Rapidly Progressive Glomerulonephritis

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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). 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

Immune complex

Pauci-immune

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.

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.

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.

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.

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.

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.

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.

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Renal biopsy specimens show a diffuse, proliferative, necrotizing glomerulonephritis with crescent formation.

Medical Care

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).

Consultations

Nephrology consultation should be obtained as early as possible in suspected cases of rapidly progressive glomerulonephritis.

Medication Summary

The goals of pharmacotherapy are to induce remission, to reduce morbidity, and to prevent complications.

Cyclophosphamide (Cytoxan)

Clinical Context:  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.

Class Summary

Has potent immunosuppressive properties.

Methylprednisolone (Solu-Medrol)

Clinical Context:  Decreases inflammation by suppressing migration of PMN leukocytes and reversing increased capillary permeability. After 3 d, switch to PO prednisone.

Prednisone (Deltasone, Sterapred, Orasone)

Clinical Context:  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.

Class Summary

Used for immunosuppressive and anti-inflammatory effects.

Azathioprine (Imuran)

Clinical Context:  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.

Class Summary

May be an effective substitution for cyclophosphamide.

Prognosis

Author

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

Coauthor(s)

Kerry C Owens, MD, Consulting Staff, Department of Internal Medicine, Section of Nephrology, Integris Baptist Medical Center of Oklahoma City

Disclosure: Nothing to disclose.

Specialty Editors

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

Chief Editor

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

Disclosure: Nothing to disclose.

References

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