C3 GLOMERULOPATHY ASSOCIATED WITH IMMUNE CHECKPOINT INHIBITOR THERAPY IN A PATIENT WITH MALIGNANT PLEURAL MESOTHELIOMA: A CASE REPORT

Immune checkpoint inhibitors (ICIs) have transformed the management of advanced malignancies but can provoke immune-related adverse events (irAEs). Renal irAEs most commonly manifest as acute tubulointerstitial nephritis; however, glomerular diseases are increasingly recognized. Several reports have indicated that glomerulonephritis induced by ICIs include C3 glomerulopathy (C3G), although its clinicopathological features under ICIs are not fully characterized. We report a biopsy-proven case of C3G during nivolumab plus ipilimumab therapy for malignant pleural mesothelioma, and describe its clinicopathological characteristics and diagnostic evaluation.

A 67-year-old man with biphasic malignant pleural mesothelioma (cT1N1M0, clinical Stage II) was treated with combined nivolumab and ipilimumab, completing eight cycles. Surveillance PET-CT performed two months before admission showed no radiographic evidence of progression. Five days prior to hospitalization, routine testing revealed new renal abnormalities: serum creatinine 1.17 mg/dL, proteinuria 3+ with urine protein/creatinine ratio 1.31 g/gCr, and hematuria 3+. He was admitted to our nephrology department for evaluation and management. A standardized work-up for secondary glomerular disease was undertaken, including complement testing, cryoglobulin assessment, and serologies for selected infections. Percutaneous renal biopsy was performed with light microscopy, immunofluorescence, and electron microscopy to define the lesion and exclude immune complex–mediated or infection-related glomerulonephritis.

Serology demonstrated hypocomplementemia (C3 8.9 mg/dL, C4 3.1 mg/dL, CH50 <10 U/mL). Secondary causes were excluded. Light microscopy showed diffuse endocapillary hypercellularity with double-contoured glomerular basement membranes and conspicuous subendothelial and subepithelial deposits. Immunofluorescence revealed granular C3 deposition along capillary walls and within the mesangium with only weak IgM staining, a pattern supportive of alternative complement pathway activation. Electron microscopy confirmed band-like, continuous, electron-dense deposits within the glomerular basement membrane, establishing the diagnosis of dense deposit disease (DDD), a subtype of C3G. High-dose methylprednisolone pulse therapy was initiated, followed by oral prednisolone 30 mg/day. Renal function, proteinuria, and hematuria improved rapidly after treatment initiation, with stabilization of kidney parameters during early follow-up. The temporal association with ICI exposure, absence of serological evidence for secondary etiologies, and complement-dominant deposition collectively supported ICI-associated C3G.

This case highlights a rare but clinically important form of ICI-related nephrotoxicity. Although tubulointerstitial nephritis remains the prototypical renal irAE, clinicians should consider glomerular disease. Prompt corticosteroid therapy achieved a favorable renal response in our patient, suggesting that timely immunosuppression can be effective even in complement-mediated injury associated with ICIs. As ICI use expands, heightened awareness of C3G as a potential irAE may facilitate earlier recognition, informed counseling, and individualized treatment strategies.