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      Reduction in Protein-Bound Solutes Unacceptable as Marker of Dialysis Efficacy during Alternate-Night Nocturnal Hemodialysis

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          Abstract

          Background: The uremic retention solutes indoxyl sulfate and p-cresyl sulfate are linked to cardiovascular disease and overall survival. Dialytic clearances are limited, which is principally attributed to tight protein binding. Extending dialysis duration would be expected to substantially increase protein-bound uremic solute removal. The aim of the current study was to study protein-bound uremic retention solute clearances and kinetics during longer-hours nocturnal hemodialysis. Methods: In a prospective cohort study of 32 maintenance alternate-night nocturnal hemodialysis patients, we followed serum concentrations, solute removals and solute clearances of p-cresyl sulfate and indoxyl sulfate. Spent dialysate sampling was fractionated to compare solute removals between the first 4 h and next 4 h of nocturnal dialysis. Single-compartment variable volume kinetics were calculated. Results: Dialytic clearances of protein-bound uremic retention solutes are maintained during nocturnal (longer-hours) dialysis. Clearances of indoxyl sulfate exceed those of p-cresyl sulfate, presumably due to less tight protein-binding. Apparent distribution volumes increase substantially during nocturnal dialysis, indicative of multi-compartmental behavior of the protein-bound uremic retention solutes indoxyl sulfate and p-cresyl sulfate. Conclusions: During nocturnal hemodialysis, serum concentrations of protein-bound solute concentrations are reduced less than predicted. Reduction ratios are not a valid tool to estimate total solute removal of protein-bound uremic retention solutes.

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          Free serum concentrations of the protein-bound retention solute p-cresol predict mortality in hemodialysis patients.

          Pieter Evenepoel, Bert Bammens, Y Vanrenterghem … (2006)
          Based on in vitro data, protein-bound uremic retention solutes have increasingly been recognized to play a pathophysiological role in the uremic syndrome. p-Cresol, a representative of this group of molecules, has been shown to be implicated in uremic immunodeficiency and endothelial dysfunction, potentially linking its serum levels to mortality. Thus far, however, no clinical information on this issue is available. To determine the relationship between p-cresol and all-cause mortality, 175 prevalent hemodialysis (HD) patients were enrolled in a prospective study. At baseline, serum levels of the water-soluble solutes urea, creatinine, and phosphate, the middle molecule beta2-microglobulin, total and free concentrations of the protein-bound solute p-cresol, and several risk factors for mortality were evaluated. During a median follow-up of 34 months, 60 patients died. Baseline comorbidity (Davies score) (hazard ratio (HR), 1.49; 95% confidence interval (95% CI), 1.19-1.86), impaired nutritional status (HR, 4.22; 95% CI, 2.15-8.29), time since initiation of dialysis (HR, 0.98; 95% CI, 0.97-1.00), and higher free concentrations of the protein-bound solute p-cresol (HR, 2.28; 95% CI, 1.12-4.64) were independently associated with mortality (multivariate Cox proportional hazards analysis). Our data suggest that free serum levels of p-cresol, a representative of the protein-bound uremic retention solutes, are associated with mortality in HD patients. These findings may encourage nephrologists to widen their field of interest beyond the scope of small water-soluble uremic solutes and middle molecules.
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            Uremia.

            Thomas Hostetter, Timothy W. Meyer (2007)
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              Removal of P-cresol sulfate by hemodialysis.

              Thomas Hostetter, Matthew Martinez, Natalie Recht … (2005)
              Protein-bound solutes are poorly cleared by dialysis. Among the most extensively studied of these solutes is p-cresol, which has been shown to be toxic in vitro. This study examined the form in which p-cresol circulates and quantified its removal by hemodialysis. HPLC analysis of plasma from hemodialysis patients contained a peak whose mobility corresponded to synthetic p-cresol sulfate (PCS) but no detectable unconjugated p-cresol. Treatment with sulfatase resulted in recovery of this peak as p-cresol, confirming its identity. Subsequent studies compared the removal of PCS and another protein-bound solute, indican, to the removal of urea during clinical hemodialysis treatments. PCS and indican were 94 +/- 1% and 93 +/- 2% bound to plasma protein, respectively. Protein-binding caused a predictable decrease in measured dialytic clearance, which averaged 20 +/- 4 ml/min for PCS and 25 +/- 5 ml/min for indican as compared with 260 +/- 20 ml/min for urea. Volumes of distribution for the protein-bound solutes were greater than the plasma volume, averaging 15 +/- 7 L for PCS and 14 +/- 3 L for indican as compared with 37 +/- 7 for urea. Solute reduction ratios were 20 +/- 9% for PCS, 30 +/- 7% for indican, and 69 +/- 5% for urea. We conclude that p-cresol circulates in the form of its sulfate conjugate, PCS. PCS is poorly removed by hemodialysis because its clearance is limited by protein binding and the ratio of its volume of distribution to its clearance is high.
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                Author and article information

                Journal
                Journal ID (publisher-id): AJN
                Journal ID (nlm-ta): Am J Nephrol
                Journal ID (doi): 10.1159/issn.0250-8095
                Title: American Journal of Nephrology
                Publisher: S. Karger AG
                ISSN (Print): 0250-8095
                ISSN (Electronic): 1421-9670
                Publication date Subscription-year: 2011
                Publication date (Print): September 2011
                Publication date (Electronic): 23 July 2011
                Volume: 34
                Issue: 3
                Pages: 226-232
                Affiliations
                aDivision of Nephrology, Department of Medicine, and bLaboratory for Gastro-Intestinal Research and Leuven Food Science and Nutrition Research Centre, University Hospital Leuven, Leuven, Belgium; cDepartment of Nephrology, Monash Medical Centre, Clayton, Vic., Australia; dDepartment of Nephrology, Stanford University, Stanford, Calif., USA
                Author notes
                *P. Evenepoel, MD, PhD, Dienst Nefrologie, Universitair Ziekenhuis Gasthuisberg, Herestraat 49, BE–3000 Leuven (Belgium), Tel. +32 16 344 591, E-Mail pieter.evenepoel@uzleuven.be
                Article
                Publisher ID: 330176 Other ID: Am J Nephrol 2011;34:226–232
                DOI: 10.1159/000330176
                PubMed ID: 21791919
                SO-VID: f59d141d-90fc-47b1-a476-c57ebce7f5a9
                Copyright © © 2011 S. Karger AG, Basel
                License:

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                Date received : 03 April 2011
                Date accepted : 17 June 2011
                Page count
                Figures: 2, Tables: 3, Pages: 7
                Categories
                Subject: Original Report: Patient-Oriented, Translational Research

                ScienceOpen disciplines: Cardiovascular Medicine,Nephrology
                Keywords: p-Cresol, p-Cresyl sulfate,Indoxyl sulfate,Kinetics,Nocturnal dialysis
                Data availability:
                ScienceOpen disciplines: Cardiovascular Medicine, Nephrology
                Keywords: p-Cresol, p-Cresyl sulfate, Indoxyl sulfate, Kinetics, Nocturnal dialysis

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