Diagnosing Hepatitis C Virus–Associated Glomerulonephritis: Key Clinical and Pathological Criteria
Understanding HCV-Associated Glomerulonephritis
Hepatitis C virus (HCV) infection—whether actively replicating or in a clinically latent phase—can trigger immune-mediated kidney injury. This condition, known as hepatitis C virus–associated glomerulonephritis (HCV-GN), is not merely a coincidental comorbidity but a well-documented extrahepatic manifestation of chronic HCV infection. It predominantly affects adults aged 40–65 and is strongly linked to cryoglobulinemic vasculitis, particularly type II mixed cryoglobulinemia.
Three Pillars of Diagnostic Confirmation
Accurate diagnosis relies on the integration of virological, clinical, and histopathological evidence—no single test suffices. Physicians must evaluate all three domains:
1. Confirmed HCV Infection
Serum testing must demonstrate persistent HCV RNA positivity (via PCR), along with detectable anti-HCV antibodies. Importantly, even patients with undetectable viral loads or prior spontaneous clearance may develop HCV-GN due to long-standing immune complex deposition—so a thorough HCV serology history remains essential.
2. Clinical Signs of Glomerular Injury
Patients typically present with one or more renal manifestations—including proteinuria (often nephrotic-range), microscopic or macroscopic hematuria, peripheral edema, and hypertension. Progressive decline in estimated glomerular filtration rate (eGFR) or elevated serum creatinine signals advancing renal dysfunction. Notably, extrarenal symptoms such as fatigue, arthralgia, and skin purpura frequently precede or accompany renal involvement.
3. Definitive Renal Biopsy Findings
Kidney biopsy remains the gold standard. Histology commonly reveals membranoproliferative glomerulonephritis (MPGN)—particularly Type I—characterized by subendothelial immune complex deposits, double contours ("tram-tracking"), and mesangial hypercellularity. Immunofluorescence confirms granular deposition of IgG, IgM, C3, and crucially, HCV core or NS3 antigens within glomeruli. Electron microscopy may identify electron-dense deposits consistent with cryoglobulin-related injury.
Recognizing Associated Systemic Features
Over 50% of HCV-GN patients exhibit cryoglobulinemia, often manifesting as palpable purpura (especially on lower extremities), peripheral neuropathy (e.g., burning pain or numbness), arthralgias, and skin ulcers. These features are red flags prompting urgent renal evaluation—even in the absence of overt urinary abnormalities.
Treatment Strategy: Targeting the Root Cause and Protecting the Kidneys
Modern management prioritizes direct-acting antiviral (DAA) therapy—which achieves >95% sustained virologic response (SVR) and significantly reduces cryoglobulin levels, proteinuria, and risk of end-stage kidney disease. Immunosuppression (e.g., corticosteroids or rituximab) is reserved for severe, rapidly progressive cases—such as those with crescentic glomerulonephritis, significant vasculitic skin lesions, or life-threatening neuropathy—and should only be initiated alongside or immediately after DAA initiation to avoid viral reactivation. Close multidisciplinary follow-up—including nephrology, hepatology, and rheumatology—is critical for optimizing long-term renal and hepatic outcomes.