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Acceleration of Proteinuria without Significant Impact on Renal Function and Its Protection by Angiotensin II Receptor Blocker in Rats Treated with Axitinib

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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.

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Authors and Affiliations

  1. Division of Urology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan

    Satoshi Imai, Hideaki Miyake & Masato Fujisawa

Authors
  1. Satoshi Imai
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  2. Hideaki Miyake
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  3. Masato Fujisawa
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Corresponding author

Correspondence to Hideaki Miyake.

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Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed, and the studies have been approved by a research ethics committee at the institution or practice at which the studies were conducted (where such a committee exists).

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None.

Conflict of Interest

Satoshi Imai, Hideaki Miyake, and Masato Fujisawa have no conflicts of interest to declare and did not receive any financial support.

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Imai, S., Miyake, H. & Fujisawa, M. Acceleration of Proteinuria without Significant Impact on Renal Function and Its Protection by Angiotensin II Receptor Blocker in Rats Treated with Axitinib. Targ Oncol 11, 309–315 (2016). https://doi.org/10.1007/s11523-015-0393-6

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  • DOI: https://doi.org/10.1007/s11523-015-0393-6

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