What is the primary treatment approach for a patient with Hepatitis C Virus (HCV) Glomerulopathy?

HCV Glomerulopathy: Primary Treatment Approach

The primary treatment for HCV glomerulopathy is direct-acting antivirals (DAAs) as first-line therapy for patients with stable kidney function and non-nephrotic proteinuria, while those with cryoglobulinemic flare or rapidly progressive glomerulonephritis require immediate combination therapy with DAAs plus immunosuppressive agents (rituximab preferred) with or without plasmapheresis. 1

Treatment Algorithm Based on Clinical Presentation

For Stable Disease (Non-Nephrotic, Stable GFR)

Initiate DAAs alone as first-line therapy 1

• DAAs should be used without dose adjustment across all CKD stages, including dialysis patients 1
• Pangenotypic DAA regimens (including sofosbuvir-based) are safe and effective even in advanced CKD (stages 4-5) 1
• This approach achieves sustained virologic response (SVR) rates of 90-100% in CKD populations 1
• Treatment leads to diminished proteinuria and increased GFR 1

For Severe/Progressive Disease

Immediately initiate combination therapy with DAAs plus immunosuppressive agents 1

This applies to patients with:

• Cryoglobulinemic flare 1
• Rapidly progressive glomerulonephritis 1
• Nephrotic syndrome (individualized decision) 1

Rituximab is the first-line immunosuppressive agent 1

• Add intravenous methylprednisolone to rituximab 1
• Consider plasmapheresis for severe presentations 1
• Alternative: cyclophosphamide can be used if rituximab unavailable 1

For Treatment-Refractory Disease

If glomerulonephritis persists despite achieving SVR with DAAs, initiate immunosuppressive therapy 1

• This is particularly important for cryoglobulinemic kidney disease 1
• Rituximab remains first-line immunosuppressive choice 1
• Histologically active disease on biopsy supports this decision 1

CKD Stage-Specific Considerations

CKD Stages 1-2

• Use combined DAA therapy (pangenotypic regimens preferred) 1
• No dose adjustment needed 1

CKD Stages 3-5 (Not on Dialysis)

• Pangenotypic DAA regimens are safe and effective 1
• Previously, pegylated interferon monotherapy was suggested (now superseded by DAAs) 1

Dialysis Patients (CKD Stage 5D)

• DAAs are highly effective without dose adjustment 1
• Avoid protease inhibitors ("-previrs" like simeprevir, paritaprevir, grazoprevir) which are contraindicated 1

Critical Pitfalls to Avoid

Do not delay immunosuppression in rapidly progressive disease while waiting for DAA response 1

• Studies of DAAs excluded patients with rapidly progressive glomerulonephritis, cryoglobulinemic vasculitis, or nephrotic-range proteinuria 1
• These patients require immediate concomitant immunosuppression 1
• Recent evidence shows DAA monotherapy may be insufficient for HCV-GN with 67% requiring additional immunosuppressive therapy 2

Screen for hepatitis B before initiating rituximab 1

• This prevents fulminant hepatitis from HBV reactivation 1

Do not perform kidney biopsy if it delays treatment in typical presentations 1

• Patients with typical immune-complex proliferative glomerulonephritis can start DAAs without confirmatory biopsy 1
• Biopsy is indicated for: atypical presentations, rapidly progressive disease, severe nephrotic syndrome, or if considering immunosuppression 1

Supportive Care Alongside Antiviral Therapy

Initiate ACE inhibitor or ARB for proteinuria >1 g/day 1

• Uptitrate to maximum tolerated dose targeting proteinuria <1 g/day 1
• Consider for proteinuria 0.5-1 g/day 1

Evidence Strength and Nuances

The 2022 KDIGO guidelines 1 represent the most recent and authoritative source, superseding the 2012 recommendations 1 that suggested interferon-based regimens. The paradigm has shifted dramatically with DAAs achieving SVR rates of 74-83% in HCV-associated glomerulonephritis studies 1. However, the critical distinction is that DAA monotherapy studies specifically excluded the most severe presentations 1, explaining why combination therapy remains essential for aggressive disease despite excellent virologic cure rates.

The recommendation for rituximab as first-line immunosuppression 1 is based on it being the best-studied agent for HCV-related glomerulonephritis, with pooled data showing mean proteinuria reduction of 1.4 g/24h 3.