eMedicine Specialties > Nephrology > Glomerular Diseases

Glomerulonephritis, Membranous

Author: Abeera Mansur, MD, Consultant Nephrologist, Doctors Hospital and Medical Center, Pakistan
Contributor Information and Disclosures

Updated: Dec 16, 2008

Introduction

Background

Membranous nephropathy (MGN) is one of the more common forms of nephrotic syndrome in the adult population. It can be idiopathic or secondary (30%). The two can be distinguished by clinical, laboratory, and histological features.

Pathophysiology

Membranous nephropathy is an immunologically mediated disease in which immune complexes deposit in the subepithelial space. The antigens associated with primary membranous nephropathy are not known. They may be located in the subepithelial space. Antigen-antibody complexes can develop by the production of immune complexes in situ or by deposition. In the experimental Heymann nephritis model of membranous nephropathy, the intrinsic antigen is a glycoprotein, megalin, synthesized by the glomerular visceral epithelial cells.

Neutral endopeptidase, a podocyte antigen that can digest biologically active peptides, was recently identified as the target antigen of antibodies deposited in the subepithelial space of glomeruli in a subset of patients with antenatal membranous nephropathy.¹

Many of the antigens associated with secondary membranous nephropathy are also not known. However, hepatitis B surface antigens and hepatitis E antigens have been identified in immune deposits, as have thyroid antigens in patients with thyroiditis.

The complement membrane attack complex (C5b-9) triggers the biosynthesis of oxygen radical–producing enzymes within the glomerular epithelial cells. The finding of urinary C5b-9 has been suggested as a diagnostic test for following disease activity.

C5b-9 in sublytic quantities stimulates podocytes to produce proteases, oxidants, prostanoids, extracellular matrix components, and cytokines, including transforming growth factor-beta (TGF-beta). C5b-9 also causes alterations of the cytoskeleton that lead to an abnormal distribution of slit diaphragm protein and detachment of viable podocytes that are shed into the Bowman space. These events result in disruption of the functional integrity of the glomerular basement membrane and the protein filtration barrier of podocytes with subsequent development of massive proteinuria.

In one study, a significant increase in the production of IgG4 in the presence of IL-4 was observed in the idiopathic membranous nephropathy group. These results indicate that the altered functions of T cells to produce Th2 cytokines and the increased production of IgG4 by B cells in response to these cytokines characterize the immune response in idiopathic membranous nephropathy.

In another study, the interstitial expression of CD20 mRNA was determined in 31 MGN patients and control subjects (tumor nephrectomies [n=4]), minimal-change disease (n=10), and focal segmental glomerulosclerosis (n=6). CD20 mRNA expression was significantly higher in patients with membranous nephropathy as compared to control subjects. B cell infiltration was confirmed by immunohistochemistry. These data suggest an involvement of B cells in the pathogenesis of membranous nephropathy, possibly as antigen-presenting cells.

Frequency

United States

Biopsy reveals an underlying glomerular lesion in 25% of adults with nephrotic syndrome. However, in patients older than 60 years, the incidence rate is 35%. Recently, the frequency of focal segmental glomerulosclerosis has exceeded that of membranous nephropathy. The variability of the relative distribution of pathologic causes of nephrotic syndrome is considerable among various centers, based on population and referral pattern factors.

In the pediatric population, membranous nephropathy is rare but serious. Membranous nephropathy accounts for approximately 3% of renal biopsies. Long-term prognosis is guarded because approximately 50% of patients may have evidence of progressive kidney disease.²

International

The frequency is the same as in the United States, although it is influenced by the prevalence of secondary causes.

Mortality/Morbidity

The course is variable, and patients may be divided into 3 groups of approximately equal size (ie, "rule of thirds"). Patients in the first and second category die from nonrenal causes.

• Spontaneous complete remission: Renal function is normal, with or without subsequent relapse.
• Persistent proteinuria of variable degree: Renal function is normal or impaired but stable.
• Progressive disease, eventually leading to end-stage renal disease (ESRD): The incidence rate of ESRD is 14% at 5 years, 35% at 10 years, and 41% at 15 years.

Race

• The incidence of secondary forms may be influenced by the prevalence of hepatitis and malaria in certain areas.
• No increased incidence is reported in African Americans.

Sex

• Membranous nephropathy has a predilection for males over females, with a male-to-female ratio of 2:1.

Age

• The peak is around the fourth and fifth decades of life.
• Onset outside the usual range is more likely to be a result of secondary causes.

Clinical

History

• Onset is insidious.
• Approximately 80% of patients describe edema.
• Patients may present with nonspecific complaints of anorexia, malaise, and fatigue.
• Some patients may present with asymptomatic proteinuria.

Physical

• The overwhelming majority of patients have edema or generalized anasarca. Hypertension may be present but is not characteristic of the disease in its early stages. This is unlike most other renal diseases, which are associated with significant hypertension.
• Ascites and pericardial and pleural effusions are uncommon, unless the nephrotic syndrome is severe.

Causes

Causes of membranous nephropathy can be idiopathic or secondary. Often, distinguishing between idiopathic and secondary causes is not possible based on clinical evidence alone. In secondary membranous nephropathy, such as lupus and hepatitis, concomitant mesangial or subendothelial deposits may be present. De novo membranous glomerulopathy (DNMG) can develop post transplant. This can be in the context of a donor-specific alloantibody (DSA) directed against HLA DQ7.³

• Autoimmune diseases
  • Ankylosing spondylitis
  • Dermatomyositis
  • Graves disease
  • Hashimoto disease
  • Mixed connective-tissue disease
  • Rheumatoid arthritis
  • Sjögren syndrome
  • Systemic lupus erythematosus: Of patients with lupus nephritis, 10-20% have membranous nephropathy.
  • Systemic sclerosis
• Infectious diseases
  • Enterococcal endocarditis
  • Filariasis
  • Hepatitis B: This occurs in children in endemic areas.
  • Hepatitis C
  • Hydatid cyst
  • Leprosy
  • Malaria
  • Schistosomiasis
  • Syphilis
• Malignancy: This is responsible for approximately 5-10% of cases of membranous nephropathy, with the higher risk occurring in patients older than 60 years.
  • Carcinoma (solid organ)
  • Leukemia
  • Lymphoma
  • Melanoma
• Drugs
  • Captopril
  • Gold
  • Lithium
  • Mercury-containing compounds
  • Nonsteroidal anti-inflammatory drugs (NSAIDs): They are an uncommon cause; they are usually associated with minimal-change disease.
  • Penicillamine
  • Probenecid
• Miscellaneous
  • De novo in renal allografts: The onset is delayed compared to recurrent disease. The rate of graft loss may be as high as 50%. Recurrence is infrequent, with rates of 3-7%. This can lead to loss of the graft. Membranous nephropathy recurs in 5-10% of patients.
  • Diabetes (uncommon)
  • Kimura disease
  • Sarcoidosis
  • Sickle cell disease: This is uncommon. It usually produces focal segmental glomerulosclerosis.
  • Systemic mastocytosis

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