Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease

Abstract

BACKGROUNDIn a previous trial involving patients with early autosomal dominant polycystic kidney disease (ADPKD; estimated creatinine clearance, ≥60 ml per minute), the vasopressin V 2 -receptor antagonist tolvaptan slowed the growth in total kidney volume and the decline in the estimated glomerular filtration rate (GFR) but also caused more elevations in aminotransferase and bilirubin levels. The efficacy and safety of tolvaptan in patients with later-stage ADPKD are unknown. METHODSWe conducted a phase 3, randomized withdrawal, multicenter, placebo-controlled, double-blind trial. After an 8-week prerandomization period that included sequential placebo and tolvaptan run-in phases, during which each patient's ability to take tolvaptan without dose-limiting side effects was assessed, 1370 patients with ADPKD who were either 18 to 55 years of age with an estimated GFR of 25 to 65 ml per minute per 1.73 m 2 of body-surface area or 56 to 65 years of age with an estimated GFR of 25 to 44 ml per minute per 1.73 m 2 were randomly assigned in a 1:1 ratio to receive tolvaptan or placebo for 12 months. The primary end point was the change in the estimated GFR from baseline to follow-up, with adjustment for the exact duration that each patient participated (interpolated to 1 year). Safety assessments were conducted monthly. RESULTSThe change from baseline in the estimated GFR was −2.34 ml per minute per 1.73 m 2 (95% confidence interval [CI], −2.81 to −1.87) in the tolvaptan group, as compared with −3.61 ml per minute per 1.73 m 2 (95% CI, −4.08 to −3.14) in the placebo group (difference, 1.27 ml per minute per 1.73 m 2 ; 95% CI, 0.86 to 1.68; P<0.001). Elevations in the alanine aminotransferase level (to >3 times the upper limit of the normal range) occurred in 38 of 681 patients (5.6%) in the tolvaptan group and in 8 of 685 (1.2%) in the placebo group. Elevations in the aminotransferase level were reversible after stopping tolvaptan. No elevations in the bilirubin level of more than twice the upper limit of the normal range were detected. CONCLUSIONSTolvaptan resulted in a slower decline than placebo in the estimated GFR over a 1-year period in patients with later-stage ADPKD. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization; REPRISE ClinicalTrials.gov number, NCT02160145.)

Tolvaptan in the treatment of autosomal dominant polycystic kidney disease: patient selection and special considerations

“…The results of this prospective double blinded, placebo-controlled trial, which included 1495 subjects, have been published recently. 34 In patients with later stage ADPKD, the use of tolvaptan was associated with a slower eGFR decline (-2.34 mL/mn/1.73 m 2 versus -3.6 mL/mn/1.73 m 2 ). These results suggest that tolvaptan may be effective over a broad range of CKD stage.…”

“…34,35 In TEMPO 3:4, uricemia increased and some patients had gout attacks. A reversible GFR reduction was observed in the first 2 weeks of treatment.…”

“…32 At the end of ≥5 years of follow-up, TKV changes between TEMPO 3:4 baseline and TEMPO 4:4 Month 24 were not statistically different (+29.9% in prior tolvaptan versus +31.6% in prior placebo). Two main factors may explain the absence of overall effect of tolvaptan on renal volume: 1) a larger effect of tolvaptan during the first year, ie, an acute reduction in cyst volume due to the antisecretory effect of tolvaptan, 34,35 with less effect during subsequent years and 2) an imbalance across study arms due to the loss of randomization at the start of TEMPO 4:4, with notably a wide predominance of males in the early tolvaptan arm (it is well known that males have a faster TKV growth). Indeed, after adjustment by imbalanced baseline characteristics and other confounding factors, differences in TKV increased from 1.7% to 4.15% in favor of early treatment group and achieved statistical significance.…”

“…34 Even if such evidence allows initiation of tolvaptan in patients with eGFR as low as 30 or maybe 25 ml/mn/1.73m 2 , long term data on safety for these patients are clearely needed. Also, when should we consider stopping treatment if renal function declines?…”

Impact of Recent Clinical Trials on Nephrology Practice: Are We in a Stagnant Era?

“…Torres et al [72] showed that tolvaptan retarded the increase in total kidney volume and slowed the progression of kidney disease in patients with ADPKD, but it was associated with high aquaresis-related adverse effects and higher discontinuation rates. Moreover, in a more recent study, tolvaptan slowed the decline in kidney function in patients with later-stage ADPKD [73]. Gansevoort et al [74] showed that tolvaptan decreased albuminuria without affecting blood pressure in patients with ADPKD.…”