Renal Prognostic Identification in Patients With Autosomal Dominant Polycystic Kidney Disease by Whole Genome Sequencing: A Prospective, Observational Study

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Rationale & Objective The association between autosomal dominant polycystic kidney disease (ADPKD) genetic variants and renal prognosis remains unclear. We conducted whole genome sequencing (WGS) to identify the factors contributing to disease severity. Study Design Prospective, observational study. Setting & Population Using data collected from a 2-year prospective cohort of 200 patients with ADPKD, gene mutations were identified using WGS. Exposure None. Outcomes The primary endpoint was the rate of increase in total kidney volume (TKV). The secondary endpoints were composite renal endpoints (induction of dialysis, renal transplantation, or a decrease in the estimated glomerular filtration rate [eGFR] of ≥ 25%). Analytical Approach Logistic regression analyses were performed to determine the factors associated with the outcomes. Results Among 169 patients for whom genetic diagnosis was performed, genetic mutations were identified in 144 cases, with 109 (75.7%) PKD1 , 34 (23.6%) PKD2 , and one (0.7%) GANAB variant identified. The median annual increase in TKV was 5.9%. Among the patients who were followed, 60 patients (33.5%) achieved the composite renal endpoint. The independent risk factors for reaching the renal composite endpoint were eGFR at enrollment (odds ratio [OR]: 0.93, 95% confidence interval [CI]: 0.91–0.96) and PKD1 truncation (OR: 3.05, 95% CI: 1.11–8.40). Hypertension and overweight exacerbated disease severity, particularly in patients with PKD1 truncation. The annual rate of renal function deterioration was faster in the order of PKD1 truncating, PKD1 non-truncating, PKD2 truncating, and PKD2 non-truncating variants. The rate of Mayo imaging classification 1C-1E was highest in the same order. Limitations Owing to the various PKD variants, the sample size for each variant was insufficient for comprehensive evaluation of renal function. Conclusions PKD1 truncation is a sensitive severity marker in patients with ADPKD, and PKD2 non-truncation is the least severe. Genetic diagnosis is useful for predicting renal prognosis.

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