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Definition, Etiology, PathogenesisTop
Rapidly progressive glomerulonephritis (RPGN) is a clinical syndrome of rapid deterioration of renal function within weeks, with histologic features of extracapillary proliferation; this forms cellular crescents in Bowman space and can be referred to as crescentic glomerulonephritis. RPGN can be kidney-limited or associated with systemic diseases.
The causes of RPGN are often categorized into 3 classes of underlying conditions:
1) Anti–glomerular basement membrane (anti-GBM) disease: Presence of autoantibodies against type IV collagen. Historically, the term “Goodpasture syndrome” referred to lung (pulmonary hemorrhage) and kidney involvement.
2) Immune complex deposition: Immune complexes deposited in the glomerulus can be seen either on immunofluorescence or electron microscopy. Serum complement levels may be low. Immune complex deposition is associated with infectious or autoimmune conditions. Common causes include systemic lupus erythematosus (SLE), IgA nephropathy, postinfectious glomerulonephritis, and endocarditis. Signs and symptoms are reflective of the underlying disease.
3) Pauci-immune RPGN: Histologically characterized by the absence of immune deposits in the vessel wall or glomerulus. The majority of patients have circulating antineutrophil cytoplasmic antibodies (ANCAs). Causes of pauci-immune glomerulonephritis include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and less commonly Churg-Strauss syndrome. Pulmonary hemorrhage can also occur. Other areas of vasculitis involvement include the eyes, skin, and nervous system.
Patients occasionally have both antibodies to the GBM and ANCAs and are then considered “double-antibody positive.”
RPGN often manifests as nephritic syndrome with hypertension, mild edema, dysmorphic red blood cells/red cell casts on microscopy, non–nephrotic range proteinuria, and decreased glomerular filtration rate (GFR). In some patients the onset of symptoms is insidious, and presenting manifestations are weakness, fatigue, fever, and arthralgias. When RPGN is secondary to an underlying condition, symptoms of that disease can be observed. Nephrotic syndrome can occur but is uncommon.
In untreated patients, end-stage renal disease (see Chronic Kidney Disease) can develop rapidly.
1. Urinalysis/microscopy: Active urine sediment, proteinuria usually below the nephrotic range.
2. Blood tests: Increased creatinine/urea and other abnormalities consistent with acute kidney injury. Tests for diagnosis include anti-GBM antibody, cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA), perinuclear antineutrophil cytoplasmic antibody (p-ANCA), antinuclear antibody (ANA), anti–double-stranded DNA (anti-dsDNA) antibody, complements, antistreptolysin O (ASO) titer, and cryoglobulins.
3. Diagnostic imaging: Renal ultrasonography. Consider echocardiography and chest radiography.
4. Renal biopsy: Biopsy is usually required for diagnosis and shows crescent formation in the glomeruli.
Treatment of RPGN varies depending on the underlying cause but should be started quickly, as permanent renal damage develops rapidly. Involvement of nearly all glomeruli, fibrotic crescents, diffuse interstitial fibrosis, and diffuse renal tubular atrophy are biopsy signs of irreversible damage, and in such cases aggressive immunosuppressive therapy has only marginal benefits and is outweighed by the risk. Dialysis is the only treatment option for such patients unless nonrenal indications for treatment exist (pulmonary hemorrhage).
1. Anti-GBM diseaseEvidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due the observational nature of data but increased due to historically very poor survival. Levy JB, Turner AN, Rees AJ, Pusey CD. Long-term outcome of anti-glomerular basement membrane antibody disease treated with plasma exchange and immunosuppression. Ann Intern Med. 2001 Jun 5;134(11):1033-42. PubMed PMID: 11388816. Johnson JP, Moore J Jr, Austin HA 3rd, Balow JE, Antonovych TT, Wilson CB. Therapy of anti-glomerular basement membrane antibody disease: analysis of prognostic significance of clinical, pathologic and treatment factors. Medicine (Baltimore). 1985 Jul;64(4):219-27. PubMed PMID: 3892220.:
1) Glucocorticoids: IV methylprednisolone 0.5 to 1 g/d for 3 days followed by oral prednisone 1 mg/kg/d titrated to 10 mg/d after 4 months and discontinued after 6 months.
2) Oral cyclophosphamide 2 mg/kg/d for 3 months (in IV pulses if the patient is unable to take oral formulations). Dose adjustment is required for reduced renal function.
3) Daily plasmapheresis with an exchange of 4 L of plasma per procedure for 14 days or until anti-GBM antibodies are undetectable.
Prolonged immunosuppression (>3 months) is not usually necessary. Individuals who present requiring dialysis very rarely derive benefit from treatment and are not usually treated with immunosuppression in the absence of pulmonary hemorrhage.
2. Immune complex disease: Treatment and the evidence supporting treatment varies depending on the underlying cause of the immune complexes. SLE is treated with glucocorticoids and either cyclophosphamide or mycophenolate mofetil. Glucocorticoids can be also considered for postinfectious glomerulonephritis and endocarditis.
3. Pauci-immune RPGN (with or without positive ANCA titer results):
1) IV methylprednisolone 0.5 to 1 g/d for 3 days followed by oral prednisone 1 mg/kg for 1 month and then tapered over 3 to 4 months. Evidence varies on the appropriate duration of glucocorticoid maintenance therapy.
2) Cyclophosphamide IV 15 mg/kg initially every 2 weeks or daily orally 1.5 to 2 mg/kg. IV cyclophosphamide may have fewer adverse effects than the oral formulation but it may be associated with higher rates of relapse. The appropriate duration of cyclophosphamide is unclear but suggested as 3 to 6 months.Evidence 2Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Walters GD, Willis NS, Craig JC. Interventions for renal vasculitis in adults. A systematic review. BMC Nephrol. 2010 Jun 24;11:12. doi: 10.1186/1471-2369-11-12. Review. PubMed PMID: 20573267; PubMed Central PMCID: PMC2914014.
3) Rituximab has been shown to be noninferior to cyclophosphamide and can be considered in patients with contraindications to cyclophosphamide.Evidence 3Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Stone JH, Merkel PA, Spiera R, et al; RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010 Jul 15;363(3):221-32. doi: 10.1056/NEJMoa0909905. PubMed PMID: 20647199; PubMed Central PMCID: PMC3137658. Jones RB, Tervaert JW, Hauser T, et al; European Vasculitis Study Group. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. 2010 Jul 15;363(3):211-20. doi: 10.1056/NEJMoa0909169. PubMed PMID: 20647198.
4) Plasmapheresis is currently recommended in guidelines for those with advanced renal disease (creatinine >500 micromol/L) and suggested for those with pulmonary hemorrhage, although recent research questions the long-term efficacy.Evidence 4Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision. Walsh M, Casian A, Flossmann O, et al; European Vasculitis Study Group (EUVAS). Long-term follow-up of patients with severe ANCA-associated vasculitis comparing plasma exchange to intravenous methylprednisolone treatment is unclear. Kidney Int. 2013 Aug;84(2):397-402. doi: 10.1038/ki.2013.131. Epub 2013 Apr 24. PubMed PMID: 23615499. A large ongoing randomized controlled trial (PEXIVAS [Plasma Exchange and Glucocorticoids for Treatment of Anti-Neutrophil Cytoplasm Antibody–Associated Vasculitis]) is further investigating the utility of plasmapheresis.
5) The appropriate duration of maintenance therapy is unknown, with suggestions ranging from 12 to 24 months. Azathioprine and rituximab both have evidence supporting their use as maintenance agents.Evidence 5Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision. Hiemstra TF, Walsh M, Mahr A, et al; European Vasculitis Study Group (EUVAS). Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial. JAMA. 2010 Dec 1;304(21):2381-8. doi: 10.1001/jama.2010.1658. Epub 2010 Nov 8. PubMed PMID: 21060104.
Unlike in anti-GBM disease, patients with pauci-immune RPGN requiring dialysis at presentation can recover renal function and should be treated even in the absence of extrarenal manifestations unless renal biopsy demonstrates a near complete loss of glomeruli and interstitial scarring. If patients remain dialysis-dependent and have no extrarenal manifestations, maintenance therapy is not necessary.
1. Anti-GBM disease relapses rarely but should be treated in the same way as at first presentation.
2. Relapses of pauci-immune glomerulonephritis are more common. If severe (life- or organ-threatening), they require a repeat of the initial therapy, although rituximab can be considered over cyclophosphamide, depending on the previous cumulative dose of cyclophosphamide.
The prognosis of RPGN is dependent on the underlying pathology and severity of the initial presentation. Anti-GBM disease is usually quickly fatal if untreated. Patient survival is greatly improved with treatment and is as high as 90%. Renal survival, unfortunately, is much poorer. Mortality in untreated pauci-immune vasculitis is 90% without therapy, although treatment is effective and has reduced mortality to between 10% and 20%. Permanent renal replacement is required in 20% to 40% of patients.