INTRODUCTION

Chronic kidney disease (CKD) is a global public health problem. In countries, such as the United States of America and Australia, it affects 10-13% of the population ^1,2. Over the last decade, there has been an increase in the incidence and prevalence of this disease, with a significant increase in the number of patients requiring dialysis therapy ³. Studies conducted in Brazil have shown a gradual increase in the prevalence of CKD, with a high proportion of patients in need of dialysis treatment. In 2016, 122.825 CKD patients were recorded to be on dialysis, and 92.3% of patients were on hemodialysis (HD) ^4,5.

Uremia is a serious complication of CKD, and it is associated with renal injury, food restriction, and hydration status. Besides activating the renin-angiotensin-aldosterone system and favoring the occurrence of vascular calcifications, uremia also changes the microbiota (known as dysbiosis) and increases intestinal permeability ^6,7,8. It results in an increased flow of urea into the intestinal lumen, which is then hydrolyzed by microbial urease. Bacterial urease catalyzes the hydrolysis of urea to produce ammonium hydroxide; this reaction leads to an increase in the local pH, facilitating the growth of pathogenic bacteria and promoting mucosal irritation and damage ^9,10. These changes allow entry of endotoxins and other harmful luminal contents into the underlying tissues and systemic circulation, favoring the manifestation of other diseases ^6,7,11,12.

Patients with CKD demonstrate significant quantitative and qualitative changes in intestinal microbiota, related to the overgrowth of aerobic and anaerobic pathogenic bacterial species ^7,11. These bacteria can use nitrogen products, thus increasing the production of uremic toxins, such as indoxyl sulfate and p-cresyl sulfate. Such toxins induce inflammation, oxidative stress, and cause a pathophysiological impact, resulting in structural and functional changes that indirectly influence patient morbidity and mortality ^13,14.

In uremic patients, oxidative stress and inflammation cause dysregulation of the immune system. This is evidenced by the presence of elevated oxidative biomarkers, such as lipid oxidation and protein oxidation products ^15,16. A cross-sectional study involving patients with chronic renal failure demonstrated that the presence of indoxyl sulfate and p-cresyl sulfate was also associated with elevated concentrations of inflammatory markers and increased arterial stiffness, a key clinical finding associated with CKD ¹⁷. In the past decade, these toxins have been associated with the progression, cardiovascular morbidity and mortality of CKD patients ¹⁸. In addition to uremia and metabolic acidosis, routine therapeutic interventions for treating CKD, such as dietary restriction of fruits, vegetables, and foods with high fiber content, iron intake, phosphate binders, and antibiotics modify the colonic environment. These modifications negatively affect the intestinal microbiota and induce the production of uremic toxins and inflammatory markers ¹⁹.

Some interventions are being used to modulate the intestinal microbiota, block LPS or attenuate inflammation, or target adsorption of uremic toxin end products of microbial fermentation ²⁰. Previously published review articles have described some of these interventions: administration of small intestine alpha-glycosidase inhibitor that increases the fermentation of carbohydrates in the colon and can reduce the colonic generation of p-cresol; utilization of essential oils as agents to treat dysbiosis; use of oral adsorbents to restore epithelial tight-junction proteins and reduce plasma endotoxin and markers of oxidative stress and inflammation; administration of synthetic TLR4 antagonists to inhibit LPS signaling; ingestion of prebiotics and/or probiotics that play an important role in the progression of CKD ^12,20.

The results of a recent study suggest that the ingestion of prebiotics and probiotics can increase the production of short chain fatty acids, modulating the intestinal microbiota ¹⁷. They can also reduce intestinal permeability via blocking the entry of endotoxins into the bloodstream and suppressing inflammation ²¹; these events are believed to play an important role in the progression of CKD. Therefore, the objective of this study was to systematically review the literature on the effects of intake of prebiotic and/or probiotic products on the intestinal microbiota, oxidative stress, and inflammation in patients with CKD.

METHODS

This systematic review was conducted according to a pre-specified protocol and is described according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement ²². This article is based on previously conducted studies, and it does not include studies conducted by any of the authors of this study.

RESULTS

SEARCH RESULTS

During the initial selection process, 1,679 articles were identified. Later, 781 duplicate articles were excluded, and 890 articles were removed after reading their titles and/or abstracts. Eight other articles were identified by reverse search and were considered as eligible; however, after reading their abstracts, six did not meet the inclusion criteria and were thus excluded from this study. Finally, we included and critically analyzed a total of ten articles (Fig. 1).

Figure 1. Flowchart of the steps for obtaining the articles selected for this systematic review. 

According to the Cochrane Collaboration's risk of bias tool for randomized trials, ten selected studies presented varying degrees of bias. All trials had a low or an unclear risk of bias for sequence generation, allocation concealment, blinding, selective outcome reporting, and other sources of bias.

PARTICIPANT CHARACTERISTICS

A total of 423 subjects participated in the clinical trials, and the sample size ranged from 12 to 125. Their mean age ranged from 26 to 82 years and 64.18% of the participants were male. The sample sizes of three studies were similar, all of which involved patients with stages 3-4 of the disease (Table I).

Table I. Characteristics of selected studies and their major results 

G1: group 1; G2: group 2; G3: group 3; GC: group control; GT: group test; IS: indoxyl sulfate; NF-kB: nuclear factor kappa beta; TC: triglycerides; CRP: C-reactive protein; TAC: total antioxidant capacity; MDA: malondialdehyde; TNF-α: tumor necrosis factor α; IL 6: interleukin 6; IL 8: interleukin 8. *Phases 3 and 4: phase of the chronic kidney disease preceding the hemodialysis phase.

DISCUSSION

In CKD, oxidative stress and inflammation occurs at the onset of the disease and increases with its progression. HD individuals experience increased oxidative stress possibly due to loss of antioxidants during dialysis, interactions between blood and dialysis membrane, and malnutrition ³⁴. However, despite the fact that HD patients present greater oxidative stress and inflammation than other outpatient-treated patients, the results of selected studies indicate that the consumption of prebiotic ^24,25, probiotic ^26,27,28,29, and symbiotic ^30,31,32,33 supplementation causes positive changes in HD and CKD patients.

Prebiotics are non-digestible food compounds that stimulate the beneficial growth of microbiota conferring health benefits to the host. They decrease oxidative stress, systemic inflammation, and the production of uremic solutes in CKD patients ^35,36. In a randomized placebo-controlled trial, prebiotic consumption for six weeks by individuals receiving HD was associated with the following changes: reduced levels of total cholesterol and LDL, increased oxidative stress through reduction of malondialdehyde and increase of total antioxidant capacity, and improvement in systemic inflammation (TNF-α, IL-6, IL-8 and CRP) ²⁴. These effects may be due to the ability of dietary fibers to hinder the process of dietary fat digestion and absorption, and favor the production of short chain fatty acids. During micelle formation phase of the digestion process, dietary fibers bind to cholesterol or bile acids forming a gel. This binding reaction delays gastric emptying, decreases dietary fat absorption and bile acid reabsorption by the enterohepatic circulation, and drives the use of hepatic cholesterol for bile acid production ³⁷. Dietary fibers are not digested by humans; they are rather fermented by the intestinal bacteria that release short chain fatty acids. These fatty acids are responsible for modulating the intestinal microbiota and exerting immunomodulatory effects ^31,37. Such changes in the intestinal microbiota were observed in a randomized controlled clinical trial. In this study, 30 mm of lactulose supplement three times a day for eight weeks increased bifidobacteria and lactobacillus counts in HD patients ²⁵.

Probiotics are live microorganisms that, when administered in appropriate amounts, may confer benefits to the host's health ²⁷.

Their effect on the immune system is evidenced by an increased expression of anti-inflammatory cytokines (interleukin 10 and nuclear factor kappa b), and a decrease in proinflammatory cytokines (interleukin 6 and TNF) and levels of systemic inflammation ^38,39.

In a randomized clinical trial, the consumption of probiotics containing 16 × 109 CFU/day of L. casei shirota for two months reduced the levels of serum urea in uremic patients with moderate to severe CKD (stages 3-4) ²⁶. Similar results were observed in a pilot study that tested the effects of a probiotic containing different bacterial strains (L. acidophilus, B. longum, and S. thermophilus) at a dose of 9 × 109 CFU/day. After three months, the majority of the participants who received probiotic had reduced concentrations of serum urea nitrogen and uric acid, contributing to a better quality of life for those individuals ²⁷. Oral administration of B. longum capsules in a placebo-controlled clinical trial was shown to reduce serum phosphorus concentrations in HD patients ²⁸. This suggests that the reduction of these metabolites in CKD patients may be associated with the ability of the microbiota to use the metabolic waste as a substrate. A possible explanation for the observed reduction in uremia is related to the ability of certain anaerobic bacteria to degrade urea and uric acid through the production of enzymes, such as uricase, allantoinase, and urease. In an in vitro study, Lactobacillus exposure to an urea-enriched environment induced the production of enzymes responsible for urea reduction ⁴⁰. Following the intake of probiotics, an increase in Lactobacillus and Streptococcus populations in the feces can be explained by the conversion of urea to ammonia, a source of nitrogen for metabolic purposes ²⁷. Probiotics can increase dietary fiber fermentation, reduce the intestinal pH, modulate the intestinal microbiota, and increase calcium ionization. Calcium, in turn, binds to phosphorus, reducing its absorption and leading to a reduction in serum phosphorus concentration ²⁸. On the other hand, serum levels of uremic toxins and inflammatory markers were not affected in HD individuals who received a daily dose of 1.8 × 1011 CFU/day of a probiotic (containing S. thermophilus, L. acidophilus, and B. longum) for two months. However, the results showed a trend for the reduction of C-reactive protein (p = 0.071), indoxyl glucuronyl (p = 0.058), and white blood cell counts (p = 0.057) ²⁹. We believe that if the probiotics were administered in combination with soluble fibers, the results would have been different; this is based on our knowledge that soluble fibers can potentiate the effects of probiotics, resulting in a reduction of these markers. A decrease in uremic toxin concentration may be associated with fermentation of soluble fiber by intestinal anaerobic bacteria. This process of fermentation increases the production of short chain fatty acids and reduces colonic pH. The modified environment favors the growth of beneficial bacteria, inhibits the enzymes involved in generation of p-cresyl sulfate and indoxyl sulfate, improves epithelial barrier function (via induction of mucin production, blocking epithelial binding receptors, and strengthening epithelial tight junctions), and reduces the influx of uremic toxins ⁴¹ (Fig. 2).

Figure 2 Potential mechanisms involved in the modulation of intestinal microbiota and the reduction of oxidative stress and inflammation by pre- and/or probiotic products in chronic kidney disease. SCFA: short-chain fatty acids; P: phosphorous. 

Supplementation of a symbiotic compound containing L. acidophilus and B. bifidum (2 × 1012 CFU/day) and inulin (2.31 g) for two months improved intestinal dysbiosis in individuals receiving HD, increasing the population of Bifidobacterium and preserving the numbers of Lactobacillus in the gut ³⁰. Symbiotic intake in different stages of CKD decreased p-cresol serum concentration and normalized bowel habits ^31,33. The symbiotic supplement (seven strains of probiotics and fructooligosaccharides), when consumed 500 mg twice a day for six weeks, can reduce blood urea nitrogen in patients with CKD at stages 3 and 4. One of the mechanisms by which this supplementation can potentially benefit the kidneys is by stimulating growth of gut microbial biomass by increased consumption of dietary fibers; this subsequently decreases ammonia production, increases the ratio of ionized ammonia, and facilitates the use of nitrogenous wastes by bacterial cells. Thus, more ammonia is excreted through the feces, and there is a low level production of potentially damaging forms of nitrogen, such as urea, uric acid, and creatinin ³². These results indicate the need to conduct a study to assess microbiota composition, uremic parameters, and inflammatory biomarkers in response to consumption of symbiotics.

In summary, the mechanism by which prebiotics and/or probiotics modulate the intestinal microbiota and decrease oxidative stress and inflammation may be due to increased intestinal anaerobic bacteria count and maintenance of intestinal barrier integrity (Fig. 2). Intestinal barrier integrity may be improved by the production of mucin, blocking of connection receptors, and strengthening of the epithelial junctions ¹⁷.

Due to the inclusion and exclusion criteria adopted in this study, we could include only ten studies in our review, and this limitation did not allow us to carry out a meta-analysis study. Our search for relevant studies was confined to the main databases; thus, it is possible that we might have limited our numbers by missing out some studies that fulfilled our inclusion criteria. Nonetheless, despite these limitations, the present study allowed us to identify "the gaps" in the literature in relation to the topic of interest, allowing us to propose future studies to unravel the mechanisms by which the prebiotics and/or probiotics can control progression of CKD.

CONCLUSIONS

Prebiotics and/or probiotics can modulate the intestinal microbiota by promoting the growth and metabolism of anaerobic bacteria, decreasing the production of uremic solutes, and resulting in oxidative stress and systemic inflammation. There is scarcity of studies that address the effects of prebiotics and/or probiotics on the intestinal microbiota, oxidative stress, and inflammation in CKD patients. Therefore, future studies are needed to provide clarification on topics, such as mechanisms that link regulation of dysbiosis and manifestation of diseases associated with CKD or its precursor diseases, such as diabetes mellitus, hypertension, and atherosclerosis.