Oblak Manca, Mlinšek Gregor, Kojc Nika, Frelih Maja, Buturović-Ponikvar Jadranka, Arnol Miha
Department of Nephrology, University Medical Centre Ljubljana, Ljubljana, Slovenia.
Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Front Med (Lausanne). 2021 Nov 16;8:781195. doi: 10.3389/fmed.2021.781195. eCollection 2021.
Urine protein excretion is routinely measured to assess kidney allograft injury, but the diagnostic value of this measurement for kidney transplant pathology remains unclear. Here we investigated whether spot urine protein excretion in the first year following transplantation associates with allograft rejection phenotype at 1-year surveillance biopsies and occurrence of donor-specific antibodies (DSA). This prospective, observational national-cohort study included 139 non-sensitized patients who received a deceased donor kidney transplant between December 2014 and 2018. All patients received basiliximab induction and tacrolimus-based immunosuppression. Estimated protein excretion rate (ePER) was calculated monthly from spot urine protein-to-creatinine ratios. At 1-year, all recipients underwent surveillance graft biopsy and were screened for DSA. Screening-positive sera were subjected to single antigen bead (SAB) testing. The occurrence of DSA was determined based on SAB reactivity patterns using a mean fluorescence intensity threshold >1,000. Among the 139 study patients, 27 patients (19%) had histologic evidence of T cell-mediated rejection (TCMR), and 9 patients (7%) had histologic evidence of antibody-mediated rejection (AMR) at 1-year surveillance biopsy. One year after transplant, 19 patients (14%) developed DSA. Compared with patients without rejection and no DSA, mixed-effects linear regression analysis showed a significant difference in slope of ePER during the first year in patients with AMR and DSA at 1-year (46, 95% CI 25-68 mg/day/1.73 m per month and 34, 95% CI 20-49 mg/day/1.73 m per month, respectively). Patients with vascular TCMR also showed a significant difference in ePER slope over time compared with patients with non-rejection findings (31, 95% CI 9-52 mg/day/1.73 m per month). The discriminatory power of ePER for intragraft rejection processes was better in patients with AMR (AUC 0.95, 95% CI 0.90-0.99; < 0.001) than in those with TCMR (AUC 0.68, 95% CI 0.59-0.79; = 0.002), with 89% sensitivity and 93% specificity for proteinuria >550 mg/day/1.73m. An increase in ePER in the first year following kidney transplantation associates with AMR, vascular TCMR and DSA at 1-year and may be used as a non-invasive clinical marker of intragraft endothelial cell injury.
常规测量尿蛋白排泄以评估肾移植受者的肾脏损伤，但该测量指标对肾移植病理的诊断价值仍不明确。在此，我们研究了移植后第一年的随机尿蛋白排泄量是否与1年监测活检时的移植肾排斥反应表型及供者特异性抗体（DSA）的出现相关。这项前瞻性观察性全国队列研究纳入了139例未致敏患者，这些患者于2014年12月至2018年期间接受了尸体供肾移植。所有患者均接受巴利昔单抗诱导治疗及以他克莫司为基础的免疫抑制治疗。根据随机尿蛋白与肌酐比值每月计算估计蛋白排泄率（ePER）。1年后，所有受者均接受移植肾监测活检并筛查DSA。筛查呈阳性的血清进行单抗原珠（SAB）检测。根据SAB反应模式，使用平均荧光强度阈值>1000来确定DSA的出现情况。在139例研究患者中，27例（19%）在1年监测活检时有T细胞介导的排斥反应（TCMR）的组织学证据，9例（7%）有抗体介导的排斥反应（AMR）的组织学证据。移植1年后，19例（14%）患者出现DSA。与无排斥反应且无DSA的患者相比，混合效应线性回归分析显示，1年时发生AMR和DSA的患者在第一年期间ePER斜率有显著差异（分别为46，95%CI 25 - 68mg/天/1.73m²/月和34，95%CI 20 - 49mg/天/1.73m²/月）。与无排斥反应表现的患者相比，血管性TCMR患者的ePER斜率随时间也有显著差异（31，95%CI 9 - 52mg/天/1.73m²/月）。ePER对移植肾内排斥反应过程的鉴别能力在AMR患者中（AUC 0.95，95%CI 0.90 - 0.99；P<0.001）优于TCMR患者（AUC 0.68，95%CI 0.59 - 0.79；P = 0.002），对于蛋白尿>550mg/天/1.73m²，敏感性为89%，特异性为93%。肾移植后第一年ePER升高与1年时的AMR、血管性TCMR和DSA相关，可作为移植肾内皮细胞损伤的非侵入性临床标志物。
