Abstract
BACKGROUND: Tolvaptan slows kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD) who are at risk of rapid progression. Given that treatment requires commitment to long-term use, we evaluated the effects of tolvaptan discontinuation on the trajectory of ADPKD progression. METHODS: This was a post hoc analysis of pooled data from two clinical trials of tolvaptan (TEMPO 2:4 [NCT00413777] and TEMPO 3:4 [NCT00428948]), an extension trial (TEMPO 4:4 [NCT01214421]), and an observational study (OVERTURE [NCT01430494]) that enrolled patients from the other trials. Individual subject data were linked longitudinally across trials to construct analysis cohorts of subjects with a tolvaptan treatment duration > 180 days followed by an off-treatment observation period of > 180 days. For inclusion in Cohort 1, subjects were required have ≥ 2 outcome assessments during the tolvaptan treatment period and ≥ 2 assessments during the follow-up period. For Cohort 2, subjects were required to have ≥ 1 assessment during the tolvaptan treatment period and ≥ 1 assessment during the follow-up period. Outcomes were rates of change in estimated glomerular filtration rate (eGFR) and total kidney volume (TKV). Piecewise-mixed models compared changes in eGFR or TKV in the on-treatment and post-treatment periods. RESULTS: In the Cohort 1 eGFR population (n = 20), the annual rate of eGFR change (in mL/min/1.73 m(2)) was -3.18 on treatment and -4.33 post-treatment, a difference that was not significant (P = 0.16), whereas in Cohort 2 (n = 82), the difference between on treatment (-1.89) and post-treatment (-4.94) was significant (P < 0.001). In the Cohort 1 TKV population (n = 11), TKV increased annually by 5.18% on treatment and 11.69% post-treatment (P = 0.06). In Cohort 2 (n = 88), the annual TKV growth rates were 5.15% on treatment and 8.16% post-treatment (P = 0.001). CONCLUSIONS: Although limited by small sample sizes, these analyses showed directionally consistent acceleration in measures of ADPKD progression following the discontinuation of tolvaptan.