Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
Clin Transplant. 2021 Nov;35(11):e14457. doi: 10.1111/ctr.14457. Epub 2021 Nov 2.
Long-term kidney transplant (KT) survival has remained relatively stagnant. Protocol biopsy studies suggest that glomerulosclerosis is a significant contributor to long-term graft failure. We previously demonstrated that podocyte loss in the first year post-transplantation predicted long-term allograft survival. However, whether increased podocyte loss continues over the lifespan of a KT remains unclear. We performed a cross-sectional analysis of 1182 urine samples from 260 KT recipients up to 19-years after transplantation. Urine pellet (UP) mRNAs were assayed for podocyte (NPHS2/podocin and nephrin/NPHS1), distal tubule (aquaporin2), and profibrotic cytokine (TGFbeta1). Multivariable generalized estimating equations were used to obtain "population-averaged" effects for these markers over time post-KT. Consistent with early stresses both podocyte and tubular markers increased immediately post-KT. However, only podocyte markers continued to increase long-term. A role for hypertrophic stresses in driving podocyte loss over time is implied by their association with donor BMI, recipient BMI, and donor-recipient BMI mismatch at transplantation. Furthermore, UP podocin mRNA was associated with urine TGFbeta1, proteinuria, and reduced estimated glomerular filtration rate, thereby linking podocyte injury to allograft fibrosis and survival. In conclusion we observed that podocyte loss continues long-term post-KT suggesting an important role in driving late graft loss.
长期肾移植（KT）的存活率一直相对停滞不前。方案活检研究表明，肾小球硬化是导致长期移植物失败的重要原因。我们之前的研究表明，移植后第一年的足细胞丢失可预测长期同种异体移植物的存活。然而，KT 患者的足细胞丢失是否会在其一生中持续增加尚不清楚。我们对 260 名 KT 受者在移植后长达 19 年的 1182 份尿液样本进行了横断面分析。对尿液沉淀物（UP）mRNA 进行了足细胞（NPHS2/足细胞蛋白和nephrin/NPHS1）、远端小管（水通道蛋白 2）和促纤维化细胞因子（TGFbeta1）的检测。使用多变量广义估计方程获得了这些标志物在 KT 后时间上的“群体平均”效应。与早期应激一致，足细胞和管状标志物在 KT 后立即增加。然而，只有足细胞标志物会长期持续增加。足细胞丢失随时间增加的原因可能是与供体 BMI、受体 BMI 和移植时供体-受体 BMI 不匹配有关的肥大应激。此外，UP 足细胞蛋白 mRNA 与尿 TGFbeta1、蛋白尿和估计肾小球滤过率降低有关，从而将足细胞损伤与同种异体移植物纤维化和存活联系起来。总之，我们观察到 KT 后足细胞丢失持续存在很长时间，这表明其在驱动晚期移植物丢失方面起着重要作用。
