Glomerulonephritis and granulomatous vasculitis in kidney as a complication of the use of BRAF and MEK inhibitors in the treatment of metastatic melanoma

Abstract

Rationale:BRAF and MEK inhibitors have significantly improved the prognosis of metastatic melanoma, by inhibiting both the mitogen-activated protein kinase (MAP-kinase) pathway. They are associated with infrequent adverse kidney events. Most of these are related to the use of BRAF inhibitors and involve interstitial nephritis with acute tubular necrosis.Patient concerns:We report a unique case of glomerulonephritis with renal granulomatous vasculitis in a patient diagnosed with metastatic melanoma treated with BRAF and MEK inhibitors. The patient was a 55-year old woman, who presented a melanoma of the right thigh with pulmonary metastasis. Treatment started in November 2015, with Encorafenib and Binimetinib, new BRAF and MEK inhibitors, respectively. Two months after the beginning of the treatment, there was a worsening of her renal function with significant proteinuria.Diagnoses:Kidney biopsy showed extracapillary proliferation in the glomeruli with a granulomatous reaction.Interventions and outcomes:Renal function recovered completely after withdrawal of the chemotherapy.Lessons:All the reported kidney adverse events secondary to BRAF and MEK inhibitors in the literature are related to the use of BRAF inhibitors. Some previous reported mechanistic investigations also provide insight between BRAF inhibitors and podocytes injuries. Therefore, encorafenib most likely is the main responsible of the disease. However, evidence has emerged that inhibition of the MAP kinase pathway could also enhance autoimmunity. Thus, binimetinib may also have played a role and the combination of BRAF and MEK inhibitors may have facilitated this autoimmune kidney disease.

Tolerability of BRAF/MEK inhibitor combinations: adverse event evaluation and management

“…Vasculitis is mainly described in single patients treated with BRAFi as cutaneous side effects in the context of panniculitis,45 50–53 and as leukocytoclastic vasculitis,45 54 but also involving the kidney as glomerulonephritis55 56 and the eye as retinal vasculitis 57…”

Severe Drug-Induced Liver Injury from Combination Encorafenib/Binimetinib

“…For advanced melanoma, BRAFi and MEKi therapies are novel treatment options, which are rapidly becoming mainstays of treatment in select cases due to their rapid and robust tumoral response and generally well-tolerated AE profile [3, 4, 8, 9]. Nonetheless, as in our patient, severe AEs may be possible, necessitating hospital admission for workup and treatment [3, 4, 10]. Drug-induced liver injury (DILI) is one such complication.…”

Safety of BRAF+MEK Inhibitor Combinations: Severe Adverse Event Evaluation

“…Herein, we report renal toxicities, neurological disorders and hypotension as additional possible safety considerations for clinicians involved in the care of patients treated with BRAFi+MEKi therapy, and specifically with E+B combination. Data on renal toxicities from V+C and D+T are relatively sparse [ 2 , 4 , 26 , 58 , 59 ] and the association with E+B is even less clear [ 19 , 60 , 61 ]. We show that nephrotoxicity associated with E+B is significantly more disproportionate among BRAFi+MEKi and portends poor outcomes.…”