Satoshi Imai1, Hideaki Miyake2, Masato Fujisawa1. 1. Division of Urology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. 2. Division of Urology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. hideakimiyake@hotmail.com.
Abstract
BACKGROUND: Proteinuria is a dose-associated adverse event induced by anti-angiogenic agents; however, the mechanism mediating the induction of proteinuria by this type of agent remains largely unknown. The objective of this study was to assess the effects of treatment with axitinib and/or angiotensin II receptor blocker (ARB) on urinary protein excretion and renal function. MATERIALS AND METHODS: Thirty-five rats were randomly selected for treatment with following agents for 4 weeks: vehicle (group A), candesartan (group B), axitinib (group C), axitinib plus candesartan (group D), or axitinib and no treatment for subsequent 2 weeks (group E). RESULTS: After completion of treatment schedule, urine protein-to-creatinine ratio (UPC) in group C was significantly higher than those in groups A and B, while the additional administration of candesartan resulted in the significant reduction of UPC in group D compared with group C. Following the no treatment interval for 2 weeks, UPC in group E significantly decreased compared with that in group C. There were no significant differences in serum creatinine or blood urea nitrogen level among the five groups. Furthermore, semiquantitative evaluation of immunofluorescence findings showed that the expression levels of both nephrin and podocin in rat kidneys were inversely associated with the UPC value throughout these five groups. CONCLUSIONS: Despite the acceleration of proteinuria involving the downregulation of slit diaphragm-associated proteins, axitinib may not have an adverse impact on renal function, and axitinib-induced proteinuria can be partially prevented by additional treatment with ARB and reversibly recovered by its transient dose-interruption.
BACKGROUND:Proteinuria is a dose-associated adverse event induced by anti-angiogenic agents; however, the mechanism mediating the induction of proteinuria by this type of agent remains largely unknown. The objective of this study was to assess the effects of treatment with axitinib and/or angiotensin II receptor blocker (ARB) on urinary protein excretion and renal function. MATERIALS AND METHODS: Thirty-five rats were randomly selected for treatment with following agents for 4 weeks: vehicle (group A), candesartan (group B), axitinib (group C), axitinib plus candesartan (group D), or axitinib and no treatment for subsequent 2 weeks (group E). RESULTS: After completion of treatment schedule, urine protein-to-creatinine ratio (UPC) in group C was significantly higher than those in groups A and B, while the additional administration of candesartan resulted in the significant reduction of UPC in group D compared with group C. Following the no treatment interval for 2 weeks, UPC in group E significantly decreased compared with that in group C. There were no significant differences in serum creatinine or blood ureanitrogen level among the five groups. Furthermore, semiquantitative evaluation of immunofluorescence findings showed that the expression levels of both nephrin and podocin in rat kidneys were inversely associated with the UPC value throughout these five groups. CONCLUSIONS: Despite the acceleration of proteinuria involving the downregulation of slit diaphragm-associated proteins, axitinib may not have an adverse impact on renal function, and axitinib-induced proteinuria can be partially prevented by additional treatment with ARB and reversibly recovered by its transient dose-interruption.
Authors: Tobias B Huber; Bernhard Schermer; Roman Ulrich Müller; Martin Höhne; Malte Bartram; Andrea Calixto; Henning Hagmann; Christian Reinhardt; Fabienne Koos; Karl Kunzelmann; Elena Shirokova; Dietmar Krautwurst; Christian Harteneck; Matias Simons; Hermann Pavenstädt; Dontscho Kerjaschki; Christoph Thiele; Gerd Walz; Martin Chalfie; Thomas Benzing Journal: Proc Natl Acad Sci U S A Date: 2006-11-01 Impact factor: 11.205
Authors: K Schwarz; M Simons; J Reiser; M A Saleem; C Faul; W Kriz; A S Shaw; L B Holzman; P Mundel Journal: J Clin Invest Date: 2001-12 Impact factor: 14.808