Atypical Anti-GBM Disease: Importance of Biopsy and Pathway Towards New Epitopes

Introduction: Anti-glomerular basement membrane (anti-GBM) disease is characterized by pathologic antibodies targeting collagen IV epitopes in basement membranes that results in rapidly progressive glomerulonephritis (RPGN). We report a case of atypical anti-GBM disease with undetectable circulating antibodies that presented as acute kidney injury (AKI) and nephrotic syndrome. Case Description: A 46 y.o. male with hypertension and uncontrolled Graves’ disease on methimazole presented with several days of nausea and vomiting and sudden onset lower extremity edema. On exam, blood pressure was 199/95 mmHg and he had 2+ pitting edema; lung sounds were normal. Labs showed a serum creatinine of 14.5 mg/dL (baseline 1.46 mg/dL), albumin of 2.1 mg/dL, and undetectable TSH. Urinalysis had 5-10 RBCs and WBCs, and a few hyaline casts; UPCR was >4 g/g. Serologic testing was negative (C3, C4, ANCA, anti-PLA2R, anti-GBM, ANA, anti-histone Ab, HIV, HBV, HCV, monoclonal protein). He initially declined kidney biopsy and received diuretics for his edema. His creatinine improved to ~4 mg/dL but urine sediment showed RBC casts and acanthocytes, and UPCR was 6 g/g. One week later, the biopsy showed crescentic glomerulonephritis with polyclonal IgG linear staining along the GBM with a concurrent collapsing FSGS. Repeat serum anti-GBM antibody testing was negative. APOL1 testing revealed 2 high risk alleles. He was treated with IV steroids and IV cyclophosphamide and discharged on a steroid taper. Creatinine improved to 2.5 mg/dL. Discussion: This is a rare case of atypical anti-GBM disease in the setting of methimazole-treated Graves’ disease. Both Graves’ disease and methimazole are associated with glomerular diseases, including membranous nephropathy, ANCA vasculitis, and minimal change disease. This case suggests that atypical anti-GBM should also be considered when such patients have RPGN or nephrotic syndrome. It also underscores the importance of kidney biopsy in the setting of an active urine sediment, even when kidney function is improving. Our case offers additional insight into this rare disease and may speed discovery of previously unknown GBM epitopes that contribute to disease.