Atypical Presentation of Monoclonal Gammopathy: Diagnostic Insights from a Case of Cryoglobulinemia-Associated Membranoproliferative Glomerulonephritis

Introduction: Cryoglobulinemia triggered by monoclonal gammopathy (MG) is a rare and diagnostically challenging condition. In uncommon cases, MG—typically regarded as benign—can cause clinically significant organ damage. This report describes a patient with IgM MG leading to cryoglobulinemia and renal injury consistent with membranoproliferative glomerulonephritis (MPGN), raising concern for monoclonal gammopathy of clinical significance (MGCS). Case Description: A 54-year-old male with a history of hypertension, peripheral arterial disease, chronic ulcers, ischemic colitis, pancreatitis, and COPD presented with shortness of breath. CT chest revealed bilateral pleural effusions and ground-glass opacities. Labs showed mild leukocytosis, hemoglobin 10 g/dL, creatinine 1.17 mg/dL, eGFR 74, hypoalbuminemia, and proteinuria. Thoracentesis showed transudative effusions. Echocardiography showed normal systolic/diastolic function. Infectious workup was negative. Serum electrophoresis revealed IgM monoclonal gammopathy with kappa light chain specificity. Bone marrow biopsy and flow cytometry were unremarkable; skeletal survey was negative. He had recurrent admissions with pleural effusions, GI symptoms (diarrhea, pain), and 15-lb weight loss. Kidney function worsened (creatinine 2.42 mg/dL, GFR in 30s), with proteinuria (1.2–1.5 g/day) and hematuria (>10 RBC/hpf). Renal biopsy revealed MPGN with IgM/kappa granular deposits. Electron microscopy showed basement membrane duplication and subendothelial electron-dense deposits. No evidence of light chain deposition disease or amyloidosis. Cryoglobulins were strongly positive (5%). Complement levels were very low (C3 <2 mg/dL, C4 70 mg/dL), with elevated D-dimer (>7.65 µg/mL). Extensive malignancy workup, including CT scans and endoscopies, was negative. He was started on prednisone 60 mg daily and rituximab. PET-CT showed benign vocal cord uptake. Post-treatment, creatinine returned to baseline, though cryoglobulins and complement abnormalities persisted. Discussion: This case underscores the diagnostic complexity of MG-related cryoglobulinemia and MPGN. While B-cell malignancy was ruled out, persistent serologic abnormalities and organ damage suggest MGCS. Treatment led to partial improvement, prompting consideration of initiating therapy for MGRS/MGUS despite traditionally conservative approaches.