Kyriazis Periklis, Tiwary Abhinav, Freeman Jonathan, Landry Daniel, Braden Gregory
Dept. of Internal Medicine, University of Massachusetts Medical School -Baystate, Springfield, MA, USA.
Division of Nephrology, University of Massachusetts Medical School -Baystate, Springfield, MA, USA.
J Med Case Rep. 2021 Apr 3;15(1):186. doi: 10.1186/s13256-021-02766-w.
Immune checkpoint inhibitors and mitogen-activated protein kinase inhibitors have become the standard of care in patients with advanced melanoma bearing V600 mutations. However, little is known about their nephrotoxicity. To date, only two cases of anti-glomerular basement membrane glomerulonephritis after exposure to checkpoint inhibitors have been documented. Herein, we report the first case of a patient with metastatic melanoma who developed linear Immunoglobulin G 3+, Immunoglobulin A 2+, kappa 2+, lambda 1+ anti-glomerular basement membrane glomerulonephritis with negative serology following treatment with checkpoint inhibitors and subsequently mitogen-activated protein kinase inhibitors.
A 58-year-old Caucasian male was referred to our outpatient nephrology clinic with acute kidney injury and proteinuria. He had received three cycles of ipilimumab and nivolumab for recurrent melanoma positive for the BRAF V600E mutation with metastasis to the lungs. Immunotherapy had been discontinued in the setting of severe adverse effects including dermatitis, colitis, and hepatitis. Because of persistent bilateral lung metastases and left pleural metastases, the patient had been initiated on dabrafenib and trametinib until his presentation to our clinic 6 months later. On presentation, his blood pressure was 172/89 mm/Hg and had 2+ edema bilaterally. His creatinine level was 2.4 mg/dL from a previous normal baseline with a urinary protein-to-creatinine ratio of 2 g/g. His urinalysis showed dysmorphic erythrocytes and red blood cell casts. Serologic testing was negative for antineutrophilic cytoplasmic antibodies, proteinase 3 antigen, myeloperoxidase, and anti-glomerular basement membrane antibody. Complement levels were normal. A renal biopsy showed focal crescentic (2 of 15 glomeruli with cellular crescents), proliferative, and sclerosing glomerulonephritis with diffuse linear staining of glomerular capillary loops dominant for IgG (3+), IgA (2+), kappa (2+), and lambda (1+) minimal changes. He was initiated on oral cyclophosphamide and pulse intravenous methylprednisolone followed by oral prednisone for 6 months, which stabilized his renal function until reinitiation of immunotherapy.
Acute kidney injury is an increasingly reported adverse effect of both drug classes, mostly affecting the tubulointerstitial compartment and infrequently the glomerulus. Although the biologic effect of these drugs on immune cells is not entirely understood, it is possible that BRAF-induced podocyte injury in combination with direct T-cell-mediated glomerular injury facilitated by checkpoint inhibitors led to the unmasking of cryptic antigens, loss of self-tolerance, and autoimmunity. More importantly, we show that treatment with corticosteroids and cyclophosphamide was able to improve and stabilize our patient's renal function until the reinitiation of immunotherapy.
免疫检查点抑制剂和丝裂原活化蛋白激酶抑制剂已成为携带V600突变的晚期黑色素瘤患者的标准治疗方案。然而，关于它们的肾毒性知之甚少。迄今为止，仅有两例接触检查点抑制剂后发生抗肾小球基底膜肾小球肾炎的病例被记录。在此，我们报告首例转移性黑色素瘤患者，在用检查点抑制剂及随后的丝裂原活化蛋白激酶抑制剂治疗后，出现线性免疫球蛋白G 3+、免疫球蛋白A 2+、κ2+、λ1+抗肾小球基底膜肾小球肾炎，血清学检查为阴性。
一名58岁的白种男性因急性肾损伤和蛋白尿被转诊至我们的门诊肾病科。他因BRAF V600E突变阳性且有肺转移的复发性黑色素瘤接受了三个周期的伊匹木单抗和纳武单抗治疗。由于包括皮炎、结肠炎和肝炎在内的严重不良反应而停用了免疫治疗。由于双侧肺转移和左胸膜转移持续存在，患者开始使用达拉非尼和曲美替尼，直到6个月后到我们诊所就诊。就诊时，他的血压为172/89 mmHg，双侧有2+水肿。他的肌酐水平从之前的正常基线升至2.4 mg/dL，尿蛋白与肌酐比值为2 g/g。他的尿液分析显示异形红细胞和红细胞管型。抗中性粒细胞胞浆抗体、蛋白酶3抗原、髓过氧化物酶和抗肾小球基底膜抗体的血清学检测均为阴性。补体水平正常。肾活检显示局灶性新月体形成（共15个肾小球，2个有细胞性新月体）、增殖性和硬化性肾小球肾炎，肾小球毛细血管袢弥漫性线性染色，以IgG（3+）、IgA（2+）κ（2+）和λ（1+）为主，改变轻微。他开始口服环磷酰胺和静脉注射甲泼尼龙冲击治疗，随后口服泼尼松6个月，这使他的肾功能稳定，直到重新开始免疫治疗。
急性肾损伤是这两类药物越来越常见的不良反应，主要影响肾小管间质，很少影响肾小球。尽管这些药物对免疫细胞的生物学作用尚未完全了解，但有可能BRAF诱导的足细胞损伤与检查点抑制剂促进的直接T细胞介导的肾小球损伤相结合，导致隐匿抗原暴露、自身耐受性丧失和自身免疫。更重要的是，我们表明，使用皮质类固醇和环磷酰胺治疗能够改善并稳定我们患者的肾功能，直到重新开始免疫治疗。
