eMedicine Specialties > Nephrology > Glomerular Diseases

Glomerulonephritis, Rapidly Progressive

Author: James W Lohr, MD, Fellowship Program Director, Professor, Department of Internal Medicine, Division of Nephrology, State University of New York at Buffalo
Coauthor(s): Kerry C Owens, MD, Consulting Staff, Department of Internal Medicine, Section of Nephrology, Integris Baptist Medical Center of Oklahoma City
Contributor Information and Disclosures

Updated: Sep 4, 2008

Introduction

Background

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).  Immunological 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.

Anti-GBM antibody

• Goodpasture syndrome (lung and kidney involvement)
• Anti-GBM disease (only kidney involvement)
• Note: 10-40% of patients may be ANCA positive.

• Postinfectious (staphylococci/streptococci)
• Collagen-vascular disease
• Lupus nephritis
• Henoch-Schönlein purpura (immunoglobulin A and systemic vasculitis)
• Immunoglobulin A nephropathy (no vasculitis)
• Mixed cryoglobulinemia
• Primary renal disease
• Membranoproliferative glomerulonephritis
• Fibrillary glomerulonephritis
• Idiopathic
• 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.

Pauci-immune

• Wegener granulomatosis (WG)
• Microscopic polyangiitis (MPA)
• Renal-limited necrotizing crescentic glomerulonephritis (NCGN)
• Churg-Strauss syndrome
• Note: 80-90% of patients 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.

Pathophysiology

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

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

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

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.

Frequency

United States

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. 

International

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.

Mortality/Morbidity

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.

Race

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.

Sex

The male-to-female ratio in all studies is approximately 1:1.

Age

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.

Clinical

History

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.

Physical

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.

• Skin
  • 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.
• Nervous system
  • 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.
• Musculoskeletal
  • 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.
• Gastrointestinal
  • 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.
• Renal
  • 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.
• Respiratory
  • 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.
• Ocular
  • Iritis, uveitis, and conjunctivitis are the most common ocular manifestations of ANCA.
  • Involvement occurs in approximately 2% of patients with ANCA-associated disease.

Causes

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.

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