Membranoproliferative Glomerulonephritis (MPGN) – Interesting Facts, Symptoms, Diagnosis, Treatment and Prognosis

Membranoproliferative Glomerulonephritis 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).

7 Interesting Facts of Membranoproliferative glomerulonephritis

1. Membranoproliferative glomerulonephritis, also referred to as mesangiocapillary glomerulonephritis, is a rare pattern of renal injury characterized by mesangial cell proliferation and glomerular capillary wall structural changes commonly attributed to dysregulation of the complement system
2. Classified into immune complex–mediated membranoproliferative glomerulonephritis with complement overactivation and complement-mediated membranoproliferative glomerulonephritis
3. Immune complex–mediated membranoproliferative glomerulonephritis is caused by deposition of circulating immune complexes that result from underlying conditions associated with complement activation via the classic pathway, such as chronic infections (eg, hepatitis B or C), autoimmune diseases, and monoclonal gammopathies
4. Complement-mediated membranoproliferative glomerulonephritis (including dense-deposit disease and C3 glomerulonephritis) is characterized by dysregulation of the alternative pathway of complement leading to persistent complement activation; attributed to the presence of abnormalities or deficiencies in complement regulatory proteins or autoantibodies
5. Membranoproliferative glomerulonephritis is a slowly progressive disease that may present with a variety of clinical syndromes including hematuria, non-nephrotic-range proteinuria, nephrotic syndrome, or acute nephritic syndrome
6. Diagnosis is based on a recognition of the clinical syndrome of glomerulonephritis and immunohistologic findings on kidney biopsy
7. Management consists of treatment of any underlying treatable cause, treatment of idiopathic immune complex–mediated disease with immunosuppressive therapy, and general measures aimed at controlling blood pressure, reducing proteinuria, controlling edema, and lowering lipid levels

• Membranoproliferative glomerulonephritis (MPGN) is diagnosed based on a kidney biopsy with renal kidney histopathology demonstrating a lobular appearance of the glomerular tuft, mesangial expansion, and hypercellularity, the characteristic “tram track” finding with a double contour of the glomerular basement membrane, and immunofluorescence staining that is usually positive for C3, IgG, and IgM in a capillary wall distribution.

• There are three subtypes:

a. Type I—subendothelial deposits

b. Type II—large, ribbon-like intramembranous deposits, so-called dense deposit disease

c. Type III—subendothelial and subepithelial deposits

A new term, C3 glomerulopathy , which highlights the presence of C3 as the dominant or codominant immunoreactant in the glomerulus and the role of the alternative pathway of complement activation, has been introduced to describe subtypes II and III of MPGN.

MPGN can be primary or idiopathic. A substantial proportion of these primary conditions are due to genetic mutations in proteins involved in the alternative complement pathway. Secondary causes of MPGN may be due to:

a. Infections

b. Autoimmune diseases

c. Chronic liver disease

d. Malignancies

e. Lymphoproliferative disorders

f. Plasma cell dyscrasias

g. Essential cryoglobulinemia

Primary MPGN is one of the least common causes of idiopathic nephrotic syndrome, accounting for at most 5% to 10% of cases and an incidence in the range of 1 to 2 per million population per year.

Together with post infectious glomerulonephritis, systemic lupus erythematosus, and cholesterol embolic disease, MPGN is one of the glomerulopathies characterized by hypocomplementemia (i.e., a low serum C3 level).

Spontaneous remission is rare and nearly 50% of patients with MPGN progress to end-stage kidney disease over 10 to 15 years.

Children with severe disease are treated with prolonged alternate daily therapy with oral steroids, prednisone 40 to 60 mg/m ² , or 2 to 2.5 mg/kg every other day for an average period of 6.5 years, with an improved outcome compared to historic controls or patients treated at other centers. The role of immunosuppressive therapy is less clear in adults. Further study is needed to clarify the role of anticomplement therapies in patients with MPGN.

• Membranoproliferative glomerulonephritis, also referred to as mesangiocapillary glomerulonephritis, is a rare pattern of renal injury characterized by mesangial cell proliferation and glomerular capillary wall structural changes commonly attributed to dysregulation of the complement system 
  • Accounts for approximately 7% to 10% of biopsy-confirmed glomerulonephritis cases 
• Represents a histologic descriptor of glomerular injury that may occur via a number of different disease mechanisms 

Classification

• Classification based on electron microscopy findings: 
  • Type I: characterized by subendothelial and mesangial deposits
  • Type II: characterized by dense deposits in the glomerular basement membrane (dense-deposit disease)
  • Type III: both subepithelial and subendothelial deposits
• Pathophysiologic classification system based on immunofluorescence staining 
  • Immune complex–mediated membranoproliferative glomerulonephritis (equivalent to type I) 
    • Characterized by positive staining for immunoglobulin and complement on immunofluorescence microscopy
  • Complement-mediated membranoproliferative glomerulonephritis 
    • Characterized by positive staining for C3 deposits in the glomeruli with minimal or no immunoglobulin deposits on immunofluorescence microscopy 
    • These cases are further divided into 2 groups according to the presence or absence of highly electron-dense deposits into the glomerular basement membrane: 
      • Cases with intramembranous deposits correspond to dense-deposit disease (equivalent to type II) 
      • Cases with C3 and no immunoglobulins on the glomeruli and no dense deposits are recognized as C3 glomerulonephritis 
  • Membranoproliferative glomerulonephritis not related to complement or immune complex 
    • No presence of specific immunofluorescence staining, but light microscopy shows a pattern of injury associated with membranoproliferative glomerulonephritis
    • Probable diagnosis of thrombotic microangiopathy
      • Injury to endothelial cells can lead to a similar pattern of glomerular injury without complement activation

Clinical Presentation

History

• Membranoproliferative glomerulonephritis is a slowly progressive disease that may present with a variety of clinical syndromes ranging from asymptomatic hematuria or proteinuria to nephrotic syndrome or acute nephritic syndrome (Related: Hematuria)
  • Nephrotic syndrome (40%-70%) 
    • Symptoms include weight gain, edema, and foamy urine 
  • Acute nephritic syndrome (20%-30%) 
    • Symptoms include edema, gross hematuria, oliguria, dyspnea, cough with mucus, headache, and blurred vision 
  • Asymptomatic proteinuria and hematuria detected on routine urinalysis (20%-30%) 
  • Recurrent episodes of gross hematuria (10%-20%) 
    • Associated with abdominal and/or flank pain, polyuria, dysuria, and fever
  • Symptoms of anemia such as dizziness and fatigue may also occur, as well as symptoms of uremia, which include nausea and vomiting 
  • Patients may also present with symptoms of peripheral neuropathy (eg, tingling or numbness of lower extremities), which are a result of cryoglobulinemia 
• A respiratory tract infection may precede or occur simultaneously with diagnosis in half of patients 
• Patients may also have a history of autoimmune disease, hepatitis B or C infection, or diseases associated with paraproteinemias (eg, Waldenström macroglobulinemia) 

Physical examination

• Physical examination findings vary according to type of clinical presentation and disease progression 
• Nephrotic syndrome 
  • Periorbital and leg edema; may become more generalized as disease progresses
  • Ascites may be present in more advanced disease 
• Acute nephritic syndrome 
  • Hypertension
  • Hepatomegaly
  • Edema of the arms, legs, and face
  • Features of cryoglobulinemia, including acrocyanosis, may also be present 
• Extra-renal manifestations
  • Patients may also present with signs related to anemia due to complement-mediated lysis of RBCs (eg, pale skin, conjunctiva) 
  • Patients with dense-deposit disease may develop drusen (whitish-yellow deposits within Bruch membrane of the retina) in the second decade of life 
  • Acquired partial lipodystrophy is also associated with dense-deposit disease, and loss of subcutaneous upper body fat generally precedes loss of kidney function 

Causes

• Membranoproliferative glomerulonephritis may be idiopathic or occur secondary to an underlying condition
• Immune complex–mediated membranoproliferative glomerulonephritis (type I) is caused by deposition of circulating immune complexes that result from underlying conditions associated with complement activation via the classic pathway, such as: 
  • Chronic infections (eg, hepatitis B or C, endocarditis, malaria, schistosomiasis, mycoplasma, visceral abscess)
  • Autoimmune diseases (eg, Sjögren syndrome, rheumatoid arthritis, scleroderma, systemic lupus erythematosus)
  • Monoclonal gammopathies (eg, Waldenström macroglobulinemia, cryoglobulinemia types 1 and 2, monoclonal gammopathy of uncertain significance, light chain deposition disease, monoclonal IgG deposition disease) 
  • Multiple myeloma and lymphoma (eg, low-grade B cell lymphoma, chronic lymphocytic leukemia) 
  • Others (eg, Castleman disease, cystic fibrosis, celiac disease, sickle cell disease) 
• Complement-mediated membranoproliferative glomerulonephritis (including dense-deposit disease and C3 glomerulonephritis) is characterized by dysregulation of the alternative pathway of complement leading to persistent complement activation 
  • There are several genetic mutations and autoantibodies to complement regulatory proteins that drive the development and progression of complement-mediated membranoproliferative glomerulonephritis 
  • These include the C3 nephritic factor autoantibody, properdin deficiency, and autoantibodies to factor B, factor H, and C3 convertase 

Risk factors and/or associations

Age

• Primarily affects children and young adults, but may also occur in older adults 

Sex

• No sex predilection 

Genetics

• Mutations associated with C3 glomerulonephritis include: 
  • Heterozygous mutation in CD46 gene (membrane cofactor protein)
  • Heterozygous mutations in factor I gene
  • Mutations in complement factor H-related protein 5 (CFHR5) gene
  • Mutations in complement factor H at H401 and V62 alleles
  • Mutations in C3 nephritic factor

Diagnostic Procedures

Primary diagnostic tools

• Evaluation of membranoproliferative glomerulonephritis begins with recognition of 1 of the clinical syndromes of glomerulonephritis based on thorough history, physical examination, and urinalysis 
• Initial laboratory testing includes:
  • Urinalysis
  • CBC, electrolytes, urea, and creatinine
  • Serum albumin
  • Serum complement
  • Erythrocyte sedimentation rate
• Pathologic diagnosis is confirmed by immunohistologic findings on kidney biopsy, which is performed on all patients with suggestive clinical features 
  • Evaluate for infections, autoimmune diseases, and monoclonal gammopathies if patient has immunoglobulin-positive, complement-positive disease 
    • Diagnostic testing is guided by clinical circumstances
    • Common investigations include hepatitis B and hepatitis C serology, serum immunoglobulins, serum protein and urine electrophoresis, and autoantibody screening
  • Evaluate the alternative complement pathway in immunoglobulin-negative, complement-positive (C3G) glomerulonephritis 
    • Obtain serum complement levels (C3 and C4), serum levels of the membrane-attack complex, an alternative pathway functional assay (AP50), and hemolytic complement assays (CH50) 
    • A genetic cause is most likely in children; mutation testing is recommended in C3; complement factors H, I, B; CD46 (membrane cofactor protein); and complement factor H-related proteins 1 through 5 
    • In adults, autoantibodies to complement factors are more likely to be responsible; testing is recommended for antibody to C3 convertase (C3 nephritic factor [C3Nef]) and anti-factor H antibody 
    • Consultation with institutions experienced with these diseases may be warranted as many of the tests are not readily accessible but may be available through selected research or clinical laboratories

Laboratory

• Serum creatinine and BUN
  • Initial nonspecific tests to determine presence and extent of kidney involvement
  • Levels may be elevated, reflecting renal parenchymal damage
• Serum albumin
  • Initial nonspecific test to determine presence and extent of kidney involvement
  • Hypoalbuminemia may be present
• Serum complement
  • C3, C4, and membrane-attack complex 
    • Persistently decreased serum levels of complement C3 and C4 are seen in cases of membranoproliferative glomerulonephritis 
    • Low C3 and C4 complement levels are more common in immune complex–mediated disease 
    • Low C3 and reference-range C4 levels are more common in alternative-pathway dysfunction 
    • Membrane-attack complex (C5b-C9) abnormalities are consistent with alternative pathway dysfunction (C3 glomerulopathy) 
  • Total hemolytic complement (CH50) assay
    • Abnormal test result indicates the presence of hereditary or acquired complement component deficiencies or complement dysfunction due to immune or autoimmune complexes 
  • Complement alternate pathway (AP50) assay
    • Abnormal test result indicates complement abnormalities in the alternative pathway 
  • C3 nephritic factor 
    • Presence associated with C3 glomerulopathy 
  • Serum factor H levels 
    • Deficiency is associated with C3 glomerulopathy and a reduction in serum C3 
• Urinalysis
  • Initial noninvasive test to determine presence and extent of kidney involvement 
  • Urine microscopy
    • May show RBCs, RBC casts, and dysmorphic RBCs
  • A 24-hour urine protein measurement is the reference (gold standard) method for quantification of proteinuria 
    • Protein to creatinine ratio or albumin to creatinine ratio on a random (spot) urine sample or a first-morning-urine sample is a practical alternative; however, it may not be accurate enough to guide therapeutic decision-making regarding high-risk medications
    • Moderate to severe proteinuria may be present
    • Excretory kidney function (GFR) can be estimated using creatinine clearance from 24-hour urine collection 
• Genetic testing
  • Specific testing for an established disease-associated variant may be indicated in complement-mediated membranoproliferative glomerulonephritis 

Imaging

• Renal ultrasonography
  • Routine investigation to detect structural kidney abnormalities

Procedures

Renal biopsy 

General explanation

• Percutaneous procedure involving placement of a long, thin needle into the kidney through a flank approach to obtain a tissue sample for immunohistologic analysis

Indication

• To confirm diagnosis when clinical syndrome and initial testing suggests glomerulonephritis

Contraindications

• Absolute contraindications
  • Solitary kidney
  • Multiple renal cysts
  • Acute pyelonephritis
• Relative contraindications
  • Uncontrolled hypertension
  • Uncorrected coagulopathy
  • Skin infection over biopsy site

Complications

• Intraperitoneal hemorrhage
• Pneumothorax
• Hematoma

Interpretation of results

• Immune complex–mediated membranoproliferative glomerulonephritis is characterized by positive staining for immunoglobulin and complement on immunofluorescence microscopy 
• Complement-mediated membranoproliferative glomerulonephritis is characterized by positive staining for C3 deposits in the glomeruli with minimal or no immunoglobulin deposits on immunofluorescence microscopy 
  • Can be further classified as either dense-deposit disease or C3 glomerulonephritis, depending on the electron-microscopy findings
    • Dense-deposit disease is characterized by osmiophilic dense deposits in the glomerular basement membrane that may also occur in the mesangium 
    • C3 glomerulonephritis disease is characterized by mesangial, subendothelial, subepithelial, and intramembranous deposits 

Differential Diagnosis

Most common

• IgA nephropathy
  • Immune complex–mediated disease characterized by deposition of IgA in the glomerular mesangium followed by the onset of mesangioproliferative glomerulonephritis 
    • Most common form of glomerulonephritis in developed countries
  • Similar to immune complex–mediated membranoproliferative glomerulonephritis, patients with IgA nephropathy present with a variety of clinical syndromes, including hematuria or nephrotic syndrome; however, the syndromes are often found incidentally
  • Definitive diagnosis is made on immunohistologic examination of renal biopsy specimen 
    • Dominant or codominant staining with IgA in glomeruli distributed in the mesangium, with or without capillary loop staining
    • IgM and IgG staining may be present but not in greater intensity than IgA 

Treatment

Goals

• Identify and manage underlying conditions
• Prevent or slow progression of the disorder
• Prevent complications (eg, chronic kidney disease, end-stage renal disease)

Admission criteria

Patients with rapidly progressive glomerulonephritis (significant hematuria and hypertension) 

Criteria for ICU admission

• Severe sepsis with septic shock, respiratory failure due to fluid overload, or hypertensive emergency

Recommendations for specialist referral

• Nephrologist for patients with suspected glomerulonephritis to diagnose and determine a course of treatment 
• Appropriate specialist (eg, rheumatologist, infectious disease specialist, hematologist) for patients with immune complex–mediated membranoproliferative glomerulonephritis for treatment of underlying disease

Treatment Options

Management consists of treatment of any underlying treatable cause, treatment of idiopathic cases with immunosuppressive therapy, and general measures aimed at controlling blood pressure, reducing proteinuria, controlling edema, and lowering lipid levels

• Treatment of underlying disease associated with immune complex–mediated membranoproliferative glomerulonephritis
  • Treat autoimmune disease with immunosuppressive agents as appropriate for primary disease 
  • Institute appropriate treatment of any underlying chronic infection (eg, antimicrobial therapy for bacterial infection, antiviral agents for hepatitis B or C) 
  • Treat underlying hematologic malignancies with appropriate chemotherapy regimen
• Treatment of idiopathic immune complex–mediated membranoproliferative glomerulonephritis 
  • Treat with prednisone plus either cyclophosphamide or mycophenolate mofetil when associated with nephrotic syndrome and progressive decline of kidney function; limit initial therapy to less than 6 months
    • This approach may be appropriate for patients with nephrotic syndrome without progressive decline in kidney function, active nephritic syndrome, or rapidly progressive disease, with or without crescents
  • Patients with reference-range GFR and non-nephrotic–range proteinuria may be treated with general measures alone
• Treatment of complement-mediated glomerulonephritis
  • There is no proved effective therapy for C3 glomerulonephritis and dense-deposit disease
  • Targeted inhibition of complement autoantibodies using the anti-C5 monoclonal antibody eculizumab is a possible approach 
  • Plasma exchange or fresh-frozen plasma infusion are options when inherited deficiencies or abnormalities in serum complement factors are present 
  • Immunosuppressive therapy with prednisone plus either cyclophosphamide or mycophenolate mofetil may be indicated in patients with rapidly deteriorating renal function
• Regardless of cause, implement general measures aimed at controlling blood pressure, reducing proteinuria, controlling edema, and lowering lipid levels 
  • Pharmacotherapy includes ACE inhibitor or angiotensin receptor blocker and statins 
  • Titrate ACE inhibitor or angiotensin receptor blocker treatment to achieve target systolic blood pressure of 120 to 129 mm Hg and reduce proteinuria to less than 1 g/day 
• Renal transplant may be necessary for patient with progressive disease leading to end-stage renal failure

Drug therapy

• Immunosuppressive agents 
  • Cyclophosphamide
    • Cyclophosphamide Oral tablet; Children and Adolescents: 2 mg/kg/day PO for 8 to 12 weeks (Max cumulative dose: 168 mg/kg).
    • Cyclophosphamide Oral tablet; Adults: 2 mg/kg PO every day has been recommended.
  • Eculizumab
    • Eculizumab Solution for injection; Adults: 900 mg IV once a week for 4 weeks; followed by 1200 mg IV on week 5 and then every other week afterward for a total medication period of 53 weeks. 
  • Mycophenolate mofetil
    • Mycophenolate Mofetil Oral tablet; Adults: Doses ranging from 500 mg to 2 g per day PO have been used. 
  • Rituximab 
    • Rituximab (Murine) Solution for injection; Adults: 1000 mg IV on days 1 and 15 has been reported. 
• ACE inhibitors 
  • Enalapril
    • Enalapril Maleate Oral tablet; Adults: 10 mg PO once daily (range, 5 mg/day up to 20 mg/day PO in 1 or 2 divided doses). Initial doses used in trials vary. Usually begin with a low dose and titrate to response and tolerance. Guidelines recommend the use of an angiotensin converting enzyme (ACE) inhibitor to slow the progression of renal disease in hypertensive patients and in diabetic patients regardless of the presence of hypertension.
  • Captopril
    • Captopril Oral tablet; Adults: The FDA-approved dosage is 25 mg PO 3 times daily.
• Corticosteroids 
  • Prednisone
    • Prednisone Gastro-resistant tablet; Adults: 40 mg/day to 80 mg/day PO until urine is protein-free; slowly taper as indicated. Some patients may require long-term therapy.
• Statins
  • Atorvastatin
    • Atorvastatin Calcium Oral tablet; Adults: 10 to 20 mg PO once daily. May start at 40 mg once daily for greater than 45% LDL-reduction. Range: 10 to 80 mg once daily.
  • Simvastatin
    • Simvastatin Oral tablet; Adults: Initially, 10 to 20 mg PO at bedtime. In patients with CHD, risk factors for CHD, or familial homozygous hypercholesterolemia, starting dose is 40 mg PO once daily in the evening. Usual dosage range: 5 to 40 mg/day PO. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Only use 80 mg in patients who have been taking 80 mg chronically without myopathy.

Nondrug and supportive care

Additional supportive measures in patients with proteinuric glomerulonephritis who are at risk of progressive loss of renal function include: 

• Control protein intake to about 0.8 g/kg per day 
• Control fluid intake
• Restrict salt intake
• Smoking cessation

Special populations

• Pregnant women with glomerulonephritis 
  • GFR at the time of conception is a major predictor of pregnancy outcome 
  • Uncontrolled proteinuric conditions may lead to adverse fetal and maternal outcomes 
  • Mycophenolate mofetil, ACE inhibitor, and angiotensin receptor blocker should not be used owing to their toxicity, and are especially contraindicated during the first trimester 

Monitoring

• Periodically evaluate blood pressure, renal function, and proteinuria

Complications

• Acute kidney injury
• Pulmonary edema
• Electrolyte imbalance
• Hypertension
• Chronic kidney disease
• Progression to end-stage renal disease
• Hyperlipidemia (in patients with nephrotic syndrome) 
• Thrombotic events (owing to hypercoagulability in nephrotic syndrome)
• Bacterial infection (common in nephrotic patients) 
  • Can lead to bacteremia and sepsis

Prognosis

• There are very few cases of spontaneous complete remission and approximately 40% of patients develop end-stage renal failure 10 years after diagnosis 
• Prognosis depends on underlying cause, immunohistologic characteristics, and patient factors
  • Successful treatment of underlying cause associated with immune complex–mediated membranoproliferative glomerulonephritis generally results in resolution of renal disease
  • Patients with reference-range GFR and non-nephrotic–range proteinuria generally have good long-term outcome with conservative treatment
  • Patients with dense-deposit disease are more likely to progress to end-stage renal disease than patients with C3 glomerulonephritis 
  • Features associated with poor outcome include nephrotic syndrome, renal dysfunction at onset, and persistent hypertension 
• In patients with end-stage kidney disease due to membranoproliferative glomerulonephritis who have received a kidney transplant, the rate of recurrence is higher than with other forms of glomerular disease 
• In patients with complement-mediated glomerulopathy who have received a kidney transplant, the rate of recurrence is high 
  • Recurrence occurs in about 60% to 70% of patients with C3 glomerulonephritis and more than 90% of those with dense-deposit disease 
• In patients with immune complex–mediated membranoproliferative glomerulonephritis, recurrence rates after kidney transplant range from 14% to 61%

Sources

Alchi B et al: Membranoproliferative glomerulonephritis. Pediatr Nephrol. 25(8):1409-18, 2010 Reference