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ESRD非常普遍（约20%），给全世界的肾病学家带来了巨大的问题；特别是在肾移植（KT）的计划、执行和监督方面。肾脏组织学是诊断各种肾脏疾病的主要依据，但在ESRD患者中常常被证明不适用或不特异性。另一方面，尽管在过去的几十年里已经发现了许多罕见的遗传性肾脏疾病，但对成年患者的遗传原因的评估尚未系统地完成。在莱比锡大学（University of Leipzig）的一项单中心试点研究中，我们重新检查了142名等待接受kt治疗的成年人的潜在肾脏状况，发现40%的病例病因不明。通过使用肾脏特异性靶向测序面板，我们将其称为Renal mendelome，我们能够显著降低未确定ESRD的发生率。有了这个建议，我们的目标是将以前测试的方法扩展到各个国家移植中心，假设系统的遗传分析能够成功地在更大范围内解决未确定的ESRD。因此，本倡议主要围绕以下四个具体目标展开：i)在德国移植研究小组（GTSG）的各个移植中心评估未确定的ESRD的患病率，ii)在GTSG的支持下，在未确定病因的病例中，通过扩展版肾门德尔组（635+35个孟德尔肾病基因）进行遗传分析，iii)在极有可能患有遗传性疾病的未确定病例中，通过全外显子组/基因组测序确定ESRD的新遗传原因。iv)随访新确诊基因诊断病例移植前后管理的临床意义。该提案旨在解决肾移植界急需解决的问题，特别是在像德国这样的国家，等待接受肾移植的人越来越多。值得注意的是，在没有肾脏组织学或非特异性组织学情况下，如局灶节段性肾小球硬化、高血压肾病、慢性肾小管间质性肾炎或血栓性微血管病，全面的遗传分析不仅可以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管理，最终提高移植肾的存活率。

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.