Pediatr Nephrol
DOI 10.1007/s00467-016-3527-x
REVIEW
The gut–kidney axis
Pieter Evenepoel 1,2,3 & Ruben Poesen 1,2 & Björn Meijers 1,2
Received: 3 May 2016 / Revised: 2 September 2016 / Accepted: 2 September 2016
# IPNA 2016
Abstract The host–gut microbiota interaction has been the
focus of increasing interest in recent years. It has been deter-
mined that this complex interaction is not only essential to
many aspects of normal Bmammalian^ physiology but that it
may also contribute to a multitude of ailments, from the obvi-
ous case of inflammatory bowel disease to (complex) diseases
residing in organs outside the gut. An increasing body of ev-
idence indicates that crosstalk between host and microbiota is
pathophysiologically relevant in patients with chronic kidney
disease (CKD). Interactions are bidirectional; on the one hand,
uremia affects both the composition and metabolism of the gut
microbiota and, on the other hand, important uremic toxins
originate from microbial metabolism. In addition, gut
dysbiosis may induce a disruption of the epithelial barrier,
ultimately resulting in increased exposure of the host to endo-
toxins. Due to dietary restrictions and gastrointestinal dys-
functions, microbial metabolism shifts to a predominantly
proteolytic fermentation pattern in CKD. Indoxyl sulfate and
p-cresyl sulfate, both end-products of protein fermentation,
and trimethylamine-N-oxide, an end-product of microbial
choline and carnitine metabolism, are prototypes of uremic
toxins originating from microbial metabolism. The vascular
and renal toxicity of these co-metabolites has been demon-
strated extensively in experimental and clinical studies.
* Pieter Evenepoel
Pieter.Evenepoel@uzleuven.be
1
Laboratory of Nephrology, Department of Immunology and
Microbiology, KU Leuven, Leuven, Belgium
2
Department of Nephrology and Renal Transplantation, University
Hospitals Leuven, Leuven, Belgium
3
Dienst Nefrologie, University Hospitals Leuven–Gasthuisberg
campus, Herestraat 49, 3000 Leuven, Belgium
These co-metabolites are an appealing target for adjuvant ther-
apy in CKD. Treatment options include dietary therapy, pre-
biotics, probiotics and host and bacterial enzyme inhibitors.
Final proof of the concept should come from randomized con-
trolled and adequately powered intervention studies.
Keywords Microbiome . Microbial metabolism .
Host–gut microbiota interaction . Chronic kidney disease .
Uremic toxins
Introduction
Gut microbiota and co-metabolism
The human intestinal tract, and especially the large intestine, is
colonized by trillions of microbes, which collectively possess
many hundredfold more genes than included in the human
genome. Humans may thus be viewed as Bsupra-organisms^
or Bmeta-organisms^. The combined genetic potential of the
endogenous flora is referred to as the ‘microbiome’ [1].
Microbiota contribute substantially to the metabolic pheno-
type of humans. Microbial metabolism, commonly referred
to as co-metabolism, comprises the synthesis of vitamins
and the fermentation of carbohydrates, lipids, proteins and bile
acids. The composition and activity of the gut microbiota co-
develops with the host from birth and is subject to a complex
interplay between host genome, nutrition and life-style factors
[2]. The microbiota of the infant is seeded at birth and is
initially undifferentiated across the various body habitats. A
variety of factors, including method of delivery (i.e. vaginal
vs. Cesarean section), breast feeding and weaning, influence
the infant microbiota. During suckling, the microbial commu-
nity develops rapidly; shifts in microbial diversity occur
throughout childhood and adult life; and in old age, there is

a decrease in Bacteroidetes species and an increase in
Firmicutes species. Extrinsic environmental and life-style fac-
tors (such as antibiotic use, diet, stress, disease, and injury)
continually influence the diversity and function of the gut
microbiota with implications for human health [1].
Among the life-style factors, diet is increasingly being ac-
knowledged as a key regulator of intestinal microbiota and its
activity [3–7] (Fig. 1). Amounts of nutrients entering the colon
mainly depend on dietary intake(s) and on the efficiency of the
assimilation process in the small intestine [8]. Dietary carbo-
hydrates (CHO) resistant to digestion in the small intestine,
i.e. dietary fibers, are the main source of CHO to the colon.
CHOs are fermented to short chain fatty acids (SCFAs), which
play an important role in maintaining energy homeostasis and
gut epithelial integrity [9]. Nitrogen is provided to the large
intestine by dietary proteins which escape digestion in the
upper gut, by endogenous proteins (pancreatic and intestinal
secretions, sloughed epithelial cells) and by blood urea
Fig. 1 The diet–gut–kidney axis. Following dietary exposures of certain
nutrients, gut microbiota can elicit both metabolism-dependent and
metabolism-independent effects on the host. Metabolism-dependent ef-
fects include: (1) microbial fermentation of dietary carbohydrates (CHO)
to generate short chain fatty acids (SCFAs) which signal the host to in-
crease energy expenditure, inhibit histone deacetylase (HDAC) activity
and enhance G protein–coupled receptor (GPCR) signaling; (2) microbial
conversion of alpha-NH3 nitrogen to protein fermentation metabolites,
including phenols and indoles, which are subsequently metabolized in
the colonocytes and liver to p-cresyl sulfate (PCS) and indoxyl sulfate
(indS), among others; (3) microbial conversion of choline and L-carnitine
to trimethylamine (TMA), which is subsequently converted by the host
Pediatr Nephrol
diffusing in intestinal contents. The colonic fate of α-amino
nitrogen (amino acids and intermediates) largely depends on
the amount of energy available for bacterial growth and cell
division. The main source of energy is fermentable CHO. In
the case of CHO excess, α-amino nitrogen is predominantly
incorporated in the bacterial biomass; conversely, in case of
CHO deprivation, α-amino nitrogen will be predominantly
fermented [4] to phenols, indoles, amines, among other end-
products. It is believed that fat does not reach the colonic
microbiota in significant amounts as it is mostly digested
and absorbed in the small intestine. Dietary fat can have an
indirect effect on the colonic microenvironment as bile acids,
which are excreted in the small intestine to aid the digestion of
fat, can reach the colon and be converted by the microbiota.
Foods rich in fats are moreover often rich in the dietary nutri-
ents phosphatidylcholine (lecithin), choline and carnitine,
which can be used by gut microbiota as a carbon fuel source.
While mammals do not have the enzyme that can cleave the
flavin monooxygenase enzyme family to trimethylamine-N-oxide
(TMAO) in the liver. SCFAs confer health benefits, while protein fermen-
tation metabolites and TMAO exert multiple toxic effects, contributing to
cardiovascular disease (CVD) and progressive renal disease (CKD), ulti-
mately culminating in premature death. Metabolism-independent effects
include gut hyperpermeability (leaky gut), allowing bacterial cell-wall
products such as lipopolysaccharide (LPS) and peptidoglycans to enter
the bloodstream. Low circulating levels of these bacterial components
collectively activate macrophages, which can reduce reverse cholesterol
transport and increase insulin resistance, hyperlipidemia and vascular
inflammation. LPS and peptidoglycans contribute to a micro-
inflammatory state
Pediatr Nephrol
C–N bond of these nutrients, gut microbes possess
trimethylamine (TMA) lyases, which are able to cleave the
C–N bond, releasing the TMA moiety as a waste product [10].
Another important and potentially modifiable determinant
of colonic microbiota composition and activity is transit time.
In a landmark study, Cummings et al. observed a significant
correlation between colonic transit time and the urinary excre-
tion rate of phenols [11]. In this study, 64 % of the variance of
the urinary excretion rate of phenols was explained by the
colonic transit time and dietary protein intake, with roughly
a doubling of the colonic transit time corresponding to a 60 %
increase of the urinary phenol excretion intake [11]. Also, in a
cohort of 53 children with autism spectrum disorder, increased
urinary excretion of p-cresol was observed in children with
increased intestinal transit time and chronic constipation [12].
A slowing down in colonic transit time induces an upstream
expansion in the number of proteolytic species, as a larger part
of the colon becomes carbohydrate deprived, resulting in an
increased generation and uptake of end-products of bacterial
protein fermentation.
Influence of gut microbiota on health and disease
The host–microbiota interaction has been the focus of increas-
ing interest in recent years. It has become clear that host–mi-
crobe interactions are essential to many aspects of normal
Bmammalian^ physiology, ranging from nutrition to immune
homeostasis. Disturbance of the gut flora (referred to as ‘gut
dysbiosis’) may contribute to a multitude of ailments, ranging
from the obvious case of inflammatory bowel disease to com-
plex diseases residing in organs outside the gut [13]. The notion
that microbiota may portend disease is not new—as early as
400 BC Hippocrates was quoted as saying, Bdeath sits in the
bowel^ and Bbad digestion is the root of all evil^. Also in the
setting of chronic kidney disease (CKD) there is mounting ev-
idence that there is intense and pathophysiologically relevant
bidirectional crosstalk between microbiota and host; on the one
hand, uremia affects both the composition and metabolism of
the microbiota and, on the other hand, important uremic toxins
originate uniquely from microbial metabolism. In addition, gut
dysbiosis may induce a disruption of the epithelial barrier, ulti-
mately resulting in increased exposure of the host to endotoxins
(lipopolysaccharides). These topics are discussed in more detail
in the following sections.
Impact of renal failure on microbiota and microbial
metabolism
Renal failure and microbiota
Studies evaluating the gut bacterial flora in uremic patients
are scarce. Hida et al. studied uremic patients undergoing
hemodialysis (HD) and found no significant difference in
the total number of bacteria between the patient group and
the healthy controls [14]. However, in terms of individual
species, they did observe several quantitative and qualita-
tive changes. More specifically, the number of aerobic bac-
teria, such as enterobacteria and enterococci, was about
100-fold higher in the HD patients than in the healthy con-
trols, and the number of the anaerobes Bifidobacteria spe-
cies and Clostridium perfringens was significantly lower
and higher, respectively, in the HD patients. In another
study, Wang et al. analyzed the microbial composition of
patients on peritoneal dialysis by real-time PCR and found
lower levels of Bifidobacteria species and Klebsiella
pneumonia [15]. Vaziri et al. recently isolated microbial
DNA from the stools of 24 patients on maintenance HD
and 12 healthy persons and analyzed these samples by
phylogenetic microarray [16]. They observed marked dif-
ferences in the abundance of 190 bacterial operational tax-
onomic units (OTUs) between the HD patients and healthy
controls. To isolate the effect of uremia from inter-
individual variations, comorbid conditions and dietary
and medicinal interventions (especially antibiotics),
Yoshifuji et al. studied rats at 8 weeks post 5/6 nephrecto-
my or post sham operation [17]. These authors found a
significant difference in the abundance of 175 bacterial
OTUs between the uremic and control animals, of which
decreases in the Lactobacillaceae were the most notable.
Thus, it would appear that uremia profoundly alters the
composition of the gut microbiome. Additional studies by
Vaziri et al. demonstrated that patients with CKD stage 5D
had increased numbers of bacteria that possess urease,
uricase, p-cresol and indole-forming enzymes and reduced
numbers of bacteria that possess SCFA-forming enzymes
[18]. It is possible that in addition to changes in nutrient
availability, an increase in luminal pH secondary to an
increase in ammonia concentration may be responsible
for CKD-induced dysbiosis [16].
Renal failure and microbial metabolism
Poesen et al. recently compared the metabolite profiles of fecal
samples obtained from uremic and non-uremic patients and in
an animal model of uremia [19]. CKD was found to be asso-
ciated with a distinct colonic microbial metabolism, although
the effect of renal function loss per se in humans may be
inferior to the effects of dietary and other CKD-related factors.
Impaired small intestinal protein assimilation [20], decreased
dietary fiber intake (due to reduced intake of fruit and vegeta-
bles, see following sections) [21] and slow colonic transit
(secondary to sedentary lifestyle, polypharmacia, restricted
intake of fluid, and uremia per se) [22] all foster protein fer-
mentation in CKD patients. The additional observation of
24 h-urinary excretion of p-cresol paralleling renal function

deterioration supports the notion of CKD being a state of
increased protein fermentation [20].
Impact of microbiota and microbial metabolism
on renal failure
Leaky gut
Chronic kidney disease is associated with increased intestinal
(colonic) permeability (often referred to as ‘leaky gut’) [23].
Gut dysbiosis may contribute to edema of the intestinal wall
and gut ischemia in patients with CKD, as well as to an im-
paired colonic epithelial barrier [24]. A marked reduction of
the tight junction proteins claudin-1, occludin and zona
occludens-1 has been described in the gut mucosa of CKD
animals, probably due to the effects of uremic toxins [17, 24].
A leaky gut may represent an underappreciated cause of
micro-inflammation [24, 25], a common condition in CKD
and thought to contribute to malnutrition, accelerated cardio-
vascular disease and CKD progression [23, 26]. It remains to
be demonstrated whether persistent bacterial leakage of the
gut triggering the phenomenon of ‘endotoxin tolerance’ may
explain the concomitant acquired immunodeficiency of CKD
patients [23].
Experimental data suggest that dietary fiber may reverse
gut dysbiosis and suppress micro-inflammation [27]. These
data are in agreement with epidemiological evidence showing
associations between higher dietary fiber intake, better kidney
function [28] and lower inflammation, at least in the general
population [28, 29].
Uremic toxins originating from microbial metabolism
Colonic microbiota are increasingly acknowledged to be an
important source of uremic toxins. Aronov et al. compared the
plasma metabolite profile of HD patients with and without
colons. Substantial amounts of p-cresyl sulfate and indoxyl
sulfate were only observed in patients with an intact colon
[30]. These findings extend data from a seminal animal study
by Wikoff et al. who compared the plasma from germ-free
mice with that of wild-type mice by means of untargeted
metabolomics analyses [31]. These authors were able to iden-
tify over 150 compounds, including p-cresyl sulfate and in-
doxyl sulfate, that were unique to the wild-type mice. Another
means to prove the microbial origin of a compound is to dem-
onstrate its plasma disappearance under broad spectrum anti-
biotic therapy, as was demonstrated for trimethylamine-N-ox-
ide (TMAO) [32]. The list of uremic toxins, including those
originating from microbial metabolism, is expanding, mainly
as a reflection of improved analytical techniques [33]. p-
Cresyl sulfate, indoxyl sulfate and TMAO are currently
attracting much attention as renovascular toxins. The
Pediatr Nephrol
metabolism and toxicity of these co-metabolites will be
discussed in more detail in subsections p-Cresyl sulfate and
indoxyl sulfate and Trimethylamine-N-oxide, respectively
(Table 1).
p-Cresyl sulfate and indoxyl sulfate
Metabolism p-Cresol is a putrefaction metabolite of tyrosine,
while indole is generated by the fermentation of tryptophan.
After absorption, the majority of the p-cresol and indole is
further metabolized and conjugated to form p-cresyl sulfate
and indoxyl sulfate, respectively. Both p-cresyl sulfate and
indoxyl sulfate circulate tightly bound to albumin [34] and
are cleared by the kidneys, mainly through tubular secretion.
The concentrations of p-cresyl sulfate and indoxyl sulfate in-
crease concomitantly with the progression of CKD [35, 36], as
a consequence of both decreased elimination and increased
production [37], to reach concentrations in patients with
end-stage renal disease (ESRD) that are 10- to 50-fold higher
than those in healthy controls. p-Cresyl sulfate and indoxyl
sulfate concentrations also increase with age [38]. Given their
strong albumin binding [39], multi-compartmental distribu-
tion [40] and dependence on tubular secretion, the elimination
of p-cresyl sulfate and indoxyl sulfate by conventional HD is
limited [41]. Following successful renal transplantation, the
concentrations of these metabolites rapidly drop below levels
encountered in CKD counterparts matched for estimated glo-
merular filtration rate (eGFR) [42].
Toxicity The toxicity of p-cresyl sulfite and indoxyl sulfate
has been demonstrated in numerous experimental studies [43]:
indoxyl sulfate and/or p-cresyl sulfate induce insulin resis-
tance [44], suppress erythropoiesis [45], suppress klotho
[46–49] and trigger premature cellular senescence [50], acti-
vate the renin–angiotensin–aldosterone system [51], cause en-
dothelial dysfunction [52, 53] and promote vascular calcifica-
tion [54, 55], atherogenesis [56], thrombosis [57–59] and left
ventricular hypertrophy and diastolic dysfunction [60]. They
also induce renal tubulo-interstial fibrosis [61]. The toxic ef-
fects of p-cresyl sulfate and indoxyl sulfate are mediated at
least in part by increased intracellular oxidative stress and
activation of the MAP kinase signaling pathway. Indoxyl sul-
fate may also exert its toxic effects through activating the aryl
hydrocarbon signaling pathway [45, 55, 59, 62]. Clinical stud-
ies have consistently demonstrated (independent) associations
between these metabolites and renal disease progression, car-
diovascular morbidity and mortality in patients with varying
degrees of renal dysfunction [4, 35, 36, 63–67].
Trimethylamine-N-oxide
Metabolism Trimethylamine-N-oxide is an end-product of
microbial choline and carnitine metabolism [68, 69]. As a first
Pediatr Nephrol

Table 1 Phenols, indoles and trimethylamine-N-oxide: pathophysiology and treatment options

Pathophysiology/ Toxin Phenols (p-cresyl sulfate, phenyl Indoles (indoxyl sulfate, indoxyl Trimethylamine-N-oxide
treatment options acetyl glutamine, …) glucuronide, ..)

Pathophysiology Origin/source Tyrosine, phenylalanine Tryptophan Choline, carnitine

Impact of CKD Retention and increased production Retention and increased production Retention causes levels to
cause levels to increase up to cause levels to increase up to increase up to 30-fold
10-fold 10-fold
Toxicity Endothelial dysfunction, vascular Endothelial dysfunction, vascular Atherosclerosis, thrombosis,
calcification, thrombosis, atrial calcification, thrombosis, atrial renal fibrosis
fibrillation, renal fibrosis fibrillation, renal fibrosis
Treatment options Diet Low protein–high fiber diet Low protein–high fiber diet Mediterranean diet associates
associates with low toxin associates with low toxin with low TMAO exposure
exposure exposure
Prebiotic–probiotic– Pilot intervention studies show Pilot studies show promising, but No data
synbiotic promising, but not always not always consistent findings
consistent findings
Adsorbents No data Large RCT failed to confirm No data
promising results seen in
experimental and pilot clinical
intervention studies

CKD, Chronic kidney disease; TMAO, trimethylamine-N-oxide; RCT, randomized controlled trial

step, trimethylamine is transported via the portal circulation to
a cluster of hepatic enzymes, the flavin-containing
monooxygenases, that efficiently oxidize it, thus forming
TMAO. TMAO enters the circulation, where it is predomi-
nantly excreted by the kidneys [70]. Concentrations of TMAO
increase concomitantly with the progression of CKD to reach
concentrations in patients with ESRD that are approximately
20-fold higher than those in healthy controls [71, 72]. TMAO
concentrations rapidly decline after successful renal transplan-
tation [71, 72] toward concentrations observed in CKD coun-
terparts matched for eGFR [42].
Toxicity Trimethylamine-N-oxide may enhance the accu-
mulation of macrophage cholesterol and the development
of atherosclerosis [69], increase platelet hyperreactivity
and thrombosis potential [73] and promote progressive
renal tubulo-interstitial fibrosis [70]. TMAO is increasing-
ly being recognized as a predictor of cardiovascular dis-
ease, both in the general population [32, 68] and in pa-
tients with CKD [71, 72]. A clinical link with progressive
renal disease is lacking as yet.
Interventions targeting toxic co-metabolites
Dietary and gastrointestinal approaches targeting colonic
co-metabolism
Dietary and gastrointestinal interventions have long been a
cornerstone of medicine. In the middle of the twentieth cen-
tury, induced diarrhea and intestinal perfusion were popular
treatments for advanced uremia. In 1990, Schloerb, a surgeon
at the Mayo Clinic, isolated a loop of ileum and by repeated
perfusions with a lactated saline solution was able to prolong
the life of otherwise fatally ill young individuals with chronic
uremia for more than 1 year [74]. As early as in 1951, Kolff
had acknowledged the large intestine as an import source/
reservoir of toxins and explored the therapeutic potential of
intestinal lavage and oral sorbents [75]. Although with the
advent of dialysis, renal transplantation and potent drug ther-
apy, interest in dietary and gastrointestinal interventions has
waned [76], it must be recognized that patients on renal re-
placement therapy do continue to suffer from the effects of
disease and face a mortality risk that greatly exceeds that of
the general population. This condition is referred to as the
residual syndrome, and there is renewed interest in dietary
and gastrointestinal interventions as adjuvant therapies.
Dietary interventions
Dietary interventions and nutriceuticals are a logical co-
strategy to re-establish microbial balance and suppress circu-
lating p-cresyl sulfate, indoxyl sulfate and TMAO levels.
Dietary measures to restrict the intake of food rich in
(phosphatidyl)choline or carnitine may be helpful to lower
the exposure to TMAO. When protein fermentation metabo-
lites are the therapeutic target, both dietary protein restriction
and dietary fiber supplementation may be considered.
Limiting dietary protein, although efficacious in limiting pro-
tein fermentation, as explained earlier in this review, may be
ill-advised because of associated risks of protein malnutrition,
especially in susceptible populations. A valuable and safe al-
ternative to dietary protein restriction to suppress protein fer-
mentation is dietary fiber supplementation, as also explained

earlier. Total dietary fiber intake reported in the third National
Health and Nutrition Examination Survey (NHANES III) av-
eraged 17 g/day, which is far below the 20–30 g/day recom-
mended by current guidelines for the general population.
Dietary fiber intake was even less in patients with CKD
(15 g/day). This observation is not unexpected as food items
rich in dietary fiber, such as fruits, vegetables and whole wheat
bread, are often restricted in patients with advanced CKD to
prevent or correct hyperkalemia [77] and hyperphosphatemia.
In these patients, non-digestible oligo- and polysaccharides
[such as inulin, its hydrolysis product oligofructose and
(trans)galacto-oligosaccharides], often referred to as prebi-
otics, may be considered to be a valuable and safe alternative
source of dietary fiber. Prebiotics are generally defined as
selectively fermented ingredients that result in specific chang-
es in the composition and/or activity of the gastrointestinal
microbiota (i.e. mainly bifidobacteria), thus conferring bene-
fit(s) upon host health [78]. In a pilot study in HD patients
(n = 22, uncontrolled), Meijers et al. demonstrated a signifi-
cant reduction in serum p-cresyl sulfate but not indoxyl sulfate
following intake of oligofructose-enriched inulin [79]. In an-
other study in HD patients (n = 56, placebo-controlled), Sirich
et al. noted that the consumption of resistant starch significant-
ly decreased serum indoxyl sulfate and, possibly, p-cresyl sul-
fate [80]. One small study also investigated the effect of inulin
in patients with CKD not yet on dialysis (n = 13, placebo-
controlled cross-over) [81], demonstrating a significant de-
crease in serum p-cresol/p-cresyl sulfate, while the effect on
other microbial metabolites was not studied; in contrast, there
was no effect of prebiotic arabinoxylan oligosaccharides
(n = 40, placebo-controlled cross-over) on solute levels of p-
cresyl sulfate, indoxyl sulfate, TMAO and various other mi-
crobial metabolites in patients with an eGFR of between 15
and 45 ml/min/1.73 m2. Therefore, further research remains
necessary to elucidate the role of prebiotic therapy in CKD.
Of interest, vegetarians and vegans have lower circulating
levels of TMAO, p-cresyl sulfate and indoxyl sulfate than
omnivores [68, 82], probably due to a concomitant higher
intake of dietary fiber and lower intake of protein.
Adsorbents
Another approach is to reduce the availability of generated
microbial metabolites by adsorption of these metabolites onto
high-affinity surfaces. AST-120 (Kremezin®; Kureha
Chemical Industry Co, Ltd., Tokyo, Japan) is an orally admin-
istered adsorbent consisting of spherical carbon particles with
a diameter of 0.2–0.4 mm [83]. It is capable of adsorbing
significant amounts of various organic compounds in the large
intestine, including indole [84, 85], p-cresol [86] and food-
derived advanced glycation end-products [87]. The efficacy
of AST-120 in decreasing circulating indoxyl sulfate levels
and preventing renal, vascular and bone damage has been
Pediatr Nephrol
demonstrated in numerous preclinical studies. Clinical studies
have been less convincing. A phase 2 dose-finding study in
U.S. patients with CKD confirmed a dose-dependent reduc-
tion in indoxyl sulfate serum concentrations [84]. Two rela-
tively small and uncontrolled trials in Japanese patients with
mild to moderate CKD [88, 89] suggested that AST-120 re-
tards the progression of renal failure. The multinational, ran-
domized, double-blind, placebo-controlled Evaluating
Prevention of Progression in CKD (EPPIC)-1 and EPPIC-2
trials evaluated the effects of AST-120 on the progression of
CKD when added to standard therapy [90]. More than 2000
patients with moderate to severe CKD were randomized to
receive either placebo or AST-120 (9 g/day). Unfortunately,
the study failed to match expectations. Time to primary end-
point, i.e. a composite of dialysis initiation, kidney transplan-
tation and serum creatinine doubling, was similar between the
AST-120 and the placebo groups in both trials. The study,
however, was hampered by several setbacks. Despite the sig-
nificant number of study participants, disease progression was
more gradual than anticipated, and fewer patients reached the
primary end-point, thus reducing statistical power. In addition,
non-adherence to the study drug, related to the large pill bur-
den, was also significant.
Sevelamer hydrochloride (Renagel®; Genzyme, Boston,
MA), a non-calcium-containing phosphate binder, has been
demonstrated in in vitro studies to also bind indole (10–
15 %) and p-cresol (40–50 %, pH-dependent) [91]. Despite
this encouraging observation, however, it did not result in
decreased serum concentrations of indoxyl sulfate or p-cresyl
sulfate either in a mouse model of CKD [92], or in a clinical
cross-over study. On the contrary, in the latter study there was
a significant rise in serum p-cresyl sulfate during sevelamer
treatment [93].
Drugs interfering with microbial or human metabolism
Probiotics [17, 94] and antimicrobials may also prove benefi-
cial, but efficacy may be short-lasting. Probiotics have been
defined as Bviable organisms that, when ingested in sufficient
amounts, exert positive health effects^. Although numerous
studies have evaluated the effects of probiotics, only a limited
number have looked at their effects in renal disease.
Moreover, these studies only assessed biochemical end-
points [76]. Preliminary data with host and bacterial enzyme
inhibitors are promising [10, 95] and call for additional
studies.
Future directions and perspectives
It has long been known that the kidneys secrete organic acids
originating from colonic microbial metabolism. However,
study of the complex bidirectional interactions between the
Pediatr Nephrol
gut and the kidneys is still in its infancy and knowledge re-
mains limited. A better understanding of the gut–kidney axis
will undoubtedly improve the care of patients with CKD and
progressive renal disease.
Growing evidence indicates that gut dysbiosis confers
health risks. A key question is how to define eubiosis. Valid
and at the same time workable biomarkers of gut eu-/dysbiosis
need to be identified. This is a challenging quest given the
complexity of the microbial ecosystem. It is unlikely that a
single co-metabolite or germ is the culprit of all evil.
Biological variability, moreover, will prove to be high. In ad-
dition, the pathophysiological mechanisms underlying gut
dysbiosis in CKD remain largely obscure. A better knowledge
of these mechanisms may help to halt the vicious circle finally
leading to ESRD and inherent comorbidity.
Gut dysbiosis in CKD can be targeted in several ways.
From a teleological point of view, nutritional therapy is the
most appealing. Pilot intervention trials with ‘nutriceuticals’
have so far assessed biochemical outcomes and, overall,
yielded promising results. Treatment response, however, was
not always consistent, nor significant, possibly due to statisti-
cal issues and shortcomings of the intervention. Once the op-
timal treatment regimen has been defined, its efficacy needs to
be tested in adequately powered randomized controlled hard
end-point trials as this is the only way to get final proof of
concept.
Pharmaceuticals may have unexpected side effects on gut
microbiome and metabolism. This may apply to drugs com-
monly used in the care of renal patients, such as phosphate
binders [93], proton pump inhibitors [96] and immunosup-
pressants, among others. Researchers and clinicians should
be aware of potential unwanted effects of drug therapy on
the gut ecosystem. More efforts should be done to inventory
these effects.
Conclusion
It is increasingly acknowledged that crosstalk between host
and endogenous microbiota is pathophysiologically relevant
in patients with CKD. The interactions are bidirectional; on
the one hand, uremia affects both the composition and metab-
olism of the gut microbiota and, on the other hand, dysbiosis is
associated with an increased generation of microbiota-derived
uremic toxins and micro-inflammation, both promoting the
progression of renal disease and premature cardiovascular dis-
ease. Knowledge is rapidly accruing, but remains fragmentary.
Additional efforts are needed to unravel factors modulating
microbiota composition and microbial metabolism as well as
the underlying pathophysiological mechanisms. A better
knowledge of the impact of the kidneys on the gut microbiota
ecosystem and vice versa is important as it may open new
avenues for preventive therapy.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
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