title: Acceleration of Proteinuria without Significant Impact on Renal Function and Its Protection by Angiotensin II Receptor Blocker in Rats Treated with Axitinib.
abstract: 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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  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.affiliation: Division of Urology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Imai
authors.affiliation: Division of Urology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. hideakimiyake@hotmail.com.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Miyake
authors.affiliation: Division of Urology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Fujisawa
mesh_terms: D057911:Angiotensin Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000077784:Axitinib; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects*; D007191:Indazoles / Q000009:adverse effects*; D007668:Kidney / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D011507:Proteinuria / Q000209:etiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D000077784:Axitinib