1. What is membranoproliferative glomerulonephritis (MPGN)?

(MPGN) is a rare form of glomerular disease that occurs in both children and adults. It is characterized by a unique histopathologic feature, namely splitting of the glomerular basement membrane (GBM) with interposition of mesangial cells and extracellular matrix material. It is associated with variable degrees of endothelial and mesangial hypercellularity. Together with postinfectious glomerulonephritis, systemic lupus erythematosus (SLE), and cholesterol embolic disease, it is one of the glomerulopathies that is marked by hypocomplementemia (i.e., a low level of serum C3).

2. How is MPGN diagnosed and classified?

Although the disease may be suspected in a patient with hematuria and/or proteinuria and a reduced level of C3, a kidney biopsy is required to confirm the diagnosis. Examination of the kidney histopathology demonstrates a lobular appearance of the glomerular tuft, mesangial expansion, hypercellularity, and the characteristic “tram track” finding with a double contour of the GBM. Immunofluorescence staining is usually positive for C3, IgG, and IgM in a capillary wall distribution. Classic complement cascade components are seen in type I but not types II and III MPGN.

Primary MPGN is divided into three subtypes based on the nature and location of electron-dense deposits in addition to the expected changes in the GBM: type I, subendothelial deposits; type II, large, ribbon-like intramembranous deposits, so-called dense deposit disease (DDD); and type III, subendothelial and subepithelial deposits. The deposits can be numerous or sparse. They are homogeneous in density and have no defining ultrastructural appearance. The presence of C4d on immunofluorescence staining has been utilized to distinguish type I (positive) from type II (negative) MPGN.

Recently the term C3 glomerulopathy has been introduced to define cases of MPGN. It corresponds to type II MPGN (DDD) as opposed to the immune-complex–mediated forms of the disease, types I and III.

The diagnostic label MPGN is focused mainly on the light microscopy appearance (hypercellular, lobulated glomerular tuft) and the ultrastructural changes in the GBM (splitting of the GBM with mesangial cell interposition) as well as the specific location of the electron-dense deposits (subepithelial, intramembranous, or subendothelial). In contrast, the term, C3 glomerulopathy, highlights the presence of C3 as the dominant or codominant molecule detected by immunofluorescence examination of the kidney tissue. In this way the diagnosis sheds light on the underlying cause of the disease—activation of the alternative pathway of complement in the pathogenesis of the glomerulopathy. Moreover, it points the way to a new therapeutic approach to MPGN and C3 glomerulopathy that reduces kidney injury by inhibiting the activity of the alternative pathway of complement (see Question 16).

3. What is the cause of MPGN?

MPGN can be primary (idiopathic) in nature. Alternatively, it can be secondary to a wide variety of medical conditions including infections (hepatitis B, hepatitis C, and bacterial endocarditis), autoimmune diseases (e.g., SLE), chronic liver disease (e.g., α1-antitrypsin deficiency), malignancies, lymphoproliferative disorders, plasma cell dyscrasias leading to monoclonal gammopathy, and essential cryoglobulinemia. MPGN has been associated rarely with Lyme disease, autoimmune thyroiditis, and type I diabetes mellitus. Some newer medications have been linked to type I MPGN, such as granulocyte colony-stimulating factor. Because MPGN is a rare condition that requires a kidney biopsy for diagnosis, there is no systematic information about the relative incidence of primary versus secondary MPGN.

Postinfectious glomerulonephritis and MPGN likely represent a spectrum of the same disease. They share common histopathologic features. Long-term follow-up and detailed assessment of the alternative pathway of complement are required to distinguish these two entities. Type II MPGN has been linked to genetic mutations in proteins involved in the regulation of the alternative pathway of complement. These include alterations in factor H, factor H–related proteins, and complement receptor 1.

4. What are the incidence and prevalence of MPGN?

Primary MPGN is one of the least common causes of primary nephrotic syndrome, accounting at most for 5% to 10% of cases. Therefore the incidence is probably in the range of 1 to 2 per million population per year; as such, it qualifies for the federal designation of a rare disease. The incidence of MPGN may have been declining over the last two decades. The secondary causes of MPGN have a less clear-cut epidemiology because of varying patterns of performing a kidney biopsy in patients with urinary abnormalities and subtle changes in glomerular filtration rate (GFR). In addition, clinical practice may differ in those with primary versus secondary disease. In primary disease, where extrarenal symptoms are limited, a kidney biopsy is essential to make a diagnosis. In contrast, the presence of a defined secondary cause may be viewed as sufficient to make a clinical diagnosis. The net result may underestimate the incidence of this complication in patients with MPGN. Nonetheless, MPGN is a rare cause of end-stage kidney disease (ESKD) in children and adults, accounting for less than 5% of patients on dialysis or receiving a kidney transplant.

5. What is the clinical presentation of patients with MPGN?

MPGN can be present with the full spectrum of glomerular disease.

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  Hematuria can be the sole manifestation in rare cases.

  
  
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  Glomerular hematuria (including gross hematuria) and proteinuria with normal kidney function may be the presenting finding in 10% to 30%.

  
  
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  New-onset nephrotic syndrome may be seen in 40% to 70%.

  
  
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  Nephritic syndrome occurs, with hypertension, azotemia, hematuria, and proteinuria.

  
  
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  There may be anemia that is out of proportion to the degree of kidney dysfunction.

6. Are there extrarenal manifestations of MPGN?

Patients with primary MPGN generally have primarily kidney manifestations. However, in nearly 25% of cases, patients with type II disease, which is more common in children, manifest partial lipodystrophy (gradual loss of subcutaneous fat tissue in the face and upper body). There may be other associated findings in patients with MPGN, such as macular degeneration and mild visual field and color defects. Retinal angiography demonstrates the presence of choroidal neovascularization.

Patients with secondary MPGN may have extrarenal abnormalities related to the underlying disease. For example, patients with MPGN in association with cryoglobulinemia may have ulcerative skin lesions, Raynaud phenomenon, peripheral neuropathy, hepatomegaly, and signs of cirrhosis.

7. What is the natural history of MPGN?

Although spontaneous remission has been described in children and adolescents with MPGN, nearly 50% progress to ESKD over 10 to 15 years. Similar outcomes are found in adults, with 50% progressing to ESKD within 5 years and 64% after 10 years of follow-up. Indicators of poor outcome include

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  Elevated serum creatinine at presentation

  
  
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  Nephrotic-range proteinuria

  
  
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  Severe hypertension

  
  
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  Crescents in more than 50% of glomeruli

  
  
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  Diffuse interstitial fibrosis and tubular atrophy

  
  
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  A reduced calculated GFR after 1 year of treatment

  
  
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  Primary versus secondary forms of MPGN

  
  
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  Type II MPGN compared as opposed to types I and III

8. Are there any patient groups at special risk of developing MPGN or adverse long-term outcomes?

MPGN appears to involve children and adults of both genders and all ethnic groups, and the prognosis is comparable in all patient groups.

9. What is the appropriate workup for patients with MPGN?

The critical laboratory test that suggests the diagnosis of MPGN is hypocomplementemia—namely, reduced C3 and CH50 levels, which are confirmed in 80% to 90% of cases. The C4 and factor B levels are also low in approximately 40% of those with type I MPGN. This is less common in those with type II or III MPGN. Molecular markers of activation of the alternative pathway of complement, such as Bb and C3d, are elevated in patients with type II MPGN. Measurement of all components of the complement cascade to distinguish between the different types of MPGN is usually not performed in clinical chemistry laboratories and currently is available only in select research facilities. Activity of C3 nephritic factor, an IgM autoantibody that stabilizes C3 convertase, should be assayed in all forms of primary and secondary MPGN. In adults with cryoglobulinemia, testing should be performed for hepatitis B and C infection. Hepatitis serology should be evaluated in pediatric patients with MPGN even in the absence of mixed cryoglobulinemia. Other laboratory abnormalities will be present depending on the underlying disease. The confirmatory test in patients with hypocomplementemia or a suggestive history is a kidney biopsy demonstrating the characteristic histopathological findings.