AUTHOR AND EDITOR INFORMATION

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
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INTRODUCTION

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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.

MPGN 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 MPGN 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 MPGN 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 C3Bb. 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 and facilitates the formation of the membrane attack complex C5b-9.

Hypocomplementemia is a characteristic finding with all types of MPGN. Low C3 levels are present in approximately 75% of patients with MPGN. Although hypocomplementemia bears no relation to the clinical course or prognosis of MPGN, 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 MPGN 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 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.

Membranoproliferative glomerulonephritis type I

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.

Membranoproliferative glomerulonephritis 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, 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.

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 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.

Frequency

United States

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

International

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 MPGN type I; type II disease is uncommon. On the other hand, 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.

Race

In the United States, MPGN predominantly affects the white population.

Sex

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

Age

The idiopathic forms of MPGN 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 MPGN predominate among adults.

CLINICAL

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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

• 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.

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

DIFFERENTIALS

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Other Problems to be Considered

Glomerulonephritis, fibrillary
IgA nephropathy
Vasculitis

WORKUP

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Lab 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.

Procedures

• Perform a kidney biopsy for definitive diagnosis.

Histologic Findings

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.

TREATMENT

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Medical Care

• The optimal treatment of idiopathic MPGN is not clearly defined (see below).
• Specific therapies should be reserved for patients with MPGN who have proteinuria exceeding 3 g/d, interstitial disease on biopsy, or impaired renal function.
• Treat the underlying cause of secondary forms of MPGN.
• Administer appropriate antimicrobial therapy for patients with infective endocarditis or infected atrioventricular shunts.
• Various small reports discuss the benefit of antiviral therapy for patients with hepatitis C-induced renal disease and cryoglobulinemia.
• • One prospective controlled trial randomized 53 patients with HCV-associated type II cryoglobulinemia to interferon alfa-2a or conventional therapy. HCV RNA fell to undetectable levels in 60% of patients in the interferon alfa group. These patients showed improvement in cutaneous vasculitis, in cryoglobulin titers, and in plasma creatinine concentration. After treatment with interferon alfa-2a was discontinued, viremia and cryoglobulinemia recurred in all 15 HCV RNA-negative patients. On resumption of treatment, 3 of 4 patients had virologic, clinical, and biochemical responses. In comparison, no clinical or serologic improvement was noted in the patients receiving conventional therapy or in those given interferon alfa in whom there was no fall in HCV RNA in the plasma.
  • The appropriate dose and length of interferon alfa-2a therapy have not been established. A short course of a much higher dose of interferon alfa may be effective in patients in whom lower dose therapy fails. Relapses are common after stopping therapy. Furthermore, in some patients, interferon therapy may cause worsening renal function.
  • Combination therapies for interferon alfa-2a and ribavirin have also been studied in a small number of patients and have shown moderate success. The use of ribavirin in patients with creatinine clearances of less than 50 mL/min is contraindicated. Ribavirin can cause a dose-related hemolysis that can be severe and even life-threatening in patients with renal disease. There are anecdotal reports of patients with moderate renal insufficiency doing well with a proportionate reduction in the ribavirin dose and close monitoring, including measurement of plasma ribavirin levels. The use of ribavirin in patients with decreased GFR at the present time cannot be recommended.
  • Aggressive immunosuppression and plasmapheresis should be reserved for patients with severe acute disease and/or vasculitis. The immunosuppression protocols usually include pulse dose methylprednisone (0.5-1 g/d for 3-5 d) followed by 0.5-1.0 mg/kg/d of prednisone and cytotoxic agents (usually oral cyclophosphamide at 2 mg/kg/d) for 8-12 weeks. Plasmapheresis (exchanges of 3 L of plasma 3-4 times/wk for 2-3 wk) helps remove cryoglobulins and inflammatory mediators. Rituximab, a monoclonal antibody to B cells may be helpful in refractory cases. There is concern that such intensive therapy may increase virus replication and viremia, but, fortunately, there are no consistent reports of acute liver damage with short-term aggressive therapy. Antiviral therapy, though capable of suppressing viremia and cryoglobulinemia, is more often than not ineffective in controlling inflammation in such patients and can be associated with worsening renal disease.
  • Patients receiving liver transplants may go into remission; however, proteinuria reappears with a relapse of hepatitis C in the liver allograft.
• Patients with hepatitis B virus–associated MPGN often go into spontaneous remission but may benefit from antiviral agents. Little role exists for immunosuppression in these patients.
• For patients with lupus and other rheumatologic conditions, offer treatment based on principles of care for those diseases.

Consultations

• Nephrologist
• Hepatologist, if hepatitis virus B or C–associated MPGN
• Nutrition specialist

Diet

• Sodium: Restrict salt intake to 4-6 g/d to help control edema and hypertension.
• Protein: 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 biological 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).
• Lipids: Recommend a low-cholesterol healthy-heart diet to patients because hyperlipidemia is common with nephrotic proteinuria.

Activity

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

MEDICATION

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MPGN is a rare glomerulonephritis with a protracted natural history, which makes studies on treatment logistically difficult to conduct. No serological 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 is now known to be an important cause of many cases that were previously thought to be idiopathic MPGN, making older treatment results difficult to interpret. Only a handful of randomized control 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.

Approaches to treatment 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, nonsteroidal, and immunosuppressive (cyclophosphamide) therapies were found to have minimal beneficial effects and were associated with severe adverse effects. Mycophenolate mofetil (MMF) may provide some benefit, but it has not been studied sufficiently. Jones et al reported on 5 patients with idiopathic membranoproliferative glomerulonephritis who were treated with oral prednisolone and MMF and a control group of 6 patients who did not receive immunosuppression. There was a significant reduction in proteinuria noted over an 18-month period in the treatment group compared with the control group. There was no significant change in serum creatinine or creatinine clearance in the treated group. However, in the control group, the serum creatinine and creatinine clearance deteriorated significantly. Anecdotal reports describe benefit of cyclosporine in steroid resistant MPGN type II. These therapies are not discussed any further.

Steroid therapy has proven effective in children, while antiplatelet therapy is of benefit in adults. Summarized below are the acceptable evidence-based modalities of treatment of MPGN.

Drug Category: Corticosteroids

Children with idiopathic MPGN type I having 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, alternate-day prednisone was administered for a mean of 130 months. Approximately 61% of the treatment group had stable renal function at the end of the study period as compared to 12% of the controls. The group at Cincinnati also has shown benefit of prolonged alternate-day steroid regimens. 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. The same group reported that patients with MPGN type III respond poorly to steroids. Several other studies also documented the benefit of steroid therapy.

Drug Category: Antiplatelet therapies

This therapy benefits adults. Inhibition of platelet inhibition, mesangial proliferation, and alteration of renal hemodynamics are the probable mechanisms that underlie the therapeutic benefits of aspirin. Dipyridamole may enhance effects of aspirin.

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. Another study using these 2 agents showed significant reduction in proteinuria at 3 years in the treated group. 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.

FOLLOW-UP

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Further Outpatient Care

• Hypertension: Aggressively control blood pressure. The target blood pressure for adults with proteinuria exceeding 1 g/d is less than 125/75 mm Hg.
• Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: Administer these drugs to decrease proteinuria and to retard the progression of glomerular disease. No direct evidence suggests that these agents are beneficial in MPGN, although their efficacy is demonstrated in other renal diseases.
• Nondihydropyridine calcium channel blockers: Verapamil and diltiazem may also have antiproteinuric effects. Combination therapy with angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers may provide additional benefit.
• Edema: Prescribe salt restriction and administer diuretics to treat patients with edema.
• Hyperlipidemia: Control lipids according to the National Cholesterol Education Program guidelines, although several nephrologists recommend low-density lipoprotein (LDL) cholesterol levels to be maintained below 70 mg/dL.
• Laboratory studies: At regular intervals, evaluate kidney function, proteinuria and clearances, lipid profiles, and serum albumin. The urine protein–to–creatinine ratio may be used as a rough guide to 24-hour urinary protein excretion.
• Immunizations: Offer the pneumococcal vaccine and yearly influenza vaccine to all patients.
• Monitor patients for medication adverse effects.
• Monitor patient nutritional status by using the subjective global assessment scale.

Complications

• Progressive decline in kidney function and end-stage renal disease (ESRD) (see Prognosis)
• Recurrent disease after transplantation: Recurrent disease is a risk among those patients who receive a renal transplant. Of patients with MPGN type I, 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 50-100%; however, recurrences tend to be mild, and fewer than 10-20% of recurrences cause graft loss. 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: Hypertension is present in 80% of patients at presentation. Patients generally develop worsening of hypertension with the progression of renal insufficiency.
• Edema
  • Dietary sodium restriction and the judicious use of diuretics are helpful in managing edema.
  • Thiazide diuretics suffice for many patients.
  • Loop diuretics may be indicated for more refractory edema with renal insufficiency.
  • 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.
• Infections: 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, protein 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
• • This condition is a significant adverse event in patients with nephrotic syndrome. Very low-density lipoprotein (VLDL), 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.
• Miscellaneous
• • Protein calorie malnutrition
  • Growth retardation
  • Anemia - Often multifactorial; urinary losses of transferrin, causing iron deficiency, decreased production of erythropoietin, and complement mediated red 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; TSH and free thyroxine levels usually normal

Prognosis

• The main predictors of an adverse outcome are nephrotic syndrome and hypertension at presentation, low GFR at 1 year, and older age.
• Histologic characteristics of crescent formation, interstitial fibrosis, tubular atrophy, and multiple sclerotic glomeruli indicate a poor prognosis.
• 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 ESRD after 10 years and 90% of patients developing ESRD after 20 years. MPGN type I without nephrotic proteinuria has a 10-year renal survival rate of 85%. MPGN type II generally is more aggressive than MPGN type I and has a median renal survival rate of 5-12 years. There is very limited data on outcomes with MPGN type III. Iitaka et al found that 7 patients who were followed for 9-17 years maintained their renal function over this period. On the other hand, Anders et al reported 4 of 8 patients in his series developed ESRD. Braun et al compared therapy with alternate day corticosteroids in 21 patients with type I and 25 patients with type III, followed for a minimum of 5 years, found that patients with type III had a greater decline in GFR, but there was no difference in the number of patients reaching ESRD in the 2 groups.

Patient Education

• Renal education: Ensure that patients with progressive azotemia receive timely education regarding renal replacement options.
• Dietary education: Recommend that patients have frequent follow-up visits with a dietitian, which are essential to ensuring patient diet compliance.
• For excellent patient education resources, visit eMedicine's Kidneys and Urinary System Center. Also, see eMedicine's patient education article Blood in the Urine.
• For further information, see Mayo Clinic - Kidney Transplant Information.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure to identify secondary causes of MPGN
• Failure to control hypertension
• Failure to monitor for complications of nephrotic syndrome

Special Concerns

• Pregnancy
• • Underlying renal diseases, including MPGN, increase the risk of fetal loss, intrauterine growth retardation, and prematurity. Patients with hypertension, renal insufficiency, and nephrotic syndrome have increased risks for a more unfavorable fetal outcome. Better fetal outcome is reported in patients with dense deposit disease who have normal renal function, as compared to patients with MPGN type I.
  • 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 prior to pregnancy.
  • Close monitoring of the patient by a high-risk obstetrician and a nephrologist is essential during pregnancy.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  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 X 250). Courtesy of John A. Minielly, MD.
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Media type:  Photo

Media file 2:  Membranoproliferative glomerulonephritis (MPGN) type I. Electron microscopy of prominent, glomerular, subendothelial, immune-type electron deposits (original magnification X 11,400). Courtesy of John A. Minielly, MD.
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Media type:  Photo

Media file 3:  Membranoproliferative glomerulonephritis (MPGN) type II. Electron microscopy of glomerular basement membrane, intramembranous, somewhat linear, electron dense deposit, ie, dense deposit disease (original magnification X 11,400). Courtesy of John A. Minielly, MD.
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Media type:  Photo

Media file 4:  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 X 400). Courtesy of John A. Minielly, MD.
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Media type:  Photo

Media file 5:  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 X 400). Courtesy of John A. Minielly, MD.
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Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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Article Last Updated: Oct 19, 2006