Wijermars Leonie G M, Bakker Jaap A, de Vries Dorottya K, van Noorden Cornelis J F, Bierau Jörgen, Kostidis Sarantos, Mayboroda Oleg A, Tsikas Dimitrios, Schaapherder Alexander F, Lindeman Jan H N
Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands.
Am J Physiol Renal Physiol. 2017 Mar 1;312(3):F457-F464. doi: 10.1152/ajprenal.00214.2016. Epub 2016 Dec 28.
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 ( = 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 ( < 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.
次黄嘌呤-黄嘌呤氧化酶（XO）轴被认为是移植相关缺血再灌注（I/R）损伤的关键驱动因素。尽管在临床前模型中干扰该轴可有效减轻I/R损伤，但XO抑制剂在临床试验中的疗效有限。在此背景下，我们认为对次黄嘌呤-XO轴在人类I/R中的作用进行临床评估具有重要意义。纳入接受同种异体肾移植的患者（n = 40），并根据缺血持续时间（短、中、长）进行分类。通过超高效液相色谱-串联质谱仪（UPLCMS/MS）方法分析再灌注肾脏排泄的嘌呤代谢产物（动静脉差异），并通过原位酶谱法评估组织XO活性。我们以肾移植作为I/R的临床模型，证实了缺血期间次黄嘌呤的逐渐积累（P < 0.006）。然而，尿酸的动静脉浓度差异以及XO的原位酶谱分析并未表明缺血和再灌注肾移植中有显著的XO活性。此外，我们通过评估再灌注期间肾脏丙二醛、异前列腺素水平和尿囊素形成，测试了次黄嘌呤积累与肾脏氧化应激之间的假定关联。这些标志物未释放与缺血性次黄嘌呤积累和再灌注后氧化应激之间的关联不一致。基于这些关于人类肾脏的数据，我们假设次黄嘌呤-XO轴在临床I/R损伤中的作用小于普遍认为的作用，因此这些数据为XO抑制剂明显有限的临床疗效提供了解释。
