Rapidly Progressive Nephritic Syndrome

Rapidly progressive nephritic syndrome is the clinical presentation of rapidly progressive glomerulonephritis: haematuria with red cell casts, proteinuria, hypertension and oedema, together with loss of at least 50% of glomerular filtration within days to 3 months. The pathological correlate is crescentic glomerulonephritis, with crescents (proliferation of parietal epithelial cells and fibrin in Bowman space) in more than 50% of glomeruli. It is a nephrological emergency because irreversible scarring develops within days.

Classification by immunofluorescence:

• Type 1, anti-GBM disease: linear IgG along the glomerular basement membrane against the alpha-3 chain of type IV collagen; with pulmonary haemorrhage it is Goodpasture disease
• Type 2, immune complex: lupus nephritis, IgA nephropathy and IgA vasculitis, post-infectious glomerulonephritis, cryoglobulinaemia, membranoproliferative disease, hepatitis B and C
• Type 3, pauci-immune: ANCA-associated vasculitis (granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis) with scant or no immune deposits
• Type 4, double positive: anti-GBM plus ANCA
• Type 5, ANCA-negative pauci-immune or drug induced (hydralazine, propylthiouracil, levamisole)

Pauci-immune disease accounts for about 50% to 60% of cases in adults, and older patients are most often affected; anti-GBM disease has peaks in the third and sixth decades.

• Dark or cola coloured urine, oliguria, oedema, hypertension (usually mild to moderate)
• Constitutional: fever, weight loss, malaise, myalgia, arthralgia
• Pulmonary haemorrhage: haemoptysis, dyspnoea, hypoxia, pulmonary infiltrates; may precede renal disease in anti-GBM disease
• ANCA vasculitis: sinusitis, nasal crusting and saddle deformity, scleritis, mononeuritis multiplex, purpura, subglottic stenosis
• Lupus: malar rash, serositis, cytopenias
• Post-infectious: preceding streptococcal pharyngitis (1 to 3 weeks) or skin infection (2 to 6 weeks), endocarditis, visceral abscess

Red flags: haemoptysis, creatinine rising more than 50% in a week, oliguria, potassium above 6.0 mmol/L, fluid overload with hypoxia, creatinine above 600 micromol/L at presentation.

• Urine microscopy: dysmorphic red cells (more than 5% acanthocytes) and red cell casts; protein:creatinine ratio usually 100 to 300 mg/mmol, rarely nephrotic
• Serology, sent concurrently: MPO-ANCA and PR3-ANCA, anti-GBM antibody, antinuclear antibody, anti-dsDNA, C3, C4, cryoglobulins, rheumatoid factor, hepatitis B surface antigen, hepatitis C antibody, HIV, ASO titre and anti-DNase B, blood cultures (three sets before antibiotics)
• Full blood count, film, CRP, ESR, creatine kinase, urate
• Chest imaging; CT chest for alveolar haemorrhage (ground glass opacities); DLCO elevation if bronchoscopy not feasible
• Kidney biopsy within 24 to 48 hours: crescents involving more than 50% of glomeruli, fibrinoid necrosis of capillary loops, immunofluorescence pattern, and chronicity (glomerulosclerosis, interstitial fibrosis, tubular atrophy) to predict recovery

Differentials: acute tubular injury, acute interstitial nephritis, thrombotic microangiopathy, myeloma cast nephropathy, atheroembolic disease, infection related glomerulonephritis in endocarditis (which crescents but requires antibiotics and not immunosuppression).

Start treatment on clinical suspicion with strongly positive serology or pulmonary haemorrhage; do not delay for biopsy.

Induction for ANCA-associated disease

• Methylprednisolone 500 mg to 1 g intravenously daily for 3 days, then prednisolone 1 mg/kg daily (maximum 60 mg) reducing to 5 mg by 6 months.
• Rituximab 375 mg/m2 weekly for 4 doses or 1 g on days 1 and 15; alternatively cyclophosphamide 15 mg/kg intravenously (maximum 1.2 g) every 2 weeks for 3 doses, then every 3 weeks for 3 to 6 months, with dose reduction for age and eGFR (12.5 mg/kg at ages 60 to 70; 10 mg/kg above age 70).
• Avacopan 30 mg twice daily with meals may be used to replace prolonged high dose glucocorticoid.
• Plasma exchange 60 mL/kg, seven sessions in 14 days, when creatinine is above 300 micromol/L or alveolar haemorrhage is present.
• Maintenance: rituximab 500 mg every 6 months for 18 months, or azathioprine 2 mg/kg daily for 18 to 24 months.

Anti-GBM disease

• Daily plasma exchange 60 mL/kg with 4% albumin until anti-GBM antibodies are undetectable (usually 14 days); use fresh frozen plasma replacement when alveolar haemorrhage is active or after biopsy.
• Cyclophosphamide 2 mg/kg daily orally (reduce to 1.5 mg/kg above age 60, and to 1 mg/kg above age 75) for 3 months.
• Prednisolone 1 mg/kg daily (maximum 60 mg), tapering to 20 mg by week 6 and stopping by 6 months.
• Poor prognosis markers: creatinine above 600 micromol/L, dialysis dependence, 100% crescents; treat only if pulmonary haemorrhage requires it.

Immune complex disease

• Lupus nephritis class III or IV: methylprednisolone 500 mg intravenously daily for 3 days, mycophenolate mofetil 1 g twice daily (increase to 1.5 g twice daily) or cyclophosphamide, with hydroxychloroquine 200 to 400 mg daily.
• Infection related disease: antibiotics for endocarditis or abscess, supportive care; steroids only for severe crescentic disease.
• IgA vasculitis with crescents: methylprednisolone 500 mg to 1 g intravenously daily for 3 days, then prednisolone 1 mg/kg daily (maximum 60 mg), with cyclophosphamide for severe disease.

Supportive

• Salt restriction below 2 g daily, furosemide 40 to 80 mg for oedema, ACE inhibitor after stabilisation.
• Prophylaxis during immunosuppression: co-trimoxazole 480 mg daily (renal dose adjusted), proton pump inhibitor, calcium and vitamin D, hepatitis B screening before rituximab (entecavir 0.5 mg daily if core antibody positive).
• Dialysis for the usual indications (refractory hyperkalaemia, acidosis, overload, uraemic complications); do not stop immunosuppression because dialysis is started, as recovery may occur over weeks.

Special groups. Pregnancy: cyclophosphamide, mycophenolate and ACE inhibitors are contraindicated; use prednisolone, azathioprine 2 mg/kg daily and plasma exchange. Frail older adults: reduce cyclophosphamide and steroid exposure and prefer rituximab with reduced dose steroid.