OVERVIEW: What every practitioner needs to know

Are you sure your patient has membranous glomerulopathy? What are the typical findings for this disease?

Membranous nephropathy can occur as a primary or idiopathic disease (IMN) or secondary to a variety of conditions. In children, the most common causes of secondary MN are SLE, medications, and infections (e.g., hepatitis B, malaria, syphilis). In general, MN is a rare illness in pediatric patients and accounts for fewer than 2% of kidney biopsies performed in children with proteinuria and/or nephrotic syndrome.

The etiology of MN is unknown in most cases. In adults, over 70% of cases are secondary to antibodies to M-type phospholipase A2 receptor. The role of this antigen in pediatric cases is unknown. A recent report linked IMN in children to exposure to bovine serum albumin. The long-term prognosis has traditionally been divided into thirds – 33% resolve, 33% have persistent proteinuria, and 33% progress to end stage kidney disease (ESKD).

Recent data suggest that the likelihood of spontaneous resolution is higher especially in those treated with an angiotensin converting enzyme inhibitor (ACEI) and/or angiotensin receptor blocker (ARB). There is no proven therapy for IMN. The current recommendation is to initiate therapy with ACEI/ARB and proceed to immunosuppressive therapy if there is no response in 1-2 years, if there is worsening edema, or if there is declining GFR. Options include steroids, cycophosphamide, tacrolimus, and rituximab. Secondary MN should be treated based on the underlying cause. This review will focus primarily on IMN because the most common cause of secondary MN, SLE, is discussed in a separate chapter.

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MN is a non-inflammatory disease that is characterized by thickening of the glomerular basement membrane, subepithelial immune complex deposits, and granular staining for IgG and C3. It presents with proteinuria and/or nephrotic syndrome. It is not associated with acute glomerulonephritis and thus gross hematuria and hypertension are uncommon. Thromoembolism can be a complication of MN.

Key signs and symptoms:

  • Proteinuria

  • Nephrotic syndrome

  • Signs and/or symptoms of an underlying secondary cause

Distinction between primary or idiopathic and secondary MN

IMN or primary disease occurs in the absence of an identifiable systemic illness. It may be linked to the development of autoantibodies to endogenous proteins such as the M-type phospholipase 2 receptor. In children, the important causes of secondary MN include; (1) SLE; (2) hepatitis B and hepatitis C; (3) HIV; (4) malaria; (5) syphilis; (6) other autoimmune disorders such as thyroiditis and Sjogren’s disease; (7) medications such as captopril, penicillamine, clopidogrel, non-steroidal anti-inflammatory drugs, and gold; (8) sickle cell disease; and (9) malignancies such as lymphoma and leukemia. Diabetic nephropathy rarely causes MN in pediatric patients because of the long latency that is required before the development of clinically overt diabetic nephopathy.


MN is an autoimmune disease that is characterized by electron dense deposits, presumably immune complexes, in the subepithelial space. In IMN, it may reflect the formation of in situ immune complexes containing m-type phospholipase A2 receptor protein and antibody. In secondary MN, the antigen may be deposited in this location with subsequent binding of antibody and formation of immune complexes within the glomerular capillary wall. Activation of the complement system plays a key role in mediating the glomerular barrier dysfunction and proteinuria. Urinary excretion of the membrane attack complex (C5b-9) is a marker of this process and parallels proteinuria.

What other disease/condition shares some of these symptoms?

MN is a non-inflammatory glomerular disease that resembles any of the other causes of nephrotic syndrome. In the list of causes of primary nephrotic syndrome, MN will have no specific clinical features that specifically point to its occurrence. In general, the diagnosis is unexpected and the entity is detected by the pathologist on examination of the kidney tissue submitted from the diagnostic biopsy.

What caused this disease to develop at this time?

MN represents an immune complex disease resulting from deposition of preformed soluble immune complexes or formation of in situ immune complexes in the subepithelial location of the glomerulus, i.e., between the outer surface of the glomerular basement membrane and the overlying podocyte or visceral epithelial cell.

There have been tremendous strides in understanding the pathogenesis of IMN in adult patients. It is now believed that over 70% of cases arise secondary to antibodies to the M-type phospholipase A2 receptor. There are single nucleotide polymorphisms (SNPs) in the gene for this protein as well as in the HLA DQA1 allele that predispose to the development of IMN. This association has not been confirmed in children. There are no specific genetic risk factors for the secondary causes of MN.

IMN occurs throughout the world and is more common in boys. The geographic distribution of IMN is homogeneous. In contrast, secondary causes of MN may vary geographically depending upon the distribution of the underlying disease. For example, infectious causes of secondary MN such as malaria and leptospirosis are more common in Africa due to the prevalence pattern of the underlying pathogen.

In neonates, IMN has been traced to autoantibodies to neutral endopeptidase. In children with IMN, there are recent data linking the occurrence of the disease to bovine serum albumin with deposition of the antigen and antibody to the protein in the the glomerulus of children with the disease. It is unknown whether this represents an aberrant reaction to early exposure to cow’s milk. There are also rare reports of membranous nephropathy occurring in association with discrete food allergens with resolution of the disease following elimination of the food item from the diet. However, there is no link between any other specific nutrient and the development of primary or secondary MN and allergy testing or changes in the diet are not routinely recommended for children with MN.

In most children, there is no proven linkage between any environmental exposures such as heavy metals, radiation, or other toxins that trigger the occurrence of MN.

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

  • Quantitation of the urine protein:creatinine ratio in a first morning urine sample.

  • Comprehensive metabolic profile with attention to the BUN, creatinine, albumin, and cholesterol.

  • Complete blood count focusing on the white blood cell and platelet counts. Leukopenia or thrombocytopenia may suggest SLE as a secondary cause.

  • Complement 3 (C3).

  • ANA, double stranded DNA in adolescent girls.

  • Testing for HIV, hepatitis B, hepatitis C, syphilis, malaria in appropriate circumstances.

  • Work-up for malignancy in suspect cases.

  • Antiphospholipid antibodies, antithrombin III, protein S, and protein C levels in patients with MN who develop renal vein thrombosis or other evidence of thromboembolism.

  • Kidney biopsy which shows minimal mesangial hypercellularity or infiltration with inflammatory cells is required to make the diagnosis of MN. By light microscopy, the key finding is thickening of the GBM and immunofluorescence staining demonstrates granular deposition primarly of IgG and C3 in a capillary wall distribution. On electron microscopy, there are subepithelial deposits that can be incorporated into the GBM and even resorbed with prolonged duration of the disease.

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

The disease effects glomeruli and in general imaging studies are not helpful in making the diagnosis or assessing the severity of MN except in advanced cases in which there may be small kidneys by ultrasound.

In patients with flank pain and where there is clinical suspicion of a renal vein thrombosis, a renal ultrasound with Doppler flow studies, a computed tomography (CT) scan, or magnetic resonance imaging (MRI) may be required to define the thromboembolism in the renal vasculature.

Specific imaging studies such as Doppler studies of the legs, ventilation-perfusion scans, or pulmonary CT angiography may be required if there is evidence of peripheral thromboembolism. These events are rare in children and the diagnostic work-up should be planned in conjunction with a radiologist and an internal medicine nephrologist who has more experience in the evaluation and treatment of renal-related thromboembolism.

Confirming the diagnosis

  • Assess kidney function, BP, and degree and duration of proteinuria.

  • Perform a kidney biopsy to evaluate cause of proteinuria.

  • Assess for presence of signs and symptoms of secondary cause of MN.

  • If the disease is secondary, perform investigations designed to clarify cause (see above).

  • If the disease is primary IMN, consider a trial of conservative management with ACEI/ARB combination.

  • If proteinuria worsens or persists in the nephrotic range, consider 6 month course of alternate day corticosteroid therapy.

  • If the patient is steroid resistant, the therapeutic options include cyclophosphamide, mycophenolate mofetil, tacroilimus, rituximab.

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

  • MN is generally an indolent slowly progressive disease and there is no need for urgent therapy.

  • A sodium restricted diet and judicious use of diuretics can ameliorate edema.

  • BP should be treated with antihypertensive drugs. ACEI/ARB agents may serve the dual purpose of controlling hypertension and reducing urinary protein excretion.

  • There is no need for fluid restriction.

  • Patients should be counseled to report any episodes of fever and abdominal pain if they have edema. In addition, they should report any new shortness of breath, flank pain or leg pain that might indicate the presence of a thromboembolism.

  • Long-term treatment in patients with persistent proteinuria, nephrotic range proteinuria, or reduced GFR may involve a combination of corticosteroids and other immunosuppressive medications. If chronic kidney disease develops it will need to be treated. Thus, patients who are not nephrotic may be treated with ACEI/ARB agents alone for up to 12 months during which they may achieve a spontaneous remission. Immunosuppresive therapy is indicated for those with persistent proteinuria beyond 12 months or nephrotic-range proteinuria.

See Table I. Drugs used in the Treatment of Membraneous Nephropathy

Table I.n

What are the adverse effects associated with each treatment option?

Steroids: Behavior changes, weight gain, acne, hypertension, growth failure, deminineralization of bone, cataracts.

Mycophenolte mofetil: Gastrointestinal upset, leukopemia, hepatoxicity.

Cyclophosphamide: leukopenia, alopecia, hemorrhagic cystitis, gonadal failure, risk of malignancy.

Tacrolimus: coarsening of facial features, hypertrichosis, gingival hyperplasia, tremor, hypertension, hepatotoxicity, nephrotoxicity, new-onset diabetes.

Rituximab: infection, malignancy, leukoencephalopathy.

What are the possible outcomes of membranous glomerulopathy?

In general, the prognosis of IMN can be divided into thirds: a 30% likelihood of spontaneous remission or resolution of proteinuria in response to treatment; 30% of patients have persistent proteinuria but stable GFR despite treatment;

30% of patients will develop progressive loss of kidney function and go on to ESKD.

Patients with IMN are transplant candidates and have a fairly low risk of recurrent disease in the renal allograft.

Male gender, older age (>9 years old), persistent nephrotic-range proteinuria, reduced GFR at the time of diagnosis, and the extent of glomerular scarring/tubulointerstitial fibrosis are features that indicate a poor prognosis.

There is much controversy about the optimal treatment of IMN in adults and even more so in children because the disease is infrequent in pediatrics and randomized clinical trials have been difficult to perform. Thus, patients should make the best decision balancing the available evidence and their own assessment of the potential side effects of a proposed therapeutic regimen.

What causes this disease and how frequent is it?

  • Detailed epidemiology:

    The incidence of MN is low in children and it is documented in 1-5% of all kidney biopsies performed in pediatric patients with proteinuria or nephrotic syndrome. Based on data compiled by the USRDS and NAPRTCS, MN accounts for approximately 0.5% of all pediatric cases of ESKD in the United States. There is no seasonal variation except possibly for infectious causes such as malaria. It occurs in all ages during childhood with a peak age in school age children in some studies. There is no clearcut predilection for boys or girls and the M:F ratio varies from 1:1 to 3:1.

    There are well described infectious causes of secondary MN including hepatitis B, hepatitis C, syphilis, malaria, and schistosomiasis. The mode of transmission for each causative agent is the same regardless of whether or not the patient develops MN.

    There are no zoonotic or environmental causes in most pediatric cases of MN. In contrast, exposure to mercury and some other heavy metals can cause MN in adults. The disease can occur following exposure to medications including penicillamine, gold salts, and captopril. Activity level has no impact on the occurrence or severity of IMN or secondary disease.

  • There is new clinical research linking the development of IMN to SNPs in the M-type phospholipase A2 receptor protein in the the HLA DQA1.

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

The SNPs in the M-type phospholipase A2 receptor and HLA DQA1 gene loci may increase the likelihood of autoantibody production to the protein, in situ immune complex formation, and development of MN.

Other clinical manifestations that might help with diagnosis and management

MN is a non-distinctive disease and can mimic the clinical appearance of other diseases that manifest primarily with proteinuria such as focal segmental glomerulosclerosis (FSGS).

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

Renal complications include: (1) persistent edema; (2) anasarca; (3) declining GFR; (4) progression to ESKD.

Infectious complications: (1) peritonitis or (2) cellulitis secondary to edema.

Thromboembolic complications: (1) renal vein thrombosis; (2) pulmonary embolus, (3) deep vein thrombosis

Treatment: see above for side effects of medications.

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

1. Anti-phopholipase A2 antibody levels for diagnosis and monitoring efficacy of therapy.

2. Genetic testing for susceptibility factors in the PLA2 gene and the HLA locus DQA1.

3. Measurement of urinary excretion of the membrane attack complex (C5b-9).

How can membranous glomerulopathy be prevented?

The cause of IMN is uncertain is most cases and cannot be prevented by prophylactic drugs or vaccinations. Secondary cases of MN are the consequence of the underlying disease. Avoidance of drugs or prophylaxis against infections linked to MN can prevent the renal disease. In patients at high risk of thrombolembolism, administration of anticoagulant such as Coumadin may lower the incidence of this serious complication.

There are no behavioral factors linked to the pathogenesis of MN.

Genetic counseling can be offered in pedigrees in which multiple family members have MN. They may be candidates for genetic testing to ascertain the presence of high risk SNPs.

Although there are case reports of MN in association with discrete food allergies, in general there are no specific nutritional factors linked to MN. Children with edema should be prescribed a low salt diet and provided the RDA for protein.

What is the evidence?

Chen, A, Frank, R, Vento, S, Crosby, V, Chandra, M, Gauthier, BG, Valderrama, E, Trachtman, H. “Idiopathic membranous nephropathy in pediatric patients: presentation, response to therapy, and long-term prognosis”. BMC Nephrology. vol. 8. 2007. pp. 11(Excellent description of a US case series.)

Wong, SN, Chan, WKY, Hui, J, Chim, S, Lee, TL, Lee, KP, Leung, LCK, Tse, NKC, Yuen, SF. “Membranous nephropathy in Chinese children – a case series and review of the literature”. Pediatr Nephrol. vol. 24. 2009. pp. 1989-1996. (Excellent description of a non-US case series.)

Menon, S, Valentini, RP. “Membranous nephropathy in children: clinical presentation and therapeutic approach”. Pediatr Nephrol. vol. 25. 2010. pp. 1419-1428. (Timely review of this entity in children and adolescents.)

Ongoing controversies regarding etiology, diagnosis, treatment

1. The role of M-type phospholipase A2 receptor and antibodies in pediatric patients with IMN is unknown.

2. The contribution of exposure to bovine serum albumin as a cause of IMN in children needs further clarification.

3. There is a need to better define genetic susceptibility factors.

4. There is a need for biomarkers to better delineate prognosis and predict response to treatment.

5. There is a need for multicenter randomized clinical trials for children and adolescents with IMN to determine optimal therapy for pediatric patients and to avoid generalization of findings in adults with this glomerular disease.