spring Horbor Laboratory Press, Cold Spring Horbor; 2001

1 gene: Evolution of alleles. Human Genetics. 1997;**99**:644-647

Society of Nephrology. 1999;**10**:2342-2351

Journal of the American Society of Nephrology. 2006;**1**:148-157

of Disease. 2005;**72**(1):16, 187-190

2006;**103**:5466-5471

Medicine. 2010;**16**:788-792

England Journal of Medicine. 2012;**367**:2407-2418

monophosphate. Gastroenterology. 2007;**132**:1104-1116


[62] Grantham JJ, Chapman AB, Torres VE. Volume progression in autosomal dominant polycystic kidney disease: The major factor determining clinical outcomes. Clinical Journal of the American Society of Nephrology. 2006;**1**:148-157

[47] Geng L, Segal Pavlova A, Barros EJ, Lohing C, Lu W, Nigam SK, Frischauf AM, Reeders ST, Zhou J. Distribution and developmentally regulated expression of murine polycystine. The

[48] Foggensteiner L, Beven AP, Thomos R, Coleman R, Boulter C, Bradely J, Klinger K, Sandford R. Cellular and subcellular distribution of polycystin-2, the protein product of

[49] Boletta A, Quian F, Onuchic LF, Cortese M, Courtoy PJ, Soria MR, Devuyst O, Monaco L. Biochemical characterization of bonafied polycystine-1 in vitro and in vivo. American

[50] Brasier J, Henske EP. Loss of the polycystic kidney disease (PKD1) region of chromosome 16p13 in renal cyst cells supports a loss of function model for cyst pathogenesis.

[51] Qian F, Watnick TJ, Onuchic LF, Germino GG. The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I. Cell. 1996;**87**:979-987 [52] Chapin HC, Caplan MJ. The cell biology of polycystic kidney disease. JCB. 2010;**191**(4):

[53] Harris PC, Bae KT, Rossetti S. Cyst number but not the rate of cystic growth is associated with the mutated gene in autosomal dominant polycystic kidney disease. Journal of the

[54] Hebert DN, Nadasd T, Nadasdy G, Agarwal G, Mauer M, Agarwal AK, Khabiri H, Nagaraja HN. Proposed pathogenesis of idiopathic loin pain-hematuria syndrome.

[55] Gross JL, de Azevedo MJ, Silveiro SP, Canani LH, Caramori LM, Zelmanovitz T. Diabetic nephropathy: Diagnosis, prevention, and treatment. Diabetes Care. 2005;**28**(1):164-176 [56] Hannah CC, Caplan MJ. The cell biology of polycystic kidney disease. The Journal of

[57] Brisman JL, Song JK, Newell DW. Cerebral aneurysms. The New England Journal of

[58] Fick GM, Johnson AM, Strain JD, Kimberling WJ, Kumar S, Manco-Johnson ML, Duley IT, Gabow PA. Characteristics of very early onset autosomal dominant polycystic kidney dis-

[59] Luft FC. Hypertensive nephrosclerosis—A cause of end-stage renal disease? Nephrology,

[60] Tylicki L, Rutkowski B. Hypertensive nephropathy: Pathogenesis, diagnosis and treat-

[61] Torres VE, Cai Y, Chen X, GQ W, Geng L, Cleghorn KA, Johnson CM, Somlo S. Vascular expression of polycystin-2. Journal of the American Society of Nephrology. 2001;**12**:1-9

ease. Journal of the American Society of Nephrology. 1994;**3**:1863-1870

ment. Polski Merkuriusz Lekarsk (in Polish). 2003;**14**(80):168-173

Dialysis, Transplantation. 2000;**15**(10):1515-1517

American Journal of Physiology. 1997;**272**:451-459

258 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

Journal of Kidney Diseases. 2002;**38**:1421-1429

701-710

The Journal of Clinical Investigation. 1997;**99**:194-199

American Society of Nephrology. 2006;**11**:3013-3019

Cell Biology. 2010;**191**:701-710

Medicine. 2006;**355**(9):928-939

American Journal of Kidney Diseases. 2006;**47**(3):419-427

PKD gene. American Society of Nephrology. 2009;**11**:814-827


[73] Brown BJ, Bihoreau MT, Sigrid BK, Iulia T, Obermiller N, Podich D, Suzanna NB, Pamela J, Kaisaki MN, Danoy P, Richard R, Jhon CB, Witzgall R, Lathrep M, Getz N, Dominique. Missense mutation in sterile α motif of novel protein Sam cystin is associated with polycystic kidney in (cyl +) rat. American Society of Nephrology. 2005;**16**:3517-3526

**Section 5**

**Clinical Management in CKD**


**Section 5**

**Clinical Management in CKD**

[73] Brown BJ, Bihoreau MT, Sigrid BK, Iulia T, Obermiller N, Podich D, Suzanna NB, Pamela J, Kaisaki MN, Danoy P, Richard R, Jhon CB, Witzgall R, Lathrep M, Getz N, Dominique. Missense mutation in sterile α motif of novel protein Sam cystin is associated with poly-

cystic kidney in (cyl +) rat. American Society of Nephrology. 2005;**16**:3517-3526

disease. Annual Review of Medicine. 2009;**60**:321-337

260 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

Medicine. 1993;**319**:913-918

720-727

1990;**27**:603-613

cystic kidney disease. BMC Medical Genetics. 2014;**15**(41):1-12

inant polycystic kidney disease. Nature Genetics. 1993;**5**:359-362

Journal of Human Genetics. 1999;**65**:1561-1571

disease. Nefrología. 2011;**31**(1):35-43

[74] Harris PC, Torres VE. Genetics disease online reviews at gene-test polycystic kidney

[75] Obeidova L, Elisakova V, Stekrova J, Reiterova J, Merta M, Tesar V, Losan F, Kohoutova M. Novel mutations of PKD genes in the Czech population with autosomal dominant poly-

[76] Kimberling WJ, Fain PR, Kenyon JB, Goldgar D, Sujansky E, Gabow PA. Linkage heterogeneity of autosomal dominant polycystic kidney disease. The New England Journal of

[77] Peters DJM, Spruit L, Saris JJ, Ravine D, Sandkuijl LA, Fossdal R, Boersma J, van Eijk R, Norby S, Constantinou-Deltas CD, Pierides A, Brissenden JE, Frants RR, van Ommen GJB and Breuning MH. Chromosome 4 localization of a second gene forautosomal dom-

[78] Chang M-Y, Chen HM, Jenq CC, Lee SY, Chen YM, Tian YC, Chen YC, Hung CC, Fang JT, Yang CW, Wu-Chou YH. Novel PKD1 and PKD2 mutations in Taiwanese patients with autosomal dominant polycystic kidney disease. Journal of Human Genetics. 2013;**58**:

[79] Watnick T, Phakdeekitcharoen B, Johnson A, Gandolph MA, Wang M, Briefel G, Klinger KW, Kimberling W, Gabow P, Germino GG. Mutation detection of PKD1 identifies a novel mutation common to three families with aneurysms and/or very-early-onset disease. American

[80] Breuning MH, Snijdewin FG, Brunner H, Verwest A, Ijdo JW, Saris JJ, Dauwerse JG, Blonden L, Keith T, Callen DF. Map of 16 polymorphic loci on the short arm of chromosome 16 close to the polycystic kidney disease gene (PKD1). Journal of Medical Genetics.

[81] Balcells RT, Criach EA. Molecular diagnosis of autosomal dominant polycystic kidney

**Chapter 12**

**Provisional chapter**

**Fluid Overload in Peritoneal Dialysis**

**Fluid Overload in Peritoneal Dialysis**

Jorge Andrade-Sierra, Luis Miguel Roman-Pintos

DOI: 10.5772/intechopen.69324

The prevalence of end-stage renal disease (ESRD) has increased globally to 10% due to diabetes mellitus, hypertension, and stroke. When chronic kidney disease (CKD) maintenance therapy fails, patients require renal replacement therapy (RRT) to survive, such as peritoneal dialysis (PD), hemodialysis, and renal transplantation. The most common therapy in Mexico is PD because it is a feasible, low-cost, and easy-to-perform procedure; however, fluid overload is a frequent condition in patients with this RRT modality. The usual adverse comorbidities in patients with PD are cardiovascular diseases (CVD) associated to atherosclerosis, uremia, inflammation, and oxidative stress. Fluid overload is intimately associated to hypertension, left ventricular hypertrophy, heart failure, and worsening of kidney failure, leading to increased hospital admissions, higher cardiovascular mortality, and reduced life expectancy. Two main pathologies are involved in the deterioration of both heart and kidney functions, namely, cardiorenal syndrome and uremic cardiomyopathy. Along with these phenomena, patients in PD with rapid peritoneal transport have reduced ultrafiltration, increased glucose absorption, and albumin loss in the dialysate, which lead to overhydration, hypertension, dyslipidemia, and malnutrition. This review focuses on the clinical, physiological, and biochemical mechanisms

Leonardo Pazarin-Villaseñor,

Leonardo Pazarin-Villaseñor,

Luis Miguel Roman-Pintos and

Jorge Andrade-Sierra,

**Abstract**

Francisco Gerardo Yanowsky-Escatell,

Francisco Gerardo Yanowsky-Escatell,

and Alejandra Guillermina Miranda-Diaz

Alejandra Guillermina Miranda-Diaz

http://dx.doi.org/10.5772/intechopen.69324

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

involved in fluid overload of patients with CKD undergoing PD.

syndrome, uremic cardiomyopathy, ultrafiltration failure

**Keywords:** end-stage renal disease, peritoneal dialysis, fluid overload, cardiorenal

## **Fluid Overload in Peritoneal Dialysis Fluid Overload in Peritoneal Dialysis**

DOI: 10.5772/intechopen.69324

Leonardo Pazarin-Villaseñor, Francisco Gerardo Yanowsky-Escatell, Jorge Andrade-Sierra, Luis Miguel Roman-Pintos and Alejandra Guillermina Miranda-Diaz Leonardo Pazarin-Villaseñor, Francisco Gerardo Yanowsky-Escatell, Jorge Andrade-Sierra, Luis Miguel Roman-Pintos and Alejandra Guillermina Miranda-Diaz

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.69324

#### **Abstract**

The prevalence of end-stage renal disease (ESRD) has increased globally to 10% due to diabetes mellitus, hypertension, and stroke. When chronic kidney disease (CKD) maintenance therapy fails, patients require renal replacement therapy (RRT) to survive, such as peritoneal dialysis (PD), hemodialysis, and renal transplantation. The most common therapy in Mexico is PD because it is a feasible, low-cost, and easy-to-perform procedure; however, fluid overload is a frequent condition in patients with this RRT modality. The usual adverse comorbidities in patients with PD are cardiovascular diseases (CVD) associated to atherosclerosis, uremia, inflammation, and oxidative stress. Fluid overload is intimately associated to hypertension, left ventricular hypertrophy, heart failure, and worsening of kidney failure, leading to increased hospital admissions, higher cardiovascular mortality, and reduced life expectancy. Two main pathologies are involved in the deterioration of both heart and kidney functions, namely, cardiorenal syndrome and uremic cardiomyopathy. Along with these phenomena, patients in PD with rapid peritoneal transport have reduced ultrafiltration, increased glucose absorption, and albumin loss in the dialysate, which lead to overhydration, hypertension, dyslipidemia, and malnutrition. This review focuses on the clinical, physiological, and biochemical mechanisms involved in fluid overload of patients with CKD undergoing PD.

**Keywords:** end-stage renal disease, peritoneal dialysis, fluid overload, cardiorenal syndrome, uremic cardiomyopathy, ultrafiltration failure

and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons © 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

## **1. Introduction**

## **1.1. Chronic kidney disease**

The prevalence of chronic degenerative diseases has recently increased due to aging of the society and advances in medical technology [1]. In Mexico, there is a significant increase in the prevalence and incidence of non-transmittable diseases, such as diabetes mellitus (DM), hypertension, and stroke, which raises the prevalence of end-stage renal disease (ESRD) up to 10% globally [2–5].

reason for why in Latin America is gaining popularity. Chile is the more prevalent country with PD as the first-line RRT, and Mexico has the second place in Latin America and eighth place around the world [3, 27]. Hemodialysis is mainly available in social security and private institutions; however, HD is more expensive for governmental institutions, and hence it is not an open resource for all patients with ESDR [28]. Renal transplant is the RRT associated with better long-term survival rates and is considered the best RRT for ESDR patients; immunosuppressive drugs have reduced mortality and improved the viability of the graft [29]. The highest proportion of renal transplantation in the world is in Jalisco, Mexico, according to the USRDS [22]. However, the waiting lists for a RT are increasing exponentially, in spite of the fact that in

Fluid Overload in Peritoneal Dialysis http://dx.doi.org/10.5772/intechopen.69324 265

Unfortunately, RRT generate high costs and are limited to treating certain populations with social security, leaving the so-called disadvantaged populations in abandonment, generating a high rate of morbidity and mortality in younger populations. In 2005, the Mexican Institute of Social Security (IMSS) reported that treating ESDR represented 21% of the total expendi-

HD increase chronic inflammation by different mechanisms. A continuous contact with artificial filter dialysis membranes that induce complement activation, cytokines, and nitric oxide production characterizes HD. There also may be exposure to dialysate contaminants, which cross the dialysis membranes with monocyte stimulation and activation. Another deleterious process contributing inflammation in HD is local or systemic infections through contamination of vascular accesses, such as endovascular catheters, synthetic grafts, and arteriovenous fistulas. Fluid overload also occurs in HD due to extracellular fluid expansion and ventricular

ESDR is among the leading causes of death worldwide; morbidity and mortality in this group of patients are mainly due to CVD [31]. CVD in patients with PD is associated to traditional risk factors, such as atherosclerosis, DM, and hypertension, in addition to uremia, inflammation, and oxidative stress [12]. Cardiorenal syndrome (CRS) is a manifestation of CVD in patients with ESRD and is manifested by acute and chronic conditions where the primary dysfunction may be renal or cardiac. Among the five categories of CRS, type 4 is characterized by pre-existing CKD that leads to ESRD with progressive worsening of cardiac function [32]. Fluid overload is one of the main characteristics of patients with late CKD. The abnormal state of fluid in the disease correlates with hypertension, left ventricular hypertrophy (LVH), and other adverse cardiovascular sequels [33]. There is evidence that fluid overload is associated with significant increased risk of mortality from all cardiovascular causes in dialysis patients [34], which makes strict volume control imperative to improve the survival of patients undergoing dialysis [35]. A previous study showed the positive relationship between fluid overload with an increased risk of initiating dialysis and decrease in rapid renal function in late CKD, which means that fluid overload is not a feature in CKD, but also a prognostic marker of rapid progression of late CKD [36]. Adverse progression of kidney disease in patients with DM is associated with changes for fluid, thus contributing to fluid overload [37]. There appears

ture of its main program, with only 0.7% of the beneficiaries' investment [22].

Mexico the donation of live donors is privileged [5].

growth, which enhances CVD risk [30].

**1.3. Peritoneal dialysis and cardiovascular mortality**

Chronic kidney disease (CKD) is defined as a severe, irreversible kidney damage, measured by the level of proteinuria and reduced glomerular filtration rate that prevents the kidneys from functioning properly and removing toxins and waste products from the blood [6, 7]. Among the many traditional risk factors for CKD, DM is the leading cause of kidney dysfunction in the developed world. CKD induce vascular damage and therefore a raise in cardiovascular mortality; it is considered an independent risk factor for cardiovascular events, even from the early stages of the disease [8–13].

When CKD maintenance therapy fails, patients will require renal replacement therapy (RRT) to survive; among the alternatives of RRT, there is peritoneal dialysis (PD), hemodialysis (HD), and renal transplantation (TR) [14, 15]. The most common cause of ESRD in the world is type 2 DM (38%) according to the study of Kidney Early Evaluation Program (KEEP) [16–18]. The second most common cause is hypertension, and the combination of DM and hypertension raises the prevalence up to 42% [3, 19]. However, ESRD of unknown origin is one of the most prevalent diagnoses due to a lack of prompt recognition of the disease, and is unclear whether hypertension is a cause or consequence of CKD [20]. Furthermore, a study including 3564 healthy subjects reported a prevalence of deteriorated creatinine clearance <60 mL/min of 37% [21].

The United States Renal Data System (USRDS), in 2013, reported that Mexico, USA, and Portugal had a rate of 63, 58, and 54 patients per million of habitants (ppmh), respectively. The overall prevalence of CKD in adults varies between 6% and 69% [22]. The Registry of Dialysis and Transplant in Jalisco and Morelos has reported an increase of patients who require a RRT in the last decade [23, 24]. In 2013, Mendez et al. reported an incidence of 421 per million and a prevalence of 1653 per million of habitants, which places Mexico in the second country with more ESRD incident cases and the sixth most prevalent [25].

Health systems are taking emergency measures to control the burden of the disease due to the health impact, elevated costs, overall risk of developing CKD, and its consequences. Thanks to the National Kidney Foundation (NKF) that produces clinical practice guidelines through the NKF Kidney Disease Outcomes Quality Initiative (NKF K/DOQI), in 2002, it has been possible to establish an early diagnosis, risk stratification, and well-defined action plans to mitigate the progression of the disease and its cardiovascular complications [26].

## **1.2. Chronic kidney disease and renal replacement therapy**

In Mexico, PD is the most frequent RRT implemented, followed by HD, which has increased rapidly over the last years [5]. The PD is a feasible, low-cost, and easy-to-perform procedure, reason for why in Latin America is gaining popularity. Chile is the more prevalent country with PD as the first-line RRT, and Mexico has the second place in Latin America and eighth place around the world [3, 27]. Hemodialysis is mainly available in social security and private institutions; however, HD is more expensive for governmental institutions, and hence it is not an open resource for all patients with ESDR [28]. Renal transplant is the RRT associated with better long-term survival rates and is considered the best RRT for ESDR patients; immunosuppressive drugs have reduced mortality and improved the viability of the graft [29]. The highest proportion of renal transplantation in the world is in Jalisco, Mexico, according to the USRDS [22]. However, the waiting lists for a RT are increasing exponentially, in spite of the fact that in Mexico the donation of live donors is privileged [5].

Unfortunately, RRT generate high costs and are limited to treating certain populations with social security, leaving the so-called disadvantaged populations in abandonment, generating a high rate of morbidity and mortality in younger populations. In 2005, the Mexican Institute of Social Security (IMSS) reported that treating ESDR represented 21% of the total expenditure of its main program, with only 0.7% of the beneficiaries' investment [22].

HD increase chronic inflammation by different mechanisms. A continuous contact with artificial filter dialysis membranes that induce complement activation, cytokines, and nitric oxide production characterizes HD. There also may be exposure to dialysate contaminants, which cross the dialysis membranes with monocyte stimulation and activation. Another deleterious process contributing inflammation in HD is local or systemic infections through contamination of vascular accesses, such as endovascular catheters, synthetic grafts, and arteriovenous fistulas. Fluid overload also occurs in HD due to extracellular fluid expansion and ventricular growth, which enhances CVD risk [30].

## **1.3. Peritoneal dialysis and cardiovascular mortality**

**1. Introduction**

**1.1. Chronic kidney disease**

264 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

from the early stages of the disease [8–13].

The prevalence of chronic degenerative diseases has recently increased due to aging of the society and advances in medical technology [1]. In Mexico, there is a significant increase in the prevalence and incidence of non-transmittable diseases, such as diabetes mellitus (DM), hypertension, and stroke, which raises the prevalence of end-stage renal disease (ESRD) up to 10% globally [2–5].

Chronic kidney disease (CKD) is defined as a severe, irreversible kidney damage, measured by the level of proteinuria and reduced glomerular filtration rate that prevents the kidneys from functioning properly and removing toxins and waste products from the blood [6, 7]. Among the many traditional risk factors for CKD, DM is the leading cause of kidney dysfunction in the developed world. CKD induce vascular damage and therefore a raise in cardiovascular mortality; it is considered an independent risk factor for cardiovascular events, even

When CKD maintenance therapy fails, patients will require renal replacement therapy (RRT) to survive; among the alternatives of RRT, there is peritoneal dialysis (PD), hemodialysis (HD), and renal transplantation (TR) [14, 15]. The most common cause of ESRD in the world is type 2 DM (38%) according to the study of Kidney Early Evaluation Program (KEEP) [16–18]. The second most common cause is hypertension, and the combination of DM and hypertension raises the prevalence up to 42% [3, 19]. However, ESRD of unknown origin is one of the most prevalent diagnoses due to a lack of prompt recognition of the disease, and is unclear whether hypertension is a cause or consequence of CKD [20]. Furthermore, a study including 3564 healthy subjects

The United States Renal Data System (USRDS), in 2013, reported that Mexico, USA, and Portugal had a rate of 63, 58, and 54 patients per million of habitants (ppmh), respectively. The overall prevalence of CKD in adults varies between 6% and 69% [22]. The Registry of Dialysis and Transplant in Jalisco and Morelos has reported an increase of patients who require a RRT in the last decade [23, 24]. In 2013, Mendez et al. reported an incidence of 421 per million and a prevalence of 1653 per million of habitants, which places Mexico in the second country with

Health systems are taking emergency measures to control the burden of the disease due to the health impact, elevated costs, overall risk of developing CKD, and its consequences. Thanks to the National Kidney Foundation (NKF) that produces clinical practice guidelines through the NKF Kidney Disease Outcomes Quality Initiative (NKF K/DOQI), in 2002, it has been possible to establish an early diagnosis, risk stratification, and well-defined action plans to

In Mexico, PD is the most frequent RRT implemented, followed by HD, which has increased rapidly over the last years [5]. The PD is a feasible, low-cost, and easy-to-perform procedure,

reported a prevalence of deteriorated creatinine clearance <60 mL/min of 37% [21].

mitigate the progression of the disease and its cardiovascular complications [26].

more ESRD incident cases and the sixth most prevalent [25].

**1.2. Chronic kidney disease and renal replacement therapy**

ESDR is among the leading causes of death worldwide; morbidity and mortality in this group of patients are mainly due to CVD [31]. CVD in patients with PD is associated to traditional risk factors, such as atherosclerosis, DM, and hypertension, in addition to uremia, inflammation, and oxidative stress [12]. Cardiorenal syndrome (CRS) is a manifestation of CVD in patients with ESRD and is manifested by acute and chronic conditions where the primary dysfunction may be renal or cardiac. Among the five categories of CRS, type 4 is characterized by pre-existing CKD that leads to ESRD with progressive worsening of cardiac function [32].

Fluid overload is one of the main characteristics of patients with late CKD. The abnormal state of fluid in the disease correlates with hypertension, left ventricular hypertrophy (LVH), and other adverse cardiovascular sequels [33]. There is evidence that fluid overload is associated with significant increased risk of mortality from all cardiovascular causes in dialysis patients [34], which makes strict volume control imperative to improve the survival of patients undergoing dialysis [35]. A previous study showed the positive relationship between fluid overload with an increased risk of initiating dialysis and decrease in rapid renal function in late CKD, which means that fluid overload is not a feature in CKD, but also a prognostic marker of rapid progression of late CKD [36]. Adverse progression of kidney disease in patients with DM is associated with changes for fluid, thus contributing to fluid overload [37]. There appears to be a complex interaction between DM, fluid overload, and progression of kidney disease [38]. Dialysis procedure by itself plays an important role in the pathogenesis of accelerated atherosclerosis in patients with ESRD [39] (**Figure 1**).of fluid retention in patients undergoing peritoneal dialysis are shown

An acute cardiac disease that leads to acute kidney injury (AKI) [33] or worsening of a chronic kidney failure characterizes acute cardiorenal syndrome or *CRS type 1*. It is also a consequence of low cardiac output due to acute coronary syndrome. When renal function worsens, it is possible to predict significantly higher rates of hospitalization and mortality from acute heart failure [44]. In *CRS type 2*, a chronic heart failure leads to CKD due to a hemodynamic imbalance. It is often manifested as a chronic renal dysfunction associated to chronic heart failure [45]. An episode of AKI that leads to acute heart failure characterizes *CRS type 3*. Retention of uremic solutes and/or volume overload may contribute to cardiac injury. According to experimental data, it is suggested that cardiac dysfunction may be related to activation of the immune system, release of inflammatory mediators, oxidative stress, and cellular apoptosis [46]. Other proposed mechanisms include electrolyte and fluid imbalance, metabolic acidosis, and uremia [47].

Fluid Overload in Peritoneal Dialysis http://dx.doi.org/10.5772/intechopen.69324 267

Chronic cardiorenal syndrome or *CRS type 4* is defined as a primary CKD that induces heart failure, ventricular hypertrophy, diastolic dysfunction, and/or greater risk of major cardiovascular events. Clinically, it is very difficult to distinguish between *CRS types 2* and *4*, since the first insult is not often recognized [39]. The prototype of *CRS type 4* is polycystic renal disease, an autosomal dominant genetic disease that leaves no doubt of the primary event. Increased fluid retention

*CRS type 5* comprises simultaneous heart and kidney dysfunction due to a systemic disease. Given the broad spectrum of diseases that contribute to this syndrome, there are several pathophysiological mechanisms consequence of the systemic disease: an overwhelming insult leads to the simultaneous development of AKI and acute cardiac dysfunction [50]. Sepsis and drug-induced toxicity are the most common causes leading to *CRS type 5*. It may develop in a patient with previously impaired organ function or when there is no discernible evidence of prior abnormality. The sequence of organ involvement may vary depending upon the acuity and nature of the underlying disorder. Other known systemic diseases that lead to *CRS type 5* are autoimmune disorders, such as lupus, Wegener's granulomatosis, and sarcoidosis. It is difficult to identify the underlying pathophysiological mechanisms in order to develop a diagnostic and therapeutic intervention strategy; thus, to identify the underlying mechanism, it is essential to consider the temporal events that initially lead to this syndrome. *CRS type 5* has the following phases: hyperacute (0–72 h after the diagnosis), acute (3–7 days after), subacute (7–30 days), and chronic (>30 days). Most of the evidence of hyperacute stage comes from clinical trials of sepsis, and patients with cirrhosis support the research from chronic stage. A precipitating event usually contributes to the development of *CRS type 5* in a chronic patient, for example, a spontaneous bacterial peritonitis in a patient with cirrhosis. Therefore, we may find superimposition of acute *CRS type 5* on an indolent chronic process with imme-

characterizes *CRS type 4*, found in approximately 70–80% of patients with ESRD [48, 49].

diate relevance for intensive care physicians, nephrologists, and cardiologists [51].

Almost 75% of the patients with ESRD have a cardiovascular pathology [31]. Kidney failure worsens the short- and long-term prognosis due to several comorbid cardiovascular conditions. Acute myocardial infarction survival is lower as the deterioration of renal function increases, and the chance for survival is even worst in patients with ESRD and congestive heart failure [52]. CKD patients have 10–20 times higher risk for cardiovascular mortality than healthy subjects; even small reductions in kidney function can induce a significant increase

#### *1.3.1. Cardiorenal syndrome*

There is a close relationship between cardiac and renal functions. It is bidirectional and has physical, chemical, and biological implications. Primary disorders of one of these two organs often result in secondary dysfunction or injury to the other [40]. Over the last decade, cardiovascular mortality in patients with CKD has remained strikingly elevated. CKD is a recognized risk factor for the development of CVD [41] and increases 10- to 20-fold the risk of cardiac death compared to non-CKD subjects, after adjusting for age and gender [42]. A glomerular filtration rate (GFR) below 60 mL/min/1.73 m<sup>2</sup> is associated with cardiovascular risk; therefore, patients with CKD should be thoroughly evaluated in the search for cardiovascular risk factors that may require aggressive management [43].

Cardiorenal syndrome is a pathophysiological disturbance of the interaction between the heart and the kidneys caused by acute or chronic dysfunction in one of the two organs, capable of inducing acute or chronic dysfunction in the other organ. In 2008, Ronco et al. proposed five subtypes according to the temporal sequence of organ failure and the clinical context [31]:

**Figure 1.** Fluid overload. The mechanisms of fluid retention in patients undergoing peritoneal dialysis are shown schematically.

An acute cardiac disease that leads to acute kidney injury (AKI) [33] or worsening of a chronic kidney failure characterizes acute cardiorenal syndrome or *CRS type 1*. It is also a consequence of low cardiac output due to acute coronary syndrome. When renal function worsens, it is possible to predict significantly higher rates of hospitalization and mortality from acute heart failure [44].

to be a complex interaction between DM, fluid overload, and progression of kidney disease [38]. Dialysis procedure by itself plays an important role in the pathogenesis of accelerated atherosclerosis in patients with ESRD [39] (**Figure 1**).of fluid retention in patients undergoing

There is a close relationship between cardiac and renal functions. It is bidirectional and has physical, chemical, and biological implications. Primary disorders of one of these two organs often result in secondary dysfunction or injury to the other [40]. Over the last decade, cardiovascular mortality in patients with CKD has remained strikingly elevated. CKD is a recognized risk factor for the development of CVD [41] and increases 10- to 20-fold the risk of cardiac death compared to non-CKD subjects, after adjusting for age and gender [42]. A glo-

therefore, patients with CKD should be thoroughly evaluated in the search for cardiovascular

Cardiorenal syndrome is a pathophysiological disturbance of the interaction between the heart and the kidneys caused by acute or chronic dysfunction in one of the two organs, capable of inducing acute or chronic dysfunction in the other organ. In 2008, Ronco et al. proposed five subtypes according to the temporal sequence of organ failure and the clinical context [31]:

**Figure 1.** Fluid overload. The mechanisms of fluid retention in patients undergoing peritoneal dialysis are shown

is associated with cardiovascular risk;

peritoneal dialysis are shown

merular filtration rate (GFR) below 60 mL/min/1.73 m<sup>2</sup>

266 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

risk factors that may require aggressive management [43].

*1.3.1. Cardiorenal syndrome*

schematically.

In *CRS type 2*, a chronic heart failure leads to CKD due to a hemodynamic imbalance. It is often manifested as a chronic renal dysfunction associated to chronic heart failure [45]. An episode of AKI that leads to acute heart failure characterizes *CRS type 3*. Retention of uremic solutes and/or volume overload may contribute to cardiac injury. According to experimental data, it is suggested that cardiac dysfunction may be related to activation of the immune system, release of inflammatory mediators, oxidative stress, and cellular apoptosis [46]. Other proposed mechanisms include electrolyte and fluid imbalance, metabolic acidosis, and uremia [47].

Chronic cardiorenal syndrome or *CRS type 4* is defined as a primary CKD that induces heart failure, ventricular hypertrophy, diastolic dysfunction, and/or greater risk of major cardiovascular events. Clinically, it is very difficult to distinguish between *CRS types 2* and *4*, since the first insult is not often recognized [39]. The prototype of *CRS type 4* is polycystic renal disease, an autosomal dominant genetic disease that leaves no doubt of the primary event. Increased fluid retention characterizes *CRS type 4*, found in approximately 70–80% of patients with ESRD [48, 49].

*CRS type 5* comprises simultaneous heart and kidney dysfunction due to a systemic disease. Given the broad spectrum of diseases that contribute to this syndrome, there are several pathophysiological mechanisms consequence of the systemic disease: an overwhelming insult leads to the simultaneous development of AKI and acute cardiac dysfunction [50]. Sepsis and drug-induced toxicity are the most common causes leading to *CRS type 5*. It may develop in a patient with previously impaired organ function or when there is no discernible evidence of prior abnormality. The sequence of organ involvement may vary depending upon the acuity and nature of the underlying disorder. Other known systemic diseases that lead to *CRS type 5* are autoimmune disorders, such as lupus, Wegener's granulomatosis, and sarcoidosis. It is difficult to identify the underlying pathophysiological mechanisms in order to develop a diagnostic and therapeutic intervention strategy; thus, to identify the underlying mechanism, it is essential to consider the temporal events that initially lead to this syndrome. *CRS type 5* has the following phases: hyperacute (0–72 h after the diagnosis), acute (3–7 days after), subacute (7–30 days), and chronic (>30 days). Most of the evidence of hyperacute stage comes from clinical trials of sepsis, and patients with cirrhosis support the research from chronic stage. A precipitating event usually contributes to the development of *CRS type 5* in a chronic patient, for example, a spontaneous bacterial peritonitis in a patient with cirrhosis. Therefore, we may find superimposition of acute *CRS type 5* on an indolent chronic process with immediate relevance for intensive care physicians, nephrologists, and cardiologists [51].

Almost 75% of the patients with ESRD have a cardiovascular pathology [31]. Kidney failure worsens the short- and long-term prognosis due to several comorbid cardiovascular conditions. Acute myocardial infarction survival is lower as the deterioration of renal function increases, and the chance for survival is even worst in patients with ESRD and congestive heart failure [52]. CKD patients have 10–20 times higher risk for cardiovascular mortality than healthy subjects; even small reductions in kidney function can induce a significant increase of cardiovascular risk: patients with stage 1–3 of CKD have 25–100 times higher risk of CVD, and stage 5 has a similar kidney and heart morbidity and mortality [31]. Almost half of the patients with ESRD in PD have cardiac arrhythmias (especially atrial fibrillation) [53]. Other risk factors for cardiovascular mortality in PD users are cardiac valvulopathies, water retention, hypertension, DM, vascular calcifications, altered oxidative status, bone mineral disorders, and uremic cardiomyopathy [54].

pericardial effusion, or pulmonary arterial hypertension [65] makes it useful to predict the damage extent of ESRD patients with recent RRT [66, 67]. Diastolic dysfunction and LVH have been described in three out of four patients, and systolic dysfunction in half of the patients who undergo initial PD. It is also very common to find aortic and mitral valve alterations, almost in one third of these patients. These findings have repercussion in the prognosis of

Fluid Overload in Peritoneal Dialysis http://dx.doi.org/10.5772/intechopen.69324 269

There are several useful biomarkers already evaluated in patients with CKD: troponin (TnT), plasminogen activator inhibitor type 1 (PAI-1), homocysteine, brain natriuretic peptide (BNP), C-reactive protein (CRP), serum amyloid-A protein, ischemia-modified albumin, and advanced glycation products (AGEs) have been shown to correlate with adverse cardiovascular (CV)

Troponin T (TnT) and BNP have a good predictive value in this population [69, 70]. They were both elevated in patients with hypervolemia and were able to identify asymptomatic patients with CKD who have 2–5 times increased CV risk. BNP is also a useful marker in patients with left ventricular dysfunction and cardiovascular congestion. Increased levels of TnT represent a strong independent predictor of overall cardiovascular mortality in asymptomatic patients with HD [31]. Renal biomarkers, such as cystatin C (CysC) and neutrophil gelatinase-associated lipcalin (NGAL), have recently been studied as prognostic and diagnostic markers of cardiovascular outcomes in CKD patients [71]. There are increased levels of CysC in atherosclerotic processes and LVH; it has association with the latter, independently of renal function. Researchers found increased levels of NGAL expression in the atherosclerotic plaque of

A useful tool for the management of patients in PD is the peritoneal equilibration test (PET). This method has proved to be effective in assessing peritoneal function. In this test, the saturation curves of the solutes in the peritoneum with respect to the plasma are evaluated; thus, it is possible to classify the peritoneal functioning in an easy and reproducible way [73, 74]. PET has been shown to have a prognostic value in patients undergoing PD [75] and allows patients to be classified according to the ratio of solute concentrations in dialysate and plasma (D/P ratio) 4 h after the test. Creatinine, urea, electrolytes, phosphate, and proteins are the commonly tested solutes, and it classifies patients in different types of transporters: (a) high or fast, (b) average high, (c) low average, and (d) low. PET allows the clinician to determine the best dialysis modality for each individual who will undergo continuous ambulatory PD

Patients with high peritoneal solute transport rates often have inadequate transport of the peritoneal fluid. It is not known whether inadequate transport of fluids is solely due to a rapid drop in osmotic pressure or if the reduction in the efficiency of liquid transport is also a contributing factor. The difference in fluid transport between the abovementioned groups is apparently due to variances in the rate of disappearance of the total osmotic pressure of the dialysate, resulting from the transport velocity of glucose and other small solutes [77]. Although glucose gradient is the main factor influencing the rate of ultrafiltration, other solutes,

patients with ESDR who start a PD program [68].

patients with heart failure due to coronary heart disease [31, 72].

or automated DP (continuous cyclic DP or intermittent nocturnal DP) [76].

events in patients with CKD [31].

**1.5. Peritoneal transport**

## *1.3.2. Uremic cardiomyopathy*

Uremic cardiomyopathy (UC) is a suitable example for *CRS type 4*, as it is characterized by cardiac dysfunction leading to fluid overload and hypertension, accentuated by the presence of high levels of myocardial urea [55, 56]. UC is found at early stages of CKD and leads to structural and functional cardiovascular damage as the kidney dysfunction progresses [57, 58]. UC can predict CVD mortality at the beginning of PD [30]. The main feature is LVH, considered as a primary manifestation of UC, but it also induces left ventricular dilation and both systolic and diastolic cardiac dysfunctions [28].

The first-line treatment for UC is conventional HD, since it leads to a reduction in LVH. HD can also reverse systolic dysfunction by improving the left ventricular ejection fraction. The earlier HD is initiated in patients with PD and fluid retention, the more damage to the myocardium induced by UC can be avoided [59]. Angiotensin-converting enzyme inhibitors decrease LVH even in normotensive subjects. Likewise, RT confers remodeling to the myocardium affected by UC in patients with ESRD undergoing PD during short or medium time lapses, although some data are contradictory because of the dyslipidemia, hypertension, and DM associated to immunosuppressants in RT recipients [60].

#### **1.4. Diagnostic methods and cardiovascular disease biomarkers**

Chronic intravascular hypervolemia in patients with PD is an important contributor to CVD. There is no simple and reliable method to assess the volume status in patients with PD [61]; ankle edema or elevated jugular venous pressure is not accurate because they can only detect abnormal body water volume. Traditionally, body fluid compartment is measured by dilution methods for solutes or isotopes, but the tests are cumbersome and rarely used in routine clinical practice. More recently, measurement of vascular pedicle width (VPW) and cardiothoracic ratio (CTR) on chest radiographs is a noninvasive surrogate marker of intravascular volume status in critically ill patients [62]. Moreover, temporary changes in fluid balance are reflected in simple chest X-rays. The objective radiographic findings of intravascular volume may be more appropriate for fluid balance than subjective measurements; the VPW is the most sensitive determination. When systematically quantified, sequential chest radiographs provide substantial information to other clinically available data to help handle fluids in patients with water retention [63]. In patients with long-standing PD, CTR is an independent predictor of hospitalization-free patient survival; this radiological parameter can be used for risk stratification of patients undergoing PD [64].

Echocardiography is the most reliable, noninvasive, diagnostic procedure, capable to identify UC-related findings. Its capacity to quantify ventricular mass, ejection fraction, valvular disease, pericardial effusion, or pulmonary arterial hypertension [65] makes it useful to predict the damage extent of ESRD patients with recent RRT [66, 67]. Diastolic dysfunction and LVH have been described in three out of four patients, and systolic dysfunction in half of the patients who undergo initial PD. It is also very common to find aortic and mitral valve alterations, almost in one third of these patients. These findings have repercussion in the prognosis of patients with ESDR who start a PD program [68].

There are several useful biomarkers already evaluated in patients with CKD: troponin (TnT), plasminogen activator inhibitor type 1 (PAI-1), homocysteine, brain natriuretic peptide (BNP), C-reactive protein (CRP), serum amyloid-A protein, ischemia-modified albumin, and advanced glycation products (AGEs) have been shown to correlate with adverse cardiovascular (CV) events in patients with CKD [31].

Troponin T (TnT) and BNP have a good predictive value in this population [69, 70]. They were both elevated in patients with hypervolemia and were able to identify asymptomatic patients with CKD who have 2–5 times increased CV risk. BNP is also a useful marker in patients with left ventricular dysfunction and cardiovascular congestion. Increased levels of TnT represent a strong independent predictor of overall cardiovascular mortality in asymptomatic patients with HD [31]. Renal biomarkers, such as cystatin C (CysC) and neutrophil gelatinase-associated lipcalin (NGAL), have recently been studied as prognostic and diagnostic markers of cardiovascular outcomes in CKD patients [71]. There are increased levels of CysC in atherosclerotic processes and LVH; it has association with the latter, independently of renal function. Researchers found increased levels of NGAL expression in the atherosclerotic plaque of patients with heart failure due to coronary heart disease [31, 72].

## **1.5. Peritoneal transport**

of cardiovascular risk: patients with stage 1–3 of CKD have 25–100 times higher risk of CVD, and stage 5 has a similar kidney and heart morbidity and mortality [31]. Almost half of the patients with ESRD in PD have cardiac arrhythmias (especially atrial fibrillation) [53]. Other risk factors for cardiovascular mortality in PD users are cardiac valvulopathies, water retention, hypertension, DM, vascular calcifications, altered oxidative status, bone mineral disor-

Uremic cardiomyopathy (UC) is a suitable example for *CRS type 4*, as it is characterized by cardiac dysfunction leading to fluid overload and hypertension, accentuated by the presence of high levels of myocardial urea [55, 56]. UC is found at early stages of CKD and leads to structural and functional cardiovascular damage as the kidney dysfunction progresses [57, 58]. UC can predict CVD mortality at the beginning of PD [30]. The main feature is LVH, considered as a primary manifestation of UC, but it also induces left ventricular dilation and both systolic

The first-line treatment for UC is conventional HD, since it leads to a reduction in LVH. HD can also reverse systolic dysfunction by improving the left ventricular ejection fraction. The earlier HD is initiated in patients with PD and fluid retention, the more damage to the myocardium induced by UC can be avoided [59]. Angiotensin-converting enzyme inhibitors decrease LVH even in normotensive subjects. Likewise, RT confers remodeling to the myocardium affected by UC in patients with ESRD undergoing PD during short or medium time lapses, although some data are contradictory because of the dyslipidemia, hypertension, and

Chronic intravascular hypervolemia in patients with PD is an important contributor to CVD. There is no simple and reliable method to assess the volume status in patients with PD [61]; ankle edema or elevated jugular venous pressure is not accurate because they can only detect abnormal body water volume. Traditionally, body fluid compartment is measured by dilution methods for solutes or isotopes, but the tests are cumbersome and rarely used in routine clinical practice. More recently, measurement of vascular pedicle width (VPW) and cardiothoracic ratio (CTR) on chest radiographs is a noninvasive surrogate marker of intravascular volume status in critically ill patients [62]. Moreover, temporary changes in fluid balance are reflected in simple chest X-rays. The objective radiographic findings of intravascular volume may be more appropriate for fluid balance than subjective measurements; the VPW is the most sensitive determination. When systematically quantified, sequential chest radiographs provide substantial information to other clinically available data to help handle fluids in patients with water retention [63]. In patients with long-standing PD, CTR is an independent predictor of hospitalization-free patient survival; this radiological parameter can be used for risk stratifica-

Echocardiography is the most reliable, noninvasive, diagnostic procedure, capable to identify UC-related findings. Its capacity to quantify ventricular mass, ejection fraction, valvular disease,

ders, and uremic cardiomyopathy [54].

268 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

and diastolic cardiac dysfunctions [28].

tion of patients undergoing PD [64].

DM associated to immunosuppressants in RT recipients [60].

**1.4. Diagnostic methods and cardiovascular disease biomarkers**

*1.3.2. Uremic cardiomyopathy*

A useful tool for the management of patients in PD is the peritoneal equilibration test (PET). This method has proved to be effective in assessing peritoneal function. In this test, the saturation curves of the solutes in the peritoneum with respect to the plasma are evaluated; thus, it is possible to classify the peritoneal functioning in an easy and reproducible way [73, 74]. PET has been shown to have a prognostic value in patients undergoing PD [75] and allows patients to be classified according to the ratio of solute concentrations in dialysate and plasma (D/P ratio) 4 h after the test. Creatinine, urea, electrolytes, phosphate, and proteins are the commonly tested solutes, and it classifies patients in different types of transporters: (a) high or fast, (b) average high, (c) low average, and (d) low. PET allows the clinician to determine the best dialysis modality for each individual who will undergo continuous ambulatory PD or automated DP (continuous cyclic DP or intermittent nocturnal DP) [76].

Patients with high peritoneal solute transport rates often have inadequate transport of the peritoneal fluid. It is not known whether inadequate transport of fluids is solely due to a rapid drop in osmotic pressure or if the reduction in the efficiency of liquid transport is also a contributing factor. The difference in fluid transport between the abovementioned groups is apparently due to variances in the rate of disappearance of the total osmotic pressure of the dialysate, resulting from the transport velocity of glucose and other small solutes [77]. Although glucose gradient is the main factor influencing the rate of ultrafiltration, other solutes, such as urea, are also important [78]. However, there is a relationship between comorbid states that lead to an elevated mortality and the rapid transport of solutes [79].

The functional study of the peritoneal membrane is useful to guide the prescription of PD, predict the response of standard exchanges, and diagnose ultrafiltration disturbances during PD treatment. Knowing the pathophysiological mechanisms can help determine the underlying etiology of UF to ensure prompt actions that can help preserve peritoneal membrane for

Fluid Overload in Peritoneal Dialysis http://dx.doi.org/10.5772/intechopen.69324 271

Salt is an ionic component composed of sodium chloride (60% chloride and 40% sodium), with a molar mass of 58,433 g/mol. Sodium is an essential nutrient for the correct functioning of nerves and muscles, as well as water self-regulation and fluid balance. Salt is widely used to preserve processed foods, cooking, and seasoning. Processed foods have higher amounts of salt than natural foods, such as meats, fruits, and vegetables, which have a significant impact on a higher daily intake of sodium derived from the consumption of these foods [91]. Excessive salt intake stimulates thirst and promotes water intake, which contributes to fluid overload and hypertension [92]; therefore, a common strategy for patients with ESRD is salt and water restriction. In patients with PD, the salt balance can be improved by different strategies, among them the reduction in dietary intake, the use of diuretics to increase urinary secretion, and the increase of extraction by peritoneal ultrafiltration. The appropriate salt intake is the first treatment option for proper maintenance of the volume state [93]. The recommendation according to the Cardiovascular and Metabolic Guidelines of the International Society for Peritoneal Dialysis is to reduce intake to <2 g of sodium or <5 g of salt per day [94]. The lack of adherence to these recommendations is an important cause of fluid gain in

Although at the beginning of PD excessive ingestion of salt and liquids is not usually a problem due to the preservation of residual renal function, as renal function decreases, it is imperative to advise patients to decrease salt and water intake [96]. The advice of diet salt and water restriction in patients with PD leads to a decrease in body weight of 2.8 ± 0.5 kg and consequently to a reduction of blood pressure from 158.2 ± 17.0/95.7 to 119.7 ± 16.0/77.9 mmHg, in addition, a decrease in CTR from 48.0% ± 5.6% to 42.9% ± 4.5%. The role of salt and water restriction for the management of volume overload is highlighted due to the impact on the maintenance of volume status in patients with PD, which makes it fundamental for the adequate control of volume status [97]. However, some contradictory studies like the one by Fine et al. found that administration of 60 mEq/day of sodium chloride was significantly associated with an increase in blood pressure. The raise in systolic blood pressure was from 135 ± 19 to 144 ± 21 and diastolic blood pressure from 77 ± 8 to 82 ± 12 mmHg, without body weight gain (72 ± 10 to 72 ± 11 kg) in 20 patients undergoing PD enrolled to a double-blinded crossover clinical trial. They concluded that patients tolerate a diet with normal sodium intake and does not lead to volume overload [98]. Nevertheless, salt restriction in these patients

has been widely recommended for adequate maintenance of volume status.

There is no gold standard for assessing dietary salt intake in PD patients. The tools used for the evaluation are food diaries, 24-h reminders, consumption frequency questionnaires, and urine analysis for 24 h. The limitations of these tools include variation in day-to-day sodium

longer periods [90].

**1.6. Salt restriction and volume status**

patients undergoing PD [95].

Patients in PD with rapid peritoneal transport have reduced ultrafiltration, increased glucose absorption, and albumin loss in the dialysate. This phenomenon induces fluid overload, hypertension, dyslipidemia, and malnutrition, along with increased mortality. In addition, systemic vascular disorders observed in DM, hypertension, atherosclerosis, sepsis, and smoking contribute to survival deterioration in these patients; vascular and endothelial disorders are closely related to malnutrition-inflammation-atherosclerosis syndrome [80]. By its own, this syndrome can explain the high mortality rate observed in patients with rapid peritoneal transport [81].

The rapid transport of solutes at the beginning of PD is closely associated with genetic, inflammatory, and structural factors of the peritoneal membrane [82]. The clinical consequences of these alterations are CVD, metabolic disturbances of glucose and lipids, hypoalbuminemia, and malnutrition. In order to treat adequately patients with rapid solute transport, it is necessary to improve their comorbidities and modify their dialytic solutions with better osmotic substances different from glucose, as well as dialysis modalities that optimize ultrafiltration [60].

### *1.5.1. Ultrafiltration failure*

Peritoneal transport dysfunction is usually associated with ultrafiltration failure (UF) or deficit. Ultrafiltration failure is defined by the Society of Peritoneal Dialysis as the impossibility to maintain a stable dry weight in spite an adequate fluid restriction, and the total ultrafiltration volume is less than 400 mL after two or more hypertonic dialytic exchange with at least 4 h inside the peritoneal cavity using dextrose solution of 3.86% [83]. The prevalence of UF increases with duration of PD, so that 30–50% of patients with PD develop UF, many patients abandon PD due to UF, and dropout increases depending on the type of PD. It has been reported up to 3% of dropouts during the first year and 31% after the next six years [59, 84].

There are four ultrafiltration failure causes:


Some mechanical problems should be discarded if fluid overload is suspected: lost from dialysate fluid due to herniation or history of multiple abdominal surgeries, poorly positioned catheters secondary to migration of the original catheter, inadequate placement during the surgical procedure, and abdominal adhesions from previous surgeries [89].

The functional study of the peritoneal membrane is useful to guide the prescription of PD, predict the response of standard exchanges, and diagnose ultrafiltration disturbances during PD treatment. Knowing the pathophysiological mechanisms can help determine the underlying etiology of UF to ensure prompt actions that can help preserve peritoneal membrane for longer periods [90].

## **1.6. Salt restriction and volume status**

such as urea, are also important [78]. However, there is a relationship between comorbid

Patients in PD with rapid peritoneal transport have reduced ultrafiltration, increased glucose absorption, and albumin loss in the dialysate. This phenomenon induces fluid overload, hypertension, dyslipidemia, and malnutrition, along with increased mortality. In addition, systemic vascular disorders observed in DM, hypertension, atherosclerosis, sepsis, and smoking contribute to survival deterioration in these patients; vascular and endothelial disorders are closely related to malnutrition-inflammation-atherosclerosis syndrome [80]. By its own, this syndrome can explain the high mortality rate observed in patients with rapid peritoneal transport [81].

The rapid transport of solutes at the beginning of PD is closely associated with genetic, inflammatory, and structural factors of the peritoneal membrane [82]. The clinical consequences of these alterations are CVD, metabolic disturbances of glucose and lipids, hypoalbuminemia, and malnutrition. In order to treat adequately patients with rapid solute transport, it is necessary to improve their comorbidities and modify their dialytic solutions with better osmotic substances different from glucose, as well as dialysis modalities that optimize ultrafiltration [60].

Peritoneal transport dysfunction is usually associated with ultrafiltration failure (UF) or deficit. Ultrafiltration failure is defined by the Society of Peritoneal Dialysis as the impossibility to maintain a stable dry weight in spite an adequate fluid restriction, and the total ultrafiltration volume is less than 400 mL after two or more hypertonic dialytic exchange with at least 4 h inside the peritoneal cavity using dextrose solution of 3.86% [83]. The prevalence of UF increases with duration of PD, so that 30–50% of patients with PD develop UF, many patients abandon PD due to UF, and dropout increases depending on the type of PD. It has been reported up to 3% of dropouts during the first year and 31% after the next six years [59, 84].

• Type I, due to an increase of the effective peritoneal surface with increase in solute transport. It appears in the acute phase of peritonitis episodes associated to PD and is character-

• Type II is characterized by a reduced effective peritoneal surface with irreversible peritoneal involvement due to peritoneal adhesions or sclerosing peritonitis secondary to previ-

• Type IV, also known as transcellular UF, is the most recently described and illustrated by a

Some mechanical problems should be discarded if fluid overload is suspected: lost from dialysate fluid due to herniation or history of multiple abdominal surgeries, poorly positioned catheters secondary to migration of the original catheter, inadequate placement during the

• Type III is due to the increased rate of peritoneal lymphatic reabsorption [87].

cellular dysfunction or disruption of aquaporins in the cellular wall [88].

surgical procedure, and abdominal adhesions from previous surgeries [89].

states that lead to an elevated mortality and the rapid transport of solutes [79].

270 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

*1.5.1. Ultrafiltration failure*

There are four ultrafiltration failure causes:

ized by an early recovery after 30 days [85].

ous surgical scars or repetitive bacterial peritonitis [86].

Salt is an ionic component composed of sodium chloride (60% chloride and 40% sodium), with a molar mass of 58,433 g/mol. Sodium is an essential nutrient for the correct functioning of nerves and muscles, as well as water self-regulation and fluid balance. Salt is widely used to preserve processed foods, cooking, and seasoning. Processed foods have higher amounts of salt than natural foods, such as meats, fruits, and vegetables, which have a significant impact on a higher daily intake of sodium derived from the consumption of these foods [91]. Excessive salt intake stimulates thirst and promotes water intake, which contributes to fluid overload and hypertension [92]; therefore, a common strategy for patients with ESRD is salt and water restriction. In patients with PD, the salt balance can be improved by different strategies, among them the reduction in dietary intake, the use of diuretics to increase urinary secretion, and the increase of extraction by peritoneal ultrafiltration. The appropriate salt intake is the first treatment option for proper maintenance of the volume state [93]. The recommendation according to the Cardiovascular and Metabolic Guidelines of the International Society for Peritoneal Dialysis is to reduce intake to <2 g of sodium or <5 g of salt per day [94]. The lack of adherence to these recommendations is an important cause of fluid gain in patients undergoing PD [95].

Although at the beginning of PD excessive ingestion of salt and liquids is not usually a problem due to the preservation of residual renal function, as renal function decreases, it is imperative to advise patients to decrease salt and water intake [96]. The advice of diet salt and water restriction in patients with PD leads to a decrease in body weight of 2.8 ± 0.5 kg and consequently to a reduction of blood pressure from 158.2 ± 17.0/95.7 to 119.7 ± 16.0/77.9 mmHg, in addition, a decrease in CTR from 48.0% ± 5.6% to 42.9% ± 4.5%. The role of salt and water restriction for the management of volume overload is highlighted due to the impact on the maintenance of volume status in patients with PD, which makes it fundamental for the adequate control of volume status [97]. However, some contradictory studies like the one by Fine et al. found that administration of 60 mEq/day of sodium chloride was significantly associated with an increase in blood pressure. The raise in systolic blood pressure was from 135 ± 19 to 144 ± 21 and diastolic blood pressure from 77 ± 8 to 82 ± 12 mmHg, without body weight gain (72 ± 10 to 72 ± 11 kg) in 20 patients undergoing PD enrolled to a double-blinded crossover clinical trial. They concluded that patients tolerate a diet with normal sodium intake and does not lead to volume overload [98]. Nevertheless, salt restriction in these patients has been widely recommended for adequate maintenance of volume status.

There is no gold standard for assessing dietary salt intake in PD patients. The tools used for the evaluation are food diaries, 24-h reminders, consumption frequency questionnaires, and urine analysis for 24 h. The limitations of these tools include variation in day-to-day sodium intake, errors related to memory lapses, patient motivation, false perception of diet, difficulty in measuring salt use, over-/under-collection of urine, among others [99].

**Conflict of interest**

**Author details**

México

**References**

2008;**86**:229-237

Practice. 2014;**33**(1):9-18

There are no conflicts of interest.

Leonardo Pazarin-Villaseñor1

Guadalajara, Jalisco, México

Guadalajara, Guadalajara, Jalisco, México

Kidney International. 2005;(98):S69-S75

Journal of Kidney Disease. 2010;**56**(2):399-417

enteen diálisis peritoneal? Nefrología. 2008;**28**(6):105-111

, Francisco Gerardo Yanowsky-Escatell1

Luis Miguel Roman-Pintos2,3 and Alejandra Guillermina Miranda-Diaz<sup>4</sup>

Tonalá, Universidad de Guadalajara, Guadalajara, Jalisco, México

1 Department of Nephrology, Hospital Civil de Guadalajara "Dr. Juan I. Menchaca"

2 Department of Sickness and Health as an Individual Process, Centro Universitario de

3 Department of Internal Medicine, Hospital Ángeles del Carmen, Guadalajara, Jalisco,

4 Department of Physiology, Centro Universitario de Ciencias de la Salud, Universidad de

[1] Choi ES, Lee J. Effects of a face-to-face self-management program on knowledge, selfcare practice and kidney function in patients with chronic kidney disease before the renal replacement therapy. Journal of Korean Academy of Nursing. 2012;**42**(7):1070-1088

[2] Correa-Rotter R, González-Michaca L. Early detection and prevention of diabetic nephropathy: A challenge calling for mandatory action for Mexico and the developing world.

[3] Parfrey PS, Foley RN. The clinical epidemiology of cardiac disease in chronic renal fail-

[4] Shastri Sh, Sarnak MJ. Cardiovascular disease and CKD: Core curriculum 2010. American

[5] Alonso Gómez AM. ¿Qué debe de conocer el nefrólogo de la afectación cardiaca del paci-

[6] White SL, Chadban SJ, Jan S, Chapmanc JR, Cass A. How can we achieve global equity in provision of renal replacement therapy? Bulletin of the World Health Organization.

[7] Jin DC, Han JS. Renal replacement therapy in Korea, 2012. Kidney Research and Clinical

ure. Journal of the American Society of Nephrology. 1999;**10**:1606-1615

\*Address all correspondence to: kindalex1outlook.com

, Jorge Andrade-Sierra1

Fluid Overload in Peritoneal Dialysis http://dx.doi.org/10.5772/intechopen.69324

\*

,

273

Urine 24-h sodium determination does not reflect the current sodium intake in patients with PD, since the elimination of sodium occurs through urine and dialysate. In addition, the removal of sodium from the dialysate depends on the convection through the peritoneal membrane, so it cannot reflect the current sodium intake in these patients [100, 101]. The measurement of total sodium withdrawal during dialysis adequacy assessment might be a simple and effective method of estimating sodium ingestion in patients with PD. Total sodium withdrawal during dialysis adequacy assessment may be a simple and effective method to estimate sodium intake [102]:

$$\text{Sodium intake (mg/dL)} = 15.64 \times \text{total sodium width} \text{mward (mEq/d)} + 646 \tag{1}$$

For example, a sodium intake of 2000 mg would correspond to a total sodium removal of approximately 87 mEq/d [102].

In a cohort of 305 PD incident patients, Dong et al. reported that low sodium ingestion was significantly associated with nutrient deficiency and poor muscle reserve and an independent predictor for mortality. It is necessary to consider whether salt restriction in the diet would improve outcomes in patients with low calorie and protein intake [100].

A correct nutritional advice can achieve a decrease in salt intake, minimizing processed foods and avoiding salt in food preparation. Certain strategies to reduce salt ingestion can be useful to improve the taste of food, such as substitution with flavor enhancers like pepper, paprika, curry, thyme, and oregano; also changing to salt substitutes, which contain potassium chloride in patients who do not require potassium restriction [103]. An advantage of salt substitutes compared to flavor enhancers is that the former have a higher salty taste, but the disadvantage is the risk of hyperkalemia [104].

Finally, another strategy is to prepare a diet containing 2 g of sodium (88 mM NaCl), by allowing to add 1/3 of tablespoon of salt for each meal during that day. It is worth noting the impact of salt intake on patients with PD. Therefore, under this context, the previously mentioned strategies to maintain a low ingestion of salt in the diet could help to avoid a deficit in the consumption of nutrients and the maintenance of the state of volume.

## **2. Conclusions**

The incidence and prevalence of ESRD are increasing, making the need for PD necessary as a demanding RRT for patients with CKD. The main morbidity and mortality cause in patients with CKD is still primarily due to CVD. It is important to start an early approach to fluid overload by performing and interpreting different assessments, such as echocardiography, PET, UF test, and an adequate food survey for the identification of factors that contribute to poor adherence to dietary recommendations in water and saline intake. Fluid overload is an important cause for hospital admissions; thus, clinicians must have this in mind for the early identification of the causes of cardiac decompensation, besides attending the individual disorders of each patient with PD.

## **Conflict of interest**

intake, errors related to memory lapses, patient motivation, false perception of diet, difficulty

Urine 24-h sodium determination does not reflect the current sodium intake in patients with PD, since the elimination of sodium occurs through urine and dialysate. In addition, the removal of sodium from the dialysate depends on the convection through the peritoneal membrane, so it cannot reflect the current sodium intake in these patients [100, 101]. The measurement of total sodium withdrawal during dialysis adequacy assessment might be a simple and effective method of estimating sodium ingestion in patients with PD. Total sodium withdrawal during dialysis adequacy assessment may be a simple and effective method to esti-

Sodium intake (mg/dL) = 15.64 × total sodium withdrawal (mEq/d) + 646 (1)

For example, a sodium intake of 2000 mg would correspond to a total sodium removal of

In a cohort of 305 PD incident patients, Dong et al. reported that low sodium ingestion was significantly associated with nutrient deficiency and poor muscle reserve and an independent predictor for mortality. It is necessary to consider whether salt restriction in the diet would

A correct nutritional advice can achieve a decrease in salt intake, minimizing processed foods and avoiding salt in food preparation. Certain strategies to reduce salt ingestion can be useful to improve the taste of food, such as substitution with flavor enhancers like pepper, paprika, curry, thyme, and oregano; also changing to salt substitutes, which contain potassium chloride in patients who do not require potassium restriction [103]. An advantage of salt substitutes compared to flavor enhancers is that the former have a higher salty taste, but the

Finally, another strategy is to prepare a diet containing 2 g of sodium (88 mM NaCl), by allowing to add 1/3 of tablespoon of salt for each meal during that day. It is worth noting the impact of salt intake on patients with PD. Therefore, under this context, the previously mentioned strategies to maintain a low ingestion of salt in the diet could help to avoid a deficit in the

The incidence and prevalence of ESRD are increasing, making the need for PD necessary as a demanding RRT for patients with CKD. The main morbidity and mortality cause in patients with CKD is still primarily due to CVD. It is important to start an early approach to fluid overload by performing and interpreting different assessments, such as echocardiography, PET, UF test, and an adequate food survey for the identification of factors that contribute to poor adherence to dietary recommendations in water and saline intake. Fluid overload is an important cause for hospital admissions; thus, clinicians must have this in mind for the early identification of the causes of cardiac decompensation, besides attending the individual disorders of each patient with PD.

in measuring salt use, over-/under-collection of urine, among others [99].

272 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

improve outcomes in patients with low calorie and protein intake [100].

consumption of nutrients and the maintenance of the state of volume.

mate sodium intake [102]:

approximately 87 mEq/d [102].

**2. Conclusions**

disadvantage is the risk of hyperkalemia [104].

There are no conflicts of interest.

## **Author details**

Leonardo Pazarin-Villaseñor1 , Francisco Gerardo Yanowsky-Escatell1 , Jorge Andrade-Sierra1 , Luis Miguel Roman-Pintos2,3 and Alejandra Guillermina Miranda-Diaz<sup>4</sup> \*

\*Address all correspondence to: kindalex1outlook.com

1 Department of Nephrology, Hospital Civil de Guadalajara "Dr. Juan I. Menchaca" Guadalajara, Jalisco, México

2 Department of Sickness and Health as an Individual Process, Centro Universitario de Tonalá, Universidad de Guadalajara, Guadalajara, Jalisco, México

3 Department of Internal Medicine, Hospital Ángeles del Carmen, Guadalajara, Jalisco, México

4 Department of Physiology, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, México

## **References**


[8] Weiner DE, Tighiouart H, Stark PC, et al. Kidney disease as a risk factor for recurrent cardiovascular disease and mortality. American Journal of Kidney Disease. 2004;**44**:198-206

[21] Amato D, Alvarez-Aguilar C, Castañeda-Limones R, et al. Prevalence of chronic kidney disease in an urban Mexican Population. Kidney International. 2005;**68**(Suppl 97):

Fluid Overload in Peritoneal Dialysis http://dx.doi.org/10.5772/intechopen.69324 275

[22] The US Renal Data System. Available at: https://www.usrds.org/adr.aspx. Accessed:

[23] Saran R, Li Y, Robinson B, et al. US Renal Data System 2015 Annual Data Report: Epidemiology of kidney disease in the United States. American Journal of Kidney Diseases.

[24] Guía de Práctica Clínica. Prevención, Diagnóstico y Tratamiento de la Enfermedad

[25] Mendez DA, Mendez-Bueno F, Tapia YT, Muñoz MA, Aguilar SL. Epidemiologia de la

[26] National Kidney Foundation. K/DOQI Clinical Practice Guidelines for chronic kidney disease: Evaluation, classification and stratification. American Journal of Kidney

[27] Garcia GG, Monteon RF, Garcia BH, et al. Renal replacement therapy among disadvantaged populations in Mexico a report from the REDTJAL. Kidney International.

[28] Durán-Arenas L, Avila-Palomares PD, Zendejas-Villanueva R, Vargas-Ruiz MM, Tirado-Gómez LL, López-Cervantes M. Direct cost analysis of hemodialysis units. Salud Pública

[29] Garcia GG, Harden P, Chapman J. El papel global del trasplante renal. Nefrología. 2012;

[30] Clementi A, Virzi GM, Go ChY, Cruz D, Granata A, Vescovo G, et al. Cardiorenal syn-

[31] Ronco C, Haapio M, House AA, Anavekar N, Bellomo R. Cardiorenal syndrome. Journal

[32] Shah BN, Greaves K. The cardiorenal syndrome. International Journal of Nephrology.

[33] Wizemann V, Schilling M. Dilemma of assessing volume state—The use and the limitations of a clinical score. Nephrology, Dialysis, Transplantation. 1995;**10**:2114-2117

[34] Paniagua R, Ventura MD, Avila-Díaz M, Hinojosa-Heredia H, Méndez-Durán A, et al. NT-proBNP, fluid volume overload and dialysis modality are independent predictors of mortality in ESRD patients. Nephrology, Dialysis, Transplantation. 2010;**25**:551-557

[35] Ozkahya M, Ok E, Toz H, Asci G, Duman S, et al. Long-term survival rates in haemodialysis patients treated with strict volume control. Nephrology, Dialysis, Transplantation.

drome type 4: A review. CardioRenal Medicine. 2013;**3**:63-70

of the American College of Cardiology. 2008;**52**:1527-1539

Renal Crónica Temprana. México; Secretaría Nacional de Salud; 2009

insuficiencia renal crónica en México. Diálisis y Trasplante. 2010;**31**(1):7-11

S11-S17

February 12, 2017

2005;**68**:s58-s61

**32**(1);1-6

2011;**2011**:920195

2006;**21**:3506-3513

2016;**67**(3 suppl 1):S1-S434

Disease. 2002;**39**(Suppl 1):S1-S266

de México. 2011;**53**(4):516-524


[21] Amato D, Alvarez-Aguilar C, Castañeda-Limones R, et al. Prevalence of chronic kidney disease in an urban Mexican Population. Kidney International. 2005;**68**(Suppl 97): S11-S17

[8] Weiner DE, Tighiouart H, Stark PC, et al. Kidney disease as a risk factor for recurrent cardiovascular disease and mortality. American Journal of Kidney Disease. 2004;**44**:198-206

[9] Zhang L, Zuo L, Wang F, et al. Cardiovascular disease in early stages of chronic kidney disease in a Chinese population. Journal of the American Society of Nephrology.

[10] Chronic Kidney Disease Prognosis Consortium. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general

[11] Van der Velde M, Matsushita K, Coresh J, et al. Lower estimated glomerular filtration rate and higher albuminuria are associated with all-cause and cardiovascular mortality. A collaborative meta-analysis of high-risk population cohorts. Kidney International.

[12] Clase CM, Gao P, Tobe SW, et al. Estimated glomerular filtration rate and albuminuria as predictors of outcomes in patients with high cardiovascular risk: A cohort study.

[13] Fox CS, Matsushita K, Woodward M, Bilo HJ, Chalmers J, et al. Chronic Kidney Disease Prognosis Consortium: Associations of kidney disease measures with mortality and endstage renal disease in individuals with and without diabetes: a meta-analysis. Lancet.

[14] Garcia-Garcia G, Briseño-Rentería G, Luquín-Arellano VH, Gao Z, Gill J, Tonelli M. Survival among patients with kidney failure in Jalisco México. Journal of the American

[15] Kim EJ, Chung CH, Park MY, Choi SJ, Kim JK, Hwang SD. Mortality predictors in patients treated with continuous renal replacement. Korean Journal of Nephrology.

[16] Kidney Disease: Improving Global Outcomes (KDIGO) CKD Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease.

[17] Cueto-Manzano A, Quintana-Piña E, Correa-Rotter R. Long term CAPD survival and analysis of mortality risk factors: 12-year experience of a single Mexican center. Peritoneal

[18] Cueto-Manzano A, Rojas-Campos E. Status of renal replacement therapy and peritoneal

[19] Obrador GT, García-García G, Villa AR, et al. Prevalence of Chronic kidney disease in the Kidney early Evaluation Program (KEEP) Mexico and comparison with KEEP US.

[20] Vasavada N, Agarwal R. Role of excess volume in the pathophysiology of hypertension

dialysis in Mexico. Peritoneal Dialysis International. 2007;**27**:142-148

in chronic kidney disease. Kidney Int. 2003 Nov;**64**(5):1772-9

Summary of Recommendation Statements. Kidney International. 2013;**3**(1):5-14

population cohorts: A collaborative meta-analysis. Lancet. 2010;**375**:2073-2081

2006;**17**:2617-2621

2011;**79**:1341-1352

2012;**380**:1662-1673

2011;**30**:73-79

Annals of Internal Medicine. 2011;**154**:310-318

274 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

Society of Nephrology. 2007;**18**:1922-1927

Dialysis International. 2001;**21**:148-153

Kidney International. 2010;**77**(Suppl 116):S2-S8


[36] Tsai YC, Tsai JC, Chen SC, Chiu YW, Hwang SJ, Hung CC, Chen TH, Kuo MC, Chen HC. Association of fluid overload with kidney disease progression in advanced CKD: A prospective cohort study. American Journal of Kidney Disease. 2014;**63**(1):68-75

[50] Mehta RL, Rabb H, Shaw AD, Singbartl K, Ronco C, McCullough PA, Kellum JA. Cardiorenal syndrome type 5: Clinical presentation, pathophysiology and management strategies from the eleventh consensus conference of the Acute Dialysis Quality Initiative

Fluid Overload in Peritoneal Dialysis http://dx.doi.org/10.5772/intechopen.69324 277

[51] Ronco C, McCullough PA, Anker SD, Anand I, Aspromonte N, Bagshaw SM, et al. Cardiorenal syndromes: An executive summary from the consensus conference of the Acute Dialysis Quality Initiative (ADQI). Contributions to Nephrology. 2010;**165**:54-67

[52] Schroten NF, Damman K, Valente MA, Smilde TD, van Veldhuisen DJ, Navis G, Gaillard CA, Voors AA, Hillege HL. Long-term changes in renal function and perfusion in heart failure patients with reduced ejection fraction. Clinical Research in Cardiology.

[53] McCullough PA, Assad H. Diagnosis of cardiovascular disease in patients with chronic

[54] Cuba M, Batista R. Cardiac calcification in patients with terminal chronic renal insuf-

[55] Chinnappa S, Hothi SS, Tan LB. Is uremic cardiomyopathy a direct consequence of chronic kidney disease? Expert Review of Cardiovascular Therapy. 2014;**12**(2):127-130

[56] Alhaj E, Alhaj N, Rahman I, Niazi T, Berkowitz R, Klapholz M. Uremic cardiomyopathy:

[57] Kunz K, Dimitrov Y, Muller S, Chantrel F, Hannedouche T. Uraemic cardiomyopathy.

[58] Riggato C, Parfrey PS. Uraemic Cardiomyopathy. Journal ofClinicalandBasic Cardiology.

[59] Codognotto M, Piccoli A, Zaninotto M, Mion M, Plebani M, Vertolli U, Tona F, Ruzza L, Barchita A, Boffa GM. Renal dysfunction is a confounder for plasma natriuretic peptides in detecting heart dysfunction in uremic and idiopathic dilated cardiomyopathies.

[60] Rosales BG, Sotelo CM, Monteon RF, Quirarte JA, Zuñiga G, Cueto-Manzano A. Metabolic and echocardiographic changes during dialysis and after renal transplanta-

[61] Szeto CC, Li PK. Salt and water balance in PD. In: Molony D, Craig J, editors, Evidence-Based Nephrology. Oxford: Wiley Blackwell (BMJ Books); 2009. pp. 488-499

[62] Ely EW, Haponik EF. Using the chest radiograph to determine intravascular volume

[63] Martin GS, Ely EW, Carroll FE, Bernard GR. Findings on the portable chest radiograph correlate with fluid balance in critically ill patients. Chest. 2002;**122**(6):2087-2095

status: The role of vascular pedicle width. Chest. 2002;**121**(3):942-950

An underdiagnosed disease. Congestive Heart Failure. 2013;**19**(4):E40-E45

ficiency and kidney transplant patients. Nefrología. 2004;**24**(2):196-197

(ADQI). Contributions to Nephrology. 2013;**182**:174-194

kidney disease. Blood Purification. 2012;**33**(1-3):112-118

Nephrology, Dialysis, Transplantation. 1998;**13**(4):39-44

Clinical Chemistry. 2007;**53**(12):2097-2104

tion. Nefrología Mexicana. 2002;**23**(1):5-10

2016;**105**(1):10-16

2001;**4**:93-95


[50] Mehta RL, Rabb H, Shaw AD, Singbartl K, Ronco C, McCullough PA, Kellum JA. Cardiorenal syndrome type 5: Clinical presentation, pathophysiology and management strategies from the eleventh consensus conference of the Acute Dialysis Quality Initiative (ADQI). Contributions to Nephrology. 2013;**182**:174-194

[36] Tsai YC, Tsai JC, Chen SC, Chiu YW, Hwang SJ, Hung CC, Chen TH, Kuo MC, Chen HC. Association of fluid overload with kidney disease progression in advanced CKD: A

[37] Tucker BJ, Collins RC, Ziegler MG, Blantz RC. Disassociation between glomerular hyperfiltration and extracellular volume in diabetic rats. Kidney International. 1991;**39**:

[38] Forbes JM, Fukami K, Cooper ME. Diabetic nephropathy: Where hemodynamics meets metabolism. Experimental and Clinical Endocrinology and Diabetes. 2007;**115**:69-84

[39] Li PK, Kwan BC, Ko GT, Chow KM, Leung CB, Szeto CC. Treatment of metabolic syndrome in peritoneal dialysis patients. Peritoneal Dialysis International. 2009;**29**(2):

[40] Stevenson LW, Nohria A, Mielniczuk L. Torrent or torment from the tubules? Challenge of the cardiorenal connection. Journal of the American College of Cardiology. 2005;**45**(12):

[41] Chertow GM, Normand S-LT, Silva LR, McNeil BJ. Survival after acute myocardial infarction in patients with end-stage renal disease: Results from the cooperative cardio-

[42] Herzog CA. Dismal long-term survival of dialysis patients after acute myocardial infarction: can we alter the outcome? Nephrology, Dialysis, Transplantation. 2002;**17**(1):7-10

[43] Clementi A, Virzì GM, Brocca A, de Cal M, Vescovo G, Granata A, Ronco C. Cardiorenal

[44] Damman K, Navis G, Voors AA, Asselbergs FW, Smilde TD, Cleland JG, van Veldhuisen DJ, Hillege HL. Worsening renal function and prognosis in heart failure: Systematic

[45] De Vecchis R, Baldi C. Cardiorenal syndrome type 2: From diagnosis to optimal manage-

[46] Bagshaw SM, Cruz DN. Epidemiology of cardiorenal syndromes. Contributions to

[47] Clementi A, Virzì GM, Brocca A, de Cal M, Pastori S, Clementi M, Granata A, Vescovo G, Ronco C. Advances in the pathogenesis of cardiorenal syndrome type 3. Oxidative

[48] Cheung AK, Sarnak MJ, Yan G, Berkoben M, Heyka R, Kaufman A, Lewis J, Rocco M, Toto R, Windus D, Ornt D, Levey AS; HEMO Study Group. Cardiac diseases in maintenance hemodialysis patients: Results of the HEMO study. Kidney International.

[49] Corradi GMVV, Panagiotou A, Gastaldon F, Cruz DN, de Cal M, et al. ADPKD: Prototype of cardiorenal syndrome type 4. International Journal of Nephrology. 2011;**2011**:490795

vascular project. American Journal of Kidney Disease. 2000;**35**(6):1044-1051

syndrome type 4: Management. Blood Purification. 2013;**36**(3-4):200-209

review and meta-analysis. Journal of Cardiac Failure. 2007;**13**:599-608

ment. Therapeutics and Clinical Risk Management. 2014;**10**:949-961

prospective cohort study. American Journal of Kidney Disease. 2014;**63**(1):68-75

1176-1183

276 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

S149-S155

2004-2007

Nephrology. 2010;**165**:68-82

2004;**65**:2380-2389

Medicine and Cellular Longevity. 2015;**2015**:1-8


[64] Gao N, Kwan BC, Chow KM, Chung KY, Leung CB, Li PK, Szeto CC. Longitudinal changes of cardiothoracic ratio and vascular pedicle width as predictors of volume status during one year in Chinese peritoneal dialysis patients. Kidney and Blood Pressure Research. 2009;**32**(1):45-50

[77] Waniewski J, Debowska M, Lindholm B. Water and solute transport through different types of pores in peritoneal membrane in CAPD patients with ultrafiltration failure.

Fluid Overload in Peritoneal Dialysis http://dx.doi.org/10.5772/intechopen.69324 279

[78] Sobiecka D, Waniewski J, Weryński A, Lindholm B. Peritoneal fluid transport in CAPD patients with different transport rates of small solutes. Peritoneal Dialysis International.

[79] Cueto-Manzano AM. Rapid solute transport in the peritoneum: Physiologic and clinical

[80] Jeznach-Steinhagen A, Słotwiński R, Szczygieł B. Malnutrition, inflammation, atherosclerosis in hemodialysis patients. Roczniki Panstwowego Zakladu Higieny. 2007;**58**(1):83-88

[81] Abe M, Okada K, Maruyama T, Maruyama N, Matsumoto K, Soma M. Relationship between erythropoietin responsiveness, insulin resistance, and malnutrition-inflammation-atherosclerosis (MIA) syndrome in hemodialysis patients with diabetes.

[82] Chung SH, Stenvinkel P, Bergström J, Lindholm B. Biocompatibility of new peritoneal dialysis solutions: What can we hope to achieve? Peritoneal Dialysis International.

[83] Teixidó-Planas J, Troya-Saborido MI, Pedreira-Robles G, Del-Rio-Lafuente M, Romero-Gonzalez R, Bonet-Sol J. Measuring peritoneal absorption with the prolonged peritoneal equilibration test from 4 to 8 hours using various glucose concentrations. Perit Dial Int.

[84] Aguirre AR, Abensur H. Protective measures against ultrafiltration failure in peritoneal

[85] Fusshoeller A. Histomorphological and functional changes of the peritoneal membrane

[86] La Milia V, Di Filippo S, Crepaldi M, Del Vecchio L, Dell'Oro C, Andrulli S, Locatelli F. Mini-peritoneal equilibration test: A simple and fast method to assess free water and small solute transport across the peritoneal membrane. Kidney International.

[87] Kawaguchi Y, Kawanishi H, Mujais S, Topley N, Oreopoulos DG. Encapsulating peritoneal sclerosis: Definition, etiology, diagnosis, and treatment. International Society for Peritoneal Dialysis Ad Hoc Committee on Ultrafiltration Management in Peritoneal

[88] Flessner MF. Peritoneal ultrafiltration: Mechanisms and measures. Contributions to

[89] Prasad N, Gupta S. Ultrafiltration failure in peritoneal dialysis: A review. Indian Journal

during long-term peritoneal dialysis. Pediatric Nephrology. 2008;**23**:19-25

dialysis patients; Clinics (São Paulo, Brazil). 2011;**66**(12):2151-2157

Dialysis. Peritoneal Dialysis International. 2000;**20**:S43-S55

consequences. Peritoneal Dialysis International. 2009;**29**(2):s90-s95

International Journal of Artificial Organs. 2011;**34**(1):16-25

Peritoneal Dialysis International. 2009;**29**(6):664-669

2004;**24**(3):240-251

2000;**20**(5):S57-S67

2014;**34**(6):605-11

2005;**68**:840-846

Nephrology. 2006;**150**:28-36

of Peritoneal Dialysis. 2012;**22**(1):15-24


[77] Waniewski J, Debowska M, Lindholm B. Water and solute transport through different types of pores in peritoneal membrane in CAPD patients with ultrafiltration failure. Peritoneal Dialysis International. 2009;**29**(6):664-669

[64] Gao N, Kwan BC, Chow KM, Chung KY, Leung CB, Li PK, Szeto CC. Longitudinal changes of cardiothoracic ratio and vascular pedicle width as predictors of volume status during one year in Chinese peritoneal dialysis patients. Kidney and Blood Pressure

[65] Stewart GA, Gansevoort RT, Mark PB, Rooney E, McDonagh TA, Dargie HJ, Stuart R, Rodger C, Jardine AG. Electrocardiographic abnormalities and uremic cardiomyopathy.

[66] Hung KC, Lee CH, Chen CC, Chu CM, Wang CY, Hsieh IC, Fang JT, Lin FC, Wen MS. Advanced left ventricular diastolic dysfunction in uremic patients with type 2 diabetes

[67] Pecoits-Filho R, Berberato SH. Echocardiography in chronic kidney disease: Diagnosticand prognostic implications. Nephron. Clinical Practice. 2010;**114**:c242-c247

[68] Pazarín-Villaseñor L, Reyes LU, León-Flores AM, Miranda-Díaz AG, Andrade-Sierra J. Miocardiopatía urémica y trasporte peritoneal en pacientes incidentes con diálisis peritoneal en el occidente de México. Nefrología. 2016 (in press). http://dx.doi.org/10.1016/j.

[69] Daniels LB, Maissel AS. Natriuretic peptides. Journal of the American College of

[70] deFillipi CR, Fink JC, Nass CM, Chen H, Christenson R. N-terminal Pro B –type natriuretic peptide for predicting coronary disease and left ventricular hypertrophy in asymptomatic CKD not requiring dialysis. American Journal of Kidney Disease. 2005;**46**:35-44

[71] Iwanaga Y, Miyazaki S. Heart Failure, chronic kidney disease, and biomarkers—An inte-

[72] Ynstead A, Landro L, Uelan T, Dahl CP, Flo TH, Vinge LE, et al. Increased Systemic and Myocardial expression of neutrophil gelatinase-associated lipocalin in clinical and

[73] Twardowski ZJ, Nolph KDA, Prowant LBF, Moore HL, Nielsen MP. Peritoneal equilib-

[74] Cueto-Manzano AM. Peritoneal dialysis in Mexico. Kidney International. 2003;**63**(83):

[75] Scott BK, Walker M, Margetts PJ, Kundhal KK, Rabbat CG. Metanalysis: Peritoneal membrane transport, mortality and technique failure in peritoneal dialysis. Journal of the

[76] Chávez Valencia V, Orizaga de la Cruz C, Pazarin Villaseñor HL, Fuentes Ramírez F, Parra Michel R, Aragaki Y, et al. Frequency of peritoneal transport in a population of the Hospital General Regional No. 46, Instituto Mexicano del Seguro Social. Gaceta Médica

experimental heart failure. European Heart Journal. 2009;**30**(10):1229-1236

grated viewpoint. Circulation Journal. 2010;**74**(7):1274-1282

rium test. Peritoneal Dialysis Bulletin. 1987;**7**(3):138-147

American Society of Nephrology. 2006;**17**:2591-2598

de México. 2014;**150**(2):186-193

on maintenance hemodialysis. Circulation Journal. 2012;**76**(10):2380-2385

Research. 2009;**32**(1):45-50

nefro.2016.11.005

s90-s92

Cardiology. 2007;**50**:2357-2368

Kidney International. 2005;**67**(1):217-226

278 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements


[90] Heimburger O, Waniewski J, Werinski A Tranaeus A, Lindholm B. Peritoneal transport in CAPD patients with permanent loss of ultrafiltration capacity. Kidney International. 1990;**38**:495-506

**Chapter 13**

**Provisional chapter**

**Subjective Wellbeing Assessment in People with**

**Chronic Kidney Disease Undergoing Hemodialysis**

**Subjective Wellbeing Assessment in People with** 

Luís Manuel Mota de Sousa, Ana Vanessa Antunes,

Cristina Rosa Soares Lavareda Baixinho,

Cristina Rosa Soares Lavareda Baixinho,

Cristina Maria Alves Marques-Vieira and

Cristina Maria Alves Marques-Vieira and

Additional information is available at the end of the chapter

affect (subjective happiness and positive affect).

Additional information is available at the end of the chapter

Sandy Silva Pedro Severino,

Sandy Silva Pedro Severino,

Luís Manuel Mota de Sousa,

Ana Vanessa Antunes,

**Abstract**

renal dialysis

public health problem [1].

**1. Introduction**

Helena Maria Guerreiro José

Helena Maria Guerreiro José

http://dx.doi.org/10.5772/intechopen.71194

**Chronic Kidney Disease Undergoing Hemodialysis**

DOI: 10.5772/intechopen.71194

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

Due to its prevalence, chronic kidney disease (CKD) has been recognized as an important

The aim of this study was to analyze the relationship between satisfaction with life in general and the sociodemographic and emotional factors and components of quality of life in people with chronic kidney disease undergoing hemodialysis. A cross-sectional and correlational study was performed on a sample of 171 people with chronic kidney disease in two hemodialysis units at a Clinic in Lisbon between May and June 2015. Subjective wellbeing (personal wellbeing index) is positively related with subjective happiness, positive affect, and quality of life and is negatively associated with negative affect. Subjective happiness, negative affect, and the physical component of quality of life influence subjective wellbeing. These conclusions can assist us in understanding that people with chronic kidney disease (CKD) encounter greater feelings of wellbeing, mainly related to pleasant

**Keywords:** subjective wellbeing, emotion, quality of life, chronic renal insufficiency,


**Provisional chapter**

## **Subjective Wellbeing Assessment in People with Chronic Kidney Disease Undergoing Hemodialysis Chronic Kidney Disease Undergoing Hemodialysis**

**Subjective Wellbeing Assessment in People with** 

DOI: 10.5772/intechopen.71194

Luís Manuel Mota de Sousa, Ana Vanessa Antunes, Cristina Rosa Soares Lavareda Baixinho, Sandy Silva Pedro Severino, Cristina Maria Alves Marques-Vieira and Helena Maria Guerreiro José Ana Vanessa Antunes, Cristina Rosa Soares Lavareda Baixinho, Sandy Silva Pedro Severino, Cristina Maria Alves Marques-Vieira and Helena Maria Guerreiro José

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.71194

Luís Manuel Mota de Sousa,

#### **Abstract**

[90] Heimburger O, Waniewski J, Werinski A Tranaeus A, Lindholm B. Peritoneal transport in CAPD patients with permanent loss of ultrafiltration capacity. Kidney International.

[92] Inal S, Erten Y, Akbulu G, et al. Salt intake and hypervolemia in the development of hypertension in peritoneal dialysis patients. Advances in Peritoneal Dialysis.

[93] Biesen WV, Vanholder R, Veys N, Lameire N. Improving salt balance in peritoneal dial-

[94] Wang AY, Brimble KS, Brunier G, et al. ISPD Cardiovascular and Metabolic Guidelines in Adult Peritoneal Dialysis Patients. Part I—Assessment and management of various

[95] Tzamaloukas AH, Saddler MC, Murata GH, et al. Symptomatic fluid retention in patients on continuous peritoneal dialysis. Journal of the American Society of

[96] Ates K. Salt and wáter in PD. The Turkish contribution. Peritoneal Dialysis International.

[97] Inal S, Erten Y, Tek N, et al. The effect of dietary salt restriction on hypertension in peritoneal dialysis patients. Turkish Journal of Medical Sciences. 2014;**44**(5):814-819

[98] Fine A, Fontaine B, Ma M. Commonly prescribed salt intake in continuous ambulatory peritoneal dialysis patients is too restrictive: results of a double-blind crossover study.

[99] McMahon EJ, Campbell KL, Mudge DW, Bauer JD. Achieving salt restriction in chronic

[100] Dong J, Li Y, Yang Z, Luo J. Low dietary sodium intake increases the death risk in peritoneal dialysis. Clinical Journal of the American Society of Nephrology. 2010;**5**:240-247

[101] Cheng LT, Wang T. Changes in total sodium intake do not lead to proportionate changes in total sodium removal in CAPD patients. Peritoneal Dialysis International.

[102] Bae SY, Kim SB, Kim SM. Simple method to estimate daily sodium intake during measurement of dialysis adequacy in chronic peritoneal dialysis patients. Clin Nutr.

[103] Haddad N, Shim R, Hebert LA. Nutritional management of water, sodium, potassium, chloride, and magnesium in kidney disease and kidney failure. Nutr Manag Renal Dis

[104] Yip T, Wan W, Hui PC, Lui SL, Lo WL. Severe hiperkalemia in a peritoneal dialysis patients after consuption of salt substitute. Perit Dial Int. 2012;**32**(2):206-208

Journal of the American Society of Nephrology. 1997;**8**:1311-1314

kidney disease. International Journal of Nephrology. 2012;**2012**:720429

cardiovascular risk factors. Peritoneal Dialysis International. 2015;**35**:379-387

ysis patients. Peritoneal Dialysis International. 2005;**25**(S3):S73-S75

[91] Ha SK. Dietary salt intake and hypertension. Electrolyte Blood Press. 2014;**12**:7-18

1990;**38**:495-506

280 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

2012;**28**:10-15

Nephrology. 1995;**6**:198-206

2008;**28**(3):224-228

2006;**26**(2):218-223

2016;**35**(1):S191-S192

Chapter 22: 323-338, 2013

The aim of this study was to analyze the relationship between satisfaction with life in general and the sociodemographic and emotional factors and components of quality of life in people with chronic kidney disease undergoing hemodialysis. A cross-sectional and correlational study was performed on a sample of 171 people with chronic kidney disease in two hemodialysis units at a Clinic in Lisbon between May and June 2015. Subjective wellbeing (personal wellbeing index) is positively related with subjective happiness, positive affect, and quality of life and is negatively associated with negative affect. Subjective happiness, negative affect, and the physical component of quality of life influence subjective wellbeing. These conclusions can assist us in understanding that people with chronic kidney disease (CKD) encounter greater feelings of wellbeing, mainly related to pleasant affect (subjective happiness and positive affect).

**Keywords:** subjective wellbeing, emotion, quality of life, chronic renal insufficiency, renal dialysis

## **1. Introduction**

Due to its prevalence, chronic kidney disease (CKD) has been recognized as an important public health problem [1].

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

It has high economic implications in health systems and is also an independent risk factor for cardiovascular disease (CVD) [2]. All six stages of CKD [3] are associated with the increased risk of cardiovascular morbidity, premature mortality, and/or decreased quality of life (QoL) [2, 3].

Despite being considered as an important indicator for the QoL in people with CKD undergoing HD, SWB is still underexplored by researchers [17]. Therefore, we found it relevant to explore the sociodemographic and emotional factors that influence the cognitive dimension of the subjective wellbeing, that is to say, the satisfaction with life in general. Therefore, our main goal is to analyze the relationship between satisfaction with life in general and the sociodemo-

Subjective Wellbeing Assessment in People with Chronic Kidney Disease Undergoing…

http://dx.doi.org/10.5772/intechopen.71194

283

A cross-sectional and correlational study [18], developed in two units of the Diaverum Dialysis Clinic in the Lisbon region, Portugal, with people with CKD undergoing HD between May

The inclusion criteria defined for the population were people undergoing HD routinely for at least 6 months and aged 18 years or over. Exclusion criteria were people with cognitive impairment and active psychiatric illness. Information regarding these conditions was obtained through medical records, 253 people with CKD met the eligibility criteria (139 in clinic 1 and 114 in clinic 2). A simple random sample of 171 people undergoing HD was selected from the dialysis clinics,

Approval was received from the ethics committees of Diaverum (Approval No 1/2015). Both the purpose of the study and the guaranteed confidentiality of data with the right to withdraw without risk to oneself were explained to the people with CKD. Informed consent was therefore obtained from those who met the inclusion criteria and agreed to participate.

One of the researchers met with these nurses to explain the objectives and how to collect the data, followed by a written roadmap to assist in completing the data collection instruments. Data were collected through a sociodemographic and health information questionnaire (age, gender, nationality, education, occupation, marital status, dialysis sessions length, presence of hypertension, and diabetes), the subjective happiness scale (SHS) [19–21], the satisfaction with life in general (SWLG), the personal wellbeing index (PWI) [22, 23], the Portuguese version of positive and negative affect schedule (PANAS) [24–26], and the 12-item short form

Interviews were performed by five trained nurses during the HD session.

Retrospective license was obtained for the use of SF-12 (license No QM030904).

graphic and emotional factors and components of quality of life.

**2. Methods**

**2.1. Study design**

and June 2015.

**2.3. Procedures**

**2.2. Subjects and setting**

93 of clinic 1 and 78 of clinic 2.

health survey (SF-12) [27, 28].

CKD has an estimated prevalence of 11–13%, mostly related with stage 3 [2]. In the United States in 2012, its prevalence in stages 3–4 was about 6.9% (5.5–8.3) [4]. The adjusted prevalence of CKD in stages 1–5 varied between 3.31% (95% confidence interval [95% CI], 3.30–3.33%) in Norway and 17.3% (IC 95%, 16.5–18.1%) in north eastern Germany [5].

Worldwide, there are about 1.9 million people with CKD undergoing renal replacement therapy [6], namely hemodialysis (HD) or peritoneal dialysis. The first is the most common treatment modality [7].

HD is a treatment method usually performed in hospitals or clinics during 3–4 hours, three times a week [8]. This complex treatment has a high impact on the life of people with CKD. It requires several radical lifestyle changes that affect social and psychological functioning [9] as well as cause pain [7]. Therefore, it is considered a long-term treatment with significant side effects on the physical and mental wellbeing [10].

Health is a state of complete physical, mental, and social wellbeing and not merely the absence of disease or infirmity [11].

People with CKD receiving HD treatment can experience emotional instability and psychological distress, financial burdens, inadequate disease knowledge, and less social support, which influences their QoL [12]. CKD directly interferes in functional capacity, independence, and quality of life [13].

QoL and wellbeing as perceived by people with CKD are important measures of patients' health outcomes [12, 14].

As stated by the World Health Organization, subjective wellbeing (SWB) is considered within the research community as an indicator for the evaluation of QoL [14]. It consists of a range of phenomena that include emotional responses, satisfaction domains, and the judgment about global satisfaction with life. The components of SWB are pleasant affect (e.g., joy, contentment, pride, affection, and happiness), unpleasant affect (e.g., guilt and shame, anxiety and worry, anger, stress, and depression), life satisfaction (e.g., desire to change, satisfaction with current life, past, and future), and a satisfaction domain (e.g., work, family, leisure, health, finances, and self) [15].

A study developed in Indonesia using people with CKD undergoing HD showed that subjective wellbeing is directly related with the positive interpretation of the dialysis process. It also showed that people with CKD have happy feelings and are still able to manage negative emotions that arise. The negative feelings experienced by these people with CKD were anger, sadness, hopelessness, boredom, annoyance, and concern. The positive affects experienced were happiness, pleasure, gratefulness, and optimism [16].

Despite being considered as an important indicator for the QoL in people with CKD undergoing HD, SWB is still underexplored by researchers [17]. Therefore, we found it relevant to explore the sociodemographic and emotional factors that influence the cognitive dimension of the subjective wellbeing, that is to say, the satisfaction with life in general. Therefore, our main goal is to analyze the relationship between satisfaction with life in general and the sociodemographic and emotional factors and components of quality of life.

## **2. Methods**

It has high economic implications in health systems and is also an independent risk factor for cardiovascular disease (CVD) [2]. All six stages of CKD [3] are associated with the increased risk of cardiovascular morbidity, premature mortality, and/or decreased quality of life (QoL)

CKD has an estimated prevalence of 11–13%, mostly related with stage 3 [2]. In the United States in 2012, its prevalence in stages 3–4 was about 6.9% (5.5–8.3) [4]. The adjusted prevalence of CKD in stages 1–5 varied between 3.31% (95% confidence interval [95% CI], 3.30–3.33%) in

Worldwide, there are about 1.9 million people with CKD undergoing renal replacement therapy [6], namely hemodialysis (HD) or peritoneal dialysis. The first is the most common treat-

HD is a treatment method usually performed in hospitals or clinics during 3–4 hours, three times a week [8]. This complex treatment has a high impact on the life of people with CKD. It requires several radical lifestyle changes that affect social and psychological functioning [9] as well as cause pain [7]. Therefore, it is considered a long-term treatment with significant side

Health is a state of complete physical, mental, and social wellbeing and not merely the absence

People with CKD receiving HD treatment can experience emotional instability and psychological distress, financial burdens, inadequate disease knowledge, and less social support, which influences their QoL [12]. CKD directly interferes in functional capacity, independence,

QoL and wellbeing as perceived by people with CKD are important measures of patients'

As stated by the World Health Organization, subjective wellbeing (SWB) is considered within the research community as an indicator for the evaluation of QoL [14]. It consists of a range of phenomena that include emotional responses, satisfaction domains, and the judgment about global satisfaction with life. The components of SWB are pleasant affect (e.g., joy, contentment, pride, affection, and happiness), unpleasant affect (e.g., guilt and shame, anxiety and worry, anger, stress, and depression), life satisfaction (e.g., desire to change, satisfaction with current life, past, and future), and a satisfaction domain (e.g., work, family, leisure, health,

A study developed in Indonesia using people with CKD undergoing HD showed that subjective wellbeing is directly related with the positive interpretation of the dialysis process. It also showed that people with CKD have happy feelings and are still able to manage negative emotions that arise. The negative feelings experienced by these people with CKD were anger, sadness, hopelessness, boredom, annoyance, and concern. The positive affects experienced

Norway and 17.3% (IC 95%, 16.5–18.1%) in north eastern Germany [5].

effects on the physical and mental wellbeing [10].

282 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

were happiness, pleasure, gratefulness, and optimism [16].

[2, 3].

ment modality [7].

of disease or infirmity [11].

and quality of life [13].

health outcomes [12, 14].

finances, and self) [15].

## **2.1. Study design**

A cross-sectional and correlational study [18], developed in two units of the Diaverum Dialysis Clinic in the Lisbon region, Portugal, with people with CKD undergoing HD between May and June 2015.

## **2.2. Subjects and setting**

The inclusion criteria defined for the population were people undergoing HD routinely for at least 6 months and aged 18 years or over. Exclusion criteria were people with cognitive impairment and active psychiatric illness. Information regarding these conditions was obtained through medical records, 253 people with CKD met the eligibility criteria (139 in clinic 1 and 114 in clinic 2).

A simple random sample of 171 people undergoing HD was selected from the dialysis clinics, 93 of clinic 1 and 78 of clinic 2.

## **2.3. Procedures**

Approval was received from the ethics committees of Diaverum (Approval No 1/2015). Both the purpose of the study and the guaranteed confidentiality of data with the right to withdraw without risk to oneself were explained to the people with CKD. Informed consent was therefore obtained from those who met the inclusion criteria and agreed to participate.

Interviews were performed by five trained nurses during the HD session.

One of the researchers met with these nurses to explain the objectives and how to collect the data, followed by a written roadmap to assist in completing the data collection instruments.

Data were collected through a sociodemographic and health information questionnaire (age, gender, nationality, education, occupation, marital status, dialysis sessions length, presence of hypertension, and diabetes), the subjective happiness scale (SHS) [19–21], the satisfaction with life in general (SWLG), the personal wellbeing index (PWI) [22, 23], the Portuguese version of positive and negative affect schedule (PANAS) [24–26], and the 12-item short form health survey (SF-12) [27, 28].

Retrospective license was obtained for the use of SF-12 (license No QM030904).

## **2.4. Outcomes measurement**

The SHS [18] consists of four items; in items two and three, participants are asked to self-characterize themselves compared to their peers in absolute and relative terms. Items one and four correspond to descriptions of happiness and unhappiness. The last item score is reversed. On this scale, respondents are asked to self-characterize within a visual analogue scale with seven positions. The scale is based on two antagonistic statements, which express the level of happiness or lack of it [19, 20]. The Portuguese version in people with CKD shows a single factor with an internal reliability with a Cronbach's α of 0.90 [21].

**3. Results**

62.1% had hypertension, and 27.1% had diabetes.

mary SF and lower levels of negative affect.

Simultaneously, negative affect values decrease.

SF-12 (ρ = −0.271, p < 0.001).

ciated to satisfaction with life in general/personal wellbeing index.

(±9.2%), and mental component summary SF-12 com 47.2 (±10.7%) (**Table 2**).

The typical characteristics of participants were male (61%), an average age of 60.2 years old (SD = 14.34). About 80.1% had Portuguese nationality and the remaining were from an African country as follows: Cape Verde 14%; São Tomé 3.5%; Angola 1.8%, and Guinea 0.6%. On what concerns the educational level, 3.6% were illiterate, 42.3% had the 4th grade, 18.5% the 6th grade, 14.9% the 9th grade, 11.8% the 12th grade, and 8.9% have completed higher education. Regarding their marital status, 56.5%were married, 26.5% were single, 11.2% widowers, and 5.8% were divorced. About 76.7% were retired, only 23.3% had a regular professional activity. Concerning health data, the subjects were undergoing HD for about 72.17 months (±54.2),

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285

Portuguese people with CKD had the higher score for satisfaction with life in general (p = 0.015), compared with the remaining population (Cape Verde, São Tomé, Angola, and Guinea).

**Table 1** shows both sociodemographic and clinical factors related with CKD, which are asso-

Satisfaction with life in general/personal wellbeing index has a mean score of 64.7% (±18.2%). Mean scores for the other variables are as follows: subjective happiness 19.9 (±5.9), positive affect 24.9 (±8.5), negative affect 14.2 (±6.1), physical component summary SF-12 41.1%

**Table 3** shows that the personal wellbeing index is positively correlated with subjective happiness (ρ = 0.605, p < 0.001), positive affect (ρ = 0.328, p < 0.001), physical component summary SF-12(ρ = 0.470, p < 0.001), and mental component summary SF-12 (ρ = 0.319, p < 0.001). However, it presents a low negative correlation with the negative affect (ρ = −0.161, p < 0.05). Higher scores on the personal wellbeing index are associated with higher levels of subjective happiness, positive affect, physical component summary SF-12, and mental component sum-

Subjective happiness shows a significant positive correlation with the positive affect (ρ = 0.415, p < 0.001), physical component summary SF-12(ρ = 0.326, p < 0.001), and mental component summary SF-12 (ρ = 0.287, p < 0.001). Nevertheless, it shows a lower negative correlation with the negative affect (ρ = −0.126, p < 0.01). When subjective happiness values increase, positive affect, physical component summary SF-12, and mental component summary SF also increase.

Positive affect shows a significant positive correlation with the physical component summary SF-12 (ρ = 0.190, p < 0.01) and a mental component summary SF-12 (ρ = 0.166, p < 0.01).

Negative affect shows a significant negative correlation with the mental component summary

The PWI [22] consists of seven domains of the overall measure of life satisfaction (satisfaction with standard of living, health, personal development, personal relationships, sense of security, connection to the community, and security for the future). For each statement, the respondents are asked to classify their satisfaction within a scale from zero (extremely dissatisfied) to 10 (very satisfied) with a neutral intermediate position. The PWI is calculated on a rating ranging from zero to 100 (maximum percentage of the scale) [22, 23]. The Portuguese version in people with CKD revealed the existence of a single factor, with an internal reliability with a Cronbach's α of 0.82 [23].

The PANAS [24] scale was adapted and translated for the Portuguese population and consists of two subscales: PA and NA, with 10 items each, in which constructs are assessed on a Likert scale of 1–5. The respondents are asked to classify their emotions (for each of the 20 items) at the present time. The PA dimension is much more present than the higher score, a maximum of 50 points [25]. The study of the Portuguese version of PANAS in people with CKD revealed the same as the original scale, the existence of two factors, internal consistency with Cronbach's α of 0.86 (in the original, α = 0.88) for the positive affect and 0.88 (in the original, α = 0.87) for the negative affect scale [26].

SF-12 [27] is a health questionnaire developed in the United States of America, validated for several countries, from different continents. It measures the perception of healthrelated QoL through the use of 12 items with a resumed physical and mental component in which the constructs are evaluated on a Likert type scale from three to five points [27, 28]. The version translated and adapted to Portuguese showed reliability and satisfactory validity [27].

## **2.5. Data analysis**

Data were analyzed with descriptive and inferential statistics using the Statistical Package for Social Sciences (SPSS) 20.0 statistical software. Data obtained by SF12 were analyzed using the Quality Metric Health Outcomes™ Scoring Software 4.5. Descriptive statistics are reported as frequency, percentage, mean, and standard deviations, while inferential procedures included Spearman correlation coefficients and multiple linear regression. A 0.05 level of significance was adopted.

## **3. Results**

**2.4. Outcomes measurement**

ity with a Cronbach's α of 0.82 [23].

α = 0.87) for the negative affect scale [26].

validity [27].

was adopted.

**2.5. Data analysis**

with an internal reliability with a Cronbach's α of 0.90 [21].

284 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

The SHS [18] consists of four items; in items two and three, participants are asked to self-characterize themselves compared to their peers in absolute and relative terms. Items one and four correspond to descriptions of happiness and unhappiness. The last item score is reversed. On this scale, respondents are asked to self-characterize within a visual analogue scale with seven positions. The scale is based on two antagonistic statements, which express the level of happiness or lack of it [19, 20]. The Portuguese version in people with CKD shows a single factor

The PWI [22] consists of seven domains of the overall measure of life satisfaction (satisfaction with standard of living, health, personal development, personal relationships, sense of security, connection to the community, and security for the future). For each statement, the respondents are asked to classify their satisfaction within a scale from zero (extremely dissatisfied) to 10 (very satisfied) with a neutral intermediate position. The PWI is calculated on a rating ranging from zero to 100 (maximum percentage of the scale) [22, 23]. The Portuguese version in people with CKD revealed the existence of a single factor, with an internal reliabil-

The PANAS [24] scale was adapted and translated for the Portuguese population and consists of two subscales: PA and NA, with 10 items each, in which constructs are assessed on a Likert scale of 1–5. The respondents are asked to classify their emotions (for each of the 20 items) at the present time. The PA dimension is much more present than the higher score, a maximum of 50 points [25]. The study of the Portuguese version of PANAS in people with CKD revealed the same as the original scale, the existence of two factors, internal consistency with Cronbach's α of 0.86 (in the original, α = 0.88) for the positive affect and 0.88 (in the original,

SF-12 [27] is a health questionnaire developed in the United States of America, validated for several countries, from different continents. It measures the perception of healthrelated QoL through the use of 12 items with a resumed physical and mental component in which the constructs are evaluated on a Likert type scale from three to five points [27, 28]. The version translated and adapted to Portuguese showed reliability and satisfactory

Data were analyzed with descriptive and inferential statistics using the Statistical Package for Social Sciences (SPSS) 20.0 statistical software. Data obtained by SF12 were analyzed using the Quality Metric Health Outcomes™ Scoring Software 4.5. Descriptive statistics are reported as frequency, percentage, mean, and standard deviations, while inferential procedures included Spearman correlation coefficients and multiple linear regression. A 0.05 level of significance The typical characteristics of participants were male (61%), an average age of 60.2 years old (SD = 14.34). About 80.1% had Portuguese nationality and the remaining were from an African country as follows: Cape Verde 14%; São Tomé 3.5%; Angola 1.8%, and Guinea 0.6%. On what concerns the educational level, 3.6% were illiterate, 42.3% had the 4th grade, 18.5% the 6th grade, 14.9% the 9th grade, 11.8% the 12th grade, and 8.9% have completed higher education. Regarding their marital status, 56.5%were married, 26.5% were single, 11.2% widowers, and 5.8% were divorced. About 76.7% were retired, only 23.3% had a regular professional activity. Concerning health data, the subjects were undergoing HD for about 72.17 months (±54.2), 62.1% had hypertension, and 27.1% had diabetes.

Portuguese people with CKD had the higher score for satisfaction with life in general (p = 0.015), compared with the remaining population (Cape Verde, São Tomé, Angola, and Guinea).

**Table 1** shows both sociodemographic and clinical factors related with CKD, which are associated to satisfaction with life in general/personal wellbeing index.

Satisfaction with life in general/personal wellbeing index has a mean score of 64.7% (±18.2%). Mean scores for the other variables are as follows: subjective happiness 19.9 (±5.9), positive affect 24.9 (±8.5), negative affect 14.2 (±6.1), physical component summary SF-12 41.1% (±9.2%), and mental component summary SF-12 com 47.2 (±10.7%) (**Table 2**).

**Table 3** shows that the personal wellbeing index is positively correlated with subjective happiness (ρ = 0.605, p < 0.001), positive affect (ρ = 0.328, p < 0.001), physical component summary SF-12(ρ = 0.470, p < 0.001), and mental component summary SF-12 (ρ = 0.319, p < 0.001). However, it presents a low negative correlation with the negative affect (ρ = −0.161, p < 0.05). Higher scores on the personal wellbeing index are associated with higher levels of subjective happiness, positive affect, physical component summary SF-12, and mental component summary SF and lower levels of negative affect.

Subjective happiness shows a significant positive correlation with the positive affect (ρ = 0.415, p < 0.001), physical component summary SF-12(ρ = 0.326, p < 0.001), and mental component summary SF-12 (ρ = 0.287, p < 0.001). Nevertheless, it shows a lower negative correlation with the negative affect (ρ = −0.126, p < 0.01). When subjective happiness values increase, positive affect, physical component summary SF-12, and mental component summary SF also increase. Simultaneously, negative affect values decrease.

Positive affect shows a significant positive correlation with the physical component summary SF-12 (ρ = 0.190, p < 0.01) and a mental component summary SF-12 (ρ = 0.166, p < 0.01).

Negative affect shows a significant negative correlation with the mental component summary SF-12 (ρ = −0.271, p < 0.001).


**Table 1.** Sociodemographic and clinical factors associated to satisfaction with life in general. Lisbon, Portugal (2017).

Both subjective happiness and physical component summary SF-12 have a positive effect on satisfaction with life in general (respectively, β = 0.426, p < 0.001; β = 0.310, p < 0.001). However, negative affect has a negative effect on satisfaction with life in general (β = −0.121, p < 0.05).

**Table 3.** Regression for personal wellbeing index with other variables and correlations. Lisbon, Portugal (2017).

**Range Minimum Maximum Mean Standard** 

0–100 6.3 100 64.7 18.2

Subjective Wellbeing Assessment in People with Chronic Kidney Disease Undergoing…

**1 2 3 4 5 β t**

0.470‡ 0.326‡ 0.190† 0.100 0.310 5.121‡

0.319‡ 0.287‡ 0.166† −0.271‡ 0.181† 0.093 1.520

2.Subjective happiness 4–28 4 28 19.9 5.9 3.Positive affect 10–50 10 44 24.9 8.5 4.Negative affect 10–50 10 40 14.2 6.1 5. Physical component summary SF-12 0–100 17.3 63.2 40.1 9.2 6. Mental component summary SF-12 0–100 21.6 66.1 47.2 10.7

Constant 1.035

2. Subjective happiness 0.605‡ 0.426 6.422‡ 3. Positive affect 0.328‡ 0.415‡ 0.,086 1.378 4. Negative affect −0.161\* −0.126† 0.084 −0.121 −2.006\*

**Table 2.** Mean and standard deviation for the different variables. Lisbon, Portugal (2017).

**deviation**

287

http://dx.doi.org/10.5772/intechopen.71194

This study is aimed at examining the relationship between satisfaction with life in general and the components of quality of life, sociodemographic characteristics, and emotional factors.

**4. Discussion**

1. Satisfaction with life in general/personal

wellbeing index

1. Satisfaction with life in general/personal wellbeing index

5. Physical component summary SF-12

6. Mental component summary SF-12

\*Significance p < 0.05, †Significance p < 0.01, ‡Significance p < 0.001.

Sample size = 171, Adjusted R<sup>2</sup> = 0.466, F = 30.637‡

The physical component summary SF-12 shows a lower positive correlation with the mental component summary SF-12 (ρ = 0.181, p < 0.01).

The adjusted R2 for the model was 46.6% with subjective happiness, negative affect, and physical component summary SF-12 that consistently contributed as best predictors of satisfaction with life in general/personal wellbeing index. The resulting R2 were statistically significant at the p < 0.00 and p < 0.05 levels.


**Table 2.** Mean and standard deviation for the different variables. Lisbon, Portugal (2017).


**Table 3.** Regression for personal wellbeing index with other variables and correlations. Lisbon, Portugal (2017).

Both subjective happiness and physical component summary SF-12 have a positive effect on satisfaction with life in general (respectively, β = 0.426, p < 0.001; β = 0.310, p < 0.001). However, negative affect has a negative effect on satisfaction with life in general (β = −0.121, p < 0.05).

## **4. Discussion**

The physical component summary SF-12 shows a lower positive correlation with the mental

**Table 1.** Sociodemographic and clinical factors associated to satisfaction with life in general. Lisbon, Portugal (2017).

**Satisfaction with life in general/personal** 

**p-Value**

p = 0.015

**wellbeing index**

Male 64.2 ± 18.0 p = 0.779

Under 63 years 66.5 ± 17.1 p = 0.060

Retired 64.4 ± 19.0 p = 0.364

Single 67.4 ± 18.2 p = 0.134

No 67.6 ± 18.1 p = 0.177

No 66.0 ± 18.4 p = 0.080

Less than 5 years 65.7 ± 17.3 p = 0.937

70.5 ± 15.9 63.2 ± 18.3

component summary SF-12 that consistently contributed as best predictors of satisfaction with life in general/personal wellbeing index. The resulting R2 were statistically significant at the

for the model was 46.6% with subjective happiness, negative affect, and physical

component summary SF-12 (ρ = 0.181, p < 0.01).

The adjusted R2

**Gender**

**Age**

**Nationality** Portuguese Other

**Professional activity**

**Arterial hypertension**

**Hemodialysis time**

**Marital status**

**Diabetes**

Female 64.8 ± 18.1

286 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

More than 63 years 62.6 ± 18.9

Active 66.8 ± 15.4

Married 64.9 ± 17.5 Other 59.5 ± 18.9

Yes 62.9 ± 17.9

Yes 60.1 ± 16.5

More than 5 yeas 63.4 ± 19.0

p < 0.00 and p < 0.05 levels.

This study is aimed at examining the relationship between satisfaction with life in general and the components of quality of life, sociodemographic characteristics, and emotional factors.

Our findings are in line with the literature on the effects of HD on the life of people with CKD and factors associated with reduced wellbeing.

Also, both clinics involved in the study are in the same region influencing sociodemographic characteristics and preventing the generalization of conclusions. Data collection environment (HD room) can lead to distraction in people with CKD. However, others studies [34, 35] were conducted in the same conditions, which do not seem to affect the results. Questionnaires were self-reported or by interview, so some might have given socially accepted answers that could lead to response bias. Finally, the small sample size might have limited the validity of the results. Therefore, a study with a larger sample might have more statistical meaning in

Subjective Wellbeing Assessment in People with Chronic Kidney Disease Undergoing…

http://dx.doi.org/10.5772/intechopen.71194

289

Nursing professionals have an important role in the promotion of wellbeing and quality of life. The SWB measured by the PWI is an important element in QoL [17]. This study results suggest that people with CKD with higher levels of subjective happiness and quality of life (mental and physical component) also have higher levels of SWB. Thus, these results may help future interventions related to the wellbeing of people with CKD, aimed at improving nurse training for the identification and monitoring of these dysfunctional behaviors. Nurses

Depressive symptoms in people with CKD are associated with decreased quality of life [36] and decreased wellbeing [17]. Dialysis nurses should therefore be encouraged to increase people with CKD's happiness through the integration of laughter yoga [37], the Fordyce's happiness program [38], and the visualization of humor films [39], during dialysis sessions. This intervention will improve both people with CKD's wellbeing and health outcomes, such

Our results show that SWB (personal wellbeing index) is positively related with subjective happiness, positive affect, and quality of life and is negatively associated with negative affect. Subjective happiness, negative affect, and the physical component of quality of life influence SWB. These conclusions can assist us in understanding that people with CKD encounter greater feelings of wellbeing, mainly related to pleasant affect (subjective happiness and positive affect). This study has confirmed that SWB is lower in people with CKD than in the general population, though this is partly explained by the negative affect. However, SWB increases when both subjective happiness perception and quality of life increase. These conclusions can assist us in understanding that people with CKD encounter higher feelings of wellbeing, not only related to pleasant affect (subjective happiness and positive affect) but also to many other aspects of QoL. Future studies should be performed in people undergoing HD that demonstrate the effect of interventions on cognitive and emotional variables of the SWB, as is the case of the visualiza-

examining associations between variables.

will be boosted to optimize patient health outcomes.

as quality of life, affect, and depressive symptoms.

**4.2. Implications for practice**

**5. Conclusion**

tion of humor films.

On what concerns sociodemographic factors, differences were only found in people with CKD of a different nationality. This may be explained by cultural differences, as people with CKD from foreign countries may experience social integration difficulties.

The economic level of countries generally influences all indicators of health and quality of life; however, the SWB in higher income countries is affected by other factors such as income inequality, social welfare, individualism, democracy and freedom, social capital, and physical health [29]. These data are reinforced by the results of a study, which report that the economic level of people negatively affects the SWB in both low income and high income countries [30].

As already mentioned, there is a scarcity of literature concerning wellbeing in people with CKD. Our study confirmed lower scores for GWLS in people with CKD (64.7 ± 18.2). Similarly, the Australian study with people with end-stage kidney disease got an average PWI of 64.7 ± 19.2 and of 74.8 ± 15.7 for the general population [17]. Lower SWB may cause adverse health behaviors in people with CKD. In a study involving people living with HIV, it was suggested that reduced SWB increased the risk of medication nonadherence [31]. Future studies should explore the relationship between wellbeing, adherence to medication, food, and physical activity levels. This association can allow the development of individualized interventions that promote wellbeing in the hemodialysed population and impact on other domains of the personal and social life of these people.

The mean scores for all domains of QoL for people with CKD were considerably below the general population norms. Similar results were found in an Irish study on the QoL of people with CKD undergoing HD treatment [32].

Our main finding is that happiness, pleasant affect, physical, and mental components of QoL are significantly higher in people undergoing HD who got higher scores for the personal wellbeing index/satisfaction with life in general. Subjective happiness and physical components of QoL are those that contribute the most for the overall life satisfaction. On the other hand, negative affect has a significant negative association and influences satisfaction with life in general.

The association between quality of life, morbidity, and mortality has already been explored in previous studies [17]. Chida and Steptoe [33] described SWB as a significant and independent variable predicting increased survival times in CKD. Our study shows the importance of evaluating the components of SWB in people with CKD undergoing HD treatment. It allows us to examine the influence of both emotional components (subjective happiness and negative affect) and physical components of QoL, in cognitive dimension of SWB (satisfaction with life in general/personal wellbeing index).

## **4.1. Limitations**

There are some limitations in this study. Our results are based on a cross-sectional design that may limit the discussion of a cause-effect relationship between SWB and the variables. Also, both clinics involved in the study are in the same region influencing sociodemographic characteristics and preventing the generalization of conclusions. Data collection environment (HD room) can lead to distraction in people with CKD. However, others studies [34, 35] were conducted in the same conditions, which do not seem to affect the results. Questionnaires were self-reported or by interview, so some might have given socially accepted answers that could lead to response bias. Finally, the small sample size might have limited the validity of the results. Therefore, a study with a larger sample might have more statistical meaning in examining associations between variables.

## **4.2. Implications for practice**

Our findings are in line with the literature on the effects of HD on the life of people with CKD

On what concerns sociodemographic factors, differences were only found in people with CKD of a different nationality. This may be explained by cultural differences, as people with

The economic level of countries generally influences all indicators of health and quality of life; however, the SWB in higher income countries is affected by other factors such as income inequality, social welfare, individualism, democracy and freedom, social capital, and physical health [29]. These data are reinforced by the results of a study, which report that the economic level of people negatively affects the SWB in both low income and high income countries [30].

As already mentioned, there is a scarcity of literature concerning wellbeing in people with CKD. Our study confirmed lower scores for GWLS in people with CKD (64.7 ± 18.2). Similarly, the Australian study with people with end-stage kidney disease got an average PWI of 64.7 ± 19.2 and of 74.8 ± 15.7 for the general population [17]. Lower SWB may cause adverse health behaviors in people with CKD. In a study involving people living with HIV, it was suggested that reduced SWB increased the risk of medication nonadherence [31]. Future studies should explore the relationship between wellbeing, adherence to medication, food, and physical activity levels. This association can allow the development of individualized interventions that promote wellbeing in the hemodialysed population and impact on other

The mean scores for all domains of QoL for people with CKD were considerably below the general population norms. Similar results were found in an Irish study on the QoL of people

Our main finding is that happiness, pleasant affect, physical, and mental components of QoL are significantly higher in people undergoing HD who got higher scores for the personal wellbeing index/satisfaction with life in general. Subjective happiness and physical components of QoL are those that contribute the most for the overall life satisfaction. On the other hand, negative affect has a significant negative association and influences satisfaction with life in general. The association between quality of life, morbidity, and mortality has already been explored in previous studies [17]. Chida and Steptoe [33] described SWB as a significant and independent variable predicting increased survival times in CKD. Our study shows the importance of evaluating the components of SWB in people with CKD undergoing HD treatment. It allows us to examine the influence of both emotional components (subjective happiness and negative affect) and physical components of QoL, in cognitive dimension of SWB (satisfaction with life

There are some limitations in this study. Our results are based on a cross-sectional design that may limit the discussion of a cause-effect relationship between SWB and the variables.

CKD from foreign countries may experience social integration difficulties.

and factors associated with reduced wellbeing.

288 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

domains of the personal and social life of these people.

with CKD undergoing HD treatment [32].

in general/personal wellbeing index).

**4.1. Limitations**

Nursing professionals have an important role in the promotion of wellbeing and quality of life. The SWB measured by the PWI is an important element in QoL [17]. This study results suggest that people with CKD with higher levels of subjective happiness and quality of life (mental and physical component) also have higher levels of SWB. Thus, these results may help future interventions related to the wellbeing of people with CKD, aimed at improving nurse training for the identification and monitoring of these dysfunctional behaviors. Nurses will be boosted to optimize patient health outcomes.

Depressive symptoms in people with CKD are associated with decreased quality of life [36] and decreased wellbeing [17]. Dialysis nurses should therefore be encouraged to increase people with CKD's happiness through the integration of laughter yoga [37], the Fordyce's happiness program [38], and the visualization of humor films [39], during dialysis sessions. This intervention will improve both people with CKD's wellbeing and health outcomes, such as quality of life, affect, and depressive symptoms.

## **5. Conclusion**

Our results show that SWB (personal wellbeing index) is positively related with subjective happiness, positive affect, and quality of life and is negatively associated with negative affect. Subjective happiness, negative affect, and the physical component of quality of life influence SWB. These conclusions can assist us in understanding that people with CKD encounter greater feelings of wellbeing, mainly related to pleasant affect (subjective happiness and positive affect).

This study has confirmed that SWB is lower in people with CKD than in the general population, though this is partly explained by the negative affect. However, SWB increases when both subjective happiness perception and quality of life increase. These conclusions can assist us in understanding that people with CKD encounter higher feelings of wellbeing, not only related to pleasant affect (subjective happiness and positive affect) but also to many other aspects of QoL.

Future studies should be performed in people undergoing HD that demonstrate the effect of interventions on cognitive and emotional variables of the SWB, as is the case of the visualization of humor films.

## **Author details**

Luís Manuel Mota de Sousa1,2\*, Ana Vanessa Antunes<sup>1</sup> , Cristina Rosa Soares Lavareda Baixinho3 , Sandy Silva Pedro Severino1,2, Cristina Maria Alves Marques-Vieira4 and Helena Maria Guerreiro José5

\*Address all correspondence to: luismmsousa@gmail.com

1 Atlântica Higher School of Health Sciences, Atlântica University, Oeiras, Portugal

2 Curry Cabral Hospital, Central Lisbon Hospital Center, Lisbon, Portugal

3 Nursing School of Lisbon – ESEL, Lisbon, Portugal

4 School of Nursing of Lisbon, Institute of Health Sciences, Catholic University of Portugal, Lisbon, Portugal

[6] Anand S, Bitton A, Gaziano T. The gap between estimated incidence of end-stage renal disease and use of therapy. PLoS One. 2013 Aug 30 [cited 2017 Aug 18];**8**(8):e72860.

Subjective Wellbeing Assessment in People with Chronic Kidney Disease Undergoing…

http://dx.doi.org/10.5772/intechopen.71194

291

[7] Sousa LM, Marques-Vieira CM, Severino SS, Pozo-Rosado JL, José HM. Validation of the brief pain inventory in persons with chronic kidney disease. Aquichan. 2017 Jan [cited

[8] Ferguson TW, Tangri N, Rigatto C, Komenda P. Cost-effective treatment modalities for reducing morbidity associated with chronic kidney disease. Expert Review of Pharmacoeconomics & Outcomes Research. 2015 Mar 4 [cited 2017 Aug 19];**15**(2):243-

[9] Nabolsi MM, Wardam L, Al-Halabi JO. Quality of life, depression, adherence to treatment and illness perception of patients on haemodialysis. International Journal of Nursing Practice. 2015 Feb 1 [cited 2017 Aug 19];**21**(1):1-10. DOI: 10.1111/ijn.12205 Epub 2013 Oct 11

[10] Mehrabi Y, Ghazavi Z, Shahgholian N. Effect of Fordyce's happiness program on stress, anxiety, and depression among the patients undergoing hemodialysis. Iranian Journal of Nursing and Midwifery Research. 2017 May 1 [cited 2017 Aug 19];**22**(3):190-194. DOI:

[11] World Health Organization. WHO Terminology Information System [Online Glossary] [cited 2017 Aug 19]. Available from: http://www.who.int/healthsystems/hss\_glossary/en/

[12] Yu HD, Petrini MA. The HRQoL of Chinese patients undergoing haemodialysis. Journal of Clinical Nursing. 2010 Mar 1 [cited 2017 Aug 19];**19**(5-6):658-665. DOI:

[13] Fassbinder TR, Winkelmann ER, Schneider J, Wendland J, Oliveira OB. Functional capacity and quality of life in patients with chronic kidney disease in pre-dialytic treatment and on hemodialysis–A cross sectional study. Jornal Brasileiro de Nefrologia. 2015 Mar

[14] Weinberg MK, Bennett PN, Cummins RA. Validation of the personal wellbeing index for people with end stage kidney disease. Applied Research in Quality of Life. 2016 Dec 1

[15] Diener E, Suh EM, Lucas RE, Smith HL. Subjective well-being: Three decades of progress. Psychological Bulletin. 1999 [cited 2017 Aug 19];**125**:276-302. Available from: http:// web.yonsei.ac.kr/suh/file/Subjective%20Well%20Being\_Three%20Decades%20of%20

[16] Setyawati R. Subjective well-being description of patients with chronic kidney disease undergoing hemodialysis. Indigenous Psychology Seminar. 2014 Apr 19 [cited 2017 Aug 19];**1**(1):301-307. Available from: http://digilib.ump.ac.id/files/disk1/27/jhptump-ump-

[cited 2017 Aug 19];**11**(4):1227-1240. https://doi.org/10.1007/s11482-015-9431-x

[cited 2017 Aug 19];**37**(1):47-54. DOI: 10.5935/0101-2800.20150008

Progress%20-Diener,%20Suh,%20Lucas&Smith.pdf

gdl-rrsetyawat-1334-1-38-roro--7.pdf

2017 Aug 19];**17**(1):42-52. http://dx.doi.org/10.5294/aqui.2017.17.1.5

252. DOI: 10.1586/14737167.2015.1012069 Epub 2015 Feb 8

https://doi.org/10.1371/journal.pone.0072860

10.4103/1735-9066.208162

10.1111/j.1365-2702.2009.03071.x

index5.html

5 Polytechnic Health Institute of Multiperfil, Luanda, Angola

## **References**


[6] Anand S, Bitton A, Gaziano T. The gap between estimated incidence of end-stage renal disease and use of therapy. PLoS One. 2013 Aug 30 [cited 2017 Aug 18];**8**(8):e72860. https://doi.org/10.1371/journal.pone.0072860

**Author details**

Lisbon, Portugal

**References**

Luís Manuel Mota de Sousa1,2\*, Ana Vanessa Antunes<sup>1</sup>

290 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

\*Address all correspondence to: luismmsousa@gmail.com

3 Nursing School of Lisbon – ESEL, Lisbon, Portugal

5 Polytechnic Health Institute of Multiperfil, Luanda, Angola

1 Atlântica Higher School of Health Sciences, Atlântica University, Oeiras, Portugal

4 School of Nursing of Lisbon, Institute of Health Sciences, Catholic University of Portugal,

[1] Du Y, Zhang S, Hu M, Wang Q, Shen H, Zhang Y, Yan D, Li Y, Zhang M, Meng Q. Prevalence of chronic kidney disease markers: Evidence from a three-million married population with fertility desire in rural China. Scientific Reports. 2017 [cited 2017 Aug 18];**7**(1):2710. DOI:

[2] Hill NR, Fatoba ST, Oke JL, Hirst JA, O'Callaghan CA, Lasserson DS, Hobbs FR. Global prevalence of chronic kidney disease–A systematic review and meta-analysis. PLoS One. 2016 Jul 6 [cited 2017 Aug 18];**11**(7):e0158765. https://doi.org/10.1371/journal.pone.0158765

[3] Inker LA, Astor BC, Fox CH, Isakova T, Lash JP, Peralta CA, Tamura MK, Feldman HI. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD. American Journal of Kidney Diseases. 2014 May 31 [cited 2017 Sep 4];**63**(5):713-735. DOI: 10.1053/j.ajkd.2014.01.416 Epub 2014 Mar 16

[4] Murphy D, McCulloch CE, Lin F, Banerjee T, Bragg-Gresham JL, Eberhardt MS, Morgenstern H, Pavkov ME, Saran R, Powe NR, Hsu CY. Trends in prevalence of chronic kidney disease in the United States trends in prevalence of CKD in the United States. Annals of Internal Medicine. 2016 Oct 4 [cited 2017 Aug 18];**165**(7):473-481. DOI: 10.7326/

[5] Brück K, Stel VS, Gambaro G, Hallan S, Völzke H, Ärnlöv J, Kastarinen M, Guessous I, Vinhas J, Stengel B, Brenner H. CKD prevalence varies across the European general population. Journal of the American Society of Nephrology. 2016 Jul 1 [cited 2017 Aug

18];**27**(7):2135-2147. DOI: 10.1681/ASN.2015050542 Epub 2015 Dec 23

2 Curry Cabral Hospital, Central Lisbon Hospital Center, Lisbon, Portugal

Cristina Rosa Soares Lavareda Baixinho3

Cristina Maria Alves Marques-Vieira4

10.1038/s41598-017-02355-2

M16-0273 Epub 2016 Aug 2

,

and Helena Maria Guerreiro José5

, Sandy Silva Pedro Severino1,2,


[17] Bennett PN, Weinberg MK, Bridgman T, Cummins RA. The happiness and subjective well-being of people on haemodialysis. Journal of Renal Care. 2015 Sep 1 [cited 2017 Aug 19];**41**(3):156-161. DOI: 10.1111/jorc.12116 Epub 2015 Mar 26

ZN, Nascimento LCG, Valentim OS, editors. Qualidade de vida e condições de saúde de

Subjective Wellbeing Assessment in People with Chronic Kidney Disease Undergoing…

http://dx.doi.org/10.5772/intechopen.71194

293

[29] Jorm AF, Ryan SM. Cross-national and historical differences in subjective well-being. International Journal of Epidemiology. 2014 Feb 28 [cited 2017 Sep 5];**43**(2):330-340. DOI:

[30] Sarracino F. Determinants of subjective well-being in high and low income countries: Do happiness equations differ across countries. The Journal of Socio-Economics. 2013 Feb 11

[31] Hutton VE, Misajon R, Collins FE. Subjective wellbeing and 'felt'stigma when living with HIV. Quality of Life Research. 2013 Feb 1 [cited 2017 Sep 1];**22**(1):65-73. DOI: 10.1093/ije/

[32] Alshraifeen A, McCreaddie M, Evans JM. Quality of life and well-being of people receiving haemodialysis treatment in Scotland: A cross-sectional survey. International Journal of Nursing Practice. 2014 Oct [cited 2017 Sep 1];**20**(5):518-523. DOI: 10.1111/ijn.12194 [33] Chida Y, Steptoe A. Positive psychological well-being and mortality: A quantitative review of prospective observational studies. Psychosomatic Medicine. 2008 Sep 1 [cited 2017 Sep 1];**70**(7):741-745. DOI: 10.1097/PSY.0b013e31818105ba Epub 2008 Aug 25

[34] Saffari M, Pakpour AH, Naderi MK, Koenig HG, Baldacchino DR, Piper CN. Spiritual coping, religiosity and quality of life: A study on Muslim patients undergoing haemodialysis. Nephrology. 2013 Apr 1 [cited 2017 Sep 1];**18**(4):269-275. DOI: 10.1111/nep.12041

[35] Vitorino LM, Soares RCS, Santos AEO, Lucchetti PALG, Cruz JP, Cortez PJO, Lucchetti G. Two sides of the same coin: The positive and negative impact of spiritual religious coping on quality of life and depression in dialysis patients. Journal of Holistic Nursing.

[36] Belayev LY, Mor MK, Sevick MA, Shields AM, Rollman BL, Palevsky PM, Arnold RM, Fine MJ, Weisbord SD. Longitudinal associations of depressive symptoms and pain with quality of life in patients receiving chronic hemodialysis. Hemodialysis International. 2015 Apr 1 [cited 2017 Sep 1];**19**(2):216-224. DOI: 10.1111/hdi.12247 Epub 2014 Nov 18

[37] Bennett PN, Parsons T, Ben-Moshe R, Neal M, Weinberg MK, Gilbert K, Ockerby C, Rawson H, Herbu C, Hutchinson AM. Intradialytic laughter yoga therapy for haemodialysis patients: A pre-post intervention feasibility study. BMC Complementary and Alternative

Medicine. 2015 Jun 9 [cited 2017 Sep 1];**15**(1):176. DOI: 10.1186/s12906-015-0705-5

[38] Mehrabi Y, Ghazavi Z, Shahgholian N. Effect of Fordyce's happiness program on stress, anxiety, and depression among the patients undergoing hemodialysis. Iranian Journal of Nursing and Midwifery Research. 2017 May 1 [cited 2017 Sep 1];**22**(3):190-194. DOI:

[39] Sousa LMM. Ganhos em saúde com a intervenção "humor" em pessoas com doença renal crónica [Gains in Health with "humor" Intervention in People with Chronic Kidney Disease]Doctoral Dissertation in Nursing. Lisbon: Catholic University of Portugal; 2017

2017 Aug [cited 2017 Sep 1]. DOI: 10.1177/0898010117725429

diversas populações. Vol. 2. Curitiba: Editora CRV; 2017 Sep. p. 139-154

[cited 2017 Sep 5];**42**(3):51-66. https://doi.org/10.1016/j.socec.2012.11.006

10.1093/ije/dyt188 Epub 2014 Feb 28

dyt188 Epub 2014 Feb 28

10.4103/1735-9066.208162


ZN, Nascimento LCG, Valentim OS, editors. Qualidade de vida e condições de saúde de diversas populações. Vol. 2. Curitiba: Editora CRV; 2017 Sep. p. 139-154

[29] Jorm AF, Ryan SM. Cross-national and historical differences in subjective well-being. International Journal of Epidemiology. 2014 Feb 28 [cited 2017 Sep 5];**43**(2):330-340. DOI: 10.1093/ije/dyt188 Epub 2014 Feb 28

[17] Bennett PN, Weinberg MK, Bridgman T, Cummins RA. The happiness and subjective well-being of people on haemodialysis. Journal of Renal Care. 2015 Sep 1 [cited 2017 Aug

[18] DVM L. Research design: A contribution to the author. Online Brazilian Journal of Nursing [Internet]. 2011 [cited 2017 Aug 19];**10**(2). Available from: http://www.objnurs-

[19] Lyubomirsky S, Lepper HS. A measure of subjective happiness: Preliminary reliability and construct validation. Social Indicators Research. 1999 [cited 2017 Aug 19];**46**(2):137-

[20] Pais-Ribeiro JL. Validação transcultural da Escala de Felicidade Subjectiva de Lyubomirsky e Lepper. Psicol Saúde Doenças [Internet]. 2012 [cited 2017 Aug 19];**13**(2):157-168. Available from: http://www.scielo.mec.pt/scielo.php?script=sci\_arttext&pid=S1645-008

[21] Sousa LM, Vieira CM, Severino SS, Pozo-Rosado JL, José HM. Validation of the subjective happiness scale in people with chronic kidney disease. Enfermeria Global. 2017 Jul [cited 2017 Aug 19];**16**(3):60-70. Available from: http://revistas.um.es/eglobal/article/view/266571

[22] Ribeiro JP, Cummins R. O bem-estar pessoal: estudo de validação da versão portuguesa da escala. In: Actas do 7° Congresso Nacional de Psicologia da Saúde [Internet]. Lisboa: ISPA; 2008 [cited 2017 Aug 19]. p. 505-508. Available from: http://repositorio-aberto.

[23] Sousa LMM, Marques-Vieira CMA, Severino SSP, Pozo Rosado JL, MHG J. Validación del Índice de Bien-estar Personal en personas con enfermedad renal crónica. Enfermería nefrológica. 2016 Jun [cited 2017 Aug 19];**19**(2):135-141. Available from: http://scielo.isciii. es/scielo.php?script=sci\_arttext&pid=S2254-28842016000200005&lng=es&nrm=iso&tlng=es

[24] Watson D, Clark LA, Tellegen A. Development and validation of brief measures of positive and negative affect: The PANAS scales. Journal of Personality and Social Psychology. 1988 [cited 2017 Aug 19];**54**:1063-1070. http://dx.doi.org/10.1037/0022-3514.54.6.1063 [25] Galinha I, Ribeiro J. Contribuição para o estudo da versão portuguesa da Positive and Negative Affect Schedule (PANAS): II–Estudo psicométrico. Analise Psicologica [Internet]. 2005 [cited 2017 Aug 19];**23**(2):219-227. Available from: http://publicacoes.ispa.

[26] Sousa LM, Marques-Vieira CM, Severino SS, Rosado JL, José HM. Validation of the positive and negative affect schedule in people with chronic kidney disease. Texto & Contexto–Enfermagem. 2016 [cited 2017 Aug 19];**25**(4) e5610015 (1-8). Available from: http://www.scielo.br/scielo.php?pid=S0104-07072016000400332&script=sci\_arttext [27] Ferreira-Valente MA, Ribeiro JLP, Jensen MP. Contribución adicional para la validación de la versión portuguesa de la Escala de Interferencia del Inventario Breve de Dolor. Clínica y Salud. 2012 [cited 2017 Aug 19];**23**(1):89-96. http://dx.doi.org/10.5093/cl2012a6

[28] Sousa LM, Antunes AV, Marques-Vieira CM, Valentim OS, José HM. Qualidade de vida e pessoa com doença renal crónica: um estudo transversal. In: Missias-Moreira R, Sales

155. Available from: http://www.cnbc.pt/jpmatos/26.%20lyubomirsky.pdf

19];**41**(3):156-161. DOI: 10.1111/jorc.12116 Epub 2015 Mar 26

ing.uff.br/index.php/nursing/article/view/3648/html\_2

292 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

62012000200003&lng=pt

up.pt/handle/10216/21065

pt/index.php/ap/article/viewFile/84/pdf


## *Edited by Thomas Rath*

Known worldwide, chronic kidney disease (CKD) is a disease that affects up to 4% of the population with increasing figures also in the developing countries. Life expectancy of patients affected by CKD is shortened compared to the overall population, and only a minority of patients reach end-stage renal disease (ESRD) with the need for dialysis or renal transplantation; death overtakes dialysis.

In the 13 chapters, this book sheds light on the different aspects related to pathophysiology and clinical aspects of CKD, providing interesting insights into not only inflammation and cardiovascular risk but also the interplay of hormones and the functional aspects of endothelial function. In addition, chapters dealing with genetic aspects of polycystic kidney disease and also the clinical handling of patients with CKD and peritoneal dialysis will be beneficial for the open-minded reader.

Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

Chronic Kidney Disease

from Pathophysiology to Clinical

Improvements

*Edited by Thomas Rath*

Photo by Josep Maria Barres / iStock