Rapidly Progressive Glomerulonephritis

Updated: Mar 31, 2015
  • Author: James W Lohr, MD; Chief Editor: Vecihi Batuman, MD, FASN  more...
  • Print
Overview

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 three 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.

Anti-GBM antibody

See the list below:

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

Immune complex

See the list below:

  • 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

See the list below:

  • Granulomatosis with polyangiitis (Wegener granulomatosis)
  • 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.

In 1982, Davies et al first noted the presence of ANCAs in 8 patients with pauci-immune rapidly progressive glomerulonephritis and systemic vasculitis. [1] In 1984, Hall et al noted this presence again, in 4 patients with a small vessel vasculitis. [2] Subsequently, ANCA positivity was found to correlate closely with the clinical syndromes of Wegener granulomatosis, Churg-Strauss syndrome, and microscopic polyangiitis.

Next:

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 two 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.

Granulomatosis with polyangiitis

Granulomatosis with polyangiitis 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 granulomatosis with polyangiitis, 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 this disorder.

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.

Previous
Next:

Epidemiology

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.

Previous
Next:

Race-, Sex-, and Age-related Demographics

White persons are affected more frequently than African Americans. In the largest US study, the ratio was 7:1. However, African-American patients 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.

Previous