Discussion
ADPKD, aquaretic adverse, orthostatic hypotension
ADPKD, SECONDARY, DRUG-INDUCED LIVER INJURY, EVENTS, ORTHOSTATIC HYPOTENSION
We report the first phase 3, interventional clinical trial of tolvaptan in children and adolescents with ADPKD. The current report focuses on the randomized, placebo-controlled, 1-year portion (phase A) of the study. In the absence of standardized criteria for identifying the potential for rapid progression in the pediatric ADPKD population,Changes from baseline in spot urine osmolality and specific gravity were greater in the tolvaptan group than in the placebo group, with results consistent across age groups. The observation of more dilute urine is supportive of vasopressin V2 receptor inhibition. The key secondary end point of percent change in htTKV from baseline to month 12 showed that participants aged 12–17 years at baseline experienced a lower rate of kidney volume growth with tolvaptan (2.6%) than placebo (5.8%), although the difference did not reach statistical significance. Similarly, the change in eGFR from week 1 to month 12 suggested that eGFR was preserved in the tolvaptan group relative to placebo. The exploratory statistical comparison did not show a significant effect of tolvaptan at month 12. The mean eGFR at baseline and at month 12 was >90 ml/min per 1.73 mTolvaptan was generally safe and well tolerated at the adjusted doses used in this trial. No participants experienced elevated transaminases or drug-induced liver injury. Events of increased blood creatinine and orthostatic hypotension in the tolvaptan group may have been effects of copious aquaresis with inadequate fluid replacement. Consistent with its mechanism of inhibiting the effects of antidiuretic hormone, tolvaptan was associated with aquaretic adverse effects in this population with high kidney function, increased urine volume, and an increased number of urine voids. The number of voids was highest at week 1 of treatment and declined thereafter. Despite the high mean 24-hour urine volume (>7000 ml) in the tolvaptan-treated subgroup evaluated—exceeding levels observed in adultsA limitation of this study is that it was not powered for the statistical comparison of htTKV and eGFR end points. The first study phase, as reported here, was only 12 months, further limiting conclusions regarding these end points. Given the challenges of identifying sufficient numbers of pediatric patients with ADPKD for clinical trials,The data here support the activity of tolvaptan at the vasopressin V2 receptor in children and adolescents with ADPKD, indicate the feasibility of a modified dosing strategy, and provide initial evidence of effects on TKV growth and eGFR decline that require further research. This trial provides information beyond case reporting on the use of tolvaptan in an infant ADPKD patient.