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

• Applicant: Professor Dr. Jan Halbritter
• Subject Area: Nephrology
• Term: from 2020 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 438567369

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.

• DFG Programme: Research Grants