Membranous nephropathy: Pathogenesis and etiology

INTRODUCTION — Membranous nephropathy (MN) is among the most common causes of the nephrotic syndrome in adults without diabetes, accounting for up to one-third of biopsy diagnoses in some regions. The term MN reflects a pattern of injury found by histopathologic examination of the kidney biopsy: glomerular basement membrane (GBM) thickening and subepithelial immunoglobulin-containing deposits with little or no cellular proliferation or infiltration.

MN in adults is most often "primary" (approximately 75 to 80 percent of cases) and caused by circulating autoantibodies against podocyte antigens. In approximately 20 to 25 percent of cases in adults, the MN lesion is associated with various disorders, including infections (such as hepatitis B and syphilis); autoimmune diseases; malignancies; allogeneic hematopoietic stem cell transplantation; and the use of certain drugs such as nonsteroidal antiinflammatory drugs (NSAIDs), alpha-lipoic acid, and certain traditional medicines.

The epidemiology, pathogenesis, and etiology of MN will be reviewed here. Other aspects of MN are presented separately:

●(See "Membranous nephropathy: Clinical manifestations and diagnosis".)

●(See "Membranous nephropathy: Treatment and prognosis".)

●(See "Membranous nephropathy and kidney transplantation".)

EPIDEMIOLOGY — MN accounts for approximately 20 to 30 percent of cases of the nephrotic syndrome in White adults [1,2]. A rising incidence has been reported in China, perhaps related to environmental pollution [3]. (See 'Environmental factors' below.)

MN is seen in all ethnic and racial groups and in all sexes, but primary MN is more common in White males over the age of 40 years. MN in young females should raise the suspicion of systemic lupus erythematosus (SLE). MN is less commonly seen in children, in whom it is often associated with hepatitis B or, less commonly, autoimmune or thyroid disease [4].

PATHOGENESIS — MN is an autoimmune disease that is characterized by thickening of the glomerular basement membrane (GBM) due to subepithelial immune complex deposition. In primary MN, circulating autoantibodies bind to endogenous antigens on the surface of glomerular podocytes, activating complement and inducing podocyte injury. In secondary MN, it is thought that circulating antigens (endogenous or exogenous), immune complexes, or even monoclonal immunoglobulins may become "planted" on the subepithelial side of the GBM and initiate immune complex formation.

Target antigens and autoantibodies — The development of autoantibodies directed against endogenous or exogenous target antigens is thought to be the initial step in the pathogenesis of MN. What exactly triggers loss of immune tolerance to these antigens and autoantibody production in MN is not known. A discussion of these target antigens is presented below.

Phospholipase A2 receptor — The M-type phospholipase A2 receptor (PLA2R), a transmembrane receptor that is highly expressed in glomerular podocytes, is the major target antigen in human primary MN (up to 80 percent of cases) [5]. The specific role of PLA2R in the glomerulus is not known.

In the original description of PLA2R as a target antigen, circulating autoantibodies to PLA2R were identified in 26 of 37 (70 percent) patients with primary MN and could be associated with disease activity in patients for whom serial serum samples were available [5]. By contrast, there was no evidence of PLA2R antibodies in serum from eight patients with secondary MN due to systemic lupus erythematosus (SLE) or hepatitis B, from 15 patients with proteinuric conditions other than MN (such as diabetic kidney disease or focal segmental glomerulosclerosis), or from 30 healthy control individuals. The circulating anti-PLA2R antibodies were predominantly immunoglobulin (Ig) G4, the IgG subclass that is most abundant in the glomerular immune deposits in primary (but not secondary) MN. PLA2R colocalized with IgG4 in immune deposits of kidney tissue obtained by kidney biopsy from patients with MN, and anti-PLA2R antibodies could be eluted from this tissue. This was in contrast to the findings in secondary MN biopsies, in which there was no colocalization of IgG4 and PLA2R and from which no anti-PLA2R antibodies could be eluted.

Most if not all patients with PLA2R-associated MN have antibodies that target the N-terminal cysteine-rich region of the PLA2R protein [6-8]. The dominant epitope for anti-PLA2R has been shown to lie within the three most N-terminal domains [6,7]. As many as 80 percent of patients exhibit reactivity to epitopes within the first and seventh C-type lectin-like domains in addition to the N-terminal cysteine-rich domain (so-called epitope spreading) [9], while a smaller proportion of patients display reactivity to the eighth C-type lectin-like domain [10]. Epitope spreading may be associated with a lower spontaneous remission rate, a higher risk of chronic kidney disease, and a lower response rate to treatment with rituximab [9,11]. However, others have argued that it is the higher antibody titer associated with epitope spreading, rather than the spreading per se, that determines the outcome and response to treatment [10]. A study that finely mapped the key amino acids within the dominant epitope in the cysteine-rich domain has suggested that all the known B cell epitopes may lie on one side of the molecule, forming an immunogenic patch [12].

Approximately 70 to 80 percent of patients with primary MN have circulating anti-PLA2R antibodies [13-18], and several studies have shown that anti-PLA2R seropositivity correlates with clinical disease activity. As examples, one study found that anti-PLA2R levels strongly correlated with clinical status [15]; another reported that lower anti-PLA2R titers were associated with a higher rate of spontaneous remission [16], and in two other studies, a decline in anti-PLA2R titers predicted the clinical response to immunosuppressive therapy [18,19]. One study identified autoantibodies in the banked serum of a substantial proportion of military recruits with PLA2R-associated MN weeks to months before the onset of clinical disease and in none of the banked samples of matched controls [20]. The sensitivity and specificity of anti-PLA2R autoantibodies in individuals with immunologically active primary MN have enabled the development of a serologic immunoassay for the noninvasive diagnosis of primary MN and monitoring of disease activity. (See "Membranous nephropathy: Clinical manifestations and diagnosis", section on 'Anti-PLA2R antibody testing'.)

Staining the kidney biopsy specimen for PLA2R, either by immunofluorescence or immunohistochemistry, provides another assay by which to identify PLA2R-associated primary MN [13,21,22]. In one study that reported a relatively low sensitivity of circulating anti-PLA2R (57 percent), an additional 24 percent of patients who did not have circulating antibodies had the PLA2R antigen detected within immune deposits by immunofluorescence of the biopsy specimen [13]. This may occur as patients enter serologic remission with still unresolved proteinuria and persistent immune deposits in glomeruli. Theoretically, it could also occur in the early stages of disease as anti-PLA2R antibodies are "soaked up" in the immune deposits and have not yet reached sufficiently high levels to be detected in the serum by existing immunoassays (figure 1) [23-25]. In general, tissue staining for PLA2R may be more sensitive (69 to 84 percent in various studies) than circulating anti-PLA2R in patients with primary MN [13,21,22,26,27]. Specificity is close to 100 percent; however, PLA2R has been detected in the immune deposits of some patients with secondary MN associated with hepatitis B virus (HBV) infection, neoplasms, nonsteroidal antiinflammatory drug (NSAID) use, or sarcoidosis but not lupus nephritis (LN) [21,22,26,27]. It is possible that this represents a coincidental association, and we regard such cases as having PLA2R-associated MN.

The association of anti-PLA2R autoantibodies with disease suggests a causal role, which has now been confirmed in passive and active immunization models in experimental animals as discussed below. (See 'Mechanisms of podocyte injury' below.)

Other antigens — Several other proteins have been identified in the glomerular immune deposits of patients with MN, several of which fulfill criteria as target antigens. Each antigen-associated MN discussed below has its own characteristic features, including patient characteristics, histopathologic characteristics, and disease associations.

Many of these novel antigens have been identified by means of laser microdissection of glomeruli followed by mass spectrometry, with the premise that the antigen has accumulated in glomerular immune deposits compared with other proteins and is unique to a subset of patients with MN. Confirmation of the antigen involves immunofluorescence/immunohistochemistry studies showing granular subepithelial staining of the antigen and colocalization of the antigen with IgG along the capillary walls, elution of antigen-specific IgG from frozen biopsy material, and demonstration of circulating antibodies to the antigen in the serum. Not all of these criteria have been met for some of the reported targeted antigens listed below. The role of these antigens in the pathogenesis of MN remains unclear for most antigens.

●Thrombospondin type-1 domain-containing 7A (THSD7A) – THSD7A is, like PLA2R, a transmembrane protein expressed on podocytes [28,29]. THSD7A may be the responsible antigen in approximately 3 percent of patients with primary MN [30]. The association of THSD7A with MN was examined in a study of 154 patients with anti-PLA2R-negative primary MN, 74 patients with anti-PLA2R-positive primary MN, 76 patients with other glomerular disease, and 44 healthy controls [28]. Autoantibodies specific for THSD7A were identified in sera from 15 of 154 patients with anti-PLA2R-negative primary MN but not in the sera from other individuals. In addition, the IgG that was eluted from the kidney biopsies of 1 of these 15 patients was specific for THSD7A, providing further support that THSD7A was the target antigen in these patients. THSD7A-associated MN has been found at a low frequency in American, European, and Chinese [31,32] cohorts, but it may be more prevalent in Japanese patients with primary MN [33].

THSD7A may also be involved in the pathogenesis of some cases of malignancy-associated MN [34]. As an example, in one case report of a patient with anti-PLA2R-negative MN and concomitantly diagnosed adenoneuroendocrine carcinoma of the gallbladder, the expression of THSD7A was detected by immunohistochemistry on tumor cells but not on normal gallbladder tissue [34]. The patient also had elevated plasma levels of anti-THSD7A antibodies, which the authors proposed were formed against abnormally expressed THSD7A by tumor cells. Treatment with chemotherapy led to the disappearance of THSD7A antibodies in the plasma within two weeks and a marked reduction in proteinuria. Other studies have found a higher rate of malignancy (ranging from 20 to 50 percent) among patients with THSD7A-associated MN [35,36]. However, in one study of 31 patients with THSD7A-associated MN, only two (6 percent) had a history of malignancy, and none were diagnosed with malignancy on follow-up [37]. (See 'Malignancy' below.)

Rare cases of primary MN with dual serologic and/or tissue positivity for THSD7A and PLA2R have been reported [30,31,38]. The immunologic explanation for this finding is unknown, and the clinical features of cases with dual positivity are not different than other cases of primary MN.

●Neural epidermal growth factor-like 1 (NELL1) – NELL1 may be the antigen responsible in approximately 16 percent of cases of PLA2R-negative primary MN or 10 percent of all biopsies showing the histologic pattern of MN [39], making it the second most common antigen after PLA2R [40]. Most patients with NELL-associated MN have no underlying disease association, but up to one-third of patients may have a concurrent malignancy [41], and cases associated with a number of drugs and toxins (alpha lipoic acid [42], bucillamine [43,44], and certain traditional indigenous medications [45]) have also been reported. Circulating anti-NELL1 antibodies have been detected patients with NELL1-associated MN. A unique histopathologic feature in NELL-associated MN is the presence of a segmental pattern of immune deposits in the glomeruli [40,46]. In addition, the predominant IgG subclass within the deposits tends to be IgG1. (See 'Drugs' below.)

●Semaphorin 3B (Sema3B) – Sema3B has been identified as the target antigen in a unique form of primary MN that appears to involve mostly children (<2 years old) and young adults [47]. Among children, kidney biopsy samples also demonstrate IgG staining along tubular basement membranes although these deposits are negative for Sema3B. Circulating antibodies against Sema3B have been detected in patients with Sema3B-associated MN. The finding of Sema3B antibodies in children with nephrotic syndrome may prove to be a valuable clue to the presence of MN rather than more common causes of childhood nephrotic syndrome like minimal change disease or focal segmental glomerulosclerosis.

●Protocadherin 7 (PCDH7) – PCDH7 was identified as a distinct target antigen in a subset (14 cases) of patients with MN whose kidney biopsies were negative for all other known antigens [48]. In this cohort, the median age was 66 years, and six patients had possible secondary associations, including Sjögren's disease/SLE, sarcoidosis, and malignancy. A unique histopathologic feature may be decreased amounts of complement factor 3, as kidney biopsy revealed only trace to 1+ staining by immunofluorescence. The presence of circulating autoantibodies to PCDH7 was demonstrated, and in one case, IgG eluted from the kidney biopsy tissue was found to be reactive with PCDH7.

●Exostosin 1 and 2 (EXT1 and EXT2) – EXT1 and EXT2 have been identified as markers of MN associated with systemic autoimmune disease such as SLE or Sjögren's disease. In a study of patients with EXT1/EXT2-associated MN, 71 percent were positive for autoimmune autoantibodies and 35 percent had a clinical diagnosis of SLE [49]; kidney biopsy findings in these cases were also characteristic of systemic autoimmune disease. Positive EXT1/EXT2 staining is present in 30 to 40 percent of patients with pure class V LN (also known as lupus membranous nephropathy). Circulating antibodies to EXT1 and EXT2 have not yet been detected. The role of EXT1/EXT2 in disease pathogenesis has yet to be defined.

●Neural cell adhesion molecule 1 (NCAM1) – NCAM1 was identified as a target antigen in a subset of patients of class V LN (lupus membranous nephropathy [LMN]) or MN of identified type [50]. In this report, circulating antibodies to NCAM1 were found in several cases. The patients were predominantly young females (average age 34 years) with positive testing for antinuclear antibodies (ANA). A higher-than-expected proportion of this cohort exhibited neuropsychiatric manifestations of SLE.

●Type III transforming growth factor beta receptor (TGFBR3) – TGFBR3 was reported as a distinct biomarker in a subset of patients with class V LN [51]. In one study, 6 percent of cases of class V LN exhibited staining for TGFBR3 within the glomerular immune deposits, as opposed to none of non-LMN cases. The cohort was nearly all female, with an average age of approximately 40 years. Circulating antibodies to TGFBR3 were not detected.

●Serine protease HTRA1 – The serine protease HTRA1 represents another target antigen in a small proportion of patients with MN [52]. In one cohort of 14 cases, the average age was 67 years, and there were only two potential secondary associations: one patient had concurrent antineutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis with crescentic glomerulonephritis, and another patient had been diagnosed with stage IV small cell lung cancer two years prior to kidney biopsy, at a time when there was no proteinuria. On histopathologic examination of the larger cohort, IgG4 was the predominant IgG subclass detected within the immune deposits on kidney biopsy, and levels of circulating anti-HTRA1 antibodies (also of the IgG4 subclass) suggested a correlation with proteinuria and clinical disease activity.

●Netrin G1 (NTNG1) – NTNG1, a glycosylphosphatidylinositol-anchored membrane protein expressed in neurons and healthy podocytes, was identified as a target antigen in three patients with MN who did not have any antibodies against other antigens and did not have any other autoimmune diseases [53]. All three patients had circulating IgG4-dominant anti-NTNG1 autoantibodies, enhanced NTNG1 expression in the kidney, and glomerular IgG4 deposits.

●Protocadherin FAT1 (FAT1) – FAT1 may be a target antigen in patients with MN associated with hematopoietic cell transplantation. This is discussed in more detail elsewhere. (See "Kidney disease following hematopoietic cell transplantation", section on 'Pathology and pathogenesis'.)

●Neuron-derived neurotrophic factor (NDNF) – NDNF may be a target antigen in some cases of syphilis-associated MN [54]. In one series, patients with NDNF-associated MN had hump-like subepithelial immune deposits, with IgG1 as the predominant IgG subclass. NDNF colocalized with IgG within the immune deposits, and IgG eluted from the biopsy tissue reacted with NDNF by immunoblotting. The reason for the particular association with syphilis is not known.

●Proprotein convertase subtilisin/kexin type 6 (PCSK6) – PCSK6 may be a target antigen in some cases of MN associated with nonsteroidal antiinflammatory drug (NSAID) use [55]. In one series of 13 patients with PCSK6-associated MN, 10 patients had a history of heavy NSAID use (naproxen, ibuprofen, or meloxicam), and 5 patients had underlying autoimmune disease. (See 'Drugs' below.)

●Neutral endopeptidase (NEP) – NEP, which is expressed on podocytes, is the probable target in a rare antenatal form of MN [56-58]. The transplacental passage of anti-NEP antibodies (from mothers genetically deficient in NEP who were alloimmunized during a prior pregnancy) caused MN with subepithelial immune deposits (anti-NEP and NEP) in the fetus/neonate. Nephrotic syndrome resolved several months after birth, with disappearance of the deposits, upon clearance of the maternal antibodies. Although non–complement-fixing IgG4 was the predominant IgG subclass of anti-NEP in alloimmunized NEP-deficient mothers, the development of proteinuria in their babies correlated with the additional presence of complement-fixing IgG1 anti-NEP [57]. This finding, together with reports showing that C5b-9, the membrane attack complex, is shed into the urine of patients with recent-onset MN [59,60], provides additional evidence that the observations in Heymann nephritis are relevant to the human disease.

●Cationic bovine serum albumin – Antibodies to a cationic form of bovine serum albumin (BSA) are present in a small number of children with MN [61]. The BSA antigen, which was found within the immune deposits of biopsy specimens from these patients, is thought to be absorbed from the relatively underdeveloped pediatric intestinal tract in a partially digested or undigested form and then serve as a planted antigen within the glomerular capillary wall. Antibodies reactive with bovine, but not human, serum albumin were eluted from the kidney biopsy specimen in one case.

●Intracellular antigens – In addition to the target antigens noted above, antibodies directed against other antigens expressed by podocytes may contribute to the pathogenesis of MN [62-64]. In one study, serum IgG4 reactivity against aldose reductase, superoxide dismutase 2, and alpha-enolase, as well as the PLA2R and NEP, was measured in 186 patients with MN, 36 patients with focal glomerulosclerosis, and 60 patients with IgA nephropathy [62]. Elevated titers of IgG4 against the PLA2R, alpha-enolase, aldose reductase, and superoxide dismutase 2 were found in 60, 43, 34, and 28 percent of patients with MN, respectively, but not in patients with other glomerular diseases. Approximately one-half of the patients who were negative for antibodies against the PLA2R had an elevated titer for one of the other three antibodies. Although these antigens are predominantly intracellular and are probably not primarily responsible for MN, it has been proposed that podocyte injury causes the intracellular enzymes to translocate to the cell surface, where they are accessible to the circulating antibodies, causing amplification of the immune injury and possibly aggravating the course of the disease. A subsequent study has suggested that the presence and higher titers of antibodies to the intracellular antigens superoxide dismutase 2 or alpha-enolase were independently associated with poor clinical outcome [65].

●Other antigens – Using a mass spectrometric analysis of immune complexes removed from biopsy tissue, researchers have identified several other putative target antigens that may define rare novel subtypes of MN [66,67].

Other components of the glomerular immune deposits have been identified in patients with secondary MN [68]. These include double-stranded DNA in SLE; thyroglobulin in thyroiditis; hepatitis B antigen, treponemal antigen, and Helicobacter pylori in the relevant infections; and carcinoembryonic antigen and prostate-specific antigen in malignancy. Their pathogenicity is unproven.

Mechanisms of podocyte injury — Several experimental models have provided insight into the mechanisms of podocyte injury in MN. These models suggest that the GBM immune deposits develop in situ with the movement across the GBM of circulating IgG antibodies directed against endogenous antigens expressed on or near the podocyte foot processes or against circulating cationic or low-molecular-weight antigens that have crossed the anionic charge barrier in the GBM.

●Rat model of Heymann nephritis – The pathogenic mechanisms leading to MN have been primarily elucidated from the rat model of Heymann nephritis, which closely resembles the human disease at both the clinical and histologic level [69,70]. In Heymann nephritis, circulating antibodies target the endocytic receptor megalin (gp330) on podocyte foot processes. The resultant subepithelial immune deposits activate complement, which leads to the assembly of C5b-9, the membrane attack complex, and its insertion into the podocyte plasma membrane [71,72]. Subsequent complement-mediated podocyte injury leads to two changes:

•Proteinuria via activation of signaling pathways in the podocyte that results in redistribution of actin and loss of slit diaphragm integrity [71-73]

•GBM expansion by the overproduction of type IV collagen and laminin by the injured podocytes [74-76]

Megalin is not expressed in the human glomerulus, although other antigens have been implicated in human MN, as discussed elsewhere in this topic. (See 'Target antigens and autoantibodies' above.)

●Experimental models of PLA2R- and THSD7A-associated MN – It has been difficult to directly establish the pathogenicity of human anti-PLA2R antibodies in animal models since PLA2R is not expressed by the podocytes of rodents and other experimental animals.

•In vitro studies have shown that anti-PLA2R autoantibodies are able to induce complement-dependent injury of cultured human podocytes [77].

•In a transgenic mouse model in which murine PLA2R is expressed by the podocyte, passive administration of rabbit anti-PLA2R antibodies to these mice induces the formation of small subepithelial deposits, C3 deposition, and features of the nephrotic syndrome [78]. However, human anti-PLA2R antibodies do not react with the mouse PLA2R and cannot be utilized in this model.

•A mouse model in which human PLA2R is expressed by mouse podocytes under the control of a podocin promoter leads to heteroimmunization with development of mouse anti-human PLA2R antibodies [79]. These mice develop full-blown nephrotic syndrome and histopathologic changes of MN by six to eight weeks of age whereas immunodeficient mice that express human PLA2R do not.

•In a transgenic mouse model in which a chimeric PLA2R (chPLA2R; consisting of three domains of human PLA2R and seven domains of murine PLA2R) is expressed by podocytes, the mice do not exhibit any phenotype at birth [80]. Immunization with human PLA2R induces humoral immunity to chPLA2R, nephrotic syndrome, and histopathologic changes of MN within 8 to 12 weeks.

•Passive transfer of anti-THSD7A serum from patients with MN into mice induces features of MN including proteinuria, granular immune complexes containing human IgG, and subepithelial electron-dense deposits [81]. In addition, mice injected with rabbit antibodies against human and mouse THSD7A produces a heterologous model of MN [82]. Mice actively immunized with four domains of THSD7A that are known to be targeted by anti-THDS7A antibodies in humans develop anti-THSD7A antibodies that react with endogenous mouse THSD7A, with the subsequent formation of subepithelial deposits and proteinuria [83].

•PLA2R is expressed at the surface of the porcine podocyte and can be recognized by human anti-PLA2R. In a proof of principle study [84], human anti-PLA2R antibodies were passively transferred to a uninephrectomized minipig, which led to features typical of human MN, including histologic changes, activation of complement, and low-level proteinuria.

Genetic susceptibility — Growing evidence suggests that genetic factors may be involved in the development of MN:

●A genome-wide association study that included 75 French, 146 Dutch, and 335 British individuals identified single-nucleotide polymorphisms (SNPs) at two loci that are highly associated with primary MN [85]. The two loci are within the genes for PLA2R on chromosome 2q24, and the human leukocyte antigen (HLA) complex class II alpha chain 1A (HLA-DQA1) on chromosome 6p21. PLA2R variants have also been found in other cohorts with primary MN, although no single variant was consistently found that could explain the association with disease [86]. (See 'Phospholipase A2 receptor' above.)

When the French, Dutch, and British cohorts from the aforementioned genome-wide study were analyzed separately, the HLA-DQA1 allele was associated with disease in all three populations; the PLA2R1 allele was associated in the Dutch and British populations but not in the French, although this may have been related to the smaller sample size in the French cohort. Homozygous expression of the HLA-DQA1 allele conferred a higher risk for disease compared with the PLA2R1 allele (odds ratios of 20.2 versus 4.2, respectively). The homozygous expression of both alleles additively increased the risk of disease (odds ratio 78.5). These variants are also associated with MN in Chinese and Spanish patients [87,88]; in the Chinese population, homozygosity for the high-risk alleles was associated with a much higher prevalence of circulating anti-PLA2R than homozygosity for the low-risk alleles [87].

●Other analyses have used high-density SNPs to impute molecular HLA haplotypes or have directly sequenced the HLA region. In individuals of European ancestry, primary MN was significantly associated with all the alleles in the ancestral MHC8.1 haplotype, including HLA-DQA1*0501, HLA-DQB1*0201, and HLA-DRB1*0301 [89]. Three studies regarding genetic risk for primary MN in Asian populations have identified a separate risk haplotype that includes HLA-DRB1*1501 [90-92], indicating that genetic risk alleles within the HLA region likely differ among ethnicities. Molecular modeling in a Chinese cohort identified putative amino acids in PLA2R that might engage the binding pocket of the corresponding major histocompatibility complex (MHC) class II risk molecules [90].

●These collective findings were confirmed in a large genome-wide association study of 3782 cases of primary MN and 9038 controls of East Asian and European ancestry [93]. This study also identified two new loci that were highly associated with MN: one in NFKB1 and another in IRF4, both encoding important molecules in immune regulation. In addition, the study described an SNP in tight linkage disequilibrium to the previously identified top locus within the first intron of PLA2R1; the risk allele at this position may be linked to increased expression of PLA2R1 exclusively in kidney tissue. A detailed analysis of the HLA locus confirmed the associations with the molecular HLA haplotypes and additionally provided evidence that the major risk in both East Asian and European populations may lie exclusively in the DR-beta chain at positions that alter discrete amino acids in the binding groove.

Immune response — Several studies provide evidence for a dysregulated immune phenotype in patients with MN. As examples:

●Patients with MN have been found to have higher proportions of T helper type 17 cells and lower proportions of regulatory T cells compared with healthy individuals [94-96]. In one study, the level of regulatory T cells substantially increased in patients with a successful clinical response to rituximab [94].

●Patients with MN have been shown to have higher levels of plasma cells and regulatory B cells when compared with healthy individuals and patients with nonimmune forms of chronic kidney disease, and the percentage of circulating plasma cells correlates with levels of anti-PLA2R antibodies [97].

●Despite the noninflammatory nature of the glomerular lesion in MN, circulating levels of tumor necrosis factor alpha (TNF alpha), interleukin 6 (IL-6), and IL-17 have been found to be higher among patients with MN than in healthy individuals [98].

●Potential T cell epitopes on the PLA2R have been identified in patients with PLA2R-associated MN [99]. Of the 10 potential epitopes, three were in the N-terminal ricin (cysteine-rich) domain, and one overlapped with the B cell immunodominant epitope for anti-PLA2R. Many of the 10 epitopes were able to induce IL-6, TNF alpha, and IL-10 expression in vitro from peripheral blood cells collected from patients with MN, supporting prior evidence of elevated proinflammatory cytokine levels in MN.

Environmental factors — Environmental factors may also play a role in the pathogenesis of MN. As an example, a study from China found an association between long-term exposure to high levels of fine particulate matter of <2.5 micrometers (PM2.5) in the air and an increased risk of MN [3].

Similarly, patients with MN may be more frequently exposed to occupational toxins than the general population. In an observational study comparing the occupations and toxic occupational exposures of 100 patients with MN with those of two large cohorts of French workers without MN, patients with MN more frequently worked in the construction sector (33 versus 7 percent) and were more frequently exposed to asbestos (16 versus 5 percent), lead (9 versus 1 percent), or organic solvents (37 versus 15 percent) [100].

ETIOLOGY — MN has traditionally been classified as either primary (or "idiopathic") or secondary, depending on the absence or presence, respectively, of diseases or exposures that were associated with and felt to be causative of the MN. The discovery of the phospholipase A2 receptor (PLA2R) and, later, thrombospondin type-1 domain-containing 7A (THSD7A), two proteins expressed by the normal podocyte, established a prototype for "primary" disease in which a humoral autoimmune response against an antigen available at the basal surface of the podocyte leads to exclusively subepithelial deposits and kidney-restricted pathology. Since then, many additional autoantigens or putative antigens have been described in forms of MN that do not fully fit this prototype of primary MN, as the proteins are not expressed by the normal podocyte (eg, neural epidermal growth factor-like 1 [NELL1]) or more often occur in association with another condition. While the field is moving toward an antigen-based classification system [39], we will continue to utilize the more traditional terms of "primary" and "secondary" in this topic, with the caveat that many if not all forms of MN may have a trigger, known or unknown, that ultimately leads to the formation of autoantibodies and/or immune complexes that target the glomerulus and result in the lesion of MN.

Primary MN — Approximately 75 percent of cases of MN in adults are considered to be primary MN. Primary MN includes forms of MN in which there is a humoral autoimmune response to a normal podocyte antigen in the absence of secondary features or etiologies of disease. Antigens implicated in primary MN include PLA2R, THSD7A, NELL1, semaphorin 3B (Sema3B), the serine protease HTRA1, protocadherin 7 (PCDH7), and others. These are discussed in more detail elsewhere in this topic. (See 'Target antigens and autoantibodies' above.)

Together, the antigens identified over the past decade account for approximately 90 percent of cases of primary MN, which means that it is likely that additional minor antigens will be added to the list in the future.

Secondary MN — Secondary MN has been attributed to a variety of agents or conditions (table 1), largely due to observations that removal of the inciting agent or treatment of the condition led to resolution of the nephrotic syndrome. These are discussed below.

Systemic lupus erythematosus and other autoimmune disorders

●Systemic lupus erythematosus – Approximately 10 to 20 percent of patients with lupus nephritis (LN) have MN, called class V LN (also called lupus membranous nephropathy [LMN]). (See "Lupus nephritis: Diagnosis and classification".)

Some patients with LMN present only with kidney disease and have no symptoms or serologic abnormalities suggestive of systemic lupus erythematosus (SLE), although such findings may arise several months after presentation with the nephrotic syndrome [101,102]. SLE should be suspected in any young female with apparently primary MN. In addition, there are some histologic findings on immunofluorescence (staining for IgG2, IgG3, IgA, IgM, and complement component C1q) and electron microscopy (subendothelial and subepithelial immune deposits and tubuloreticular structures in the glomerular endothelial cells) that are suggestive of underlying SLE [101,102]. PLA2R antibodies are typically negative in patients with class V LN. However, patients with PLA2R-associated primary MN may coincidently have a positive antinuclear antibody (ANA) if they also have SLE without kidney involvement. Additional features on biopsy, such as positive staining for PLA2R, lack of C1q staining, IgG4 predominance, exclusively subepithelial electron-dense deposits, and absence of tubular basement membrane staining will further help distinguish primary MN from class V LN. (See "Membranous nephropathy: Clinical manifestations and diagnosis", section on 'Features distinguishing primary and secondary MN'.)

Positive immunostaining for the proteins exostosin 1 (EXT1), exostosin 2 (EXT2), neural cell adhesion molecule 1 (NCAM1), or type III transforming growth factor beta receptor (TGFBR3) may help to identify patients with class V LN. These are discussed elsewhere in this topic. (See 'Other antigens' above.)

In case reports, LMN has been associated with a concurrent crescentic glomerulonephritis, a relationship that has also been described in primary MN. (See 'Crescentic glomerulonephritis' below.)

●IgG4-related disease – IgG4-related disease is an increasingly recognized systemic syndrome of unknown etiology characterized by tumor-like swelling of involved organs, a lymphoplasmacytic infiltrate enriched in IgG4-positive plasma cells, and variable degrees of fibrosis that have a characteristic "storiform" pattern. In addition, elevated serum concentrations of IgG4 are found in 60 to 70 percent of patients with IgG4-related disease. The major kidney manifestation associated with IgG4-related disease is tubulointerstitial nephritis.

However, IgG4-related disease may also be associated with MN [103-107]. This was described in nine patients with MN who also had other manifestations of IgG4-related disease (mostly pancreatitis, tubulointerstitial nephritis, or sialadenitis) [103]. Antibodies against the PLA2R, commonly present in patients with primary MN, were absent in all patients. In addition, none of the nine patients had evidence for SLE, hepatitis virus infection, or cancer.

●Other autoimmune disorders – MN has been less commonly associated with other autoimmune disorders, including Sjögren's disease [108], sarcoidosis [109-111], autoimmune thyroiditis [112-114], and ankylosing spondylitis [115-117]. (See "Kidney disease in sarcoidosis" and "Kidney disease in primary Sjögren's disease".)

Drugs — Exposure to a variety of drugs has been implicated in the development of MN, including the following [42,45,118-129]:

●Nonsteroidal antiinflammatory drugs (NSAIDs)

●Alpha lipoic acid

●Traditional indigenous medications (in India, especially those contaminated with mercury)

●Alemtuzumab

●Mercurial salts and elemental mercury

●Anti-tumor necrosis factor (anti-TNF) agents (etanercept, infliximab, or adalimumab)

●Penicillamine

●Gold salts

●Bucillamine

●Tiopronin (2-mercaptopropionylglycine)

●High-dose captopril

●Immune checkpoint inhibitors (nivolumab, pembrolizumab, tislelizumab, atezolizumab, durvalumab) [130]

The association of NSAIDs with MN was illustrated in a study of 125 patients with a biopsy diagnosis of MN [118]. Twenty-nine patients were taking an NSAID, and 13 (10 percent of the study population) fulfilled criteria for NSAID-associated MN. Many of the patients who developed MN had been treated with diclofenac, but probably any NSAID can be involved [118], including cyclooxygenase 2 inhibitors [120]. Proprotein convertase subtilisin/kexin 6 (PCSK6) may be a target antigen in patients with NSAID-associated MN. (See 'Other antigens' above and "NSAIDs: Acute kidney injury".)

The mechanisms responsible for drug-induced MN are uncertain. Human and experimental data suggest that induction of gold-specific and autoreactive T cells may lead to polyclonal B cell activation and autoantibody production in gold-induced MN [131,132]. Interestingly, it has been suggested that patients carrying the SLE-associated human leukocyte antigen (HLA) alleles DRB1*0301 (DR3) and DQA1*0501 are particularly susceptible to develop MN, as well as drug-induced lupus, after exposure to gold salts [133]. Of note, these HLA alleles have also been identified as risk alleles for primary MN in White European individuals. (See 'Genetic susceptibility' above.)

Proteinuria generally develops within the first 6 to 12 months of drug therapy but can occur as late as three to four years [134]. Discontinuation of the drug leads to resolution of the proteinuria in virtually all cases [134,135]. However, studies with penicillamine, gold, and bucillamine indicate that protein excretion may continue to rise for the first 1 to 12 months (two months on average) after the cessation of therapy [134]. The mean time to resolution of the proteinuria is 9 to 12 months although two to three years are required in some cases [122,134,135]. The prolonged time to recovery may be related, in part, to the slow rate of clearance of subepithelial immune deposits and to slow remodeling of the disorganized glomerular basement membrane (GBM) [75,136].

It should be noted that MN is not the only glomerulopathy seen with these drugs. Gold and NSAIDs can lead to minimal change disease [134], whereas penicillamine can induce an immune complex crescentic glomerulonephritis. Anti-TNF therapy has also been associated with the new onset of LN and pauci-immune necrotizing and crescentic glomerulonephritis [123].

Alpha lipoic acid, bucillamine, and certain traditional indigenous medications in India have been associated with NELL1-associated MN. (See 'Other antigens' above.)

Infections

●Hepatitis B virus – MN due to hepatitis B virus (HBV) infection primarily occurs in children in endemic areas, many of whom are asymptomatic carriers with no history of active hepatitis [4,137-139]. The serum transaminases tend to be normal or only mildly elevated, and the serology is positive for HBV surface antigen, anti-core antibody, and usually e antigen. It appears that it is the e antigen and cationic anti-e antibody that are primarily deposited in the glomeruli [4,101,138].

HBV infection and SLE represent the only forms of MN that may be associated with hypocomplementemia [137].

Spontaneous resolution of the proteinuria is common in children with MN associated with HBV infection but not in adults, many of whom will have progressive disease [138]. (See "Kidney disease associated with hepatitis B virus infection".)

There is strong epidemiological and clinical evidence that HBV infection is responsible for secondary MN, especially in children:

•The prevalence of childhood MN closely parallels the geographic distribution of HBV.

•The frequency of HBV and MN in children with nephrotic syndrome in Taiwan declined from approximately 12 percent to less than 1 percent over a 20-year period following a universal vaccination program between 1984 and 2009 [140], and similar results were reported in China and South Africa.

•Antiviral therapy induces remission of proteinuria, especially in children and in individuals without advanced disease [141].

Most, but not all, studies have shown a low prevalence of anti-PLA2R antibodies and/or PLA2R staining of the immune deposits in hepatitis B-associated MN [5,14]. However, one retrospective study of 39 cases of hepatitis B-associated MN found that 64 percent of cases exhibited strong PLA2R staining of immune deposits [142]. Staining for the hepatitis B surface antigen colocalized with PLA2R within the deposits. Among the six cases for which serum was available, all were positive for anti-PLA2R antibodies.

In a series of 16 patients with MN and HBV infection, none of the patients who were positive for anti-PLA2R antibodies entered remission with antiviral therapy, whereas all of those who were negative for anti-PLA2R antibodies achieved complete remission with antiviral therapy alone [14].

The association between hepatitis B infection and PLA2R-positive MN is likely to be coincidental in most cases given the high prevalence of hepatitis B infection in certain populations [14].

●Hepatitis C virus – MN may also be uncommonly associated with chronic hepatitis C virus infection [143]. This is discussed separately. (See "Overview of kidney disease associated with hepatitis C virus infection".)

●Syphilis – Congenital and secondary syphilis have been associated with MN [144-149]. Treponemal antigens have been identified in the glomeruli by immunofluorescence microscopy, and eluates from glomerular deposits contain antibodies specific for Treponema pallidum antigen [145,146,148]. Furthermore, effective treatment of syphilis can lead to resolution of the glomerular disease [145,147-149]. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Clinical manifestations'.)

Neuron-derived neurotrophic factor (NDNF) is a target antigen in some cases of syphilis-associated MN. (See 'Other antigens' above.)

●Less common infections – MN has also been infrequently reported in association with hepatosplenic schistosomiasis, quartan malaria, and leprosy [150-154]. (See "Schistosomiasis and glomerular disease".)

Malignancy — Up to 5 to 20 percent of adults with MN, particularly those over the age of 65 years, have been reported to have a malignancy, most commonly a solid tumor (principally carcinoma of the prostate, lung, breast, bladder, or gastrointestinal tract) and, less frequently, a hematologic malignancy, such as chronic lymphocytic leukemia [144,155-161].

Based upon the population examined, the risk of malignancy among those with MN can vary from 2 to 12 times higher than that observed in the general population after adjustment for age and sex [159,160]. The malignancy is presumed to be etiologically associated when there is a temporal relationship between the tumor and the MN, when removal of the tumor is followed by gradual remission of the proteinuria, and when recurrence of the malignancy is followed by return of the proteinuria. Ultimate proof of causality is the detection of tumor antigens in the GBM, but this is only rarely described [162-165]. There is a strong association between malignancy and NELL1-associated MN, in which up to one-third of patients may have a concurrent malignancy [41].

One proposed mechanism is that deposition of tumor antigens in the glomeruli promotes antibody deposition and complement activation, leading to epithelial cell and GBM injury, and consequent proteinuria [162]. The production of antibodies produced against tumor antigens that also recognize similar or identical molecules present on podocytes may be an alternative mechanism for malignancy-associated MN. (See 'Other antigens' above.)

Despite these reports, many other cases of malignancy-associated MN may represent coincident disease processes, rather than a direct causal relationship, for the following reasons:

●The putatively associated tumors are common in males over the age of 50 years, the same population that tends to get MN.

●Remission of the nephrotic syndrome with removal of the tumor does not necessarily imply a therapeutic response, since there is a relatively high rate of spontaneous remission in MN (figure 2).

Regardless of whether the malignancy is a causal factor or simply coincident, in many cases it has already been diagnosed or is clinically apparent at the onset of proteinuria [159]. A diagnosis of MN preceding that of malignancy is more likely in older adults [155,159]. (See "Membranous nephropathy: Clinical manifestations and diagnosis", section on 'Screening for malignancy'.)

Hematopoietic cell transplantation — Nephrotic syndrome occasionally arises in recipients of allogeneic stem cell or, less commonly, bone marrow transplants and is often temporally correlated with chronic graft-versus-host disease (GVHD).

MN is the most frequently reported underlying histology although minimal change disease is also seen. The occurrence of MN is often associated with a decrease in immunosuppression. FAT1 may be a target antigen in patients with MN associated with hematopoietic cell transplantation. (See "Clinical manifestations and diagnosis of chronic graft-versus-host disease" and "Kidney disease following hematopoietic cell transplantation", section on 'Nephrotic syndrome'.)

Enzyme replacement therapy — MN has also been documented in rare patients with hereditary enzyme deficiencies receiving enzyme replacement therapy (ERT) with recombinant human acid alglucosidase alfa (rhGAA) for lysosomal acid alpha-glucosidase deficiency (Pompe disease) and with recombinant aryl-sulfatase B (rhASB) for mucopolysaccharidosis type VI (MPS VI) [166,167]. In both cases, the recombinant enzyme was detected and colocalized with IgG in the glomerular immune deposits, and in the case of MPS VI, IgG eluted from the glomeruli was reactive with rhASB [167]. Whereas proteinuria improved in both cases with reduction or cessation of ERT, the patient with MPS VI relapsed when the lifesaving ERT was resumed and required tolerance induction therapy. Although circulating alloantibodies to porcine insulin and recombinant enzymes occur commonly, it is unclear why the "foreign" protein localizes in the glomeruli to serve as a planted antigen in such rare cases. (See "Lysosomal acid alpha-glucosidase deficiency (Pompe disease, glycogen storage disease II, acid maltase deficiency)", section on 'Treatment'.)

MN with light chain–restricted deposits — Cases of MN with light chain isotype–restricted deposits have been reported [161,168-170]. In the two largest series comprising 42 patients, a hematological malignancy was identified in approximately 25 percent of patients, few of whom had a detectable monoclonal protein in the serum or urine [161,169]. Systemic autoimmunity (two cases) and one case with hepatitis B and syphilis were also reported in one series; the remaining patients did not have a recognizable secondary etiology [161]. Immunofluorescence microscopy revealed kappa light chain restriction in 39 of 42 patients (93 percent) [161,169], and positive staining for PLA2R was reported in 7 of 27 patients (26 percent) in one series [161]. IgG1 subclass restriction was present in 70 percent of cases in which IgG subclass staining was available [161,169]. Patients with negative staining for PLA2R, positive staining for a single IgG subclass, and/or the presence of focal proliferation and/or crescents by light microscopy were more likely to have an underlying lymphoproliferative disorder [161].

In rare circumstances, circulating anti-PLA2R autoantibodies may be monoclonal in nature, representing a monoclonal gammopathy of renal significance. One report details a patient with monoclonal IgG3 kappa anti-PLA2R [168]. Clinical manifestations were similar to those in primary PLA2R-associated MN although immunofluorescence of the biopsy revealed the additional presence of C1q and restriction to kappa light chain and the IgG3 subclass. The monoclonal autoantibody was also shown to cause recurrent disease in the allograft after transplantation. (See "Diagnosis and treatment of monoclonal gammopathy of renal significance" and 'MN after kidney transplantation' below.)

Other associated conditions — MN has been infrequently reported in association with other conditions in case reports or small series, including chronic formaldehyde exposure [171] and shortly after administration of COVID-19 mRNA vaccines [172].

MN after kidney transplantation — MN may recur after kidney transplantation, especially if anti-PLA2R is positive at the time of transplantation, or it may occur de novo [173]. Alloimmunization against minor histocompatibility antigens or privately expressed donor epitopes may play a role in de novo MN [68]. Patients with de novo MN do not have PLA2R antigen deposits in glomerular capillaries and are nearly always anti-PLA2R antibody negative. (See "Membranous nephropathy and kidney transplantation".)

MN with other glomerular diseases — MN may be seen in conjunction with other glomerular diseases. These include:

●Diabetic kidney disease (see 'Diabetes mellitus' below)

●Crescentic (rapidly progressive) glomerulonephritis (see 'Crescentic glomerulonephritis' below)

●Focal segmental glomerulosclerosis (see "Focal segmental glomerulosclerosis: Clinical features and diagnosis")

●IgA nephropathy (see "IgA nephropathy: Clinical features and diagnosis", section on 'Associated conditions')

It is unclear if these disorders are causally related to MN or have developed concurrently. In addition, the mechanism may vary with the second disease. With focal segmental glomerulosclerosis, for example, the sclerotic lesions may reflect a response to injury induced by the membranous disease and/or secondary intraglomerular hypertension, rather than a separate disorder [174]. Patients with these sclerotic lesions have a much higher likelihood of progressive kidney function impairment than those with uncomplicated MN and may respond less well to treatment with immunosuppressive agents [175,176]. (See "Focal segmental glomerulosclerosis: Clinical features and diagnosis" and "Membranous nephropathy: Treatment and prognosis".)

Diabetes mellitus — MN (as well as other glomerular diseases) can occur in patients with diabetes with or without diabetic kidney disease [177,178]. In a biopsy study of 220 type 2 patients with diabetes and proteinuria, nondiabetic kidney disease was present in 37 percent of patients with heavy proteinuria (average urine protein-to-creatinine ratio of 10±7.3 g/g), and of those, 42 percent had MN [179]. In most cases, the diseases are not related, but porcine insulin may be the inciting antigen in some patients. (See 'Enzyme replacement therapy' above.)

Crescentic glomerulonephritis — MN is infrequently associated with a crescentic glomerulonephritis that in some patients may be related to antineutrophil cytoplasmic antibodies (ANCA) or, less often, anti-GBM antibodies [180-188]. This relationship has mostly been described in patients with primary MN, but there are also case reports in patients with LMN [189]. (See "Anti-GBM (Goodpasture) disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Anti-GBM disease associated with membranous nephropathy' and 'Systemic lupus erythematosus and other autoimmune disorders' above.)

Crescentic glomerulonephritis and the associated nephritic sediment can be superimposed upon preexisting MN or occur in conjunction with MN. In a report of 10 patients, for example, 9 had concurrent disease at presentation, and one developed crescentic glomerulonephritis five years after the original presentation of MN [180].

Why these disorders are associated with MN is not clear. One possibility is the coincident production of ANCA or anti-GBM antibodies and the antibody responsible for MN in an individual predisposed to autoimmune disorders. An alternative mechanism is that GBM injury induced by the membranous lesion may expose previously "unseen" antigens, leading to anti-GBM antibody production.

A study from a major kidney pathology laboratory identified 14 patients with both MN and ANCA-associated necrotizing and crescentic glomerulonephritis; both conditions were diagnosed simultaneously in most of these patients [184]. In a review of over 13,000 native kidney biopsies processed by the same laboratory, primary MN was present in 8.8 percent and ANCA-associated necrotizing and crescentic glomerulonephritis was present in 3.4 percent. Based upon these numbers, concurrent disease would have been expected by chance in 39 patients, well above the observed 14 cases. It was therefore concluded that concurrent disease represented a chance occurrence of two unrelated disease processes.

The findings were different in a retrospective review of 218 patients with MN; 10 (4.6 percent) had crescentic glomerulonephritis [180]. The incidence was much higher than would be expected for the random co-occurrence of the two disorders. ANCA were present in four of the nine patients who were tested. In one such case, the patient tested positive for both ANCA and anti-PLA2R [190].

Membranous-like nephropathy with masked IgG-kappa — A glomerulopathy has been described in 14 patients that is indistinguishable from MN by light microscopy and electron microscopy [191]. However, standard immunofluorescence microscopy was negative for the typical granular deposition of IgG. Only after the formalin-fixed tissue was digested with pronase were IgG deposits "unmasked." In addition, all IgG deposits consisted of IgG-kappa and not IgG-lambda. The etiology of this condition is unknown, but most of the 14 affected patients were young and had autoimmune phenomena such as inflammatory arthritis or hemolytic anemia. Another study found that the detection of serum amyloid P by immunostaining within the immune deposits may be a specific marker for this type of disease [192].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults".)

SUMMARY

●Epidemiology – Membranous nephropathy (MN) is a pattern of injury found to commonly underlie the nephrotic syndrome in adults without diabetes, accounting for up to one-third of biopsy findings. MN accounts for approximately 20 to 30 percent of cases of nephrotic syndrome in White adults, and a rising incidence has been reported in China, perhaps related to environmental pollution. (See 'Epidemiology' above.)

●Pathogenesis – MN is an autoimmune disorder that is characterized by thickening of the glomerular basement membrane (GBM) due to subepithelial immune complex deposition. In primary MN, circulating autoantibodies bind to endogenous antigens on the surface of glomerular podocytes, activating complement and inducing podocyte injury. In secondary MN, it is thought that circulating antigens (endogenous or exogenous), immune complexes, or even monoclonal immunoglobulins may become "planted" on the subepithelial side of the GBM and initiate immune complex formation. (See 'Pathogenesis' above.)

●Etiology

•Primary MN – Approximately 75 percent of cases of MN in adults are primary MN. Primary MN includes forms of MN in which there is a humoral autoimmune response to a normal podocyte antigen in the absence of secondary features or etiologies of disease. Antigens implicated in primary MN include the phospholipase A2 receptor (PLA2R), thrombospondin type-1 domain-containing 7A (THSD7A), neural epidermal growth factor-like 1 (NELL1), semaphorin 3B (Sema3B), the serine protease HTRA1, protocadherin 7 (PCDH7), and others. (See 'Primary MN' above.)

•Secondary MN – MN has also been associated with a variety of agents or conditions (table 1), largely due to observations that removal of the inciting agent or treatment of the condition led to resolution of the nephrotic syndrome. These include autoimmune diseases (eg, systemic lupus erythematosus [SLE]), certain drugs, infections (such as hepatitis B), malignancy, and others. (See 'Secondary MN' above.)

•MN after kidney transplantation – MN may recur after kidney transplantation, especially if anti-PLA2R is positive at the time of transplantation, or it may occur de novo. (See "Membranous nephropathy and kidney transplantation".)

•MN with other glomerular diseases – MN may also be seen in conjunction with other glomerular diseases such as diabetic kidney disease and crescentic glomerulonephritis. (See 'MN with other glomerular diseases' above.)