Genomic Testing in Patients with Kidney Failure of an Unknown Cause: A National Australian Study

Background The cause of kidney failure is unknown in approximately 10% of patients with stage 5 chronic kidney disease (CKD). For those who first present to nephrology care with kidney failure, standard investigations of serology, imaging, urinalysis, and kidney biopsy are limited differentiators of etiology. We aimed to determine the diagnostic utility of whole genome sequencing (WGS) with analysis of a broad kidney gene panel in patients with kidney failure of unknown cause. Methods We prospectively recruited 100 participants who reached CKD stage 5 at the age of ≤50 years and had an unknown cause of kidney failure after standard investigation. Clinically accredited WGS was performed in this national cohort after genetic counseling. The primary analysis was targeted to 388 kidney-related genes with second-tier, genome-wide, and mitochondrial analysis. Results The cohort was 61% male and the average age of participants at stage 5 CKD was 32 years (9 months to 50 years). A genetic diagnosis was made in 25% of participants. Disease-causing variants were identified across autosomal dominant tubulointerstitial kidney disease (6), glomerular disorders (4), ciliopathies (3), tubular disorders (2), Alport syndrome (4), and mitochondrial disease (1). Most diagnoses (80%) were in autosomal dominant, X-linked, or mitochondrial conditions (UMOD; COL4A5; INF2; CLCN5; TRPC6; COL4A4; EYA1; HNF1B; WT1; NBEA; m.3243A>G). Participants with a family history of CKD were more likely to have a positive result (odds ratio, 3.29; 95% confidence interval, 1.10 to 11.29). Thirteen percent of participants without a CKD family history had a positive result. In those who first presented in stage 5 CKD, WGS with broad analysis of a curated kidney disease gene panel was diagnostically more informative than kidney biopsy, with biopsy being inconclusive in 24 of the 25 participants. Conclusions In this prospectively ascertained Australian cohort, we identified a genetic diagnosis in 25% of patients with kidney failure of unknown cause.