eMedicine Specialties > Nephrology > Glomerular Diseases

Glomerulonephritis, Membranoproliferative

Author: Pranay Kathuria, MD, MBBS, FACP, FASN, Chief, Section of Nephrology, Associate Professor of Medicine, Associate Director, Clinical Research Center, Schusterman Center, University of Oklahoma College of Medicine
Coauthor(s): Martin Senitko, MD, Fellow, Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center; Sandeep Singh, MD, Fellow, Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center
Contributor Information and Disclosures

Updated: Sep 4, 2008

Introduction

Background

Membranoproliferative glomerulonephritis (MPGN) is an uncommon cause of chronic nephritis that occurs primarily in children and young adults. This entity refers to a pattern of glomerular injury based on characteristic histopathologic findings, including (1) proliferation of mesangial and endothelial cells and expansion of the mesangial matrix; (2) thickening of the peripheral capillary walls by subendothelial immune deposits and/or intramembranous dense deposits; and (3) mesangial interposition into the capillary wall, giving rise to a double-contour or tram-track appearance on light microscopy.

Membranoproliferative glomerulonephritis can be subdivided into idiopathic and secondary types. The secondary types are more common than the idiopathic types and are diagnosed by carefully reviewing clinical features, laboratory data, and renal histopathology. Types I, II, and III are the 3 distinctive types of idiopathic membranoproliferative glomerulonephritis that are described based on immunofluorescence staining, ultrastructural appearance, and complement profiles. The light microscopy features are mostly indistinguishable among the 3 types. Clinical presentation is similar among the 3 types, but they manifest somewhat different mechanisms of complement activation and predisposition to recur in renal transplants. Conversion from one type to another is not reported. Familial forms of all 3 types of membranoproliferative glomerulonephritis have been described.

Pathophysiology

Hypocomplementemia in membranoproliferative glomerulonephritis

Briefly, the normal complement system consists of the classic and alternative pathways. The classic pathway is activated by the interaction of C1 with an antigen-antibody complex. This interaction results in the formation of C4b2a, which is the classic pathway C3b convertase. The alternative pathway utilizes C3 and factors B and D to form the alternative pathway convertase C3b,Bb. Small amounts of C3b are constantly being formed in the circulation, which are inactivated by factors H and I. The binding of C3b to a foreign antigen decreases its affinity for factor H and allows for the formation of increasing amounts of the alternate pathway convertase. The classic and alternate pathway convertases cause C3 activation, forming C3a and C3b. C3b is an opsonin itself, and C3 convertase facilitates the activation of the terminal pathway and the formation of the membrane attack complex C5b-9.

Hypocomplementemia is a characteristic finding with all types of membranoproliferative glomerulonephritis. Low C3 levels are present in approximately 75% of patients with membranoproliferative glomerulonephritis. Although hypocomplementemia bears no relation to the clinical course or prognosis of membranoproliferative glomerulonephritis, it may play a role in initiating glomerular inflammation and injury. Hypocomplementemia results from increased catabolism and decreased C3 synthesis. The decreased C3 synthesis likely is caused by the negative feedback by C3 breakdown products. Three nephritic antibodies are described in membranoproliferative glomerulonephritis that play a role in the development of hypocomplementemia, (1) nephritic factor of the classic pathway (NFc or C4NeF), (2) nephritic factor of the amplification loop (NFa or C3NEF), and (3) nephritic factor of the terminal pathway (NFt).

The reason for genesis of nephritic antibodies is not known. These autoantibodies are not specific for membranoproliferative glomerulonephritis and are also seen in poststreptococcal and lupus glomerulonephritis. NFc stabilizes the classic pathway C3 convertase C4b,2a. This nephritic factor does not cause C3 conversion unless C4b,2a production is ongoing. NFa (C3NEF) is an autoantibody to C3b,Bb. The binding of NFa to C3b,Bb stabilizes the complex, preventing degradation by its normal inactivators, resulting in complement activation and chronic consumption of C3. NFt stabilizes the alternative pathway properdin-dependent C3/C5 convertase (C3Bb2,Bb,P) and leads to C3 activation and consumption. The consumption of C3 caused by NFt is much slower than that caused by NFa. NFt also activates the terminal complement components forming C5b-C9, the membrane attack complex.

Membranoproliferative glomerulonephritis type I

Circulating immune complexes are present in approximately 33% of patients with membranoproliferative glomerulonephritis type I. In all patients with type I, immune complexes are found in the mesangium and subendothelial spaces, and they trigger complement activation and the release of cytokines and chemokines. The release of inflammatory mediators causes an influx of inflammatory cells and leads to mesangial and endothelial cell proliferation. Most patients with circulating immune complexes do not develop membranoproliferative glomerulonephritis; thus, additional pathogenic factors (eg, nature of the antigen, size of complexes, type and charge on antibodies, local glomerular factors) must play a role.

In addition to circulating immune complexes becoming entrapped in the glomerular basement membrane (GBM), experimental evidence indicates that complexes may be formed in situ when antigens adhere to the GBM and antibodies subsequently bind to these antigens. Formation of such immune complexes triggers the same cascade as described above.

Activation of complement and the resulting hypocomplementemia may cause defective clearance of circulating immune complexes. The nephritic factor of the classic pathway (ie, NFc or C4NeF) is found in approximately 15% of patients. This nephritic factor stabilizes the classic pathway C3 convertase C4b,2a and potentiates C3 activation and consumption. The role of this nephritic factor in the pathogenesis of membranoproliferative glomerulonephritis type I is unclear. Approximately 20% of patients have the nephritic factor of the terminal pathway.

Membranoproliferative glomerulonephritis type II or dense deposit disease

Membranoproliferative glomerulonephritis type II (or dense deposit disease) is a separate entity that has been conventionally classified with membranoproliferative glomerulonephritis because of the similarities of light microscopic appearance. The pathogenesis of membranoproliferative glomerulonephritis type II is not known. This disease is systemic, as evidenced by dense deposits in the kidney, splenic sinusoids, Bruch membrane of the retina, as well as its association with acquired partial lipodystrophy. This disease also has a high incidence of recurrence in renal allografts. The chemical composition and origin of the dense deposits are not known, although bright staining with thioflavine-T and wheat germ agglutinin suggests the presence of N-acetyl-glocosamine. No circulating immune complexes are observed in membranoproliferative glomerulonephritis type II.

Dense deposit disease is associated with multiple complement abnormalities, including a persistent reduction of C3 levels. One hypothesis is that the dense deposits cause complement activation. This hypothesis is supported by the tram-track distribution of C3 deposits along the basement membrane.

NFa is present in 80% of patients with dense deposit disease. NFa stabilizes the alternative pathway convertase and results in complement activation and chronic C3 consumption. Deficiency of factor H, functionally defective factor H, mutant factor H binding site of C3 (Marder disease), and presence of inhibitory or blocking factor H antibodies, described in membranoproliferative glomerulonephritis, may lead to an accumulation of the alternative pathway convertase and chronic C3 consumption.

Partial lipoid dystrophy (PLD) is associated commonly with membranoproliferative glomerulonephritis type II and the presence of NFa. Adipocytes produce adipsin, which is identical to complement factor D and is responsible for activating the preconvertase C3b,Bb. NFa causes a lysis of adipocytes that produce adipsin, and the distribution of fat atrophy in PLD follows variations in the amount of adipsin produced by adipocytes. By analogy, NFa may cause damage to glomerular cells that produce complement.

Membranoproliferative glomerulonephritis type III

The glomerular deposits contain C3, C5, and properdin, indicating activation of the alternative complement pathway. Signs of activation of the classic pathway are minimal, and circulating immune complexes do not appear to play a role in the genesis of this variant.

Changes in the capillary wall are hypothesized to be the primary event leading to activation of the complement pathway. This hypothesis is supported by the deposition of C3Bb2,Bb convertase components in the basement membrane. The deposits of convertase and membrane attack complex may lyse the basement membrane and stimulate new membrane formation. NFt is present in 60-80% of patients with membranoproliferative glomerulonephritis type III. NFt stabilizes the alternative pathway properdin-dependent C3/C5 convertase (C3Bb2,Bb,P) and also activates the terminal complement components, forming C5b-C9 (ie, the membrane attack complex).

A familial form of membranoproliferative glomerulonephritis type III with an autosomal dominant pattern of inheritance has been identified with genetic linkage to band 1q31-32. Genes in this area of chromosome 1 code for proteins that regulate the C3 convertase activity.

Frequency

United States

Membranoproliferative glomerulonephritis is observed in 6-12% of patients receiving renal biopsies to evaluate glomerular diseases.

Membranoproliferative glomerulonephritis accounts for 7% of children and 12% of adults with idiopathic nephrotic syndrome.

International

Membranoproliferative glomerulonephritis causes a significant proportion of the cases of nephritis among patients in nonindustrialized countries. For example, in Mexico, membranoproliferative glomerulonephritis accounts for 40% of all patients with nephritis. Most of these patients have membranoproliferative glomerulonephritis type I; type II disease is uncommon. On the other hand, the incidence of membranoproliferative glomerulonephritis type I is decreasing progressively in developed countries, which may be explained by a change in environmental factors, especially a decline in infections.

Race

In the United States, membranoproliferative glomerulonephritis predominantly affects the white population.

Sex

• Membranoproliferative glomerulonephritis type I affects women more often than men.
• A nearly equal sex distribution is seen in membranoproliferative glomerulonephritis type II.

Age

The idiopathic forms of membranoproliferative glomerulonephritis are more common in children and young adults (6-30 y). Isolated reports of involvement in patients as young as 2 years and as old as 80 years are noted in the literature. Secondary types of membranoproliferative glomerulonephritis predominate among adults.

Clinical

History

• Patients with membranoproliferative glomerulonephritis may present in 1 of 5 ways, as follows:
  • Asymptomatic proteinuria and hematuria detected on routine urinalysis (23-30%)
  • Nephrotic syndrome (42-67%)
  • Acute nephritic syndrome (16-30%)
  • Recurrent episodes of gross hematuria (10-20%)
  • Azotemia
• Asymptomatic presentation: Proteinuria and hematuria may be detected on routine urinalysis, prompting further investigations.
• Gross hematuria: Patients may have episodes of gross hematuria similar to those observed with immunoglobulin A (IgA) nephropathy. These episodes are usually associated with upper respiratory infection.
• Edema: Periorbital or dependent edema may develop in patients with nephritic or nephrotic presentations.
• Fatigue: This symptom is secondary to anemia or azotemia. The anemia often is disproportional to the degree of renal insufficiency and relates to complement-mediated lysis of red cells.
• Oliguria: Patients with an acute nephritic presentation may develop a decrease in urine output.
• Azotemic symptoms: Patients may develop acute renal failure with the acute nephritic syndrome, which usually correlates with crescentic transformation on histology. Other patients may present with advanced chronic renal insufficiency.

Physical

• Hypertension is present in approximately 80% of patients at initial presentation. Hypertension typically is mild, although an occasional patient with dense deposit disease may present with severe hypertension.
• Conjunctival pallor indicative of anemia
• Periorbital or dependent edema may occur in patients with a nephritic or nephrotic presentation. Anasarca is present in a few patients.
• A strong association is present between partial lipodystrophy and dense deposit disease. Fat atrophy usually affects the upper limbs, trunk, and face.
• Retinal changes: A finding of drusen in a patient with chronic glomerulonephritis suggests membranoproliferative glomerulonephritis type II. Drusen are yellowish deposits of extracellular material that are found between the basement membrane of the retinal pigment epithelium and the inner collagenous zone of the Bruch membrane. Choroidal neovascularization, macular degeneration, and visual loss also may develop in dense deposit disease.

Causes

Conditions associated with a membranoproliferative pattern of injury are listed as follows:

• Immune complex–mediated disease
  • Idiopathic forms of membranoproliferative glomerulonephritis or of unknown association
    • Membranoproliferative glomerulonephritis type I
    • Membranoproliferative glomerulonephritis type II or dense deposit disease and PLD
    • Membranoproliferative glomerulonephritis type III
  • Autoimmune diseases
    • Systemic lupus erythematosus (SLE)
    • Sjögren syndrome
    • Rheumatoid arthritis
    • Inherited complement deficiencies, in particular, C2 deficiency
    • Scleroderma
    • Celiac disease
  • Chronic infections
    • Viral - Hepatitis B, hepatitis C, and cryoglobulinemia type II
    • Bacterial - Endocarditis, infected ventriculoatrial (or jugular) shunt, multiple visceral abscesses, leprosy
    • Protozoal - Malaria, schistosomiasis
    • Other infections - Mycoplasma
  • Miscellaneous - Chronic liver disease (cirrhosis and alpha1-antitrypsin deficiency)
• Chronic and recovered thrombotic microangiopathies
  • Healing phase of hemolytic uremic syndrome and/or thrombotic thrombocytopenic purpura
  • Syndromes of circulating antiphospholipid (anticardiolipin) antibodies
  • Radiation nephritis
  • Nephropathy associated with bone marrow transplantation
  • Sickle cell anemia and polycythemia
  • Transplant glomerulopathy
• Paraprotein deposition diseases
  • Glomerulonephropathies associated with cryoglobulinemia type I
  • Waldenström macroglobulinemia
  • Immunotactoid glomerulopathy
  • Immunoglobulin light chain or heavy chain deposition diseases
  • Fibrillary glomerulonephritis
  • Monoclonal gammopathy of unknown significance
• Malignant neoplasms
  • Lymphoma
  • Leukemia
  • Carcinoma

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