Web viewWord count main body: 4204. ... 56. de Almeida Duarte JB, de Aguilar ... Eldehni MT, Jefferies HJ, Szeto CC, John SG, Sigrist MK, Burton JO, Hothi D

The Colon: An Overlooked Site for Therapeutics in Dialysis Patients

Ruben Poesen 1, Björn Meijers 1, Pieter Evenepoel 1

1 Department of Microbiology and Immunology, Division of Nephrology, University Hospitals

Leuven, B-3000 Leuven, Belgium

Word count abstract: 164

Word count main body: 4204

Figures: 1

Tables: 1

Key words: colon, chronic kidney disease, dialysis

Address for correspondence: P. Evenepoel, MD, PhD

Dienst nefrologie

Universitair Ziekenhuis Gasthuisberg

Herestraat 49

B-3000 Leuven

BELGIUM

Tel. +32-16-344591

Fax. +32-16-344599

e-mail: [email protected]

Acknowledgments:

RP is recipient of a Ph.D. fellowship of the Research Foundation - Flanders (FWO) (grant 11E9813N)

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ABSTRACT

Morbidity and mortality related to chronic kidney disease remains unacceptable high, despite

tremendous progress in its prevention and treatment. In an ongoing quest to improve outcome in

chronic kidney disease patients, the colon might be an appealing but largely underexplored

therapeutic target. A clear bi-directional functional relationship exists between the colon and kidney,

also referred as to the colo-renal axis. Uremia has an important impact on the colonic microbiome.

The microbiome, in turn, is an important source of uremic toxins, with p-cresyl sulfate and indoxyl

sulfate as important prototypes. These co-metabolites accumulate in the face of a falling kidney

function, and may accelerate the progression of renal and cardiovascular disease. Several therapeutic

interventions, including prebiotics and adsorbants, specifically target these colon-derived uremic

toxins originating from bacterial metabolism. As kidney function declines, the colon also gains

importance in the homeostasis and disposal of potassium and oxalate. Their colonic secretion may be

increased by drugs increasing the expression of cAMP and by probiotics (e.g., Oxalobacter

formigenes).

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INTRODUCTION

Chronic kidney disease (CKD) has become a global health issue and reaches epidemic proportions

(1,2). Mounting data point to the lethal synergy between CKD and cardiovascular disease (3-5) with a

cardiovascular mortality in CKD patients treated with hemodialysis that is more than fivefold higher

than in the general population (5,6). Improving this poor prognosis is an ongoing challenge for the

nephrology community. Conventional dialysis techniques, however, seem to have reached their

limits. Indeed, recent large randomized controlled trials (HEMO, ADEMEX) failed to show an

improvement of patient outcome by increasing the removal of low-molecular-mass water-soluble

solutes and even middle molecules above standard of care (7,8). Renal transplantation, undoubtedly

the best treatment option in patients with end-stage renal disease (9), is hampered by organ

shortage, and morbidity related to the surgical procedure and life-long immunosuppression.

Therefore, a need for alternative or adjuvant therapeutic strategies persists. It is well established that

the large intestine plays a non-negligible role in the homeostasis of several electrolytes and minerals,

and disposal of nitrogenous waste products. Finally, the large intestine is an important source of

uremic toxins (10). Therefore, targeting the large intestine might be a promising adjuvant approach

to tackle the high morbidity and mortality burden in CKD. Gastrointestinal interventions in medicine

are not new, but date back to ancient times. For example, in 40 B.C., Dioscorides, a Greek physician,

pharmacologist and botanist advocated terra sigillata for treating multiple disorders, including

diseases of the kidney. More recently, induced diarrhea and intestinal perfusion have been used with

variable success and tolerance to treat uremia (11). With the advent of dialysis (Dr. W. Kolff, first

successful dialysis in 1945 (12)) and renal transplantation (Dr. J. Murray, first successful

transplantation in 1954 (13)) and potent drug therapy (e.g., angiotensin converting enzyme

inhibitors, 1975 (14)), interest in gastrointestinal interventions in CKD patients has waned. An

increased awareness of the limitations of current treatment options has renewed interest in

alternative therapeutics in recent years. This review aims to summarize important functions of the

colon, both in health and CKD, and to discuss the colon as a therapeutic target in CKD.

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THE COLON IN HEALTH

The human large intestine is approximately 150 cm long with an internal surface area of 1.3 m², and

weighs approximately 220 g, of which 80 % is moisture. The colonic transit time ranges from 20 to

140 hours (mean 60 hours) (15). It has long been thought that the principal role of the colon was to

confer a mechanism for the orderly disposal of waste products of digestion, and to absorb salt and

water. Approximately 1.5 liters of electrolyte-rich fluid per day, accounting for 90 % of the salt and

water entering the proximal colon, is absorbed by the colonic epithelium. The key determinant of

colonic water absorption is the rate of sodium absorption, which can be electrogenic via the

epithelial sodium channel or electroneutral via parallel sodium/hydrogen and chloride/bicarbonate-

exchange. The colon also contributes to acid-base homeostasis by secreting bicarbonate via the

chloride/bicarbonate-exchanger, which helps in buffering organic acids produced by colonic bacteria.

These organic acids mainly originate from carbohydrate fermentation (vide infra), which is most

prominent in the proximal colon, thereby explaining the acidic intraluminal mean pH of 5.6 in this

part of the colon. The pH then gradually increases along the length of the colon, reaching a mean pH

of 6.6 at the distal part of the colon. Finally, a significant net potassium secretion occurs in the colon

via several apical potassium channels with a total fecal potassium excretion averaging 10-15 mmol/d

(15,16).

The large intestine provides an important reservoir for a microbial community, which is complex and

diverse, biochemically very active, and interacts with its host (17,18). The colonic microbiome has a

clear role in the development and modulation of the human gut immune system (19). In addition, a

number of vitamins are partly derived from the colonic microbial flora: vitamin K, nicotinic acid,

folate, pyridoxine, vitamin B12 and thiamine (15). Furthermore, it has become clear that the colon is

responsible for salvaging energy and nitrogen from carbohydrate and protein not digested in the

upper gastrointestinal tract, a process known as fermentation. Colonic bacterial species can roughly

be categorized as saccharolytic (i.e., those that predominantly ferment carbohydrates) or proteolytic

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(i.e., those that are predominantly protein fermenters). In general, carbohydrate fermentation is

considered beneficial to the host, mainly by production of short-chain fatty acids (20,21). Butyrate,

for example, is a major energy source for the colonic epithelium (22). Protein fermentation

(putrefaction), on the other hand, leads to a variety of end-products including short- or branched-

chain fatty acids, and other co-metabolites, some of which are potentially toxic such as ammonia,

amines, thiols, phenols, and indoles (23,24). It is generally accepted that the most important

regulator of bacterial metabolism, besides colonic transit time, is nutrient availability and especially

the ratio of available carbohydrate to nitrogen (25,26). In case of carbohydrate excess, the

fermentation process shifts towards lower production of amino acid metabolites through three

different mechanisms. Firstly, as carbohydrate fermentation results in a decrease of the intraluminal

pH through production of short-chain fatty acids, large intestinal protease activity will decrease

resulting in a lower availability of amino acids (27). Secondly, bacterial amino acid metabolism is

decreased through the so-called “catabolite repression” (27,28). This implies that, in the presence of

fermentable carbohydrates, the expression of genes involved in bacterial metabolism of amino acids

is suppressed. Finally, fermentation of carbohydrates provides energy to the microflora, thereby

increasing incorporation of α-amino nitrogen, provided to the large intestine by protein escaping

digestion in the upper gut and from blood urea that has diffused into intestinal contents (i.e., urea

recycling into the bacteria), into the expanding bacterial biomass (29,30). Conversely, in case of

carbohydrate deprivation, nitrogen will be predominantly fermented, thereby increasing the

production of potentially toxic co-metabolites (25). These waste products are largely absorbed,

metabolized and subsequently excreted by the kidneys, at least partly through renal tubular

secretion (31).

THE COLON IN CHRONIC KIDNEY DISEASE

The kidneys play an important role in preserving the “milieu intérieur”. As the number of nephrons

declines, compensatory hormonal and non-hormonal mechanisms are activated to maintain

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homeostasis of electrolytes and minerals, and to limit the accumulation of waste products. These

mechanisms not only involve the kidneys but also the colon. It is noticed that many patients with

progressive CKD remain normokalemic despite a deteriorating excretory renal function (32). This

observation is only partly explained by an adaptive increase in renal tubular potassium excretion,

because urinary potassium losses still are substantially lower than in healthy individuals, even after

adjustment for potassium intake (32,33). It has long been known that fecal potassium losses in

patients with CKD are elevated, suggesting either decreased intestinal absorption or increased

secretion (33,34). Subsequent animal studies pointed to increased colonic potassium secretion in

CKD (35,36). The mechanisms involved include an increased sodium/potassium ATPase-mediated

potassium uptake at the basolateral membrane, a secondary rise in intracellular potassium

concentration, and an increase in apical membrane permeability for potassium (32,37,38), likely

reflecting an increased expression of cAMP-regulated apical BK channels (32,39). Literature data

suggest that aldosterone at least partly mediate the increased colonic potassium secretion (40-42).

Whether the colon also plays a role in the maintenance of phosphate homeostasis is unknown. It is

well established that in normal circumstances most of dietary phosphate is absorbed in the small

intestine (43). Nonetheless, the observation that phosphate enemas induce severe

hyperphosphatemia unequivocally demonstrates the colonic capacity to absorb phosphate (44,45).

Available evidence indicates that phosphate transport across the colonic epithelium is passive and

paracellular (45), and therefore electrochemical gradient-driven. Data on free phosphate

concentrations in colonic contents are non-existing. Therefore, it is not known whether under

physiological conditions the electrochemical gradient favors absorption or secretion. From a

theoretical point of view, CKD-related hyperphosphatemia may be hypothesized to push the balance

toward secretion.

Furthermore, there also are colon-related adaptive mechanisms in oxalate homeostasis in CKD. As

oxalate is accumulating in the face of a declining renal function, reversal of the normal colonic

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absorptive state to a net secretory state has been observed (46). The exact mechanism behind this

phenomenon is largely unknown, although cAMP might herein also be a relevant mediator (47).

Like other disease states, including obesity (48) and inflammatory bowel disease (49), CKD goes along

with a distinct gut microbiome (50). Decreases of both the Lactobacillaceae and Prevotellaceae

families are most remarkably. Dietary restrictions and drug therapy (e.g., phosphate binders,

frequent antibiotic use) may at least partly account for this change in gut microbiome. Hemodialysis

patients, as compared with control subjects, consume significantly less dietary fiber, an important

source of fermentable carbohydrates in the colon (51). This low dietary fiber intake most probably

reflects restricted ingestion of fruits and vegetables. It should however be of note that changes in the

gut microbiome were also observed in a uremic rat model without dietary restrictions, suggesting

that uremia per se also has an impact (50). Clinical evidence furthermore suggests that protein

assimilation in the small intestine is impaired (52). As a consequence, an increased amount of dietary

protein will become available in the colon. The decreased ratio of available carbohydrate to protein

(α-amino nitrogen) in the large intestine may favor a shift from a saccharolytic to a proteolytic

fermentation pattern. This shift is accentuated by high ammonia concentrations resulting from

bacteria-mediated hydrolysis of urea. High levels of ammonia are responsible for elevated pH and

foster overgrowth of proteolytic species. In addition, colonic transit time is significantly prolonged in

CKD (53,54). As a consequence, a larger part of the colon becomes carbohydrate deprived which in

turn will induce an upstream expansion of proteolytic species (24).

Besides a different gut microbiome, uremia might also impair the intestinal barrier function with an

increase in intestinal permeability (55-58). Putative mechanisms include disruption of the colonic

epithelial tight-junction apparatus (59) and presence of subclinical chronic inflammation along the

intestinal tract (60). Other contributing factors are intestinal mucosal ischemia due to splanchnic

hypoperfusion (especially during hemodialysis treatment) and venous congestion due to heart failure

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(61,62). Dysfunction of the intestinal barrier in CKD is associated with bacterial translocation and

endotoxemia, which is related to systemic inflammation, malnutrition, cardiovascular disease, and

possibly reduced survival (56,58,59,63,64).

The large intestine is increasingly recognized to be a relevant source of uremic retention solutes in

CKD (10) (Figure 1). Important prototypes of uremic retention solutes originating from colonic

bacterial metabolism include p-cresyl sulfate and indoxyl sulfate (10). p-Cresyl sulfate is the end-

product of the combined actions of bacterial fermentation of tyrosine to p-cresol and endogenous

sulfate conjugation. Likewise, indoxyl sulfate is the end-product of bacterial fermentation of the

amino acid tryptophan to indole followed by endogenous oxidation and sulfate conjugation (65).

Observational studies in patients at various stages of CKD linked both p-cresyl sulfate and indoxyl

sulfate to overall mortality (66-68), cardiovascular disease (69,70) and CKD progression (71). Further

mechanistic studies demonstrated uremic concentrations of p-cresyl sulfate and indoxyl sulfate to

elicit oxidative stress (72,73), to induce endothelial dysfunction (74-76) and cardiac remodeling (77),

and to accelerate CKD progression (78,79). Both p-cresyl sulfate and indoxyl sulfate are highly

protein-bound, which explains their limited removal by conventional dialysis techniques (80). Besides

renal retention, increased colonic generation most probably contributes to the high circulating levels

of these co-metabolites (up to 10 fold increase) in CKD. Indeed, 24h urinary excretion rates of p-

cresol (as a surrogate for 24h colonic generation rates) were found to be significantly higher in

subjects with glomerular filtration rate < 60 ml/min per 1.73m² than in those with glomerular

filtration rate ≥ 60 ml/min per 1.73m² (52). This observation supports the thesis that CKD favors a

proteolytic fermentation pattern, as outlined above. Finally, it should be of note that the survival

time of anephric, germ-free rats is nearly twice that of conventionally raised rats (81)

THE COLON AS THERAPEUTIC TARGET IN CHRONIC KIDNEY DISEASE

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The role of the colon in the homeostasis of electrolytes and minerals, and in the clearance of waste

products is limited in patients with normal renal function, but gains importance as renal function

declines.

In the following section, current evidence with regard to therapeutic interventions targeting the

colon in CKD is summarized.

Potassium

Hyperkalemia remains a frequent and life-threatening complication in patients receiving

hemodialysis. It is estimated that more than 10 % of dialysis patients are facing higher than normal

potassium values, conferring an increased mortality risk (82). Since cAMP-regulated apical BK

channels regulate colonic potassium secretion (32,39), drugs increasing colonic cAMP expression

such as the laxative bisacodyl might prove useful when renal excretion becomes deficient. In a study

by Mathialahan et al., bisacodyl (titrated according desirable stool frequency) was administered to 8

control subjects and 13 hemodialysis patients (83). After 2 weeks of treatment, bisacodyl significantly

decreased the mean interdialytic serum potassium concentration (0.4 ± 0.1 mmol/l) in hemodialysis

patients, but no effect was observed in control subjects. Treatment with lactulose, on the other

hand, had no effect on the serum potassium concentration, making a solvent drag effect due to

laxatives less plausible. Thus, bisacodyl might be a valuable adjuvant treatment option for

hyperkalemia, but larger and longer-term studies are required to confirm these finding.

Given the putative role of aldosterone as an activator of colonic potassium secretion (40,41),

aldosterone agonists, e.g., fludrocortisone, may also be considered a valuable option(84-88). Nyman

et al., treating symptomatic hypotension in 5 anuric dialysis patients with fludrocortisone for 3 to 9

months (85), noted a decrease in serum potassium from 4.7 to 4.0 mmol/l. This finding was also

reported by Singhal et al. (86); they observed a similar decrease in patients treated with 0.1 - 0.3

mg/d fludrocortisone for 3 to 6 months. A note of caution is, however, warranted, as a recent study

in oligo- to anuric hemodialysis patients demonstrated a survival benefit with mineralocorticoid

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receptor antagonist spironolactone (89). The long-term effects of fludrocortisone on clinical

outcomes have not been studied to date.

Finally, polystyrene sulfonate potassium binding resins, already reported in 1961 (90), remains a

valuable and efficient treatment option for hyperkalemia (91). Recent case reports of colon necrosis

complicating the use of this resin warrant caution (92,93). Treatment, however, should be considered

safe when precautions are taken into account. These include the avoidance of high-sorbitol mixtures

(max. 33 % sorbitol), and exclusion of patients with functional and structural intestinal abnormalities

(91).

Phosphate

Hyperphosphatemia is a common complication in patients with advanced CKD with up to 52 % of

dialysis patients having serum phosphate levels > 5.5 mg/dl (94). As hyperphosphatemia is associated

with cardiovascular disease (95) and mortality (96), therapeutic interventions seem mandatory.

Dietary phosphate restriction is usually insufficient to maintain phosphate levels within the normal

range and up to 90 % of dialysis patients need treatment with phosphate binders (97). Hereby,

increasing amounts of phosphate are disposed in the colon as calcium phosphate, lanthanum

phosphate or bound to resins. Remarkably little is known about the fate of this complexed phosphate

in the colon. Equally little is known about the role of the microbiome in overall phosphate

homeostasis. Theoretically, the microbiome may lower the phosphate exposure to the host either by

lowering the colonic bioavailability (98) or by storing phosphate in the bacterial biomass as

polyphosphate (99). Bacteria use inorganic phosphate as the preferred phosphate source. When

inorganic phosphate is available in excess, it is taken up by the inorganic phosphate transport (Pit)

system that is constitutively expressed in the bacterial cell membranes (100). It should be of note

that colonic bacteria, as opposed to human metabolism, possess phytase and thus can release

phosphate from phytate containing nutrients such as plants. Suppressing microbial phytase activity

may be another theoretical tool to lower the phosphate exposure. Of interest, leavened bread (i.e.,

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must breads) have a higher phosphate bioavailability than unleavened products as yeast is also

capable of hydrolyzing phytate (101).

Oxalate

Massive oxalate retention is rather uncommon in dialysis patients, except in primary hyperoxaluria

(102). Dialysis patients with secondary hyperoxaluria exhibited approximately fivefold increases in

oxalate levels (103), but clinically relevant secondary oxalosis is rarely seen with current dialysis

techniques due to its relatively easy dialytic removal. Of note, calcium-oxalate nephrocalcinosis is a

frequent finding in the early post-transplant period and is related to oxalate accumulation during

dialysis. Preliminary evidence suggest that calcium-oxalate nephrocalcinosis may compromise graft

survival (104,105). Thus, oxalate accumulation in dialysis patients, and especially those listed for

transplantation, might be more relevant than currently acknowledged. In normal circumstances,

intestinal (i.e., exogenous) oxalate uptake is not important (106). Nonetheless, certain disease states,

e.g., inflammatory bowel disease and malabsorption following anti-obesity surgery, are associated

with a significant increase in intestinal (i.e., colonic) oxalate absorption, also known as enteric or

secondary hyperoxaluria (107-109). One way to reduce intestinal absorption is to decrease dietary

intake, but formal advice about dietary restrictions is challenging (106). Besides dietary intake of

oxalate itself, bioavailability also depends on co-ingested nutrients (106). For example, high dietary

calcium intake is associated with a decreased oxalate uptake due to an intraluminal calcium-oxalate

binding effect (110).

Phosphate binders are related with a diminished urinary oxalate excretion, and, not surprisingly, this

effect was most pronounced in the case of calcium-based phosphate binders (111,112). Oral

ingestion of conjugated bile acids might be another oxalate lowering treatment, certainly when

dealing with patients with steatorrhea due to bile acid malabsorption (113). Cholestyramine has also

been used to bind oxalate in the gut and to reduce its uptake, but results are not consistent

(114,115).

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Similar to potassium, active colonic oxalate secretion is cAMP-mediated (39). Therefore, upregulating

intestinal cAMP (e.g., bisacolyl) might theoretically also attenuate oxalate accumulation, but studies

evaluating this effect are lacking.

There is increasing evidence that colonic microbiota in general, and Oxalobacter formigenes more

specifically, are important in oxalate homeostasis (116,117). Higher rates of colonization with

Oxalobacter formigenes are associated with a reduced prevalence of oxalate stones in the general

population (117). It is hypothesized that Oxalobacter formigenes not only degrades ingested oxalate,

but also triggers colonic secretion (118), which is possibly mediated by an anion exchanger (putative

anion transporter-1) (119). Oxalobacter formigenes therapy normalizes serum oxalate levels in an

animal model of primary hyperoxaluria (120). Human studies, however, show mixed results, possibly

due to small sample size. In a clinical intervention study, Oxalobacter formigenes-containing capsules

induced a > 35 % decrease (range 38.5 – 92 %) in urinary oxalate excretion in 4 out of 6 patients after

1 month (121). A substantial serum oxalate lowering effect was also observed in 2 infants with

primary hyperoxaluria (122). Although encouraging, these finding were not confirmed in a

randomized controlled trial including 19 patients with primary hyperoxaluria (123). The exact role of

Oxalobacter formigenes therefore remains uncertain. Larger studies, also including patients with

enteric hyperoxaluria, are needed to establish the added value of Oxalobacter formigenes

administration.

Besides Oxalobacter formigenes, probiotics mainly containing lactobacilli have been evaluated in the

treatment of hyperoxaluria (124-126). Results are, however, discordant, either due to differences in

lactobacilli strains or case-mix.

Uremic retention metabolites originating from bacterial protein fermentation

p-Cresyl sulfate and indoxyl sulfate are the most extensively studied colon-derived uremic retention

solutes. Both are related to overall mortality (66-68) and cardiovascular disease (69,70). Due to their

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high protein binding, their removal with current dialysis techniques is rather limited. Interventions to

decrease the intestinal production and/or absorption may be an appealing alternative (Figure 1).

Interventions targeting intestinal production

The generation of toxic microbial co-metabolites can be modulated by selectively increasing

saccharolytic and reducing proteolytic bacteria in the colon.

Probiotics

Probiotics have been defined as “viable organisms that, when ingested in sufficient amounts, exert

positive health effects” (127). Although numerous studies have evaluated the effects of probiotics,

only a limited number have looked at their effects in renal disease, studying intermediate end-points,

e.g., change in serum concentrations or urinary excretion of marker molecules (124,126,128-131)

(Table 1). Studies investigating the impact of probiotics on hard clinical end-points (e.g.,

cardiovascular events, mortality) in renal disease have not been conducted to date.

Antibiotics

The composition of the colonic microbiome can be influenced by antibiotic therapy. Experience

herein is mainly limited to patients with liver failure where therapy with rifaxamin appeared

successful in preventing relapses of hepatic encephalopathy (132). Preliminary own data suggest that

broad spectrum antibiotics lower p-cresol serum levels in maintenance peritoneal dialysis patients

(unpublished). An ongoing prospective clinical trial aims to confirm these findings (ClinicalTrials.gov

ID: NCT00433342).

Prebiotics

Another approach to reduce generation of bacterial metabolites is to increase the ratio of available

carbohydrate to nitrogen, which, as outlined previously, is an important regulator of bacterial α-

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amino nitrogen metabolism (25,26). The term prebiotic, first coined by Gibson and Roberfroid, refers

to “a non-digestible food ingredient that beneficially affects the host by selectively stimulating the

growth and/or activity of one or a limited number of bacteria in the colon, and thus improves host

health” (127). Whereas numerous compounds are known to escape digestion in the small intestine, a

limited number of molecules result in selective stimulation of microbiota. At present, only

bifidogenic, non-digestible oligo- and polysaccharides (particularly inulin, its hydrolysis product

oligofructose, and (trans)galacto-oligosaccharides) fulfill all the criteria for prebiotic classification

(133). In a study of 9 patients with CKD but not yet on dialysis, it was found that fermentable

carbohydrates shifted nitrogen excretion from the urinary route to fecal excretion, thereby reducing

plasma urea concentrations (134). Whether this resulted in a decreased generation of other uremic

retention solutes was not studied. A study in healthy volunteers has demonstrated lowering of

urinary p-cresol excretion by the ingestion of a 50/50 v/v mixture of inulin and fructo-

oligosaccharides (135). A recent phase I/II trial confirmed that p-cresol generation and p-cresyl

sulfate serum concentrations were also lowered in hemodialysis patients by this prebiotic (136).

Wheat bran extract, a food-grade preparation highly enriched in arabinoxylan oligosaccharides, is

another prebiotic which has been shown to reduce urinary p-cresol excretion in healthy volunteers

(137). A pilot study, investigating its benefits in CKD, will be initiated in the near future.

Dietary fiber

Fruit and vegetables are important sources of dietary fibers (i.e., non-digestible carbohydrates), and

it was demonstrated that a vegetarian diet reduced urinary excretion of indoxyl sulfate and p-cresyl

sulfate (138). Nonetheless, fruit and vegetables are often restricted in CKD because of their high

potassium content. Limiting protein intake might also reduce generation of bacterial waste products,

but its feasibility is questionable as it confers a risk of malnutrition.

Drug therapy

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An alternative method to increase delivery of fermentable carbohydrate to the colon is to inhibit

small intestine assimilation by means of α-glucosidase inhibitors such as acarbose. This was already

evaluated in healthy volunteers, showing significantly lower serum concentrations of p-cresol and the

24h urinary excretion of p-cresol (as a surrogate for colonic generation rate) (139). An intervention

study looking at the effects of acarbose in patients with CKD is ongoing.

Theoretically, the colonic transit time might be another therapeutic target. As colonic transit time is

significantly prolonged in CKD (53), it could be hypothesized that selectively accelerating the colonic

transit might be of benefit. Decreasing its transit time, e.g. by laxatives, might result in less time for

bacterial proliferation, and less generation and absorption of their toxic waste products.

Adsorptive strategies

Therapeutic interventions may also reduce intestinal absorption through intraluminal adsorption

onto high-affinity surfaces. AST-120 (Kremezin®, Kureha Chemical Industry) is an orally administered

adsorbent consisting of spherical carbon particles 0.2–0.4 mm in diameter (140). It is capable of

adsorbing significant amounts of various organic compounds in the large intestine, including indoxyl

sulfate (141,142), p-cresol (143), and food-derived advanced glycation end-products (144). It has

been shown to retard the progression of renal failure in Japanese patients with mild-to-moderate

CKD (145,146). A phase II dose-finding study in US patients with CKD confirmed a dose-dependent

reduction in indoxyl sulfate serum concentrations (142). A large, multicenter randomized trial is

currently testing whether AST-120 can slow the progression of CKD (Evaluating Prevention of

Progression In Chronic Kidney Disease (EPPIC-1/2); ClinicalTrials.gov ID:

NCT00500682/NCT00501046). Preliminary results, however, appeared rather disappointing with no

proven efficacy of AST-120, although subgroup analysis suggested that AST-120 may have its value in

patients with acceptable compliance and risk factors of progression of CKD (147). Further studies are

thus needed to clarify the role and benefit of AST-120 in CKD. Sevelamer hydrochloride (Renagel®,

Genzyme), a non-metal-based phosphate binder, is another potentially useful adsorbent therapy. In

15

addition to phosphate binding, it has been shown to bind uremic retention solutes in vitro, including

indole (10–15 %) and p-cresol (40–50 %, dependent on pH) (148). Despite this observation,

sevelamer did not result in decreased serum concentrations of indoxyl sulfate or p-cresol, neither in a

mouse model of CKD (149), nor in hemodialysis patients (150).

CONCLUSION

As is shown, a clear bi-directional interplay exists between the large intestine and the kidney. Many

of these interactions are at least partly mediated by the colonic microbiome. The large intestine plays

an ambiguous role in CKD. On the one hand, the colon contributes to the homeostasis of potassium

and the disposal of nitrogenous waste products and oxalate, but on the other hand, the large

intestine is an important source of uremic toxins. Parallel to the increased awareness of the

importance of the host-microbiome interaction, therapies targeting the colon will undoubtedly gain

interest in CKD and beyond.

ACKNOWLEDGEMENTS

RP is recipient of a Ph.D. fellowship of the Research Foundation - Flanders (FWO) (grant 11E9813N)

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FIGURES

Figure 1: The colon as a source of uremic retention solutes: pathophysiology and therapeutic targets

Colonic microbial metabolism can be roughly categorized as saccharolytic (carbohydrate

fermentation, e.g., Prevotella) or proteolytic (protein fermentation, e.g., Bacteroides). Carbohydrate

and protein fermentation predominate in the right and left colon, respectively. Saccharolytic

metabolism is considered beneficial with generation of short-chain fatty acids, whereas proteolytic

metabolism may generate toxic solutes such as p-cresol and indole. Colon-related therapies

targeting these solutes can be divided in those modulating the microbiome, microbial metabolism

and adsorption. (SCFA’s: Short-chain fatty acids; CHO: Carbohydrate)

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TABLES

Table 1: Studies with probiotic preparations in kidney disease

Study Primary end-point n Strain ResultHida et al.(128) Indoxyl sulfate

p-Cresol20 Lactic acid bacilli (Lebenin) ─30% serum indoxyl sulfate

No change serum p-cresolCampieri et al.(129) Urinary oxalate excretion 6 Lactic acid bacilli ─40% Urinary oxalate excretionLieske et al.(124) Urinary oxalate excretion 10 Lactic acid bacilli (Oxadrop) ─19% Urinary oxalate excretionGoldfarb et al.(126) Urinary oxalate excretion 10a Lactic acid bacilli (Oxadrop) No significant changesTakayama et al.(130).

Indoxyl sulfate 11 Bifidobacterium longum (Bifina)

─30% serum indoxyl sulfate

Taki et al.(131) Indoxyl sulfateHomocysteine

27 Bifidobacterium longum (Bifina)

─9% serum indoxyl sulfate─9% plasma homocysteine

n, number of patients in active treatment armaRandomized controlled trial

29