title: The hypoxanthine-xanthine oxidase axis is not involved in the initial phase of clinical transplantation-related ischemia-reperfusion injury.
abstract: The hypoxanthine-xanthine oxidase (XO) axis is considered to be a key driver of transplantation-related ischemia-reperfusion (I/R) injury. Whereas interference with this axis effectively quenches I/R injury in preclinical models, there is limited efficacy of XO inhibitors in clinical trials. In this context, we considered clinical evaluation of a role for the hypoxanthine-XO axis in human I/R to be relevant. Patients undergoing renal allograft transplantation were included (n= 40) and classified based on duration of ischemia (short, intermediate, and prolonged). Purine metabolites excreted by the reperfused kidney (arteriovenous differences) were analyzed by the ultra performance liquid chromatography-tandem mass spectrometer (UPLCMS/MS) method and tissue XO activity was assessed by in situ enzymography. We confirmed progressive hypoxanthine accumulation (P< 0.006) during ischemia, using kidney transplantation as a clinical model of I/R. Yet, arteriovenous concentration differences of uric acid and in situ enzymography of XO did not indicate significant XO activity in ischemic and reperfused kidney grafts. Furthermore, we tested a putative association between hypoxanthine accumulation and renal oxidative stress by assessing renal malondialdehyde and isoprostane levels and allantoin formation during the reperfusion period. Absent release of these markers is not consistent with an association between ischemic hypoxanthine accumulation and postreperfusion oxidative stress. On basis of these data for the human kidney we hypothesize that the role for the hypoxanthine-XO axis in clinical I/R injury is less than commonly thought, and as such the data provide an explanation for the apparent limited clinical efficacy of XO inhibitors.
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Leonie G M
authors.initials: LG
authors.lastname: Wijermars
authors.affiliation: Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jaap A
authors.identifier: 0000-0002-2918-7361
authors.initials: JA
authors.lastname: Bakker
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Dorottya K
authors.initials: DK
authors.lastname: de Vries
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, The Netherlands.
authors.forename: Cornelis J F
authors.initials: CJ
authors.lastname: van Noorden
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Jörgen
authors.initials: J
authors.lastname: Bierau
authors.affiliation: Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands; and.
authors.forename: Sarantos
authors.initials: S
authors.lastname: Kostidis
authors.affiliation: Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands; and.
authors.forename: Oleg A
authors.initials: OA
authors.lastname: Mayboroda
authors.affiliation: Bioanalytical Research Laboratory for NO, Oxidative Stress, and Eicosanoids, Centre of Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Tsikas
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Schaapherder
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands; Lindeman@lumc.nl.
authors.forename: Jan H N
authors.initials: JH
authors.lastname: Lindeman
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D051799:Delayed Graft Function / Q000175:diagnosis / Q000201:enzymology* / Q000209:etiology; D005260:Female; D006801:Humans; D019271:Hypoxanthine / Q000378:metabolism*; D007668:Kidney / Q000201:enzymology* / Q000601:surgery*; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000097:blood; D015427:Reperfusion Injury / Q000175:diagnosis / Q000201:enzymology* / Q000209:etiology; D015398:Signal Transduction; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D016896:Treatment Outcome; D014527:Uric Acid / Q000097:blood; D014969:Xanthine Oxidase / Q000097:blood / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D017382:Reactive Oxygen Species; D014527:Uric Acid; D019271:Hypoxanthine; D014969:Xanthine Oxidase
keywords: clinical; ischemia-reperfusion injury; kidney transplantation; radical oxygen species