C3-Glomerulonephritis in the setting of immune checkpoint inhibitor and tyrosine kinase inhibitor use: A rare unintended complication

Introduction: Kidney-related adverse events associated with Immune Checkpoint Inhibitors occur at an incidence range of 2%–5%, with an incidence of KDIGO class III acute kidney injury of 0.6%. We report a case of C3-Glomerulonephritis associated with concomitant use of Pembrolizumab and Lenvatinib that resulted in kidney failure. Case description: A 52-year-old male with a prior medical history notable for stage IV Renal Cell Carcinoma with lung metastasis, treated with Lenvatinib and Pembrolizumab, presented to the emergency room with hypertensive urgency, worsening anasarca, and was found to have nephrotic-range proteinuria and hematuria. The patient was empirically started on Prednisone and underwent kidney biopsy which was notable for Immunoglobulin positive C3 diffuse proliferative glomerulonephritis. He was found to have low complement C3, elevated sC5b-9 (SMAC) with elevated CBb, and low Factor H which are consistent with alternative pathway activation. Complement factor H antibody testing was negative, and genetic testing was unrevealing, though there were variants of undetermined significant noted. Eculizumab was planned at time of discharge, however, administration was delayed by 2 months. Clinic follow-up 1 month after initiation of Eculizumab revealed no improvement in kidney function. The patient remains dialysis dependent. Discussion: The case we describe highlights a unique diagnostic challenge associated with ICI-induced AKI with respect to concomitant VEGF use. The case adds to the repertoire of C3GN associated with these drugs that, unlike the reported cases of partial or complete recovery, instead resulted in kidney failure. We revisit the role of kidney biopsy in patients who present with AKI after treatment with these drugs, instead of empiric treatment, especially if there is suggestion of any alternate process.