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

F. Gerald Wade, MD; Elie Ghoulam, MD; Thomas Fay, MD; George Vasquez Rios, MD; Kamran Qureshi, MD


October 02, 2019


Extrahepatic manifestations of HCV infection are common and increase morbidity and mortality among HCV-infected patients, even in the absence of cirrhosis.[1,2] In addition to the healthcare costs of HCV-associated liver disease, the economic burden of extrahepatic manifestations of HCV was $1.5 billion in 2014.[3] Extrahepatic manifestations of HCV include mixed cryoglobulinemia, Sjögren syndrome, type 2 diabetes, porphyria cutanea tarda, hypothyroidism, lymphoproliferative disorders, and cardiovascular disease, among others.[4,5,6,7,8,9]

Chronic HCV infection is highly prevalent in liver and kidney transplant recipients, with an increased incidence of clinically significant extrahepatic manifestations due to concurrent immunosuppression.[10,11,12] Lymphoproliferative disorders and HCV-related kidney disease are serious consequences of untreated HCV posttransplant.[13] Clinically aggressive cases of mixed cryoglobulinemia can lead to rapidly progressive posttransplant renal failure due to immune-complex deposition that damages the glomerulus. HCV infection also further increases the risk for diabetes mellitus in transplant recipients, which can also contribute to progressive renal dysfunction.[10,14]

Cryoglobulinemia is most strongly associated with HCV but also occurs less often from hepatitis B virus (HBV), HIV, monoclonal gammopathies, and some autoimmune disorders.[15,16,17,18] Mixed cryoglobulinemia is caused by an immune complex reaction to HCV virion with HCV immunoglobulin G, rheumatoid factor, and complement to form polyclonal cryoglobulins. Immune complex deposition in small-vessel walls and cryoprotein precipitation in vessel lumens lead to cryoglobulinemia syndrome.[19]

Patients with HCV commonly have circulating cryoglobulins, with symptomatic disease occurring in about 20% of patients with cryoglobulins in the serum.[16,20] Rates are similar in liver transplant recipients.[21] HCV-associated mixed cryoglobulinemia most often leads to subclinical or mild disease and can present with the Meltzer triad of purpura, arthralgia, and weakness.[22] Aggressive disease course is seen in 15%-20% of patients with HCV who have cryoglobulinemia. Cryoglobulinemia vasculitis syndromes can cause renal disease, digital ischemia, neuropathy, pulmonary disease, gastrointestinal hemorrhage and ischemia, and liver disease.[15] Among such patients, renal failure is the most common cause of death.

HCV-cryoglobulinemic renal disease typically presents with microscopic hematuria and mild proteinuria without significant renal dysfunction.[20] Approximately 30% of patients with HCV-associated mixed cryoglobulinemia develop some degree of renal dysfunction, with a small percentage developing fulminant renal failure. Overall mortality is high in patients with mixed cryoglobulinemia and renal insufficiency.[19] Thus, early diagnosis and treatment of HCV in patients with cryoglobulin-related renal disease is important to curb progression of renal dysfunction.[23,24] Patients with HCV who have proteinuria and microscopic hematuria should have renal biopsy to evaluate for cryoglobulinemia or other HCV-related glomerular diseases.[25]


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