Comparing Effects of Tolvaptan and Instruction to Increase Water Consumption in ADPKD: Post Hoc Analysis of TEMPO 3:4

Abstract

Key Points:

1. In a post hoc analysis, short-term reduction in spot urine osmolality (Uosm) was associated with decreased kidney volume growth in autosomal dominant polycystic kidney disease for both tolvaptan and instruction to increase hydration alone.

2. For the same spot Uosm reduction, however, the kidney volume benefit was greater with tolvaptan, possibly because of greater cumulative 24-hour Uosm suppression by tolvaptan.

Background: In addition to decreasing water excretion and increasing urinary concentration, the antidiuretic hormone vasopressin plays a role in the pathophysiology of autosomal dominant polycystic kidney disease. It has been hypothesized that by suppressing vasopressin release, drinking large amounts of water might exert therapeutic effects in autosomal dominant polycystic kidney disease similar to those of tolvaptan, an antagonist of the vasopressin type 2 receptor, but evidence is lacking. We analyzed data from tolvaptan clinical trials to evaluate relationships among water intake, urine osmolality (Uosm), and change in total kidney volume (TKV).

Methods: Analysis of the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes 3:4 clinical trial in which participants were randomized to tolvaptan or placebo and instructed to drink large amounts of water. The relationship between change in spot Uosm from baseline to week 3 and change in TKV to month 12 was assessed using linear regression modeling. Two short-term tolvaptan trials were analyzed to explore relationships between intermittent Uosm sampling and 24-hour Uosm suppression.

Results: With both tolvaptan and placebo (i.e., mandated high water intake alone), Uosm reduction at week 3 was associated with reduction in TKV growth at month 12. However, for the same decrease in spot Uosm, the corresponding reduction in TKV growth was greater for tolvaptan (e.g., a −250 mOsm/kg reduction in Uosm at week 3 was associated with a −1% change in TKV at month 12 for tolvaptan versus +4.5% for placebo). In short-term trials, similar reductions in spot or trough Uosm values were achievable with tolvaptan and high water intake, but cumulative 24-hour suppression was greater with tolvaptan.

Conclusions: This analysis supports a relationship between effects on Uosm and inhibition of disease progression by tolvaptan and high water intake alone. The findings further suggest that 24-hour Uosm measurement is superior to spot Uosm for assessing suppression of vasopressin activity by tolvaptan.

Trial registration: ClinicalTrials.gov NCT00428948 NCT01210560.

Graphical abstract

Figure 1

Relationship between changes in spot Uosm at week 3 and percentage changes in TKV at month 12 for placebo (mandated high water intake alone) and tolvaptan in TEMPO 3:4. The graph represents a linear regression line and 95% CI using participant-level data. The quartiles are overlaid to represent trends in the raw data. CI, confidence interval; TEMPO, Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes; TKV, total kidney volume; Uosm, urine osmolality.

Figure 2

Relationship between Uosm at the trough interval (16–24 hours postdose) and Uosm AUC₂₄ for placebo and tolvaptan in trial 248. Data are shown for all participants from pretreatment baseline and placebo on other occasions (hollow circles) and for participants who received 60 or 120 mg tolvaptan (filled circles). Similar trough values for tolvaptan and placebo in the presence of lower AUC₂₄ for tolvaptan were driven by higher 24-hour urine volume with tolvaptan. AUC₂₄, 24-hour area under the Uosm time curve.

Figure 3

Relationship between spot Uosm and Uosm AUC₂₄ for placebo and tolvaptan in trial 285. Data are shown for participants at baseline (hollow circles) and for participants who received MR 120 mg, MR 60 mg, or IR 90+30 mg tolvaptan (filled circles). Similar spot values for tolvaptan and placebo in the presence of lower AUC₂₄ for tolvaptan were driven by higher 24-hour urine volume with tolvaptan. IR, immediate release; MR, modified release.