Renal Clearance and Intestinal Generation of p-Cresyl Sulfate and Indoxyl Sulfate in CKD

Poesen, Ruben; Viaene, Liesbeth; Verbeke, Kristin; Claes, Kathleen; Bammens, Bert; Sprangers, Ben; Naesens, Maarten; Vanrenterghem, Yves; Evenepoel, Pieter; Meijers, Björn

doi:10.2215/cjn.00300113

Cited by 96 publications

(89 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indole and p-cresol, the precursors of indoxyl sulfate and p-cresol sulfate, are thought to be produced by different microbes, and prior studies have shown limited correlation between the generation rates of indoxyl sulfate and p-cresol sulfate both in healthy participants and hemodialysis patients (31,32). We found, however, that the changes in indoxyl sulfate and p-cresol sulfate in response to dietary fiber were closely related, as depicted in Figure 2.…”

Section: Discussionmentioning

confidence: 54%

Effect of Increasing Dietary Fiber on Plasma Levels of Colon-Derived Solutes in Hemodialysis Patients

Sirich

Plummer

Gardner

et al. 2014

Clinical Journal of the American Society of Nephrology

256

227

View full text Add to dashboard Cite

Background and objectives Numerous uremic solutes are derived from the action of colon microbes. Two such solutes, indoxyl sulfate and p-cresol sulfate, have been associated with adverse outcomes in renal failure. This study tested whether increasing dietary fiber in the form of resistant starch would lower the plasma levels of these solutes in patients on hemodialysis.Design, setting, participants, & measurements Fifty-six patients on maintenance hemodialysis were randomly assigned to receive supplements containing resistant starch (n=28) or control starch (n=28) daily for 6 weeks in a study conducted between October 2010 and May 2013. Of these, 40 patients (20 in each group) completed the study and were included in the final analysis. Plasma indoxyl sulfate and p-cresol sulfate levels were measured at baseline and week 6.Results Increasing dietary fiber for 6 weeks significantly reduced the unbound, free plasma level of indoxyl sulfate (median 229% [25th percentile, 75th percentile, 256, 212] for fiber versus 20.4% [220,34] for control, P=0.02). The reduction in free plasma levels of indoxyl sulfate was accompanied by a reduction in free plasma levels of p-cresol sulfate (r=0.81, P,0.001). However, the reduction of p-cresol sulfate levels was of lesser magnitude and did not achieve significance (median 228% [246,5] for fiber versus 4% [228,36] for control, P=0.05).Conclusions Increasing dietary fiber in hemodialysis patients may reduce the plasma levels of the colon-derived solutes indoxyl sulfate and possibly p-cresol sulfate without the need to intensify dialysis treatments. Further studies are required to determine whether such reduction provides clinical benefits.

show abstract

Section: Discussionmentioning

confidence: 54%

Effect of Increasing Dietary Fiber on Plasma Levels of Colon-Derived Solutes in Hemodialysis Patients

Sirich

Plummer

Gardner

et al. 2014

Clinical Journal of the American Society of Nephrology

256

227

View full text Add to dashboard Cite

show abstract

“…19 Because these two solutes are less well cleared than HA and CMG 25 and because their excretion variability correlates strongly with filtration, they may not represent independent secretory solutes, despite having somewhat more a priori information regarding their primary transporters. 18,26,27 They may also be subject to a high degree of protein binding, reducing availability for proximal tubule transport and thereby, possibly leading to measurement error in solute clearance.…”

Section: Discussionmentioning

confidence: 99%

Tubular Secretion in CKD

Suchy‐Dicey¹,

Laha²,

Hoofnagle³

et al. 2015

JASN

View full text Add to dashboard Cite

Renal function generally is assessed by measurement of GFR and urinary albumin excretion. Other intrinsic kidney functions, such as proximal tubular secretion, typically are not quantified. Tubular secretion of solutes is more efficient than glomerular filtration and a major mechanism for renal drug elimination, suggesting important clinical consequences of secretion dysfunction. Measuring tubular secretion as an independent marker of kidney function may provide insight into kidney disease etiology and improve prediction of adverse outcomes. We estimated secretion function by measuring secreted solute (hippurate, cinnamoylglycine, p-cresol sulfate, and indoxyl sulfate) clearance using liquid chromatography-tandem mass spectrometric assays of serum and timed urine samples in a prospective cohort study of 298 patients with kidney disease. We estimated GFR by mean clearance of creatinine and urea from the same samples and evaluated associations of renal secretion with participant characteristics, mortality, and CKD progression to dialysis. Tubular secretion rate modestly correlated with eGFR and associated with some participant characteristics, notably fractional excretion of electrolytes. Low clearance of hippurate or p-cresol sulfate associated with greater risk of death independent of eGFR (hazard ratio, 2.3; 95% confidence interval, 1.1 to 4.7; hazard ratio, 2.5; 95% confidence interval, 1.0 to 6.1, respectively). Hazards models also suggested an association between low cinnamoylglycine clearance and risk of dialysis, but statistical analyses did not exclude the null hypothesis. Therefore, estimates of proximal tubular secretion function correlate with glomerular filtration, but substantial variability in net secretion remains. The observed associations of net secretion with mortality and progression of CKD require confirmation.

show abstract

“…Although it can be hypothesized that this imbalance is caused by differences in phase 2 metabolism, possibly influenced by renal dysfunction, this has not been studied to date. Furthermore, renal handling of PCG is unknown but may be different compared with PCS, which mainly depends on tubular secretion (13)(14)(15)(16). In addition, although it is well established that serum PCS is highly protein bound (17,18), protein binding characteristics of serum PCG are less clear, possibly contributing to differential renal clearance of PCS and PCG.…”

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Renal Clearance and Intestinal Generation of p-Cresyl Sulfate and Indoxyl Sulfate in CKD

Cited by 96 publications

References 27 publications

Effect of Increasing Dietary Fiber on Plasma Levels of Colon-Derived Solutes in Hemodialysis Patients

Effect of Increasing Dietary Fiber on Plasma Levels of Colon-Derived Solutes in Hemodialysis Patients

Tubular Secretion in CKD

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

Contact Info

Product

Resources

About