Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna, Vienna, Austria; Department of Urology, Medical University Vienna, Vienna, Austria.
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
Kidney Int. 2023 Feb;103(2):365-377. doi: 10.1016/j.kint.2022.10.024. Epub 2022 Nov 25.
Antibody-mediated rejection (ABMR) is a major cause of kidney allograft failure. Biopsy-based surrogate endpoints reflecting ABMR progression on sequential biopsies that predict long-term outcome offer the potential to make treatment trials for ABMR feasible. However, the Banff transplant glomerulopathy (TG) scoring system (chronic glomerular injury score [cg]) relies on relatively crude and arbitrary ordinal grades and has low inter-observer concordance that currently limits its usefulness as a surrogate endpoint for ABMR progression in clinical drug trials. Here, we describe and validate a novel quantitative method for quantifying progression of TG in ABMR. Using digital pathology in sequential biopsies from 75 patients at various stages of ABMR, we scored all capillaries in the most affected glomeruli for basement membrane duplication that were correlated with allograft function, outcome, Banff lesion scores, and gene expression. Our digital scoring reflected TG progression better than the categorical Banff cg score and correlated with Banff ABMR and chronicity lesions, but not transcript changes. In multivariate analysis, the delta change between biopsies with serum creatinine and mean percent duplicated glomerular basement membranes was significantly associated with graft loss. Neither the delta in any Banff lesion scores (including cg) nor in gene expression was associated with outcome. Receiver operating characteristic curve analysis showed that the digital pathology approach was superior to the conventional score for predicting graft failure. Thus, our digital pathology-based approach for scoring TG accurately assessed progression in TG. However, further validation as a potential surrogate endpoint in clinical trials for the treatment of ABMR is warranted.
抗体介导的排斥反应（ABMR）是导致肾移植失败的主要原因。基于活检的替代终点可以反映连续活检中 ABMR 的进展情况，从而预测长期结果，这为 ABMR 的治疗试验提供了可行性。然而，Banff 移植肾小球病（TG）评分系统（慢性肾小球损伤评分[cg]）依赖于相对粗糙和任意的序数等级，并且观察者之间的一致性较低，目前限制了其作为临床药物试验中 ABMR 进展替代终点的用途。在这里，我们描述并验证了一种用于量化 ABMR 中 TG 进展的新定量方法。使用来自 75 名处于 ABMR 不同阶段患者的连续活检中的数字病理学，我们对受影响最严重的肾小球中所有毛细血管的基底膜进行了重复评分，这些评分与同种异体移植物功能、结果、Banff 病变评分和基因表达相关。我们的数字评分比分类的 Banff cg 评分更好地反映了 TG 的进展，并与 Banff ABMR 和慢性病变相关，但与转录变化无关。在多变量分析中，血清肌酐和平均百分比重复肾小球基底膜之间活检的差值与移植物丢失显著相关。任何 Banff 病变评分（包括 cg）或基因表达的差值与结果均无关。受试者工作特征曲线分析表明，数字病理学方法在预测移植物衰竭方面优于传统评分。因此，我们基于数字病理学的 TG 评分方法准确评估了 TG 的进展。然而，需要进一步验证作为 ABMR 治疗临床试验的潜在替代终点。
