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

Rationale & Objective

The association between autosomal dominant polycystic kidney disease (ADPKD) genetic variants and renal prognosis remains unclear. We conducted whole genome sequencing 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 whole genome sequencing.

Exposure

None.

Outcomes

The primary endpoint was the rate of increase in total kidney volume. The secondary endpoints were composite renal endpoints (induction of dialysis, kidney transplantation, or a decrease in the estimated glomerular filtration rate 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 1 (0.7%) GANAB variants identified. The median annual increase in total kidney volume 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 estimated glomerular filtration rate at enrollment (OR, 0.93; 95% 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 kidney function deterioration was higher 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 kidney 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.

Plain-Language Summary

This prospective study included 200 patients with autosomal dominant polycystic kidney disease (ADPKD), with the objectives of the following: (1) ascertaining the feasibility of conducting comprehensive ADPKD genetic diagnosis using whole genome sequencing with next-generation sequencing, and (2) identifying factors associated with renal prognosis and disease severity. This study showed that differences in genotype influence the rate of kidney function deterioration and disease severity. Furthermore, we found that hypertension and being overweight are particularly important factors that worsen the severity of ADPKD. Consequently, blood pressure and weight management are crucial in patients with ADPKD.