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VEGF-VEGFR2 inhibitor-associated hyaline occlusive glomerular microangiopathy: a Japanese single-center experience

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Abstract

Background

Inhibitors of vascular endothelial growth factor (VEGF)-VEGF receptor 2 (VEGFR2) signaling, such as bevacizumab (Bmab), are used for the treatment of various advanced cancers. However, these inhibitors induce renal thrombotic microangiopathy (TMA). Recently, two European cohort studies showed a distinctive histopathological pseudothrombotic pattern different from TMA in Bmab-treated patients.

Methods

We analyzed 9 renal biopsies from proteinuric cancer patients treated with VEGF-VEGFR2 inhibitors in our Japanese cohort. Clinical and laboratory features were also assessed in these patients.

Results

All 9 patients had moderate to heavy proteinuria with normal or slightly elevated serum creatinine levels. On light microscopy, a patchy pattern of hemispherical/spherical lesions along glomerular capillary walls was a characteristic finding. On immunofluorescence microscopy, staining for immunoglobulins (IgM dominant) at varying intensities was observed mainly along glomerular capillary walls. Especially, hemispherical/spherical positive staining for immunoglobulins was a characteristic pattern. Immunohistochemical studies showed positive staining for immunoglobulins and negative staining for CD61-positive platelets in capillary hemispherical/spherical lesions and positive VEGF staining in podocytes. On electron microscopy, variably electron-dense material in dilated glomerular capillaries and partial effacement of podocyte foot processes were observed. After the withdrawal of VEGF-VEGFR2 inhibitors, proteinuria improved without any specific treatment in 8 patients.

Conclusions

Histopathological findings in our patients treated with VEGF-VEGFR2 inhibitors were consistent with those observed in the recently described new form of Bmab-associated hyaline occlusive glomerular microangiopathy. This form should be considered in proteinuric cancer patients treated with VEGF-VEGFR2 inhibitors. Discontinuing VEGF-VEGFR2 inhibitors may lead to improvement of glomerular microangiopathy induced by these drugs.

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Acknowledgements

The authors thank all the doctors at our affiliated hospitals for the referral of the patients. This study was supported in part by private donations from Dr. Ken Satoh, Satoh Naika Clinic, Sakata, Japan, and Dr. Masaru Togashi, Akita Renal, Collagen and Rheumatic Disease Clinic, Akita, Japan.

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Authors and Affiliations

  1. Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan

    Masatoyo Ozawa, Atsushi Komatsuda & Naoto Takahashi

  2. Department of Nephrology, Akita Kousei Medical Center, Akita, Japan

    Hiroshi Ohtani

  3. Department of Life Science, Graduate School of Engineering Science, Akita University, 1-1 Tegatagakuen-machi, Akita, 010-8502, Japan

    Hideki Wakui

Authors
  1. Masatoyo Ozawa
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  2. Hiroshi Ohtani
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  3. Atsushi Komatsuda
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  4. Hideki Wakui
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  5. Naoto Takahashi
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Corresponding author

Correspondence to Hideki Wakui.

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Conflict of interest

Dr. Naoto Takahashi has received grants and personal fees from Novartis Pharmaceuticals, grants and personal fees from Pfizer, grants and personal fees from Otsuka Pharmaceutical, grants from Kyowa Kirin, grants from Astellas Pharma, grants from Chugai Pharmaceutical, grants from Asahi Kasei Pharma, grants from Ono Pharmaceutical, and grants from Eisai Pharmaceuticals, outside of the submitted work. The remaining authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee at which the studies were conducted (IRB approval number 1026), and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Ozawa, M., Ohtani, H., Komatsuda, A. et al. VEGF-VEGFR2 inhibitor-associated hyaline occlusive glomerular microangiopathy: a Japanese single-center experience. Clin Exp Nephrol 25, 1193–1202 (2021). https://doi.org/10.1007/s10157-021-02090-z

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  • DOI: https://doi.org/10.1007/s10157-021-02090-z

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