Feeling gutted in chronic kidney disease (CKD): Gastrointestinal disorders and therapies to improve gastrointestinal health in individuals CKD, including those undergoing dialysis

Abstract

Chronic kidney disease (CKD) affects 9.1% of the population worldwide. CKD may lead to structural and functional gastrointestinal alterations, including impairment in the intestinal barrier, digestion and absorption of nutrients, motility, and changes to the gut microbiome. These changes can lead to increased gastrointestinal symptoms in people with CKD, even in early grades of kidney dysfunction. Gastrointestinal symptoms have been associated with lower quality of life and reduced nutritional status. Therefore, there has been considerable interest in improving gastrointestinal health in this clinical population. Gastrointestinal health can be influenced by lifestyle and medications, particularly in advanced grades of kidney dysfunction. Therapies focused on gastrointestinal health have been studied, including the use of probiotics, prebiotics, and synbiotics, yielding limited and conflicting results. This review summarizes the alterations in the gastrointestinal tract structure and function and provides an overview of potential nutritional interventions that kidney disease professionals can provide to improve gastrointestinal health in individuals with CKD.

1 |. INTRODUCTION

Chronic kidney disease (CKD) affects 9.1% of the population worldwide.¹ The progression of kidney dysfunction is associated with impairments in several organs and systems, including the gastrointestinal tract.² Gastrointestinal symptoms have been reported in up to 80% of individuals with CKD, and while they tend to increase with the degree of kidney dysfunction, they are still highly prevalent in the non-dialysis-dependent CKD population.² The most commonly reported gastrointestinal symptoms are nausea, vomiting, abdominal pain, constipation, and diarrhea.² Importantly, gastrointestinal symptoms are associated with poor patient-centered outcomes, including lower quality of life.³ Therefore, there is a need for therapies that limit gastrointestinal symptoms and improve gastrointestinal health.

Gastrointestinal changes resulting from CKD can be classified as structural and functional changes (Figure 1). Some of the structural changes include a direct effect of the uremic milieu on intestinal epithelial cells, particularly impacting tight junction protein expression and assembly that impair intestinal barrier function in the small intestine and the colon.⁴ Some of the functional changes include impaired digestion, absorption, and motility. Furthermore, the community of microorganisms that reside in the gastrointestinal tract, the gut microbiota, is affected with CKD.^5,6 In addition to the compositional changes, there is an overall shift in the microbially derived metabolites away from the production of beneficial short-chain fatty acids (SCFA) to an increased production of uremic toxins derived from the microbiota, including indoxyl sulfate, p-cresyl sulfate, trimethylamine-N-oxide (TMAO), phenylacetylglutamine, and others.^7,8 These microbial metabolites can have a local impact in the gastrointestinal tract and in distal organs.

FIGURE 1.

Gastrointestinal alterations related to chronic kidney disease. Several factors related to chronic kidney disease (CKD), including the uremic milieu, dietary restrictions including overall phosphorus and potassium restriction, pharmacological therapies, and low physical activity and exercise levels, may lead to gastrointestinal alterations. These gastrointestinal alterations include impaired intestinal barrier function, motility, gut microbiome, and digestion and absorption. Impaired gastrointestinal barrier function may lead to an increased translocation of microorganisms and their components, such as lipopolysaccharide, that can activate the immune system leading to a pro-inflammatory response. Meanwhile, impaired gastrointestinal motility can lead to clinical symptoms and functional disorders, such as constipation, diarrhea, and dyspepsia. Additionally, the gut microbiome is altered in CKD, which is characterized by a decrease in the relative abundance of short-chain fatty acid-producers and an increase in the uremic toxin-producers. Finally, CKD may lead to impairments in digestion and absorption of nutrients, particularly protein, that, in conjunction with a low dietary fiber intake, may lead to the increased production of uremic toxins. Putting all of the aforementioned gastrointestinal alterations may lead to irritable bowel syndrome in CKD. Figure abbreviations: GI, gastrointestinal; CKD, chronic kidney disease; SCFA, short-chain fatty acids; IBS, irritable bowel syndrome

Besides the intrinsic effect of CKD on the gastrointestinal tract, extrinsic factors (e.g., diet, physical activity, and medications) can affect gastrointestinal structure and function. Kidney disease professionals, particularly registered dietitians, are often challenged with guiding one of the most complex medical nutrition therapies.^9–11 This traditional nutrient-focused approach to the CKD diet indirectly led to many dietary changes, such as reduced fiber intake and increased intake of ultra-processed foods, which may be considered detrimental to gastrointestinal health.^11,12 CKD is also associated with low physical activity levels, which may reduce gastrointestinal motility and increase symptoms.¹³ Finally, there has been a recent proliferation of therapies focused on the gut microbiome that may exert effects within the gastrointestinal tract and systemically.^5,14,15 This review aims to summarize the alterations in the gastrointestinal tract and to provide an overview of the evidence for potential nutritional interventions that can be provided by professionals to improve gastrointestinal health in individuals with CKD.

2 |. STRUCTURAL AND FUNCTIONAL GASTROINTESTINAL CHANGES IN CKD

2.1 |. Intestinal barrier

The intestinal barrier is composed of mucus, intestinal epithelial cells, and the mucosal immune system in the lamina propria (Figure 2).¹⁶ The mucus layer provides a chemical and physical barrier between the lumen and the epithelial cells and contains products of Paneth cells and immune cells from the lamina propria, such as defensins, secretory immunoglobulin-A, and lysozymes.^16,17 The epithelium is not a traditional epithelial cell layer but rather is composed of a variety of cell types, including absorptive cells (enterocytes), goblet cells, Paneth cells, enteroendocrine cells, and tuft cells, that form a continuous barrier and are connected through the apical junctional complex formed by intercellular junctions, tight junctions, and adherence junctions.¹⁷ Tight junction components include transmembrane proteins (e.g., claudins, occludins, and junctional adhesion molecules [JAMs]) connected to intracellular scaffold proteins, such as Zona Occludens (ZO) proteins.¹⁸ These tight junctions exist near the apical side of the polarized intestinal epithelial cells, where they control paracellular transport of water, ions, and other molecules.¹⁸

FIGURE 2.

The intestinal barrier in health and chronic kidney disease. In the absence of chronic kidney disease (left panel), the components of the intestinal barrier function (i.e., mucus layer; epithelial layer connected by the correct configuration of JAMs, claudins, and occludins; and mucosal immune system located in the lamina propria) work in tandem to maintain homeostasis. The intestinal lumen, particularly in the distal gastrointestinal tract, contains commensal microorganisms that degrade the nutrients available. In homeostasis, most protein, fats, and digestible carbohydrates are digested and absorbed in the small intestine. Undigestible carbohydrates, particularly fermentable fiber, can be metabolized by members of the microbiota producing short-chain fatty acids. In chronic kidney disease (right panel), the intestinal barrier function is impaired. Notably, there may be a reduced mucus layer thickness and inadequate tight junction proteins assembly, leading to translocation of microorganisms and their components, including lipopolysaccharide, promoting a pro-inflammatory immune response. This impaired barrier function may also lead to an enhanced paracellular transport of nutrients such as phosphorus. Figure abbreviations: JAMs, junctional adhesion molecules; ZO, Zona Occludens; LPS, lipopolysaccharide; SCFA, short-chain fatty acids

In CKD, the uremic milieu can compromise the intestinal barrier. Experimentally, culturing intestinal cell lines in uremic serum or specific uremic toxins leads to impairment in tight junction proteins and intestinal barrier function. Vaziri et al⁴ reported a toxic effect of urea by demonstrating that exposing a human cell line that behaves like polarized intestinal epithelial cells (T84 cells) to urea led to a dose-dependent decrease in the protein expression of ZO-1, occludin, and claudin-1, as well as a reduction of transepithelial electrical resistance, a measure of enhanced intestinal permeability. Moreover, by adding urease to the media, mimicking a uremic environment and an increase in urease-producing bacteria, the detrimental effects were amplified.⁴ Furthermore, by exposing T84 cells to predialysis serum of patients undergoing hemodialysis, there was a reduced protein expression of ZO-1, occludin, and claudin-1 compared to control serum, but this was prevented by exposing the cells to postdialysis serum.¹⁹ Overall, these in vitro studies suggest that the uremic milieu impairs intestinal permeability by reducing the protein expression of tight junction proteins.

Similar to in vitro studies, there is an impairment of the intestinal barrier function in experimental rodent models of CKD. In two rat models of CKD (5/6 nephrectomy and 0.7% adenine diet), there was a lower protein expression of claudin-1, ZO-1, and occludin.²⁰ CKD rats also had increased leukocyte infiltration in the lamina propria, suggesting increased translocation of bacteria or bacterial components.²⁰ Similarly, 5/6 nephrectomized rats had increased permeability, edema, and inflammatory infiltration in the ileum particularly 8–10 weeks after the partial nephrectomy.²¹ In 5/6 nephrectomized mice, increased intestinal permeability, as demonstrated by the increased appearance of a 4-kDa FITC-dextran, was coupled with a reduction in the mRNA expression of ZO-1, occludin, claudin-1, and claudin-2.²² In the same study, mice injected with indoxyl sulfate also had similar effects. We have also observed consistent increased intestinal permeability in Cy/+ rats as CKD progresses (unpublished observation). These preclinical studies suggest that CKD impairs the intestinal barrier, regardless of the animal model.

In humans with CKD, few studies directly assess the changes in the intestinal barrier. In colonic tissues from 12 individuals with CKD and healthy controls, patients with CKD had more villi necrosis, ulceration, fibroplasia, and damaged tight junctions using transmission electron microscopy.²² Similarly, in colonic biopsies from individuals that had a segmental colectomy, patients on hemodialysis had lower immunostaining of claudin-1, ZO-1, and occludin, while patients with advanced CKD only had lower occludin staining, but similar claudin-1 and ZO-1 to controls.²³ In postmortem biopsies from patients on hemodialysis, there was marked inflammation across the gastrointestinal tract.²⁴ Finally, using video capsule endoscopy, ~40% of the studied individuals undergoing hemodialysis had mucosal lesions, including erosions and ulcers; however, biopsies were not included to assess intestinal barrier components.²⁵

Obtaining gastrointestinal biopsies from individuals to assess the intestinal barrier is challenging and requires an invasive procedure. Therefore, researchers and clinicians have assessed intestinal barrier function using noninvasive probe molecules administered orally and measured systemically, such as lipopolysaccharide (LPS) or endotoxin, LPS-binding protein, polyethylene glycols (PEG), and blood microbiome assessment. In patients with CKD, the concentration of endotoxin increased as kidney function declines, and people undergoing kidney replacement therapy had the highest concentrations.²⁶ In individuals with CKD not yet on dialysis, there is an inverse relationship between estimated glomerular filtration rate (eGFR) and soluble CD14, the pattern-recognition receptor of endotoxin.²⁷ In individuals with CKD, there was a greater serum recovery of larger molecules of PEG than in the controls.²⁸ These large molecules should not be translocated into circulation, suggesting increased intestinal permeability. Finally, the blood microbiome of individuals with CKD had a higher relative abundance of proteobacteria, including unclassified Enterobacteriaceae, than healthy controls suggesting increased bacterial translocation from the intestinal lumen in CKD.²⁹ Overall, similar to the in vitro and experimental models of CKD, the intestinal barrier is impaired in individuals with CKD across different grades of kidney dysfunction.

2.2 |. Digestion and absorption of nutrients

Digestion is the process of breaking down complex macronutrients into their simplest form by chemical, enzymatic, and mechanical means to be absorbed along the gastrointestinal tract. CKD may disturb digestion and absorption of macronutrients and micronutrients directly or indirectly. Impairments in digestion and absorption of macronutrients are of interest in CKD as these can promote protein-energy wasting, which has a prevalence of 11%–54% in people with nondialysis CKD and 28%–54% in those undergoing dialysis.^30,31 In patients with CKD, there was a lower assimilation (digestion and absorption) of protein assessed by both, ¹³C-leucine breath test and increased urinary p-cresol.³² Similar results were also reported in individuals undergoing peritoneal dialysis and hemodialysis.³³ Providing a mixed macronutrient meal with L-leucine-labeled eggs, van Vliet et al³⁴ showed that patients on hemodialysis had a lower rate of appearance of the labeled leucine compared to matched controls, suggesting impaired protein assimilation. Reduced protein digestion can occur if there is impaired gastric hydrochloric acid production and secretion, reduced exocrine pancreatic function, and rapid gastrointestinal transit time. Proton pump inhibitors (PPIs) are commonly prescribed to patients with CKD, and their use may impair protein digestion by increasing the gastric pH.^35,36 In healthy individuals, the use of omeprazole impaired protein assimilation and increased urinary p-cresol.³⁷ The hydrochloric acid binder veverimer is an emerging pharmaceutical seeking approval for the treatment of metabolic acidosis in CKD.³⁸ There are limited studies on exocrine pancreatic function in CKD. Griesche-Philippi et al³⁹ found that 10% of hemodialysis patients had mild-to-moderate exocrine pancreatic insufficiency measured by fecal elastase-1. However, to our knowledge, the effects of the use of PPIs, acid binders, and reduced exocrine pancreatic function on protein assimilation has not been explored in CKD.

Unlike protein assimilation, there is not extensive data on carbohydrate and fat digestion and absorption in CKD. In individuals undergoing dialysis, el-Lakany et al⁴⁰ showed that there was a lower activity of mucosal maltase and sucrase, but not lactase. However, they concluded that overall, hemodialysis patients did not have carbohydrate malabsorption. In a pilot study, we recently studied the effects of inulin supplementation, a fermentable prebiotic fiber, against maltodextrin as a placebo.⁴¹ Maltodextrin is a highly digestible polysaccharide. Interestingly, we found that after a 4-week supplementation, the fecal SCFAs acetate and propionate were increased and were numerically higher after maltodextrin, suggesting that it may escape absorption in the small intestine to be fermented by the gut microbiome. Furthermore, acute changes in carbohydrate digestion can occur in the setting of intestinal damage due to intradialytic hypotension during hemodialysis and in acute enteritis, which may reduce the activity of brush border disaccharidases.⁴² However, evidence of changes in disaccharidase activity in CKD is lacking. To our knowledge, there are no data on the effect of CKD on fat digestion. Interestingly, lipase inhibitors can cause kidney damage due to oxalate crystal depositions in the kidney,⁴³ although this remains controversial.⁴⁴ A proposed mechanism is through the binding of calcium to unabsorbed fat, leaving oxalate free to be absorbed in the intestine and causing its deposition in the kidneys.⁴³

Impairment of vitamin absorption has also been reported in experimental models of CKD. In 5/6 nephrectomized rats using the in vivo perfusion of an isolated proximal jejunal loop, there was an impairment in the absorption of riboflavin,⁴⁵ pyridoxine,⁴⁶ folate,⁴⁷ vitamin D,⁴⁸ vitamin C,⁴⁹ biotin,⁵⁰ and vitamin E,⁵¹ but not vitamin A.⁵² There is limited translation of these studies in people with CKD despite the evidence that individuals with CKD may be at risk of some vitamin deficiencies.⁵³ However, it is unclear if this is due to altered intestinal transport. In light of these observations, the 2020 Kidney Disease Outcomes Quality Improvement (KDOQI) Nutrition Clinical Practice Guidelines suggest that in case of inadequate intake a multivitamin supplement can be considered.⁹

Similar to vitamins, there is limited information on the absorption of electrolytes and minerals in the context of CKD. The minerals with the most data available in the context of CKD are calcium and phosphorus.^54–56 Calcium absorption was decreased in a stepwise matter even in the early stages of CKD compared to healthy controls, and this was partially explained by lower concentrations of calcitriol and age.⁵⁷ However, at adequate calcium intake, calcium’s fractional absorption rate is similar to healthy adults.⁵⁸ Historically, the transcellular transport of electrolytes and minerals has been studied extensively. Recently, however, the paracellular route has gained attention, particularly with the increased prevalence of intestinal barrier dysfunction. This is relevant as nutrients, such as phosphorus, can be absorbed paracellularly, increasing its burden and leading to hyperphosphatemia. In a recent experimental study, the sodium/hydrogen exchanger isoform-3 (NHE3) inhibitor, tenapanor, was shown to reduce intestinal permeability by changing intracellular pH limiting paracellular absorption of phosphorus.⁵⁹

2.3 |. The gut microbiome and microbial metabolites

The gut microbiome is the community of microorganisms, their microbial structural elements including genomes, environmental conditions, and microbial metabolites that reside in the gastrointestinal tract ecosystem.^60,61 The gut microbiome has gained attention in health and diseases as its composition and function are altered in several disease states, including CKD. Several reviews provide an in-depth summary of what is currently known on the microbiome in CKD.^5,6,62 The gut microbiome and its metabolites may modulate the pathogenesis and progression of CKD. Comparing germ-free mice and conventionally raised mice given an adenine diet to induce CKD, germ-free mice had exacerbated kidney damage.^63,64 Although germ-free mice had a lower concentration of microbially-derived uremic toxins, they also had lower concentrations of SCFA, which appeared to prevent exacerbated kidney damage in conventionally raised mice. In an in-depth assessment of the fecal microbiome using shotgun metagenomics, fecal metabolomics, and serum metabolomics, patients on hemodialysis were enriched in Eggerthella lenta, Fusobacterium nucleatum, Clostridioides difficile, Alistipes finegoldi, and Flavonifractor spp. and depleted Faecalibacterium prausnitzii, Roseburia, Prevotella, and Eubacterium spp. compared to healthy controls.⁸ Along these microbial composition alterations, patients on hemodialysis had enriched pathways related aromatic amino acid degradation, while healthy controls had enriched SCFA biosynthetic pathways. In tandem with microbial composition and function, there were increased fecal indole, p-cresol, phenol, phenylacetaldehyde, benzoic acid, and trimethylamine and their respective circulating uremic toxins: indoxyl sulfate, p-cresol sulfate, phenyl sulfate, phenylacetylglutamine, hippuric acid, and trimethylamine-N-oxide. Importantly, the authors then showed that specific members of the microbiota, E. lenta and F. nucleatum, contributed to enhanced kidney damage and production of gut-derived uremic toxins in 5/6 nephrectomy rats, and these effects were reduced by Bifidobacterium animalis A6.⁸

The changes in the gut microbiome composition and function may impact gastrointestinal function. The low production of SCFA by the microbiota can be detrimental to the epithelial integrity, as butyrate is the preferred source of energy of the colonocyte, and experimental data has shown intestinal barrier function can be enhanced by increasing the production of SCFA with fermentable fiber.⁶⁵ Furthermore, microbially derived uremic toxins, including indoxyl sulfate, can also impair intestinal barrier function.²² In addition to impairing intestinal barrier integrity, changes within the gut microbiome in CKD can affect gastrointestinal motility. In 5/6 nephrectomized mice, ileal and colonic contractility was reduced compared to control mice; this reduction was corrected with the use of antibiotics.⁶⁶ Therefore, therapies focused on targeting the gut microbiome and their derived metabolites are of interest to the CKD community.

2.4 |. Functional gastrointestinal disorders

2.4.1 |. Functional dyspepsia

In the absence of an organic cause, dyspepsia is a functional gastroduodenal functional disorder that is characterized by epigastric pain and/or burning, postprandial fullness, or early satiety.⁶⁷ Using the Gastrointestinal Symptom Rating Scale, compared to controls, individuals with nondialysis CKD, peritoneal dialysis, and hemodialysis had a higher score of the abdominal pain domain, a typical symptom of dyspepsia.⁶⁸ In patients on hemodialysis without diabetes mellitus, the prevalence of dyspepsia is 48%–70%.⁶⁹ The pathophysiology of functional dyspepsia is hypothesized to be multifactorial and may include a number of factors including abnormal gastric motility, altered visceral sensation, dysregulation of the gut–brain axis, and low-grade inflammation.⁶⁷ Of these factors, most clinical studies examining mechanisms of dyspepsia in CKD have focused on the role of gastric motility. In one study of individuals on hemodialysis and healthy volunteers, van Vlem et al⁶⁹ showed a significant increase in gastric emptying half time (T_1/2) in individuals on hemodialysis with dyspepsia compared to those without dyspepsia and healthy volunteers. Furthermore, the degree of dyspepsia based on the Dysmotility-like Dyspepsia Score was positively correlated with gastric emptying. Gastric emptying was evaluated by scintigraphy after ingestion of a radio-labeled solid–liquid meal in patients on hemodialysis (with normal glucose tolerance, glucose intolerance, and type 2 diabetes) and age, sex, and BMI-matched controls.⁷⁰ The investigators reported that all three groups of patients on hemodialysis had delayed gastric emptying at multiple time points (15 min, gastric emptying T_1/2, and gastric mean emptying time) for the solid meal component, and prolonged gastric mean emptying time for the liquid meal component compared to controls. These data suggest that impairment in gastric emptying may be an important contributor to symptoms of dyspepsia in kidney failure.

2.4.2 |. Chronic constipation

Constipation is one of the most common functional gastrointestinal disorders reported by individuals with CKD.⁷¹ The prevalence of constipation in CKD has been reported to be 1.6%–90.3%, depending on the classification method. Additionally, most studies evaluating medication adverse events do not use strict criteria, limiting our knowledge. However, the data appears consistent that the overall prevalence is higher in individuals on hemodialysis compared to those on peritoneal dialysis and with nondialysis CKD.^71–73 Constipation can be diagnosed based on clinical history and using validated tools and instruments such as the Rome criteria, the Bristol Stool Form Scale, and the constipation domain of the Gastrointestinal Symptom Rating Scale.^71,74 Constipation can be classified as primary or secondary, although both can co-exist in the case of CKD as the causes are likely multifactorial.⁷¹ Primary constipation can be subclassified as (a) normal transit constipation; (b) slow transit constipation secondary to impairment in colonic motor activity; (c) defecatory disorders including dyssynergic defecation; (d) or a combination of the three.^71,75 Secondary constipation may be related to other comorbidities or systemic diseases (e.g., diabetes mellitus and hypothy-roidism), electrolyte imbalances, and extrinsic factors, such as medication use.^71,75

Constipation has been associated with an increased risk of CKD incidence and progression,⁷¹ cardiovascular disease,⁷⁶ and reduced quality of life.^3,68 The high prevalence of constipation in CKD can be explained by the presence of comorbidities, such as diabetes mellitus and thyroid disorders, as well as the traditional renal diet which is low in dietary fiber, low physical activity levels,¹³ and medication use.⁷⁷ Dietary fiber intake has been reported to be low,⁷⁸ a consequence of the focus on limiting foods that are high in potassium and phosphorus, leading to limited intake of fruits, vegetables, nuts, whole grains, legumes, and seeds.¹¹ Prolonged gastrointestinal transit time coupled with a low fermentable dietary fiber intake may result in increased production of protein fermentation products by the gut microbiome, including indoxyl sulfate and p-cresyl sulfate.⁷⁹ In a cross-sectional analysis in individuals with nondialysis CKD and peritoneal dialysis, constipation was associated with higher p-cresyl sulfate, but not indoxyl sulfate.^80,81 Due to the multifactorial nature of constipation, comprehensive therapies are needed; the nutritional-focused therapies are described below.

2.4.3 |. Functional diarrhea

Functional diarrhea is a functional gastrointestinal disorder that is defined as the recurrent passage of loose or watery stools in the absence of structural or physiologic disease.⁸² The diagnosis of functional diarrhea can be aided by the use of the Rome criteria and other validated tools including the Bristol Stool Form Scale and the diarrhea domain of the Gastrointestinal Symptom Rating Scale.^71,74 Using the Gastrointestinal System Rating Scale, the prevalence of diarrhea of any cause has been reported between 5.3% and 38.3% in patients on dialysis⁷³; however the prevalence of functional diarrhea has not been well described. The cause of diarrhea in individuals with CKD and particularly in those with advanced stages is complex as there may a number of organic causes, such as the use of medications (e.g., antibiotics, some phosphate binders, potassium binders, and mycophenolate mofetil), nutrient malabsorption, and increased risk of gastrointestinal infections (e.g., Clostridioides difficile). In a meta-analysis, individuals with CKD had an increased relative risk (RR 1.95 [95% CI 1.81–2.10]) of Clostridioides difficile-associated diarrhea compared to those without CKD and the risk was higher in individuals with kidney failure (2.63 [95% CI 2.04–3.38]).⁸³

2.4.4 |. Irritable bowel syndrome

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by abdominal pain associated with defecation or altered bowel habits.^84,85 Pathophysiologic mechanisms of IBS may include abnormal gastrointestinal motility, visceral hypersensitivity, altered immune activation in the gut, and disturbances in the gut microbiome.^85,86 The diagnostic criteria for IBS are the presence of recurrent abdominal pain for at least 1 day per week that is associated with at least two of the following: defecation, change in stool frequency, and change in stool form.⁸⁵ Criteria should be fulfilled for at least the last 3 months with onset of symptoms occurring at least 6 months prior to the diagnosis.⁸⁵ IBS can be classified into subtypes based on the predominant bowel pattern: IBS with constipation, diarrhea, mixed, and unclassified.⁸⁴ Individuals with CKD and kidney failure may be at increased risk of IBS, as there are structural changes that can cause intestinal mucosal inflammation, changes in the gut microbiome, as well as increased stress, anxiety, and depression, all of which have been implicated in IBS pathogenesis.⁸⁷ In a systematic review, IBS-like symptoms were present in 7.3%–44% of patients on hemodialysis and 33%–45% of patients on peritoneal dialysis, well above the prevalence of the general population.^73,85 Lifestyle factors such as exercise or stress reduction and dietary modifications are common first steps in the management of IBS. For example, the use of soluble fiber (e.g., psyllium) may improve global symptoms, while a low FODMAP diet (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) may be utilized to reduce flatulence and abdominal pain.⁸⁵ However, the evidence for these therapies is moderate to low. Several pharmacological agents are also available for the treatment of IBS. Tricyclic antidepressants may be useful for global IBS symptoms.^82,88 Chloride channel activators, guanylate cyclase activators, and 5-HT₄ agonists such as tegaserod (in women less than 65 years of age) may be used to treat those with constipation-predominant symptoms.⁸⁸ Meanwhile, nonabsorbable antibiotics (rifaximin), bile acid sequestrants, and 5-HT₃ antagonists may be considered in diarrhea-predominant IBS.⁸⁸ However, data regarding the effect of these therapies in IBS in individuals with CKD is limited and should be explored.

2.5 |. Lifestyle and medications and their relationship to gastrointestinal health

The traditional renal diet has been characterized by its focus on nutrients, with a proactive approach of limiting the intake of potassium, phosphorus, and sodium, as well as the modulation of dietary protein depending on the grade of CKD.⁸⁹ This medical nutrition therapy has been regarded as one of the most difficult to prescribe and to follow. The cumulative grouping of some or all of these recommendations may leave individuals with CKD with limited food options and encourage individuals to disregard the recommendations altogether.^11,90 Moreover, the traditional restriction of dietary potassium and phosphorus without consideration for bioavailability can lead to a low intake of fruits, vegetables, whole grains, nuts, and legumes. These food groups contain nutrients and food components that are important for gastrointestinal health, including dietary fiber.⁹¹ Indeed, the dietary fiber intake of people with CKD is low and well below the adequate intake of 25 and 38 g/day for females and males 19–50 years of age and 21 and 30 g/day for females and males ≥51 years of age, or 14 g/1000 kcal/day.^78,92,93

Medications can also impair gastrointestinal function leading to a higher incidence of gastrointestinal symptoms. Polypharmacy is common in people with CKD, particularly those undergoing kidney replacement therapies.⁹⁴ Some of the commonly prescribed medications in CKD can lead to gastrointestinal symptoms.⁹⁵ These medications include oral iron supplements or replacement products, phosphate binders, potassium binders, calcimimetics, antihypertensives, nonsteroidal anti-inflammatory agents (NSAIDs), and antibiotics.^96–98 Particularly, phosphate binders represent almost 50% of the total pills/day in patients on dialysis, contributing to the high pill burden.⁹⁹ Phosphate binders can lead to adverse outcomes and gastrointestinal symptoms are very common as summarized in Figure 3.⁹⁸ The enhanced side effects of medications can lead to lower adherence and, thus, suboptimal treatment of the complications of CKD.^94,96 However, it should be emphasized that most of our knowledge on gastrointestinal side effects are derived from studies that do not use validated assessment stools. This creates difficulty in comparing drugs as constipation may be defined differently by different patients.

FIGURE 3.

Gastrointestinal symptoms reported with the use of phosphate binders. The main adverse effect of phosphate binder use are gastrointestinal symptoms. This figure describes the gradient of gastrointestinal side effects going from lower to higher. *Calcium carbonate is an over-the-counter medication and, thus, not reviewed and approved by the Food and Drug Administration (FDA); ^¥Gastrointestinal symptoms were obtained from the FDA drug sheet adverse reactions. ^§Only available in Japan

2.6 |. Nutritional therapies centered in the gastrointestinal tract in CKD

Several nutritional therapies have been postulated to improve gastrointestinal health (summarized in Figure 4), including overall healthy dietary patterns, specific types of dietary fiber, and gut microbiome-centered therapies, including prebiotics, probiotics, and synbiotics.

FIGURE 4.

Nutritional interventions and proposed benefits to the gastrointestinal tract in CKD. Proposed nutritional interventions for preventing and treating gastrointestinal effects varying from dietary patterns, single nutrients, and microbiota-mediated therapies. The proposed beneficial effects of these interventions include (a) improvements in GI motility and GI symptoms, (b) improvements in the composition and function of the gut microbiome leading to lower production of microbially derived uremic toxins and increased SCFA production; and (c) improved intestinal barrier function. Figure abbreviations: DASH, dietary approaches to stop hypertension; PLADO, plant-dominant low-protein diet; FOS, fructooligosaccharides; RS, resistant starch; GI, gastrointestinal; SCFA, short-chain-fatty acids

2.7 |. Dietary patterns

The nutritional management of CKD has been shifting from a nutrient-centered treatment to overall dietary patterns and outcomes.^100,101 In particular, plant-based diets have been highlighted for the prevention of CKD and the management of the complications derived from progressive kidney dysfunction such as metabolic acidosis, muscle wasting, cardiovascular disease, and CKD-mineral and bone disorder (CKD-MBD).^15,102–105 Plant-based diets are characterized by an emphasis on the intake of plant-based foods, such as fruits, vegetables, whole grains, legumes, and nuts, and a limited to moderate intake of animal-based foods, such as meat, seafood, fish, eggs, and dairy.¹⁵ As such, plant-based diet is a relative term that does not necessarily mean the restriction of animal-based foods. Therefore, several dietary patterns recommended for the general population, those at risk of CKD, and people diagnosed with CKD including the Dietary Approaches to Stop Hypertension (DASH) diet,¹⁰⁶ the Mediterranean diet,¹⁰⁷ and the newly described plant-dominant low-protein diet (PLADO)¹⁰⁸ can fit this definition.

Overall, a dietary pattern, such as the DASH, Mediterranean, and PLADO diets will contain a combination of foods and a wide variety of dietary fibers that can confer benefits to gastrointestinal health and the gut microbiome. However, as dietary fiber is delivered in a food matrix, the physiological benefit, particularly the degree of fermentability, may depend on the food particle size and porosity.⁹¹ While plant-based diets can have several benefits in the context of CKD, the study of their effects on gastrointestinal health is limited. In individuals on peritoneal dialysis, Sutton et al¹⁰⁹ evaluated the effects of (a) a high-fiber diet by asking participants to increase foods high in fiber; (b) high-fiber supplement (partially hydrolyzed guar gum) titrated to reach a Bristol Stool Score of 3–4; or (c) placebo. The investigators found that participants in the high-fiber supplement group, but not the high-fiber diet group, had lower use of laxatives. However, it is important to note that the dietary fiber intake did not truly increase in the participants randomized to the high-fiber diet, but this was likely due to the small sample size and dietary assessment tool used (constructed food chart). In a cross-sectional analysis, Stanford et al¹¹⁰ showed that a healthy plant-based diet was associated with lower concentrations of indoxyl sulfate in patients on hemodialysis. In addition to plant-based dietary patterns, patients may benefit from individual food groups or even individual foods. In an observational study in people on hemodialysis, Dos Santos et al¹¹¹ reported that fruit intake was associated with a lower risk of constipation. Similarly, Lambert et al¹¹² showed that in patients on hemodialysis, 40 g of raw almonds for 4 weeks reduced constipation. With the relatively recent push for the use of plant-based diets in CKD, researchers should include the assessment of gastrointestinal health and gastrointestinal symptoms in prospective trials assessing the effects of plant-based diets.

While plant-based diets may improve gastrointestinal health, they may also induce gastrointestinal symptoms. Recently, a secondary analysis of the DASH-sodium trial¹¹³ showed that there was a dose-dependent relationship between bloating and the quantity of sodium. Moreover, bloating was higher in the DASH diet groups compared to control groups, and dietary fiber was 32 g versus 11 g of fiber/day, respectively. Similarly, a secondary analysis of the OmniHeart trial¹¹⁴ evaluated the risk of bloating of three versions of the DASH diet containing ~30 g of fiber/2100 kcal with different macronutrient distributions: (a) carbohydrate-rich (58% carbohydrates, 15% protein, and 27% fat); (b) protein-rich (48% carbohydrates, 25% protein, and 27% fat); and (c) unsaturated fat-rich (48% carbohydrates, 15% protein, and 37% fat). The investigators reported that when comparing within diets, there was an increased risk of bloating in the protein-rich diet compared to the carbohydrate-rich diet, while acknowledging that in the protein-rich diet there was an emphasis on plant-based protein foods, such as legumes and beans, which contain fermentable oligosaccharides that can increase flatulence. Therefore, it may be reasonable to recommend a stepwise approach to the introduction of high fiber foods to help promote long-term tolerance; however, this approach requires further research.

2.8 |. Dietary fiber

The term dietary fiber refers to nondigestible carbohydrates and lignin that are intrinsic and intact in plants, while functional fiber is the isolated, nondigestible carbohydrates that provide a benefit to the host.⁹² Dietary fiber is traditionally classified into water-soluble or insoluble. However, this classification does not provide enough information about their physiological function. Therefore, other characteristics can be included to provide a better description of the functional effects, including viscosity and fermentability (Table 1). Gill et al⁹¹ recently performed an in-depth review of dietary fiber and its clinical application for the management of gastrointestinal disorders. Overall, the benefits of the types of dietary fiber on gastrointestinal health include improvements in gut integrity mediated by the production of SCFA, gastrointestinal transit time, and stool output.

TABLE 1.

Examples of dietary fiber by their physicochemical characteristics

Type	Characteristic	Example	Proposed Benefits in CKD
Soluble fiber	Viscous, fermentable	Pectin Guar gum β-glucans	Nutrient availability: delayed glycemia, lower cholesterolemia mediated by lower bile acid ileal reabsorption SCFA production
	Viscous, nonfermentable	Psyllium husk	Water-holding with dual benefit for constipation and diarrhea Nutrient availability: delayed glycemia, lower cholesterol mediated by lower bile acid ileal reabsorption
	Nonviscous, fermentable	Inulin FOS GOS Dextrins Resistant starcha (variability in viscosity)	SCFA production Mineral absorption Improved barrier function
Insoluble fiber	Nonviscous, nonfermentable	Cellulose Coarse wheat bran	Stool bulking

^aVariable viscosity depending on the type.

Abbreviations: FOS, fructooligosaccharides; GOS, galactooligosaccarides; SCFA, short-chain fatty acids.

Dietary guidelines usually focus on an overall intake of total dietary fiber coming from foods because a combination of food groups likely provides a variety of dietary fiber types, including insoluble and water-soluble fiber with a variety of viscous, nonviscous, fermentable, and nonfermentable sources.¹¹⁵ Unfortunately, the complex nutritional recommendations in CKD may lead individuals to consume a monotonous diet, particularly in advanced stages of CKD.¹¹⁶ Consequently, dietary fiber diversity intake may be reduced, and the gastrointestinal tract deprived of the benefits of fiber. Moreover, studies consistently have shown that the dietary fiber intake is below the general adequate intake across the CKD spectrum. Therefore, some studies have supplemented isolated sources of dietary fiber to assess its impact on several outcomes, including gastrointestinal-related outcomes, although there is limited data on the latter.

The main proposed benefit of fermentable fiber is the increased production of SCFA, namely acetate, propionate, and butyrate. SCFA have a variety of autocrine, paracrine, and endocrine effects. Alexander et al¹¹⁷ and Blaak et al⁶⁵ provide a useful overview of the overall physiological effects of SCFA. However, it is important to note that in individuals with CKD, fecal SCFA (used as a proxy of production) are reduced compared to healthy controls.^7,8 Within the gastrointestinal tract, some of the benefits of SCFA, especially butyrate, include serving as an energy source for colonocytes and bacteria, limiting pathogen growth through decreased pH, improving intestinal epithelial and mucus layers, and modulation of intestinal and immune cells through the activation of G-protein-coupled receptors (GPCR), such as GPCR41, GPCR43, and GPCR109a.^65,117,118 A secondary benefit of dietary fiber is sparing of protein that is fermented and a reduction of protein fermentation products, such as p-cresol and indoles, that may affect the intestinal barrier by promoting intestinal inflammation.^79,119

Fermentable fibers from foods and isolated sources include resistant starch, inulin-type fructans, fructooligosaccharides (FOS), β-glucans, pectin, guar gum, arabinoxylans, and galactooligosaccharides (GOS). The production and proportion of SCFA, however, varies depending on the type of fermentable fiber and degree of polymerization. According to in vitro fermentation studies with human fecal inoculum, inulin-type fructans appear to promote higher production of butyrate, pectin and arabinoxylans a higher production of acetate, and guar gum a higher production of propionate.¹¹⁷ As these dietary fibers are substrates for members of the gut microbiota, they are considered prebiotics. Trials assessing the effects of prebiotic fibers are presented in the subsequent section.

Viscosity is the other characteristic of fiber that provides a physiological benefit. Viscosity is the ability to form a gel when hydrated. The physiological benefits of viscous fibers include decreased postprandial glycemia and lowering of cholesterol by decreasing reabsorption of bile acids, as well as beneficial effects within the gastrointestinal tract including improved laxation and diarrhea control.^91,120 Improvement in constipation and diarrhea with viscous fibers depends on the ability of the fiber to maintain the formed gel throughout the gastrointestinal tract to avoid fermentation. To this end, psyllium husk improves stool consistency and bulk by binding water and passing intact through the gastrointestinal tract.^91,121,122 Importantly, the water-binding capacity can be beneficial for both constipation and diarrhea.¹²¹ Other viscous fibers such as β-glucans and pectins, however, are highly fermentable; therefore, while they may have other positive physiological benefits, they may not help with laxation and improvement in diarrhea. Surprisingly, to our knowledge, there is only one study on the effects of psyllium husk in patients on peritoneal dialysis, where it was found that psyllium was an effective laxative.¹²³ Future studies should assess if psyllium husk supplementation improves constipation and diarrhea in people with CKD and kidney failure.

In addition to nonfermentable viscous fibers, insoluble fiber, such as coarse wheat bran, but not finely milled wheat bran, may be helpful in constipation. Coarse bran improves stool consistency by physically micro-damaging and stimulating the intestinal mucosa and water secretion into the lumen.^121,122 Using plastic particles with similar size and shape as wheat bran particles; researchers showed that only wheat bran and plastic that were coarse and large increased stool output.^124,125 Furthermore, the fine wheat bran only increased the dry mass of the stool, which is the opposite effect wanted in a person with constipation.^124,125 These results highlight that only recommending wheat bran to improve constipation may not be helpful. Commercial products often contain multiple ingredients and the size of the wheat bran particles may not be known, but there are products available labeled as coarse wheat in the market and individuals should be made aware of these distinctions.

Isolated dietary fiber supplements may be commonly recommended by healthcare professionals or self-prescribed by individuals as these can be found over the counter. However, it is important to recognize that a blanket recommendation to increase dietary fiber in the form of supplements to improve gastrointestinal health may not be useful. Therefore, future studies should assess the efficacy of specific dietary fiber supplements to improve gastrointestinal health and limit gastrointestinal symptoms in CKD.

2.9 |. Prebiotics

Prebiotics are defined by the International Scientific Association for Probiotics and Prebiotics (ISAPP) as substrates that are selectively utilized by members of the gut microbiota and confer a health benefit, including benefits to gastrointestinal health.¹²⁶ These substrates include some types of fermentable dietary fiber, but also polyphenols, polyunsaturated fatty acids, and conjugated linoleic acid. Some of the prebiotic fibers that may confer effects related to gastrointestinal health include inulin-type fructans, FOS, resistant starch, pectin, and GOS.^127,128 The effects are likely mediated by the production of SCFA and their local effects in the gastrointestinal tract. Because of the effects of CKD on the gastrointestinal tract, prebiotic fibers have been proposed as therapies to improve aspects of gastrointestinal function, including gut barrier and gastrointestinal motility.

A double-blind, placebo-controlled, randomized clinical trial evaluated the effects of 12 g of FOS compared to maltodextrin in individuals with non-dialysis-dependent CKD and found that constipation, the overall Gastrointestinal Symptom Rating Score, and a marker of intestinal permeability (zonulin) was similar between those supplemented with either FOS or maltodextrin.¹²⁹ We recently assessed the effects of oligofructose-enriched inulin (10 g/day for females and 15 g/day for males) in patients on hemodialysis and observed an increase in fecal acetate and propionate, and a trend towards increased butyrate. However, we did not observe an improvement in lipopolysaccharide-binding protein (unpublished data), bowel movements, bowel movement consistency, or ease of passage. In a randomized clinical trial in patients on hemodialysis, biscuits supplemented with 20 g/day of amylose resistant starch during the first 4 weeks and 25 g/day in the next 4 weeks improved stool frequency from 3.5 to 4.2 bowel movements per week compared to 3.6 to 3.7 in the control group.¹³⁰ In a single-blind study lasting 12 weeks of which 2 weeks consisted of consuming control muffins, 4 weeks of muffins with 10 g of pea hull fiber, and 6 weeks of muffins with 10 g of pea hull fiber and 15 g of inulin only pea hull fiber increased stool frequency from 1.4 ± 0.2 to 1.9 ± 0.3 stools/day.¹³¹ While the evidence for the benefits of prebiotic fibers is increasing in healthy and clinical populations, the data on gastrointestinal beneficial effects remains limited in CKD and should be explored in future studies to justify their use.

Despite their potentially beneficial effects, microbial fermentation of prebiotic fibers may also lead to enhanced gastrointestinal symptoms, such as flatulence. In a meta-analysis of randomized clinical trials of prebiotics in individuals with IBS and functional gastrointestinal disorders (unclear if people with CKD were included), Wilson et al¹³² found no improvements in abdominal pain, bloating or flatulence with prebiotic therapy upon pooling data for various prebiotics (short-chain FOS, inulin, partially hydrolyzed guar gum, GOS, and pectin). In subgroup analyses, flatulence improved with a lower dose (≤6 g/day) and non-inulin-type fructans but worsened with inulin-type fructans. The latter are nonviscous highly fermentable fibers that can be found in onions, garlic, Jerusalem artichokes, agave, and chicory root, and are commonly used as an added fiber in manufactured products and sold as a supplement.¹³³ When we supplemented 10–15 g of oligofructose-enriched inulin to patients on hemodialysis, participants reported an increase in flatulence. Similarly, in patients on hemodialysis, receiving 20 g/day of oligofructose-enriched inulin led to increased flatulence in 77% of participants, diarrhea in 14%, but overall good tolerance and adherence.¹³⁴ Other prebiotic fibers may also increase gastrointestinal symptoms. In a study supplementing 20–25 g/day of high-amylose resistant starch, there was mild to moderate gastrointestinal symptoms (particularly abdominal distention) in 23% of the participants receiving the high-amylose resistant starch compared to ~10% in the control group. In a randomized, placebo-controlled, crossover study in patients with CKD, 20 g/day of arabinoxylans for 4 weeks increased flatulence compared to placebo, but stool frequency and consistency was not modified.¹³⁵ Overall, the use of prebiotic fibers may increase gastrointestinal symptoms derived from the increased bacterial fermentation, but in most studies, this did not affect adherence. If prebiotic fibers are used in patients with CKD, it may be reasonable to utilize a dose escalation to limit gastrointestinal symptoms and improve adherence; however, the efficacy of prebiotic fibers needs to be comprehensively studied.

2.10 |. Probiotics

Probiotics are defined by the ISAPP as live microorganisms that when administered in adequate amounts (minimum of 1 × 10⁹ colony forming units [CFU]) confer a benefit to the host.¹³⁶ There are a variety of probiotic products, such as probiotic drugs, probiotic medical foods, probiotic foods, and probiotic dietary supplements.¹³⁶ Regulation of the gastrointestinal tract is included among the purported effects of probiotics, while some species-level effect includes gut barrier reinforcement.¹³⁶ However, in CKD there is extensive variability in probiotic strains utilized and limited data on gastrointestinal symptoms or barrier function.¹³⁷ In a randomized, placebo-controlled, double-blind trial in peritoneal dialysis patients, the use of a probiotic containing 1 × 10⁹ CFU of Bifidobacterium bifidum A218, 1 × 10⁹ CFU of Bifidobacterium catenulatum A302, 1 × 10⁹ CFU of Bifidobacterium longum A101, and 1 × 10⁹ CFU of Lactobacillus plantarum A87 daily for 6 months, resulted in a decrease in circulating endotoxin compared to placebo, implying a benefit in intestinal barrier function.¹³⁸ Overall, there is not extensive evidence of the widespread beneficial effects in the gastrointestinal tract in CKD, and thus, this question should be explored in future studies that incorporate rigorous clinical endpoints.

2.11 |. Synbiotics

Synbiotics are defined by the ISAPP as a mixture of live microorganisms and substrates that are selectively used by host microorganisms, including resident or colonizing and probiotic microorganisms, to confer a benefit or benefits to the host.¹³⁹ There are two types of synbiotics: the synergistic synbiotics, which contain a substrate that is selectively utilized by the administered probiotic; and the complementary synbiotics, in which the prebiotic is beneficial for a resident microorganism.¹³⁹

Similar to prebiotics and probiotics, the majority of studies on synbiotics in CKD and kidney failure have been limited to outcomes related to uremic toxins, gut microbial profile, and inflammatory markers, with limited studies on the effects of synbiotics on gastrointestinal symptoms or gastrointestinal function.¹⁴⁰ In a randomized, placebo-controlled study, 2 months of a synbiotic gel that contained 11 × 10⁶ CFU of Lactobacillus acidophilus NCFM and Bifidobacterium lactis Bi-07, 2.31 g of inulin, 1.5 g of omega-3 fatty acids, and a mix of vitamins and showed that using the Gastrointestinal Symptom Questionnaire, there was an overall decrease in gastrointestinal symptoms, particularly vomiting, heartburn, and bloating.¹⁴¹ A clinical trial of a synbiotic containing 15 g of prebiotic fibers (inulin, FOS, GOS) and a probiotic with 45 × 10⁹ CFU with nine strains across Lactobacillus, Bifidobacterium, and Streptococcus found no changes in gastrointestinal symptoms using the Gastrointestinal Symptom Rating Scale, although this was not a primary outcome.¹⁴² Similarly, gastrointestinal symptoms were not improved in an RCT comparing a synbiotic that contained 5 × 10⁹ CFU of L. plantarum, 2 × 10⁹ CFU Lactobacillus casei rhamnosus, 2 × 10⁹ CFU Lactobacillus gasseri, 1 × 10⁹ CFU Bifidobacterium infantis, 1 × 10⁹ CFU B. longum, 1 × 10⁹ CFU L. acidophilus, 1 × 10⁹ CFU Lactobacillus salivarus, 1 × 10⁹ CFU Lactobacillus sporogenes, 5 × 10⁹ CFU Streptococcus termophilus, 2.2 g of oligofructose-enriched inulin, and 1.3 g of tapioca-resistant starch consumed three times per day for 4 weeks.¹⁴³ Overall, while there are limited data on the effects of synbiotics in the gastrointestinal tract, synbiotics seem to be better tolerated than prebiotic fibers alone.

2.12 |. Laxatives

Laxatives are pharmacological therapies recommended to individuals with constipation when lifestyle recommendations (nutrition and physical activity) do not improve symptoms.¹⁴⁴ Laxatives can be classified as bulk-forming (e.g., psyllium and methylcellulose), osmotic (e.g., lactulose, polyethylene glycol, and magnesium hydroxide), stimulants (e.g., sennosides and bisacodyl), stool softeners (e.g., docusate sodium and docusate calcium), and lubricants (e.g., mineral oil).⁷¹ Additionally, there are newer therapies that increase water secretion into the lumen and motility, including chloride channel activators, guanylate cyclase C receptor agonists, selective serotonin receptor agonists, and ileal bile acid transporter inhibitors.⁷¹ However, the main side effects of these therapies are gastrointestinal symptoms, including bloating, flatulence, abdominal discomfort, and diarrhea. In a retrospective study, laxative use increased once patients transitioned to dialysis and the use of medications, such as oral iron supplements, phosphate binders, and opioid analgesics was associated with higher odds of having a laxative prescription.¹⁴⁵ Interestingly, bulk laxatives, which include psyllium, were used only in 3% of the cohort, while ~30% used stool softeners (e.g., docusate sodium and docusate calcium), ~20% used osmotics, and ~10% stimulants. Importantly, 30%–40% used multiple types. In the same cohort, there was no difference in decline in kidney function between people with a laxative prescription vs. those that did not.

3 |. CONCLUSIONS

Alterations in gastrointestinal structure, function, and the gut microbiome are common in CKD, leading to increased gastrointestinal symptoms, particularly in advanced stages of the disease. Although there are limited data on the effects of interventions in individuals with CKD, numerous treatment options are available, including diet-based approaches such as changes in the overall diet or increased dietary fiber intake, and targeted interventions such as probiotics, prebiotics, synbiotics, and laxatives. Due to the effect of gastrointestinal alterations on patient-centered outcomes, including quality of life, continued efforts to pursue interventional studies that target the gastrointestinal tract in CKD are warranted.