Fibrillary Glomerulonephritis

Fibrillary glomerulonephritis is a glomerular disease defined by randomly arranged, non-branching fibrils 12 to 24 nm in diameter (mean about 20 nm) in the mesangium and glomerular basement membrane, which are Congo red negative. It accounts for about 1% of native kidney biopsies. DNAJB9, a heat shock protein 40 chaperone, is deposited in almost all cases and is the reliable diagnostic marker.

The deposits are polyclonal IgG (IgG4 and IgG1 predominant) with C3, and about 15% of patients have a monoclonal gammopathy. Typical age at diagnosis is 50 to 60 years, with a slight female predominance and white ancestry predominating.

Associations. Autoimmune disease (systemic lupus erythematosus, Graves disease, Sjögren syndrome), hepatitis C, malignancy (about 20% of patients), and monoclonal gammopathy; most cases are idiopathic.

Natural history. About 40 to 50% reach kidney failure within 2 to 4 years; poor prognostic factors are baseline eGFR under 60, crescents, interstitial fibrosis above 50%, and nephrotic range proteinuria.

• Proteinuria (nephrotic range in about 50%), microscopic haematuria in about 70%, hypertension in 60 to 70%, progressive loss of kidney function.
• Rapidly progressive course with crescents in a minority.
• No characteristic extrarenal manifestations.

Red flags

• Rapid decline in eGFR with crescents.
• Weight loss or other features of malignancy; monoclonal protein.
• Nephrotic syndrome with albumin below 25 g/L (thrombosis risk).

• Urine protein:creatinine ratio, creatinine, eGFR, albumin, lipids, urine microscopy; C3 and C4 (usually normal); anti-nuclear antibodies, hepatitis B and C, HIV; serum protein electrophoresis, immunofixation and free light chains; thyroid function; age appropriate cancer screening.
• Kidney biopsy: light microscopy shows mesangial expansion with membranoproliferative, mesangial proliferative or diffuse proliferative patterns, with crescents in a minority.
• Immunofluorescence has IgG (IgG4-predominant) and C3 with smudgy mesangial and capillary wall staining, kappa and lambda both present in polyclonal disease.
• Electron microscopy shows randomly oriented fibrils 12 to 24 nm in diameter; Congo red negative.
• DNAJB9 immunostain strongly positive (sensitive and specific); mass spectrometry confirms DNAJB9.

Differential diagnosis

• Amyloid (Congo red positive, fibrils 7 to 12 nm), immunotactoid glomerulopathy (microtubules above 30 nm, DNAJB9 negative), cryoglobulinaemic glomerulonephritis (organised fibrillar or microtubular deposits, cryoglobulin), lupus nephritis (fingerprint deposits), diabetic fibrillosis (fibrils in diabetes), monoclonal immunoglobulin deposition disease, membranoproliferative glomerulonephritis.

No proven disease modifying therapy exists; treatment rests on supportive care.

• Blood pressure below 130/80 mmHg; ACE inhibitor or angiotensin receptor blocker (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).
• SGLT2 inhibitor: dapagliflozin 10 mg daily (eGFR at least 25) or empagliflozin 10 mg daily (eGFR at least 20).
• Sodium restriction under 2 g daily; furosemide 40 to 80 mg once or twice daily for oedema; statin; anticoagulation if albumin is under 20 g/L with additional risk factors.

Immunosuppression (individualised; reserved for progressive disease or crescents)

• Rituximab 1 g intravenously on days 1 and 15 (or 375 mg/m² weekly for 4 doses) has been associated with stabilisation in about half of patients with eGFR above 30 in observational series; repeat every 6 months if responding.
• Crescentic disease: methylprednisolone 500 mg to 1 g intravenously daily for 3 days, then prednisolone 1 mg/kg daily (maximum 60 mg) tapered over 6 months.
• This is given with 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, then every 3 weeks, or mycophenolate mofetil 1 g twice daily. Corticosteroids alone are ineffective.
• Treat any associated condition: hepatitis C (glecaprevir and pibrentasvir 300 mg and 120 mg daily for 8 weeks), autoimmune disease, malignancy, or a monoclonal clone (haematology).
• Prophylaxis during immunosuppression: co-trimoxazole 480 mg daily, proton pump inhibitor, hepatitis B screening before rituximab.

Kidney replacement therapy and transplantation. Dialysis at eGFR 5 to 10 with symptoms or complications. Recurrence in the allograft occurs in about 40 to 50% of patients, usually after months to years; graft loss from recurrence is uncommon in the first 5 years, so transplantation is appropriate.

Monitoring. Creatinine, urine protein:creatinine ratio, albumin and blood pressure every 1 to 3 months; repeat biopsy for unexplained decline.

Referral and escalation. Nephrology with access to renal pathology and DNAJB9 staining; haematology for monoclonal gammopathy; transplant centre when eGFR is under 20.

Special groups

• Older adults: lower intensity treatment; cancer screening is essential.
• Pregnancy: stop ACE inhibitors and mycophenolate before conception; risk of relapse and hypertension.