Colonic Contribution to Uremic Solutes

Aronov, Pavel A.; Luo, Frank J.-G.; Plummer, Natalie S.; Quan, Zhe; Holmes, Susan; Hostetter, Thomas H.; Meyer, Timothy W.

doi:10.1681/asn.2010121220

Cited by 354 publications

(320 citation statements)

References 33 publications

(38 reference statements)

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“…In the original study, follow-up was available until December 1,2008. For this study, follow-up was extended until December 31, 2010.…”

Section: Outcome Analysesmentioning

confidence: 99%

“…There has been mounting evidence that the colonic microbial metabolism contributes substantially to uremic retention solutes accumulating in patients with CKD (1,2). p-Cresyl sulfate (PCS) can be considered representative of this group of solutes and has been associated with overall mortality, cardiovascular disease, and progression of CKD (3)(4)(5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

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

Poesen

Evenepoel

Loor

et al. 2016

CJASN

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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.

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“…In the original study, follow-up was available until December 1,2008. For this study, follow-up was extended until December 31, 2010.…”

Section: Outcome Analysesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Poesen

Evenepoel

Loor

et al. 2016

CJASN

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“…More recently, scientific and technological progress resulted in the identification of many new uremic retention solutes, particularly thanks to nontargeted approaches such as metabolomic and proteomic profiling. 4,5 To maintain experimental guidelines in keeping with current knowledge, it seemed necessary to propose an update of the encyclopedic review. 1 It was decided to study the publications from after the first review and compare results with previous findings.…”

mentioning

confidence: 99%

Normal and Pathologic Concentrations of Uremic Toxins

Duranton¹,

Cohen

Smet

et al. 2012

Journal of the American Society of Nephrology

803

764

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An updated review of the existing knowledge regarding uremic toxins facilitates the design of experimental studies. We performed a literature search and found 621 articles about uremic toxicity published after a 2003 review of this topic. Eighty-seven records provided serum or blood measurements of one or more solutes in patients with CKD. These records described 32 previously known uremic toxins and 56 newly reported solutes. The articles most frequently reported concentrations of b2-microglobulin, indoxyl sulfate, homocysteine, uric acid, and parathyroid hormone. We found most solutes (59%) in only one report. Compared with previous results, more recent articles reported higher uremic concentrations of many solutes, including carboxymethyllysine, cystatin C, and parathyroid hormone. However, five solutes had uremic concentrations less than 10% of the originally reported values. Furthermore, the uremic concentrations of four solutes did not exceed their respective normal concentrations, although they had been previously described as uremic retention solutes. In summary, this review extends the classification of uremic retention solutes and their normal and uremic concentrations, and it should aid the design of experiments to study the biologic effects of these solutes in CKD. The uremic syndrome is characterized by the retention of various solutes that would normally be excreted by the kidneys. The substances that interact negatively with biologic functions are called uremic toxins. In the past years, research on uremic toxicity has been very dynamic and resulted in the identification of dozens of retention solutes, including several uremic toxins. In 2003, the European Uremic Toxin Work Group (http://www.uremic-toxins.org/) proposed a classification of 90 retention solutes providing data on normal and pathologic serum concentrations. 1 In 2007, results were further discussed and expanded with the addition of 14 solutes. 2,3 This collaborative work focused on the highest mean or median concentration of the solutes measured in a uremic population and the highest individual uremic concentration. These data were particularly relevant for researchers on uremic toxicity, and they became a successful tool for allowing use of standardized and biologically relevant concentrations in experimental settings. More recently, scientific and technological progress resulted in the identification of many new uremic retention solutes, particularly thanks to nontargeted approaches such as metabolomic and proteomic profiling. 4,5 To maintain experimental guidelines in keeping with current knowledge, it seemed necessary to propose an update of the encyclopedic review.

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“…The CKD-induced changes in the composition and function of the gut microbiota represent a dysbiotic state that has adverse consequences. For example, increased generation of toxic solutes (e.g., indoxyl sulfate [IS], p-cresol sulfate [PCS], and trimethylamine-N-oxide) and diminished production of beneficial micronutrients may contribute to systemic inflammation, CKD progression, and cardiovascular complications (8,9).…”

mentioning

confidence: 99%

Effect of Synbiotic Therapy on Gut–Derived Uremic Toxins and the Intestinal Microbiome in Patients with CKD

Vaziri¹

2016

Clinical Journal of the American Society of Nephrology

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Colonic Contribution to Uremic Solutes

Cited by 354 publications

References 33 publications

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

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

Normal and Pathologic Concentrations of Uremic Toxins

Effect of Synbiotic Therapy on Gut–Derived Uremic Toxins and the Intestinal Microbiome in Patients with CKD

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