Rapidly progressive glomerulonephritis (RPGN), a type of nephritic syndrome Overview of Nephritic Syndrome Nephritic syndrome is defined by hematuria, variable degrees of proteinuria, usually dysmorphic red blood cells (RBCs), and often RBC casts on microscopic examination of urinary sediment. Often... read more , 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); if left untreated, RPGN progresses to end-stage kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more 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 ).
Antiglomerular basement membrane antibody disease
Antiglomerular 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 Goodpasture Syndrome Goodpasture syndrome, a type of pulmonary-renal syndrome, is an autoimmune syndrome consisting of alveolar hemorrhage and glomerulonephritis caused by circulating anti-glomerular basement membrane... read more 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 systemic rheumatic diseases 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 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 Overview of Vasculitis Vasculitis is inflammation of blood vessels, often with ischemia, necrosis, and organ inflammation. Vasculitis can affect any blood vessel—arteries, arterioles, veins, venules, or capillaries... read more .
Double-antibody disease occurs 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 but no obvious cause such as infection, systemic rheumatic disease, or glomerular disorder
Pauci-immune features but absence of ANCA antibodies
Symptoms and Signs of RPGN
Manifestations are usually insidious, with weakness, fatigue, fever, nausea, vomiting, anorexia, arthralgia, and abdominal pain. Some patients present similarly to those with postinfectious glomerulonephritis Postinfectious Glomerulonephritis (PIGN) Postinfectious glomerulonephritis occurs after infection, usually with a nephritogenic strain of group A beta-hemolytic streptococcus. Diagnosis is suggested by history and urinalysis and confirmed... read more , 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 findings suggestive of diffuse alveolar infiltrates on lung imaging (pulmonary-renal syndrome Pulmonary-Renal Syndrome Pulmonary-renal syndrome is diffuse alveolar hemorrhage plus glomerulonephritis, often occurring simultaneously. Cause is almost always an autoimmune disorder. Diagnosis is by serologic tests... read more or diffuse alveolar hemorrhage syndrome Diffuse Alveolar Hemorrhage Diffuse alveolar hemorrhage is persistent or recurrent pulmonary hemorrhage that originates from the lung parenchyma (ie, the alveoli) as opposed to the airways. There are numerous causes, but... read more ).
Diagnosis of RPGN
Progressive renal failure over weeks to months
Nephritic urinary sediment
Serum complement levels
Diagnosis is suggested by acute kidney injury Acute Kidney Injury (AKI) Acute kidney injury is a rapid decrease in renal function over days to weeks, causing an accumulation of nitrogenous products in the blood (azotemia) with or without reduction in amount of urine... read more 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 (serum C3 and C4) 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.
Treatment of RPGN
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 Overview of Renal Replacement Therapy Renal replacement therapy (RRT) replaces nonendocrine kidney function in patients with renal failure and is occasionally used for some forms of poisoning. Techniques include continuous hemofiltration... read more . Treatment becomes less effective as these features become more prominent and may be harmful in some patients (eg, older patients, patients with infection).
Corticosteroids and either cyclophosphamide or rituximab are usually given. For immune complex and pauci-immune disease, corticosteroids (methylprednisolone 1 g IV once a 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 (1, 2 Treatment references Rapidly progressive glomerulonephritis is acute nephritic syndrome accompanied by microscopic glomerular crescent formation with progression to renal failure within weeks to months. Diagnosis... read more ).
Cyclophosphamide is usually given and may particularly benefit antineutrophil cytoplasmic antibody (ANCA)–positive patients; IV monthly pulse regimens may cause fewer adverse effects (eg, leukopenia, infection) than oral therapy because of reduced cumulative dosing. 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 may be dosed at 375 mg/m2 IV per week for 4 weeks as used in the RAVE trial (formal title: Rituximab in ANCA-Associated Vasculitis; [ 2 Treatment references Rapidly progressive glomerulonephritis is acute nephritic syndrome accompanied by microscopic glomerular crescent formation with progression to renal failure within weeks to months. Diagnosis... read more ]). 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 Plasma exchange Apheresis refers to the process of separating the cellular and soluble components of blood using a machine. Apheresis is often done on donors where whole blood is centrifuged to obtain individual... read more (daily 3- to 4-L exchanges for 14 days) is recommended for anti-GBM antibody disease. Plasma exchange may 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 Hemodialysis In hemodialysis, a patient’s blood is pumped into a dialyzer containing 2 fluid compartments configured as bundles of hollow fiber capillary tubes or as parallel, sandwiched sheets of semipermeable... read more dependency), but its use remains controversial. Plasma exchange is thought to rapidly remove free antibody, intact immune complexes, and mediators of inflammation (eg, fibrinogen, complement). While some evidence suggested that plasma exchange improved short-term kidney outcomes, a subsequent randomized trial did not show that it reduced the incidence of death or end-stage kidney disease (3 Treatment references Rapidly progressive glomerulonephritis is acute nephritic syndrome accompanied by microscopic glomerular crescent formation with progression to renal failure within weeks to months. Diagnosis... read more ).
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 Overview of Renal Replacement Therapy Renal replacement therapy (RRT) replaces nonendocrine kidney function in patients with renal failure and is occasionally used for some forms of poisoning. Techniques include continuous hemofiltration... read more , even if creatinine levels were elevated above 5 to 7 mg/dL (442 to 618.8 micromol/L; [ 4 Treatment references Rapidly progressive glomerulonephritis is acute nephritic syndrome accompanied by microscopic glomerular crescent formation with progression to renal failure within weeks to months. Diagnosis... read more ]).
Kidney transplantation Kidney Transplantation Kidney transplantation is the most common type of solid organ transplantation. (See also Overview of Transplantation.) The primary indication for kidney transplantation is End-stage renal failure... read more 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.
1. Ponticelli C, Altieri P, et al: A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy. J Am Soc Nephrol 9(3):444, 1998. doi: 10.1681/ASN.V93444
2. 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
3. Walsh M, Merkel PA, Peh C-A, et al: Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis. N Engl J Med 382(7):621-631, 2020. doi: 10.1056/NEJMoa1803537
4. 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. doi: 10.7326/0003-4819-134-11-200106050-00009
Prognosis for RPGN
Spontaneous remission is rare, and 80 to 90% of untreated patients progress to end-stage kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more within 6 months. Prognosis improves with early treatment.
Favorable prognostic factors include RPGN caused by the following:
Anti-GBM disease Antiglomerular basement membrane antibody disease Rapidly progressive glomerulonephritis is acute nephritic syndrome accompanied by microscopic glomerular crescent formation with progression to renal failure within weeks to months. Diagnosis... read more if treated early, especially when treated before oliguria occurs and when creatinine level is < 7 mg/dL (618.8 micromol/L)
Unfavorable prognostic factors include the following:
Age > 60 years
Oliguric renal failure
Higher serum creatinine level
Circumferential crescents in > 75% of glomeruli
About 30% of patients with pauci-immune RPGN do not respond to treatment; among nonresponders, about 40% require dialysis Hemodialysis In hemodialysis, a patient’s blood is pumped into a dialyzer containing 2 fluid compartments configured as bundles of hollow fiber capillary tubes or as parallel, sandwiched sheets of semipermeable... read more , 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.
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).
Evaluate with serologic tests and early renal biopsy.
Initiate treatment early, with corticosteroids, cyclophosphamide, and in some cases plasma exchange.
Consider kidney transplantation after disease activity is controlled.