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Rapidly Progressive Glomerulonephritis (RPGN)

(Crescentic Glomerulonephritis)

by Navin Jaipaul, MD, MHS

Rapidly progressive glomerulonephritis (RPGN) is usually accompanied by microscopic glomerular crescent formation with progression to renal failure within weeks to months. Diagnosis is based on history, urinalysis, serologic tests, and renal biopsy. Treatment is with corticosteroids, with or without cyclophosphamide, and sometimes plasmapheresis.

RPGN, a type of nephritic syndrome (see Overview of Nephritic Syndrome), is accompanied by extensive glomerular crescent formation (which can be seen in a biopsy specimen) that, if untreated, progresses to end-stage renal disease over weeks to months. It is relatively uncommon, affecting 10 to 15% of patients with glomerulonephritis (GN), and occurs predominantly in patients 20 to 50 yr. Types and causes are classified by findings using immunofluorescence microscopy (see Classification of Rapidly Progressive Glomerulonephritis Based on Immunofluorescence Microscopy).

Classification of Rapidly Progressive Glomerulonephritis Based on Immunofluorescence Microscopy

Type

Percentage of RPGN Cases

Causes

Type 1: Anti-GBM antibody–mediated

10%

Anti-GBM GN (without lung hemorrhage*)

Goodpasture syndrome (with lung hemorrhage)

Type 2: Immune complex

40%

Postinfectious causes:

  • Antistreptococcal antibodies (eg, poststreptococcal GN)

  • Infective endocarditis

  • Vascular prosthetic nephritis

  • Viral hepatitis B infection

  • Visceral abscess or sepsis

Connective tissue disorders:

  • Anti-DNA autoantibodies (eg, lupus nephritis)

  • IgA immune complexes (eg, immunoglobulin A–associated vasculitis GN, formerly Henoch-Schönlein purpura GN)

  • Mixed IgG-IgM cryoglobulins (eg, cryoglobulinemic GN)

Other glomerulopathies:

  • IgA nephropathy

  • Membranoproliferative GN

Type 3: Pauci-immune

50%

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)

Pulmonary necrotizing granulomas (eg, granulomatosis with polyangiitis)

Renal-limited disease (eg, idiopathic crescentic GN)

Systemic necrotizing arteritis (eg, polyarteritis nodosa)

Type 4: Double-antibody positive

Rare

Same as for as types 1 and 3

Idiopathic

Rare

No clear cause

*When the lung is also affected, anti-GBM glomerulonephritis is called Goodpasture syndrome.

GBM = glomerular basement membrane; GN = glomerulonephritis; RPGN = rapidly progressive glomerulonephritis.

Antiglomerular basement membrane (GBM) antibody disease (type 1 RPGN) is autoimmune GN and accounts for up to 10% of RPGN cases. It may arise when respiratory exposures (eg, cigarette smoke, viral URI) or some other stimulus exposes alveolar capillary collagen, triggering formation of anticollagen antibodies. The anticollagen antibodies cross-react with GBM, fixing complement and triggering a cell-mediated inflammatory response in the kidneys and usually the lungs. The term Goodpasture syndrome refers to a combination of GN and alveolar hemorrhage in the presence of anti-GBM antibodies (see Goodpasture Syndrome). GN without alveolar hemorrhage in the presence of anti-GBM antibodies is called anti-GBM glomerulonephritis. Immunofluorescent staining of renal biopsy tissue demonstrates linear IgG deposits.

Immune complex RPGN (type 2 RPGN) complicates numerous infectious and connective tissue disorders and also occurs with other primary glomerulopathies. Immunofluorescent staining demonstrates nonspecific granular immune deposits. The condition accounts for up to 40% of RPGN cases. Pathogenesis is usually unknown.

Pauci-immune RPGN (type 3 RPGN) is distinguished by the absence of immune complex or complement deposition on immunofluorescent staining. It constitutes up to 50% of all RPGN cases. Almost all patients have elevated antineutrophil cytoplasmic antibodies (ANCAs, usually antiproteinase 3-ANCA or myeloperoxidase-ANCA) and systemic vasculitis.

Double-antibody disease (type 4 RPGN) has features of types 1 and 3, with the presence of anti-GBM and ANCA antibodies. It is rare.

Idiopathic cases are rare. They include patients with either of the following:

  • Immune complexes (similar to type 2) but no obvious cause such as infection, connective tissue disorder, or glomerular disorder

  • Pauci-immune features (similar to type 3) but absence of ANCA antibodies

Symptoms and Signs

Manifestations are usually insidious, with weakness, fatigue, fever, nausea, vomiting, anorexia, arthralgia, and abdominal pain. Some patients present similarly to those with PIGN, with abrupt-onset hematuria. About 50% of patients have edema and a history of an acute influenza-like illness within 4 wk of onset of renal failure, usually followed by severe oliguria. Nephrotic syndrome is present in 10 to 30%. Hypertension is uncommon and rarely severe. Patients with anti-GBM antibody disease may have pulmonary hemorrhage, which can manifest with hemoptysis or be detectable only by finding diffuse alveolar infiltrates on chest x-ray (pulmonary-renal or diffuse alveolar hemorrhage syndrome—).

Diagnosis

  • Progressive renal failure over weeks to months

  • Nephritic urinary sediment

  • Serologic testing

  • Renal biopsy

Diagnosis is suggested by acute kidney injury in patients with hematuria and dysmorphic RBCs or RBC casts. Testing includes serum creatinine, urinalysis, CBC, serologic tests, and renal biopsy. Diagnosis is usually by serologic tests and renal biopsy.

Serum creatinine is almost always elevated. Hematuria is always present, and RBC casts are usually present. Telescopic sediment (ie, sediment with multiple elements, including WBCs, dysmorphic RBCs, and WBC, RBC, granular, waxy, and broad casts) is common.

On CBC , anemia is usually present, and leukocytosis is common.

Serologic testing should include anti-GBM antibodies (anti-GBM antibody disease); antistreptolysin O antibodies, anti-DNA antibodies, or cryoglobulins (immune complex RPGN); and ANCA titers (pauci-immune RPGN). Complement measurement may be useful in suspected immune complex RPGN, because hypocomplementemia is common.

Early renal biopsy is essential. The feature common to all types of RPGN is focal proliferation of glomerular epithelial cells, sometimes interspersed with numerous neutrophils, that forms a crescentic cellular mass (crescents) and that fills Bowman space in > 50% of glomeruli. The glomerular tuft usually appears hypocellular and collapses. Necrosis within the tuft or involving the crescent may occur and may be the most prominent abnormality. In such patients, histologic evidence of vasculitis should be sought.

Immunofluorescence microscopy findings differ for each type.

  • In anti-GBM antibody disease (type 1), linear or ribbon-like deposition of IgG along the GBM is most prominent and is often accompanied by linear and sometimes granular deposition of C3.

  • In immune complex RPGN (type 2), immunofluorescence reveals diffuse, irregular mesangial IgG and C3 deposits.

  • In pauci-immune RPGN (type 3), immune staining and deposits are not detected. However, fibrin occurs within the crescents, regardless of the fluorescence pattern.

  • In double antibody RPGN (type 4), linear staining of the GBM is present (similar to type 1).

  • In idiopathic RPGN some patients have immune complexes (similar to those of type 2) and others have absence of immune staining and deposits (similar to type 3).

Prognosis

Spontaneous remission is rare, and 80 to 90% of untreated patients progress to end-stage renal disease within 6 mo. Prognosis improves with early treatment.

Favorable prognostic factors include RPGN caused by the following:

  • Anti-GBM disease if treated early, especially when treated before oliguria occurs and when creatinine level is < 7 mg/dL

  • PIGN

  • SLE

  • Granulomatosis with polyangiitis

  • Polyarteritis nodosa

Unfavorable prognostic factors include the following:

  • Age> 60 yr

  • Oliguric renal failure

  • Higher serum creatinine level

  • Circumferential crescents in > 75% of glomeruli

  • Among patients with pauci-immune RPGN, no response to treatment

About 30% of patients with pauci-immune RPGN do not respond to treatment; among nonresponders, about 40% require dialysis, and 33% die within 4 yr. In contrast, among patients who respond to treatment, < 20% of patients require dialysis, and about 3% die.

Patients with double-antibody disease appear to have a renal prognosis somewhat better than patients with only anti-GBM antibody disease and worse than patients with pauci-immune RPGN.

Patients who recover normal renal function after RPGN demonstrate residual histologic changes principally in glomeruli, consisting chiefly of hypercellularity, with little or no sclerosis within the glomerular tuft or the epithelial cells and minimal fibrosis of the interstitium.

Death is usually due to infectious or cardiac causes, providing that a uremic death is prevented by dialysis.

Treatment

  • Corticosteroids

  • Cyclophosphamide

  • Plasma exchange

Treatment varies by disease type, although no regimens have been rigorously studied. Therapy should be instituted early, ideally when serum creatinine is < 5 mg/dL and before the biopsy shows crescentic involvement of all glomeruli or organizing crescents as well as fibrotic interstitium and atrophic tubules. Treatment becomes less effective as these features become more prominent and may be harmful in some patients (eg, the elderly, patients with infection).

Corticosteroids and cyclophosphamide are usually given. For immune complex and pauci-immune RPGN, corticosteroids (methylprednisolone 1 g IV once/day over 30 min for 3 to 5 days followed by prednisone 1 mg/kg po once/day) may reduce serum creatinine levels or delay dialysis for > 3 yr in 50% of patients. Cyclophosphamide 1.5 to 2 mg/kg po once/day is usually given and may particularly benefit ANCA-positive patients; monthly pulse regimens may cause fewer adverse effects (eg, leukopenia, infection) than oral therapy because of reduced cumulative dosing, but their role is not defined. Prednisone and cyclophosphamide are typically started concurrent with plasma exchange for anti-GBM antibody disease and continued to minimize new antibody formation. Patients with idiopathic disease are usually treated with corticosteroids and cyclophosphamide, but data regarding efficacy are scarce.

Plasma exchange (daily 3- to 4-L exchanges for 14 days) is recommended for anti-GBM antibody disease. Plasma exchange should also be considered for immune complex and pauci-immune ANCA-associated RPGN with pulmonary hemorrhage or severe renal dysfunction on presentation (serum creatinine > 5.7 mg/dL or dialysis dependency). Plasma exchange is believed to be effective because it rapidly removes free antibody, intact immune complexes, and mediators of inflammation (eg, fibrinogen, complement).

Lymphocytapheresis, a technique to remove peripheral lymphocytes from circulation, may benefit pauci-immune RPGN but requires further investigation.

Renal transplantation is effective for all types, but disease may recur in the graft; risk diminishes with time. In anti-GBM antibody disease, the anti-GBM titers should be undetectable for at least 12 mo before transplantation. For patients with pauci-immune RPGN, disease activity should be quiescent for at least 6 mo before transplantation; ANCA titers do not need to be suppressed.

Key Points

  • Consider RPGN if patients have acute kidney injury with hematuria and dysmorphic RBCs or RBC casts, particularly with subacute constitutional or nonspecific symptoms (eg, fatigue, fever, anorexia, arthralgia, abdominal pain).

  • Do serologic tests and early renal biopsy.

  • Initiate treatment early, with corticosteroids, cyclophosphamide, and often plasma exchange.

  • Consider renal transplantation after disease activity is controlled.

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Drugs Mentioned In This Article

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  • CYTOXAN (LYOPHILIZED)
  • MEDROL
  • RAYOS

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