cryoglobulins are either immunoglobulins or a mix of immunoglobulin and complement , which precipitate when cooled . they typically develop in the context of malignancy , chronic infection or connective tissue disease . there is a significant false - negative rate when testing for cryoglobulin , largely due to suboptimal sample collection and processing . a 75-year - old male was referred to the nephrology service for evaluation of hematuria , proteinuria and an elevated serum creatinine . his antinuclear antibody was positive with a homogenous pattern and he was hypo - complementemic ; however , his anti - double - stranded dna was negative . a renal biopsy was performed , which demonstrated a diffuse endocapillary proliferative glomerulonephritis ( fig . capillary wall kappa , igg , igm and c3 were noted on immunofluorescence ( fig . 2 ) and there were scattered subendothelial electron - dense immune - type deposits on electron microscopy . there was a florid intimal arteritis involving the interlobular caliber arteries . remarkably , coincidental sampling of perinephric fat demonstrated infiltration by a monomorphic population of cd20-positive b lymphocytes , which was suggestive of a low - grade b cell lymphoma ( fig . the suspected diagnosis was type 1 cryoglobulinemia due to an underlying lymphopro - liferative disorder . computed tomography of the thorax , abdomen and pelvis revealed moderate hepatosplenomegaly and enlarged lymph nodes in the anterior mediastinum . however , an initial attempt did not confirm the presence of serum cryoglobulin . due to the strong histological evidence and supportive clinical , radiological and laboratory findings , further sampling was performed and , this time , was positive . a subsequent bone marrow trephine biopsy was consistent with a diagnosis of low - grade follicular b cell lymphoma . the patient 's initial clinical course was complicated by a nosocomial pneumonia and respiratory failure . following stabilization , three months after initiation of therapy , the patient was normotensive and euvolemic , without constitutional symptoms . a 75-year - old male was referred to the nephrology service for evaluation of hematuria , proteinuria and an elevated serum creatinine . his antinuclear antibody was positive with a homogenous pattern and he was hypo - complementemic ; however , his anti - double - stranded dna was negative . a renal biopsy was performed , which demonstrated a diffuse endocapillary proliferative glomerulonephritis ( fig . capillary wall kappa , igg , igm and c3 were noted on immunofluorescence ( fig . 2 ) and there were scattered subendothelial electron - dense immune - type deposits on electron microscopy . there was a florid intimal arteritis involving the interlobular caliber arteries . several arterioles contained eosinophilic material within the vessel wall consistent with cryoprecipitates . remarkably , coincidental sampling of perinephric fat demonstrated infiltration by a monomorphic population of cd20-positive b lymphocytes , which was suggestive of a low - grade b cell lymphoma ( fig . the suspected diagnosis was type 1 cryoglobulinemia due to an underlying lymphopro - liferative disorder . computed tomography of the thorax , abdomen and pelvis revealed moderate hepatosplenomegaly and enlarged lymph nodes in the anterior mediastinum . however , an initial attempt did not confirm the presence of serum cryoglobulin . due to the strong histological evidence and supportive clinical , radiological and laboratory findings , further sampling was performed and , this time , was positive . a subsequent bone marrow trephine biopsy was consistent with a diagnosis of low - grade follicular b cell lymphoma . the patient 's initial clinical course was complicated by a nosocomial pneumonia and respiratory failure . following stabilization , the patient underwent combination chemotherapy ( rituximab , cyclophosphamide , vincristine and prednisolone ) . three months after initiation of therapy , the patient was normotensive and euvolemic , without constitutional symptoms . cryoglobulins are serum immunoglobulins that precipitate , usually with complement components , in temperatures less than 37c and redissolve upon warming . clinical manifestations are therefore myriad with ischemic and/or vasculitic phenomena as well as generalized systemic upset . cryoglobulins are subdivided into three main categories on the basis of the clonality of the immunoglobulins in question . type 1 ( simple ) cryoglobulinemia involves a monoclonal immunoglobulin , usually seen in the context of a hematological malignancy such as chronic lymphocytic leukemia , multiple myeloma or waldenstrm 's macroglobulinemia . type 2 cryoglobulinemia has mixed monoclonal and polyclonal elements , usually seen in the setting of chronic infection , most commonly chronic hepatitis c. in type 3 cryoglobulinemia , polyclonal immunoglobulin precipitates , often in the setting of connective tissue disease . are based almost entirely on the underlying cause , an intensive effort must be made to identify it . there is also significant interlaboratory and intralaboratory variation in storage and testing . as a result , cryoglobulin testing is probably underutilized in general . the main sampling criterion is that the blood sample is taken in a pre - warmed collection tube and kept at 37c on the way to and in the laboratory to avoid premature precipitation of the immunoglobulin and , therefore , a false - negative laboratory test . in the laboratory , warm centrifugation occurs and the serum is cooled and observed at 4c for cryoprecipitate formation , which can take several days in some cases . the cryopre - cipitate is washed and re - warmed to 37c where it dissolves again and is subjected to a variety of immunoanalyses to characterize the immunoglobulin and the complement components . as in the case above , a significant false - negative rate exists when testing for serum cryoglobulin , largely due to handling and storage errors . with that in mind , if there is strong clinical suspicion for cryoglobulinemia but a cryoglobulin is not detected , careful repeat sampling and direct liaison with the laboratory are crucial .
we present a case of type 1 cryoglobulinemia with an underlying hematological malignancy . 
 unusually , the entire unifying diagnosis was made on the basis of the renal biopsy . 
 initially , serum cryoglobulin was not identified ; repeat samples were positive . 
 it is important to note that there is a significant false - negative rate with laboratory testing for cryoglobulin , due , at least in part , to the specific conditions required for collection and processing . with that in mind , in all cases with strong clinical or histological evidence of cryoglobulin but negative testing 
 , carefully repeated samples should be sent .