The Second Slice Tells the Story: Evolving Cryoglobulinemia in Mesangial Glomerulonephritis

Introduction: Mesangial proliferative glomerulonephritis (MesPGN) is a non-specific histologic finding that may reflect infection, autoimmunity, or lymphoproliferative disease. We present a rare case in which repeat kidney biopsy revealed evolving type II cryoglobulinemia in a patient initially presumed to have drug-induced lupus. This case highlights the diagnostic value of re-biopsy in patients with atypical progression or treatment resistance. Case Description: A 78-year-old male with hypertension, atrial fibrillation, pulmonary hypertension, peripheral arterial disease, and type 2 diabetes presented with intermittent weakness, subjective fevers, and pancytopenia. Initial serologies were notable for positive ANA, anti-dsDNA, and mildly elevated anti-histone antibodies, raising concern for drug-induced lupus. Renal function was normal and he was started on prednisone and hydroxychloroquine. Weeks later, he developed hematuria, sub nephrotic range proteinuria, and worsening renal function. A kidney biopsy for presumed lupus nephritis instead revealed MesPGN with 3+ mesangial IgM and weak C3 on immunofluorescence (IF). He remained on immunosuppressive therapy. With clinical relapse, labs showed false-positive Hepatitis B IgM, positive pertussis IgM (treated), and normalized lupus serologies followed by the steroid taper. He re-presented with oliguric acute kidney injury with repeat work up revealing low C3, pancytopenia, elevated ESR and significantly high rheumatoid factor levels. Repeat renal biopsy showed worsening mesangial proliferation, intracapillary PAS+ hyaline thrombi, and RBC casts. IF showed persistent 3+ IgM, new 1+ nuclear IgG, and 1+ C3 with EM showing subendothelial dense deposits —suspicious for type II cryoglobulinemic GN. He was subsequently given pulse-dose steroids with immediate renal response and clinical improvement. Rituximab was planned for long-term management. Discussion: This case highlights the diagnostic complexity of MesPGN in an elderly patient with multiple autoimmune and infectious risk factors. The initial biopsy dispelled a presumed diagnosis and shifted management, but persistent deterioration prompted further evaluation. The repeat biopsy demonstrated an evolving disease process and uncovered a rare etiology. This case underscores the importance of not anchoring on initial biopsy findings in patients with ongoing or worsening disease.