Investigation of the Monogenic Causation of Kidney Disease

Chronic kidney disease (CKD) affects 11-13% of the global population; the third fastest growing cause of death worldwide. On average, 2% of CKD patients will develop end-stage kidney disease (ESKD), resulting in the need for dialysis or transplantation. Kidney transplantation is the most common transplant surgery in Canada, with living donation offering the best outcomes for recipients. It is now predicted that 10-20% of adults with CKD have a genetic cause of disease, though implementation into the diagnostic pathway has not been routinely available. My thesis aims to determine the monogenic causes of kidney disease by determining the diagnostic yield and clinical utility of genetic testing in patients with CKD seen in a Kidney Genetics Clinic, older adults (³50 years), transplant recipients, living kidney donors, and by systematically reviewing reported CKD populations across literature. Testing strategies included: 1) multigene-panel approach, testing a subset of genes for a specific phenotype for patients with a presumed known etiology of CKD, and 2) comprehensive testing including exome sequencing (ES) for patients with unknown etiology or transplant recipients and donors. Our systematic review including 60 studies determined the overall diagnostic yield of genetic testing in adults with CKD to be 40%. This was reflected in the clinical setting (34%), and in older adults (38%). Participants seen in the clinic also had high clinical utility, with direct treatment changes for a third of genetically solved participants. ES in patients unsolved with multigene panels determined the novel association of ABCC6 pathogenic variants with CKD due to vascular calcification. A high proportion of genetic CKD (26%) was observed in transplant recipients. Living kidney donors prospectively recruited had a low positivity rate of 4%, whereas the rate in donors with adverse outcomes after donation was 20%. Overall, these findings support the integration of genetic testing in the diagnostic assessment for CKD patients, including those ³50 years of age, and in transplant recipients. The low yield in donors supports the current donor workup process with the integration of genetic testing through targeted-gene panels in living donors biologically related to the recipient who has a known genetic disease.