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Rapidly Progressive Glomerulonephritis (RPGN)

(Crescentic Glomerulonephritis)

By

Frank O'Brien

, MD, Washington University in St. Louis

Last full review/revision Jan 2020| Content last modified Jan 2020
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Rapidly progressive glomerulonephritis is acute nephritic syndrome 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 or rituximab, and sometimes plasma exchange.

Rapidly progressive glomerulonephritis (RPGN), a type of nephritic syndrome, is a pathologic diagnosis accompanied by extensive glomerular crescent formation (ie, > 50% of sampled glomeruli contain crescents 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, and occurs predominantly in patients 20 to 50 years. Types and causes are classified by findings using immunofluorescence microscopy and serologic tests (eg, anti-glomerular basement membrane [GBM] antibody, anti-neutrophil cytoplasmic antibody [ANCA]—see table Classification of Rapidly Progressive Glomerulonephritis Based on Immunofluorescence Microscopy).

Table
icon

Classification of Rapidly Progressive Glomerulonephritis Based on Immunofluorescence Microscopy

Type

Percentage of RPGN Cases

Causes

Anti-GBM antibody–mediated

10%

Anti-GBM GN (without lung hemorrhage*)

Goodpasture syndrome (with lung hemorrhage)

Immune complex-mediated

40%

Postinfectious causes:

Connective tissue disorders:

Other glomerulopathies:

Pauci-immune

50%

Renal-limited disease (eg, idiopathic crescentic GN)

Double-antibody positive

Rare

Same as for anti-GBM antibody-mediated and pauci-immune types

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

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

Antiglomerular basement membrane antibody disease

Anti-glomerular basement membrane (GBM) antibody disease is an autoimmune glomerulonephritis and accounts for up to 10% of RPGN cases. It may arise when respiratory exposures (eg, cigarette smoke, viral upper respiratory infection) 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 glomerulonephritis and alveolar hemorrhage in the presence of anti-GBM antibodies. Glomerulonephritis 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

Immune complex 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

Pauci-immune 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

Double-antibody disease occurs with the presence of anti-GBM and ANCA antibodies. It is rare.

Idiopathic RPGN

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

  • Immune complexes but no obvious cause such as infection, connective tissue disorder, or glomerular disorder

  • Pauci-immune features 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 postinfectious glomerulonephritis, with abrupt-onset hematuria. About 50% of patients have edema and a history of an acute influenza-like illness within 4 weeks 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 syndrome or diffuse alveolar hemorrhage syndrome).

Diagnosis

  • Progressive renal failure over weeks to months

  • Nephritic urinary sediment

  • Serologic testing

  • Serum complement levels

  • Renal biopsy

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

Serum creatinine is almost always elevated.

Urinalysis shows hematuria is always present, and RBC casts are usually present. Telescopic sediment (ie, sediment with multiple elements, including white blood cells [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 antineutrophil cytoplasmic antibodies (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, 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, immunofluorescence reveals diffuse, irregular mesangial IgG and C3 deposits.

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

  • In double antibody RPGN, linear staining of the GBM is present.

  • In idiopathic RPGN, some patients have immune complexes and others have absence of immune staining and deposits.

Prognosis

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

Favorable prognostic factors include RPGN caused by the following:

Unfavorable prognostic factors include the following:

  • Age > 60 years

  • 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 years. 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 disease.

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

  • Rituximab

  • 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 (442 micromol/L) and before the biopsy shows crescentic involvement of all glomeruli or organizing crescents as well as fibrotic interstitium and atrophic tubules. Even patients with kidney involvement and higher creatinine levels should be aggressively treated if they do not require immediate renal replacement therapy. Treatment becomes less effective as these features become more prominent and may be harmful in some patients (eg, older patients, patients with infection).

Treatment varies by disease type, although no regimens have been rigorously studied.

Corticosteroids and either cyclophosphamide or rituximab are usually given. For immune complex and pauci-immune disease, corticosteroids (methylprednisolone 1 g IV once/day over 30 minutes for 3 to 5 days followed by prednisone 1 mg/kg orally once a day) may reduce serum creatinine levels or delay dialysis for > 3 years in 50% of patients.

Cyclophosphamide 1.5 to 2 mg/kg orally once a day is usually given and may particularly benefit antineutrophil cytoplasmic antibody (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 (glomerular basement membrane) 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.

Rituximab 375mg/m2 per week for 4 weeks as used in the RAVE trial (formal title: Rituximab in ANCA-Associated Vasculitis) (1). An alternative regimen is an initial dose of 1g followed by another 1-g dose 2 weeks later. Rituximab has not been used in the treatment of anti-GBM disease.

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 to 7 mg/dL [442 to 618.8 micromol/L] 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).

Aggressive immunosuppressive therapy may also be beneficial in patients who present with higher creatinine levels. Plasmapheresis combined with prednisone and cyclophosphamide benefited patients with renal involvement who did not require immediate renal replacement therapy, even if creatinine levels were elevated above 5 to 7 mg/dL (442 to 618.8 micromol/L) (2).

Kidney 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 months before transplantation. For patients with pauci-immune RPGN, disease activity should be quiescent for at least 6 months before transplantation; ANCA titers do not need to be suppressed.

Treatment references

  • Jones RB, Cohen Tervaert JW, Hauser T: Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med 363:211-220, 2010. doi: 10.1056/NEJMoa0909169. 

  • Levy JB, Turner AN, Rees AJ, et al: Long-term outcome of anti-glomerular basement membrane antibody disease treated with plasma exchange and immunosuppression. Ann Intern Med 134(11):1033-1042, 2001.

Key Points

  • Consider rapidly progressive glomerulonephritis 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 kidney transplantation after disease activity is controlled.

Drugs Mentioned In This Article

Drug Name Select Trade
MEDROL
CYTOXAN (LYOPHILIZED)
RAYOS
RITUXAN
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