Tolvaptan in patients with autosomal dominant polycystic kidney disease
Vicente E Torres, Arlene B Chapman, Olivier Devuyst, Ron T Gansevoort, Jared J Grantham, Eiji Higashihara, Ronald D Perrone, Holly B Krasa, John Ouyang, Frank S Czerwiec, TEMPO 3:4 Trial Investigators, P Gross, B Schulze, D Bichet, D Chauveau, P Peeters, M Voiculescu, P Manunta, J Tuazon, T Watnick, S Goral, S Horie, K Nutahara, V Torres, A Chapman, O Devuyst, R Gansevoort, E Higashihara, R Perrone, J Ouyang, F Czerwiec, S Goldstein, B Cowley, M Fukagawa, R Torra, L J Wei, T Cook, R Toto, R Agarwal, P August, G Bakris, S Beddhu, H Corwin, L Ruilope, G Rosa-Diez, J De La Fuente, R Martin, P Massari, P Novoa, M Rial, A Wasserman, R Faull, I Fraser, D Johnson, E Pedagagos, M Lian, C Pollock, B Cooper, G Rangan, G Russ, S McDonald, M Thomas, D Khoo, R Walker, O Devuyst, Y Pirson, P Peeters, V Laecke, P Van der Niepen, J Sennesael, P Barre, A Alam, D Bichet, S Soroka, H Dieperink, S Strandgaard, L Juhl Petersen, F Berthoux, F Berthoux, B Canaud, A Gontiers-Picard, D Chauveau, A Huart, C Combe, Y Delmas, B Dussol, F Berthoux, M Laville, F Guebre-Egziabher, F Mignon, C Michel, P Rieu, N Noel, J P Ryckelynck, T Lobbedez, F H Dellanna, W Kleophas, P Gross, T Feldkamp, O Witzke, J Nurnberger, B D Schulze, R Zeltner, G Walz, M Zeier, C Sommerer, S Bianchi, G Capasso, N Miranda, R Magistroni, P Manunta, M Bracale, G Remuzzi, S Rota, G Villa, P Tilocca, K Asahi, T Kato, M Endo, T Umezono, Y Fujigaki, A Kato, A Fukatsu, H Hasegawa, Y Tayama, M Hasegawa, S Horie, T Hosoya, K Hanaoka, N Iehara, A Fukatsu, Y Iino, S Tsuruoka, E Imai, Y Isaka, E Imai, E Ishimura, S Ito, H Sato, K Kamata, H Sakamoto, K Kamura, T Kato, E Kusano, S Muto, M Kuwahara, A Matsubara, N Yorioka, T Mochizuki, S Muto, S Horie, I Narita, Y Naya, N Nihei, N Yukio, S Nishio, K Nitta, K Tsuchiya, K Nutahara, M Okamura, S Sasaki, T Rai, K Seta, A Sugawara, S Shibazaki, A Sugawara, S Sugiyama, K Tabei, K Takaichi, K Tomita, K Kitamura, Y Tsukamoto, K Tsuruya, T Nakano, Y Ubara, T Watanabe, T Yamamoto, N Yorioka, K Yoshida, D Ishii, Y Yuzawa, M Hasegawa, R Gansevoort, E Meijer, M Vervloet, K Ciechanowski, M Wisniewska, M Gutowska-Jablonska, M Marcinkowska-Królewicz, W Klatko, T Wiśniewski, M Klinger, M Krajewska, A Ksiazek, G Orłowska, R Malecki, J Gontarek-Kacprzak, M Nowicki, A Makówka, B Rutkowski, W Wołyniec, A Rydzewski, W Sulowicz, P Jasik, A Covic, C Volovat, G Mircescu, L Petrescu, M Voiculescu, R Bobeica, O Barbarash, L Chesnokova, S Borovoy, L Demina, G Shostka, M Idovu, L Tkalich, O Geynits, N Tomilina, L Foggensteiner, S Holt, J Kingswood, S Lambie, R Peel, I MacDougall, B Tucker, I MacPhee, A Maxwell, H Brown, A Mikhail, L Bastin, N Turner, J Neary, D Wheeler, P Maxwell, M Wilkie, A Ong, D Zehnder, N Aldridge, S Adler, M Klein, D Battle, W Bennett, B Berger, K Dell, J Blumenfeld, S Donahue, P Bolin, R Browder, A Perry, A Chapman, F Rahbari Oskoui, M Culpepper, N Dahl, C Edelstein, L Clegg, D Fischer, S Goral, M Kaplan, K Kaveh, R Pankhaniya, M Koren, K Mansur, R Lafayette, W Bibb Lamar, J Lee, R Mahnensmith, P Nachman, A Mottl, R Perrone, D Miskulin, J Petersen, J Radhakrishnan, M Roppolo, M Basireddy, M Rosner, W K Bolton, G Schulman, L Steed, W M Bennett, T Steinman, V Torres, M Hogan, J Tuazon, R Venuto, T Watnick, S Turban, F Winklhofer, Vicente E Torres, Arlene B Chapman, Olivier Devuyst, Ron T Gansevoort, Jared J Grantham, Eiji Higashihara, Ronald D Perrone, Holly B Krasa, John Ouyang, Frank S Czerwiec, TEMPO 3:4 Trial Investigators, P Gross, B Schulze, D Bichet, D Chauveau, P Peeters, M Voiculescu, P Manunta, J Tuazon, T Watnick, S Goral, S Horie, K Nutahara, V Torres, A Chapman, O Devuyst, R Gansevoort, E Higashihara, R Perrone, J Ouyang, F Czerwiec, S Goldstein, B Cowley, M Fukagawa, R Torra, L J Wei, T Cook, R Toto, R Agarwal, P August, G Bakris, S Beddhu, H Corwin, L Ruilope, G Rosa-Diez, J De La Fuente, R Martin, P Massari, P Novoa, M Rial, A Wasserman, R Faull, I Fraser, D Johnson, E Pedagagos, M Lian, C Pollock, B Cooper, G Rangan, G Russ, S McDonald, M Thomas, D Khoo, R Walker, O Devuyst, Y Pirson, P Peeters, V Laecke, P Van der Niepen, J Sennesael, P Barre, A Alam, D Bichet, S Soroka, H Dieperink, S Strandgaard, L Juhl Petersen, F Berthoux, F Berthoux, B Canaud, A Gontiers-Picard, D Chauveau, A Huart, C Combe, Y Delmas, B Dussol, F Berthoux, M Laville, F Guebre-Egziabher, F Mignon, C Michel, P Rieu, N Noel, J P Ryckelynck, T Lobbedez, F H Dellanna, W Kleophas, P Gross, T Feldkamp, O Witzke, J Nurnberger, B D Schulze, R Zeltner, G Walz, M Zeier, C Sommerer, S Bianchi, G Capasso, N Miranda, R Magistroni, P Manunta, M Bracale, G Remuzzi, S Rota, G Villa, P Tilocca, K Asahi, T Kato, M Endo, T Umezono, Y Fujigaki, A Kato, A Fukatsu, H Hasegawa, Y Tayama, M Hasegawa, S Horie, T Hosoya, K Hanaoka, N Iehara, A Fukatsu, Y Iino, S Tsuruoka, E Imai, Y Isaka, E Imai, E Ishimura, S Ito, H Sato, K Kamata, H Sakamoto, K Kamura, T Kato, E Kusano, S Muto, M Kuwahara, A Matsubara, N Yorioka, T Mochizuki, S Muto, S Horie, I Narita, Y Naya, N Nihei, N Yukio, S Nishio, K Nitta, K Tsuchiya, K Nutahara, M Okamura, S Sasaki, T Rai, K Seta, A Sugawara, S Shibazaki, A Sugawara, S Sugiyama, K Tabei, K Takaichi, K Tomita, K Kitamura, Y Tsukamoto, K Tsuruya, T Nakano, Y Ubara, T Watanabe, T Yamamoto, N Yorioka, K Yoshida, D Ishii, Y Yuzawa, M Hasegawa, R Gansevoort, E Meijer, M Vervloet, K Ciechanowski, M Wisniewska, M Gutowska-Jablonska, M Marcinkowska-Królewicz, W Klatko, T Wiśniewski, M Klinger, M Krajewska, A Ksiazek, G Orłowska, R Malecki, J Gontarek-Kacprzak, M Nowicki, A Makówka, B Rutkowski, W Wołyniec, A Rydzewski, W Sulowicz, P Jasik, A Covic, C Volovat, G Mircescu, L Petrescu, M Voiculescu, R Bobeica, O Barbarash, L Chesnokova, S Borovoy, L Demina, G Shostka, M Idovu, L Tkalich, O Geynits, N Tomilina, L Foggensteiner, S Holt, J Kingswood, S Lambie, R Peel, I MacDougall, B Tucker, I MacPhee, A Maxwell, H Brown, A Mikhail, L Bastin, N Turner, J Neary, D Wheeler, P Maxwell, M Wilkie, A Ong, D Zehnder, N Aldridge, S Adler, M Klein, D Battle, W Bennett, B Berger, K Dell, J Blumenfeld, S Donahue, P Bolin, R Browder, A Perry, A Chapman, F Rahbari Oskoui, M Culpepper, N Dahl, C Edelstein, L Clegg, D Fischer, S Goral, M Kaplan, K Kaveh, R Pankhaniya, M Koren, K Mansur, R Lafayette, W Bibb Lamar, J Lee, R Mahnensmith, P Nachman, A Mottl, R Perrone, D Miskulin, J Petersen, J Radhakrishnan, M Roppolo, M Basireddy, M Rosner, W K Bolton, G Schulman, L Steed, W M Bennett, T Steinman, V Torres, M Hogan, J Tuazon, R Venuto, T Watnick, S Turban, F Winklhofer
Abstract
Background: The course of autosomal dominant polycystic kidney disease (ADPKD) is often associated with pain, hypertension, and kidney failure. Preclinical studies indicated that vasopressin V(2)-receptor antagonists inhibit cyst growth and slow the decline of kidney function.
Methods: In this phase 3, multicenter, double-blind, placebo-controlled, 3-year trial, we randomly assigned 1445 patients, 18 to 50 years of age, who had ADPKD with a total kidney volume of 750 ml or more and an estimated creatinine clearance of 60 ml per minute or more, in a 2:1 ratio to receive tolvaptan, a V(2)-receptor antagonist, at the highest of three twice-daily dose regimens that the patient found tolerable, or placebo. The primary outcome was the annual rate of change in the total kidney volume. Sequential secondary end points included a composite of time to clinical progression (defined as worsening kidney function, kidney pain, hypertension, and albuminuria) and rate of kidney-function decline.
Results: Over a 3-year period, the increase in total kidney volume in the tolvaptan group was 2.8% per year (95% confidence interval [CI], 2.5 to 3.1), versus 5.5% per year in the placebo group (95% CI, 5.1 to 6.0; P<0.001). The composite end point favored tolvaptan over placebo (44 vs. 50 events per 100 follow-up-years, P=0.01), with lower rates of worsening kidney function (2 vs. 5 events per 100 person-years of follow-up, P<0.001) and kidney pain (5 vs. 7 events per 100 person-years of follow-up, P=0.007). Tolvaptan was associated with a slower decline in kidney function (reciprocal of the serum creatinine level, -2.61 [mg per milliliter](-1) per year vs. -3.81 [mg per milliliter](-1) per year; P<0.001). There were fewer ADPKD-related adverse events in the tolvaptan group but more events related to aquaresis (excretion of electrolyte-free water) and hepatic adverse events unrelated to ADPKD, contributing to a higher discontinuation rate (23%, vs. 14% in the placebo group).
Conclusions: Tolvaptan, as compared with placebo, slowed the increase in total kidney volume and the decline in kidney function over a 3-year period in patients with ADPKD but was associated with a higher discontinuation rate, owing to adverse events. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization; TEMPO 3:4 ClinicalTrials.gov number, NCT00428948.).
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Source: PubMed