Tolvaptan in autosomal dominant polycystic kidney disease: three years' experience
Eiji Higashihara, Vicente E Torres, Arlene B Chapman, Jared J Grantham, Kyongtae Bae, Terry J Watnick, Shigeo Horie, Kikuo Nutahara, John Ouyang, Holly B Krasa, Frank S Czerwiec, TEMPOFormula and 156-05-002 Study Investigators, Akira Hishida, Fumitake Gejyo, Toshiaki Nitatori, Sidney Goldstein, Benjamin Cowley, Roser Torra, Lee-Jen Wei, Harvard School, Osamu Sato, Tadashi Okada, William Bennett, Michael Walczyk, Jon Blumenfeld, Stephanie Donahue, Martin Prince, W Kline Bolton, Mitchell Rosner, Arlene Chapman, Frederick Rahbari-Oskoui, Diego Martin, Charles Edelstein, Tomas Berl, Janis Cicerchi, Brian L Burke, Michael Koren, Susan N Greco, Jeffry Jacqmein, Darlene Bartilucci, Mark Frisk, Gerald Schulman, Julia Lewis, Thomas Golper, Ronald Arildsen, Suzanne Swan, Courtney Cannon, James Cunningham, Vicente Torres, Marie Hogan, Fernando Fervenza, James Glockner, Terry Watnick, Sharon Turban, Katarzyna J Macura, Franz Winklhofer, Judson Bertsch, Connie Wang, Louis Wetzel, Yasuhiko Iino, Kouju Kamata, Hisato Sakamoto, Koichi Kamura, Tatsuhiko Kanno, Hidetomo Nakamoto, Musashi Ranzan, Satoru Muto, Mitsuko Yasuda, Shigeo Horie, Hisamitsu Ide, Yukio Naya, Naoki Nihei, Kazuhiro Araki, Kosaku Nitta, Ken Tsuchiya, Junko Arai, Takatsugu Okegawa, Kenmei Takaichi, Yoshifumi Ubara, Yusuke Tsukamoto, Tomokazu Okado, Michio Kuwahara, Mikiko Ayata, Shigeru Takada, Seiji Inoshita, Tamaki Kuyama, Tomoki Asai, Eiji Higashihara, Vicente E Torres, Arlene B Chapman, Jared J Grantham, Kyongtae Bae, Terry J Watnick, Shigeo Horie, Kikuo Nutahara, John Ouyang, Holly B Krasa, Frank S Czerwiec, TEMPOFormula and 156-05-002 Study Investigators, Akira Hishida, Fumitake Gejyo, Toshiaki Nitatori, Sidney Goldstein, Benjamin Cowley, Roser Torra, Lee-Jen Wei, Harvard School, Osamu Sato, Tadashi Okada, William Bennett, Michael Walczyk, Jon Blumenfeld, Stephanie Donahue, Martin Prince, W Kline Bolton, Mitchell Rosner, Arlene Chapman, Frederick Rahbari-Oskoui, Diego Martin, Charles Edelstein, Tomas Berl, Janis Cicerchi, Brian L Burke, Michael Koren, Susan N Greco, Jeffry Jacqmein, Darlene Bartilucci, Mark Frisk, Gerald Schulman, Julia Lewis, Thomas Golper, Ronald Arildsen, Suzanne Swan, Courtney Cannon, James Cunningham, Vicente Torres, Marie Hogan, Fernando Fervenza, James Glockner, Terry Watnick, Sharon Turban, Katarzyna J Macura, Franz Winklhofer, Judson Bertsch, Connie Wang, Louis Wetzel, Yasuhiko Iino, Kouju Kamata, Hisato Sakamoto, Koichi Kamura, Tatsuhiko Kanno, Hidetomo Nakamoto, Musashi Ranzan, Satoru Muto, Mitsuko Yasuda, Shigeo Horie, Hisamitsu Ide, Yukio Naya, Naoki Nihei, Kazuhiro Araki, Kosaku Nitta, Ken Tsuchiya, Junko Arai, Takatsugu Okegawa, Kenmei Takaichi, Yoshifumi Ubara, Yusuke Tsukamoto, Tomokazu Okado, Michio Kuwahara, Mikiko Ayata, Shigeru Takada, Seiji Inoshita, Tamaki Kuyama, Tomoki Asai
Abstract
Background and objectives: Autosomal dominant polycystic kidney disease (ADPKD), a frequent cause of end-stage renal disease, has no cure. V2-specific vasopressin receptor antagonists delay disease progression in animal models.
Design, setting, participants, and measurements: This is a prospectively designed analysis of annual total kidney volume (TKV) and thrice annual estimated GFR (eGFR) measurements, from two 3-year studies of tolvaptan in 63 ADPKD subjects randomly matched 1:2 to historical controls by gender, hypertension, age, and baseline TKV or eGFR. Prespecified end points were group differences in log-TKV (primary) and eGFR (secondary) slopes for month 36 completers, using linear mixed model (LMM) analysis. Sensitivity analyses of primary and secondary end points included LMM using all subject data and mixed model repeated measures (MMRM) of change from baseline at each year. Pearson correlation tested the association between log-TKV and eGFR changes.
Results: Fifty-one subjects (81%) completed 3 years of tolvaptan therapy; all experienced adverse events (AEs), with AEs accounting for six of 12 withdrawals. Baseline TKV (controls 1422, tolvaptan 1635 ml) and eGFR (both 62 ml/min per 1.73 m(2)) were similar. Control TKV increased 5.8% versus 1.7%/yr for tolvaptan (P < 0.001, estimated ratio of geometric mean 0.96 [95% confidence interval 0.95 to 0.97]). Corresponding annualized eGFR declined: -2.1 versus -0.71 ml/min per 1.73 m(2)/yr (P = 0.01, LMM group difference 1.1 ml/min per 1.73 m(2)/yr [95% confidence interval 0.24 to 1.9]). Sensitivity analyses including withdrawn subjects were similar, whereas MMRM analyses were significant at each year for TKV and nonsignificant for eGFR. Increasing TKV correlated with decreasing eGFR (r = -0.21, P < 0.01).
Conclusion: ADPKD cyst growth progresses more slowly with tolvaptan than in historical controls, but AEs are common.
Trial registration: ClinicalTrials.gov NCT00413777 NCT00841568.
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Source: PubMed