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Medicine » Urology and Nephrology » "Updates in Hemodialysis", book edited by Hiromichi Suzuki, ISBN 978-953-51-2162-6, Published: September 9, 2015 under CC BY 3.0 license. © The Author(s).

Chapter 6

Dyspepsia — An Underestimated Problem among End-stage Renal Disease Patients

By Paulo Roberto Santos
DOI: 10.5772/59426

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Dyspepsia — An Underestimated Problem among End-stage Renal Disease Patients

Paulo Roberto Santos1, 2

1. Introduction

Dyspepsia is the most common gastrointestinal disorder in primary medical assistance. In the general population, 40% of people will suffer from dyspepsia during their lifetime [1]. The most frequent category of dyspepsia is functional dyspepsia (FD). Among categories of dyspepsia, FD accounts for roughly 50% of the cases and is defined as dyspeptic symptoms not explained by structural or organic upper gastrointestinal disease [2]. The categories associated with organic alterations of the upper gastrointestinal tract are: reflux disease with normal endoscopy (20%); reflux esophagitis (20%); peptic ulcer disease (10%); and more rarely, Barret’s esophagus and malignancy [2].

Dyspeptic symptoms comprise a heterogeneous group of symptoms that have in common their location. The symptoms must be located in the epigastrium and can be included in two syndromes: postprandial distress syndrome (PDS) and epigastric discomfort syndrome (EDS). PDS comprises bothersome postprandial fullness and early satiation; EDS includes epigastric pain or burning. In practice, it is common for symptoms to overlap, and as a rule patients are defined as dyspeptic when suffering symptoms of both syndromes [3]. Heartburn is not considered a dyspeptic symptom, as established in the latest definition by the Rome III consensus in 2006 [4].

The current definition of FD according to the Rome III consensus is the presence of one or more symptoms, with onset at least six months beforehand, being present during the last three months, in the absence of structural disease of the upper gastrointestinal tract (in clinical practice, ruled out by endoscopy and testing for Helicobacter pylori). The Rome III consensus gives the definitions of each of the four dyspeptic symptoms (Table 1). Nonetheless, even judicious criteria like these are not totally accurate to diagnose FD. There are reports showing only modest performance of the Rome III criteria, reaching only 60.7% sensitivity and 68.7% specificity for diagnosis of FD [5].

Symptom Definition
Postprandial fullness Unpleasant sensation of prolonged persistence of food in the stomach after a meal
Early satiation Feeling that the stomach is overfilled soon after starting to eat, out of proportion to the size of the meal being eaten, so that the meal cannot be finished
Epigastric pain Subjective, intense and unpleasant sensation in the epigastrium, which can lead patients to believe that some tissue damage is occurring
Epigastric burning Unpleasant subjective sensation of heat in the epigastrium

Table 1.

Definition of dyspeptic symptoms as proposed by the Rome III consensus

Why do I classify FD as underestimated among end-stage renal disease (ESRD) patients? In my view, dyspepsia really deserves special attention among ESRD patients on hemodialysis (HD) for many reasons:

  1. The most common non-renal complaints in HD patients are gastrointestinal symptoms, mainly dyspeptic symptoms [6].

  2. The negative effect of dyspepsia on quality of life (QOL) is well known [7]. From the perspective of ESRD, the association between dyspepsia and impaired quality of life has greater implications due to central role of QOL among HD patients [8-13].

  3. Dyspepsia is also associated with another important condition: nutritional status [14].

  4. ESRD allows several lines of investigations about the pathophysiology of FD. The clinical research about the interactions between typical features of ESRD (like neuropathy, uremic toxins, abnormal gut motility and excess of extracellular volume) and FD need to advance [15-23]. Meanwhile, the pathophysiology of FD in ESRD is still not completely understood and the clinical therapy of dyspeptic symptoms typically fails.

  5. Treatment challenge of FD is specific in HD patients due to the polypharmacy imposed on these patients, the high prevalence of depressive feelings, which can modulate dyspeptic symptoms, and the multi-factorial mechanisms of uremia acting on the gastrointestinal tract.

Despite the above, from my observations dyspepsia is not routinely screened in dialysis units as is done for cardiovascular disease, osteodystrophy and nutritional status. There is also a lack of randomized, placebo-controlled studies about treatment of FD among HD patients, and a clear explanation of the physiopathological mechanisms regarding FD in ESRD is missing.

In my institution, Federal University of Ceará in Brazil, data have been collected since the 1980s on the relationships between volemic status and gastric motility, especially in animal models, but also among healthy subjects [18-23]. As an attending physician, I have under my care at the dialysis unit of Santa Casa de Sobral Hospital ESRD patients who form an ideal sample for studying FD, gastric dismotility and hypervolemia. Thus, currently I am trying to find clinical evidence of the link between the results coming from bench research about the relationships of volemia and gastric emptying with gastroparesis, hypervolemia and FD, which are highly prevalent among HD patients. Therefore, I propose in this chapter to organize bench and clinical data on gastric motility, volume expansion and FD in ESRD patients, to provide insight to help the daily approach to FD among HD patients.

2. How to assess dyspeptic symptoms

Dyspeptic symptoms can be easily assessed by interview. This can be done by applying the Functional Dyspepsia Module [24], one of several diagnostic questionnaires based on the Rome III Consensus [25]. The Functional Dyspepsia Module allows quantitative analysis of dyspeptic symptoms. It contains 18 items. Responses are given according to 4-item and 6-item Likert scales. If a symptom is absent, the respondent skips the questions, so opening the possibility of completing the test without answering all the 18 items. Diagnostic criteria include: one of the symptoms (bothersome postprandial fullness or early satiation or epigastric pain or epigastric burning) with a minimum intensity as assessed by the Likert scale plus a normal endoscopy and a “yes” answer to the “yes-no-questions” about the persistence of a symptom for the past three months, with symptoms’ onset at least six months ago.

The Functional Dyspepsia Module is an important and validated diagnostic tool of FD. However, a validated instrument is lacking to specifically detect changes of dyspeptic symptoms over time. This gap could be filled by a kind of patient-reported outcomes questionnaire in line with the Rome III consensus aiming to evaluate the evolution of symptoms. Such a questionnaire would encourage clinicians to routinely check the effects of therapies, and would allow increased studies on treatment of FD. In this sense, it is important to mention a recent pilot study designed to develop a questionnaire to evaluate the outcomes of PDS [26].

3. Impact of dyspepsia on quality of life and nutritional condition

It is well-known that dyspepsia can lower QOL in the general population [7]. In the context of ESRD, quality of life deserves special attention. Compared to the most frequent chronic diseases, like heart failure, angina, diabetes, chronic lung disease, arthritis and cancer, ESRD impairs quality of life the most [27]. Furthermore, high mortality among ESRD patients is stationary despite the recent technical advances in dialysis therapy and the availability of several updated guidelines and recommendations for ESRD treatment. Indeed, in recent years, QOL has become the main outcome of dialysis treatment, either as a self-perceived outcome by the patient or as an objective quality parameter of the dialysis procedure. Unfortunately, many factors associated with low QOL in HD patients are non-modifiable. Consequently, both physical and mental aspects of QOL among HD patients have not been improving during the last decade [12].

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 patients treated in the only two dialysis units in an area of 34.560 km2 (37.3 inhabitants/ km2) 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, role-emotional and mental health. We used the Functional Dyspepsia Module of Rome III Diagnostic 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 among HD patients.

Another crucial impact of dyspepsia is related to nutritional condition. In the general population, 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 malnutrition 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 inflammation. Again, as happens in the context of FD and QOL, clinical trials about the beneficial effects of treating FD on caloric and protein intake are necessary.

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.

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 extracellular 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 Pharmacology of the Faculty of Medicine have been performing experiments to understand the relationships 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 electrolytes 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 detecting hypervolemia.

• 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
• 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
• Removed stomach placed in 100 ml of 0.1 N NaOH, cut into small pieces and homogenized for 30 seconds
• Settling for 30 min
• 10 ml of the resulting supernatant centrifuged for 10 min (2800 r.p.m.)
• Proteins in 5 ml of this supernatant precipitated with 0.5 ml of trichloroaetic acid, centrifuged for 20 min and 3 mL of the supernatant added to 4 mL of 0.5 N NaOH
• Absorbance of the sample read at a wavelength of 560 nm by spectrophotometry
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.


Figure 1.

Body Composition Monitor® by Fresenius

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 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

Evidence Sample Year [Reference]
Gastric compliance is modulated by blood volumeAnesthetized dogs1983 [18]
Blood volume expansion decreases gastrointestinal flow while blood volume retraction increases itRats1990 [19]
Expansion of blood volume delays gastrointestinal transitAwake rats1998 [20]
Vagal pathway is involved in the delay of gastric emptying elicited by acute blood volume expansionAwake rats1999 [21]
Stomach is an adjustable reservoir according to blood volume levelAnesthetized rats2002 [22]
Acute blood shedding increases gastric complianceHumans (healthy subjects)2005 [23]
Gastric emptying delay is associated to functional dyspepsiaPatients on hemodialysis2013 [15]
Fluid overload is associated to higher prevalence of functional dyspepsiaPatients on hemodialysis2013 [49]

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].

Effective Ineffective Under investigation
Metoclopramide (not tolerated in some) [64,71]
Domperidone (not used in USA) [57]
Levosulpiride [63]
Mosapiride [65]
Tegaserod [66]
Itopride [67]
ABT-229 [68]
Acotiamide [69]

Table 6.

Prokinetics for relief of dyspeptic symptoms

[i] - References in square brackets

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].

6. Alternative medications and emerging therapies

Due to high therapy failure and risk of drug side effects from FD treatment, alternative medicine is attractive. Alternative medicine includes herbal medicine, traditional Chinese medicine and the emerging therapies, especially invasive procedures for gastroparesis.

STW 5 (also known as Iberogast) is one of the most studied mixtures of herbs proven to be effective in relieving dyspeptic symptoms. The main and active ingredient of STW 5 is Iberis amara, which acts both to reduce acid secretion and accelerate gastric emptying [77]. The last action is a result of its different effects on gastric portions, inhibiting the proximal portion of the stomach while exciting the tonus of the distal stomach [78]. Its prokinetic action is similar to cisapride [79]. Usual dosage of STW 5 is 20 drops three times a day. Data on other alternative medications are limited, such as artichoke leaf extract, blend of peppermint oil and caraway oil, banana powder capsules, and antioxidant astaxanthin [80].

Less available in other cultures, Xiaoban Xiatang and Zhizhu Tang are the two herbal infusions most used by traditional Chinese physicians to treat dyspeptic symptoms [81]. However, regarding traditional Chinese medicine, acupuncture is undoubtedly the procedure that deserves most attention. It has been shown that acupuncture accelerates gastric emptying time and reduces postprandial fullness, early satiety and bloating [82].

Among emerging therapies for gastroparesis, there are invasive procedures like gastric electrical stimulation and pyloric botulinum toxin injection. Gastric electrical stimulation consists of surgical implantation of electrodes into the muscle layer of the gastric antrum. A pulse generator in the abdominal wall delivers low-energy electrical pulses at high frequency to the electrodes. Meta-analyses have shown benefits of this technique, and isolated studies have demonstrated improvement of dyspeptic symptoms, quality of life, weight, body mass index and albumin level [83-86]. Gastric electrical stimulation seems to work less because of its motor effects on gastric motility, and more because of its effects in altering the sensory function of afferent nerves of the stomach. Surgical complications occur in 10% of cases, indicating that this method should be prescribed only for refractory cases and not as routine therapy. Another invasive procedure for gastroparesis is the injection of the botulinum toxin (botox) in a circumferential manner into the pyloris. Due to its effect of inhibiting acetylcholine release, botox accelerates gastric emptying and improves dyspeptic symptoms in open-label trials [87-89]. The procedure consists of intrapyloric injection of 100-200 units of botox during endoscopy and has been proven to be safe. However, botox injection cannot be currently recommended since at least two double-blind placebo controlled studies showed the same effects of botox and placebo [90,91]. Table 7 summarizes the treatment options for FD.

Established interventions
Alternative medicine
STW 5 (Iberogast)
Xiaoban Xiatang
Zhizhu Tang
Artichoke leaf extract
Peppermint oil + caraway oil
Banana powder capsules
Antioxidant astaxanthin
Emerging therapies for gastroparesis
Gastric electrical stimulation
Pyloric botulinum toxin injection

Table 7.

Treatment options for functional dyspepsia

7. How to treat: My opinion

It is clear that the traditional algorithm indicating use of anti-secretory agents for ulcer-like FD and prokinetics for dysmotility-like FD does not meet the complexity of FD in the context of ESRD. The ordinary exclusion of patients with inadequate dialysis clearance from studies about FD implies that hypervolemia can be involved in the high prevalence of FD in the cases of more typical patients on HD (those excluded from the studies). In these cases, hypervolemia could trigger gastric emptying delay. I think that patients on HD with FD should first have their dry-weight re-evaluated. Indeed, FD can be an extra tool to help estimate real dry-weight of our HD patients. Second, metoclopramide can be used before each meal and at bedtime. Its beneficial effects on nutritional status are widely documented [62,69]. Third, screening for depressive symptoms and psychotherapy are essential in the treatment of FD among HD patients. Concerning anti-depressant drugs, sertraline is a good option because of its anti-inflammatory effects. Finally, acupuncture can be tried to ameliorate dyspeptic symptoms. Acupuncture’s action in accelerating gastric emptying is particularly attractive.

8. Conclusion

Dyspepsia is highly prevalent among ESRD patients undergoing HD. It can affect central aspects, like QOL and nutritional status. The division of FD into PDS and EDS is didactic but not reasonable in clinical practice. The fact is that most dyspeptic patients present symptoms of both syndromes. Treatment is known to be ineffective. Therapy directed toward the main physiopathological pathways can be crucial, yet the pathogenesis of FD in ESRD remains virtually unknown. Gastroparesis seems to be important, independent of the presence or absence of diabetes. The association of actions to accelerate gastric emptying and to improve depressive feelings should be more effective than traditional treatment algorithms. The hypothesis is that the relief of dyspeptic symptoms would lead to better QOL and nutritional status.


1 - Zagari R, Fuccio L, Bazzoli F. Investigating dyspepsia. British Medical Journal 2008;337: a1400.
2 - Overland MK. Dyspepsia. Medical Clinics of North America 2014;98: 549-564.
3 - Tack J, Talley NJ, Camilleri M, Holtmann G, Hu P, Malagelada JR, Stanghellini V. Functional gastroduodenal disorders. Gastroenterology 2006;130: 1466-1479.
4 - Rome Foundation. Rome III diagnostic criteria for functional gastrointestinal disorders. (accessed 31 August 2014).
5 - Ford AC, Bercik P, Morgan DG, Bolino C, Pintos-Sanchez MI, Moayyedi P. The Rome III criteria for the diagnosis of functional dyspepsia in secondary care are not superior to previous definition. Gastroenterology 2014;46: 932-940.
6 - Shiazian S, Radhakrishnan J. Gastrointestinal disorders and renal failure: exploring the connection. Nature Reviews Nephrology 2010;6: 480-492.
7 - Aro P, Talley NJ, Agréus L, Johansson SE, Bolling-Sternevald E, Storskrubb T, Ronkainen J. Functional dyspepsia impairs quality of life in the adult population. Alimentary Pharmacology & Therapeutics 2011;33: 1215-1224.
8 - Santos PR, Capote Junior JRFG, Cavalcanti JU, Vieira CB, Rocha ARM, Apolônio NAM, Oliveira EB. Quality of life among women with sexual dysfunction undergoing hemodialysis: a cross-sectional observational study. Health and Quality of Life Outcomes 2012;10: 103.
9 - Santos PR. Depression and quality of life of hemodialysis patients living in a poor region of Brazil. Revista Brasileira de Psiquiatria 2011;33: 332-337.
10 - Santos PR, Daher EF, Silva Jr GB, Libório AB, Kerr LR. Quality of life assessment among hemodialysis patients in a single centre: a two-year follow-up. Quality of Life Research 2009;18: 541-546.
11 - Santos PR (2011). Subjective well-being measures of hemodialysis patients. In: Penido MG (ed.) Technical problems in patients on hemodialysis. Rijeka: InTech; 2011. p69-86.
12 - Gabbay E, Meyer KB, Griffith JL, Richardson MM, Miskulin DC. Temporal trends in health-related quality of life among hemodialysis patients in the United States. Clinical Journal of the American Society of Nephrology 2010;5: 261-267.
13 - Cukor D, Cohen SD, Peterson RA, Kimmel PL. Psychosocial aspects of chronic disease: end-stage renal disease as a paradigmatic illness. Journal of the American Society of Nephrology 2007;18: 3042-3055.
14 - Jones MP, Talley NJ, Eslick GD, Dubois D, Tack J. Community subgroups in dyspepsia and their association with weight loss. The American Journal of Gastroenterology 2008;103: 2051-2060.
15 - Salles Jr LD, Santos PR, Santos AA, Souza MHLP. Dyspepsia and gastric emptying in end-stage renal disease patients on hemodialysis. BMC Nephrology 2013;14: 275.
16 - Ravelli AM. Gastrointestinal function in chronic renal failure. Pediatric Nephrology 1995;9: 756-762.
17 - Dumitrascu DL, Barnert J, Kirschner T, Wienbeck M. Antral emptying of semisolid meal measured by real-time ultrasonography in chronic renal failure. Digestive Diseases and Sciences 1995;40: 636-644.
18 - Capelo LR, Cavalcante DM, Leitão IA, Cristino Filho G, da-Silva EAT. Modifications of gastric compliance in dogs related to changes of extracellular fluid volume. Brazilian Journal of Medical and Biological Research 1983;16: 673-676.
19 - Xavier-Neto J, Santos AA, Rola FH. Acute hypervolemia increases the gastroduodenal resistance to the flow of saline in rats. Gut 1990;31: 1006-1010.
20 - Oliveira GR, Gondim FAA, Graça JRV, Xavier-Neto J, Gondim RBM, Santos AA, Rola FH. Acute blood volume expansion delays the gastrointestinal transit of a charcoal meal in awake rats. Brazilian Journal of Medical and Biological Research 1998;31: 835-840.
21 - Gondim FAA, Oliveira GR, Graça JRV, Gondim RBM, Alencar HMP, Dantas RP, Santos AA, Rola FH. Neural mechanisms involved in the delay of gastric empting of liquid elicited by acute blood volume expansion in awake rats. Neurogastroenterology and Motility 1999;11: 93-99.
22 - Graça JRV, Gondim FAA, Rola FH, Santos AA. Variations in gastric compliance induced by acute blood volume changes in anesthetized rats. Brazilian Journal of Medical and Biological Research 2002;35: 405-410.
23 - Macedo GM, Maia APM, Lira GHS, Santos CL, Leal PR, Souza MH, Oliveira RB, Santos AA, Souza MA. Acute blood shedding increases gastric compliance in health subjects. Neurogastroenterology and Motility 2005;17(Suppl 2): 83.
24 - Rome Foundation. Functional dyspepsia module. (accessed 31 August 2014).
25 - Rome Foundation. Rome III Diagnostic Questionnaires. (accessed 31 August 2014).
26 - Carbone F, Holvoet L, Vandenberghe A, Tack J. Functional dyspepsia: outcome of focus groups for the development of a questionnaire for symptom assessment in patients suffering from postprandial distress syndrome. Neurogastroenterology and Motility 2014;26: 1266-1274.
27 - Mittal SK, Ahern L, Flaster E, Maesaka JK, Fishbane S. Self-assessed physical and mental function of haemodialysis patients. Nephrology Dialysis Transplantation 2001;16: 1387-1394.
28 - Santos PR, Arcanjo FPN. Social adaptability and substance abuse: predictors of depression among hemodialysis patients? BMC Nephrology 2013;14: 12.
29 - Santos PR, Arcanjo FPN. Distance between residence and the dialysis unit does not impact self-perceived outcomes in hemodialysis patients. BMC Research Notes 2012;5: 548.
30 - Santos PR. Evaluation of objective and subjective indicators of death in a period of one year in a sample of prevalent patients under regular hemodialysis. BMC Research Notes 2012;5: 24.
31 - Santos PR. Comparison of quality of life between hemodialysis patients waiting and not waiting for kidney transplant from a poor region of Brazil. Brazilian Journal of Nephrology 2011; 33: 166-172.
32 - Santos PR. Correlation between coping style and quality of life among hemodialysis patients from a low-income area in Brazil. Hemodialysis Internationl 2010;14: 316-321.
33 - Santos PR, Kerr LRFS. Clinical and laboratory variables associated with quality of life in Brazilian haemodialysis patients: a single-centre study. Revista Medica do Chile 2008;136: 1264-1271.
34 - Santos PR. Erectile dysfunction and quality of life in young patients on hemodialysis. Brazilian Journal of Nephrology 2008;30: 132-136.
35 - Santos PR. Relationship between gender and age with quality of life in chronic hemodialysis patients. Revista da Associação Médica Brasileira 2006;52: 356-359.
36 - Santos PR, Coelho MR, Gomes NP, Josué EP. Association of nutritional markers with quality of life in chronic kidney disease patients on hemodialysis. Brazilian Journal of Nephrology 2006; 28: 57-64.
37 - Santos PR. Dyspeptic symptoms are independent predictors of quality of life in end-stage renal disease patients on hemodialysis. In: XVII Paulista Congress of Nephrology, September 18-21, 2013, Bourbon Convention & Spa Resort, Atibaia, Brazil.
38 - Tack J, Bisschops R, Sarnelli G. Pathophysiology and treatment of functional dyspepsia. Gastroenterology 2004;127: 1239-1255.
39 - Bossola M, Muscaritoli M, Tazza L, Panocchia N, Liberatori M, Giungi S, Tortorelli A, Fanelli FR, Luciani G. Variables associated with reduced dietary intake in hemodialysis patients. Journal of Renal Nutrition 2005;15: 244-252.
40 - Santos PR. Dyspepsia: an underestimated problem among end-stage renal disease patients. In: Third International Conference on Nephrology & Therapeutics, June 26-27, 2014, Valencia Conference Centre, Valencia, Spain.
41 - Graybar GB, Tarpey H. Kidney transplantation. In Gelman S (ed.) Anesthesia and organ transplantation. Philadelphia: WB Saunders; 1987. p61-110.
42 - Horváth VJ, Izbéki F, Lengyel C, Kempler P, Várkonyi T. Diabetic gastroparesis: functional/morphologic background, diagnosis, and treatment options. Current Diabetes Reports 2014;14: 527.
43 - Choung RS, Locke GR III, Schleck CD, Zinsmeister AR, Melton LJ III, Talley NJ. Risk of gastroparesis in subjects with type 1 and 2 diabetes in the general population. American Journal of Gastroenterology 2012;107: 82-88.
44 - Strid H, Simrén M, Johansson AC, Svedlund J, Samuelsson O, Björnsson ES. The prevalence of gastrointestinal symptoms in patients with chronic renal failure is increased and associated with impaired psychological general well-being. Nephrology Dialysis Transplantation 2002;17: 1434-1439.
45 - Bytzer P, Talley NJ, Leemon M, Young LJ, Jones MP, Horowitz M. Prevalence of gastrointestinal symptoms association with diabetes mellitus: a population-based survey of 15,000 adults. Archives of Internal Medicine 2001;161: 1989-1996.
46 - Higgins Jr JT, Blair NP. Intestinal transport of water and electrolyte during extracellular fluid volume expansion in dogs. Journal of Clinical investigation 1971;30: 2569-2579.
47 - Levens NR. Control of intestinal absorption by the rennin-angiotensin system. American Journal of Physiology 1985;249: G3-G15.
48 - Lee JS. Relationship between intestinal motility, tone, water absorption and lymph flow in the rat. Journal of Physiology 1983;345: 489-499.
49 - Santos PR. Correlation between hypervolemia and gastric emptying time among end-stage renal disease patients on hemodialysis. In: XVII Paulista Congress of Nephrology, September 18-21, 2013, Bourbon Convention & Spa Resort, Atibaia, Brazil.
50 - Abell TL, Camilleri M, Donokoe K. Consensus recommendation for gastric emptying scintigraphy: a joint of the American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine. American Journal of Gastroenterology 2008;103: 753-763.
51 - Willems M, Quartero O, Numans M. How useful is the paracetamol absorption as a marker of gastric emptying? A systematic literature study. Digestive Diseases and Sciences 2001;46: 2256-2262.
52 - Gentilcore D, Hausken T, Horowitz M. Measurement of gastric empyting of low-and high-nutrient liquids using 3D ultrasonography and scintigraphy in health subjects. Neurogastroenterology & Motility 2006;18: 1062-1068.
53 - Schwizer W, Maecke H, Fried M. Measurement of gastric emptying by magnetic resonance imaging in humans. Gastroenterology 1992;103: 369-376.
54 - Kuo B, McCallum RW, Koch KL. Comparison of a gastric emptying of a non digestible capsule to a radio-labelled meal in healthy and gastroparetic subjects. Alimentary Pharmacology & Therapeutics 2008;27: 186-196.
55 - Ghoos YF, Maes BD, Geypens BJ, Mys G, Hiele MI, Rutgeerts PJ, Vantrappen G. Measurement of gastric emptying rate of solids by means of a carbon-labelled octanoic acid breath test. Gastroenterology 1993;104: 1640-1647.
56 - Monkemuller K, Malfertheiner P. Drug treatment of functional dyspepsia. World Journal of Gastroenterology 2006; 12: 2694-2700.
57 - Moayyedi P, Shelly S, Deeks JJ. Pharmacological interventions for non-ulcer dyspepsia. Cochrane Database of Systematic Reviews 2011;2: CD01960.
58 - Moayyedi P. The efficacy of proton pump inhibitors on functional dyspepsia: a systematic review and economic analysis. Gastroenterology 2004;127: 1329-1337.
59 - Lee KJ, Vos R, Janssens J, Tack J. Influence of duodenal acidification on the sensormotor function of the proximl stomch in humans. American Journal of Physiology-Gastrointestinal and Liver Physiology 2004;286: G278-G284.
60 - Miwa H, Nakajima K, Yamaguchi K, Fujimoto K, Veldhuyzen VAN, Zanten SJ, Kinoshita Y, Adachi K, Kusunoki H, Haruma K. Generation of dyspeptic symptoms by direct acid infusion into the stomach of healthy subjects. Alimentary Pharmacology & Therapeutics 2007;26: 257-264.
61 - Wang WH, Huang JQ, Zheng GF, Xia HH, Wong WM, Liu XG, Karlberg J, Wong BC. Effects of proton pump inhibitors on functional dyspepsia: a meta-analysis of randomized placebo-controlled trials. Clinical Gastroenterology and Hepatology 2007;5: 178-185.
62 - Wysowski DK, Bacsanyi J. Cisapride and fatal arrhythmia. New England Journal of Medicine 1996; 335: 290-291.
63 - Mearin F, Rodrigo L, Pérez-Mota A, Balboa A, Jiménez I, Sebastián JJ, Patón C. Levosulpiride and cisapride in the treatment of dysmotility-like functional dyspepsia: a randomized, double-masked trial. Clinical Gastroenterology 2004;2: 301-308.
64 - Ross EA, Koo LC. Improved nutrition after detection and treatment of occult gastroparesis in nondiabetic dialysis patients. American Journal of Kidney Diseases 1998;31: 62-66.
65 - Hallerback BI, Bommelaer G, Bredberg E, Campbell M, Hellblom M, Lauritsen K, Wienbeck M, Holmgren LL. Dose finding study of mosapride in functional dyspepsia: a placebo-controlled, randomized study. Alimentary Pharmacology & Therapeutis 2002;16: 959-967.
66 - Vakil N Laine L, Talley NJ, Zakko SF, Tack J, Chey WD, Kralstein J, Earnest DL, Ligozio G, Cohard-Radice M. Tegaserod treatment for dysmotility-like functional dyspepsia: results of two randomized, controlled trials. American Journal of Gastroenterology 2008;103: 1906-1919.
67 - Talley NJ, Tack J, Ptak T, Gupta R, Giguère M. Itopride in functional dyspepsia: results of two phase III multicenter, randomized, double-blind, placebo-controlled trials. Gut 2008;57: 740-746.
68 - Talley NJ, Verlinden M, Snape W, Beker JA, Ducrotte P, Dettmer A, Brinkhoff H, Eaker E, Ohning G, Miner PB, Mathias JR, Fumagalli I, Staessen D, Mack RJ. Failure of a motilin receptor agonist (ABT-229) to relieve the symptoms of functional dyspepsia in patients with and without delayed gastric emptying: a randomized double-blind placebo-controlled trial. Alimentary Pharmacology & Therapeutics 2000;14: 1653-1661.
69 - Yoshii K, Hirayami M, Nakamura T, Toda R, Hasegawa J, Takei M, Mera Y, Kawabata Y. Mechanism for distribution of acotiamide, a novel gastroprokinetic agent for the treatment of functional dyspepsia, in rat stomach. Journal of Pharmaceutical Sciences 2011;100: 4965-4973.
70 - Hsu YC, Liou JM, Yang TH, Hsu WL, Lin HJ, Wu HT, Lin JT, Wang HP, Wu MS. Proton pump inhibitor therapy versus prokinetic therapy in patients with functional dyspepsia: is therapeutic response predicted by Rome III subgroups? Journal of Gastroenterology 2011; 46: 183-190.
71 - Silang R, Regalado M, Cheng TH, Wesson DE. Prokinetic agents increase plasma albumin in hypoalbuminemic chronic dialysis patients with delayed gastric emptying. American Journal of Kidney Diseases 2001;37: 287-293.
72 - Hojo M, Miwa H, Yokoyama T, Ohkusa T, Nagahara A, Kawabe M, Asaoka D, Izumi Y, Sato N. Treatment of functional dyspepsia with anxiety or antidepressive agents: systematic review. Journal of Gastroenterology 2005;40: 1036-1042.
73 - Otaka M, Jin M, Odashima M, Matsuhashi T, Wada I, Horikawa Y, Komatsu K, Ohba R, Oyake J, Hatakeyama N, Watanabe S. New strategy of therapy for functional dyspepsia using famotidine, mosapride and amitriptyline. Alimentary Pharmacology & Therapeutics 2005;21(Suppl 2): 42-46.
74 - Taraz M, Khatami M, Dashti-Khavidaki S, Akhonzadeh S, Noorbala A, Ghaeli P, Taraz S. Sertraline decreases serum level of interleukin-6 (IL-6) in hemodialysis patients with depression: results of a randomized double-blind, placebo-controlled clinical Trial. International Immunopharmacology 2013;17: 917-923.
75 - Santos PR, Capote Jr JRFG, Cavalcanti JU, Vieira CB, Rocha ARM, Apolônio NAM, Oliveira EB. Sexual dysfunction predicts depression among women on hemodialysis. International Urology Nephrology 2013;45: 1741-1746.
76 - Faramarzi M, Azadfallah P, Book HE. A randomized controlled trial of brief psychoanalytic psychotherapy in patients with functional dyspepsia. Asian Journal of Psychiatry 2013;6: 228-234.
77 - Sebastián-Domingo JJ. La medicina integrative en el manejo de la dyspepsia functional: papel del preparado herbal STW5. Gastroenterología y Hepatología 2014;37: 256-261.
78 - Pilichiewicz AN, Horowitz M, Russo A, Maddox AF, Jones KL, Schemann M, Holtmann G, Feinle-Bisset C. Effects of Iberogast on proximal gastric volume, antro-pyloro-duodenal motility and gastric emptying in healthy men. American Journal of Gastroenterology 2007;102: 1276-1283.
79 - Rosch W, Vinson B, Sassin I. A randomized clinical trial comparing the efficacy of a herbal preparation STW 5 with the prokinetic drug cisapride in patients with dysmotility type of functional dyspepsia. Zeitschrift für Gastroenterologie;40: 401-408.
80 - Lacy BE, Talley NJ, Locke III GR, Bouras EP, DiBaise JK, El-Serag HB, Abraham BP, Howden CW, Moayyedi P, Prather C. Review article: current treatment options and management of functional dyspepsia. Alimentary Pharmacology & Therapeutics 2012;36: 3-15.
81 - Pang B, Zhou Q, Li J, Zhao L, Tong X. Treatment of refractory diabetic gastroparesis: Western medicine and traditional Chinese medicine therapies. World Journal of Gastroenterology 2014;20: 6504-6514.
82 - Xu S, Zha H, Hou X, Gao Z, Zhang Y, Chen JD. Electroacupuncture accelerates solid gastric emptying in patients with functional dyspepsia. Gastroenterology 2004;126: A-437.
83 - O’Grady G, Rgbuji JU, Du P, Cheng LK, Pullan AJ, Windsor JA. High-frequency gastric electrical stimulation for the treatment of gastroparesis: a meta-analysis. World Journal of Surgery 2009;33: 1693-1701.
84 - Chu H, Lin Z, Zhong L, McCallum RW, Hou X. Treatment of high-frequency gastric electrical stimulation for gastroparesis. Journal of Gastroenterology and Hepatology 2012;27: 1017-1026.
85 - Abell T, McCallum R, Hocking M,. Gastric electrical stimulation for medically refractory gastroparesis. Gastroenterology 2003;125: 421-428.
86 - Abell T, Lou J, Tabbaa M, Batista O, Malinowski S, Al-Juburi A. Gastric electrical stimulation for gastroparesis improves nutritional parameters at short, intermediate, and long-term follow-up. Journal of Parenteral and Enteral Nutrition 2003;27: 277-281.
87 - Miller LS, Szych GA, Kantor SB, Bromer MQ, Knight LC, Maurer AH, Fisher RS, Parkman HP. Treatment of idiopathic gastroparesis with injection of botulinum toxin into the pyloric sphincter muscle. American Journal of Gastroenterology 2002;97: 1653-1660.
88 - Lacy BE, Zayat EN, Crowell MD, Schuster MM. Botulinum toxin for the treatment of gastroparesis: a preliminary report. American Journal of Gastroenterology 2002;97: 1548-1552.
89 - Arts J, van Gool S, Caenepeel P, Verbeke K, Janssens J, Tack J. Influence of intrapyloric botulinum toxin injection on gastric emptying and meal-related symptoms in gastroparesis patients. Alimentary Pharmacology & Therapeutics 2006;24: 661-667.
90 - Arts J, Holvoet L, Caenepeel P, Bisschops R, Sifrim D, Verbeke K, Janssens J, Tack J. Clinical trial: a randomized-controlled crossover study of intrapyloric injection of botinum toxin in gastroparesis. Alimentary Pharmacology & Therapeutics 2007;26: 1251-1258.
91 - Friedenberg FK, Palit A, Parkman HP, Hanlon A, Nelson DB. Botulinum toxin A for the treatment of delayed gastric emptying. American Journal of Gastroenterology 2008;103: 416-423.