Presentation Authors: Caleb Nelson*, Michael Kurtz, Bartley Cilento, Alyssia Venna, Michelle Baum, Boston, MA
Introduction: Current treatments for cystinuria have limited effectiveness as well as short and long-term side effects. Dilutional therapy reduces recurrence, but many patients have difficulty maintaining high fluid intake. The vasopressin V2-receptor antagonist tolvaptan increases urinary excretion of free water. We sought to perform a pilot study of short-term safety, tolerability, and impact of oral tolvaptan on urinary stone risk parameters.
Methods: We enrolled cystinuria patients age 12-25 yrs. Subjects were treated for 4 days at lower dose (0.3 mg/kg daily, up to 30 mg) and 4 days at higher dose (0.6 mg/kg daily, up to 60 mg). Subjects were closely monitored throughout the study period. 24 hour urine collections were done at baseline, at day 3-4 of the dosing period, at day 7-8 of the dosing period, and 3-6 days after washout. Primary outcome was cystine capacity (mg/L), a measure of supersaturation unaffected by concurrent treatment with sulfhydryl drugs. Target capacity is a positive value. Secondary outcomes included other urinary/serum parameters, tolerability, and thirst response. Subjects continued their home medical regimen (including tiopronin) during the study period.
Results: 2 females (17, 23 yrs) and 2 males (13, 24 yrs) were enrolled. Cystine capacity respectively went from baseline of -312, -82, -353 and -628 mg/L to 97, 111, 75 and -3 mg/L on high dose (Figure 1). 24-hour volume went from 1.96, 3.0, 2.1 and 0.91 L to 11.74, 6.5, 9.9 and 2.8 L on high dose (Figure 2). There were no abnormalities in serum electrolytes or liver enzymes during the treatment period. Subjects did experience severe thirst, with thirst rated 9/10 on a visual analog scale, but all completed treatment and none terminated or reduced dose.
Conclusions: Dilutional therapy with tolvaptan increased both cystine capacity and urinary volumes. This treatment approach has the potential to reduce recurrence of stones in this population. Further investigation should study longer term effects and safety, and determine optimal dosing to improve tolerability.
Source of Funding: Otsuka Pharmaceuticals provided the study drug at no cost. The authors otherwise have no financial or other interest in Otsuka or in the study medication.