Membranoproliferative glomerulonephritis

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Overview
Membranoproliferative glomerulonephritis or MPGN is a type of glomerulonephritis caused by immune complexes depositing in the kidney glomerular mesangium and basement membrane (GBM), activating complement and damaging the glomeruli. The GBM is rebuilt ontop of the deposits, causing a "tram-tracking" appearance under the microscope.

Type
There are three types of MPGN.

Type I
The most common type.

Circulating immune complexes are present in approximately 33% of patients with MPGN 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 MPGN; 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 MPGN type I is unclear. Approximately 20% of patients have the nephritic factor of the terminal pathway.

Type II
Type II (dense deposit disease) is very similar, except the material deposited is not immune complexes and is not yet known. MPGN type II (or dense deposit disease) is a separate entity that has been conventionally classified with MPGN because of the similarities of light microscopic appearance. The pathogenesis of MPGN type II is not known. This disease is systemic, as evidenced by dense deposits in the kidney, splenic sinusoids, and Bruch membrane of the retina. This disease also has a high incidence of recurrence in renal allografts. The chemical composition and origin of the dense deposits are not known. No circulating immune complexes are observed in MPGN 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. Deficiencies of factor H or resistance to factor H, described in MPGN, may lead to an accumulation of the alternative pathway convertase and chronic C3 consumption.

Partial lipoid dystrophy (PLD) is associated commonly with MPGN 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.

Type III
Type III is very rare, it is characterized by a mixture of subepithelial deposits and the typical pathological findings of Type I disease.

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 MPGN 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 MPGN 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.

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


 * Immune complex–mediated disease
 * Idiopathic forms of MPGN or of unknown association
 * MPGN type I
 * MPGN type II or dense deposit disease and PLD
 * MPGN 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


 * Malignant neoplasms
 * Lymphoma
 * Leukemia
 * Carcinoma

Medical History

 * Patients with MPGN 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 Examination

 * 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 MPGN 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.

Laboratory Studies

 * Urinalysis
 * Glomerular hematuria; characterized by dysmorphic red blood cells (RBCs) and RBC casts
 * Proteinuria is almost always present.
 * Urine protein creatinine ratio is a good estimate of 24-hour urinary protein excretion.
 * Nephrotic proteinuria is present in approximately 50% of patients.


 * Serum chemistries
 * Elevated serum creatinine and blood urine nitrogen and a decreased estimated glomerular filtration rate (GFR) are evident in 20-50% of patients at presentation. Patients with a nephritic presentation typically have a decreased GFR.
 * Hyperlipidemia and low albumin may be seen with nephrotic syndrome.


 * CBC with differential: Most often, patients have a normocytic normochromic anemia.
 * Complement profile - MPGN type I
 * C3 levels are low in about half of the patients.
 * Evidence of activation of the classic pathway of complement (ie, low C4, C2, C1q, B, C3)
 * Terminal complement components C3, C5, C8, and C9 may be low or within the reference range.
 * NFc (C4NeF) or NFt may be present.


 * Complement profile - MPGN type II
 * C3 levels are low in 70-80% of patients.
 * Early and terminal complement components are within the reference range.
 * NFa (C3NeF) is present in more than 70% of patients.


 * Complement profile - MPGN type III
 * C3 levels are decreased in 50% of patients.
 * C1q and C4 levels are within the reference range.
 * Terminal complement components are low, especially if C3 is markedly depressed.
 * NFa is absent and NFt is present in 60-80% of patients.
 * Antistreptolysin-O (ASO) titers may be elevated in as many as 50% of patients at presentation.


 * To rule out secondary causes, obtain antinuclear antibodies, hepatitis screens, cryoglobulins, urine, and serum protein electrophoresis.

Invasive Diagnostic Procedures

 * Kidney biopsy for definitive diagnosis.

Light microscopy
Glomeruli generally are enlarged and hypercellular, with an increase in mesangial cellularity and matrix. Mesangial increase, when generalized throughout the glomeruli, causes an exaggeration of their lobular form, giving rise to the alternative name of lobular nephritis. Infiltrating neutrophils and monocytes contribute to glomerular hypercellularity.

The capillary basement membranes are thickened by interposition of mesangial cells and matrix into the capillary wall. This gives rise to the tram-track or double-contoured appearance of the capillary wall, best appreciated with the methenamine silver stain or the periodic acid-Schiff reagent.

Crescents may be visible in 10% of patient biopsy specimens. Interstitial changes, including inflammation, interstitial fibrosis, and tubular atrophy, are observed in patients with progressive decline in GFR.

Membranoproliferative glomerulonephritis type I
On electron microscopy, electron dense deposits in subendothelial sites are characteristic of this disease. Mesangial and occasional subepithelial deposits also may be present. Irregular new basement membrane material is formed around the subendothelial deposits and mesangial projections, producing the tram-track appearance on light microscopy.

By immunofluorescence, prominent C3 deposition in a granular pattern is noted in the capillary walls, with variable mesangial C3 deposits. Early components of complement, immunoglobulin G (IgG), and, less commonly, immunoglobulin M (IgM) may be found in a distribution similar to C3.

Membranoproliferative glomerulonephritis type II or dense deposit disease
The basement membranes of the glomerulus, Bowman capsule, tubules, and peritubular capillaries are thickened. The basement membrane appears irregular and ribbonlike on special stains (eg, periodic acid-Schiff, thioflavine-T, toluidine blue).

On electron microscopy, the basement membrane is thickened by discontinuous, amorphous electron dense deposits that reside in the lamina densa layer, hence the alternative name of dense deposit disease. Mesangial and subepithelial dense deposits may be noted.

Immunofluorescence reveals complement component C3 deposited in an irregular granular pattern in the basement membranes on either side but not within the dense deposits or in nodular ring forms in the mesangium. Little or no deposition of immunoglobulins occurs in the glomeruli.

Membranoproliferative glomerulonephritis type III
This variant of MPGN, also called the Burkholder variant, displays combined features of MPGN type I and membranous nephropathy.

Subepithelial, subendothelial, and mesangial deposits are present on electron microscopy. Successive generations of subendothelial and subepithelial deposits disrupt the basement membrane, and concurrent formation of new lamina densa material is present, giving the basement membrane a complex laminated appearance.

Immunohistology shows granular deposition of C3, C5, properdin, IgG, and IgM, predominantly in the capillary walls.

Membranoproliferatiivne glomerulonefriit Glomerulonefrite membranoproliferativa