Membranoproliferative Glomerulonephritis 

Updated: Dec 17, 2019
Author: Pranay Kathuria, MD, FACP, FASN, FNKF; Chief Editor: Vecihi Batuman, MD, FASN 

Overview

Practice Essentials

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 the following three characteristic histopathologic findings:

  1. Proliferation of mesangial and endothelial cells and expansion of the mesangial matrix (see the first image below)
  2. Thickening of the peripheral capillary walls by subendothelial immune deposits and/or intramembranous dense deposits (see the second image below)
  3. Mesangial interposition into the capillary wall, giving rise to a double-contour or tram-track appearance on light microscopy (see the third image below)
Membranoproliferative glomerulonephritis (MPGN) ty Membranoproliferative glomerulonephritis (MPGN) type I. Glomerulus with lobular accentuation from increased mesangial cellularity. A segmental increase occurs in the mesangial matrix, and the peripheral capillary walls are thickened (hematoxylin and eosin stained section; original magnification × 250). Courtesy of John A. Minielly, MD.
Membranoproliferative glomerulonephritis (MPGN) ty Membranoproliferative glomerulonephritis (MPGN) type I. Immunofluorescent stained section. Intense, peripheral, glomerular, capillary loop deposition of immunoglobulin G (IgG) in an interrupted linear pattern corresponding to extensive subendothelial immune deposits (original magnification × 400). Courtesy of John A. Minielly, MD.
Membranoproliferative glomerulonephritis (MPGN) ty Membranoproliferative glomerulonephritis (MPGN) type I. Glomerulus with mesangial interposition producing a double contouring of basement membranes, which, in areas, appear to surround subendothelial deposits (Jones silver methenamine–stained section; original magnification × 400). Courtesy of John A. Minielly, MD.

MPGN may be idiopathic or secondary in etiology. The secondary types are more common than the idiopathic types and are diagnosed by carefully reviewing clinical features, laboratory data, and renal histopathology. Idiopathic MPGNs are subdivided into types I, II, and III based on ultrastructural appearance. The types are characterized by the following:

  • Type I – Subendothelial deposits
  • Type 2 – Dense deposits in the glomerular basement membrane
  • Type 3 – Subepithelial and subendothelial deposits

The light microscopy features are mostly indistinguishable among the three types.

An alternative classification system has been proposed based on pathogenetic mechanism, as follows[1] :

  • Immune complex-mediated MPGN
  • Complement-mediated MPGN
  • MPGN from mechanisms unrelated to immunoglobulin or complement deposition

Clinical presentations are similar for the three types of MPGN, but they manifest somewhat different mechanisms of complement activation and predisposition to recur in renal transplants.[2]

Conversion from one type to another is not reported. Familial forms of all 3 types of MPGN have been described.

See also Pediatric Nephritis, Tubulointerstitial Nephritis, and Radiation Nephritis.

Pathophysiology

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 in MPGN

Hypocomplementemia is a characteristic finding with all types of membranoproliferative glomerulonephritis (MPGN). Low C3 levels are present in approximately 75% of patients with this condition. Although hypocomplementemia bears no relation to the clinical course or prognosis of MPGN, it plays a role in initiating glomerular inflammation and injury. Hypocomplementemia results from increased catabolism and decreased C3 synthesis. The decreased C3 synthesis is likely caused by the negative feedback by C3 breakdown products.

Three nephritic antibodies are described in MPGN that play a role in the development of hypocomplementemia[3, 4] : (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 MPGN 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.

MPGN type I

Circulating immune complexes are present in approximately 33% of patients with MPGN type I. In all patients with type I disease, 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.[5] 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.

MPGN type II (or dense deposit disease)

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, Bruch membrane of the retina, as well as its association with acquired partial lipodystrophy.[6, 7] MPGN type II 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-glucosamine. 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.[8] 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 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 partial lipoid dystrophy follows variations in the amount of adipsin produced by adipocytes. By analogy, NFa may cause damage to glomerular cells that produce complement.

MPGN 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,Bbconvertase 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.[9] Genes in this area of chromosome 1 code for proteins that regulate the C3 convertase activity.

C3 glomerulonephritis[10]

C3 glomerulonephritis is a recently described entity with immunofluorescence findings of isolated glomerular C3 deposits. C3 glomerulonephritis is similar in etiology to dense deposit disease, arising as a result of alternate complement activation or mutations in the complement-regulating proteins. C3NeF is commonly present. C3 glomerulonephritis has been associated with antifactor H activity and monoclonal gammopathies. Serum C3 levels are usually low, but they can be normal along with normal C4 levels.[11] It is important to note that a normal serum C3 level does not exclude C3 glomerulonephritis. Dense deposit disease and C3GN both lack immunoglobulin staining on immunofluorescence and are the result of alternative pathway dysregulation.[12] These 2 entities are often referred to as C3 glomerulopathy in literature.

Etiology

Immune complex–mediated conditions, autoimmune diseases, chronic infections, chronic and recovered thrombotic microangiopathies, paraprotein deposition diseases, and malignant neoplasms associated with a membranoproliferative pattern of injury are summarized below.

Immune complex–mediated disease

Idiopathic

In the past, most patients were thought to have idiopathic membranoproliferative glomerulonephritis (MPGN). With the discovery of secondary causes, especially hepatitis C, the number of patients deemed to have idiopathic MPGN has declined.

Autoimmune diseases

Autoimmune diseases associated with a membranoproliferative pattern of renal injury include the following:

  • Systemic lupus erythematosus (SLE)
  • Sjögren syndrome
  • Rheumatoid arthritis
  • Inherited complement deficiencies (in particular, C2 deficiency)
  • Scleroderma
  • Celiac disease

Chronic infections

Chronic viral, bacterial, protozoal, and mycoplasmal infections, as well as chronic liver disease (cirrhosis and alpha1-antitrypsin deficiency), are associated with a membranoproliferative pattern of renal injury, as follows:

  • Viral – Hepatitis B, hepatitis C, [13] cryoglobulinemia type II
  • Bacterial – Endocarditis, infected ventriculoatrial (or jugular) shunt, multiple visceral abscesses, leprosy
  • Protozoal – Malaria, schistosomiasis

Chronic and recovered thrombotic microangiopathies

The following are chronic and recovered thrombotic microangiopathies associated with a membranoproliferative pattern of renal injury[14] :

  • Healing phase of hemolytic uremic syndrome (HUS) and/or thrombotic thrombocytopenic purpura (TTP)
  • Syndromes of circulating antiphospholipid (anticardiolipin) antibodies
  • Radiation nephritis
  • Nephropathy associated with bone marrow transplantation
  • Sickle cell anemia and polycythemia
  • Transplant glomerulopathy

Paraprotein deposition diseases

Paraprotein deposition diseases that are associated with a membranoproliferative pattern of renal injury include the following:

  • 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, and carcinoma are associated with a membranoproliferative pattern of renal injury.

Epidemiology

United States statistics

Membranoproliferative glomerulonephritis (MPGN) is observed in 6-12% of US patients receiving renal biopsies to evaluate glomerular diseases. This entity accounts for 7% of children and 12% of adults with idiopathic nephrotic syndrome.

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

In an investigation of the changing patterns of adult primary glomerular disease occurrence in a single region of the United Kingdom, Hanko et al analyzed the results of 1844 native renal biopsies taken between 1976 and 2005 (inclusive) and found the presence of primary glomerulonephritis was revealed in 49% of the biopsies, with the most common forms being immunoglobulin A (IgA) nephropathy (38.8%).[15] Other common forms were membranous nephropathy (29.4%), minimal-change disease (MCD) (9.8%), MPGN type 1 (9.6%), and focal segmental glomerulosclerosis (FSGS) (5.7%). The incidence of IgA nephropathy increased significantly over the study period, whereas the occurrence of membranous nephropathy decreased.[15]

Racial, sexual, and age differences in incidence

In the United States, MPGN predominantly affects the white population. Type I disease affects women more often than men, whereas a nearly equal sex distribution is seen in MPGN type II.

The idiopathic forms of MPGN are more common in children and young adults (range, 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 MPGN predominate among adults.[16]

Prognosis

The main predictors of an adverse outcome in membranoproliferative glomerulonephritis (MPGN) are nephrotic syndrome and hypertension at presentation, low glomerular filtration rate (GFR) at 1 year, and older age.[17, 18] Histologic characteristics of crescent formation, interstitial fibrosis, tubular atrophy, and multiple sclerotic glomeruli indicate a poor prognosis. However, hypocomplementemia is not a predictor of disease severity or prognosis.

MPGN type I with nephrotic syndrome is a progressive disease, with 50% of patients developing end-stage kidney disease (ESKD) after 10 years and 90% of patients developing ESKD after 20 years. MPGN type I without nephrotic proteinuria has a 10-year renal survival rate of 85%.[19]

MPGN type II is generally more aggressive than type I disease and has a median renal survival rate of 5-12 years. ESKD develops in 50% of the patients within 10 years of diagnosis. C3 glomerulonephritis, on the other hand, has been associated with preserved renal function in about 50% of patients, whereas approximately 15% of patients progress to ESKD.[1]

Data on outcomes with MPGN type III are very limited. Iitaka et al found that 7 patients who were followed for 9-17 years maintained their renal function over this period,[20] whereas Anders et al reported that 4 of 8 patients in their series developed ESKD.[21] In a study comparing therapy with alternate-day corticosteroids in 21 patients with type I disease and 25 patients with type III disease (followed for a minimum of 5 y), the investigators found that patients with MPGN type III had a greater decline in GFR, but there was no difference in the number of patients reaching ESKD in the 2 groups.[22]

In a study of all adult ESKD patients in Australia and New Zealand who commenced kidney replacement therapy from 1996 through 2016, rates of survival on dialysis and following kidney transplantation were comparable in the 456 patients with MPGN and the 12,660 patients with another form of glomerulonephritis. However, patients with MPGN had significantly higher rates of allograft loss due to disease recurrence.[23]

Kawasaki et al reported worse prognosis in pediatric patients with MPGN related to complement component C3 than in those with immune complex–mediated MPGN. In their study of 37 patients, those with C3-related MPGN were more likely to be nonresponsive to therapy or progress to ESKD.[24]

 

Presentation

History and Physical Examination

Patients with membranoproliferative glomerulonephritis (MPGN) may present in 1 of 5 ways, as follows:

  • Asymptomatic proteinuria and hematuria detected on routine urinalysis (23-30%), prompting further investigations

  • Nephrotic syndrome (42-67%): Periorbital or dependent edema may develop in patients with nephritic or nephrotic presentations; anasarca is present in a few patients

  • Acute nephritic syndrome (16-30%): Patients with an acute nephritic presentation may develop a decrease in urine output (oliguria)

  • Recurrent episodes of gross hematuria (10-20%): Patients may have episodes of gross hematuria similar to those observed with IgA nephropathy—these episodes are usually associated with upper respiratory infections

  • Azotemia: Patients may develop acute kidney injury with the acute nephritic syndrome, which usually correlates with crescentic transformation on histology; other patients may present with advanced chronic renal insufficiency

Fatigue may also occur and is secondary to anemia or azotemia. The anemia is often disproportional to the degree of renal insufficiency and relates to complement-mediated lysis of red cells. Conjunctival pallor is also indicative of anemia.

Hypertension is present in approximately 80% of patients at initial presentation. It is typically mild, although an occasional patient with dense deposit disease (MPGN type II) may present with severe hypertension.

A strong association is present between partial lipodystrophy (PLD) and dense deposit disease; Fat atrophy usually affects the upper limbs, trunk, and face.

The finding of a drusen on fundus examination of a patient with glomerulonephritis suggests the diagnosis of dense deposit disease. 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 may also develop in dense deposit disease.

Complications

Progressive decline in kidney function and end-stage renal disease (ESRD) are among the complications seen in patients with membranoproliferative glomerulonephritis (MPGN) (see Prognosis).

Recurrent disease after transplantation

Recurrent disease is a risk among those patients who receive a renal transplant.[2] Of patients with type I disease, 30-70% develop recurrent MPGN, and 30-40% of the recurrences lead to graft failure. The rate of recurrence of MPGN type II ranges from 50% to 100%; although recurrences may be mild, eventually 50% of the grafts fail. Recurrence rates of MPGN type III are not known.

Recurrent MPGN needs to be differentiated from transplant glomerulopathy, which has a similar histology but lacks immune deposits.

Secondary hypertension, edema, and infections

Hypertension is present in 80% of patients at presentation; patients generally develop worsening of hypertension with the progression of renal insufficiency.

Periorbital or dependent edema may occur in patients with a nephritic or nephrotic presentation, and anasarca is present in a few patients.

The propensity for infections with encapsulated bacteria, including Streptococcus, Haemophilus, and Klebsiella species, is increased. Prophylactic antibiotics and hyperimmune globulins may be useful in some patients. Administer the pneumococcal vaccine and yearly influenza vaccination to all patients.

Thromboembolism tendency

Loss of anticoagulant antithrombin III, proteins C and S, increased procoagulants, defective fibrinolysis, increased platelet aggregability, hyperlipidemia, endothelial cell injury, and steroids may lead to thrombosis. The renal vein is a common site of thrombosis because of hemoconcentration and loss of the anticoagulants through glomerular filtration.

Hyperlipidemia

Hyperlipidemia is a significant adverse event in patients with nephrotic syndrome. Very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and intermediate density lipoprotein (IDL) levels are increased early in the disease. High-density lipoprotein (HDL) levels may be variable, but levels of the cardioprotective fraction HDL2 usually are decreased. Lipoprotein-a levels are increased.

Hyperlipidemia in patients with nephrotic syndrome may cause accelerated atherosclerosis and increased coronary events. Also, hyperlipidemia may accelerate the progression of renal disease.

Other complications of MPGN include the following:

  • Protein calorie malnutrition

  • Growth retardation

  • Anemia is often multifactorial; urinary losses of transferrin cause iron deficiency, decreased production of erythropoietin, and complement-mediated red blood cell lysis

  • Hypocalcemia and secondary hyperparathyroidism may result from vitamin D deficiency due to urinary losses of cholecalciferol-binding globulin and failure to form activated vitamin D

  • Depressed total thyroxine levels may be caused by loss of the thyroxine-binding globulin; however, thyroid stimulating hormone (TSH) and free thyroxine levels are usually normal

 

DDx

Diagnostic Considerations

When evaluating a patient with suspected membranoproliferative glomerulonephritis (MPGN), also consider conditions such as postinfectious glomerulonephritis, fibrillary glomerulonephritis, immunoglobulin A (IgA) nephropathy, and vasculitis. In addition, recurrent MPGN needs to be differentiated from transplant glomerulopathy, which has a similar histology but lacks immune deposits.

Differential Diagnoses

 

Workup

Approach Considerations

Patients with membranoproliferative glomerulonephritis (MPGN) may demonstrate abnormalities in their complete blood cell count (CBC) and other laboratory tests. Most often, patients have a normocytic normochromic anemia. Hyperlipidemia and low albumin levels may be seen with nephrotic syndrome.

Because hypocomplementemia is a characteristic finding in all types of MPGN, obtain complement profiles in patients with suspected MPGN.

To rule out secondary causes of MPGN, obtain antinuclear antibody studies (ANA), hepatitis screens, cryoglobulins, urine studies, and serum protein electrophoresis or serum free light-chain analysis.

Urine Studies and Kidney Function Tests

Urinalysis in patients with membranoproliferative glomerulonephritis (MPGN) may reveal glomerular hematuria, which is characterized by dysmorphic red blood cells (RBCs) and RBC casts. Proteinuria is almost always present.

The urine protein-to-creatinine ratio is a good estimate of 24-hour urinary protein excretion. Nephrotic proteinuria is present in approximately 50% of patients.

Elevated serum creatinine and blood urine nitrogen (BUN) levels and a decreased estimated glomerular filtration rate (GFR) are evident in 20-50% of patients with MPGN at presentation. Patients with a nephritic presentation typically have a decreased GFR.

Complement Profile

The complement profiles of types I-III membranoproliferative glomerulonephritis membranoproliferative glomerulonephritis (MPGN) are summarized below.

MPGN type I

C3 levels are low in about half of the patients with MPGN type I. There is 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, and nephritic factor of the amplification loop (NFc or C4NeF) or nephritic factor of the terminal pathway (NFt) may be present.

MPGN type II

C3 levels are low in 70-80% of patients with MPGN type II. Early and terminal complement components are within the reference range. NFa (C3NeF) is present in more than 70% of patients, but factor H levels may be low.

MPGN type III

C3 levels are decreased in 50% of patients with MPGN type III. 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.

Kidney Biopsy and Histologic Features

Perform a kidney biopsy for definitive diagnosis of membranoproliferative glomerulonephritis (MPGN). Under light microscopy, the glomeruli are generally 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 (as demonstrated in the image below), giving rise to the alternative name of lobular nephritis. Infiltrating neutrophils and monocytes contribute to glomerular hypercellularity.

Membranoproliferative glomerulonephritis (MPGN) ty Membranoproliferative glomerulonephritis (MPGN) type I. Glomerulus with lobular accentuation from increased mesangial cellularity. A segmental increase occurs in the mesangial matrix, and the peripheral capillary walls are thickened (hematoxylin and eosin stained section; original magnification × 250). Courtesy of John A. Minielly, MD.

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, which is best appreciated with the methenamine silver stain or the periodic acid-Schiff (PAS) 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 glomerular filtration rate (GFR).

MPGN type I

On electron microscopy, electron dense deposits in subendothelial sites (as seen in the image below) are characteristic of MPGN type I. 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.

Membranoproliferative glomerulonephritis (MPGN) ty Membranoproliferative glomerulonephritis (MPGN) type I. Electron microscopy of prominent, glomerular, subendothelial, immune-type electron deposits (original magnification × 11,400). Courtesy of John A. Minielly, MD.

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),[25, 26] and, less commonly, IgM may be found in a distribution similar to C3. See the following image.

Membranoproliferative glomerulonephritis (MPGN) ty Membranoproliferative glomerulonephritis (MPGN) type I. Immunofluorescent stained section. Intense, peripheral, glomerular, capillary loop deposition of immunoglobulin G (IgG) in an interrupted linear pattern corresponding to extensive subendothelial immune deposits (original magnification × 400). Courtesy of John A. Minielly, MD.

MPGN type II (dense deposit disease)

The basement membranes of the glomerulus, Bowman capsule, tubules, and peritubular capillaries are thickened in type 2 disease. The basement membrane appears irregular and ribbonlike on special stains (eg, PAS, thioflavine-T, toluidine blue).

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

Membranoproliferative glomerulonephritis (MPGN) ty Membranoproliferative glomerulonephritis (MPGN) type II. Electron microscopy of glomerular basement membrane, intramembranous, somewhat linear, electron dense deposit (ie, dense deposit disease; original magnification × 11,400). Courtesy of John A. Minielly, MD.

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.

MPGN type III

The type III 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,[25, 26] and IgM, predominantly in the capillary walls.

C3 glomerulonephritis

Immunofluorescence microscopy in C3 glomerulonephritis reveals extensive C3 deposition along the capillary wall and mesangium with no immunoglobulin deposition. On the other hand, electron microscopy does not reveal intramembranous and mesangial deposits in C3 glomerulonephritis as it does in dense deposit disease.

 

Treatment

Approach Considerations

Membranoproliferative glomerulonephritis (MPGN) is a rare glomerulonephritis with a protracted natural history, which makes studies on treatment logistically difficult to conduct. No serologic markers are available to assess disease activity. Most studies are confined to MPGN type I and have a relatively short-term follow-up period; furthermore, hepatitis C virus (HCV) is now known to be an important cause of many cases that were previously thought to be idiopathic MPGN,[21, 22, 25, 26, 27, 28] making older treatment results difficult to interpret.

Only a handful of randomized controlled trials have been published with sufficient power to determine the benefits of therapy for MPGN. The use of variable end points (eg, reduction in proteinuria, renal function measured using variable techniques) further confounds the data.

Thus, the optimal treatment of idiopathic MPGN is not clearly defined. Specific therapies should be reserved for patients with MPGN who have one or more of the following indications:

  • Proteinuria exceeding 3 g/d
  • Active interstitial or glomerular disease (crescents) on biopsy
  • Impaired renal function at presentation
  • A progressive decline in renal function

Consultations with nephrology, hepatology (if hepatitis virus B– or HCV-associated MPGN), and nutrition specialists may be helpful in managing patients with this rare disease.

Treatment of Idiopathic MPGN

General measures

The Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines[29] recommend treating patients with albuminuria of greater than 30 mg/24 hours with blood pressure–lowering drugs to achieve a blood pressure consistently less than 130 mm Hg systolic and 80 mm Hg diastolic. The guidelines also recommend using an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) when the proteinuria exceeds 30 mg in 24 hours, for patients in whom treatment with blood pressure–lowering drugs is indicated. Normotensive patients with proteinuria should also be treated with angiotensin inhibition.

The combination of ACE inhibitors and ARBs may result in additive antiproteinuric activity, although there is conflicting evidence as to the risk-benefit ratio of this strategy, especially if the glomerular filtration rate (GFR) is significantly reduced.[29] Nondihydropyridine calcium channel blockers such as verapamil and diltiazem may also have antiproteinuric effects.

Diuretics are usually needed to control hypertension and manage edema. Thiazide diuretics suffice for many patients. Loop diuretics are indicated for more refractory edema with renal insufficiency. A combination of diuretics acting at different sites in the tubule may be needed in some patients. Potassium-sparing diuretics may be used concomitantly to prevent hypokalemia. Patients with severe and refractory edema and those with hypovolemia and orthostatic hypotension may respond to salt-free albumin infusions.

Lipids must be controlled according to the National Cholesterol Education Program (NCEP) guidelines, although several nephrologists recommend low-density lipoprotein (LDL) cholesterol levels to be maintained below 70 mg/dL.

Patients should be given the pneumococcal vaccine and yearly influenza vaccine.

Specific measures

Approaches to treatment of idiopathic membranoproliferative glomerulonephritis (MPGN) have included immunosuppression, inhibiting platelet-induced injury with aspirin and dipyridamole, minimizing glomerular fibrin deposition with anticoagulants, and use of steroidal and nonsteroidal anti-inflammatory agents. Anticoagulant and nonsteroidal therapies have been found to have minimal beneficial effects and are associated with severe adverse effects.

Immunosuppression may be indicated for patients with nephrotic syndrome, progressive decline in kidney function, or very active inflammation (crescents) on the biopsy. Patients with normal GFR and non-nephrotic proteinuria should be managed conservatively and followed closely.

Corticosteroids

Children with idiopathic MPGN type I who have nephrotic-range proteinuria, interstitial disease, or renal insufficiency may benefit from corticosteroid therapy. No systemic evaluation of corticosteroid therapy has occurred in adults.

Benefits in children include stabilization of the renal function, slowing of the decline in GFR, and a decrease in proteinuria. These therapies are associated with multiple complications, including hypertension and seizures in children. Because active inflammation is more likely to be present early in the disease, prompt initiation of therapy may provide better outcomes.

In the International Study of Kidney Disease in Children, investigators suggested the outcome of children with MPGN may be improved with long-term use of prednisone.[30] Alternate-day prednisone was administered for a mean of 130 months; at the end of the study period, approximately 61% of the treatment group had stable renal function relative to 12% of the control group.[30]

The group at Cincinnati has also shown benefit of prolonged alternate-day steroid regimens.[31] Renal survival rates improved, and findings on repeat kidney biopsy at 2 years demonstrated an increase in capillaries with open lumina and a decrease in mesangial matrix and cellularity; however, an increase in glomerular sclerosis and tubular atrophy occurred.[31] The same group reported that patients with MPGN type III respond poorly to steroids.[18] Several other studies also documented the benefit of steroid therapy in types I and II MPGN.[32]

Antiplatelet therapy

Antiplatelet therapies benefit adults with MPGN. Probable mechanisms that underlie the therapeutic benefits of aspirin include inhibition of platelet aggregation, mesangial proliferation, and alteration of renal hemodynamics. Dipyridamole may enhance the effects of aspirin.

In one randomized controlled study, the use of antiplatelet agents administered over 1 year reduced the incidence of renal failure at 3-5 years, but the renal survival rate was no different at 10 years.[33] In another study of 18 patients with biopsy-proven MPGN (15 type I, 3 type II) and nephrotic syndrome and moderately reduced kidney function, dipyridamole and aspirin caused a significant reduction in proteinuria at 3 years, with no impact on renal function.[34] Reduction in proteinuria to a non-nephrotic range was documented in a group of 14 patients treated with this combination for 2 years by Harmakayaet al.[35] One small uncontrolled study of MPGN type I in children found improved outcome and attenuated inflammation on biopsy with the administration of a combination of prednisolone and dipyridamole.[32]

Cyclophosphamide

Cyclophosphamide therapy is generally recommended for rapidly progressive kidney failure (crescentic glomerulonephritis) in conjunction with intravenous steroids.

In a 10-month study of 19 pediatric and adult patients with MPGN, therapy was induced with pulse methylprednisone and cyclophosphamide and maintained with cyclophosphamide and every-other-day prednisone. Steroids were tapered in the third phase of the study. Lastly, cyclophosphamide was stopped and prednisone gradually withdrawn. Fifteen patients remitted, 3 improved, and 1 progressed. There were 8 relapses in 6 patients: 4 in 3 patients were treated with repeat cycles and remitted completely. Four patients who had relapsed after 4, 8, 11, and 13 years of remission refused retreatment and progressed rapidly to ESRD.[36]

A study by Cattran et al found no benefit with a treatment regimen of cyclophosphamide, warfarin, and dipyridamole in MPGN types I and II with a GFR of less than 80 mL/min and/or proteinuria greater than 2 g/day.[37]

Mycophenolate mofetil

Data on the use of mycophenolate in MPGN are very limited. An observational study reported that 5 patients with idiopathic MPGN had significant reduction in proteinuria over an 18-month period when they were treated with oral prednisolone and mycophenolate mofetil relative to a control group of 6 patients who did not receive immunosuppression.[38] No significant change occurred in serum creatinine or creatinine clearance in the treatment group; however, in the control group, serum creatinine and creatinine clearance deteriorated significantly.[38]

Calcineurin inhibitors

A small case series demonstrated that cyclosporine was effective in the treatment of MPGN that had failed alternative treatments. Eighteen patients were treated with cyclosporine plus low-dose prednisone and were followed for an average 108 weeks. Partial or complete remission of proteinuria occurred in 94% of the patients (P< 0.01). Relapse occurred in one (14.2%) of the remitters after discontinuation of the drug.[39]

Rituximab

Anecdotal reports have demonstrated the efficacy or rituximab in treating MPGN secondary to chronic lymphocytic leukemia.[40, 41] Rituximab has also been shown to be effective in patients with MPGN related to a monoclonal gammopathy.[42]

In an open label trial with rituximab, six patients with MPGN type I were treated with rituximab 1000 mg on days 1 and 15 and followed for 1 year. Proteinuria fell in all patients, at all time points, after rituximab administration. Renal function did not change.[43]

Other treatment options

New treatments on the horizon include eculizumab, an anti-C5 antibody, to decrease C5-mediated glomerular damage. Case reports have supported the use of eculizumab in refractory MPGN secondary to complement dysregulation. In a single-arm trial in 10 patients, eculizumab blunted terminal complement activation in all patients with immune complex–mediated MPGN or C3 glomerulonephritis and nephrotic syndrome, but persistently reduced proteinuria in only a subgroup.[44] Other clinical trials are still under way to establish the role of eculizumab in MPGN and C3 glomerulonephritis.

Other potential treatments of MPGN type II include plasma infusion/plasmapheresis and reducing C3NeF (nephritic factor of the amplification loop). Plasma infusion or plasmapheresis with plasma exchange may provide functionally intact factor H in patients with defined pathologic mutation of the factor H gene.

Secondary MPGN

Every patient with membranoproliferative glomerulonephritis (MPGN) must be carefully evaluated for a secondary cause of the disease. An excellent history, histopathologic findings, and serologies may help identify the underlying cause.

Appropriate treatment of infections such as endocarditis or infected ventriculoatrial shunts may induce remissions. Antiviral therapy is indicated for hepatitis B and C. Aggressive immunosuppression and plasmapheresis should be reserved for patients with severe acute MPGN and/or vasculitis with hepatitis C. For patients with lupus and other rheumatologic conditions, offer treatment based on principles of care for those diseases.

Diet and Activity

Dietary considerations include sodium, protein, and lipid intake.

Dietary sodium needs to be restricted to 3 to 4g/d. These measures, along with the judicious use of diuretics, can be very useful in managing hypertension and edema.

Ensure that patients with normal renal function receive a protein intake of approximately 1 g/kg/d, plus the amount lost in urine. Confirm that the protein is of high biologic value. Higher protein intake does not improve nutrition, because protein catabolism increases proportionally; however, once renal insufficiency develops, recommend moderate protein restriction (eg, 0.65-0.80 g/kg/d, plus urinary losses).

Recommend a low-cholesterol healthy-heart diet to patients, because hyperlipidemia is common with nephrotic proteinuria.

No restriction of activity is recommended, unless the patient has uncontrolled severe hypertension. Note that diuretics are most effective when the patient is supine. In patients with resistant edema, lying down after taking diuretics may increase their efficacy.

Pregnant Patients

Underlying renal diseases, including membranoproliferative glomerulonephritis (MPGN), increase the risk of fetal loss, intrauterine growth restriction, and prematurity. Patients with hypertension, renal insufficiency, and nephrotic syndrome have increased risks for a more unfavorable fetal outcome. Preeclampsia develops in 20-40% of patients with underlying renal disease. The development of preeclampsia increases the risks of fetal wastage.

Patients with MPGN are more likely than those with most other glomerular diseases to develop deterioration of renal function, increasing proteinuria, or worsening of hypertension during pregnancy. The risk for adverse outcomes depends on the patient's severity of hypertension, 24-hour proteinuria, and the level of renal function before pregnancy.

Better fetal outcome is reported in patients with MPGN type II (dense deposit disease) who have normal renal function, as compared with patients with MPGN type I.[45]

Close monitoring of the patient by a high-risk obstetrician and a nephrologist is essential during pregnancy.

Long-Term Monitoring

Patients should be followed at regular intervals. The frequency of visits should be dictated by the level of kidney function, level of proteinuria, and nature of intervention prescribed. Kidney function, proteinuria and clearances, lipid profiles, and serum albumin should be followed during these visits. The urine albumin–to–creatinine ratio may be used as a rough guide to 24-hour urinary albumin excretion. The nutritional status should be assessed using the subjective global assessment (SGA) scale.

Patient Education

Ensure that patients with progressive azotemia receive timely education regarding renal replacement options.[46] In addition, recommend that patients have frequent follow-up visits with a dietitian, which are essential to ensuring patient diet compliance.

For patient information, see Chronic Kidney Disease, and Kidney Transplant. Further information is available at the Mayo Clinic's Kidney Transplant Web pages.

 

Medication

Medication Summary

Approaches to treatment of idiopathic membranoproliferative glomerulonephritis (MPGN) have included the following:

  • Immunosuppression
  • Inhibiting platelet-induced injury with aspirin and dipyridamole
  • Minimizing glomerular fibrin deposition with anticoagulants
  • Use of steroidal and nonsteroidal anti-inflammatory agents

Corticosteroids

Class Summary

Corticosteroids may be used as monotherapy or in combination with other medications. While corticosteroids appear to be effective in children, there is no convincing evidence of their efficacy as monotherapy in adults with idiopathic membranoproliferative glomerulonephritis (MPGN).

Prednisone

Prednisone is an immunosuppressant drug used for the treatment of autoimmune disorders. This agent may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear lymphocyte (PMN) activity.

Antiplatelet Therapies

Class Summary

Platelet consumption is increased in membranoproliferative glomerulonephritis (MPGN) and platelets may play a role in glomerular injury.

Aspirin (Bayer Aspirin, Ascriptin, Ecotrin)

Aspirin inhibits prostaglandin synthesis, which prevents formation of platelet-aggregating thromboxane A2.

Dipyridamole (Persantine)

Dipyridamole is a platelet adhesion inhibitor that possibly inhibits red blood cell (RBC) uptake of adenosine, itself an inhibitor of platelet reactivity. In addition, this agent may inhibit phosphodiesterase activity, leading to increased cyclic-3', 5'-adenosine monophosphate within platelets and formation of the potent platelet activator thromboxane A2.