**4. Hypervolemia and gastroparesis in ESRD: Associated pathways explaining dyspepsia?**

As commented above, two groups of dyspeptic symptoms can be distinguished: PDS and EDS. However, in clinical practice there is an overlap between these two groups. Most of the time patients classified as having PDS also present EPS and vice versa [3]. Thus, more than a classification of the symptoms, we need to understand the physiopathological mechanisms involved in order to establish more effective treatment for FD. Gut dismotility can have a central role in the genesis of dyspeptic symptoms among ESRD patients. Moreover, volemic status may be a modulator of gastric emptying.

The first reports of gastric emptying delay in ESRD appeared at the end of the 1970s [41]. Nonetheless, currently the pathogenesis of gastroparesis in ESRD patients is still unknown. Several features of ESRD have at least a partial role in gastric delay, like anemia, metabolic acidosis and uremic neuropathy [16,17]. However, none of these is considered the main cause of FD, and the treatment of each one of these features is not effective in decreasing the prevalence of FD among HD patients.

My main research line is self-perceived outcomes among HD patients. Since 2006 my research group has been producing studies in this area [8-10, 28-36]. Our sample consists of ESRD

in the northern region of Ceará state, northeast Brazil. There we found, as others, a very low level of QOL in HD patients, mainly related to physical aspects. Recently, we presented our results about QOL in dyspeptic patients at the Paulista Congress of Nephrology, in Atibaia, São Paulo, Brazil [37]. We used the SF-36 instrument to evaluate QOL. SF-36 gives results on a scale from 0 (worst result) to 100 (best result) related to eight dimensions of QOL: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, roleemotional and mental health. We used the Functional Dyspepsia Module of Rome III Diag‐ nostic Questionnaires to search for dyspeptic symptoms. Our results showed that physical (bodily pain, general health and vitality) and also mental (role-emotional and mental health) aspects are lower in dyspeptic compared to non-dyspeptic HD patients. Notably, general health and role-emotional are the two dimensions rated below 50 according to the SF-36 scale among dyspeptics. It is exciting to think about FD as a modifiable factor associated with QOL. We urgently need randomized, controlled studies to test the effect of FD treatment on QOL

Another crucial impact of dyspepsia is related to nutritional condition. In the general popu‐ lation, weight loss is taken as an alarm symptom that raises suspicion of organic disease. However, weight loss also occurs in FD [38]. In nephrology, there are many studies on nutrition among HD patients. The most well-known factors associated with malnutrition in ESRD are anorexia and chronic inflammation [39]. FD is not well studied as a factor linked to malnutri‐ tion among ESRD patients. We exposed our preliminary data on this question at the Third Conference on Nephrology, held in Valencia, Spain [40]. In our experience, dyspeptic HD patients have a lower calorie and protein intake compared to non-dyspeptics. Like in the case of QOL, it is encouraging to think about FD as a modifiable factor associated with malnutrition, particularly because to same extent FD is easier to treat than anorexia and chronic inflamma‐ tion. Again, as happens in the context of FD and QOL, clinical trials about the beneficial effects

**4. Hypervolemia and gastroparesis in ESRD: Associated pathways**

As commented above, two groups of dyspeptic symptoms can be distinguished: PDS and EDS. However, in clinical practice there is an overlap between these two groups. Most of the time patients classified as having PDS also present EPS and vice versa [3]. Thus, more than a classification of the symptoms, we need to understand the physiopathological mechanisms involved in order to establish more effective treatment for FD. Gut dismotility can have a central role in the genesis of dyspeptic symptoms among ESRD patients. Moreover, volemic

(37.3 inhabitants/ km2

)

patients treated in the only two dialysis units in an area of 34.560 km2

of treating FD on caloric and protein intake are necessary.

status may be a modulator of gastric emptying.

among HD patients.

96 Updates in Hemodialysis

**explaining dyspepsia?**

In theory, among diabetics on HD features of ESRD act together with alterations of diabetes to cause gastroparesis. Hyperglycemia and decreased action of insulin provoke slow gastric emptying by compromising cellular elements of the stomach (loss or damage of the interstitial cells of Cajal and enteric glial cells), altering motor gastric functions (autonomic neuropathy of the vagal innervations of the stomach), and triggering disturbances of enteral hormones (especially, glucagon-like polypeptide-1) [42]. Despite all this, two facts should be highlighted. First, in primary medical assistance the prevalence of gastroparesis among diabetics is as low as 5% for type 1 diabetes and 1% for type 2 diabetes [43]. Indeed, it is likely that reports of high prevalence of gastroparesis in patients with diabetes are due to a bias caused by reports covering diabetics treated in tertiary medical care. Second, specifically among ESRD patients undergoing HD, the prevalence of FD is the same among diabetics and non-diabetics [15,44,45]. In the future perhaps a specific therapy for gastroparesis among diabetics could be developed, targeting alterations of gastric motility provoked by diabetes. However, as things now stand except for glycemic control, treatment of FD and gastroparesis does not differ between diabetics and non-diabetics on HD.

One attractive hypothesis is that volemia is the main modulator of gastric motility, and that hypervolemia elicits gastroparesis. Since ESRD is typically a condition of excessive extracel‐ lular volume, this hypothesis could explain the high prevalence of FD among patients on HD (the prevalence is nearly 70%) [15]. It also opens a field for therapeutic strategies to control extracellular volume among HD patients, aiming to relieve dyspeptic symptoms. At the Federal University of Ceará, researchers from the Department of Physiology and Pharmacol‐ ogy of the Faculty of Medicine have been performing experiments to understand the relation‐ ships between extracellular volume and gastrointestinal motility during the past 35 years. Data have been accumulated suggesting a negative correlation between extracellular volume and gastric emptying time, especially in animal models (see Table 2 for details about the method of evaluating gastric emptying in rats), but also in humans. Results converge to clearly show that hypervolemia decreases gastric and intestinal motility [18-23]. Neural and humoral pathways have been suggested to explain this correlation [21]. Also, gastric motility and permeability are closely related, and hypervolemia increases secretion of fluids and electro‐ lytes while dehydration decreases secretion [46-48]. Healthy blood donors make good subjects for *in vivo* experiments to test the relationship between volemic status and gastric emptying [23]. Among them, it was found that gastric compliance (measured by barostat) increases after donating 450 ml of blood (functioning as acute hypovolemia). Conversely, compliance returns to physiologic levels after infusion of the same volume of saline.

No doubt ESRD patients compose an ideal model to study the effects of hypervolemia on gastric motility *in vivo*. The drawback is the lack of simple and accurate methods for assessing volemia in clinical studies. Table 3 shows the available clinical tools for detect‐ ing hypervolemia.


#### **The formula for calculating gastric emptying:**

• % Gastric emptying = 1 – [(amount of phenol red covered from test stomach)/ (average amount of phenol red covered from standard stomachs] x 100

#### **Standard stomachs:**

• Rats killed immediately after gavage

**Table 2.** Step-by-step description of the method for measuring gastric emptying of liquid in rats

#### Atrial natriuretic peptic

Cyclic guanidine monophosphate (post dialysis level higher than 20 pmol/L indicates fluid overload) Bioimpendane analysis Blood volume monitoring (change in hematocrit or protein during hemodialysis procedure)

Inferior vena cava diameter (by echocardiography)

**Table 3.** Tools for clinical estimation of fluid overload

Based on results of bioimpedance analysis, we have shown that among HD patients, relative fluid overload higher than 15% is associated with higher prevalence of FD compared to patients with lower fluid overload (66% *versus* 34%) [49]. Figure 1 shows the bioimpedance device used by us: a body composition monitor specifically designed to assess extracellular water in patients with kidney failure. In addition, we found that dyspeptic patients on HD present longer gastric emptying time compared to non-dyspeptics (238 minutes *versus* 185 minutes) [15]. Since gastric dismotility seems to be crucial to trigger FD, and due to the complexity of measuring gastric emptying time *in vivo*, I summarize this study below.

The simplicity of assessing FD by interview contrasts with the complexity of assessing gastric emptying time *in vivo*. The tools available for clinical estimation of gastric emptying time are: technetium-99m scintigraphy (gold standard) [50]; time of appearance of acetaminophen in blood after its ingestion [51]; imaging studies using 3D ultrasonography and nuclear resonance [52, 53]; the smart pill (which seems to be a practical and promising method) [54]; and octanoic Dyspepsia — An Underestimated Problem among End-stage Renal Disease Patients http://dx.doi.org/10.5772/59426 99

**Figure 1.** Body Composition Monitor® by Fresenius

assessing volemia in clinical studies. Table 3 shows the available clinical tools for detect‐

• 1.5 ml of the test meal (0.5 mg mL-1 phenol red in 5% glucose solution) given orally through a stainless steel tube

• Proteins in 5 ml of this supernatant precipitated with 0.5 ml of trichloroaetic acid, centrifuged for 20 min and 3 mL of

• % Gastric emptying = 1 – [(amount of phenol red covered from test stomach)/ (average amount of phenol red

**Table 2.** Step-by-step description of the method for measuring gastric emptying of liquid in rats

Cyclic guanidine monophosphate (post dialysis level higher than 20 pmol/L indicates fluid overload)

Based on results of bioimpedance analysis, we have shown that among HD patients, relative fluid overload higher than 15% is associated with higher prevalence of FD compared to patients with lower fluid overload (66% *versus* 34%) [49]. Figure 1 shows the bioimpedance device used by us: a body composition monitor specifically designed to assess extracellular water in patients with kidney failure. In addition, we found that dyspeptic patients on HD present longer gastric emptying time compared to non-dyspeptics (238 minutes *versus* 185 minutes) [15]. Since gastric dismotility seems to be crucial to trigger FD, and due to the complexity of

The simplicity of assessing FD by interview contrasts with the complexity of assessing gastric emptying time *in vivo*. The tools available for clinical estimation of gastric emptying time are: technetium-99m scintigraphy (gold standard) [50]; time of appearance of acetaminophen in blood after its ingestion [51]; imaging studies using 3D ultrasonography and nuclear resonance [52, 53]; the smart pill (which seems to be a practical and promising method) [54]; and octanoic

Blood volume monitoring (change in hematocrit or protein during hemodialysis procedure)

measuring gastric emptying time *in vivo*, I summarize this study below.

• Removed stomach placed in 100 ml of 0.1 N NaOH, cut into small pieces and homogenized for 30 seconds

• Animals killed by i.v. thiopental overdose at 0 (standard) or 10 min after the test meal • Stomach exposed by laparotomy, clamped at the pylorus and cardia ends, and excised

• 10 ml of the resulting supernatant centrifuged for 10 min (2800 r.p.m.)

• Absorbance of the sample read at a wavelength of 560 nm by spectrophotometry

the supernatant added to 4 mL of 0.5 N NaOH

**The formula for calculating gastric emptying:**

Inferior vena cava diameter (by echocardiography)

**Table 3.** Tools for clinical estimation of fluid overload

covered from standard stomachs] x 100

• Rats killed immediately after gavage

ing hypervolemia.

98 Updates in Hemodialysis

• Settling for 30 min

**Standard stomachs:**

Atrial natriuretic peptic

Bioimpendane analysis

acid breath test using 13carbon (a very attractive method with 89% sensitivity compared to the gold standard technetium-99m scintigraphy) [55]. We used the last method in our study to assess gastric emptying time in a sample of HD patients from our clinic [15]. See Table 4 for details about the method of evaluating gastric emptying time in humans. Patients ate a scrambled egg with carbon linked to octanoic acid. Octanoic acid remains firmly attached to the egg in its passage through the stomach, but after that it is absorbed in the duodenum and eliminated in the breath. Patients breathe into bags before the test meal (baseline), every 15 minutes during 2 hours and then every 30 minutes for a further 2 hours. The gastric emptying time was defined by half-emptying time (the so-called T ½). T ½ is the time in minutes for the first half of the carbon dose in the test meal to be eliminated. Dyspeptic symptoms were assessed by a validated Brazilian version of a standardized questionnaire named the Porto Alegre Dyspeptic Symptoms Questionnaire (PADYQ). We found longer T ½ (longer gastric emptying time) among dyspeptics compared to non-dyspeptics. Moreover, we found a positive linear correlation between T ½ and dyspepsia score, in other words, the longer the gastric emptying time, the more severe the dyspeptic symptoms [15].

In short, the series of studies at our university demonstrate two findings to support clinical approaches to FD among ESRD patients: first, hypervolemia elicits gastric emptying delay [18-23]; second, dyspeptic patients on HD have longer gastric emptying time and higher fluid overload than non-dyspeptics [15, 49]. Table 5 summarizes the body of evidence on the relationships between volemia, gastric motility and dyspepsia produced in my Institution.

• Patients are instructed to avoid smoking and eating foods rich in C-4 plants, like corn (including baked goods made with cornmeal) and pineapples, in the week before the study

• For the test: a minimum of 10 hours of fasting

• The test meal consists of a scrambled egg with the yolk labeled with 100 µg of 13carbon octanoic acid (after

homogenizing the yolk, the egg white is added, beaten and baked)

• The test meal is ingested with 60 g of white bread and 5 g of margarine during 1 to 5 min and followed immediately by 150 mL of water

• To collect the breath samples, the patient exhales into closed aluminized plastic bags, before the test meal (baseline), and then at 15-minute intervals during 2 hours and then every 30 min for a further 2 hours

• Patients are advised to remain seated and refrain from physical activity during the test

• The gastric emptying time is defined by half-emptying time (T ½)

**The formula for calculating** T ½:

• T ½ = time in minutes for the first half of the 13carbon dose in the test meal to be metabolized

**The cut-off:**

• T ½ of more than 200 minutes identifies gastric emptying delay

**Table 4.** Step-by-step description of the method for measuring gastric emptying time in humans


**Table 5.** Studies of volemia, gastric motility and dyspepsia produced at Federal University of Ceará, Brazil

#### **5. Treatment**

Confirming our finding that dyspepsia is underestimated despite the well-known impacts of FD on QOL and nutritional condition, there is a lack of randomized, placebo-controlled studies of treatment strategies for FD in ESRD patients. Most data on treatment of FD come from studies in the general population. This fact is worrying due to many peculiarities of uremia and its effects on gastrointestinal tract. Nevertheless, a common finding in the general population and among dialysis patients is the inefficiency of drug therapy. Only half of the dyspeptic patients become asymptomatic in population samples [56]. This is similar to our finding of 60% symptomatic HD patients under treatment for FD [15].

Initial treatment of FD in HD patients is usually empirical after performing an endoscopy to exclude ulcer (and other sorts of organic lesions) and a test for absence of *Helicobacter pylori*. The first step for treating FD can be to try acid-suppression therapy, either by an H2-receptor antagonist (H2-RA) or proton pump inhibitor (PPI) [57,58]. Favoring the initial use of PPI instead of H2-RA is the consensus of the superior acid secretion suppression of PPIs over H2- RAs. Favoring acid suppression therapy is the recent evidence coming from studies in healthy subjects that acid secretion can impair gastric motility [59,60]. Thus, theoretically PPIs can ameliorate FD by acting on both pain and dysmotility-like symptoms. Even though widely used clinically, the double-dose of PPIs in case of persistence of dyspeptic symptoms is not supported. There are reports that standard and double doses have the same results [61].


**Table 6.** Prokinetics for relief of dyspeptic symptoms

• Patients are instructed to avoid smoking and eating foods rich in C-4 plants, like corn (including baked goods made

• The test meal is ingested with 60 g of white bread and 5 g of margarine during 1 to 5 min and followed immediately

• To collect the breath samples, the patient exhales into closed aluminized plastic bags, before the test meal (baseline),

**Evidence Sample Year [Reference]**

Rats 1990 [19]

Awake rats 1999 [21]

Anesthetized rats 2002 [22]

• The test meal consists of a scrambled egg with the yolk labeled with 100 µg of 13carbon octanoic acid (after

and then at 15-minute intervals during 2 hours and then every 30 min for a further 2 hours • Patients are advised to remain seated and refrain from physical activity during the test

• T ½ = time in minutes for the first half of the 13carbon dose in the test meal to be metabolized

**Table 4.** Step-by-step description of the method for measuring gastric emptying time in humans

Gastric compliance is modulated by blood volume Anesthetized dogs 1983 [18]

Expansion of blood volume delays gastrointestinal transit Awake rats 1998 [20]

Acute blood shedding increases gastric compliance Humans (healthy subjects) 2005 [23] Gastric emptying delay is associated to functional dyspepsia Patients on hemodialysis 2013 [15]

functional dyspepsia Patients on hemodialysis 2013 [49]

Confirming our finding that dyspepsia is underestimated despite the well-known impacts of FD on QOL and nutritional condition, there is a lack of randomized, placebo-controlled studies of treatment strategies for FD in ESRD patients. Most data on treatment of FD come from studies in the general population. This fact is worrying due to many peculiarities of uremia and its effects on gastrointestinal tract. Nevertheless, a common finding in the general population and among dialysis patients is the inefficiency of drug therapy. Only half of the

**Table 5.** Studies of volemia, gastric motility and dyspepsia produced at Federal University of Ceará, Brazil

with cornmeal) and pineapples, in the week before the study

homogenizing the yolk, the egg white is added, beaten and baked)

• The gastric emptying time is defined by half-emptying time (T ½)

• T ½ of more than 200 minutes identifies gastric emptying delay

Blood volume expansion decreases gastrointestinal flow

Vagal pathway is involved in the delay of gastric emptying

Stomach is an adjustable reservoir according to blood volume

Fluid overload is associated to higher prevalence of

while blood volume retraction increases it

elicited by acute blood volume expansion

• For the test: a minimum of 10 hours of fasting

by 150 mL of water

100 Updates in Hemodialysis

**The cut-off:**

level

**5. Treatment**

**The formula for calculating** T ½:

Prokinetics can be a second drug to add to PPI in case of treatment failure, or the first option if PDS is the main clinical presentation, or in most cases of overlap of PDS and EDS. At least, two drugs are individually superior over placebo in the treatment of FD: domperidone and cisapride [57]. Unfortunately, the accumulated data on the effects of cisapride (one of the most studied prokinetics) is of no value since the use of cisapride has been withdrawn due to risk of arrhythmia [62]. Domperidone is used in Brazil, but it is not available in many countries including the United States. A newer drug named levosulpiride shows the same positive results found with the use of cisapride [63]. In our daily practice, we prefer an old drug in use since 1960, metoclopramide. Metoclopramide is traditionally used for gastroparesis in diabetics before each meal and at bedtime, and has proven to improve the nutritional status in non-diabetics on dialysis [64]. However, metoclopramide has a limitation on its use, because it can provoke dyskinesia. New prokinetics, like mosapride, tegaserod, itopride and ABT-229, seem to be no better than the former drugs [65-68]. Currently, acotiamed is under investigation [69]. In comparison to PPIs, prokinetics have no advantage in the treatment of dyspepsia, based on studies performed in the general population [70]. However, in light of the extensive evidence of the close relationship between gastric delay and FD in ESRD discussed previously, it is my opinion that prokinetics should have a leading role in the treatment of FD in patients undergoing HD. Furthermore, there are reports favoring prokinetics regarding improvement of nutritional condition in ESRD patients [64,71]. Table 6 shows a list of effective, ineffective and under-investigation prokinetics.

Among the peculiarities of FD in ESRD patients, there is the extensive list of stressors associated with HD: illness effects, dietary constraints, time restriction, functional limitations, changes in employment, sexual dysfunction, and high mortality [13]. This explains why depression and anxiety are highly prevalent among HD patients [9,11]. Anxiety and depression can be manifested by dyspepsia (somatization). This fact forces the inclusion of depression in the differential diagnosis of FD alongside gallbladder, pancreatitis, medications, and hepatobiliary causes. On the other hand, dyspeptic symptoms of FD are more likely to be severe in depressive patients. There are several studies showing benefits of anxiolytics and antidepressants, especially tricyclic antidepressants, in the relief of dyspeptic symptoms, although their results are not superior to those of PPIs or prokinetics in the general population [72]. Once again, we have to be careful to extrapolate these population data to specific samples of ESRD patients. Due to the previously reported list of associated stressors and high prevalence of depression among HD patients, it is plausible that the effects of antidepressants can be more pronounced among HD patients than in the general population. Taking two specific drugs: amitriptyline (tricyclic antidepressant) and sertroline (selective serotonin reuptake inhibitor antidepressant) can be effective. Amitriptyline ameliorates dyspeptic symptoms in subjects who did not obtain relief with antacids and prokinetics [73]. Sertroline is a very attractive drug to test for FD in HD patients because of its additional effect of decreasing the serum level of interleukin-6 in HD patients on HD [74]. However, treatment of depression among HD patients is not simple. Drug therapy alone for depression has proven to be ineffective among HD patients. One of the reasons is that drug therapy by itself cannot eliminate the powerful stressors associated with HD therapy. For instance, among women undergoing HD, the sole use of drugs for depression will fail if there is not a concurrent approach to sexual dysfunction [75]. To my thinking, it is clear that treatment of FD in HD patients should include screening for depressive symptoms, and if depression exists, psychotherapy is necessary along with the use of drugs. Supporting this opinion, psychotherapy was proved to be beneficial for FD in controlled random trials [76].
