**4. Discussion**

In this cross-sectional study, we compared levels of oxidative stress markers on PD patients with and without diabetes. The DM patients were older, had higher BMI, had more prevalence of hypertension, and had higher triglycerides and VLDL levels that corresponded to the classic metabolic syndrome [14]. The prevalence of metabolic syndrome in patients with ESRD on PD is quite frequent, and its presence is reported in ~40–60% of patients with DN depending on the population studied [15].

DM is the main cause of ESRD and represents 58% of incident cases [16]. Several interventions have been suggested for the prevention and control of DM. A directed selection study is followed by a randomized controlled trial by groups, with randomization where participants were at risk for DM. The subjects received standard care or intervention. The intervention consisted of a group structured education program of 6 h with an annual update and regular telephone contact with follow-up for 3 years. About 29.1% attended all the sessions; 22.6% did not attend the education. The authors found a 26% reduction in the risk of type 2 DM of those who received the intervention compared with the standard care. They found no statistical significance, which suggests that the effectiveness of all interventions is not promising [17].

When the patient already has DM, a variety of risk factors that promote the development and progression of DN have been reported: persistent high glucose levels, time of duration of DM, arterial hypertension, obesity, endothelial dysfunction, and dyslipidemia. Most of these risk factors are modifiable through antidiabetic, antihypertensive, lipid-lowering, and primarily lifestyle change [18]. It has been previously reported that patients with ESRD and DM who require dialysis have higher rates of various morbidities and worse clinical outcomes compared to non-DM patients. It has also been shown that glycemic decontrol is associated with more micro- and macrovascular complications, in addition to higher mortality [19].

In the present study, a significant increase in LPO was found in DM and No-DM patients undergoing PD *vs*. the levels found in healthy controls. It has been shown that patients in PD manifest excessive OS compared to healthy controls. OS in PD

**345**

*Increase of Oxidants and Antioxidant Consumption in Patients with Type 2 Diabetes…*

in RRT has been reported before undergoing kidney transplantation [25].

type 2 DM [28]. In this study, the 8-IP in residual urine was not measured.

In patients with DM and No-DM, we found significantly decreased serum levels of NO. NO is a potent biological vasodilator produced by the vascular endothelium from L-arginine. NO is synthesized by endothelial NO synthase (eNOS). Vascular NO deficiency may be involved in accelerated atherosclerosis and the dramatic cardiovascular mortality observed in patients with CKD [29]. Vascular changes can induce OS and inflammation, favoring the probability of morbidity and mortality by aggravating CVD [30]. In CKD, endothelial dysfunction is characterized by the altered capacity of the vascular endothelium to stimulate vasodilation. NO plays a key role in the development of atherosclerosis in this pathology. The decrease in the bioavailability of NO is a key factor of endothelial dysfunction. In addition, NO plays an important role in the protection of the vascular wall because it induces its own metabolic products [31]. In the present study, a significant increase in the activity of the SOD enzyme was found in DM and No-DM patients undergoing PD. The accumulated scientific evidence suggests that the main antioxidant systems are impaired in patients on PD [32]; possibly the previous finding could be explained in an attempt to compensate the oxidative state that characterized the patients included in the study. Antioxidants can be divided into intracellular and extracellular antioxidants. The intracellular enzymatic antioxidants are SOD, catalase, and glutathione peroxidase, which convert substrates (anion radicals O2<sup>−</sup> and H2O2) into less reactive forms. The first line of defense against free radicals is SOD. Free radicals are the source of lipid peroxidation derived from oxygen, and the function of SOD is to catalyze the conversion of O2<sup>−</sup> radicals into H2O2. Therefore, if the activity of SOD in PD had been found to be decreased, it would suggest accumulation of the O2<sup>−</sup> radical

In the results obtained in the patients undergoing PD with DM and No-DM, the 8-IP were significantly diminished versus the healthy controls; possibly, the clearance of this marker by PD participates in the decrease of serum levels. Previous reports have shown that the residual glomerular filtration rate is independently associated with the levels of advanced glycation end products in plasma effluents and peritoneum [26]. It has been previously reported that DM is associated with increased lipid peroxidation and persistent platelet activation with increased in vivo formation of F2-isoprostane 8-iso-prostaglandin (PG) F2alfa (bioactive product of arachidonic acid peroxidation). 8-IP improves their levels in presence of DM by contributing to platelet activation related to altered glycemic control and increased lipid peroxidation by providing an important biochemical link between altered glycemic control and persistent platelet activation [27]. However, in our study this marker was found to be significantly decreased in serum in both DM and No-DM patients in inverse relation to published reports where they found increased levels in urine [18]. Kant et al. mentioned that when lipid peroxidation products were elevated in the prediabetic stage, the determination of this marker is useful in the detection of patients at risk of

is closely related to chronic inflammation, atherogenesis, peritoneal fibrosis, and loss of residual renal function. The unfavorable serum lipid profile and the chronic exposure of peritoneal cells to super-physiological levels of glucose in patients undergoing PD could increase glycosylation and lipid oxidation, favoring the increase of LPO and consequently greater OS [20]. When there is greater permeability and biocompatibility of the peritoneal membrane, with better preserved residual renal function, it can be assumed that patients could have a lower oxidative load [21, 22]; however, reports in the literature indicate that the oxidative metabolism of peripheral and peritoneal phagocytes is activated during PD with conventional dialysate, by the products of glucose degradation, by low pH, and by high osmolarity [23]. The bio-incompatibility of DP solutions seems to play a central role in increasing ROS production [24]. Previously increased OS in patients with ESRD

*DOI: http://dx.doi.org/10.5772/intechopen.82880*

#### *Increase of Oxidants and Antioxidant Consumption in Patients with Type 2 Diabetes… DOI: http://dx.doi.org/10.5772/intechopen.82880*

is closely related to chronic inflammation, atherogenesis, peritoneal fibrosis, and loss of residual renal function. The unfavorable serum lipid profile and the chronic exposure of peritoneal cells to super-physiological levels of glucose in patients undergoing PD could increase glycosylation and lipid oxidation, favoring the increase of LPO and consequently greater OS [20]. When there is greater permeability and biocompatibility of the peritoneal membrane, with better preserved residual renal function, it can be assumed that patients could have a lower oxidative load [21, 22]; however, reports in the literature indicate that the oxidative metabolism of peripheral and peritoneal phagocytes is activated during PD with conventional dialysate, by the products of glucose degradation, by low pH, and by high osmolarity [23]. The bio-incompatibility of DP solutions seems to play a central role in increasing ROS production [24]. Previously increased OS in patients with ESRD in RRT has been reported before undergoing kidney transplantation [25].

In the results obtained in the patients undergoing PD with DM and No-DM, the 8-IP were significantly diminished versus the healthy controls; possibly, the clearance of this marker by PD participates in the decrease of serum levels. Previous reports have shown that the residual glomerular filtration rate is independently associated with the levels of advanced glycation end products in plasma effluents and peritoneum [26]. It has been previously reported that DM is associated with increased lipid peroxidation and persistent platelet activation with increased in vivo formation of F2-isoprostane 8-iso-prostaglandin (PG) F2alfa (bioactive product of arachidonic acid peroxidation). 8-IP improves their levels in presence of DM by contributing to platelet activation related to altered glycemic control and increased lipid peroxidation by providing an important biochemical link between altered glycemic control and persistent platelet activation [27]. However, in our study this marker was found to be significantly decreased in serum in both DM and No-DM patients in inverse relation to published reports where they found increased levels in urine [18]. Kant et al. mentioned that when lipid peroxidation products were elevated in the prediabetic stage, the determination of this marker is useful in the detection of patients at risk of type 2 DM [28]. In this study, the 8-IP in residual urine was not measured.

In patients with DM and No-DM, we found significantly decreased serum levels of NO. NO is a potent biological vasodilator produced by the vascular endothelium from L-arginine. NO is synthesized by endothelial NO synthase (eNOS). Vascular NO deficiency may be involved in accelerated atherosclerosis and the dramatic cardiovascular mortality observed in patients with CKD [29]. Vascular changes can induce OS and inflammation, favoring the probability of morbidity and mortality by aggravating CVD [30]. In CKD, endothelial dysfunction is characterized by the altered capacity of the vascular endothelium to stimulate vasodilation. NO plays a key role in the development of atherosclerosis in this pathology. The decrease in the bioavailability of NO is a key factor of endothelial dysfunction. In addition, NO plays an important role in the protection of the vascular wall because it induces its own metabolic products [31].

In the present study, a significant increase in the activity of the SOD enzyme was found in DM and No-DM patients undergoing PD. The accumulated scientific evidence suggests that the main antioxidant systems are impaired in patients on PD [32]; possibly the previous finding could be explained in an attempt to compensate the oxidative state that characterized the patients included in the study. Antioxidants can be divided into intracellular and extracellular antioxidants. The intracellular enzymatic antioxidants are SOD, catalase, and glutathione peroxidase, which convert substrates (anion radicals O2<sup>−</sup> and H2O2) into less reactive forms. The first line of defense against free radicals is SOD. Free radicals are the source of lipid peroxidation derived from oxygen, and the function of SOD is to catalyze the conversion of O2<sup>−</sup> radicals into H2O2. Therefore, if the activity of SOD in PD had been found to be decreased, it would suggest accumulation of the O2<sup>−</sup> radical

*Antioxidants*

*r*

**4. Discussion**

**Table 4.**

*\*p < 0.05, \*\*p < 0.01.*

*total antioxidant capacity.*

not promising [17].

In this cross-sectional study, we compared levels of oxidative stress markers on PD patients with and without diabetes. The DM patients were older, had higher BMI, had more prevalence of hypertension, and had higher triglycerides and VLDL levels that corresponded to the classic metabolic syndrome [14]. The prevalence of metabolic syndrome in patients with ESRD on PD is quite frequent, and its presence is reported in ~40–60% of patients with DN depending on the population studied [15]. DM is the main cause of ESRD and represents 58% of incident cases [16]. Several interventions have been suggested for the prevention and control of DM. A directed selection study is followed by a randomized controlled trial by groups, with randomization where participants were at risk for DM. The subjects received standard care or intervention. The intervention consisted of a group structured education program of 6 h with an annual update and regular telephone contact with follow-up for 3 years. About 29.1% attended all the sessions; 22.6% did not attend the education. The authors found a 26% reduction in the risk of type 2 DM of those who received the intervention compared with the standard care. They found no statistical significance, which suggests that the effectiveness of all interventions is

*DM, diabetes mellitus; No-DM, without DM; BMI, body mass index; TSAT, transferrin saturation; HDL, highdensity lipoprotein; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein; HCO3, bicarbonate; RCP, reactive C protein; LPO, lipoperoxides; 8-IP, 8-isoprostanes; NO, nitric oxide; SOD, superoxide dismutase; TAC,* 

*Correlation between demographic, bioquimical, and oxidative stress markers.*

**<sup>2</sup> LPO 8-IP NO SOD TAC** Iron 0.003 0.05 −0.007 0.05 −0.10 TSAT −0.65 0.21 −0.14 0.09 −0.06 Cholesterol **0.42\*\*** 0.08 **0.42\*** −0.24 0.09 HDL −0.21 −0.03 −0.33 **0.39\* −0.38\*** LDL **0.55\*\*** 0.05 **0.52\*\*** −0.24 0.19 Triglycerides **0.46\*\*** 0.003 **0.54\*\* −0.46\*\*** 0.32 VLDL 0.34 0.04 **0.57\*\* −0.41\* 0.35\*** HCO3 −0.03 −0.14 0.09 −0.03 −0.20 RCP −0.03 **0.50\*** 0.09 −0.38 **0.44\***

When the patient already has DM, a variety of risk factors that promote the development and progression of DN have been reported: persistent high glucose levels, time of duration of DM, arterial hypertension, obesity, endothelial dysfunction, and dyslipidemia. Most of these risk factors are modifiable through antidiabetic, antihypertensive, lipid-lowering, and primarily lifestyle change [18]. It has been previously reported that patients with ESRD and DM who require dialysis have higher rates of various morbidities and worse clinical outcomes compared to non-DM patients. It has also been shown that glycemic decontrol is associated with more micro- and macrovascular complications, in addition to higher mortality [19]. In the present study, a significant increase in LPO was found in DM and No-DM patients undergoing PD *vs*. the levels found in healthy controls. It has been shown that patients in PD manifest excessive OS compared to healthy controls. OS in PD

**344**

anion responsible for the increase in lipid peroxidation [21]; however, in the patients included in the study, SOD was found to be significantly increased and TAC decreased in patients undergoing PD with DM and No-DM, which could suggest that peritoneal replacements could purge the systemic buffering levels of the TAC. In a recently reported study, the authors underwent to hemodialysis session in patients with ESRD; they found a significant reduction in TAC according to our findings [33]. The depletion of TAC found in patients undergoing PD is contrary to that reported by other authors in relation to increased levels of these systemic buffers in patients undergoing hemodialysis. [34]. The concentrations of bilirubin, uric acid, and plasma albumin are the main defense in the extracellular fluids generated during the normal metabolism or are ingested by the consumption of dietary products rich in antioxidants [35]. These extracellular antioxidants prevent the reaction of free radicals by sequestering transition metal ions by plasma chelation [36]; the TAC is able to determine these extracellular antioxidants. In the present study, TAC was found to be significantly consumed in all patients included.

The addition of exogenous antioxidants to the management of patients who are in PD is an incomplete and little studied subject; however, this topic is interesting that is well worth considering in these patients. In a report of the literature, the authors studied the N-acetylcysteine (NAC) which is considered as a potential antioxidant with anti-inflammatory effects for dialysis patients. Vitamin C could play an important role in helping PD patients to use iron for erythropoiesis and achieve better hemoglobin response during the treatment of anemia [37].
