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

Abstract

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.

Microbiota-derived uremic retention solutes: perpetrators of altered nonrenal drug clearance in kidney disease

“…Therefore, competitive SULT metabolic interactions between p-cresol and acetaminophen likely facilitate acetaminophen shunting towards NAPQI formation. Alterations to SULT function may also have cardiovascular implications, since shifts from p-cresol sulfate to glucuronide conjugation are associated with cardiovascular disease and mortality [64]. …”

Uremic Solutes in Chronic Kidney Disease and Their Role in Progression

“…and Van der Kloet et al ., our patients had more advanced CKD. Other metabolic pathways may play a role as CKD progresses,[35] and therefore the effects of some solutes will only become prominent at lower levels of GFR. For example, Wu et al .…”

The cross-talk between the kidney and the gut: implications for chronic kidney disease

“…Moreover, the accumulation of these toxins in individuals with CKD has been associated with progression of CKD [12], inflammation [98,111], cardiovascular disease [11], vascular calcification [13], and mortality from cardiovascular disease and from all causes [13,14,112,113].…”

“…Intestinal barrier disruption [6,7], inflammation [8], impairment of the immune system [9], and higher generation of colon-derived uremic toxins p-cresyl sulfate (PCS) and indoxyl sulfate (IS) [10] seem to be some of the consequences of an unbalanced gut ecosystem. Furthermore, the progressive accumulation of PCS and IS has been associated with cardiovascular disease [11], progression of CKD [12], and mortality [13,14]. Thus, it is important to understand the complex interactions within and between the gut and other body systems in healthy individuals and in those with CKD.…”