title: The uremic toxin oxythiamine causes functional thiamine deficiency in end-stage renal disease by inhibiting transketolase activity.
abstract: Decreased transketolase activity is an unexplained characteristic of patients with end-stage renal disease and is linked to impaired metabolic and immune function. Here we describe the discovery of a link to impaired functional activity of thiamine pyrophosphate cofactor through the presence, accumulation, and pyrophosphorylation of the thiamine antimetabolite oxythiamine in renal failure. Plasma oxythiamine was significantly increased by 4-fold in patients receiving continuous ambulatory peritoneal dialysis and 15-fold in patients receiving hemodialysis immediately before the dialysis session (healthy individuals, 0.18 [0.11-0.22] nM); continuous ambulatory peritoneal dialysis patients, 0.64 [0.48-0.94] nM; and hemodialysis patients (2.73 [1.52-5.76] nM). Oxythiamine was converted to the transketolase inhibitor oxythiamine pyrophosphate. The red blood cell oxythiamine pyrophosphate concentration was significantly increased by 4-fold in hemodialysis (healthy individuals, 15.9 nM and hemodialysis patients, 66.1 nM). This accounted for the significant concomitant 41% loss of transketolase activity (mU/mg hemoglobin) from 0.410 in healthy individuals to 0.240 in hemodialysis patients. 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. Experimentally, trace levels of oxythiamine were not formed from thiamine degradation under physiologic conditions but rather under acidic conditions at 100(°)C. Thus, monitoring of the plasma oxythiamine concentration in renal failure and implementation of high-dose thiamine supplements to counter it may help improve the clinical outcome of patients with renal failure.
authors.affiliation: Warwick Medical School, Clinical Sciences Research Laboratories, University of Warwick, University Hospital, Coventry, United Kingdom.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Warwick Medical School, Clinical Sciences Research Laboratories, University of Warwick, University Hospital, Coventry, United Kingdom.
authors.forename: Jinit
authors.initials: J
authors.lastname: Masania
authors.affiliation: Warwick Medical School, Clinical Sciences Research Laboratories, University of Warwick, University Hospital, Coventry, United Kingdom.
authors.forename: Attia
authors.initials: A
authors.lastname: Anwar
authors.affiliation: Warwick Medical School, Clinical Sciences Research Laboratories, University of Warwick, University Hospital, Coventry, United Kingdom.
authors.forename: Mingzhan
authors.initials: M
authors.lastname: Xue
authors.affiliation: Warwick Medical School, Clinical Sciences Research Laboratories, University of Warwick, University Hospital, Coventry, United Kingdom; Department of Nephrology, University Hospital Coventry, Warwickshire NHS Trust, Coventry, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Zehnder
authors.affiliation: Department of Nephrology, University Hospital Coventry, Warwickshire NHS Trust, Coventry, United Kingdom.
authors.forename: Hemali
authors.initials: H
authors.lastname: Kanji
authors.affiliation: Warwick Medical School, Clinical Sciences Research Laboratories, University of Warwick, University Hospital, Coventry, United Kingdom.
authors.forename: Naila
authors.initials: N
authors.lastname: Rabbani
authors.affiliation: Warwick Medical School, Clinical Sciences Research Laboratories, University of Warwick, University Hospital, Coventry, United Kingdom. Electronic address: P.J.Thornalley@warwick.ac.uk.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Thornalley
mesh_terms: D000328:Adult; D000963:Antimetabolites / Q000633:toxicity*; D004032:Diet / Q000009:adverse effects; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood / Q000378:metabolism* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D010119:Oxythiamine / Q000097:blood / Q000378:metabolism / Q000633:toxicity*; D011499:Protein Processing, Post-Translational; D006435:Renal Dialysis; D065667:Renal Elimination; D013836:Thiamin Pyrophosphokinase / Q000378:metabolism; D013831:Thiamine / Q000627:therapeutic use; D013832:Thiamine Deficiency / Q000139:chemically induced* / Q000188:drug therapy; D013835:Thiamine Pyrophosphate / Q000378:metabolism*; D014174:Transketolase / Q000037:antagonists & inhibitors*; D014803:Vitamin B Complex / Q000627:therapeutic use
chemical_list: D000963:Antimetabolites; D014803:Vitamin B Complex; D010119:Oxythiamine; D014174:Transketolase; D013836:Thiamin Pyrophosphokinase; D013835:Thiamine Pyrophosphate; D013831:Thiamine
keywords: chronic kidney disease; hemodialysis; peritoneal dialysis; uremic toxins