IgG4 Related Kidney Disease

IgG4 related kidney disease is the kidney manifestation of IgG4 related disease, a fibroinflammatory condition. It is characterised by dense lymphoplasmacytic infiltrates rich in IgG4 positive plasma cells, storiform fibrosis, obliterative phlebitis and often a raised serum IgG4.

Kidney involvement occurs in 10 to 30% of patients with IgG4 related disease. The disease typically affects men over 50 years, usually with other organ involvement (autoimmune pancreatitis, salivary and lacrimal glands, retroperitoneum, biliary tract, aorta, lungs, thyroid). It can be silent for years and be discovered by imaging of the kidney, or by acute or chronic loss of function.

Kidney lesions:

• IgG4 related tubulointerstitial nephritis is commonest (about 85%).
• Membranous nephropathy occurs in about 7%.
• Membranoproliferative or mesangial proliferative disease is less common.
• Obstructive uropathy from retroperitoneal fibrosis or ureteric inflammatory masses may cause postrenal failure.

Pathophysiology. Clonal T helper 2 and T follicular helper cells and B cells promote IgG4 production and fibrosis through transforming growth factor beta, interleukin 4, interleukin 13 and interleukin 10. Complement activation (low C3 and C4) occurs in 30 to 50% of patients with tubulointerstitial involvement.

• Acute or subacute rise in creatinine with a bland sediment, little or mild proteinuria (under 1 g daily; nephrotic range with membranous disease), mild haematuria and sterile pyuria.
• Low C3 and C4, high IgG, IgE and eosinophilia in about 30 to 50%.
• Radiological abnormalities: multiple bilateral low attenuation cortical nodules or wedge shaped lesions on contrast CT, diffuse parenchymal thickening, renal pelvic wall thickening, a hypovascular mass.
• Obstruction: retroperitoneal fibrosis around the aorta and ureters with hydronephrosis.
• Other organs: autoimmune pancreatitis (obstructive jaundice, diabetes), sialadenitis (submandibular swelling), dacryoadenitis, lymphadenopathy, aortitis, orbital pseudotumour, thyroiditis, sclerosing cholangitis, pachymeningitis, lung nodules.

Red flags

• Rapid decline in function with hydronephrosis.
• Obstructive jaundice, weight loss and a pancreatic mass.
• Aortic or periaortic involvement (aneurysm risk).
• Proteinuria above 3 g daily (membranous nephropathy).
• Raised IgG4 with lymphadenopathy and suspicion of lymphoma.

• Creatinine, eGFR, urine protein:creatinine ratio, urine microscopy, C3, C4, total IgG, IgE, eosinophil count, antinuclear antibodies, ANCA, rheumatoid factor.
• Serum IgG subclasses: IgG4 above 1.35 g/L in about 60 to 70%; a normal level does not exclude disease.
• Anti-phospholipase A2 receptor antibody (negative in IgG4 related membranous disease).
• Imaging: contrast CT or MR urography (avoid contrast when eGFR is under 30: use ultrasound or non-contrast MR), whole body positron emission tomography for organ distribution; ultrasound for hydronephrosis.
• Biopsy (kidney or other accessible organ) shows:
  • Dense lymphoplasmacytic infiltrate and storiform fibrosis.
  • IgG4 positive plasma cells more than 10 each high power field, with IgG4 to IgG positive ratio above 40%.
  • Tubular basement membrane immune complex deposits on immunofluorescence and electron microscopy.
  • Obliterative phlebitis and eosinophils.
  • Relatively abrupt demarcation of fibrosis from normal parenchyma.
• Exclude mimics: ANCA vasculitis, sarcoidosis, Sjögren syndrome, lymphoma, malignancy, multicentric Castleman disease, infection.

Differential diagnosis

• Sarcoid and Sjögren tubulointerstitial nephritis, drug induced interstitial nephritis, ANCA associated vasculitis, lymphoma, retroperitoneal malignancy, renal cell carcinoma and urothelial carcinoma (focal lesions), Castleman disease, lupus nephritis, primary membranous nephropathy.

First line: glucocorticoids for all active, symptomatic or organ threatening disease

• Prednisolone 0.6 mg/kg daily (30 to 40 mg) for 2 to 4 weeks. Then taper by 5 mg every 1 to 2 weeks to 5 to 10 mg daily by 3 to 6 months.
• Continue 2.5 to 5 mg daily maintenance for up to 3 years to reduce relapse (more than 50% relapse when steroids stop within 6 months).
• Response is judged at 2 to 4 weeks (creatinine, imaging, IgG4, symptoms); about 90% respond.
• Severe or rapidly progressive disease: methylprednisolone 500 mg to 1 g intravenously daily for 3 days, then prednisolone 0.6 to 1 mg/kg daily (maximum 60 mg).
• Cover: proton pump inhibitor, glucose monitoring, bone protection (calcium 500 mg elemental calcium with meals, cholecalciferol 800 to 2000 units daily, alendronic acid 70 mg weekly when eGFR is at least 35), co-trimoxazole 480 mg daily with additional immunosuppression.

Steroid sparing, relapse and high risk disease

• Rituximab 1 g intravenously on days 1 and 15 (or 375 mg/m² weekly for 4 doses) for relapse, steroid dependence, intolerance or high risk disease. Maintenance 1 g every 6 months for 2 years reduces relapse.
• Azathioprine 2 mg/kg daily (maximum 150 mg; thiopurine methyltransferase activity first) or mycophenolate mofetil 1 g twice daily as maintenance (modest effect).
• Methotrexate 10 to 15 mg weekly with folic acid 5 mg weekly when eGFR is at least 30.
• Inebilizumab 300 mg intravenously on days 1 and 15 then every 6 months is an option where available; verify current licensing.
• Check hepatitis B and tuberculosis before rituximab and prolonged steroids.

Obstruction

• Relieve ureteric obstruction urgently with ureteric stents or nephrostomy (creatinine and hydronephrosis often improve rapidly).
• Treat retroperitoneal fibrosis with steroids and rituximab; ureterolysis is rarely needed.

Renoprotection and supportive care

• Blood pressure below 130/80 mmHg: ramipril 2.5 mg daily increased to 10 mg daily (creatinine and potassium at 1 to 2 weeks; accept a rise up to 30%; stop if potassium exceeds 6.0 mmol/L).
• Dapagliflozin 10 mg daily (eGFR at least 25) for proteinuria.
• IgG4 related membranous nephropathy: steroids plus rituximab, with supportive care of nephrotic syndrome (sodium under 2 g daily, furosemide 40 to 80 mg for oedema, atorvastatin 20 mg daily, prophylactic enoxaparin 40 mg daily when albumin is under 25 g/L).
• Treat pancreatic exocrine insufficiency, diabetes and biliary disease with gastroenterology.

Kidney failure. Dialysis at eGFR 5 to 10 with symptoms. Transplantation is possible with recurrence risk. Lifelong surveillance.

Monitoring. Creatinine, eGFR, urine protein:creatinine ratio, IgG4, IgG and complement every 2 to 4 weeks during the taper, then every 3 months. Imaging at 3 to 6 months then yearly. Yearly cancer surveillance (association with lymphoma and solid cancers).

Referral and escalation. Nephrology with rheumatology and gastroenterology; urgent for obstruction, rapid loss of function or biliary obstruction.

Special groups

• Older adults: lower steroid doses with early rituximab to limit steroid toxicity.
• Pregnancy: rare; continue prednisolone and azathioprine; avoid mycophenolate, methotrexate and rituximab (unless essential).
• People with diabetes: monitor glucose closely during steroid therapy.