Ron T Gansevoort1, Esther Meijer1, Arlene B Chapman2, Frank S Czerwiec3, Olivier Devuyst4,5, Jared J Grantham6, Eiji Higashihara7, Holly B Krasa3, John Ouyang3, Ronald D Perrone8, Vicente E Torres9. 1. Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands. 2. Division of Nephrology, Emory University School of Medicine, 201 Dowman Drive, Atlanta, Ga. 30322, US. 3. Otsuka Pharmaceutical Development and Commercialization, Inc., Rockville, MD 20850 USA. 4. Division of Nephrology, Cliniques Universitaires St. Luc, Université Catholique de Louvain Medical School, 10 Avenue Hippocrate 1200, Brussels, Belgium. 5. Institute of Physiology, Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Häldeliweg 2, 8044 Zürich, Switzerland. 6. Kidney Institute and the Department of Internal Medicine, Kansas University Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160 Kansas City, KS, USA. 7. Department of Urology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo. 181-8611 Japan. 8. Department of Medicine, Division of Nephrology, TuftsMedical Center, Tufts University School of Medicine, 800 Washington St # 400, Boston, MA 02111, USA. 9. Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, 200 First St. SW Rochester, MN 55905, USA.
Abstract
BACKGROUND: The TEMPO 3:4 Trial results suggested that tolvaptan had no effect compared with placebo on albuminuria in autosomal-dominant polycystic kidney disease (ADPKD) patients. However, the use of categorical 'albuminuria events' may have resulted in a loss of sensitivity to detect changes. The aim of this study is to investigate the effects of tolvaptan on albuminuria as a continuous variable. METHODS: Post hoc analysis of a 3-year prospective, blinded randomized controlled trial, including 1375 ADPKD patients. Albuminuria was measured in a spot morning urine sample prior to tolvaptan dosing and expressed as albumin-to-creatinine ratio (ACR). RESULTS: Baseline median (interquartile range) ACR was 3.2 (1.7-7.1) mg/mmol. Of note, 47.9% of ADPKD patients had normal, 48.7% moderately increased and 3.4% severely increased ACR. Subjects with higher baseline ACR had higher blood pressure and total kidney volume (TKV) and lower estimated glomerular filtration rate (eGFR). During follow-up, higher baseline ACR was associated with more rapid eGFR loss (P < 0.0001 for trend), but not with rate of growth in TKV. During the 3-year trial, ACR rose in placebo- and decreased in tolvaptan-treated patients (+0.23 versus -0.40 mg/mmol). The difference ACR increased over time, reaching a maximum of 24% at Month 36 (P < 0.001). At that time only a minor difference in blood pressure was observed (mean arterial pressure -1.9 mmHg for tolvaptan). The decrease in ACR was similar in all subgroups investigated, and remained after withdrawal of study drug. The beneficial effect of tolvaptan on TKV growth and eGFR loss was stronger in patients with higher baseline ACR. CONCLUSIONS: In ADPKD, higher baseline albuminuria was associated with more eGFR loss. Tolvaptan decreased albuminuria compared with placebo, independent of blood pressure. Treatment efficacy of tolvaptan on changes in TKV and eGFR was more readily detected in patients with higher albuminuria.
RCT Entities:
BACKGROUND: The TEMPO 3:4 Trial results suggested that tolvaptan had no effect compared with placebo on albuminuria in autosomal-dominant polycystic kidney disease (ADPKD) patients. However, the use of categorical 'albuminuria events' may have resulted in a loss of sensitivity to detect changes. The aim of this study is to investigate the effects of tolvaptan on albuminuria as a continuous variable. METHODS: Post hoc analysis of a 3-year prospective, blinded randomized controlled trial, including 1375 ADPKDpatients. Albuminuria was measured in a spot morning urine sample prior to tolvaptan dosing and expressed as albumin-to-creatinine ratio (ACR). RESULTS: Baseline median (interquartile range) ACR was 3.2 (1.7-7.1) mg/mmol. Of note, 47.9% of ADPKDpatients had normal, 48.7% moderately increased and 3.4% severely increased ACR. Subjects with higher baseline ACR had higher blood pressure and total kidney volume (TKV) and lower estimated glomerular filtration rate (eGFR). During follow-up, higher baseline ACR was associated with more rapid eGFR loss (P < 0.0001 for trend), but not with rate of growth in TKV. During the 3-year trial, ACR rose in placebo- and decreased in tolvaptan-treated patients (+0.23 versus -0.40 mg/mmol). The difference ACR increased over time, reaching a maximum of 24% at Month 36 (P < 0.001). At that time only a minor difference in blood pressure was observed (mean arterial pressure -1.9 mmHg for tolvaptan). The decrease in ACR was similar in all subgroups investigated, and remained after withdrawal of study drug. The beneficial effect of tolvaptan on TKV growth and eGFR loss was stronger in patients with higher baseline ACR. CONCLUSIONS: In ADPKD, higher baseline albuminuria was associated with more eGFR loss. Tolvaptan decreased albuminuria compared with placebo, independent of blood pressure. Treatment efficacy of tolvaptan on changes in TKV and eGFR was more readily detected in patients with higher albuminuria.
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