The uremic toxin oxythiamine causes functional thiamine deficiency in end-stage renal disease by inhibiting transketolase activity
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, accumu...
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Veröffentlicht in: | Kidney international 2016-08, Vol.90 (2), p.396-403 |
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description | 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. |
doi_str_mv | 10.1016/j.kint.2016.03.010 |
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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.</description><identifier>ISSN: 0085-2538</identifier><identifier>EISSN: 1523-1755</identifier><identifier>DOI: 10.1016/j.kint.2016.03.010</identifier><identifier>PMID: 27198804</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adult ; Antimetabolites - toxicity ; chronic kidney disease ; Diet - adverse effects ; Female ; hemodialysis ; Humans ; Kidney Failure, Chronic - blood ; Kidney Failure, Chronic - metabolism ; Kidney Failure, Chronic - therapy ; Male ; Middle Aged ; Oxythiamine - blood ; Oxythiamine - metabolism ; Oxythiamine - toxicity ; peritoneal dialysis ; Protein Processing, Post-Translational ; Renal Dialysis ; Renal Elimination ; Thiamin Pyrophosphokinase - metabolism ; Thiamine - therapeutic use ; Thiamine Deficiency - chemically induced ; Thiamine Deficiency - drug therapy ; Thiamine Pyrophosphate - metabolism ; Transketolase - antagonists & inhibitors ; uremic toxins ; Vitamin B Complex - therapeutic use</subject><ispartof>Kidney international, 2016-08, Vol.90 (2), p.396-403</ispartof><rights>2016 International Society of Nephrology</rights><rights>Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c400t-e0a83c96bb58d92e4a0ed50da75703518ce1127b7a49eca70b47f3862dd639b23</citedby><cites>FETCH-LOGICAL-c400t-e0a83c96bb58d92e4a0ed50da75703518ce1127b7a49eca70b47f3862dd639b23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27198804$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Fang</creatorcontrib><creatorcontrib>Masania, Jinit</creatorcontrib><creatorcontrib>Anwar, Attia</creatorcontrib><creatorcontrib>Xue, Mingzhan</creatorcontrib><creatorcontrib>Zehnder, Daniel</creatorcontrib><creatorcontrib>Kanji, Hemali</creatorcontrib><creatorcontrib>Rabbani, Naila</creatorcontrib><creatorcontrib>Thornalley, Paul J.</creatorcontrib><title>The uremic toxin oxythiamine causes functional thiamine deficiency in end-stage renal disease by inhibiting transketolase activity</title><title>Kidney international</title><addtitle>Kidney Int</addtitle><description>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.</description><subject>Adult</subject><subject>Antimetabolites - toxicity</subject><subject>chronic kidney disease</subject><subject>Diet - adverse effects</subject><subject>Female</subject><subject>hemodialysis</subject><subject>Humans</subject><subject>Kidney Failure, Chronic - blood</subject><subject>Kidney Failure, Chronic - metabolism</subject><subject>Kidney Failure, Chronic - therapy</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Oxythiamine - blood</subject><subject>Oxythiamine - metabolism</subject><subject>Oxythiamine - toxicity</subject><subject>peritoneal dialysis</subject><subject>Protein Processing, Post-Translational</subject><subject>Renal Dialysis</subject><subject>Renal Elimination</subject><subject>Thiamin Pyrophosphokinase - metabolism</subject><subject>Thiamine - therapeutic use</subject><subject>Thiamine Deficiency - chemically induced</subject><subject>Thiamine Deficiency - drug therapy</subject><subject>Thiamine Pyrophosphate - metabolism</subject><subject>Transketolase - antagonists & inhibitors</subject><subject>uremic toxins</subject><subject>Vitamin B Complex - therapeutic use</subject><issn>0085-2538</issn><issn>1523-1755</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMFu1DAURS0EokPhB1ggL9kkPNtx4khsUAUUqRKbsrYc-6XjaeIU26k6W74cp1O6ZGVb99wr-RDynkHNgLWfDvWtD7nm5V6DqIHBC7JjkouKdVK-JDsAJSsuhTojb1I6QHn3Al6TM96xXiloduTP9R7pGnH2lublwQe6PBzz3pvZB6TWrAkTHddgs1-Cmehz5HD01mOwR1pKGFyVsrlBGnHDnE9oEtJhS_d-8NmHG5qjCekW8zJtmSmb9z4f35JXo5kSvns6z8mvb1-vLy6rq5_ff1x8uapsA5ArBKOE7dthkMr1HBsD6CQ408kOhGTKImO8GzrT9GhNB0PTjUK13LlW9AMX5-TjafcuLr9XTFnPPlmcJhNwWZNmRYhqBW83lJ9QG5eUIo76LvrZxKNmoDf3-qA393pzr0Ho4r6UPjztr8OM7rnyT3YBPp8ALL-89xh1ejSIzke0WbvF_2__L3apmJ0</recordid><startdate>201608</startdate><enddate>201608</enddate><creator>Zhang, Fang</creator><creator>Masania, Jinit</creator><creator>Anwar, Attia</creator><creator>Xue, Mingzhan</creator><creator>Zehnder, Daniel</creator><creator>Kanji, Hemali</creator><creator>Rabbani, Naila</creator><creator>Thornalley, Paul J.</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>201608</creationdate><title>The uremic toxin oxythiamine causes functional thiamine deficiency in end-stage renal disease by inhibiting transketolase activity</title><author>Zhang, Fang ; Masania, Jinit ; Anwar, Attia ; Xue, Mingzhan ; Zehnder, Daniel ; Kanji, Hemali ; Rabbani, Naila ; Thornalley, Paul J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c400t-e0a83c96bb58d92e4a0ed50da75703518ce1127b7a49eca70b47f3862dd639b23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Adult</topic><topic>Antimetabolites - toxicity</topic><topic>chronic kidney disease</topic><topic>Diet - adverse effects</topic><topic>Female</topic><topic>hemodialysis</topic><topic>Humans</topic><topic>Kidney Failure, Chronic - blood</topic><topic>Kidney Failure, Chronic - metabolism</topic><topic>Kidney Failure, Chronic - therapy</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Oxythiamine - blood</topic><topic>Oxythiamine - metabolism</topic><topic>Oxythiamine - toxicity</topic><topic>peritoneal dialysis</topic><topic>Protein Processing, Post-Translational</topic><topic>Renal Dialysis</topic><topic>Renal Elimination</topic><topic>Thiamin Pyrophosphokinase - metabolism</topic><topic>Thiamine - therapeutic use</topic><topic>Thiamine Deficiency - chemically induced</topic><topic>Thiamine Deficiency - drug therapy</topic><topic>Thiamine Pyrophosphate - metabolism</topic><topic>Transketolase - antagonists & inhibitors</topic><topic>uremic toxins</topic><topic>Vitamin B Complex - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Fang</creatorcontrib><creatorcontrib>Masania, Jinit</creatorcontrib><creatorcontrib>Anwar, Attia</creatorcontrib><creatorcontrib>Xue, Mingzhan</creatorcontrib><creatorcontrib>Zehnder, Daniel</creatorcontrib><creatorcontrib>Kanji, Hemali</creatorcontrib><creatorcontrib>Rabbani, Naila</creatorcontrib><creatorcontrib>Thornalley, Paul J.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Kidney international</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Fang</au><au>Masania, Jinit</au><au>Anwar, Attia</au><au>Xue, Mingzhan</au><au>Zehnder, Daniel</au><au>Kanji, Hemali</au><au>Rabbani, Naila</au><au>Thornalley, Paul J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The uremic toxin oxythiamine causes functional thiamine deficiency in end-stage renal disease by inhibiting transketolase activity</atitle><jtitle>Kidney international</jtitle><addtitle>Kidney Int</addtitle><date>2016-08</date><risdate>2016</risdate><volume>90</volume><issue>2</issue><spage>396</spage><epage>403</epage><pages>396-403</pages><issn>0085-2538</issn><eissn>1523-1755</eissn><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.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>27198804</pmid><doi>10.1016/j.kint.2016.03.010</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Adult Antimetabolites - toxicity chronic kidney disease Diet - adverse effects Female hemodialysis Humans Kidney Failure, Chronic - blood Kidney Failure, Chronic - metabolism Kidney Failure, Chronic - therapy Male Middle Aged Oxythiamine - blood Oxythiamine - metabolism Oxythiamine - toxicity peritoneal dialysis Protein Processing, Post-Translational Renal Dialysis Renal Elimination Thiamin Pyrophosphokinase - metabolism Thiamine - therapeutic use Thiamine Deficiency - chemically induced Thiamine Deficiency - drug therapy Thiamine Pyrophosphate - metabolism Transketolase - antagonists & inhibitors uremic toxins Vitamin B Complex - therapeutic use |
title | The uremic toxin oxythiamine causes functional thiamine deficiency in end-stage renal disease by inhibiting transketolase activity |
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