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Kidney Week

Abstract: TH-PO834

Long-Term Safety and Tolerability of Tolvaptan (TLV) in Later-Stage ADPKD

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic


  • Torres, Vicente E., Mayo Clinic, Rochester, Minnesota, United States
  • Chapman, Arlene B., University of Chicago, Chicago, Illinois, United States
  • Devuyst, Olivier, University of Zurich, Zurich, Switzerland
  • Gansevoort, Ron T., University Medical Center Groningen, Groningen, Netherlands
  • Perrone, Ronald D., Tufts Medical Center, Boston, Massachusetts, United States
  • Lee, Jennifer, Otsuka Pharmaceutical Development & Commercialization, Rockville, Maryland, United States
  • Hoke, Molly E., Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey, United States
  • Estilo, Alvin, Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey, United States
  • Sergeyeva, Olga, Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey, United States

Group or Team Name

  • for the REPRISE Trial Investigators

A hepatic safety signal for TLV emerged in the TEMPO clinical ADPKD program with the 1st 18 months (m) of treatment the time of greatest susceptibility. This phase 3b, open-label extension study (NCT02251275) evaluated long-term TLV safety in ADPKD pts; liver enzyme monitoring frequency was q1m for the first 18 m of treatment and q3m thereafter.


Pts entered from REPRISE, TEMPO 4:4, or prior trials (9 pts). TLV exposure before entry was ≤5 yrs for TEMPO 4:4 pts and ~1 yr for REPRISE TLV pts. Hepatic safety was monitored q1m in pts with <18m TLV treatment, then q3m thereafter. Starting TLV dose depended on prior trial; maintenance regimens in this study were daily split doses 45/15mg, 60/30mg, and 90/30mg, with down-titration allowed for tolerability.


Of 1803 pts enrolled, 1800 received ≥1 TLV dose. Range of duration TLV exposure in this study was 1-1435 days (d); median exposure 651d (mean 697; SD 334, IQR: 538-924).

Percentages of treatment-emergent AEs (TEAEs) were similar across the 3 subgroups but REPRISE PBO pts reported more TEAEs (3678) vs TLV (2965) and TEMPO 4:4 (3297). Most common TEAEs overall: thirst (23%), renal pain (20%), polyuria (20%), hypertension (17%), nasopharyngitis (15%), nocturia (15%). Aquaretic AEs (AAEs) were most frequent in REPRISE PBO (thirst 32%, polyuria 32%, nocturia 22%). No Hy’s Law cases. TEAE ALT increased 2.8%; AST increased 0.6%. Median 245d to ALT increased, 251d to AST increased.


AAEs and discontinuations due to AEs were less frequent in pts with longer TLV exposure. No new Hy’s Law cases with monthly monitoring during the first 18m of treatment, nor in previously TLV treated pts, nor in the 570 pts who started TLV in the present study. (Funding: Otsuka.)

Prior trial participationREPRISETEMPO 4:4
Number of pts (% of total)570 (31.6%)506 (28.1%)718 (39.8%)
Pts with eGFR ≤45 mL/min/1.73 m2, %67.4%65.0%30.5
Pts with TEAEs, n (%)531 (93.3%)473 (93.7%)643 (89.7%)
Pts with serious TEAEs, n (%)96 (16.9%)87 (17.2%)103 (14.4%)
Pts discontinued due to AEs, n (%)65 (11.4%)33 (6.5%)38 (5.3%)
Deaths,* n513

*None considered TV-related; causes: cardiac arrest; CKD/septic shock; acute respiratory distress syndrome; cerebral aneurysm; aortic dissection; subarachnoid hemorrhage; sudden death; meningeal metastases; tuberculosis.


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