TRIPLE HIT NEPHROPATHY: A CASE OF ATYPICAL ANTI-GBM DISEASE WITH CONCURRENT MEMBRANEOUS NEPHROPATHY AND ANCA ASSOCIATED VASCULITIS

Anti-glomerular basement membrane (GBM) disease targets the α3 chain of type IV collagen within the GBM, causing rapidly progressive glomerulonephritis. Typical Anti-GBM disease involves circulating antibodies and rapid progression, whereas atypical disease lacks detectable antibodies and is often more indolent. Though anti-GBM can co-exist with  antineutrophil cytoplasmic antibodies (ANCA), representing a “dual-positive” overlap, it  rarely coexists with membranous nephropathy (MN). Here, we describe an exceptionally rare “triple-hit” glomerulopathy involving atypical anti-GBM disease, MN, and ANCA-associated vasculitis.

Case presentation: A 61-year-old man with nephrolithiasis and vitiligo presented initially with a purpuric rash and biopsy-proven leukocytoclastic vasculitis (LCV). He had elevated CRP, positive c-ANCA (1:160) and strong PR3 positivity. He also had nasal congestion, perineal and finger ulcers, but no systemic involvement. Following recurrence of LCV, he was diagnosed with granulomatosis with polyangiitis and was started on prednisone and rituximab. One year later, he developed worsening creatinine from a baseline of 0.8 mg/dl to 1.65 mg/dl in April 2025 and 2.15 mg/dl in July 2025, together with persistent PR3 positivity. His Urinalysis showed hematuria and his urine protein/creatinine was 0.4g/g. His kidney biopsy showed focal crescentic GN (cellular crescents in 5/59 glomeruli) with linear IgG deposition along the GBM, stage 1 membranous nephropathy, and chronic changes (Figure 1).  Anti-GBM serology was negative in two different laboratories consistent with atypical anti-GBM disease. PLA2R and THSD7A antibodies were negative. He was treated with IV methylprednisolone, plasmapheresis and oral cyclophosphamide. Despite therapy, creatinine stabilized at ~2 mg/dL. 

Discussion
This case represents an extraordinary overlap of three immune-mediated glomerular pathologies that might have facilitated the development of each other. The association between MN and anti-GBM disease has been described in limited reports, either concurrently or sequentially. One proposed mechanism is a biphasic process in which GBM injury exposes cryptic epitopes, triggering in situ subepithelial immune complex deposition and antibody formation against the GBM or podocyte antigens.

In this patient, isolated PR3-ANCA vasculitis preceded renal involvement, which later showed crescentic glomerulonephritis, linear IgG along the GBM and subepithelial deposits. We hypothesize that ANCA-associated vasculitis might have initiated the cascade by disrupting the GBM, unmasking cryptic antigens and triggering an immune response with subsequent development of MN and atypical anti-GBM disease. Thus, ANCA could have been a priming factor in the evolution of overlapping immune-mediated glomerular injury.

This case underscores the complex nature and plausible interaction of different auto-immune diseases. It also highlights the need for high clinical suspicion and thorough histopathologic evaluation in affected patients, as early identification of multifaceted immune injury may meaningfully influence outcomes.

Teaching Points

Atypical anti-GBM disease present with negative serology but classic linear IgG staining.

ANCA vasculitis may precede or trigger anti-GBM autoimmunity through GBM antigen exposure.

Concurrent membranous nephropathy with Anti-GBM disease suggests a biphasic glomerular injury exposing underlying GBM or podocyte antigens and secondary immune complex formation