Thesis Format
Integrated Article
Degree
Doctor of Philosophy
Program
Biochemistry
Supervisor
Connaughton, Dervla M.
Abstract
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.
Summary for Lay Audience
Our two kidneys have the important function of removing waste and extra fluid from our body as urine. One in ten people have kidney disease (KD). KD is a general term for any damage that reduces the kidney’s function. End-stage kidney disease (ESKD) is when kidney failure has occurred. The best option for ESKD patients is to receive a kidney (recipient) from a healthy living person (living donor). Kidney disease can run in families. Genes, which are pieces of DNA (instructions in our cells for how to make the body) that carry information to control one trait, like eye colour, are passed on to us from our parents. Changes in DNA (variants) can occur, like a spelling mistake, in genes that help our kidney to function, sometimes causing KD. Tests that sequence the DNA (genetic tests) have been shown to identify variants in 10-20% of adults with KD. Currently, genetic testing in adult patients with KD has not been fully understood. Genetic testing has also not been integrated into the testing process for kidney recipients or donors. In my thesis, patients being seen in a Kidney Genetics Clinic or a kidney transplant clinic received genetic testing to identify variants in their genes that may be causing KD. We also performed a search in the literature and found 60 papers that performed genetic testing on adults with KD to summarize the total number of patients with known genetic causes, which was 40%. In all patients seen in the Kidney Genetics Clinic, 34% had a genetic cause. In patients just 50 years of age or older, 38% had a genetic cause. A third of these patients also had a change in their medications, showing the benefits of genetic testing. In kidney recipients there was a high percent (26%) that had a genetic cause, but this was low in donors (4%). Overall, my thesis shows the importance of genetic testing for patients with KD, as it can provide a cause for their disease and lead to changes in their medications, and available kidney donors. Therefore, genetic testing should be available for KD patients.
Recommended Citation
Schott, Clara, "Investigation of the Monogenic Causation of Kidney Disease" (2025). Electronic Thesis and Dissertation Repository. 10784.
https://ir.lib.uwo.ca/etd/10784
Creative Commons License
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