A 58-Year-Old Man With a Rash and Elevated Creatinine Levels

Clinicians should have a high index of suspicion for cryoglobulinemia in patients known to have HCV infection who present with nephritic syndrome, proteinuria, or renal dysfunction.^[25] HBV and HIV are also associated with cryoglobulinemia; thus, clinicians also should screen for these viruses in cases of suspected cryoglobulinemia syndromes.^[17,18] To test for cryoglobulins, blood is placed in a prewarmed test tube without anticoagulants to prevent false-positive results. It is then cooled to detect precipitation of cryoglobulins.^[26] Unfortunately, serologic testing for circulating cryoglobulins is not sensitive for cryoglobulinemic glomerulonephritis, which can obscure the diagnosis. A combination of a positive rheumatoid factor, hypocomplementia with low C4 levels, and typical manifestations of cryoglobulinemia suggests the presence of cryoglobulinemia, even without serologic evidence for cryoprecipitate.^[27]

Diagnosis of cryoglobulinemia-associated renal disease is confirmed by tissue biopsy with characteristic histologic features of cryoglobulinemia. Light microscopy reveals a membranoproliferative pattern, with mesangial proliferation and hyaline pseudothrombi representing cryoglobulin deposits. Arteriole leukocytoclastic vasculitis and glomerular crescents are often present.^[19] Immunofluorescence shows subendothelial and intracapillary deposits with IgM and C3. Electron microscopy reveals a double contour appearance of glomerular basement membrane and foot process effacement. It also reveals subendothelial, luminal, and mesangial deposits, which are typically polyclonal but can sometimes be monoclonal with cylindrical and curvilinear substructure.^[19]

This patient's clinical triad of weakness, arthralgias, and a new rash, in addition to his initial elevated aminotransferase levels and urinalysis suggestive of nephritis, raised suspicion for HCV-associated mixed cryoglobulinemia. The differential diagnosis for this patient's acute kidney injury was wide, but the main considerations were rejection; tacrolimus toxicity; lupus nephritis; or another HCV-associated vasculitis, such as polyarteritis nodosa or membranoproliferative glomerulonephritis.

Suspicion for a vasculitis in this patient was further heightened when his creatinine level continued to rise despite appropriate tacrolimus dose adjustment. Additional laboratory investigation found a low C4 level, positive rheumatoid factor, and negative lupus-associated antibodies. Cryoglobulins were also detected in the patient's serum. Diagnosis was confirmed by renal biopsy. Hematoxylin and eosin stain showed hyaline pseudothrombi (Figure 2). Electron microscopy showed subendothelial, mesangial, and luminal deposits (Figure 3).

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Figure 2.

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Figure 3.

After successful diagnosis of cryoglobulinemia and/or cryoglobulinemia-associated renal disease, treatment should target the underlying etiology. For mild disease, treatment should focus on eradication of HCV infection. Sustained viral response of HCV reduces proteinuria; improves renal function; and resolves other cryoglobulinemia symptoms, including purpura, neuropathy, and arthralgias.^[24,25,28] Treatment of the underlying HCV infection shows benefit for not only mixed cryoglobulinemia but also several other extrahepatic manifestations of HCV infection, including diabetes mellitus, cardiovascular disease, non-Hodgkin lymphoma, and cognitive function.^{[29,30,31,32]} One retrospective study showed that diabetic patients with HCV infection who were treated with interferon gamma and ribavirin had a lower incidence of end-stage renal disease, stroke, and acute coronary syndrome.^[30]

Moderate or severe cryoglobulinemic vasculitis with rapidly progressing glomerulonephritis, respiratory failure, severe skin ulcers, intestinal vasculitis, or central nervous system involvement requires immunosuppression.^[25] HCV treatment is typically delayed until after immunosuppressive therapy is completed. Treatment algorithms for moderate to severe mixed cryoglobulinemia typically include a combination of initial high-dose glucocorticoid therapy with prednisone taper and rituximab.^[25] Plasma exchange can be used for patients with life-threatening disease or for those who do not respond to high-dose immunosuppression. Despite these interventions, the prognosis for patients with cryoglobulinemia who present with severe disease and life-threatening organ involvement is poor.^[33]

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