What is Immunoglobulin G4 (IgG4) related nephritis?

From the Guidelines

IgG4-related nephritis should be treated with corticosteroids as first-line treatment, with a common regimen being oral prednisolone 40 mg daily for 2–4 weeks, subsequently reduced by 5 mg every week over approximately 8–12 weeks, as this approach has been shown to achieve rapid and favourable disease control 1.

Key Characteristics of IgG4-Related Nephritis

• IgG4-related nephritis is a rare autoimmune disorder characterized by kidney inflammation associated with elevated IgG4 antibodies.
• It typically presents as tubulointerstitial nephritis with dense lymphoplasmacytic infiltrates, storiform fibrosis, and increased IgG4-positive plasma cells in kidney tissue.
• Patients may experience kidney dysfunction, proteinuria, or be asymptomatic with abnormal laboratory findings.

Diagnosis and Treatment Approach

• Diagnosis requires kidney biopsy showing characteristic histopathology, elevated serum IgG4 levels, and often involvement of other organs like the pancreas or salivary glands.
• Corticosteroids are the recommended first-line treatment, with the goal of achieving clinical response and improvement in radiological findings.
• For patients with a high risk of relapse or those who experience relapse after cessation of steroid treatment, introduction of an immunomodulator such as azathioprine, mercaptopurine, or mycophenolate may be considered, along with further steroids 1.
• Biological therapy using anti-CD20 monoclonal antibodies such as rituximab may be effective for patients who fail to respond to first- or second-line treatment or whose disease flares on withdrawal of steroids, particularly in those with multisystem or complex disease.

Management Considerations

• Given the complexity of management, it is advisable for patients with possible IgG4-related nephritis to be referred to specialists or centers with experience of the disease to establish the diagnosis, plan management, and recruit into trials.
• Regular monitoring of kidney function, proteinuria, and IgG4 levels is essential, as relapses are common when treatment is reduced or stopped.
• Early diagnosis and treatment are crucial to prevent permanent kidney damage and fibrosis.

From the Research

Definition and Characteristics of IgG4 Nephritis

• IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory disorder characterized by elevated serum IgG4 concentrations, dense tissue infiltration of IgG4-positive plasma cells, and storiform fibrosis 2, 3.
• IgG4-related kidney disease is a major manifestation of IgG4-RD, often presenting as tubulointerstitial nephritis (TIN) with potential glomerular involvement 4, 3.
• The diagnosis of IgG4-RD relies on histopathology, with typical features including a dense lymphoplasmacytic infiltrate and storiform fibrosis, as well as a high percentage of plasma cells staining positively for IgG4 3.

Treatment and Management of IgG4 Nephritis

• Treatment for IgG4-RD is usually based on steroids, but relapses and long-term adverse effects are frequent 2.
• Rituximab, a B-cell depleting agent, has been shown to be effective in treating IgG4-related TIN, particularly in cases refractory to steroid treatment 2, 5, 6.
• A study found that treatment with rituximab was associated with a substantial and persistent increase in estimated glomerular filtration rate (eGFR) and a definite improvement in immunologic, radiologic, and histological parameters 2.
• First-line therapy with rituximab has been found to be protective against relapse, whereas the number of organs involved and low C3 and C4 concentrations were independently associated with a higher risk of relapse 4.

Prognostic Factors and Outcomes

• Age, peak serum creatinine, and serum IgG4 level ≥5 g/L have been found to be independently predictive of severe chronic kidney disease (CKD) in patients with IgG4-related kidney disease 4.
• Complement consumption and the number of organs involved have been associated with a higher relapse rate, whereas first-line therapy with rituximab has been associated with a lower relapse rate 4.
• A study found that 32% of patients with IgG4-related kidney disease had an eGFR below 30 ml/min per 1.73 m2 at the last follow-up, and 34% of patients experienced a relapse 4.