Determinants of Urine Volume in ADPKD Patients Using the Vasopressin V2 Receptor Antagonist Tolvaptan

Abstract

Rationale & objective: The vasopressin V2 receptor antagonist (V2RA) tolvaptan is the first drug that has been shown to slow the rate of kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD). However, V2RAs also cause polyuria, with urine output that averages 6L/d. We assessed determinants of urine volume in patients with ADPKD using V2RAs because such information may help develop strategies to improve V2RA tolerability.

Study design: Clinical trial of patients with ADPKD studied at baseline, after 3 weeks of V2RA treatment (tolvaptan, 90/30mg, in the last week), and after a 3-week washout period.

Setting & participants: The trial included patients with ADPKD with a wide range of kidney function (measured glomerular filtration rates [mGFRs]; range, 18-148mL/min/1.73m²).

Intervention: Tolvaptan treatment for 3 weeks.

Outcomes: 24-hour urine volume.

Analytical approach: Multivariable regression analysis with stepwise backward elimination was performed both during and without V2RA treatment to evaluate the influence of 24-hour osmolar excretion, mGFR, and total kidney volume on associations between tolvaptan and urine volume.

Results: Included were 27 patients (48% men, aged 46±9.8 years with mGFRs of 61±35mL/min/1.73m²). V2RA treatment caused a median increase in urine volume of 128% (interquartile range, 75%-202%), to 5,930±1,790mL. 24-hour osmolar excretion was strongly associated with 24-hour urine volume (standardized β = 0.73; P < 0.001). During V2RA use, no independent associations were detected between 24-hour urine volume and mGFR, total kidney volume, or V2RA concentration.

Limitations: Limited sample size, no standardized diets.

Conclusions: Osmolar excretion is the major determinant of urine volume in patients taking V2RAs as a consequence of the inability to concentrate urine. Restriction of osmolar intake may therefore limit V2RA-induced polyuria, giving patients more control over the aquaretic side effects and improving the tolerability of these drugs.

Keywords: Autosomal dominant polycystic kidney disease (ADPKD); aquaresis; glomerular filtration rate (GFR); kidney function; osmolar load; osmoles; polyuria; salt; side effect; sodium; tolvaptan; total kidney volume (TKV); urine volume; vasopressin (AVP); vasopressin V2 receptor antagonist (V2RA).