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

肾移植前未确定的终末期肾病的多中心评估

• 批准号: 438567369
• 负责人: Professor Dr. Jan Halbritter
• 金额: --
• 依托单位: Medizinische Klinik mit Schwerpunkt Nephrologie (CCM)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/438567369?language=en
• 关键词: Multicenter; evaluation; undetermined; end; stage

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.

成人终末期肾病（ESRD）的潜在病因通常仍未得到解决或确定。不幸的是，病因不明的终末期肾病非常普遍（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、执行和监测方面。肾组织学是诊断各种肾脏疾病的主要方法，但在ESRD患者中通常不适用或不具有特异性。另一方面，尽管在过去的几十年中已经发现了许多罕见的遗传性肾病，但尚未在成人患者中系统地评估遗传原因。在莱比锡大学的一项单中心试点研究中，我们重新访问了KT等待名单上142名成人的基础肾脏疾病，发现40%的病例病因不明。通过使用肾脏特异性靶向测序面板，我们称之为肾孟德尔基因组，我们能够显着降低未确定的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在更大范围内成功解决未确定的ESRD。因此，本提案侧重于以下四个具体目标：i）在德国移植研究组（GTSG）的各个移植中心评估未确定的ESRD的患病率，ii）通过肾孟德尔基因组的扩展版本进行遗传分析，（635 + 35个孟德尔肾病基因），在GTSG的支持下，iii）通过全外显子组/基因组测序在具有巨大可能性的遗传性疾病的未解决病例中鉴定ESRD的新遗传原因，以及iv）在具有新建立的遗传诊断的病例中随访移植前和移植后管理的临床意义。该提案旨在解决肾移植界的一个紧迫问题，特别是在德国等国家，KT等待名单上的人口不断增加。值得注意的是，在缺乏肾组织学或在非特异性组织学条件下，如局灶节段性肾小球硬化症，高血压肾病，慢性肾小管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，但可能有助于优化移植前和移植后的管理，并最终肾移植存活。