Etiology

It is not possible to distinguish between primary and secondary membranous nephropathy (MN) based on clinical features. A diagnosis of primary MN is made if no cause can be identified. This accounts for around 80% of cases. Up to 20% of cases have an underlying etiologic cause:​​​​​​​​​​​​​​​[1][4]​​

  • Autoimmune: systemic lupus erythematosus, mixed connective tissue disease, rheumatoid arthritis, Sjogren syndrome

  • Infectious: hepatitis B and C, syphilis

  • Malignancy: solid organ carcinoma (colorectal, lung, etc.), lymphoma, or melanoma

  • Drugs: gold, captopril, lithium, penicillamine, nonsteroidal anti-inflammatory drugs (NSAIDs)

  • Other: sarcoidosis, postrenal transplant.

Pathophysiology

The Heymann nephritis model is an experimental rat model that has provided an insight into the proposed pathophysiology of membranous nephropathy (MN). In this model, megalin, the target antigen of the nephritogenic antibodies, is expressed on the surface of podocytes. First, IgG immune complexes are deposited onto the surface of the subepithelial space of the glomerular capillary wall. Next, complement factors C5b to C9 are activated. Activation of the complement system recruits inflammatory cells and allows the release of various oxidants, proteases, and cytokines that damage the glomerular basement membrane (GBM). This inflammatory cascade leads to functional and physical disruption of the GBM with podocyte effacement, which allows increased protein permeability and increased levels of protein excretion in the urine.​[5]​​

However, megalin has not been found in human podocytes or detected in subepithelial immune deposits in patients with MN where immune complexes are formed. In a subgroup of infants with prenatal MN, neutral endopeptidase has been identified as the first protein target on human podocytes of nephritogenic antibodies.​[6]​​[7]​​

It has been demonstrated that a high proportion of patients with primary MN have circulating antibodies to the M-type phospholipase A2 receptor (PLA2R), a transmembrane protein located on podocytes.[8][9]​​​ PLA2R appears to be a major antigen in the pathogenesis of primary MN in humans. In one Japanese study, nearly 10% of patients with primary MN who tested negative for antibodies against PLA2R were found to have a high prevalence of another transmembrane protein expressed on podocytes, called thrombospondin type-1 domain-containing 7A (THSD7A); therefore, THSD7A may also be involved in the pathogenesis of primary MN in humans.[10]

Classification

Etiologic classification[1]​

Idiopathic or primary membranous nephropathy (MN)

  • A diagnosis is made if no etiologic agent can be identified.

  • This accounts for around 80% of cases.

Secondary MN

  • Up to 20% of cases have an underlying cause.​​​​

  • Autoimmune causes include systemic lupus erythematosus, mixed connective tissue disease, rheumatoid arthritis, and Sjogren syndrome.

  • Infectious: hepatitis B and C, and syphilis, have been implicated.

  • Malignancy: solid organ carcinoma (colorectal, lung, etc.), lymphoma, or melanoma may underlie some cases of MN.

  • Drugs: gold, captopril, lithium, penicillamine, and nonsteroidal anti-inflammatory drugs (NSAIDs) have been suggested as etiologic agents.

  • Other possible causes are sarcoidosis and postrenal transplant.

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