Opportunities and Challenges for Genetic Studies of End-Stage Renal Disease in Canada

Abstract

Purpose of review:Genetic testing can improve diagnostic precision in some patients with end-stage renal disease (ESRD) providing the potential for targeted therapy and improved patient outcomes. We sought to describe the genetic architecture of ESRD and Canadian data sources available for further genetic investigation into ESRD.Sources of information:We performed PubMed searches of English, peer-reviewed articles using keywords “chronic kidney disease,” “ESRD,” “genetics,” “sequencing,” and “administrative databases,” and searched for nephrology-related Mendelian diseases on the Online Mendelian Inheritance in Man database.Methods:In this narrative review, we discuss our evolving understanding of the genetic architecture of kidney disease and ESRD, the risks and benefits of using genetic data to help diagnose and manage patients with ESRD, existing public Canadian biobanks and databases, and a vision for future genetic studies of ESRD in Canada.Key findings:ESRD has a polygenic architecture including rare Mendelian mutations and common small effect genetic polymorphism contributors. Genetic testing will improve diagnostic accuracy and contribute to a precision medicine approach in nephrology. However, the risk and benefits of genetic testing needs to be considered from an individual and societal perspective, and further research is required. Merging existing health data, linking biobanks and administrative databases, and forming Canadian collaborations hold great potential for genetic research into ESRD. Large sample sizes are necessary to perform the suitably powered investigations required to bring this vision to reality.Limitations:This is a narrative review of the literature discussing future directions and opportunities. It reflects the views and academic biases of the authors.Implications:National collaborations will be required to obtain sample sizes required for impactful, robust research. Merging established datasets may be one approach to obtain adequate samples. Patient education and engagement will improve the value of knowledge gained.

Diagnostic Yield of Next-Generation Sequencing in Patients With Chronic Kidney Disease of Unknown Etiology

“…Most inherited kidney diseases have a high degree of genetic heterogeneity and are associated with a wide range of phenotypes (Kalatharan et al, 2018). This can make it challenging to distinguish certain kidney diseases based on clinical presentation, and may lead to misdiagnosis.…”

COVID-19 and Multisystem Inflammatory Syndrome in Children

“…(26,29) As shown in Figure 1, propensity scores incorporating traditional risk factors, biomarkers and predictive genetic variants might identify individuals at-risk for progressive CKD and guide clinical management through modifiable risk reduction and could guide clinical management even for those reaching kidney failure and requiring renal replacement therapy. (31) It is worth noting that the PRS was based on the summary Application of genetic testing to personalized and precision medicine for CKD and ESKD. Genetic risk factors, biomarkers (e.g.…”

“…proteinuria) and environmental exposures are used to develop a propensity polygenic risk score to predict individuals at greatest risk for developing progressive kidney disease, with the goal of preventing or delaying progression to kidney failure and improving health outcomes for those requiring renal replacement therapy. The figure is adapted and modified from Kalatharan et al (31) statistics of over 850,000 individuals and validated in a cohort of nearly 9000 European-American participants, a relatively homogenous population. (29) Disease-associated variants and PRSs derived from these variants (identified by GWAS of European populations) frequently fail to replicate or perform well in non-European populations due to differences in allelic frequencies, linkage disequilibrium and haplotype structure, and confounding by environmental risk factors.…”

Genome-Wide Study Updates in the International Genetics and Translational Research in Transplantation Network (iGeneTRAiN)

“…The findings of genome-wide studies may also provide new therapeutic targets to slow the progression of CKD to ESRD, which may delay or impact the need for transplantation in some patient populations (Wuttke & Kottgen, 2016; Kalatharan et al, 2018). For example, nephropathic cystinosis, a rare autosomal recessive disease, is caused by a 57-kb deletion in the CTNS gene in ∼75% of patients of European ancestry and progresses to ESRD if left untreated (Brodin-Sartorius et al, 2012).…”