Urine Osmolality, Response to Tolvaptan, and Outcome in Autosomal Dominant Polycystic Kidney Disease: Results from the TEMPO 3:4 Trial

Abstract

The vasopressin-cAMP-osmolality axis is abnormal in autosomal dominant polycystic kidney disease (ADPKD). In the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes 3:4 Trial, a 3-year randomized, placebo-controlled trial in adults, the vasopressin V2 receptor antagonist tolvaptan slowed ADPKD progression in patients with preserved GFR. Here, we investigated the determinants of baseline urine osmolality (Uosm) and its value as a severity marker of ADPKD, the factors influencing the response to tolvaptan, and whether change in Uosm associated with key trial end points. At baseline, lower Uosm independently associated with female sex, presence of hypertension, lower eGFR, higher total kidney volume (TKV), and higher age. Tolvaptan consistently reduced Uosm by 200-300 mOsm/kg over 36 months. The Uosm response to tolvaptan depended on baseline eGFR and Uosm. Subjects with greater change in Uosm experienced a significant reduction in clinical progression events. Among subjects receiving tolvaptan, those with a greater suppression of Uosm had slower renal function decline. Assessment at follow-up, off medication, revealed a significant decrease in Uosm in both placebo and treated groups. Tolvaptan significantly increased plasma osmolality, which returned to baseline at follow-up. In conclusion, baseline Uosm in ADPKD reflects age, renal function, and TKV, and baseline Uosm, eGFR, and TKV influence the effect of tolvaptan on Uosm. The greatest renal benefit occurred in subjects achieving greater suppression of Uosm, that is, those with better eGFR at baseline. These results support the link between vasopressin V2 receptor signaling and ADPKD progression.

Keywords: collecting ducts; cyclic AMP; polycystic kidney disease; vasopressin; water transport.

Copyright © 2017 by the American Society of Nephrology.

Figures

Figure 1.

Factors correlating with Uosm in the ADPKD population at baseline. Correlations of fasting baseline Uosm with age, TKV, and eGFR in the ADPKD population.

Figure 2.

Influence of baseline characteristics on the response to tolvaptan and distribution of Uosm during the trial. (A) Effect of baseline Uosm and baseline eGFR on the magnitude of change in Uosm (EOT compared with baseline) induced by tolvaptan in 666 patients with ADPKD. (B) Distribution of average Uosm during the trial in the tolvaptan (n=666) and placebo (n=332) groups (percentage of patients for each threshold of Uosm as indicated).

Figure 3.

Evolution of Uosm and Posm during exposure to tolvaptan or placebo. (A) Uosm (fasting baseline and follow-up visits and nonfasting visits included). (B) Estimated Posm at the same time points. M12, Month 12; M24, Month 24; M36, Month 36; FU, Follow-up; BL, Baseline.

Figure 4.

Change in Uosm from baseline to EOT and time to multiple ADPKD clinical progression events in the ADPKD population. Quartiles of changes in Uosm from baseline to EOT are presented for the whole population (A) and the placebo (B) and tolvaptan (C) groups, in relation to ADPKD clinical progression events defined as worsening renal function or pain. Q1–Q4, quartiles 1–4.

Figure 5.

Relationship between Uosm and eGFR outcome during the trial. (A) Relationship between mean baseline Uosm and quartiles of annual eGFR slope over 3 years in the total population. The proportion of tolvaptan (blue shaded boxes) and placebo (red shaded boxes) for each quartile are represented as a stacked bar chart with decreasing eGFR slope from dark to light (2). Slower progression is reflected by a progressively higher Uosm at baseline and a higher proportion of treatment with tolvaptan. (B) Relationship between mean baseline Uosm and quartiles of annual eGFR slope over 3 years in tolvaptan (blue shaded boxes; darkest to lightest, <−4.5 to ≥−0.6 ml/min per 1.73 m2) and placebo groups (red shaded boxes; darkest to lightest, <−5.8 to ≥−1.3 ml/min per 1.73 m2). Arrows indicate the significant trend between increased Uosm at baseline and slower rate of eGFR decrease as tested by ANOVA. Slower progression is reflected by a progressively higher Uosm at baseline in both groups. (C) Correlation between baseline eGFR and average Uosm during the trial (blue symbols, tolvaptan; red symbols, placebo). (D) Relationship between change in Uosm (EOT compared with baseline) and quartiles of annual eGFR slopes over 3 years in tolvaptan (blue shaded boxes; darkest to lightest, <−4.5 to >−0.6 ml/min per 1.73 m2) and placebo groups (red shaded boxes; darkest to lightest, <−5.8 to >−1.3 ml/min per 1.73 m2). Arrows indicate a significant trend between change in Uosm and slower rate of eGFR decrease in the tolvaptan group, as tested by ANOVA. Slower progression is reflected by a higher initial response to Uosm in the tolvaptan but not in the placebo group. Q1–Q4, quartiles 1–4.