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Revisiting the middle molecule hypothesis of uremic toxicity: A systematic review of beta 2 microglobulin population kinetics and large scale modeling of hemodialysis trials in silico

Roumelioti, ME and Nolin, T and Unruh, ML and Argyropoulos, C (2016) Revisiting the middle molecule hypothesis of uremic toxicity: A systematic review of beta 2 microglobulin population kinetics and large scale modeling of hemodialysis trials in silico. PLoS ONE, 11 (4).

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Abstract

© 2016 Roumelioti et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background Beta-2 Microglobulin (β2M) is a prototypical "middle molecule" uremic toxin that has been associated with a higher risk of death in hemodialysis patients. A quantitative description of the relative importance of factors determining β2M concentrations among patients with impaired kidney function is currently lacking. Methods Herein we undertook a systematic review of existing studies reporting patient level data concerning generation, elimination and distribution of β2M in order to develop a population model of β2M kinetics. We used this model and previously determined relationships between predialysis β2M concentration and survival, to simulate the population distribution of predialysis β2M and the associated relative risk (RR) of death in patients receiving conventional thrice-weekly hemodialysis with low flux (LF) and high flux (HF) dialyzers, short (SD) and long daily (LD) HF hemodialysis sessions and on-line hemodiafiltration at different levels of residual renal function (RRF). Results We identified 9 studies of 106 individuals and 156 evaluations of or more compartmental kinetic parameters of β2M. These studies used a variety of experimental methods to determine β2M kinetics ranging from isotopic dilution to profiling of intra/inter dialytic concentration changes. Most of the patients (74/106) were on dialysis with minimal RRF, thus facilitating the estimation of non-renal elimination kinetics of β2M. In large scale (N = 10000) simulations of individuals drawn from the population of β2M kinetic parameters, we found that, higher dialytic removal materially affects β2M exposures only when RRF (renal clearance of β2M) was below 2 ml/min. In patients initiating conventional HF hemodialysis, total loss of RRF was predicted to be associated with a RR of death of more than 20%. Hemodiafiltration and daily dialysis may decrease the high risk of death of anuric patients by 10% relative to conventional, thrice weekly HF dialysis. Only daily long sessions of hemodialysis consistently reduced mortality risk between 7-19% across the range of β2M generation rate. Conclusions Preservation of RRF should be considered one of the therapeutic goals of hemodialysis practice. Randomized controlled trials of novel dialysis modalities may require large sample sizes to detect an effect on clinical outcomes even if they enroll anuric patients. The developed population model for β2M may allow personalization of hemodialysis prescription and/ or facilitate the design of such studies by identifying patients with higher β2M generation rate.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Roumelioti, ME
Nolin, Tnolin@pitt.eduNOLIN
Unruh, ML
Argyropoulos, C
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorD'Addio, FrancescaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 1 April 2016
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: PLoS ONE
Volume: 11
Number: 4
DOI or Unique Handle: 10.1371/journal.pone.0153157
Institution: University of Pittsburgh
Refereed: Yes
Date Deposited: 25 Aug 2016 17:20
Last Modified: 02 Feb 2019 14:56
URI: http://d-scholarship.pitt.edu/id/eprint/28273

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