Hepatitis C Associated Glomerulonephritis

Hepatitis C associated glomerulonephritis is immune complex glomerular disease caused by chronic hepatitis C virus infection. The commonest lesion is membranoproliferative glomerulonephritis, usually with type II mixed cryoglobulinaemia (monoclonal IgM kappa rheumatoid factor bound to polyclonal IgG); membranous nephropathy, focal segmental glomerulosclerosis, IgA nephropathy and mesangial proliferative disease are less frequent.

About 58 million people worldwide have chronic hepatitis C infection, and clinically evident kidney disease develops in a small minority, typically after 10 to 20 years of infection. Hepatitis C also independently raises the risk of chronic kidney disease, and kidney disease raises the risk of acquiring hepatitis C in dialysis units.

Pathophysiology. Viral antigen and cryoglobulin immune complexes deposit in the glomerulus and activate the classical complement cascade (low C4, relatively preserved C3). Monocyte infiltration, endocapillary proliferation, intraluminal precipitates and subendothelial deposits follow. Chronic B-cell stimulation drives the rheumatoid factor and cryoglobulin production.

• Proteinuria (nephrotic range in about 20%), microscopic haematuria, hypertension and slowly progressive loss of function; acute nephritic presentation or acute kidney injury in about 20 to 30%.
• Cryoglobulinaemic vasculitis: palpable purpura, arthralgia, weakness, peripheral neuropathy (sensory or mononeuritis multiplex), skin ulcers, Raynaud phenomenon.
• Liver disease is often silent; transaminases may be normal or mildly raised, and cirrhosis develops in a proportion of patients.
• Low C4 with normal or mildly low C3, strongly positive rheumatoid factor.
• Hepatitis C associated membranous nephropathy and focal segmental glomerulosclerosis present with nephrotic syndrome and usually normal complement.

Red flags

• Rapid rise in creatinine, oliguria or crescents on biopsy.
• Necrotising skin lesions, digital ischaemia, mononeuritis multiplex or gastrointestinal ischaemia.
• Hyperviscosity (headache, visual change, confusion, bleeding).
• Decompensated cirrhosis (ascites, encephalopathy, variceal bleeding, jaundice) or hepatocellular carcinoma.
• Coexisting hepatitis B or HIV infection.

• Hepatitis C antibody, with HCV RNA (quantitative) to confirm active infection; genotype is not needed when a pangenotypic regimen is used.
• Cryoglobulins (warm tubes and syringes kept at 37°C until the serum separates; serum held at 4°C for 7 days; cryocrit), rheumatoid factor, C3, C4, serum protein electrophoresis with immunofixation, free light chains.
• Hepatitis B surface antigen, core antibody, HIV, antinuclear antibodies, ANCA.
• Creatinine, eGFR, urine protein:creatinine ratio, urine microscopy for dysmorphic red cells and casts, albumin, lipids.
• Liver assessment: transaminases, bilirubin, albumin, INR, platelets, fibrosis staging by elastography (above 12.5 kPa suggests cirrhosis), upper gastrointestinal endoscopy if cirrhosis, ultrasound with alpha fetoprotein every 6 months in cirrhosis.
• Kidney biopsy when proteinuria is above 1 g daily, the sediment is active or function is declining: membranoproliferative pattern with double contours, monocyte infiltration and intraluminal thrombi (precipitated cryoglobulin); immunofluorescence with IgM, IgG and C3; electron microscopy with fibrillary or microtubular substructure within deposits.

Differential diagnosis

• Membranoproliferative glomerulonephritis from other infections (hepatitis B, endocarditis, HIV), C3 glomerulopathy, fibrillary glomerulonephritis, lupus nephritis, ANCA vasculitis, IgA vasculitis, monoclonal immunoglobulin disease, thrombotic microangiopathy.

First line: eradicate the virus (all patients with active infection and kidney involvement)

• Glecaprevir and pibrentasvir 300 mg and 120 mg (three combination tablets) orally once daily with food for 8 weeks in patients without cirrhosis; 12 weeks for compensated cirrhosis. No dose adjustment for any degree of kidney failure, including dialysis.
• Alternative: sofosbuvir and velpatasvir 400 mg and 100 mg once daily for 12 weeks (usable at all eGFR values; check for interactions).
• Decompensated cirrhosis: protease inhibitor regimens are contraindicated; use sofosbuvir and velpatasvir with weight based ribavirin for 12 weeks, in a liver unit, adjusting ribavirin and monitoring haemoglobin closely when eGFR is under 50.
• Interactions to check before starting: proton pump inhibitors (reduce sofosbuvir and velpatasvir absorption; limit to omeprazole 20 mg daily), statins (stop atorvastatin and simvastatin during glecaprevir and pibrentasvir), amiodarone (severe bradycardia with sofosbuvir), carbamazepine, phenytoin, rifampicin and St John's wort (contraindicated), tacrolimus and ciclosporin (monitor levels).
• Confirm sustained virological response by undetectable HCV RNA 12 weeks after the end of treatment (achieved in over 95%). Proteinuria and cryoglobulins improve in 60 to 90%, but renal improvement may lag behind viral clearance by months.

Immunosuppression (severe, rapidly progressive or organ threatening disease; give with the antiviral)

• Rituximab 375 mg/m² intravenously weekly for 4 doses, or 1 g on days 1 and 15, with methylprednisolone 500 mg to 1 g intravenously daily for 3 days, then prednisolone 0.5 to 1 mg/kg daily (maximum 60 mg) tapered over 8 to 12 weeks.
• Plasma exchange (60 mL/kg, 3 to 7 sessions over 2 weeks) for hyperviscosity, rapidly progressive glomerulonephritis or life threatening vasculitis.
• Cyclophosphamide intravenously 15 mg/kg (12.5 mg/kg at age 60 to 70; 10 mg/kg over age 70) every 2 weeks for 3 doses if rituximab cannot be used.
• Check hepatitis B surface and core antibody before rituximab; give co-trimoxazole 480 mg daily and a proton pump inhibitor during high dose steroids.

Renoprotection and supportive care

• Blood pressure below 130/80 mmHg: ramipril 2.5 mg daily increased to 10 mg daily; check creatinine and potassium at 1 to 2 weeks, accept a creatinine rise up to 30%, stop if potassium exceeds 6.0 mmol/L.
• Dapagliflozin 10 mg daily (eGFR at least 25) or empagliflozin 10 mg daily (eGFR at least 20) for persistent proteinuria; sodium under 2 g daily; furosemide 40 to 80 mg once or twice daily for oedema.
• Neuropathic pain: gabapentin 100 mg after dialysis or at night (maximum 300 mg daily in kidney failure). Keep extremities warm in cryoglobulinaemia.
• Hepatitis A and B vaccination, alcohol avoidance, hepatocellular carcinoma surveillance in cirrhosis.

Kidney replacement therapy and transplantation. Dialysis at eGFR 5 to 10 with symptoms or complications; haemodialysis units isolate patients or follow strict infection control. Transplant candidates can be treated before or after transplantation; transplants from hepatitis C positive donors are an option for recipients who will be treated afterwards. Relapse of cryoglobulinaemic glomerulonephritis is possible after rituximab alone (30 to 50%).

Monitoring. HCV RNA at the end of treatment and at 12 weeks; cryocrit, C4, rheumatoid factor, creatinine and urine protein:creatinine ratio monthly for 3 months, then every 3 months; liver ultrasound every 6 months if cirrhotic.

Referral and escalation. Nephrology with hepatology; rheumatology or haematology for vasculitis or lymphoproliferative disease; intensive care for hyperviscosity or vasculitic crisis; liver transplant assessment for decompensated cirrhosis.

Special groups

• Dialysis patients: no dose change for glecaprevir and pibrentasvir; screen every 6 months in units.
• Pregnancy: defer direct acting antivirals until after delivery unless disease is life threatening; avoid ribavirin, cyclophosphamide and mycophenolate.
• Children: glecaprevir and pibrentasvir is licensed from age 3 years with weight based dosing; specialist dosing is required.