IgM Dominant Proliferative Glomerulonephritis (GN), Undetectable Serum C4, and Chronic Lymphocytic Leukemia (CLL) with Persistently Negative Serological Testing for Type 1 Cryoglobulins

Introduction: Cryoglobulins are immunoglobulins (Ig) that precipitate at < 37°C and dissolve on rewarming. Type I cryoglobulinaemia consists of 1 isotype of monoclonal Ig, whereas type II and type III are classified as mixed cryoglobulinaemia [include IgG & IgM]. We describe a likely longstanding type 1 cryoglobulinemia with persistently negative serological testing in a patient with chronically suppressed/undetectable C4 levels, leukocytoclastic vasculitis, IgM kappa paraproteinemia, and IgM dominance in the kidney biopsy with CLL eventually being diagnosed much later. Case Description: 87-year-old male with diabetes mellitus, chronic leukocytoclastic vasculitis, and persistently low C4 presented with AKI on CKD. Baseline Cr 1.3 mg/dL. Had serum cryoglobulins checked multiple times at different labs that were all negative. Exam sig. for purupuric lesions in LE. Cr 2.3 mg/dL, Sr albumin 3.7 g/dL, UA 1(+) protein, UPCR 340 mg/g, C3 102, C4 <1, RF 72, Sr Kappa (376) and Lambda (138) with FLC 2.7. SPEP/SIFE negative. UPEP/UIFE revealed M-spike with monoclonal IgM kappa LC. Sr cryoglobulin, HCV [Ab & Quant], CCP, and comprehensive GN screen (-). Blood cultures and testing for indolent infections including Bartonella/coxiella (-). ECHO [TTE/TEE] normal. Kidney bx revealed focal proliferative glomerulonephritis. IFTA 50%. IF: Diffuse global granular mesangial staining for IgM [3+], C3 [2+], kappa [2+], and lambda [3+]. Pronase IF negative. EM: No immune deposits. Congo red (-). Patient became sick with worsening abdominal lymphadenopathy that demonstrated IgM kappa CLL [BM Bx neg]. Serum testing for cryoglobulin again (-). Patient subsequently died. Discussion: Testing for cryoglobulins is complicated by lack of reference range, standards, and stringency in maintaining testing temperature conditions. Despite the overall diagnosis favoring a likely an indolent Type 1 cryoglobulinemic process, our case is rare in that it was never detectable [blood, kidney, skin biopsy] and that the eventual diagnosis of CLL appeared 7 years after initial clinical manifestations. Better modalities to diagnose Type 1 cryoglobulins are therefore warranted.