Colonic microbial metabolism substantially contributes to uremic solute production. p -Cresyl sulfate and indoxyl sulfate are the main representatives of solutes of microbial origin and also, protein-bound solutes, exhibiting high protein-binding affinity and dependence on tubular secretion. Phenylacetylglutamine is another microbial metabolite with high dependence on tubular secretion but low protein-binding affinity. The relevance of such solutes is unknown. Therefore, we prospectively followed 488 patients with CKD stages 1–5 and a measurement of serum phenylacetylglutamine by liquid chromatography-mass spectrometry. In a subgroup, we determined 24-hour urinary excretion as a surrogate of intestinal uptake as well as renal clearance of phenylacetylglutamine. We performed outcome analysis for mortality (51 events) and cardiovascular disease (75 events). Serum phenylacetylglutamine level correlated with 24-hour urinary excretion (rho=0.55; P <0.001) and clearance of phenylacetylglutamine (rho=−0.76; P <0.001). Phenylacetylglutamine clearance also correlated with eGFR (rho=0.84; P <0.001). Furthermore, serum phenylacetylglutamine level associated with mortality (hazard ratio per 1-SD increase, 1.77; 95% confidence interval, 1.22 to 2.57; P =0.003) and cardiovascular disease (hazard ratio, 1.79; 95% confidence interval, 1.32 to 2.41; P <0.001) after adjustment for age, sex, presence of diabetes mellitus, prior cardiovascular disease, and eGFR. Thus, serum phenylacetylglutamine level is elevated in patients with more advanced CKD and determined by intestinal uptake and renal clearance, and it is not fully accounted for by differences in eGFR. High serum phenylacetylglutamine level is a strong and independent risk factor for mortality and cardiovascular disease, suggesting the relevance of microbial metabolism and/or tubular dysfunction in CKD, irrespective of protein binding.

10.1681/asn.2015121302

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The Colon: An Overlooked Site for Therapeutics in Dialysis Patients

Seminars in Dialysis (2013)

Ruben Poesen Björn Meijers Pieter Evenepoel

Abstract Morbidity and mortality related to chronic kidney disease remain unacceptably 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., O xalobacter formigenes ).

Uremia

10.1111/sdi.12082

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Hemolytic anemia associated with severe hypophosphatemia in a renal transplant recipient

Transplant International (2011)

Ruben Poesen Daan Dierickx P. Evenepoel

Hypophosphatemia

Nephrology

Transplant surgery

10.1111/j.1432-2277.2011.01393.x

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Metabolism, Protein Binding, and Renal Clearance of Microbiota–Derived p-Cresol in Patients with CKD

Clinical Journal of the American Society of Nephrology (2016)

Ruben Poesen Pieter Evenepoel Henriëtte de Loor Dirk Kuypers Patrick Augustijns

Background and objectives Colonic microbial metabolism substantially contributes to uremic retention solutes in CKD. p -Cresyl sulfate is the main representative of this group of solutes, relating to adverse outcomes. Other than sulfate conjugation, p -cresol is subjected to endogenous glucuronide conjugation. Whether the balance between sulfate and glucuronide conjugation is relevant in CKD is unexplored. Design, setting, participants, & measurements We prospectively followed 488 patients with CKD stages 1–5 (enrollment between November of 2005 and September of 2006; follow-up until December of 2010). Serum and urine levels of p -cresyl sulfate and p -cresyl glucuronide were measured using liquid chromatography-mass spectrometry. Total amount of microbial p -cresol was calculated by the sum of serum p –cresyl sulfate and p -cresyl glucuronide. Outcome analysis was performed for mortality and cardiovascular disease. Results Serum p –cresyl sulfate was a median of 193.0-fold (interquartile range, 121.1–296.6) higher than serum p –cresyl glucuronide, with a significant correlation between eGFR and proportion of serum p –cresyl sulfate to glucuronide (rho=0.23; P =0.001). There was also a significant correlation between eGFR and proportion of 24-hour urinary excretion of p -cresyl sulfate to glucuronide (rho=0.32; P <0.001). Higher serum p –cresol and lower proportion of serum p –cresyl sulfate to glucuronide were jointly and significantly associated with mortality (hazard ratio per SD higher, 1.58; 95% confidence interval, 1.10 to 2.29; P =0.01 and hazard ratio, 0.65; 95% confidence interval, 0.47 to 0.89; P <0.01, respectively) and cardiovascular disease (hazard ratio, 1.68; 95% confidence interval, 1.27 to 2.22; P <0.001 and hazard ratio, 0.55; 95% confidence interval, 0.42 to 0.72; P <0.001, respectively) after adjustment for eGFR, Framingham risk factors, mineral bone metabolism markers, C-reactive protein, and albumin. Conclusions p -Cresol shows a preponderance of sulfate conjugation, although a relatively diminished sulfotransferase activity can be suggested in patients with advanced CKD. Along with total p –cresol burden, a relative shift from sulfate to glucuronide conjugation is independently associated with mortality and cardiovascular disease, warranting increased focus to the dynamic interplay between microbial and endogenous metabolism.

Cresyl violet

Glucuronide

10.2215/cjn.00160116

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Citations (64)