Pediatrics

Membranoproliferative GN

OVERVIEW: What every practitioner needs to know

Are you sure your patient has membranoproliferative GN? What are the typical findings for this disease?

Membranoproliferative glomerulonephritis (MPGN) is as hard to understand as it is to pronunce. It is a rare entity which is characterized by a unique histopathological feature - splitting of the glomerular basement membrane (GBM) with interposition of mesangial cells and extracellular matrix. This leads to a double contour or "tram-track" appearance of the GBM. It is divided into three subtypes based on the histopatholgy - type I, immune complex, with subendothelial deposits; type II, dense deposit disease within the GBM; type III, subepithelial and subendothelial deposits.

MPGN can be a primary glomerulopathy and present with nephrotic syndrome or acute glomerulonephritis. Alternatively, it can be secondary to variety of conditions including infections (e.g., hepatitis B and C, bacterial endocarditis), inflammatory conditions (e.g., SLE), chronic liver disease (e.g., alpha1-antitrypsin deficiency), essential cryoglobulinemia, lymphoproliferative disorders, plasma cell dyscrasias, or malignancies. Rare secondary causes include Lyme disease, thyroiditis, and administration of granulocyte stimulating factor. There is hypocomplementemia in nearly all cases.

The primary cases are generally the consequence of perturbations in the regulation of the alternative pathway of complement with constitutive activation of this cascade. This can be due to abnormalities in factor H or autoantibodies to C3 convertase.

The long-term prognosis is that 50% of patients will progress to end stage kidney disease (ESKD) over 10-15 years. The only proven therapy in pediatric cases is prolonged administration of alternate day steroids. The role of angiotensin converting enzyme inhibitors and other immunosuppresive medications is unproven. Patients with MPGN are transplant candidates but the disease may recur in 20-35% of renal allograft recipients.

The antecedent history is usually not distinctive in children with MPGN. They can present either with asymptomatic urinary findings, nephrotic syndrome or an acute glomerulonephritis. In primary MPGN, the clinical findings are similar to any child with acute glomerular disease. In contrast, in patients secondary causes, there will be signs and symptoms of the underlying illness. Hematuria alone in less than 10% of cases.

  1. Hematuria and proteinuria in 10-30% of cases

  2. Nephrotic syndrome in 40-70% of cases

  3. Acute glomerulonephritis in 20-30%

  4. Hypocomplementemia in nearly all cases

  5. Anemia that is disproportionate to the degree of renal insufficiency

  6. Partial lipodystrophy in 25% of cases

  7. Signs and symptoms of underlying secondary illness

MPGN and other diseases linked to the alternative pathway of complement

MPGN is one of a group of rare disorders that includes atypical hemolylic uremic syndrome (HUS) and macular degeneration that are characterized by abnormal activation of the alternative pathway of complement. Genetic abnormalities in the complement proteins or regulators of the cascade in the circulation or on cell surfaces appear to predipose individual patients to these disorders.

What other disease/condition shares some of these symptoms?

Diseases/conditions that can mimic MPGN:

The association of glomerular disease and hypocomplementemia is observed in the following three conditions: (1) Post-infectious acute glomerulonephritis; (2) SLE nephritis; (3) shunt nephritis; and (4) cholesterol embolic disease in adults.

In patients with post-infectious glomerulonephritis, the C3 will normalize in 8-12 after the acute episode. Children with SLE have other serological test results that indicate the correct diagnosis. Shunt nephritis is suggested by the clinical history and cholesterol emboli are a rare cause of renal disease in pediatric patients.

What caused this disease to develop at this time?

Genetic predisposition to MPGN is linked to mutations in factor H or other complement proteins such as C3 that lead to abnormal activation of the alternative pathway of complement. It is a rare disease that occurs more commonly in girls and adolescents but affects all racial and ethnic groups.

There is no known nutritional, environmental, or physical triggers to the disease.

The history is positive for the detection of asymptomatic urinary abnormalities, nephrotic syndrome, or an acute nephritic picture.

The physical examination is usually normal except for edema and/or hypertension in those with a nephrotic or nephritic presentation.

The history and physical examination may reveal symptoms and signs related to the underlying disease in those with secondary MPGN.

The key laboratory finding is persistent hypocomplementemia in the context of glomerular disease.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

  • Microscopic examination of the urine.

  • Quantitation of urinary protein excretion.

  • Complete metabolic profile and calculation of GFR.

  • Serum C3 and C4 concentrations and CH50 level.

  • C3 nephritic factor, an autoantibody to the alternative pathway C3 convertase C3bBb, is seen in 60-70% of those with type II MPGN versus 20-25% of those with type I or III disease. Some patients with type III MPGN have a nephroitic factor of the terminal complement pathway that stabilizes properdin-dependent C6\5 convertase.

  • Tests for secondary causes such as SLE or hepatitis B/C infection as indicated by the clinical assessment.

  • Kidney biopsy.

Would imaging studies be helpful? If so, which ones?

The disease involves the glomeruli and therefore imaging such as a renal ultrasound, computed tomography (CT) scan or magnetic resonance imaging (MRI) are generally not required and do not shed light on the cause or course of the disease.

Confirming the diagnosis

In children with acute glomerulonephritis in whom post-infectious glomerulonephritis is most common, MPGN should be considerd if the C3 fails to return normal after 3 months.

Children with new-onset nephrotic syndrome and a low C3 should be suspected of having MPGN, especially if they are girls over the age of 8 years.

A kidney biopsy is mandatory to establish the diagnosis in all patients suspected of having MPGN.

If you are able to confirm that the patient has membranoproliferative GN, what treatment should be initiated?

  • Immediate therapy should focus on control of blood pressure and limitation of edema. This is achieved by salt restriction, initiation of diuretics such as furosemide, and use of antihypertensive drugs such as nifedipine (0.3 mg/kg per dose), labetalol (0.5-1 mg/kg per dose), or enalapril (0.1-0.4 mg/kg per dose) to lower the mean BP by 20%.

  • Patients with low-grade proteinuria may be treated with an ACEI or ARB alone.

  • Pediatric patients with MPGN and significant proteinuria are treated with prolonged alternate day prednisone, 1.5-2.0 mg/kg PO every other day. The appropriate length of treatment is based on a follow-up biopsy performed after 2-3 years of therapy and confirmation of resolution of glomerular inflammation.

  • Patients who fail to respond to corticosteroids may be treated with mycophenolate mofetil or cyclosporine. These last two agents have not been studied in a systematic way. Plasmapheresis may be an option in severe cases with rapidly declining GFR at the time of diagnosis.

  • The role of eculizumab, a monoclonal antibody to C5, for the treatment of MPGN is under evaluation.

  • Adults with MPGN are generally not treated with alternate steroids like pediatric patients and instead they may be given a combination of cyclophosphamide, warfarin, and dipyridamole.

  • Secondary causes of MPGN are treated based on the underlying cause. Administration of interferon-alpha, with or without concomitant ribavirin, for 6-12 months can achieve remission in 60% of patients with hepatitis C related disease.

Table I. Advantages and Disadvantages of Drug Treatment

Table I.

Advantages and Disadvantages of Drug Treatment
Drug Dose Advantages Disadvantages
Corticosteroids 1.5-2 mg/kg PO every other day Only tested therapy in children Side effects are comon
Mycophenolate mofetil 600 mg/m2 per dose PO BID Few somatic complications GI upset, leukopenia, liver injury
Enalapril (ACEI) 0.1-0.5 mg/kg/dose PO Reduces proteinuria Cough, lowering ofGFR, edema
Losartan (ARB) 0.7-1.4 mg/kg/dose PO Reduces proteinuria Lowering of GFR

What are the adverse effects associated with each treatment option?

Corticosteroids: behavior changes, weight gain, acne, hypertension, cataracts, decreased bone density, impaired growth, diabetes.

Mycophenolate mofetil: gastrointestinal upset, leukopenia, hepatotoxicity.

What are the possible outcomes of membranoproliferative GN?

What will you tell the family about prognosis?

The natural history of MPGN is one of slow indolent progression such that 50% of patients will develop ESKD over 10-15 years of follow-up. An elevated serum creatinine level and reduced GFR, severe hypertension, >50% of glomeruli with crescents, and diffuse interstitial fibrosis at the time of diagnosis are poor prognostic signs. The prognosis of primary MPGN is worse than for secondary MPGN. Of the primary forms, patients with Type II MPGN or dense deposit disease, do worse than those with the other two types.

Children and adults with MPGN have a comparable long-term course if left untreated. The impact of treatment may differ in pediatric versus adult patients because steroids are used more commonly in the former group.

If definitive treatment of MPGN is initiated within 1 year of the onset of disease, the outcome is favorable and the risk:benefit ratio for the medications prescribed for this condition justify their use.

What causes this disease and how frequent is it?

  • Detailed epidemiology:

    • Primary MPGN accounts for at most 5-10% of cases of primary nephrotic syndrome. Therefore, the annual incidence is in the range of 1-5 per million population and, therefore, qualifies for the federal designation of a rare disease. It occurs throughout the year without any obvious seasonal variation. It occurs in children and adults but is equally rare in both age groups. Unlike primary FSGS which is more common in African Americans, MPGN appears to involve all racial and ethnic groups.

    • MPGN can be secondary to hepatitis B, hepatitis C, bacterial endocarditis, and Lyme disease and, therefore, its occurrence is linked to the transmission of each infectious agent.

    • The linkage with Lyme disease implicates spread by exposure to a tick bite. In addition, unlike Goodpasture disease which can be triggered by exposure to hydrocarbons, the onset of MPGN is not known to be provoked by any environmental or toxic exposure. Physical activities have no impact on the onset or progression of the disease.

    • Genetic mutations in factor H or other proteins in the alternative pathway of complement can result in a predisposition to the development of MPGN.

How do these pathogens/genes/exposures cause the disease?

The genetic mutations in factor H or other complement related proteins lead to dysregulation of the alternative pathway and glomerular injury.

Other clinical manifestations that might help with diagnosis and management

Any child with glomerular disease and a persistently low C3 level may have MPGN. However, the clinical picture overlaps all of the common causes of glomerulonephritis in children.

The role of anticomplement agents in the treatment of MPGN requires further study.

What complications might you expect from the disease or treatment of the disease?

The main complications of the disease relate to persistence of nephrotic syndrome or progression to ESKD. Toxicity arising from long-term use of corticosteroids is the major limiting factor in the treatment of MPGN.

Are additional laboratory studies available; even some that are not widely available?

Complete assay of all components of the complement cascade. Type I MPGN is associated with a low C3 and reduced levels of terminal components of the complement cascade, C6, C7, and C9. Type II MPGN has very low C3 levels and Type II disease has reduced C3 and C5 levels.

Genetic testing for mutations in factor H and other complement proteins.

How can membranoproliferative GN be prevented?

There are no known ways to prevent the occurrence of primary or secondary MPGN.

There are no behavioral factors linked to the onset or severity of MPGN.

Genetic counseling is useful but not mandatory because not all patients with mutations develop disease and there is no proven therapy for those with mutations and documented disease.

The best nutritional advice for children with MPGN is to consume a balanced healthy diet.

What is the evidence?

Alchi, B, Jayne, D. "Membranoproliferative glomeulonephritis". Pediatr Nephrol. vol. 25. 2010. pp. 1409-1418.

(Excellent review of MPGN from a pediatric perspective.)

Appel, GB, Cook, HT, Hageman, G. "Membranoproliferative glomerulonephritis type II (dense deposit disease): An update". J Am Soc Nephrol. vol. 16. 2005. pp. 1392-1403.

(Excellent adult series of this difficult form of MPGN.)

Nasr, SH, Valeri, AM, Appel, GB. "Dense deposit disease: Clinicopathologic study of 32 pediatric and adult patients". Clin J Am Soc Nephrol. vol. 4. 2009. pp. 22-32.

(Large contemporaneous series of children and adults with MPGN.)

Smith, RJ, Alexander, J, Barlow, PN. "New approaches to the treatment of dense deposit disease". J Am Soc Nephrol. vol. 18. 2007. pp. 2447-2456.

(Excellent review of therapy for this severe form of MPGN.)

Ongoing controversies regarding etiology, diagnosis, treatment

1. The optimal duration of corticosteroid treatment in pediatric patients.

2. The value of repeat kidney biopsies.

3. The availability of non-invasive biomarkers to assess disease activity and response to treatment.

4. The potential role of therapy that targets the alternative pathway of complement. such as eculizumab (monoclonal antibody to C5a).

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