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BRAF Signaling Pathway Inhibition, Podocyte Injury, and Nephrotic Syndrome

  • Author Footnotes
    ∗ L.P., M.M., and A.S. contributed equally to this work.
    Luca Perico
    Footnotes
    ∗ L.P., M.M., and A.S. contributed equally to this work.
    Affiliations
    IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
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  • Author Footnotes
    ∗ L.P., M.M., and A.S. contributed equally to this work.
    Mario Mandalà
    Footnotes
    ∗ L.P., M.M., and A.S. contributed equally to this work.
    Affiliations
    Unit of Medical Oncology, Azienda Socio Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy
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  • Author Footnotes
    ∗ L.P., M.M., and A.S. contributed equally to this work.
    Arrigo Schieppati
    Footnotes
    ∗ L.P., M.M., and A.S. contributed equally to this work.
    Affiliations
    Rare Disease Unit, Azienda Socio Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy
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  • Camillo Carrara
    Affiliations
    Rare Disease Unit, Azienda Socio Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy
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  • Paola Rizzo
    Affiliations
    IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
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  • Sara Conti
    Affiliations
    IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
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  • Lorena Longaretti
    Affiliations
    IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
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  • Ariela Benigni
    Affiliations
    IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
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  • Giuseppe Remuzzi
    Correspondence
    Address correspondence to Giuseppe Remuzzi, MD, FRCP, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, 24126 Bergamo, Italy.
    Affiliations
    IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy

    Unit of Nephrology and Dialysis, Azienda Socio Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy

    Department of Biomedical and Clinical Sciences, University of Milan, Milano, Italy
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  • Author Footnotes
    ∗ L.P., M.M., and A.S. contributed equally to this work.
Published:February 24, 2017DOI:https://doi.org/10.1053/j.ajkd.2016.12.013
      Dabrafenib and trametinib, BRAF and MEK inhibitors, respectively, are effective targeted metastatic melanoma therapies, but little is known about their nephrotoxicity. Although tubulointerstitial injury has been the most widely reported renal side effect of targeted melanoma therapy, nephrotic syndrome has not been reported before. We report on a patient with metastatic melanoma who developed nephrotic syndrome during dabrafenib and trametinib treatment. Kidney biopsy showed diffuse loss of podocyte cytoarchitecture, extensive foot-process effacement, and glomerular endothelial injury. Kidney function and glomerular ultrastructural changes recovered fully after drug withdrawal. In vitro, BRAF inhibition decreased PLCε1 expression in podocytes, accompanied by a reduction in nephrin expression and an increase in permeability to albumin. Additionally, these drugs inhibited the podocyte–vascular endothelial growth factor (VEGF) system. In addition to implications for nephrotic syndrome pathophysiology, we suggest that patients given dabrafenib and trametinib be monitored closely for potential glomerular damage.

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