Hepatitis B Associated Glomerulonephritis

Hepatitis B associated glomerulonephritis is immune complex glomerular disease caused by chronic hepatitis B virus infection. Hepatitis B surface, core and e antigens form immune complexes that deposit in or form in situ within the glomerulus.

The commonest pattern in children in endemic regions (sub-Saharan Africa, Southeast Asia, China) is membranous nephropathy with HBe antigen in the deposits; in adults, membranoproliferative glomerulonephritis, IgA nephropathy and mesangial proliferative disease are also found. Hepatitis B related polyarteritis nodosa is a separate vasculitis, usually with renal artery involvement. Kidney involvement occurs in 1 to 7% of chronic carriers. Prevalence of chronic hepatitis B worldwide exceeds 250 million.

Natural history. In children with membranous disease, spontaneous remission occurs in 30 to 60% over 2 to 3 years with HBe antigen seroconversion; in adults, disease usually persists and progresses to chronic kidney disease in 30 to 40% over 10 years.

• Nephrotic syndrome (especially in children), microscopic or macroscopic haematuria, hypertension, oedema, variable kidney function.
• Often silent liver disease (normal or mildly raised transaminases), hepatomegaly, jaundice in acute flares.
• Systemic: fever, arthralgia, rash, mononeuritis, hypertension and renal infarcts in polyarteritis nodosa; cryoglobulinaemia occasionally.
• Low C3 and C4 in membranoproliferative disease.

Red flags

• Rapid decline in eGFR or crescents.
• Acute hepatitis flare (alanine transaminase above 10 times the upper limit, jaundice, coagulopathy) or hepatic decompensation.
• Hepatitis B reactivation on immunosuppression (rise in HBV DNA).
• Hypertensive crisis or renal infarct (polyarteritis nodosa).

• Hepatitis B surface antigen, HBe antigen, anti-HBe, anti-HBc IgG, HBV DNA (quantitative), liver tests, INR, albumin, platelet count, alpha fetoprotein, liver ultrasound and fibrosis assessment (elastography); hepatitis C, HIV and hepatitis D serology.
• Creatinine, urine protein:creatinine ratio, albumin, urine microscopy, C3 and C4, cryoglobulins, rheumatoid factor, antinuclear antibodies.
• Kidney biopsy: membranous nephropathy (spikes and subepithelial deposits, often with mesangial and subendothelial deposits, a hint to secondary cause), membranoproliferative pattern, or IgA nephropathy; immunofluorescence with IgG, C3 and sometimes C1q; HBsAg, HBcAg or HBeAg staining in deposits supports the diagnosis; absence of anti-phospholipase A2 receptor staining and serum anti-PLA2R antibody favours a secondary cause.
• Angiography or CT angiography for suspected polyarteritis nodosa.

Differential diagnosis

• Primary membranous nephropathy (anti-PLA2R positive, which can coexist with carriage), lupus nephritis, hepatitis C glomerulonephritis, IgA nephropathy, post-infectious glomerulonephritis, drug induced membranous nephropathy (NSAIDs, penicillamine), malignancy associated disease.

First line: suppress hepatitis B replication

• Entecavir 0.5 mg orally daily on an empty stomach, adjusted for kidney function: eGFR 30 to 49 mL/min/1.73 m², 0.25 mg daily (or 0.5 mg every 48 hours); eGFR 10 to 29, 0.15 mg daily (or 0.5 mg every 72 hours); eGFR under 10 or haemodialysis, 0.05 mg daily (or 0.5 mg every 7 days, given after dialysis). Or tenofovir alafenamide 25 mg daily (eGFR at least 15; dialysis patients 25 mg daily given after dialysis). Avoid tenofovir disoproxil in kidney disease; if used, give 300 mg every 48 hours at eGFR 30 to 49. Lamivudine has higher resistance and is not preferred.
• Continue antiviral therapy until sustained HBe antigen seroconversion and normalisation of proteinuria, and indefinitely in HBe antigen negative disease with cirrhosis or high HBV DNA.
• Monitor HBV DNA every 3 months, alanine transaminase, creatinine and urine protein; alpha fetoprotein and ultrasound every 6 months in high risk patients.
• Children with membranous disease: entecavir 0.015 mg/kg daily (maximum 0.5 mg) or tenofovir alafenamide 25 mg for weight at least 35 kg, balancing spontaneous remission; consider peginterferon alfa in selected children.

Supportive care

• Blood pressure below 130/80 mmHg; ramipril 2.5 mg daily increased to 10 mg daily; sodium restriction under 2 g daily; furosemide 40 to 80 mg for oedema; statin; thromboprophylaxis if albumin is under 20 g/L with additional risk.

Immunosuppression (only for rapidly progressive disease or severe nephrotic syndrome, always with antiviral cover)

• Start entecavir or tenofovir alafenamide before and continue for at least 6 to 12 months after stopping immunosuppression (18 months after rituximab). Prednisolone 0.5 mg/kg daily (maximum 40 mg) for crescentic or membranoproliferative disease; avoid high dose steroids in untreated replicating infection. Rituximab with antiviral prophylaxis is an option in refractory disease.
• Polyarteritis nodosa: antiviral therapy with a short course of prednisolone 1 mg/kg daily and plasma exchange (60 mL/kg, 4 to 6 sessions over 2 weeks) in severe disease; avoid long term cyclophosphamide.

Vaccination and prevention. Hepatitis B vaccination for household contacts and healthcare workers; infant vaccination with immunoglobulin for babies of carrier mothers.

Kidney failure. Dialysis with hepatitis B isolation precautions; kidney transplantation is possible with controlled HBV DNA and antiviral prophylaxis for life.

Referral and escalation. Nephrology and hepatology together; urgent hepatology for flares or decompensation; liver transplant assessment for decompensated cirrhosis or hepatocellular carcinoma.

Special groups

• Children: membranous nephropathy with HBe antigen; watch for spontaneous remission over 2 to 3 years.
• Pregnancy: tenofovir alafenamide or tenofovir disoproxil in the third trimester for mothers with HBV DNA above 200 000 IU/mL; avoid entecavir.
• Transplant and chemotherapy recipients: prophylactic antivirals for hepatitis B surface antigen positive patients, and for core antibody positive patients receiving rituximab.