Multicenter evaluation of undetermined end-stage renal disease prior to kidney transplantation

成人终末期肾病(ESRD)的潜在病因通常仍未解决或未确定。不幸的是，病因不明的终末期肾病非常普遍(约20%)，给世界各地的肾病学家带来了巨大的问题；特别是在肾移植(KT)的计划、实施和监测方面。在定义各种肾脏疾病时，肾组织学代表了诊断的主流，但通常被证明不适用于ESRD患者或不具特异性。另一方面，尽管在过去的几十年里，许多罕见的遗传性肾脏疾病已经被揭开，但对成年患者的遗传原因的评估还没有系统地进行。在莱比锡大学的一项单中心试点研究中，我们重新检查了KT等待名单上142名成年人的潜在肾脏疾病，发现40%的病例病因不明。通过使用肾脏特异性靶向测序小组，我们将其命名为肾脏Mendeliome，我们能够显著降低未确定的终末期肾病的发生率。通过这项建议，我们的目标是将先前测试的方法扩展到不同的国家移植中心，假设系统的基因分析能够成功地在更大范围内解决未确定的ESRD。因此，这项建议侧重于以下四个具体目标：i)评估未确定的终末期肾病在德国移植研究小组(GTSG)内各移植中心的患病率；ii)在德国移植研究小组的支持下，通过扩展版本的肾脏Mendeliome(635+35个孟德尔肾脏疾病基因)对病因不明的病例进行基因分析；iii)通过对极有可能携带遗传性疾病的未解决病例进行完整的外显子/基因组测序，确定导致终末期肾病的新的遗传原因；以及iv)在新确诊的基因诊断病例中，跟踪移植前和移植后处理的临床意义。这项提案旨在解决肾移植社区的一个紧迫问题，特别是在像德国这样的国家，KT等待名单上的人口不断增加。值得注意的是，在缺乏肾脏组织学或在非特异性组织学条件下，如局灶性节段性肾小球硬化、高血压肾病、慢性肾小管间质性肾炎或血栓性微血管病，全面的基因分析不仅可能提供缺失的临床诊断，而且可能有助于优化移植前和移植后的处理，并最终帮助肾移植存活。

The underlying etiology of end-stage renal disease (ESRD) in adults often remains unresolved or undetermined. Unfortunately, ESRD of undetermined etiology is highly prevalent (about 20%) and poses tremendous problems to nephrologists worldwide; particularly when it comes to planning, execution, and surveillance of kidney transplantation (KT). Renal histology represents the mainstay of diagnostics while defining various kidney disorders, but often proves inapplicable or unspecific in patients with ESRD. On the other hand, assessment of genetic causes is not yet done systematically in adult patients although a multitude of rare genetic kidney disorders have been unraveled over the last few decades. In a single center pilot study at the University of Leipzig, we revisited the underlying renal conditions of 142 adults on the KT-waitlist and found an undetermined etiology in 40% of all cases. By using a kidney-specific targeted sequencing panel, which we termed Renal Mendeliome, we were able to significantly reduce the rate of undetermined ESRD. With this proposal, we aim at extending the previously tested approach to various national transplant centers, hypothesizing that systematic genetic analysis is able to successfully address undetermined ESRD on a larger scale. Therefore, this proposal focuses on the following four specific aims: i) to evaluate the prevalence of undetermined ESRD in various transplant centers within the German Transplant Study Group (GTSG), ii) to perform genetic analysis by an extended version of the Renal Mendeliome (635+35 Mendelian kidney disease genes) in cases of undetermined etiology with the support of the GTSG, iii) to identify novel genetic causes of ESRD by whole exome/genome sequencing among unresolved cases with a huge likelihood of bearing a heritable disorder, and iv) to follow-up on the clinical implications of pre and post-transplant management in cases with a newly established genetic diagnosis. This proposal aims at tackling an urging problem in the renal transplant community, especially in countries like Germany, with a growing population on the KT-waitlist. Notably in the absence of renal histology or in unspecific histological conditions, such as focal segmental glomerulosclerosis, hypertensive nephropathy, chronic tubulointerstititial nephritis or thrombotic microangiopathy, comprehensive genetic analysis may not only provide the missing clinical diagnosis, but may help to optimize pre and post-transplant management and eventually renal graft survival.