Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, Amsterdam, The Netherlands.
Kidney Int. 2010 Nov;78(10):1033-40. doi: 10.1038/ki.2010.274. Epub 2010 Aug 18.
The distinction between T-cell-mediated rejection (TCMR) and other causes of kidney transplant dysfunction such as tubular necrosis requires biopsy. Subclinical rejection (SCR), an established risk factor for chronic allograft dysfunction, can only be diagnosed by protocol biopsy. A specific non-invasive biomarker to monitor immunological graft status would facilitate diagnosis and treatment of common transplantation-related complications. To identify possible markers, we measured urinary mRNA levels of several cytolytic proteins by quantitative PCR. Our cohort of 70 renal transplant recipients had biopsy proven type I and type II TCMR, acute tubular necrosis, SCR, calcineurin inhibitor-toxicity, cytomegalovirus infection, and stable graft function with normal histology. Granzyme A (GzmA) mRNA was significantly higher in subclinical and acute cellular rejection compared to patients with stable grafts or those with tubular necrosis with 80% sensitivity and up to 100% specificity. Granzyme B and perforin mRNA levels could significantly discriminate acute rejection from stable or tubular necrosis, but were not significantly elevated during SCR. Importantly, only GzmA mRNA remained below detection limits from grafts that were stable and most with tubular necrosis. Hence, the presented data indicate that urinary GzmA mRNA levels may entail a diagnostic non-invasive biomarker to distinguish patients with subclinical and acute cellular rejection from those with tubular necrosis or stable grafts.
T 细胞介导的排斥反应（TCMR）与其他导致肾移植功能障碍的原因（如肾小管坏死）之间的区别需要通过活检来确定。亚临床排斥反应（SCR）是慢性移植物功能障碍的一个既定危险因素，只能通过协议活检来诊断。一种用于监测免疫性移植物状态的特定非侵入性生物标志物将有助于诊断和治疗常见的移植相关并发症。为了确定可能的标志物，我们通过定量 PCR 测量了几种细胞溶解蛋白的尿 mRNA 水平。我们的 70 例肾移植受者队列中，活检证实存在 I 型和 II 型 TCMR、急性肾小管坏死、SCR、钙调神经磷酸酶抑制剂毒性、巨细胞病毒感染以及组织学正常的稳定移植物功能。与稳定移植物或肾小管坏死患者相比，在亚临床和急性细胞排斥反应患者中，颗粒酶 A（GzmA）mRNA 明显升高，具有 80%的灵敏度和高达 100%的特异性。颗粒酶 B 和穿孔素 mRNA 水平可显著区分急性排斥反应与稳定或肾小管坏死，但在 SCR 期间并未明显升高。重要的是，只有稳定且大多数肾小管坏死的移植物中的 GzmA mRNA 仍低于检测限。因此，这些数据表明，尿 GzmA mRNA 水平可能成为一种诊断性非侵入性生物标志物，用于区分亚临床和急性细胞排斥反应患者与肾小管坏死或稳定移植物患者。
