Rapidly progressive glomerulonephritis (RPGN) is a disease of the kidney characterized clinically by a rapid decrease in the glomerular filtration rate (GFR) of at least 50% over a short period, from a few days to 3 months. The main pathologic finding is extensive glomerular crescent formation. The ubiquitous pathological feature of crescentic glomerulonephritis is a focal rupture of glomerular capillary walls that can be seen by light microscopy and electron microscopy.
The term rapidly progressive glomerulonephritis was first used to describe a group of patients who had an unusually fulminant poststreptococcal glomerulonephritis and a poor clinical outcome. Several years later, the antiglomerular basement membrane (anti-GBM) antibody was discovered to produce a crescentic glomerulonephritis in sheep, and, following this discovery, the role of anti-GBM antibody in Goodpasture syndrome was elucidated. Soon afterward, the role of the anti-GBM antibody in rapidly progressive glomerulonephritis associated with Goodpasture disease was established.
In the mid 1970s, a group of patients was described who fit the clinical criteria for rapidly progressive glomerulonephritis but in whom no cause could be established. Many of these cases were associated with systemic signs of vascular inflammation (systemic vasculitis), but some cases were characterized only by renal disease. A distinct feature of these cases was the virtual absence of antibody deposition after immunofluorescence staining of the biopsy specimens, which led to the label pauci-immune rapidly progressive glomerulonephritis. More than 80% of patients with pauci-immune rapidly progressive glomerulonephritis were subsequently found to have circulating antineutrophil cytoplasmic antibodies (ANCAs), and, thus, this form of rapidly progressive glomerulonephritis is now termed ANCA-associated vasculitis.
Rapidly progressive glomerulonephritis is classified pathologically into 3 categories, as follows: (1) anti-GBM antibody disease (approximately 3% of cases), (2) immune complex disease (45% of cases), and (3) pauci-immune disease (50% of cases). Immunologic classification is based on the presence or absence of ANCAs. The disorders are also classified based on their clinical presentation.
A classification based on pathology, with the clinical syndromes and the ANCA status described under each pathological description, is outlined below.
Goodpasture syndrome (lung and kidney involvement)
Anti-GBM disease (only kidney involvement)
Note: 10-40% of patients may be ANCA positive.
Henoch-Schönlein purpura (immunoglobulin A and systemic vasculitis)
Immunoglobulin A nephropathy (no vasculitis)
Primary renal disease
Note: Of all patients with crescentic immune complex glomerulonephritis, 25% are ANCA positive; however, less than 5% of patients with noncrescentic immune complex glomerulonephritis are ANCA positive.
The conditions listed above, under the Anti-GBM antibody heading and the Immune complex heading, are discussed in other articles. The remainder of this article addresses the ANCA-associated diseases. This article also only focuses on the adult population affected by rapidly progressive glomerulonephritis.
In 1982, Davies et al first noted the presence of ANCAs in 8 patients with pauci-immune rapidly progressive glomerulonephritis and systemic vasculitis. In 1984, Hall et al noted this presence again, in 4 patients with a small vessel vasculitis. Subsequently, ANCA positivity was found to correlate closely with the clinical syndromes of Wegener granulomatosis, Churg-Strauss syndrome, and microscopic polyangiitis.
The link between ANCAs and the pathogenesis of ANCA-associated disease is unclear; however, it is postulated that ANCAs induce a premature degranulation and activation of neutrophils at the time of their margination, leading to the release of lytic enzymes and toxic oxygen metabolites at the site of injury. There is now substantial evidence that ANCAs are directly involved in the pathogenesis of pauci-immune small vessel vasculitis or glomerulonephritis. In vitro data demonstrate that these autoantibodies activate normal human polymorphonuclear (PMN) leukocytes.
ANCAs react with antigens in the primary granules in the cytoplasm of neutrophils (antiproteinase-3 [PR3]) and in lysosomes of monocytes (MPO).
ANCA demonstrates 2 major types of staining patterns. Cytoplasmic ANCA (cANCA) produces a cytoplasmic staining pattern with central accentuation in alcohol-fixed neutrophils. Perinuclear pattern ANCA (pANCA) demonstrates a perinuclear staining pattern of alcohol-fixed neutrophils, which is actually an artifact of the fixation process. ANCA specificity is determined by enzyme-linked immunosorbent assay (ELISA), with cANCA most commonly an antibody directed against PR3 and with pANCA most commonly an antibody directed against MPO.
Nonspecific pANCA can occur in association with other autoimmune or inflammatory diseases, but they do not have the MPO specificity. The most common occurrence is in systemic lupus erythematosus. Other associated diseases include inflammatory bowel disease, sclerosing cholangitis, autoimmune hepatitis, rheumatoid arthritis, and Felty syndrome.
The ANCA-associated diseases are closely related and are distinguished by only a few clinical and pathologic criteria.
Wegener granulomatosis is characterized by the presence of upper airway lesions, pulmonary infiltrates, and rapidly progressive glomerulonephritis. Patients often present with pulmonary hemorrhage and renal failure. Pathologically, the lungs (and sometimes the upper airway lesions) show granulomatous inflammation.
Of patients with Wegener granulomatosis, 80-90% have findings positive for ANCA and almost all have a cANCA (anti-PR3). A negative test result for ANCA does not exclude the presence of Wegener granulomatosis.
Churg-Strauss disease is characterized by allergic asthma and eosinophilia. Of patients with Churg-Strauss disease, 70-90% are positive for ANCA, primarily pANCAs.
Microscopic polyangiitis is characterized by pulmonary infiltrates and rapidly progressive glomerulonephritis, often coupled with musculoskeletal system abnormalities or with neuropathy or central nervous system abnormalities. The term polyangiitis is used in preference to arteritis because vessels other than arteries are normally involved in the disease.
Of patients with microscopic polyangiitis, 80-90% have positive findings for ANCA and almost all have a pANCA (anti-MPO). A negative test result for ANCA does not exclude the presence of microscopic polyangiitis. Isolated necrotizing crescentic glomerulonephritis is the renal-limited form of microscopic polyangiitis.
The exact frequency of ANCA-associated disease is unknown.
The incidence of rapidly progressive glomerulonephritis is 7 reported cases per 1 million persons per year.
In the United Kingdom, the frequency is estimated at 2 cases per 100,000 persons. In Sweden, the frequency is estimated at 1 case per 100,000 persons.
Massive pulmonary hemorrhage is the most common cause of death in patients presenting with ANCA-associated disease. However, once immunosuppressive therapy has begun, infection is more common.
White persons are affected more frequently than African American persons. In the largest US study, the ratio was 7:1. However, African American persons were more likely to have a worse outcome. The reasons for this are not clear.
The male-to-female ratio in all studies is approximately 1:1.
The age range is 2-92 years. However, the disease is rare in the pediatric population. The peak incidence occurs in the middle of the sixth decade of life.
The most common prodrome of ANCA-associated vasculitis is flulike symptoms characterized by malaise, fever, arthralgias, myalgias, anorexia, and weight loss. This occurs in more than 90% of patients and can occur within days to months of the onset of nephritis or other manifestations of vasculitis.
Following the prodrome, the most common complaints are abdominal pain, painful cutaneous nodules or ulcerations, and a migratory polyarthropathy.
When pulmonary or upper airway involvement is present, patients complain of sinusitis symptoms, cough, and hemoptysis.
Hypertension can be present but is not common. Unless specific findings are present, such as those listed below, the physical examination results are usually normal. Organs or systems affected by ANCA-associated disease are listed below.
Leukocytoclastic vasculitis is common (40-60%) and usually affects the lower extremities.
Necrotizing arteritis can result in painful erythematous nodules, focal necrosis, ulceration, and livedo reticularis.
Patients with Wegener granulomatosis or Churg-Strauss syndrome can also have granulomatous cutaneous nodules.
Nail fold infarcts can be present.
Mononeuritis multiplex is the most common nervous system manifestation of ANCA-associated disease. This condition is caused by inflammation of the epineural arteries and arterioles, which results in ischemia of the nerve tissue.
Central nervous system disease can result from involvement of meningeal vessels and manifest as generalized seizures.
Nervous system involvement is present in 30% of patients with microscopic polyangiitis and 70% of patients with Churg-Strauss disease.
Pain and elevation in tissue enzyme levels can result from inflammation in the arteries of skeletal muscle.
Musculoskeletal involvement is present in 60% of patients with ANCA-associated disease.
Arthritis is a very common symptom. It is usually symmetrical and migratory and usually involves the small joints.
Arthralgias are also common, but this is not considered a marker of active vasculitis.
Arteritis can result in ischemic ulceration in the GI tract, causing pain and bleeding, which is usually occult.
The most serious complications of GI ischemia are intussusception and pancreatitis.
GI involvement occurs in 50% of patients with ANCA.
The diagnostic biopsy finding is proliferative necrotizing crescentic glomerulonephritis.
If overt renal disease is not present upon presentation, then the most common finding is microscopic hematuria.
The prevalence rate of renal disease is 90% for those with microscopic polyangiitis, 80% for those with Wegener granulomatosis, and 45% for those with Churg-Strauss disease.
Pulmonary manifestations range from fleeting focal infiltrates to hemorrhagic alveolar capillaritis resulting in massive pulmonary hemorrhage and hemoptysis. This is the most deadly complication of ANCA disease.
The prevalence rate of pulmonary findings is 50% in those with microscopic polyangiitis, 90% in those with Wegener granulomatosis, and 80% in those with Churg-Strauss disease.
Upper respiratory manifestations include sinusitis, otitis media, ulcers in the nasal mucosa, and subglottic stenosis.
Iritis, uveitis, and conjunctivitis are the most common ocular manifestations of ANCA.
Involvement occurs in approximately 2% of patients with ANCA-associated disease.
The cause of ANCA-associated disease is unknown. A genetic predisposition may exist for the development of this disease. Patients with Wegener granulomatosis are more likely to have abnormal alpha1-antitrypsin phenotypes. Patients who have the Z phenotype are more likely to have aggressive disease. Multiple studies have demonstrated that ANCA-activated neutrophils attack vascular endothelial cells. Because 97% of patients have a flulike prodrome, a viral etiology is possible. However, to date, no evidence exists to support this postulate.
The most important requirement in the diagnosis of ANCA-associated disease is a high index of suspicion. Rapid diagnosis is essential for organ preservation. Laboratory studies include the following:
CBC count with differential: Results are most likely normal, but anemia may be present if the patient has renal failure or is bleeding from the GI tract. Eosinophilia of 13% or greater is suggestive of Churg-Strauss disease.
Serum electrolytes, BUN, creatinine, lactate dehydrogenase (LDH), creatine phosphokinase (CPK), and liver function tests: The most common abnormality is an increased serum creatinine level. However, the level can be normal at presentation. Tissue enzyme (ie, lactate dehydrogenase, creatine kinase) levels may be elevated if the amount of inflammation is significant enough to result in myalgias.
Urinalysis with microscopy: Proteinuria is almost always present but is rarely greater than 2-3 g in 24 hours. Microscopic hematuria is invariably present and may be the only clue to renal disease at presentation. The presence of red cell casts indicates glomerular inflammation and is a very helpful clue.
Erythrocyte sedimentation rate: Although a nonspecific finding, the rate is usually elevated with active disease.
C-reactive protein: levels are elevated and correspond with disease activity.
Antinuclear antibody (ANA) titer: The ANA titer result is not positive in patients with ANCA-associated disease. A high ANA titer should direct the diagnosis toward systemic lupus erythematosus.
ANCA with ELISA subtyping: More than 80% of patients with microscopic polyangiitis are ANCA-positive, and most of these demonstrate pANCA with MPO specificity. Of patients with Wegener granulomatosis, 90% are ANCA-positive and most have cANCA with PR3 specificity, especially in pulmonary involvement. However, ANCA type and specificity is not pathognomonic for each of these clinical syndromes because some patients with Wegener granulomatosis are pANCA-positive and some patients with microscopic polyangiitis are cANCA-positive.
Cryoglobulins: The symptoms of cryoglobulinemia are very similar to those of ANCA-related disease. However, in persons with ANCA-related diseases, the cryoglobulin titer result should be negative.
Hepatitis profile: ANCA-associated disease is not associated with hepatitis. However, hepatitis B is associated with polyarteritis nodosa and hepatitis C is associated with mixed cryoglobulinemia.
Urine and serum protein electrophoresis: Perform this in any middle-aged or elderly person presenting with rapidly progressive glomerulonephritis to exclude the presence of light-chain disease or overt multiple myeloma as a cause of the clinical findings.
Because the sensitivity and the specificity of ANCA testing for pauci-immune glomerulonephritis is only 80-90%, a renal biopsy is recommended to be performed on patients with rapidly progressive glomerulonephritis to establish a definite diagnosis and to determine the severity of the disease. The initiation of therapy should not be delayed for biopsy results to be obtained.
Therapy for ANCA-associated disease consists of a combination of corticosteroids and cyclophosphamide. Treatment with steroids alone results in a 3-fold increase in the risk of relapse compared to combination therapy. The only predictor of renal survival is the serum creatinine value at the time of diagnosis. Therefore, a high index of suspicion is imperative to establish the diagnosis quickly and to institute treatment as soon as possible. Renal failure requiring dialysis is not a contraindication to treatment. Many patients can be removed from dialysis for an extended period (18 mo to 2 y).
The regimen used by the Glomerular Disease Collaborative Network at the University of North Carolina at Chapel Hill[3, 4] is as follows:
Administer methylprednisolone at 7 mg/kg/d intravenously (not to exceed 1 g) for 3 days, followed by oral prednisone at 1 mg/kg/d (not to exceed 80 mg) for 3 weeks, and then oral prednisone at 2 mg/kg every other day (not to exceed 120 mg) for 3 months. This dose is decreased by 25% every 4 weeks until the patient stops taking prednisone.
Administer cyclophosphamide either intravenously or orally. Intravenous therapy is initially administered at a dose of 0.5 g/m2, and the oral dose is 2 mg/kg. Both are adjusted according to a 2-week leukocyte nadir count (goal 3000-4000/µL). The maximum intravenous dose is 1 g/m2. Oral and intravenous cyclophosphamide appears to be equally efficacious. However, this remains an area of controversy, particularly in the case of Wegener granulomatosis, for which some advocate oral therapy. The advantage to using the intravenous preparation is that the risk of cumulative toxicity is lower because a lower total dose is used.
Another protocol, which has been used widely and with success in Europe, is the substitution of azathioprine for cyclophosphamide after a 3-month induction period. Azathioprine is administered at 2 mg/kg orally in a single daily dose. This is continued for 6-12 months.
Methotrexate has been substituted for cyclophosphamide in the initial treatment of Wegener granulomatosis for mild disease and has been used for treatment after initial induction therapy with cyclophosphamide in more severe disease.
Plasmapheresis may be a beneficial addition to therapy for patients who present with severe renal failure (serum creatinine >6 mg/dL) or those who progress despite treatment.
Rituximab may improve renal outcomes in antineutrophil cytoplasmic antibody–associated vasculitis; in addition to anti–B-cell therapy, therapy directed at T cells may improve renal outcome, according to a study conducted by Berden et al.
Other medications have been used in an attempt to attain a remission, such as intravenous immunoglobulin, antithymocyte antibody, and humanized monoclonal antibody to CD4 and CD25. None of these therapies has been well studied. They appear in the literature as case reports.
Chemically related to nitrogen mustards. Transformed primarily in the liver to active alkylating metabolites. The mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells. PO and IV administration appear to be equally efficacious, although controversy exists.
Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.
Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity. Protocol widely and successfully used in Europe is substitution of azathioprine for cyclophosphamide after 3-mo induction period.
Close follow-up care is extremely important in any patient with active vasculitis. The therapies for ANCA-associated vasculitides are not proven in large, randomized, controlled trials but are the standard of care according to consensus. The same can be said for the definitions of relapse, response, and treatment failure.
The following criteria were established by Nachman et al before they performed a randomized control trial comparing immunosuppression regimens in patients diagnosed with microscopic polyangiitis or isolated pauci-immune rapidly progressive glomerulonephritis only (patients with Wegener granulomatosis were excluded).
Stabilization or improvement of renal function (as measured by serum creatinine value), resolution of hematuria, and resolution of extrarenal manifestations of systemic vasculitis
Persistence of proteinuria not considered indicative of persistent disease activity
Remission by therapy - Achievement of remission while still receiving immunosuppressive medication or corticosteroids (prednisone dose or equivalent at >7.5 mg/d)
Progressive decline in renal function with the persistence of an active urine sediment
Persistence or new appearance of any extrarenal manifestation of vasculitis despite immunosuppressive therapy
Relapse (at least one of the following)
Rapid rise in serum creatinine concentration, accompanied by an active urine sediment
Renal biopsy findings demonstrating active necrosis or crescent formation
Hemoptysis, pulmonary hemorrhage, or new or expanding nodules without evidence for infection
Active vasculitis of the respiratory or GI tracts as demonstrated by findings from endoscopic biopsy
Iritis or uveitis
New mononeuritis multiplex
Necrotizing vasculitis identified based on findings from biopsy specimen of any tissue
James W Lohr, MD, Professor, Department of Internal Medicine, Division of Nephrology, Fellowship Program Director, University of Buffalo State University of New York School of Medicine and Biomedical Sciences
Disclosure: Alexion Salary Employment
Kerry C Owens, MD, Consulting Staff, Department of Internal Medicine, Section of Nephrology, Integris Baptist Medical Center of Oklahoma City
Disclosure: Nothing to disclose.
F John Gennari, MD, Associate Chair for Academic Affairs, Robert F and Genevieve B Patrick Professor, Department of Medicine, University of Vermont College of Medicine
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
George R Aronoff, MD, Director, Professor, Departments of Internal Medicine and Pharmacology, Section of Nephrology, Kidney Disease Program, University of Louisville School of Medicine
Disclosure: Nothing to disclose.
Rebecca J Schmidt, DO, FACP, FASN, Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine
Disclosure: Renal Ventures Ownership interest Other
Vecihi Batuman, MD, FACP, FASN, Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Medicine Service, Southeast Louisiana Veterans Health Care System