Tolvaptan and Autosomal Dominant Polycystic Kidney Disease Progression in Individuals Aged 18-35 Years: A Pooled Database Analysis

Rational & Objective: Data are limited regarding the long-term efficacy of tolvaptan in adults aged 18-35 years with autosomal dominant polycystic kidney disease (ADPKD) at increased risk of rapid progression. We assessed the effects of tolvaptan within a larger population of younger adults and over longer follow-up than individual clinical trials could provide. Study Design: Pooled database study. Setting & Study Populations: A consolidated clinical study database with ADPKD patients aged 18-35 years. Selection Criteria for Studies: Studies that enrolled patients who received either tolvaptan or standard-of-care treatment not including tolvaptan. Data Extraction: Annual rate of change in estimated glomerular filtration rate (eGFR) and time to kidney failure. Analytical Approach: For individuals participating in multiple studies, their data were longitudinally linked to extend the follow-up period. We matched tolvaptan-treated patients with controls based on age, sex, chronic kidney disease stage, eGFR, and, where possible, Mayo Imaging Classification. We compared eGFR decline between groups using mixed-effects modeling. Results: The matched analysis set encompassed 204 tolvaptan-treated individuals and 204 controls. Median follow-up was 4.6 years for the tolvaptan group and 1.7 years for controls. In the mixed-effects model, the eGFR decline rate (in mL/min/1.73 m²/year) was –2.58 for the tolvaptan cohort and -4.28 for controls. This indicates reduction in the eGFR decline rate by 1.69 mL/min/1.73 m²/year (95% confidence interval: 0.87-2.52; P < 0.001) with tolvaptan, a 40% improvement. Extrapolating eGFR over 35 years, tolvaptan could delay kidney failure onset by approximately 11 years. Limitations: Median follow-up was shorter in the control cohort than the tolvaptan cohort. The projection of time to kidney failure assumed a linear model of eGFR decline. Conclusions: This analysis offers insights into the anticipated treatment benefits of tolvaptan for young adults with ADPKD. These findings are crucial for weighing treatment benefits against any associated risks. Plain-Language Summary: Tolvaptan is the only approved treatment for delaying kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD) at high risk of rapid progression. Clinical trials have included few patients aged 18-35 years, a group potentially benefiting significantly from early tolvaptan initiation. We pooled clinical study data, matching tolvaptan-treated patients with untreated controls by baseline characteristics. The results showed a statistically significant reduction in kidney function decline with tolvaptan. Extrapolating this 5-year data to a 35-year disease trajectory suggests an 11-year delay in the onset of kidney failure. This analysis underscores the potential long-term benefits of early treatment with tolvaptan in younger ADPKD patients.