Atypical anti-glomerular basement membrane glomerulonephritis in a patient with metastatic melanoma treated with mitogen-activated protein kinase and immune checkpoint inhibitors: a case report

Abstract

Background 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. Case presentation 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. Conclusions 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.

Dabrafenib- and trametinib-associated glomerular toxicity

“…To date, 3 cases of tubulointerstitial nephritis [4,9,10] and 1 case of nephrotic syndrome [5] have been reported following combined treatment with dabrafenib and trametinib. An additional case of glomerulonephritis has been described, but this patient had been treated earlier with the immune checkpoint inhibitors ipilimumab and nivolumab [11] . We found one similar case who received the immune checkpoint inhibitor pembrolizumab, but kidney biopsy data were lacking [12] .…”

“…An additional case of glomerulonephritis has been described, but this patient had been treated earlier with the immune checkpoint inhibitors ipilimumab and nivolumab. [ 11 ] We found one similar case who received the immune checkpoint inhibitor pembrolizumab, but kidney biopsy data were lacking. [ 12 ] Reports on BRAF–mitogen-activated protein kinase combination therapies using drugs other than dabrafenib and trametinib have indicated that acute tubular necrosis and tubulointerstitial nephritis are quite common, [ 13 – 15 ] but only 1 case of glomerulonephritis combined with granulomatous vasculitis has been reported.…”

Atypical anti-glomerular basement membrane disease with membranous hyperplasia: diagnostic challenges and treatment variability

“… linear deposition Negative No electron-dense deposits 30/M [ 26 ] Normal IgG (+);C3 (+);kappa (+); and lambda (+). linear deposition Negative NA 58/M [ 27 ] Focal crescents and proliferative, and sclerosing glomerulonephritis IgG (+); IgA (+); kappa (+); and lambda (+). linear deposition Negative NA 79/M [ 28 ] NA IgG (+); IgA (+); C3 (+); and lambda (+); fibrinogen (+).…”

Acute Kidney Injury Induced by Immune Checkpoint Inhibitors

“…If improvement to stage 1 or remission is more conspicuous, corticosteroids can be reduced gradually and the necessity of resuming ICIs can be discussed if sCr does not increase after withdrawal. However, methylprednisolone or prednisone treatment may not be effective in ICI-induced AIN [13], and in such patients whose symptoms are refractory to corticosteroid therapy or have significant steroid side effects, other immunosuppressant drugs such as mycophenolate, azathioprine, cyclophosphamide, cyclosporine, or infliximab should be considered [53][54][55]. If these measures do not afford effective relief from kidney damage, timely RRT is necessary.…”