title: BRAF Signaling Pathway Inhibition, Podocyte Injury, and Nephrotic Syndrome.
abstract: 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.
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Perico
authors.affiliation: Unit of Medical Oncology, Azienda Socio Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Mandalà
authors.affiliation: Rare Disease Unit, Azienda Socio Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Arrigo
authors.initials: A
authors.lastname: Schieppati
authors.affiliation: Rare Disease Unit, Azienda Socio Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Camillo
authors.initials: C
authors.lastname: Carrara
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Rizzo
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Conti
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Lorena
authors.initials: L
authors.lastname: Longaretti
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Ariela
authors.initials: A
authors.lastname: Benigni
authors.affiliation: 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. Electronic address: giuseppe.remuzzi@marionegri.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects*; D008545:Melanoma / Q000188:drug therapy*; D009404:Nephrotic Syndrome / Q000139:chemically induced*; D010091:Oximes / Q000009:adverse effects*; D050199:Podocytes / Q000187:drug effects*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000502:physiology; D011728:Pyridones / Q000009:adverse effects*; D011744:Pyrimidinones / Q000009:adverse effects*; D015398:Signal Transduction / Q000187:drug effects*; D012878:Skin Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D010091:Oximes; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib
keywords: BRAF inhibitor; BRAF signaling pathway; Dabrafenib; MEK inhibitor; PLCε1; case report; glomerulopathy; melanoma; nephrotic syndrome; nephrotoxicity; podocyte injury; proteinuria; renal biopsy; targeted cancer therapy; trametinib