Double Trouble? When Myeloperoxidase (MPO) and Proteinase 3 (PR3) "Lie": A Cryoglobulinemia Case Report

Introduction: Cryoglobulinemia, a rare immune-mediated condition can mimic systemic vasculitis leading to diagnostic challenges. Cryoglobulin-induced glomerulonephritis can present with serologic profiles suggestive of ANCA-associated vasculitis with positive PR3 or MPO antibodies. Misinterpretation can result in inappropriate diagnostic-therapeutic approach. Case Description: We present a case of a 44-year-old woman referred for new-onset hypertension and gross hematuria. Physical examination was noted for elevated blood pressure. Labs revealed progressively worsening creatinine, low C4 and dual PR3/MPO positivity. Urinalysis showed microscopic hematuria and proteinuria. Cryoglobulin testing was positive. (Table 1) Kidney biopsy showed immune complex–mediated glomerulonephritis with MPGN pattern. Immunofluorescence revealed polytypic IgG/IgM staining. No crescents were observed. Mycophenolate mofetil 1 g BID was initiated. Upon referral to our clinic, cryoglobulin testing confirmed type II cryoglobulinemia. PR3 transfected cell IFA test was read as negative, suggesting false dual ANCA positivity, leading to mixed cryoglobulinemia-associated MPGN. Evaluations for infections and malignancy was negative. Due to persistent urine sediment activity, glucocorticoids were initiated. Discussion: This case underscores the diagnostic challenge posed by overlapping serologic patterns in cryoglobulinemia and ANCA-associated vasculitis. Confirmatory testing, and integration of serologic, clinical, and histopathologic findings are essential to avoid misdiagnosis. Cryoglobulinemia should be considered in glomerulonephritis with atypical or dual ANCA positivity. Accurate interpretation of serologic and histopathologic findings is essential for accurate diagnosis and targeted therapy.