Membranous nephropathy (MN) is an immune complex deposition disease. IgG and complements predominantly deposit beneath the podocytes on the sub-epithelial region of glomerular capillaries. Hence, the sub-epithelial deposits are considered to be pathognomonic for MN. Glomerular basement membrane (GBM) injury due to immune deposition causes podocyte structural damage which results in proteinuria. Autoimmune diseases, medications, malignancies, infections, among others, are responsible for generating antibodies that account for about 25% of MN (secondary MN). In about 75% cases of MN, the inciting events for these immune depositions are not known, but specific antigen-antibody complexes have been discovered (primary MN).
M-type phospholipase A receptor (PLA2R) are the transmembrane proteins expressed on the podocytes. Circulating antibodies against PLA2R are responsible for 85% of the primary MN. These antibodies are not commonly seen in secondary MN. Other antigen-antibody complexes include anti-thrombospondin type-1 domain-containing 7A (THSD7A; 3% of primary MN), anti-neutral endopeptidase (uncommon), anti-altered (cationic) plasma proteins like cationic bovine serum albumin (children only). Ten percent to 15% of the primary MN remain idiopathic.
Secondary MN, which is 25% of overall disease burden, are caused by autoimmune diseases like class V lupus nephritis (most common cause of secondary MN), RA, autoimmune thyroid disease, IgG4-related systemic diseases, and ANCA associated vasculitis. Infectious etiologies include HBV, HCV, HIV, syphilis, sarcoid, and schistosomiasis. Lung, colon, stomach, and prostate cancer are the most common solid tumors involved in secondary MN. Other malignancies include non-Hodgkin lymphoma, CLL, and melanoma. Medications like NSAIDs and toxins including heavy metals are also implicated. Alloimmune diseases include graft versus host disease, autologous stem cell transplants, and de novo MN in transplant patients.
The incidence of MN In the United States is about 12 per million per year. Typically, patients with primary MN are white adult males in their fourth and fifth decade of life. There is 2:1 male predominance. MN is rare in children with less than 5% having nephrotic syndrome. After Caucasians, Asians followed by African Americans and Hispanics are involved. Familial MN is rare. 
In primary MN, circulating antibodies bind to intrinsic podocyte antigen. In the 1970s, Heymann nephritis model of MN in rats showed antibodies to megalin, a transmembrane protein on the rat podocyte, being responsible sub-epithelial immune deposits. In 2002, Debiec et al. showed that maternal anti-NEP (neutral endoproteinase) antibodies cause alloimmune MN in babies of NEP deficient mothers. Subsequently, in 2009, anti PLA2R antibodies (mostly IgG4) were found to be present in about 70% of patient with PMN by Beck et al.
As for secondary MN, antigen gets deposited on the podocyte, followed by antibody deposition. Another proposed mechanism is the deposition of circulating immune complexes in the serum on the basolateral surface of podocytes. These antigen-antibody complexes cause activation of membrane attack complex C5b-9 which results in oxidative damage and DNA injury to podocyte causing damage to the actin cytoskeleton. Actin cytoskeleton collapse and loss of GBM adhesion cause proteinuria.
Four stages of the disease process have been identified on the microscopic evaluation. In the early stages of the disease (Stage I) the thickness and architecture of GBM and podocyte under light microscopy are normal with no GBM thickening. Under electron microscopy, the sub-epithelial deposits are seen confluent to specific locations and are not widespread. As the disease advance (stages II and III), GBM extends around the deposits, eventually encircling immune globulin deposits. Periodic acid-Schiff (PAS) stain under light microscopy shows the thickening of the GBM and Silver methenamine stain shows characteristic spike-like formations. In stage IV, Immune complex deposits are incorporated in the GBM. At this stage, the thickness of GBM is more appreciated than spikes.
Immunofluorescence microscopy shows a granular pattern with IgG and c3 staining. For primary MN, the predominance of IgG4 is seen, as compared to secondary MN where IgG1 predominates. Other features of primary MN include absence or negativity of IgA, IgM, C1q, all of which could be present with secondary MN.
History and Physical
Although rare, children suspected of MN should be inquired about the familial cases. Up to 25% of the patients could be asymptomatic. At diagnosis, only up to 20% patients with MN manifest hypertension. Clinical manifestation of heavy proteinuria can also be seen with edema and anasarca. Hyperlipidemia due to nephrotic range proteinuria increases cardiovascular risk and thromboembolic events. Hence, attention must be given to the cardiovascular examination (carotids and peripheral pulses for example).
Besides the thorough history and physical exam, urinalysis for the evaluation of proteinuria and hematuria is important. Up to 80% of patients with MN present with nephrotic range proteinuria with preserved renal function. RBC casts are rare but microscopic hematuria is common (up to 40%). Laboratory and radiographic evaluation should be performed to rule out secondary causes which include but not limited to checking HIV, Hepatitis panel, ANA, Anti-DS DNA, ANCA, RF, c3, c4 and serum cholesterol levels. Despite the evidence of complement activation at the GBM level, serum complements are within normal limits. Anti-PLA2R antibody and anti-THSD7A antibody assay can be performed for presumed primary MN. Imaging includes chest x-ray, renal venous dopplers and possible renal biopsy for unexplained proteinuria. Age-related cancer screening should be performed in every patient suspected of MN.
Treatment / Management
Traditionally, initial supportive care which includes controlling the blood pressure, salt restriction, ACE-I/ARB, statins, and diuretics should be provided for all patients with MN. Treatment of secondary MN should be achieved by treating the underlying cause. For patients with primary MN, the addition of immunosuppressive (IS) therapy to the supportive care is indicated for patients with progressive loss of GFR (greater than 50% in serum creatinine or a level greater than 1.5 mg/dl) or refractory proteinuria. Toronto risk score can be used to categorize patients in low (less than 4% g per day), moderate (4 to 8 g per day) and high risk (greater than 8 g per day) after 6 months of supportive care. Moderate and high-risk patients should be provided with IS therapy. Other criteria suggest starting IS therapy right away (without waiting six months) in the patient with positive serum anti-PLA2R/THSD7A antibodies and greater than 3.5 g proteinuria per day.
For IS therapy, KDIGO recommend initial 6 months of “Ponticelli Regimen” which include the alternating monthly cycle of oral/intravenous (IV) corticosteroids and oral cyclophosphamide. For patients on whom Ponticelli Regimen cannot be applied, KDIGO recommends the use of cyclosporine or tacrolimus. Monotherapy with corticosteroids and MMF is not recommended for initial therapy. Rituximab has been used in patients resistant to cytotoxic drugs and calcineurin inhibitors and has been showen to be safe and more efficacious compared to the conventional treatment.
Nephrotic range proteinuria is the initial manifestation of other diseases like minimal change diseases, FSGS, MPGN, amyloidosis, light-chain deposition disease, lupus nephritis and diabetic nephropathy.
Up to 35% of the patients with primary MN undergo spontaneous remission. High likelihood of spontaneous remission is associated with female gender and non-nephrotic range proteinuria. About 50% of the patient with persistent high-grade proteinuria eventually progress to ESRD.
Pearls and Other Issues
Renal transplant is effective in the 10% to 20% of patients who do develop end-stage renal disease (ESRD). The disease may recur in up to 50% of the patients. Within few days, sub-epithelial deposits can appear in the allograft. For primary MN patients, delaying transplantation until antibodies are no longer detected is preferred. Treatment for recurrent MN in transplant patients is usually considered only when protein excretion exceeds 1 g per day.
Enhancing Healthcare Team Outcomes
MN is best managed by an interprofessional team that includes dialysis nurses. Traditionally, initial supportive care which includes controlling the blood pressure, salt restriction, ACE-I/ARB, statins, and diuretics should be provided for all patients with MN. Treatment of secondary MN should be achieved by treating the underlying cause. For patients with primary MN, clinicians should be aware that the addition of immunosuppressive (IS) therapy to the supportive care is indicated for patients with progressive loss of GFR (greater than 50% in serum creatinine or a level greater than 1.5 mg/dl) or refractory proteinuria. The Toronto risk score can be used to categorize patients in low (less than 4% g per day), moderate (4 to 8 g per day) and high risk (greater than 8 g per day) after 6 months of supportive care. Moderate and high-risk patients should be provided with IS therapy.
Unfortunately, about 10-20% of patients may not respond to treatment and may go on to develop ESRD requiring dialysis or renal transplant. Even thoose who respond to treatment, may develop recurrence.