The hypoxanthine-xanthine oxidase axis is not involved in the initial phase of clinical transplantation-related ischemia-reperfusion injury

Leonie G. M. Wijermars, Jaap A. Bakker, Dorottya K. de Vries, Cornelis J. F. van Noorden, Jörgen Bierau, Sarantos Kostidis, Oleg A. Mayboroda, Dimitrios Tsikas, Alexander F. Schaapherder, Jan H. N. Lindeman*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

6 Citations (Web of Science)


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.

Original languageEnglish
Pages (from-to)F457-F464
Number of pages8
JournalAmerican Journal of Physiology-Renal Physiology
Issue number3
Publication statusPublished - 1 Mar 2017


  • ischemia-reperfusion injury
  • radical oxygen species
  • clinical
  • kidney transplantation

Cite this