Proximal tubular efflux transporters involved in renal excretion of p-cresyl sulfate and p-cresyl glucuronide: Implications for chronic kidney disease pathophysiology

Mutsaers, Henricus A M; Caetano-Pinto, Pedro; Seegers, Andries E M; Dankers, Anita C. A.; Broek, P.H.H. van den; Wetzels, Jack F.M.; Brand, Jan van den; Heuvel, Lambertus P. van den; Hoenderop, Joost G. J.; Wilmer, Martijn J.; Masereeuw, Rosalinde

doi:10.1016/j.tiv.2015.07.020

Cited by 49 publications

(39 citation statements)

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“…Furthermore, we observed a lower proportion of both serum and 24-hour urinary excretion of PCS to PCG in patients with lower eGFR, which is indicative of a relatively diminished sulfotransferase activity in patients with advanced CKD. These findings confirm and extend a previous observation of a decreased serum total PCS-to-PCG ratio in patients on maintenance hemodialysis, in whom a different dialytic clearance should be taken into account (23). In agreement, glucuronide conjugation of paracetamol was also more pronounced compared with sulfate conjugation when administered to patients with CKD, again pointing to a decrease in sulfotransferase function, especially for sulfotransferase 1A1 (24).…”

Section: Discussionsupporting

confidence: 90%

“…Although mechanisms underlying tubular secretion of PCS are increasingly being unraveled (13,14,27), less is known about renal handling of PCG. Recent data point to potential involvement of breast cancer resistance protein and multidrug resistance-associated protein 4 for tubular transport of PCG, whereas secretion of PCS may depend on multidrug resistance-associated protein 4 but not on breast cancer resistance protein (23). Differences in free renal clearance of PCS and PCG may also be derived from their binding characteristics, because it has been suggested that protein binding enhances clearance by providing a readily accessible reservoir for efficient removal of the solute throughout its passage within the native kidney (15).…”

Section: Discussionmentioning

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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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

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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“…The activities of multidrug resistance protein (MRP) 4 and BRCP elux transporters have also been demonstrated to be downregulated by PCS in vitro [63] and may be potential therapeutic targets.…”

Section: Reduced Proximal Tubular Retentionmentioning

confidence: 99%

The Roles of Indoxyl Sulphate and p-Cresyl Sulphate in Patients with Chronic Kidney Disease: A Review of Therapeutic Options

Nataatmadja¹,

Cho²,

Campbell³

et al. 2018

Chronic Kidney Disease - From Pathophysiology to Clinical Improvements

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Indoxyl sulphate (IS) and p-cresyl sulphate (PCS) are products of proteolytic bacterial fermentation by gut microbiota. They accumulate in the sera of patients with chronic kidney disease (CKD) and have been associated with CKD progression and cardiovascular and all-cause mortality. Therapeutic strategies for lowering IS and PCS include increased clearance (enhanced dialysis), gastrointestinal sequestration (oral adsorbents), reduced synthesis (dietary protein restriction, dietary ibre augmentation and pre-, pro-or synbiotics), antioxidants and organic anion transporter modulators. This review will discuss the roles of IS and PCS as therapeutic targets and examine the clinical evidence for diferent treatment options and their efects on CKD and cardiovascular disease risk. We will include our group's research with pre-, pro-and synbiotic interventions to mitigate serum uraemic toxin accumulation and modify cardiovascular and renal risk.Keywords: indoxyl sulphate, p-cresyl sulphate, uraemic toxins, chronic kidney disease, gut microbiome IntroductionThe reciprocal relationship observed between gut microbiota and chronic kidney disease (CKD) has led to the recent recognition of the 'gut-kidney axis'. Patients with CKD, including those with end-stage kidney disease (ESKD), often experience impaired uraemic toxin clearance, salt and water retention, dietary restrictions, anorexia, dysgeusia and malnutrition, © 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.which in turn leads to quantitative and qualitative alterations in gut microbiome composition (gut dysbiosis). Further efects include gut wall oedema, intestinal barrier impairment, translocation of bacteria and endotoxins across the intestinal wall and resultant systemic inlammation [1][2][3]. Gut dysbiosis may in turn lead to the production of various toxins and metabolites that contribute to uraemic toxicity, cardiovascular disease and progressive kidney scarring and failure [4][5][6]. The central role of the gut microbiome in kidney health therefore makes it an appealing therapeutic target in patients with CKD [7,8].Two key nephrovascular toxins produced by proteolytic bacterial fermentation in the gut are indoxyl sulphate (IS) and p-cresyl sulphate (PCS). IS is produced by tryptophan metabolism facilitated by Escherichia coli and Clostridium sporogenes, while PCS is generated by break down of tyrosine and phenylalanine by intestinal anaerobes, such as Clostridium diicile, Faecalibacterium prausnizii, Subdoligranulum and selected strains within the Biidobacterium and Lactobacillus genus [8]. IS and PCS are both solely produced by the gut microbiota [9][10][11][12] and accumulate in the serum of patients with CKD due to both increased intestinal production and reduced glomerular iltration and proximal tubular sec...

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“…Uremic solutes, such as hippuric acid, indole-3-acetic acid, kynurenic acid have been shown to inhibit tubular excretion by competing for organic anion uptake transporters and efflux pumps. [5, 27, 28] Therefore, elevated uremic solute plasma concentrations increase the risk of drug interactions and toxicity. Moreover, several uremic solutes contribute to epithelial-to-mesenchymal transition in the renal tubule.…”

Section: Discussionmentioning

confidence: 99%

“…[6–8] In addition, uremic solutes are substrates but also inhibitors of tubular transport proteins that are responsible for the excretion of drugs, solutes and waste products. [5, 9–16] Furthermore, uremic solutes can alter mitochondrial functioning, resulting in increased superoxide and hydroxyl radical production and increased rates of apoptosis. [17, 18] Uremic solutes have been associated with clinical outcome as well.…”

Section: Introductionmentioning

confidence: 99%

Uremic Solutes in Chronic Kidney Disease and Their Role in Progression

et al. 2016

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BackgroundTo date, over 150 possible uremic solutes have been listed, but their role in the progression of CKD is largely unknown. Here, the association between a selected panel of uremic solutes and progression in CKD patients was investigated.MethodsPatients from the MASTERPLAN study, a randomized controlled trial in CKD patients with a creatinine clearance between 20 and 70 ml/min per 1.73m2, were selected based on their rate of eGFR decline during the first five years of follow-up. They were categorized as rapid (decline >5 ml/min per year) or slow progressors. Concentrations of eleven uremic solutes were obtained at baseline and after one year of follow-up. Logistic regression was used to compare the odds for rapid to slow progression by uremic solute concentrations at baseline. Variability in uremic solute levels was assessed using scatter plots, and limits of variability were calculated.ResultsIn total, 40 rapidly and 40 slowly progressing patients were included. Uremic solutes were elevated in all patients compared to reference values for healthy persons. The serum levels of uremic solutes were not associated with rapid progression. Moreover, we observed substantial variability in solute levels over time.ConclusionsElevated concentrations of uremic solutes measured in this study did not explain differences in rate of eGFR decline in CKD patients, possibly due to lack of power as a result of the small sample size, substantial between patient variability, and variability in solute concentrations over time. The etiology of intra-individual variation in uremic solute levels remains to be elucidated.

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Proximal tubular efflux transporters involved in renal excretion of p-cresyl sulfate and p-cresyl glucuronide: Implications for chronic kidney disease pathophysiology

Cited by 49 publications

References 49 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

The Roles of Indoxyl Sulphate and p-Cresyl Sulphate in Patients with Chronic Kidney Disease: A Review of Therapeutic Options

Uremic Solutes in Chronic Kidney Disease and Their Role in Progression

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