Non-extracorporeal methods for decreasing uremic solute concentration:
a future way to go?
Björn Meijers1 MD, PhD, Griet Glorieux2PhD, Ruben Poesen MD and Stephan J.L. Bakker3
MD, PhD
1Department
of Nephrology, University Hospitals Leuven, Leuven, Belgium and Department
of immunology and microbiology, KU Leuven, Leuven, Belgium, 2Nephrology Section,
Department of Internal Medicine, Ghent University Hospital, Ghent, Belgium
and3Department of Internal Medicine, University Medical Center Groningen and University
of Groningen, Groningen, The Netherlands
Corresponding author:
Björn Meijers
University Hospitals Leuven
Herestraat 49
B-3000 Leuven
Email :
Bjorn.meijers@uzleuven.be
Tel :
+32 16 344580
Fax :
+32 16 344599
1
Financial disclosure and conflict of interest statement:
BM has received consultancy fees from Bellco, Belgium. RP is the recipient of a fellowship of
the Research Foundation - Flanders (Grant 11E9813N))
Estimated manuscript length
24 pages text
:
8 pages
4 tables/ figures
:
1 page
References
:
3 pages
Sum
:
12 pages
2
Abstract
The uremic milieu is consequential to a disrupted balance between availability of retention
solutes and the excretory capacity of the kidneys. While metabolism is the prime contributor
to the internal milieu, a significant fraction of uremic retention solutes originates from other
sources. The main route of entrance is via the intestinal tract, directly from the diet and
indirectly form commensal microbial metabolism. This latter dynamic interplay between the
intestines and kidney has been coined the gut-kidney axis. This review summarizes current
understanding of the gut-kidney axis and explores the impact of dietary and other nonextracorporeal therapeutic interventions in patients with chronic kidney disease.
Keywords
Uremic retention solutes – intestine – diet – microbiome - metabolism
3
Introduction
Accumulation of uremic retention solutes (URS) is consequential to a disrupted balance
between exposure to waste products mainly coming from the diet, their subsequent
metabolism and the excretory capacity of the kidneys (Figure 1)1.These URS constitute a long
and ever-expanding list of molecules. A widely accepted classification, endorsed by the
European Toxin Work Group (EUTox), divides all known URS into three groups according to
characteristics affecting their removal pattern during dialysis 2. This physicochemical
classification categorizes URS into: (1) small water-soluble molecules (<500 Da) that readily
pass any dialysis filter; (2) larger molecules (500 Da), for which passage through a dialysis
filter may belimited and dependent on membrane characteristics (this group is often
referred to as ‘middle molecules’); and (3) protein-bound molecules, for which dialysance
largely depends on the equilibrium between the bound and free fractions. An update of this
classification was recently published 3.Representatives of these groups are discussed more in
detail in chapters 1 to 5 of ththise issue4-8.
Alternatively, uremic retention solutes can be classified according to their origin (see Table
1) 9. Obviously, the majority of URS originate endogenously from mammalian metabolism.
Exogenous dietary URS may also be an important additional source of URS, such as oxalate10
and the advanced glycation end products (AGEs)11;12. Apart from these well-recognized
sources of URS, it is nowadays clear that also the intestinal microbial metabolism results in
the generation of numerous URS9;13. Classifying the URS according to their site of origin may
be of great help to identify therapeutic options beyond extracorporeal removal and should
be considered complementary to the EUTox classification (Table 1). The current review will
focus on the non-endogenous (i.e. exogenous molecules and microbial metabolites) URS to
explore non-extracorporeal methods to reduce their uremic serum concentrations.
4
The gut-kidney axis
It has long been accepted that the principal role of the colon is to absorb salt and water, and
to provide a mechanism for the orderly disposal of waste products of digestion. We now
understand that the advantages of the microbial metabolism to the host are manifold,
including energy harvesting by fermentation of dietary carbohydrates resistant to digestion
in the small intestine (e.g. dietary fibers and non-starch polysaccharides), the formation of
essential molecules such as several vitamins and the development and modulation of the
human gut immune system14. Untargeted metabolomic analyses demonstrate that the gut
microbiota contribute substantially to the mammalian metabolome and that at least part of
these metabolites are unique microbial metabolites that otherwise would not be part of the
human metabolome
13;15.
In general, the relation between host and bacteria is considered
symbiotic. Nonetheless, the microbial metabolism may also lead to the production of
potentially detrimental molecules. Bacterial metabolism of phosphatidylcholine (lecithin),
particularly present in eggs and processed foods, and of L-carnitine, particularly present in
red meat, leads to the bacterial production of trimethylamine (TMA), which after intestinal
absorption is further metabolized towards trimethylamine-oxide (TMAO) 16;17. Accumulation
of TMAO induces atherosclerosis in animal models and serum concentrations of TMAO are
linked with cardiovascular events in a dose-dependent manner 18.
Already in 1870, Jaffé suggested the intestine to be the source of some metabolites excreted
in the urine when he wrote ‘… und bei der nahenVerwandtschaft, welche zwischen indigo
und indican besteht, darf man somitvermuten, daβ das bei der Verdauungsthätigkeit im
Darm auftretende indole eine der Quellen der Indican bildung ist’ (‘Taking into account the
close relationship between indigo and indoxyl sulfate, it is quite conceivable that the indole
5
produced by intestinal digestion is one of the origins of (urinary) indoxyl sulfate’)19. One of
the first experimental studies on the interaction between the gut microbiome and kidney
function of the mammalian host was the observation that while survival of germ-free rats
under starvation conditions was shorter than their conventional counterparts (longer
survival by presence of gut bacteria in animals with normal kidney function), the survival
advantage was reversed when uremic rats were starved to death (shorter survival by
presence of gut bacteria in animals with uremia) 20. Over the years, several URS derived from
microbial metabolism were identified. Bacterial metabolism of tryptophan under anaerobic
conditions leads to the formation of indole, which after intestinal absorption is oxidized to
indoxyl and finally is sulfated to indoxyl sulfate
21;22.
Likewise, bacterial fermentation of
tyrosine results in p-cresol, which after intestinal absorption is sulfated resulting in the
formation of p-cresyl sulfate
23;24.
Apart from sulfate conjugation as a major pathway, to a
lesser extent also other phase II reactions take place, including glucuronidation resulting in
e.g. the formation of p-cresyl glucuronide and indoxyl glucuronide
25;26.
The interplay between intestinal uptake of bacterial metabolites, human metabolism and
the urinary excretion has been coined the gut-kidney axis
9;27;28.
In this paradigm, intestinal
adsorption and renal excretion are independent determinants of the uremic milieu (Figure 1)
29.
The gut metabolism
The mechanisms regulating the bacterial metabolism are only partly understood. It is
generally accepted that the most important determinant of the gut microbial metabolism is
nutrient availability, especially the ratio of available carbohydrates to nitrogenous molecules
including amino acids. Dietary intake and the small intestinal assimilation process both affect
6
this ratio, thereby controlling the degree of saccharolytic versus proteolytic fermentation
30;31.
Dietary sugars resistant to small intestinal digestion (i.e., resistant starch and dietary
fibers or non-starch polysaccharides) compose the main carbohydrate supply in the colon.
Carbohydrate sources available for fermentation in lower amounts include oligosaccharides
and a variety of sugars and non-absorbable sugar alcohols. Nitrogen is provided to the large
intestine from exogenous dietary proteins that have escaped digestion in the upper gut,
endogenous proteins coming from pancreatic and intestinal secretions and sloughed
epithelial cells, and from blood urea that has diffused into the intestinal contents9.Enteric
urea recirculation is discussed more in detail in chapter 5 of this issue32. The colonic
handlingof α-amino nitrogen (amino acids and intermediates) largely depends on the
amount of energy available for bacterial growth and cell division, which in the large intestine
mainly comes from fermentable carbohydrates. In case of carbohydrate excess, α-amino
nitrogen is predominantly incorporated in the expanding bacterial biomass. In addition,
carbohydrate fermentation leads to a reduced intraluminal pH through production of shortchain fatty acids, thereby suppressing large intestinal protease activity resulting in a lower
availability of amino acids33. Conversely, in case of carbohydrate deprivation, α-amino
nitrogen is predominantly fermented, resulting in potentially toxic end-products that may be
absorbed to form bacterial URS (Figure 1).
Along the length of the large intestine, the ratio of available carbohydrate to nitrogen
progressively declines, which impacts bacterial composition and metabolism
34;35.
Slowing
down colonic transit times may induce upstream expansion of proteolytic species, as a larger
part of the colon will become deprived of carbohydrates, and this may result in increased
generation of bacterial toxins. In a landmark study by Cummings et al., 64% of the variance
in the urinary excretion rate of phenols was explained by the colonic transit time and dietary
7
protein intake 36.The colonic transit time is prolonged in patients with CKD, as indicated by
reported prevalences of constipation that are as high as 63% in HD patients and 29% in
continuous ambulatory peritoneal dialysis (CAPD) patients compared to 10% to 20% in
healthy persons37;38. Data on patients with mild-to-moderate CKD to our knowledge are not
available.
Another factor determining intestinal metabolic activity is the composition of the colon
microbiota. While literally thousands of different bacterial species inhabit the colon, this will
lead to a limited number of stable poly-bacterial populations coined enterotypes39. Targeted
studies, investigating the effects of CKD already demonstrated significant differences in the
microbial composition of the colon of patients treated with hemodialysis
dialysis
41
40
and peritoneal
as compared to healthy controls. Untargeted genomics studies confirm that
uremia profoundly alters the composition of the gut microbiome 42. The effect of the altered
microbial species composition on the metabolic activity43 awaits further studies.
Apart from these, several other factors including age, drug treatment, comorbidities, local
immunity, luminal pH, and physicochemical properties of the nutrients affect the
fermentation process. The effects of CKD on these aspects have not yet been explored in
depth.
Interventions
Potassium and phosphorus restriction
Nutrient intake is the main source of the inorganic molecules potassium and phosphorus. In
the general population, experts recommend eating a diet that contains at least 4700 mg of
8
potassium per day (Nutrition and Your Health: Dietary Guidelines for Americans. Available
online at www.health.gov/dietaryguidelines/dga2005/report/HTML/D7_Fluid.htm).
Hyperkalemia, usually defined as a serum potassium concentration > 5.5 mmol/l, originates
when intake and absorption of potassium from the gut exceed the excretionary capacity.
While it is hardly ever seen in individuals with normal kidney function, circulating levels of
potassium will rise with progressive loss of kidney function. Hyperkalemia will impair
electrical conduction in muscles, including the heart, and thereby lead to muscle weakness,
paralysis, ECG changes, cardiac arrhythmia, ventricular fibrillation and sudden death. It is
therefore very common to prescribe a low potassium diet in patients with CKD stage 4 or 5
not on dialysis and CKD stage 5 on dialysis (CKD5D) and most people with moderate to
severe chronic kidney disease or acute kidney injury should eat less than 1500 to 2700 mg of
potassium per day. A registered dietitian or nutritionist can be very helpful to create a low
potassium meal plan, usually mainly by cutting down on intake of fruit, vegetables, coffee
and chocolate.
While potassium-restricted diets unequivocally help to maintain normokalemia, it is worth
noticing that low fruit – low vegetable diets may also have some disadvantages that are less
noticeable on the short-term but may contribute to disease load on the long-term. Cutting
back intake of fruits and vegetables will contribute to metabolic acidosis, leads to vitamin K
deficiency and results in lower intake of dietary fibers.
Fruits and vegetables are particularly rich in precursors of bicarbonate
44;45.
Acting as a
buffer, the bicarbonate-yielding organic anions found in fruits and vegetables neutralize
acids generated from meats and other high-protein foods. In the setting of inadequate
intake of bicarbonate precursors, excess acid in the blood is titrated by bone buffer thereby
contributing to bone demineralization. Increased bone breakdown and calcium-containing
9
kidney stones are adverse consequences of excess acid derived from the diet. Therefore,
diets rich in potassium and bicarbonate precursors might help prevent kidney stones and
bone loss. More importantly, recent evidence also suggests that intake of a diet with low
bicarbonate generating capacity leads to an accelerated decline of renal function
46;47.
The
realization that acidosis may contribute to progression of renal disease has focused
attention on therapeutic neutralization, usually by means of sodium bicarbonate. While
effective for correcting metabolic acidosis, the increased sodium intake may lead to higher
blood pressure, particularly in salt-sensitive patients with renal disease, which by itself may
contribute to accelerated progression of renal disease and cardiovascular disease48;49.
Another detrimental side-effect of a low potassium diet is that vitamin K intake is reduced.
Vitamin K1 is particularly present in green leafs of vegetables and intake in case of a low
potassium diet frequently is deficient50. Vitamin K is required to keep matrix Gla protein, the
natural anti-vascular calcification agent, in its active carboxylated state51. A low potassium
diet, through vitamin K1 depletion, may actually promote vascular calcification, as
commonly seen in patients with CKD. Thus, while routinely prescribed to most patients with
advanced CKD, much about the long-term consequences of a low-potassium diet and how to
avoid those remains unresolved.
Dietary phosphate restriction equally is prescribed on a routine basis. In a recent
observational study, the prevalence of a low phosphate diet prescribed to hemodialysis
patients was 69.6%.Of those phosphate-restricted diets, 75.6% contained 1000 mg per day
or less 52. In western countries, average daily dietary phosphate content is about 1600 mg in
adult men and 1000 mg in adult women
53.Actual
dietary phosphate load varies
substantially, largely dependent on the amount of dietary protein with each gram of protein
10
bringing 13-15 mg of phosphate. The source of protein is relevant, as phosphate absorption
from plant protein is significantly lower (bioavailability 30-40%) than from animal protein
(bioavailability ~70%) 54. The differential dietary phosphate load between plant protein and
animal protein is ascribed to the fact that phosphate in plants is present in the form of
phytates, which are poorly digested due to low phytase activity in the human gut53.
Importantly, it is often not taken into account that phosphate present as food additives, as in
processed foods and beverages (e.g. in Coca-Cola in a concentration of 170 mg/L), has a
bioavailability of 100% 53;55.
Beginning in CKD stage 3, the ability of the kidneys to appropriately excrete the dietary
phosphate load is diminished, leading to hyperphosphatemia (defined as a serum phosphate
concentration > 1.45 mmol/L), elevated PTH, decreased 1,25(OH)2D, and elevated FGF-23.
Large observational studies in hemodialysis patients have consistently found strong dosedependent associations between serum phosphate and all-cause mortality
cardiovascular morbidity and mortality
58;61
56-60,
and increased rates of hospitalization 62. Higher
levels of serum phosphate, even within the normal range, have been found associated with
increased risk of cardiovascular events and cardiovascular and all-cause mortality in healthy
subjects with a normal renal function 63, in patients with coronary artery disease and normal
renal function
64,
and in patients with CKD stages 3-5
65.
Taking all these data together,
current Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend to limit
dietary phosphate intake as a first-line therapy (with or without phosphate binders) for
treatment of hyperphosphatemia and secondary hyperparathyroidism in patients with CKD
stage 3-5
66.
The KDIGO CKD-MBD guideline work group however recognizes that these
recommendations are solely based on observational studies as intervention studies
demonstrating a cause-effect relationship are lacking. It should be noted that high dietary
11
phosphate intake often goes along with high salt intake, thus possibly confounding observed
associations between high phosphate intake (hyperphosphatemia) and outcome.
Intriguingly, a recent study in hemodialysis patients challenges the relevance of prescribing
phosphate lowering diets for prevention of hyperphosphatemia as a low phosphate diet was
associated with increased subsequent risk of premature death 52. When comparing different
subgroups of patients, the investigators found a more pronounced survival benefit of nonrestricted dietary phosphate intake among non-blacks, patients without elevated phosphate
levels, and those not taking vitamin D. The results of these subgroup analyses suggest a
greater benefit from intake of plant protein with poorly bioavailable phosphate rather than
animal protein and also a benefit of low intake of phosphate in the form of food additives,
which both would translate in lower serum phosphate for the same intake. Overall, the
results may also relate to unintended compromised intake of other essential
macronutrients, such as protein, that offset or supersede any beneficial effects on
phosphate mitigation, e.g. by malnutrition. A recent study on the association between
phosphate binder therapy and mortality in hemodialysis patients is also suggestive of such
an effect
67.
These investigators found longer survival and better nutritional status in
hemodialysis patients on phosphate binder therapy. Mortality started to rise once serum
phosphate exceeded 1.78 mmol/L despite phosphate binder therapy. In these patients,
about 50% of the beneficial effect of the phosphate binders on mortality could be explained
by nutritional parameters 68.
Taken together, it seems that hyperphosphatemia should be avoided as much as possible,
preferably with measures that protect against induction of protein-energy malnutrition,
which from the perspective of dietary advices, would consist of preferable ingestion of
protein from plant sources and avoidance of animal protein and products that contain
12
phosphate as food additives. Of note, phosphate metabolism and its impact on uremia will
be discussed more in detail in chapter 6 of this issue69.
Protein restriction
A dietary measure that is commonly prescribed in patients with CKD is protein restriction.
Central in the rationale for the low protein diets is the so-called Brenner hypothesis, which
states that ageing, renal ablation, uninephrectomy and intrinsic renal disease all lead to
increased glomerular pressure and compensatory hyperfiltration of remaining nephrons,
causing glomerular injury and increased urinary protein excretion, ultimately compromising
renal function
70.
Primarily based on observations in animal studies
71;72,
it was suggested
that a high protein intake exacerbates the otherwise already existing increased glomerular
pressure, compensatory hyperfiltration and urinary protein excretion, thereby accelerating
loss of renal function
70.
Numerous studies have investigated the hypothesis that dietary
protein restriction indeed results in retarding decline of renal function in CKD. Although
criticized
72;73,
meta-analyses of such studies have concluded that low protein diets are
effective in achieving this goal, with more pronounced effects in diabetic CKD than in nondiabetic CKD
74-76.
Apart from these reviews, even a modest reduction of dietary protein
from 1.02 g/kg/day to 0.89 g/kg/day resulted in a decrease of the relative risk for
progressing towards CKD5 or death in patients with type 1 diabetes and CKD2 77.
Based on this evidence, the KDOQI working group on clinical practice guidelines and clinical
practice recommendations for diabetes and CKD concluded that limiting dietary protein
intake to a level of 0.8 g/kg/day should stabilize or reduce albuminuria, slow the decrease in
GFR and may prevent development of CKD5, both in patients with and without
diabetes78.Protein intake can be safely reduced from a western type diet containing about
13
1.3-1.4 g protein/kg/day to a nutritionally and metabolically optimal intake of 0.6-0.8 g
protein/kg/day
79;80.
Several studies however indicate that the renal benefits and the
prevention of development of CKD5 are easily outbalanced by induction of protein-energy
malnutrition and an associated excess in morbidity and mortality if protein intake goes lower
than 0.8 g/kg/day or protein losses or catabolism are one way or another higher than in
patients with relatively uncomplicated CKD 81-83. Consistent with this suggestion, a post-hoc
analysis of the modification of diet in renal disease (MDRD) study found no further renal
benefit for a very low protein diet (0.28 g/kg/day) as compared to a low protein diet (0.58
g/kg/day) in patients with predominantly stage 4 non-diabetic CKD. Instead, a very low
protein diet was associated with excess mortality 83.
In extension hereof, it should be noted that once patients develop CKD5 and enter dialysis,
dialysis induces protein catabolism and protein losses, that must be compensated.
Guidelines recommend a dietary protein intake of at least 1.1 g/ kg/day and preferably 1.2
to 1.3 g protein/kg/day for clinically stable dialysis patients
84;85.
These recommended
protein intakes are larger than the usually ingested protein intakes of maintenance
hemodialysis and peritoneal dialysis patients, which usually approximate 0.8-1.0 g/kg/day
86;87,
and are also larger than the recommended protein intakes for healthy adults84. The
possible mechanisms that engender these increased protein needs include (1) the
substantial quantity of amino acids, peptides, and proteins removed by the dialysis
procedure and (2) the protein catabolic state caused by the uremic milieu, the inflammatory
state, the oxidative and carbonyl stress, and the bio-incompatible dialysis materials to which
dialysis patients are exposed. Indeed, in an analysis of more than 50,000 hemodialysis
patients, survival improved with increasing protein intake, until a plateau was reached when
protein intake was 1.4 g/kg/day or above88, in line with findings on the relation between
14
protein intake and mortality in a much smaller cohort of 3,000 French hemodialysis
patients89. In conclusion, protein intake should be restricted in patients with CKD stages 1 to
4, while protein intake in dialysis patients should not be restricted and even promoted.
Little is known about the optimal dietary protein source, i.e. animal vs. plant
85.
Theoretically, ingestion of high quality plant protein would be the preferential choice as this
has been associated with a lower phosphorus bioavailability, a lower acid load and higher
amounts of dietary fibers delivered to the colon. As discussed above, this will reduce
generation of several bacterial URS90 and may promote enteral generation of vitamin K,
which could antagonize the cardiovascular calcification process in patients with CKD49;50;91-93.
Not completely in line with this, a recent post-hoc analysis of the ONTARGET trial suggests
that a high intake of animal protein is particularly protective against progression of CKD in
patients with type 2 diabetes, while it is indifferent with respect to risk for mortality. A high
intake of plant protein was also protective against of progression of CKD, albeit to a lesser
extent than animal protein intake, but with the advantage of a greater tendency of providing
protection against mortality
94.
It is obvious that further studies are required to disclose
what would be the optimal source of protein or protein mix that would minimize the risks
for mortality and development of cardiovascular disease, while retarding the progression of
CKD
Food supplements
Targeted interventions to change the intestinal function and especially the microbial
metabolic activity may be an attractive alternative to the broad dietary interventions
described above and may have less negative impact on the health-related quality of life.
15
Both probiotics and prebiotics have been shown to influence the composition of the colonic
microbiota.
Probiotics have been defined as ‘live microorganisms that, when administered in adequate
amounts, confer a health benefit on the host’95. For regulatory purposes, the US Food and
Drug Administration (FDA) prefers to use“live biotherapeutics” for live microbes intended for
use as human drugs
95.
The most frequently used strains include Lactobacillus,
Streptococcus, and Bifidobacterium9;92;96.Over the last years, numerous studies reported
health-promoting effects of probiotics for the treatment of various ailments and the interest
in these therapies continues to be on the rise. In healthy individuals without kidney disease,
probiotics reduced production and urinary excretion of a number of intestinal metabolites
that are uremic retention solutes in patients with CKD 97-99.
While these studies suggest probiotics to be a useful therapeutic strategy to reduce serum
concentrations of uremic retention solutes, surprisingly few studies looked at the effects of
probiotics in patients with CKD. Part of these studies aimed to reduce the intestinal
absorption of oxalate as a treatment of calcium-oxalate stone formers (Table 2). While initial
studies were promising, controlled trials did not demonstrate a significant effect on urinary
oxalate excretion10;100-102. Only a few studies investigated whether probiotics reduce serum
concentrations of URS40;103-105. While they show promise, more and larger studies are
required to judge the usefulness of probiotics in CKD and dialysis patients.
Prebiotics may also be useful to reduce the intestinal production of URS. The definition of
what constitutes a prebiotic has slightly evolved over the last decade and was recently
formulated as ‘A dietary prebiotic is a selectively fermented ingredient that results in specific
changes, in the composition and/or activity of the gastrointestinal microbiota, thus
conferring benefit(s) upon host health’ 106. According to this definition, one has to make the
16
distinction between the prebiotic effect and the dietary fiber effect. Being resistant (partly or
totally) to digestion and being fermented (at least the so-called soluble dietary fibers) both
may interact with gut microbiota composition and activity. The key difference lies in the
selectivity to stimulate metabolic profile(s) and/ or molecular signaling, prokaryote–
eukaryote cell–cell interaction linked to one specific microbial genus/species or resulting
from the coordinated activity of a limited number of microbial genus(era)106. Most studies
on prebiotics have been obtained using food ingredients/supplements belonging to either
inulin-type fructans or the galacto-oligosaccharides. As for the probiotics, while a large
number of trials suggest health-promoting effects in a wide array of conditions,
investigational studies exploring the potential benefits of prebiotics in CKD are scanty (Table
3). In one animal study exploring the contribution of p-cresyl sulfate to CKD-induced insulin
resistance, serum concentrations of p-cresyl sulfate were reduced by the prebiotic arabinoxylo-oligosaccharide107. While this type of prebiotics reduced the urinary excretion of pcresyl sulfate in healthy individuals
108,
studies demonstrating effects on serum
concentrations of p-cresyl sulfate or other URS in CKD patients have not been performed to
date. In a study on nine patients with CKD but not yet on dialysis, Younes et al. found that
fermentable carbohydrates shifted nitrogen excretion from the urinary route to fecal
excretion, thereby reducing plasma urea concentrations
109.
A similar effect was also
reported in another group of 16 patients with CKD but not yet on dialysis after treatment
with gum Arabic fiber
110.
Whether this resulted in decreased generation of other URS was
not studied. One single publication investigated the effects of the prebiotic oligofructoseinulin on URS in hemodialysis patients. p-Cresyl sulfate serum concentrations were
significantly reduced. In contrast, serum indoxyl sulfate was not affected111.
17
Prebiotics and probiotics may also be used in combination and are then referred to as
symbiotics. Again, only one study explored the effects of such a symbiotic to reduce serum
concentrations of URS in patients with CKD. Nakabayashi et al. performed a short-term study
investigating the effects of Lactobacillus caseistrain Shirota and Bifidobacterium breve strain
Yakult as probiotics in combination with the prebiotic galacto-oligosaccharides in
hemodialysis patients112. In alignment with the prebiotic study, serum p-cresyl sulfate
concentrations were significantly reduced, while a clear effect on serum indoxyl sulfate
could not be demonstrated.
In summary, to date only a limited number of mostly uncontrolled studies with small sample
size investigated the potential role of pre- and probiotics to alter URS. A recent metaanalysis including all published studies in CKD concluded there is limited but supportive
evidence for the effectiveness of pre-biotics and probiotics on reducing PCS and IS in the
CKD population113. Further studies are needed to provide more definitive findings before
routine clinical use can be recommended.
Adsorptive therapies
Next to dietary restriction of phosphate (described above) and phosphate removal by
effective dialysis in patients with CKD5 which is beyond the scope of this chapter, phosphate
binders can be used to reduce high phosphate levels 66. There are several different types of
phosphate binders: (1) the most commonly used are calcium-based phosphate binders,
either calcium carbonate or calcium acetate; others include (2) the anion exchange resin
sevelamer of which sevelamer hydrochloride has been studied more extensively than
sevelamer carbonate, (3) lanthanum carbonate, (4) the magnesium based phosphate
binders, (5) aluminum based phosphate binders and (6) a novel polynuclear iron(III)18
oxyhydroxide phosphate binder, PA21. The degree to which hyperphosphatemia can be
ameliorated using the different available types of binders is comparable 114-116.
Whether phosphate binder therapy unequivocally translates into better patient outcomes
remains matter of debate. While Isakova et al
117
found that phosphate binder therapy in
incident HD patients was independently associated with decreased mortality, such a
mortality difference could not be demonstrated in the study by Winkelmayer et al.
118.In
addition, superiority in view of surrogate outcome such as vascular calcification or hard
clinical endpoints like cardiovascular events and mortality of current phosphate binders,
evaluated in several RCTs, was not convincing either, as summarized in a meta-analysis by
Navaneethan et al. and recently reviewed by Tonelli et al.114;119.
The question arises whether phosphate retention and its related complications may be
prevented by prescribing phosphate binders to patients with moderate to advanced CKD. In
a prospective randomized blinded clinical trial by Block et al. CKD stage 3b-4 patients were
treated with calcium acetate, lanthanum carbonate, sevelamer carbonate or placebo for 9
months. Serum phosphorus was moderately but significantly reduced by phosphate binder
therapy and urinary phosphate excretion was reduced by 22%, indicating effective chelation
of phosphate in CKD patients not yet on dialysis. Neither serum iPTH nor plasma C-terminal
FGF-23 levels were significantly changed in those receiving phosphate binder therapy.
Surprisingly, phosphate binder therapy was associated with increased calcification of both
the coronary arteries and the abdominal aorta
115.
Additional RCTs in larger groups of CKD
patients are needed to confirm these worrisome findings120;121.
It is of note that sevelamer, apart from its phosphate binder effect, reduces LDLcholesterol122 as well as CRP and beta2-microglobulin in dialysis patients pointing to a
possible anti-inflammatory effect 123. There is, however, no evidence that sevelamer reduces
19
serum levels of protein-bound uremic retenion solutes, by absorbing their intestinal
precursors 124;125. On the contrary, HD patients treated with sevelamer for 8 weeks showed
increased serum levels of p-cresol (including p-cresyl conjugates)
125.
On the opposite side,
sevelamer hydrochloride adsorbs folic acid thereby promoting higher homocysteine
levels126. Whether this translates into augmentation of the cardiovascular risk has not been
explored in depth.
The oral sorbent AST-120 (Kremezin®), composed of spherical porous carbon particles with a
diameter of approximately 0.2-0.4 mm, has a superior adsorptive capacity for several small
molecular weight organic compounds that originate from the microbial metabolism in the
large intestines. Historically, emphasis has been on the capacity of AST-120 to decrease
serum levels of indoxyl sulfate. Already in the early nineties, Niwa et al demonstrated that
AST-120 administration to nephrectomized rats reduced serum concentrations of indoxyl
sulfate
127
and p-cresol as a surrogate of p-cresyl sulfate 128. Administration of AST-120 was
also shown to significantly decrease serum levels of AGEs in non-diabetic CKD patients via
adsorption of N(6)-carboxymethyllysine (CML)129. Recently, a metabolomic approach
applying liquid chromatography/electrospray ionization-tandem mass spectrometry (LC/ESIMS/MS)] on AST-120 treated CKD rats demonstrated that, apart from indoxyl sulfate, serum
levels of a number of other URS were reduced, including hippuric acid, phenyl sulfate and 4ethylphenyl sulfate and p-cresyl sulfate by intestinal adsorption of their precursors, i.e.
indole, benzoic acid, phenol, 4-ethylphenol, and p-cresol respectively
130.
A recent
publication identified several additional compounds that were decreased in CKD rat serum
after oral administration of AST-120: N-acetyl-neuraminate, 4-pyridoxate, 4-oxopentanoate,
20
glycine, γ-guanidinobutyrate, N-γ-ethylglutamine, allantoin, cytosine, 5-methylcytosine and
imidazole-4-acetate 131.
Both CKD animal models and patient studies suggested clinically relevant benefits of AST120. It ameliorated low bone turnover in nephrectomized and parathyroidectomized rats
administered a physiological level of parathyroid hormone
132.
In addition, AST-120
suppressed the progression of cardiac hypertrophy and fibrosis in uremic rats
133.
In a more
recent study, normalization of cardiac fibrosis, independent of blood pressure, in ASTtreated CKD rats was also demonstrated
134.
Amelioration of epithelial-to-mesenchymal
transition (EMT) and interstitial fibrosis in kidneys from CKD rats was suggested135. Finally,
AST-120 treatment of subtotally nephrectomized mice significantly decreased Mac-1
expression and ROS production by peripheral blood monocytes
136.
Thus, these in vivo
animal studies suggest that AST-120 might improve various complications related to CKD
such as osteodystrophy, progression of cardiovascular disease and oxidative stress.
Nakamura et al. performed a randomized clinical trial of 50 non-dialysis CKD patients to
evaluate the effect of AST-120 on intima-media thickness and carotid artery stiffness. Intimamedia thickness was reduced in those on AST-120. AST-120 also reduced stiffness of the
carotid artery, whereas those who did not receive AST-120 showed little change in intimamedia thickness and a slight increase in arterial stiffness 137.
Several trials suggested a benefit for administration of AST-120 on the progression of kidney
disease. In a prospective randomized study in patients with moderately impaired renal
function (GFR: 20-70 ml/min), a decrease in the slope of iothalamate clearance after the
start of AST-120 was demonstrated
138.
In diabetics with proteinuria and moderate CKD, a
less pronounced rise in serum creatinine was observed in the AST-120 treated group 139. In a
more elaborated multicenter randomized controlled trial by Akizawa et al. in non-dialyzed
21
CKD patients, a slower decline of estimated glomerular filtration rate (eGFR), although a
secondary endpoint, in patients treated with AST-120 versus placebo was observed140. As a
possible consequence AST-120 was shown to postpone the start of dialysis
141.
Finally, AST-
120 administration in the pre-dialysis stage also improved survival outcome (72 vs. 56%)
once dialysis was started 142. Although these studies all point in the same direction, the long
awaited two phase III, randomized, placebo-controlled, double-blind studies [EPPIC
(Evaluating Prevention of Progression In Chronic kidney disease)], including 2035 patients
(CKD3-5) from 240 centers in 13 countries in America and Europe, failed to demonstrate a
significant difference on the primary endpoints of time to initiation of dialysis, kidney
transplantation or doubling of serum creatinine (Schulman et al. abstract ASN 2012). In a
post-hoc analysis, the subgroup of patients with baseline urinary protein/creatinine ratio
exceeding 1.0 g/g, presence of hematuria and ≥80% adherence to active therapy, the
reduction in CKD progression with AST-120 was statistically significant
143.
While promising,
these results do not support widespread use of AST-120 in advanced chronic kidney disease.
Pharmacological therapy to alter gastro-intestinal physiology
As described above, augmented delivery of carbohydrates to the colon will shift the colonic
microbial metabolism more towards saccharolytic fermentation. Prebiotics are resistant to
the small intestinal carbohydrate assimilation and reach the colonic metabolism unchanged.
An alternative approach is to inhibit the normal carbohydrate assimilation by means of small
intestinal α-glucosidase inhibitors, thereby allowing part of the (oligo-)saccharides to enter
the colon. Acarbose (Glucobay®, Bayer) in a pilot study in healthy volunteers reduced serum
concentrations and the 24-h urinary excretion of p-cresyl sulfate
144.
The results of an
22
ongoing randomized controlled trial evaluating the effects of acarbose in patients with CKD
not yet on dialysis are to be awaited.
There are no approved drugs to selectively reduce colonic transit times in patients with CKD.
However, several therapies—including prebiotics—also reduce colonic transit times, in
addition to the abovementioned metabolic effects. Treatments that prolong colonic transit
might theoretically result in increased generation and absorption of URS. The relevance of
this phenomenon has not been studied yet and it is unclear whether such therapies should
be avoided.
Renal handling
Apart from interfering with the generation and metabolism of URS, influencing renal tubular
handling may be an alternative and novel therapeutic approach to reduce serum
concentrations of URS. Transport of uremic toxins across the tubular cell membrane is
facilitated by specific influx and efflux pumps, such as the organic anion and cation
transporters (OATs and OCTs), the multidrug and toxin extrusion (MATE) and the multidrugresistance-associated protein (MRP). Affecting influx transporter expression and/or function
on the basolateral membrane of transporters such as OAT1 and 3, OATP4 and OCT1-3 could
in the first place help to decrease local toxicity to renal tubular cells and might also affect
circulating concentrations if combined with effective efflux transport at the apical site by
e.g.OAT4, MDR1, MATE1 and 2K. Indoxyl sulfate, 3-carboxy-4-methyl-5-propyl-2furanpropanoic acid(CMPF), hippuric acid and p-cresylsulfate are substrates for OAT1 and
OAT3145, and are pumped from the circulation into the cell where they can exert their
toxicity. A metabolomic profile study in OAT1-knockout mice identified additional substrates
of OAT1 including indole-3-lactate, kynurenine, phenylsulfate as well as several other
23
compounds146. Recent studies revealed that increased intracellular levels of p-cresyl sulfate
and CMPF cause tubular damage by inducing oxidative stress147;148. Drugs interfering with
the function of these pumps, e.g. probenecid, inhibit the influx of uremic toxins149;150. In vitro
studies showed that inhibition of the influx of indoxyl sulfate by blocking OAT1 by
probenecid increased viability of proximal tubular cells from mice that stably express rOAT1
and OAT3. It also reduced hypertrophy of cardiac myocytes and collagen synthesis of
fibroblasts, on which these transporters are also expressed151. Inhibition of these influx
pumps will eventually contribute to the increase in serum concentrations and further
accumulation of uremic toxins may in turn inhibit their own renal elimination by inhibiting
transport via OATs. In addition, expression of OAT1, OAT3
152;153
and the basolaterally
located organic anion transporter is OAT polypeptide 4C1 (SCLO4C1) are shown to be
decreased in CKD while MDR1 expression remains unaffected154. Interestingly, Toyohara
demonstrated that the transcription of SLCO4C1can be upregulated by statins, which leads
to a higher expression on the cell membrane resulting in a decreased URS concentration154.
It is of note that basolateral uptake of uremic toxins in renal proximal tubules cells is fairly
well characterized. However, little is known about the transport of uremic toxins via the
apical membrane into the urine. Mutsaers et al. recently reported that hippuric acid, indoxyl
sulfate and kynurenic acid inhibit substrate specific uptake by both MRP4 and Breast Cancer
Resistance Protein (BCRP), two important renal efflux pumps at the apical membrane,
whereas indole-3-acetic acid and phenylacetic acid only reduce transport by MRP4155. It
remains to be elucidated whether these uremic toxins are substrates for these efflux pumps
and further studies exploring this aspect are needed. Tubular transport of uremic solutes will
be discussed in more detail in chapter 9 of this issue 156.
24
Conclusions
The uremic milieu is the resultant of a disrupted balance between availability of candidate
retention solutes and the excretory capacity of the kidneys. While the human metabolism is
the prime contributor of URS, a significant fraction finds its origin outside of the human
metabolism. Both exogenous intake, predominantly via ingestion, as well as the commensal
microbial metabolism, significantly contribute to the accumulation of the URS.
Only recently the full relevance of the microbial metabolism to the human metabolome has
been recognized. The kidneys are a key modifier of the effect of the microbiome
contribution towards health. The normally functioning kidneys prevent accumulation of toxic
waste products of the microbial metabolism, while maintaining the beneficial effects (energy
conservation, production of vitamins). With progressive loss of kidney function, the balance
is reversed and the adverse effects related to the accumulation of microbiome-derived
uremic retention solutes outweigh the beneficial contribution of the microbial metabolism
to the human metabolism.
For decades, several unselective dietary interventions have been mainstay therapy to treat
patients with CKD. These include dietary potassium and phosphate restriction in CKD and in
dialysis-dependent patients, as well as protein restriction in advanced CKD. While strongly
supported by observational data linking hyperkalemia and hyperphosphatemia to hard
clinical endpoints including overall mortality and cardiovascular outcomes, dietary
intervention studies failed to unequivocally demonstrate beneficial effects of broad and
unselective dietary restrictions. The proposed dietary interventions imply restriction of fruit
and vegetable intake, as well as restricted intake of essential protein sources. While
undoubtedly successful to minimize hyperkalemia and hyperphosphatemia, the pleiotropic
25
effects of dietary intake of fruits and vegetables deserve re-appreciation. Plant protein
reduces phosphorous load while maintaining amino acid supply. Fruits and vegetables are
rich in bicarbonate precursors, thereby limiting the metabolic acidosis accompanying
progressive CKD. Fruits and vegetables are rich in dietary fibers, stimulating the production
of key vitamins such as vitamin K1, essential for activation of the important calcification
inhibitor matrix-Gla protein and other glutamine-domain containing proteins. Dietary fibers
also shift the intestinal microbial metabolism towards saccharolytic fermentation while
reducing proteolytic fermentation. This will reduce production of the end products of amino
acid fermentation thereby limiting accumulation of several URS, e.g. indoxyl sulfate and pcresyl sulfate. Overall, the pleiotropic effects of the broad and unselective dietary
interventions regularly prescribed to a large fraction of patients at various stages of CKD are
poorly characterized. Hard endpoint studies are lacking, but circumstantial evidence
suggests that these pleiotropic effects may partially offset or in selected cases may even
outbalance the beneficial effects to the patient.
Targeted dietary interventions include prebiotics, probiotics and synbiotics. While promising,
the number of available studies is limited. A recent meta-analysis of available studies
suggests a benefit of using such therapies in patients at various stages of CKD. Although
promising, it is too early to implement such therapies. More experimental and
investigational data are needed to support their use in CKD, to identify which patient
populations would benefit most and what would be the best therapeutic choice.
Apart from interfering with the generation and metabolism of URS, influencing renal tubular
handling may be an alternative and novel therapeutic approach to reduce serum
concentrations of URS. While our understanding of the basolateral and apical transporter
26
systems has increased substantially, it is far from complete and therapeutic strategies are
yet to be developed.
In conclusion, non-extracorporeal therapies show great promise to reduce URS. Several
dietary interventions already are part of the nephrologist’s armamentarium, but recent
findings suggest these strategies may introduce unintended compromised intake of essential
macronutrients. This may partially offset or even supersede the benefits of such
interventions. Identification of the involved metabolic pathways and specific transporter
systems confers great promise to design more targeted therapies to minimize accumulation
of URS and is the future way to go.
27
Figure legends
Figure 1
Schematic overview of the gastro-intestinal tract metabolism contributing to the internal
milieu. In patients with kidney disease, the gastro-intestinal uptake outweighs the renal
excretory capacity leading to retention of so-called uremic retention solutes. This altered
composition of the internal milieu contributes to the uremic syndrome. Retention of
anorganic electrolytes may lead to hyperkalemia and hyperphosphatemia. Organic uremic
retention solutes include the indoles (e.g. indoxyl sulfate), phenols (e.g. p-cresyl sulfate,
phenyl acetic acids and the amines.
28
Table 1 – Proposed classification of URS
Physicochemical properties
Origin of URS
(EuTOX classification2)
Mammalian metabolism
Diet
Microbial metabolism
Small water-soluble molecules
Urea
Phosphate
Urea
Oxalate
Potassium
Origin unknown
Oxalate
Middle molecules
β2-microglobulin
Free light chains
Protein-bound molecules
Homocysteine
AGE
AGE
Indoxyl sulfate
Phenyl sulfate
p-cresol sulfate
Phenyl acetic acid
No consensus
Trimethylamine-N-oxide
A proposal for a classification of the URS taking into account both origin (mammalian metabolism vs. exogenous sources vs. microbial
metabolism) and physicochemical properties that determine dialysance.
AGE, advanced glycation end products.
29
Table 2 – Probiotic studies
Study
Population
Primary end-point
n
Strain
Result
Campieri et al. 100
Urolithiasis
Urinary oxalate excretion
6
Lactic acid bacilli
─40% Urinary oxalate excretion
Lieske et al. 101
Urolithiasis
Urinary oxalate excretion
10
Oxadrop
─19% Urinary oxalate excretion
Lactobacillus acidophilus
Lactobacillus brevis
Streptococcus thermophilus
Bifidobacterium infantis
Goldfarb et al.10
Urolithiasis
Urinary oxalate excretion
10a
Oxadrop
No significant changes
Lactobacillus acidophilus
Lactobacillus brevis
Streptococcus thermophilus
Bifidobacterium infantis
Lieske et
al.102
Urolithiasis
Urinary oxalate excretion
14
Oxadrop + controlled diet
No significant changes
Lactobacillus acidophilus
Lactobacillus brevis
Streptococcus thermophilus
Bifidobacterium infantis
Ranganathan et al.105
CKD
Blood urea nitrogen
46
Kibowbiotics
-9 % BUN
30
Serum creatinine
L. acidophilus KB27
Serum uric acid
Bifidobacterium longum KB31
No change creatinine
No change uric acid
Streptococcus thermophilus KB19
Hida et al.40
HD
Indoxyl sulfate
20
p-Cresol
Takayama et al.103
HD
Indoxyl sulfate
Lebenin
Lactic acid bacilli
11
Bifina
─30 % serum indoxyl sulfate
No change serum p-cresol
─30 % serum indoxyl sulfate
Bifidobacterium longum
Taki et al.104
HD
Indoxyl sulfate
27
Homocysteine
Bifina
Bifidobacterium longum
─9 % serum indoxyl sulfate
─9 % plasma homocysteine
n, number of patients in active treatment arm
aRandomized
controlled trial
31
Table 3 – Prebiotic studies
Study
Population
Primary endpoint
n
Intervention
Result
Meijers et al. 111
HD
Serum p-cresyl sulfate
22
OF-IN (Orafti®Synergi1)
─17% serum p-cresyl sulfate
(oligofructose – inulin)
(─6% blood urea nitrogen, no
change serum indoxyl sulfate)
Nakabayashi et
HD
al.101;112
Synbiotic:
─20% serum p-cresyl sulfate
Serum phenol
(i) Oligomate 55N®
No change serum phenol
Serum indoxyl sulfate
(galacto-oligosaccharides)
No change serum indoxyl sulfate
Serum p-cresol
7
(ii) Yakult BL Seichoyaku®
(Lactobacillus casei,
Bifidobacterium breve)
Younes et al.109
CKD
Blood urea nitrogen
9
Fermentable carbohydrate
─23% Blood urea nitrogen
Bliss et al.110
CKD
Blood urea nitrogen
16a
Gum Arabic fiber
─12% Blood urea nitrogen
n, number of patients in active treatment arm
aRandomized
controlled trial
32
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