Division of Nephrology, University of Colorado School of Medicine, Aurora, Colorado.
Division of Nephrology, School of Medicine, Johns Hopkins University, Baltimore, Maryland.
Am J Physiol Renal Physiol. 2019 Sep 1;317(3):F650-F657. doi: 10.1152/ajprenal.00130.2019. Epub 2019 Jul 17.
Experiments in mouse models have shown that the complement cascade is activated within the kidney after ischemia-reperfusion and that complement activation contributes to tubular injury in this setting. Less is known, however, about complement activation in human kidneys after ischemia or whether complement activation in the tubulointerstitium can be detected by measurement of complement fragments in the urine. We hypothesized that urine biomarkers of complement activation would rapidly increase in patients who develop ischemic acute kidney injury, signaling complement activation within the kidney. We confirmed that the alternative pathway of complement is activated in the kidneys of mice after ischemia-reperfusion, and we found that levels of factor B fragments (generated during alternative pathway activation) rapidly increase in the urine. We next performed a case-control study in which we measured complement fragments in human urine samples from patients undergoing cardiac surgery using ELISAs. The level of Ba increased after cardiac surgery and was significantly higher in patients who developed acute kidney injury. The increase in Ba also correlated with magnitude of the subsequent rise in serum creatinine and with the need for hemodialysis during the hospitalization. These findings demonstrate that the alternative pathway of complement is activated in patients who develop acute kidney injury after cardiac surgery and that increases in the level of urine Ba may be a predictive and functional biomarker of severe kidney injury.
在小鼠模型中的实验表明，补体级联反应在缺血再灌注后会在肾脏内被激活，并且补体的激活会导致这种情况下的肾小管损伤。然而，人们对人类肾脏在缺血后的补体激活知之甚少，或者是否可以通过测量尿液中的补体片段来检测肾小管间质中的补体激活。我们假设，发生缺血性急性肾损伤的患者尿液中的补体激活生物标志物将迅速增加，提示肾脏内的补体激活。我们证实，补体的替代途径在缺血再灌注后的小鼠肾脏中被激活，并且我们发现，替代途径激活过程中产生的 B 因子片段的水平在尿液中迅速增加。接下来，我们进行了一项病例对照研究，使用 ELISA 法测量接受心脏手术的患者的人尿液样本中的补体片段。心脏手术后 Ba 的水平增加，并且在发生急性肾损伤的患者中显著更高。Ba 的增加也与随后血清肌酐升高的幅度以及住院期间需要血液透析相关。这些发现表明，补体的替代途径在发生心脏手术后急性肾损伤的患者中被激活，并且尿液 Ba 水平的升高可能是严重肾损伤的预测和功能性生物标志物。
