Maanaoui Mehdi, Saint-Jacques Camille, Gnemmi Viviane, Frimat Marie, Lionet Arnaud, Hazzan Marc, Noël Christian, Provot François
Department of Nephrology, CHU Lille, University of Lille, Lille, France Department of Pathology, University of Lille, Inserm, CHU Lille, UMR-S 1172 - JPARC - Jean-Pierre Aubert Research Center, Lille, France.
Medicine (Baltimore). 2017 Jun;96(25):e7196. doi: 10.1097/MD.0000000000007196.
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.
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.
Kidney biopsy showed extracapillary proliferation in the glomeruli with a granulomatous reaction.
Renal function recovered completely after withdrawal of the chemotherapy.
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.
BRAF和MEK抑制剂通过抑制丝裂原活化蛋白激酶（MAP激酶）途径，显著改善了转移性黑色素瘤的预后。它们与罕见的肾脏不良事件相关。其中大多数与BRAF抑制剂的使用有关，涉及间质性肾炎伴急性肾小管坏死。
我们报告了一例独特的肾小球肾炎合并肾肉芽肿性血管炎病例，患者为一名被诊断为转移性黑色素瘤的患者，正在接受BRAF和MEK抑制剂治疗。患者为一名55岁女性，右大腿出现黑色素瘤并伴有肺转移。治疗于2015年11月开始，分别使用新型BRAF抑制剂恩考芬尼和MEK抑制剂比美替尼。治疗开始两个月后，她的肾功能恶化，出现大量蛋白尿。
肾活检显示肾小球毛细血管外增生并伴有肉芽肿反应。
停止化疗后肾功能完全恢复。
文献中报道的所有继发于BRAF和MEK抑制剂的肾脏不良事件均与BRAF抑制剂的使用有关。一些先前报道的机制研究也为BRAF抑制剂与足细胞损伤之间的关系提供了见解。因此，恩考芬尼很可能是该疾病的主要病因。然而，有证据表明抑制MAP激酶途径也可能增强自身免疫。因此，比美替尼可能也起到了作用，BRAF和MEK抑制剂的联合使用可能促使了这种自身免疫性肾病的发生。
