BACKGROUND AND OBJECTIVES: The two largest studies of mammalian target of rapamycin inhibitor treatment of autosomal dominant polycystic kidney disease (ADPKD) demonstrated no clear benefit on the primary endpoint of total kidney volume (TKV) or on eGFR. The present study evaluated two levels of rapamycin on the 12-month change in (125)I-iothalamate GFR (iGFR) as the primary endpoint and TKV secondarily. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a 12-month open-label pilot study, 30 adult patients with ADPKD were randomly assigned to low-dose (LD) rapamycin (rapamycin trough blood level, 2-5 ng/ml) (LD group, n=10), standard-dose (STD) rapamycin trough level (>5-8 ng/ml) (STD group, n=10), or standard care (SC group, n=10). They were evaluated with iGFR and noncontrast computed tomography. RESULTS:Change in iGFR at 12 months was significantly higher in the LD group (7.7±12.5 ml/min per 1.73 m(2); n=9) than in the SC group (-11.2 ± 9.1 ml/min per 1.73 m(2); n=9) (LD versus SC: P<0.01). Change in iGFR at 12 months in the STD group (1.6 ± 12.1 ml/min per 1.73 m(2); n=8) was not significantly greater than that in the SC group (P=0.07), but it was in the combined treatment groups (LD+STD versus SC: P<0.01). Neither eGFR calculated by the CKD-Epidemiology Collaboration equation nor TKV (secondary endpoint) changed significantly from baseline to 12 months in any of the groups. On the basis of results of the mixed model, during the study, patients in the LD group had significantly lower trough blood levels of rapamycin (mean range ± SD, 2.40 ± 0.64 to 2.90 ± 1.20 ng/ml) compared with those in the STD group (3.93 ± 2.27 to 5.77 ± 1.06 ng/ml) (P<0.01). CONCLUSION:Patients with ADPKD receivingLD rapamycin demonstrated a significant increase in iGFR compared with those receiving standard care, without a significant effect on TKV after 12 months.
RCT Entities:
BACKGROUND AND OBJECTIVES: The two largest studies of mammalian target of rapamycin inhibitor treatment of autosomal dominant polycystic kidney disease (ADPKD) demonstrated no clear benefit on the primary endpoint of total kidney volume (TKV) or on eGFR. The present study evaluated two levels of rapamycin on the 12-month change in (125)I-iothalamate GFR (iGFR) as the primary endpoint and TKV secondarily. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a 12-month open-label pilot study, 30 adult patients with ADPKD were randomly assigned to low-dose (LD) rapamycin (rapamycin trough blood level, 2-5 ng/ml) (LD group, n=10), standard-dose (STD) rapamycin trough level (>5-8 ng/ml) (STD group, n=10), or standard care (SC group, n=10). They were evaluated with iGFR and noncontrast computed tomography. RESULTS: Change in iGFR at 12 months was significantly higher in the LD group (7.7±12.5 ml/min per 1.73 m(2); n=9) than in the SC group (-11.2 ± 9.1 ml/min per 1.73 m(2); n=9) (LD versus SC: P<0.01). Change in iGFR at 12 months in the STD group (1.6 ± 12.1 ml/min per 1.73 m(2); n=8) was not significantly greater than that in the SC group (P=0.07), but it was in the combined treatment groups (LD+STD versus SC: P<0.01). Neither eGFR calculated by the CKD-Epidemiology Collaboration equation nor TKV (secondary endpoint) changed significantly from baseline to 12 months in any of the groups. On the basis of results of the mixed model, during the study, patients in the LD group had significantly lower trough blood levels of rapamycin (mean range ± SD, 2.40 ± 0.64 to 2.90 ± 1.20 ng/ml) compared with those in the STD group (3.93 ± 2.27 to 5.77 ± 1.06 ng/ml) (P<0.01). CONCLUSION:Patients with ADPKD receiving LD rapamycin demonstrated a significant increase in iGFR compared with those receiving standard care, without a significant effect on TKV after 12 months.
Authors: Richard Fox; Thomas Q Nhan; G Lynn Law; David R Morris; W Conrad Liles; Stephen M Schwartz Journal: EMBO J Date: 2007-01-24 Impact factor: 11.598
Authors: Jonathan M Shillingford; Noel S Murcia; Claire H Larson; Seng Hui Low; Ryan Hedgepeth; Nicole Brown; Chris A Flask; Andrew C Novick; David A Goldfarb; Albrecht Kramer-Zucker; Gerd Walz; Klaus B Piontek; Gregory G Germino; Thomas Weimbs Journal: Proc Natl Acad Sci U S A Date: 2006-03-27 Impact factor: 11.205
Authors: Peter C Harris; Kyongtae T Bae; Sandro Rossetti; Vicente E Torres; Jared J Grantham; Arlene B Chapman; Lisa M Guay-Woodford; Bernard F King; Louis H Wetzel; Deborah A Baumgarten; Philip J Kenney; Mark Consugar; Saulo Klahr; William M Bennett; Catherine M Meyers; Qin Jean Zhang; Paul A Thompson; Fang Zhu; J Philip Miller Journal: J Am Soc Nephrol Date: 2006-10-11 Impact factor: 10.121
Authors: Andrew D Rule; Vicente E Torres; Arlene B Chapman; Jared J Grantham; Lisa M Guay-Woodford; Kyongtae T Bae; Saulo Klahr; William M Bennett; Catherine M Meyers; Paul A Thompson; J Philip Miller Journal: J Am Soc Nephrol Date: 2006-02-01 Impact factor: 10.121
Authors: Dos D Sarbassov; Siraj M Ali; Shomit Sengupta; Joon-Ho Sheen; Peggy P Hsu; Alex F Bagley; Andrew L Markhard; David M Sabatini Journal: Mol Cell Date: 2006-04-06 Impact factor: 17.970
Authors: Jared J Grantham; Vicente E Torres; Arlene B Chapman; Lisa M Guay-Woodford; Kyongtae T Bae; Bernard F King; Louis H Wetzel; Deborah A Baumgarten; Phillip J Kenney; Peter C Harris; Saulo Klahr; William M Bennett; Gladys N Hirschman; Catherine M Meyers; Xiaoling Zhang; Fang Zhu; John P Miller Journal: N Engl J Med Date: 2006-05-18 Impact factor: 91.245