Zhang, Fang, Masania, Jinit , Anwar, Attia, Xue, Mingzhan, Zehnder, Daniel, Kanji, Hemali, Rabbani, Naila and Thornalley, Paul J. (2016) The uremic toxin oxythiamine causes functional thiamine deficiency in end-stage renal disease by inhibiting transketolase activity. Kidney International, 90 (2). pp. 396-403. doi:10.1016/j.kint.2016.03.010

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Abstract

Decreased transketolase activity is an unexplained characteristic of patients with end stage renal disease (ESRD) and is linked to impaired metabolic and immune function. Herein we describe the discovery of a link to impaired functional activity of thiamine pyrophosphate co-factor through the presence, accumulation and pyrophosphorylation of the thiamine antimetabolite, oxythiamine, in renal failure. Plasma oxythiamine was increased 4-fold in patients receiving continuous ambulatory peritoneal dialysis (CAPD) and 15-fold in patients receiving haemodialysis (HD) immediately before a dialysis session: healthy controls 0.18 (0.11 – 0.22) nM, CAPD, 0.64 (0.48-0.94) nM and HD (2.73 (1.52-5.76) nM); P<0.001, Mann-Whitney U test. Oxythiamine was converted to the transketolase inhibitor oxythiamine pyrophosphate (OTPP). Red blood cell OTPP concentration was increased 4-fold in HD: healthy controls, 15.9 ± 10.4 nM and HD patients, 66.1 ± 26.7 nM; P<0.001, t-test. This accounted for the concomitant 41% loss of transketolase activity (mU/mg Hb): healthy controls, 0.410 ± 0.144 nM and HD, 0.240 ± 0.107 nM; P<0.01, paired t-test. This may be corrected by displacement with excess thiamine pyrophosphate and explain lifting of decreased transketolase activity by high dose thiamine supplementation in previous studies. Oxythiamine is likely of dietary origin, through cooking of acidic thiamine-containing foods. Trace level oxythiamine was not formed from thiamine degradation under physiological conditions but rather under acidic conditions at 100 oC. Monitoring of plasma oxythiamine concentration in renal failure and implementation of high dose thiamine supplements to counter it may help improve clinical outcome of patients with renal failure.

Item Type:	Journal Article
Subjects:	R Medicine > RC Internal medicine
Divisions:	Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Metabolic and Vascular Health (- until July 2016) Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Chronic renal failure, Peritoneal dialysis , Hemodialysis, Transketolase
Journal or Publication Title:	Kidney International
Publisher:	Nature Publishing Group
ISSN:	0085-2538
Official Date:	August 2016
Dates:	Date Event August 2016 Published 16 May 2016 Available 3 March 2016 Accepted 13 October 2015 Submitted
Date of first compliant deposit:	12 May 2016
Volume:	90
Number:	2
Page Range:	pp. 396-403
DOI:	10.1016/j.kint.2016.03.010
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Diabetes UK, Seventh Framework Programme (European Commission) (FP7)
Grant number:	244995 (BIOCLAIMS Project) (FP7)

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