Borski Anita, Kainz Alexander, Kozakowski Nicolas, Regele Heinz, Kläger Johannes, Strassl Robert, Fischer Gottfried, Faé Ingrid, Wenda Sabine, Kikić Željko, Bond Gregor, Reindl-Schwaighofer Roman, Mayer Katharina A, Eder Michael, Wahrmann Markus, Haindl Susanne, Doberer Konstantin, Böhmig Georg A, Eskandary Farsad
Department of Nephrology and Dialysis, Medical University Vienna, Vienna, Austria.
Department of Pathology, Medical University Vienna, Vienna, Austria.
Front Med (Lausanne). 2022 Apr 21;9:817127. doi: 10.3389/fmed.2022.817127. eCollection 2022.
Late antibody-mediated rejection (ABMR) after kidney transplantation is a major cause of long-term allograft loss with currently no proven treatment strategy. Design for trials testing treatment for late ABMR poses a major challenge as hard clinical endpoints require large sample sizes. We performed a retrospective cohort study applying commonly used selection criteria to evaluate the slope of the estimated glomerular filtration rate (eGFR) within an early and short timeframe after biopsy as a surrogate of future allograft loss for clinical trials addressing late ABMR.
Study subjects were identified upon screening of the Vienna transplant biopsy database. Main inclusion criteria were (i) a solitary kidney transplant between 2000 and 2013, (ii) diagnosis of ABMR according to the Banff 2015 scheme at >12 months post-transplantation, (iii) age 15-75 years at ABMR diagnosis, (iv) an eGFR > 25 mL/min/1.73 m at ABMR diagnosis, and (v) a follow-up for at least 36 months after ABMR diagnosis. The primary outcome variable was death-censored graft survival. A mixed effects model with linear splines was used for eGFR slope modeling and association of graft failure and eGFR slope was assessed applying a multivariate competing risk analysis with landmarks set at 12 and 24 months after index biopsy.
A total of 70 allografts from 68 patients were included. An eGFR loss of 1 ml/min/1.73 m per year significantly increased the risk for allograft failure, when eGFR slopes were modeled over 12 months [HR 1.1 (95% CI: 1.01-1.3), = 0.020] or over 24 months [HR 1.3 (95% CI: 1.1-1.4), = 0.001] after diagnosis of ABMR with landmarks set at both time points. Covariables influencing graft loss in all models were histologic evidence of glomerulonephritis concurring with ABMR as well as the administration of anti-thymocyte globulin (ATG) at the time of transplantation.
Our study supports the use of the eGFR slope modeled for at least 12 months after biopsy-proven diagnosis of late ABMR, as a surrogate parameter for future allograft loss. The simultaneous occurrence of glomerulonephritis together with ABMR at index biopsy and the use of ATG at the time of transplantation-likely representing a confounder in pre-sensitized recipients-were strongly associated with worse transplant outcomes.
肾移植术后晚期抗体介导的排斥反应（ABMR）是长期移植肾丢失的主要原因，目前尚无经证实的治疗策略。设计针对晚期ABMR治疗的试验面临重大挑战，因为严格的临床终点需要大样本量。我们进行了一项回顾性队列研究，应用常用的选择标准，在活检后的早期和短时间内评估估计肾小球滤过率（eGFR）的斜率，作为针对晚期ABMR的临床试验中未来移植肾丢失的替代指标。
通过筛查维也纳移植活检数据库确定研究对象。主要纳入标准为：（i）2000年至2013年间接受单肾移植；（ii）根据2015年班夫标准在移植后>12个月诊断为ABMR；（iii）ABMR诊断时年龄为15 - 75岁；（iv）ABMR诊断时eGFR>25 mL/min/1.73 m²；（v）ABMR诊断后至少随访36个月。主要结局变量为死亡截尾的移植肾存活。使用带有线性样条的混合效应模型进行eGFR斜率建模，并应用多变量竞争风险分析评估移植失败与eGFR斜率的关联，地标设定在索引活检后的12个月和24个月。
共纳入68例患者的70个移植肾。当在诊断ABMR后12个月[风险比（HR）1.1（95%置信区间：1.01 - 1.3），P = 0.020]或24个月[HR 1.3（95%置信区间：1.1 - 1.4），P = 0.001]对eGFR斜率进行建模时，每年eGFR下降1 ml/min/1.73 m²会显著增加移植肾失败的风险，两个时间点均设定地标。所有模型中影响移植肾丢失的协变量包括与ABMR同时存在的肾小球肾炎组织学证据以及移植时使用抗胸腺细胞球蛋白（ATG）。
我们的研究支持在活检证实诊断晚期ABMR后至少12个月对eGFR斜率进行建模，作为未来移植肾丢失的替代参数。索引活检时肾小球肾炎与ABMR同时出现以及移植时使用ATG（可能代表致敏受者中的一个混杂因素）与较差的移植结局密切相关。
