Version May 2024
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 [1]. (See "Overview of heavy proteinuria and the nephrotic syndrome", section on 'Etiology'.)
Historically, MN was 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. Some examples of traditional secondary associations include hepatitis B antigenemia, autoimmune diseases (such as systemic lupus erythematosus [SLE]), thyroiditis, malignancies, and the use of certain drugs such as nonsteroidal antiinflammatory drugs (NSAIDs), alpha-lipoic acid, and certain traditional medicines. 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, 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.
The clinical manifestations, pathology, and diagnosis of MN will be reviewed here. The epidemiology, pathogenesis, etiology, treatment, and prognosis of MN are presented separately:
●(See "Membranous nephropathy: Pathogenesis and etiology".)
●(See "Membranous nephropathy: Treatment and prognosis".)
CLINICAL MANIFESTATIONS
Adults — Most adult patients with MN (approximately 80 percent) present with the nephrotic syndrome; the remainder are diagnosed following an evaluation for asymptomatic proteinuria. Marked proteinuria in the absence of hypoalbuminemia is seldom seen, in contrast with secondary focal segmental glomerulosclerosis (FSGS). (See "Overview of heavy proteinuria and the nephrotic syndrome".)
Because the underlying pathology is due to the gradual accumulation of subepithelial deposits and resultant podocyte damage, the features of the nephrotic syndrome, especially weight gain and lower extremity edema, develop at a slower pace than those observed in patients with minimal change disease or primary FSGS. Thus, the precise onset of disease is less likely to be noticed by the patient or clinician.
The amount of proteinuria is highly variable, ranging from subnephrotic (less than 3.5 g/day) to more than 20 g/day. Proteinuria is typically present for several months prior to the diagnosis of MN by kidney biopsy, which highlights the more gradual development of this disease process. Other common abnormalities on urinalysis and urine microscopy include oval fat bodies, lipid droplets, and fatty casts. Microscopic hematuria occurs in up to 50 percent, but red blood cell casts are rare [2]. Glucosuria in the presence of normal blood glucose levels is common in patients with nephrotic syndrome, probably a consequence of tubular dysfunction from the heavy albuminuria.
Severe hyperlipidemia is almost always present at diagnosis in patients with the nephrotic syndrome but usually not in patients with subnephrotic proteinuria. (See "Lipid abnormalities in nephrotic syndrome".)
Approximately 70 percent of patients have normal blood pressure and glomerular filtration rate at presentation. Acute kidney injury is uncommon and may be due to hypovolemia due to aggressive diuresis, acute interstitial nephritis due to diuretics or other offending drugs, superimposed crescentic glomerulonephritis (which is associated with an active sediment), or, rarely, from acute renal vein thrombosis leading to renal infarction. (See "Acute kidney injury (AKI) in minimal change disease and other forms of nephrotic syndrome" and "Clinical manifestations and diagnosis of acute interstitial nephritis", section on 'Drugs' and "Hypercoagulability in nephrotic syndrome".)
The usual course of patients with MN is either spontaneous or treatment-induced complete or partial remission or persistent nephrotic syndrome with or without slow progression to end-stage kidney disease (figure 1). The prognosis of MN is discussed separately. (See "Membranous nephropathy: Treatment and prognosis", section on 'Prognosis'.)
Patients with subnephrotic proteinuria have a benign long-term prognosis as long as they remain subnephrotic. However, these patients require long-term monitoring of protein excretion since many progress to nephrotic-range proteinuria, with its associated higher rate of progressive disease. The rationale for prolonged monitoring was provided by a review of 395 patients with MN, 108 (27 percent) of whom presented with subnephrotic proteinuria (less than 3.5 g/day) [3]. Among these patients, 66 (61 percent) progressed to nephrotic syndrome, 20 after the first year of follow-up, including nine after more than four years. (See "Membranous nephropathy: Treatment and prognosis", section on 'Low risk of progression'.)
Children — MN is an uncommon cause of nephrotic syndrome in children, and studies on the clinical features of pediatric MN are limited [4-6]. In general, children and adolescents with MN have a clinical presentation that is similar to that in adults with MN. The majority of patients present with nephrotic-range proteinuria and preserved kidney function; approximately two-thirds of patients have the nephrotic syndrome [4,5]. Microscopic hematuria can be seen in 30 to 60 percent [4,5]. In contrast with MN in adults, which has a male predominance, MN in children and adolescents appears to affect males and females equally.
PATHOLOGY
Characteristic histologic features — The characteristic histologic features of MN are described below. These findings are seen in both primary and secondary MN although there are certain histologic clues that are suggestive of secondary MN. (See 'Features distinguishing primary and secondary MN' below.)
●Light microscopy – The characteristic histologic lesion on light microscopy is diffuse thickening of the glomerular basement membrane (GBM) throughout all glomeruli in the absence of significant hypercellularity (picture 1A-E) [1]. However, the glomeruli may appear entirely normal by light microscopy in early cases of MN, and "spikes" of GBM extending between the immune deposits may be seen with appropriate stains in more advanced cases. Chronic sclerosing glomerular and tubulointerstitial changes develop as the disease progresses.
●Immunofluorescence microscopy – Immunofluorescence microscopy reveals a diffuse granular pattern of immunoglobulin (Ig) G and C3 staining along the GBM.
●Electron microscopy – The hallmark lesions on electron microscopy are subepithelial electron-dense deposits on the outer aspect of the GBM, effacement of the foot processes of the overlying podocyte, and expansion of the GBM by deposition of new extracellular matrix between the deposits (which are the "spikes" seen with special stains). Mesangial deposits of immunoglobulin are infrequently seen, and subendothelial deposits are virtually never seen in primary MN. While most patients with MN have globally distributed immune deposits, a rare subset of patients has segmental immune deposits (involving 25 to 75 percent of the GBM) [7].
Expansion of the GBM occurs over time as the immune deposits separate from the basal surface of the podocytes and become incorporated into the expanded GBM as new extracellular matrix is deposited by the injured podocytes. Thus, the disease may be staged according to the extent to which the subepithelial immune deposits are surrounded by the GBM. This staging, though, bears no relationship to the severity of the proteinuria or responsiveness to treatment. (See "Mechanisms of immune injury of the glomerulus".)
Features distinguishing primary and secondary MN — The prototype for primary MN is phospholipase A2 receptor (PLA2R)-associated MN, in which an IgG4-predominant humoral response against a normal podocyte protein leads to exclusively subepithelial deposits and kidney-restricted pathology. Secondary MN occurs in response to infections, malignancies, systemic autoimmune diseases, and medications, such that elimination of the initiating process can lead to remission of the MN. The distinction between primary and secondary MN can be blurred when the target antigen and histopathology suggest primary disease, while another disease process, such as hepatitis B infection or concurrent malignancy, may raise the possibility of a secondary etiology. (See "Membranous nephropathy: Pathogenesis and etiology".)
In addition, the field of MN continues to rapidly evolve with the identification of new proteins that are enriched within the subepithelial immune deposits [8]. While some of these likely represent true glomerular antigens that are targeted in situ by circulating autoantibodies, others have been described as tissue biomarkers as no antibodies have been detected. It is not always possible to place each new MN-associated protein neatly into a primary or secondary category, and some have recommended classifying MN based upon the target antigen (or biomarker) when identified, commenting on the absence of presence of known or suspected secondary features or associations [9,10]. We will continue to use the terms primary and secondary in this topic review, referencing target antigens or biomarkers as appropriate.
Several histologic characteristics by immunofluorescence and electron microscopy have been identified that may help to distinguish between primary and secondary forms of MN (see "Membranous nephropathy: Pathogenesis and etiology", section on 'Phospholipase A2 receptor'):
●Immunofluorescence characteristics
•The subepithelial immune deposits in primary MN predominantly stain positive for IgG and C3 by immunofluorescence. The presence of additional IgA, IgM, and C1q (a "full house" pattern) suggests the presence of a secondary etiology such as class V lupus nephritis. (See "Lupus nephritis: Diagnosis and classification", section on 'Lupus membranous nephropathy (class V)'.)
•The presence of certain target antigens such as PLA2R, thrombospondin type-1 domain-containing 7A (THSD7A), or serine protease HTRA1 [11] within immune deposits in a fine, granular capillary-loop pattern by immunofluorescence or immunohistochemistry is strongly suggestive of primary MN (image 1). (See "Membranous nephropathy: Pathogenesis and etiology", section on 'Target antigens and autoantibodies'.)
•The IgG deposits in PLA2R-associated and THSD7A-associated primary MN are predominantly IgG4, whereas predominance of other IgG isotypes has been described in certain causes of secondary MN [12,13] or in certain subtypes of antigen-defined MN (neural epidermal growth factor-like 1 [NELL1]-, semaphorin 3B [Sema3B]-, protocadherin 7 [PCDH7]-associated MN) [9,14,15]. As an example, in lupus-associated MN, IgG1 and IgG3 may predominate [16,17]; by contrast, a predominance of IgG1 and IgG2 has been reported in the putative malignancy-associated MN [18].
•Tubular basement membrane staining for IgG on immunofluorescence is rare in primary MN but is common in secondary forms such as systemic lupus erythematosus (SLE). In addition, some patients develop antitubular basement membrane antibodies with tubulointerstitial nephritis [19].
•Granular GBM staining for exostosin-1 and exostosin-2, neural cell adhesion molecule 1 (NCAM1), or type III transforming growth factor beta receptor (TGFBR3) by immunostaining is suggestive of SLE or other underlying autoimmune disease [20-22]. (See "Membranous nephropathy: Pathogenesis and etiology", section on 'Other antigens'.)
●Electron microscopy characteristics
•In primary MN, electron-dense deposits on electron microscopy are typically subepithelial and intramembranous. Mesangial deposits are uncommon but can be present [23]. The presence of mesangial and subendothelial deposits is suggestive of secondary forms of MN [24-26].
•The presence of tubuloreticular structures in the glomerular endothelial cells (which are induced by interferon alpha) strongly suggests a diagnosis of lupus MN, which may present before the typical systemic and serologic manifestations of the disease. (See "Membranous nephropathy: Pathogenesis and etiology", section on 'Systemic lupus erythematosus and other autoimmune disorders'.)
•In advanced MN, substantial remodeling and thickening of the GBM may be present. In exceptional cases the immune deposits may be scanty and electron lucent.
DIAGNOSIS
When to suspect the diagnosis — MN should be suspected in all adult patients who present with features of the nephrotic syndrome, such as unexplained proteinuria, hypoalbuminemia, and edema or weight gain. MN occurs uncommonly in children, but the diagnosis may be suspected in patients with steroid-resistant nephrotic syndrome. (See "Glomerular disease: Evaluation and differential diagnosis in adults", section on 'Nephrotic syndrome (heavy proteinuria and hypoalbuminemia)' and "Steroid-resistant nephrotic syndrome in children: Etiology".)
Initial evaluation
Evaluation for secondary causes — In all patients who are suspected of having MN, we obtain a thorough history to determine if the patient has any potential secondary causes of MN, including the following (algorithm 1):
●Exposures to drugs and/or toxins associated with MN (eg, nonsteroidal antiinflammatory drugs [NSAIDs], alpha-lipoic acid, and certain mercury-containing traditional indigenous medicines [27] and skin-lightening creams) (see "Membranous nephropathy: Pathogenesis and etiology", section on 'Drugs')
●History of infections (such as hepatitis B or C or syphilis) (see "Membranous nephropathy: Pathogenesis and etiology", section on 'Infections')
●History of autoimmune diseases (such as systemic lupus erythematosus [SLE], Sjögren's disease, or autoimmune thyroiditis) (see "Membranous nephropathy: Pathogenesis and etiology", section on 'Systemic lupus erythematosus and other autoimmune disorders')
●History of malignancy (see 'Screening for malignancy' below and "Membranous nephropathy: Pathogenesis and etiology", section on 'Malignancy')
●History of monoclonal gammopathy (see "Membranous nephropathy: Pathogenesis and etiology", section on 'MN with light chain–restricted deposits' and "Membranous nephropathy: Pathogenesis and etiology", section on 'Membranous-like nephropathy with masked IgG-kappa')
We then obtain the following laboratory and radiological studies:
●Comprehensive chemistry panel including serum albumin
●Complete blood count
●Urinalysis with examination of the urinary sediment
●24-hour urine collection for protein quantification or spot urine protein-to-creatinine ratio
●Antinuclear antibodies (ANA) and, if positive, anti-double-stranded DNA (anti-dsDNA), anti-Smith, anti-Ro/SSA, and anti-La/SSB antibodies
●Tests for hepatitis B and C viruses and human immunodeficiency virus (HIV)
●Serum C3 and C4 complement levels
●In patients older than 50 years, serum free light chains (SFLCs) and serum protein electrophoresis (SPEP) with immunofixation
●Chest radiograph (or computed tomography of the chest in patients with a history of smoking or asbestos exposure)
Anti-PLA2R antibody testing — All patients with suspected MN should be tested for autoantibodies against the phospholipase A2 receptor (PLA2R), the major antigen in primary MN (algorithm 1). Commercially available tests include an indirect immunofluorescence assay (IFA) and an enzyme-linked immunosorbent assay (ELISA).
Patients with positive anti-PLA2R serology (ELISA and IFA), normal kidney function, and no evidence of secondary causes of MN or diabetes mellitus may be diagnosed with primary PLA2R-associated MN without the need for a kidney biopsy. However, a negative serological test for anti-PLA2R does not exclude a diagnosis of primary MN, as up to 20 percent of cases may be seronegative at presentation with nephrotic syndrome. (See 'Establishing the diagnosis' below.)
A discussion of the role of PLA2R in the pathogenesis of primary MN is presented elsewhere. (See "Membranous nephropathy: Pathogenesis and etiology", section on 'Phospholipase A2 receptor'.)
Diagnostic utility — The diagnostic utility of anti-PLA2R antibody testing is summarized as follows:
●Approximately 70 to 80 percent of patients presumed to have primary MN have a positive test (ELISA and/or IFA). The IFA test is slightly more sensitive than the ELISA, but both are approximately equally specific for anti-PLA2R antibody at the time of kidney biopsy diagnosis of MN. By contrast, some patients with primary MN will have a negative anti-PLA2R antibody test. This may mean that the target antigen is not PLA2R; that the target antigen is PLA2R, but the patient is in immunologic remission; or that the target antigen is PLA2R, and the patient is in the early stages of the disease with deposition of all antibody in the glomerular deposits. In addition, a small percentage of patients presumed to have secondary MN will have a positive test for anti-PLA2R antibody; some of these patients may in fact have primary MN with superimposed but unrelated infection, autoimmune disease, cancer, or medication use [28-30]. Thus, a positive test, although highly suggestive of primary MN, does not exclude the coexistence of infection, malignancy, or another associated rheumatologic or inflammatory disease. (See "Membranous nephropathy: Pathogenesis and etiology", section on 'Phospholipase A2 receptor'.)
●Nephrotic patients without MN seldom (and perhaps never) have a positive test for the anti-PLA2R antibody. We are aware of rare cases with nephrotic syndrome with a positive ELISA and a pathological diagnosis other than MN [31]. However, in such cases the anti-PLA2R IFA was negative, indicating the nonspecificity of the ELISA. Thus, a truly positive anti-PLA2R serology by ELISA and IFA essentially rules out other causes of nephrotic syndrome (such as minimal change disease or focal segmental glomerulosclerosis [FSGS]) [32,33]. In our opinion, a positive ELISA and negative IFA should raise a question about the specificity of the ELISA result and is an indication to proceed to kidney biopsy.
●Among patients with primary MN, testing for anti-PLA2R antibodies may provide additional information regarding treatment response. In one study involving 514 patients with primary MN and positive staining for PLA2R on kidney biopsy, patients with anti-PLA2R antibodies at the time of biopsy had a lower rate of complete remission (proteinuria of <0.4 g/day) at 24 months compared with those without anti-PLA2R antibodies (36 versus 61 percent) [34]. In addition, some data suggest that a falling anti-PLA2R titer indicates that an immunological remission is underway, whereas a persistently high titer is associated with a less favorable clinical course [32,34,35]. (See "Membranous nephropathy: Treatment and prognosis", section on 'Risk factors for disease progression'.)
Serial assessment of anti-PLA2R antibody titers may also be useful for monitoring the immunological activity of disease when treatment decisions are being considered. (see "Membranous nephropathy: Treatment and prognosis", section on 'Clinical utility of anti-PLA2R antibody levels')
Defining a positive result — Assessment of seropositivity for anti-PLA2R can vary depending upon the specific assay used for its detection and quantitation and upon the cutoff value that defines a positive result. There are two US Food and Drug Administration-approved commercial assays available for anti-PLA2R: a cell-based IFA and an ELISA, both of which detect total IgG against PLA2R [36]. According to manufacturer instructions, a positive signal at 1:10 in the IFA defines seropositivity. In the ELISA, a clear positive assay is represented by a titer above 20 RU/mL, whereas a titer in the 14 to 20 RU/mL range is considered borderline. Many clinical laboratories, as well as most publications in the literature, use these definitions for seropositivity.
However, several experts have suggested that ELISA titers above a much lower cutoff of 2 to 3 RU/mL may be a better level to determine seropositivity [37-40] and can increase sensitivity of the test without sacrificing specificity. Studies comparing ELISA, IFA, and Western blotting for the detection of anti-PLA2R have shown that IFA is more sensitive for the detection of anti-PLA2R than ELISA when the cutoff for positivity is >20 RU/mL [38,41]. As an example, in one study of 359 patients with primary MN, the seropositivity rate was 56 percent when an ELISA cutoff of 20 RU/mL was used, compared with 65 percent when IFA with a cutoff 1:10 was used [41]. However, the ELISA can perform as well as or better than the IFA when the cutoff is lowered to 2 RU/mL [38].
Several centers use both the ELISA and IFA to confirm seropositivity, especially when using the lower cutoff of 2 RU/mL [37]. In a cohort of 480 patients who had been tested by both methods for anti-PLA2R and had a biopsy of their native kidney, there were 110 cases in which the ELISA result was ≥2 and ≤20 RU/mL [37]. Thirty of these cases also had a positive IFA for anti-PLA2R, and all 30 (100 percent) showed MN on biopsy. However, among the 80 cases with a negative IFA, only 46 (57 percent) had evidence of MN on biopsy. Thus, we suggest that if a lower ELISA threshold is used to define seropositivity for anti-PLA2R, it should be confirmed with IFA or be used in a situation when a patient is initially known to be seropositive due to ELISA titers >20 RU/mL and is being followed with serial titers for the achievement of immunological remission (ELISA titer <2 RU/mL).
Testing for other autoantibodies — In addition to PLA2R, several other antigens or biomarkers have been identified among patients with MN. However, immunoassays for circulating antibodies are not widely available for most of these antigens, and, therefore, serological testing for these antibodies is not routinely performed in clinical practice. Anti-thrombospondin type-1 domain-containing 7A (THSD7A) and anti-neural epidermal growth factor-like 1 (NELL1) antibody testing (IFA or ELISA) may soon become more widely available. However, antibodies specific for these antigens are commercially available and can be used to stain kidney biopsy samples at specialized pathology laboratories to assess for the presence of these antigens within the immune deposits. (See 'Negative serum anti-PLA2R antibody test' below and "Membranous nephropathy: Pathogenesis and etiology", section on 'Target antigens and autoantibodies' and "Membranous nephropathy: Pathogenesis and etiology", section on 'Other antigens'.)
Establishing the diagnosis — Historically, a kidney biopsy was required to establish the diagnosis of MN; however, due to the identification of target antigens and the specificity of serologic assays for anti-PLA2R antibodies [37,42,43], we, and many clinicians, elect to begin with a serologic-based diagnostic approach (algorithm 1), particularly if there are relative contraindications to performing a biopsy. (See 'Positive serum anti-PLA2R antibody test' below and 'Negative serum anti-PLA2R antibody test' below.)
The validity of a serologic-based diagnostic approach was evaluated in a study of 838 patients who underwent serologic testing for anti-PLA2R antibodies as part of the evaluation for nephrotic syndrome or nephrotic-range proteinuria [37]. Of these patients, 132 tested positive for anti-PLA2R antibodies and had a native kidney biopsy performed; the primary diagnosis was MN in all biopsies. The following observations were noted:
●Among 60 patients who had positive anti-PLA2R antibodies, no secondary causes of MN, and preserved kidney function (estimated glomerular filtration rate [eGFR] >60 mL/min/1.73 m2), only two (3 percent) had additional biopsy findings superimposed on the diagnosis of MN (FSGS in one patient and diabetic kidney disease in one patient), but these findings did not alter management.
●Among 37 patients who had positive anti-PLA2R antibodies, no secondary causes of MN, and impaired kidney function (eGFR <60 mL/min/1.73 m2), kidney biopsy identified additional diagnostic findings in five patients (14 percent) that could have impacted management. These findings included acute interstitial nephritis, FSGS, acute tubular necrosis, crescentic glomerulonephritis, and diabetic nephropathy.
A subsequent validation study in which the diagnosis of MN was confirmed by biopsy showed that in patients with preserved eGFR and no secondary causes of MN or diabetes, a positive anti-PLA2R antibody test (>20 RU/mL by ELISA or a positive IFA) could confirm the diagnosis of MN without the need for a kidney biopsy [44]. (See 'Diagnostic utility' above.)
These results suggest that a serologic-based diagnostic approach to MN is reasonable in patients with positive anti-PLA2R serology, no evidence of secondary causes of MN or diabetes mellitus, and normal kidney function. However, further validation of this approach in prospective studies is warranted to confirm these findings and to determine impact on long-term outcomes.
Positive serum anti-PLA2R antibody test — In patients with a positive serum anti-phospholipase A2 receptor (PLA2R) antibody test, the approach depends upon whether the patient has kidney function impairment and/or evidence of secondary disease (ie, positive testing for ANA and anti-dsDNA, hepatitis B or C, or HIV; low serum complement levels; abnormal SFLCs or SPEP; or radiographic findings consistent with sarcoidosis), diabetes, or atypical features (such as red blood cell or white blood cell casts on examination of the urinary sediment) (algorithm 1):
●If the patient has normal kidney function and no evidence of secondary causes of MN, diabetes, or other atypical features, a diagnosis of primary PLA2R-associated MN can be established without the need to perform a kidney biopsy.
●If the patient has abnormal kidney function (ie, serum creatinine above the upper limit of the normal range adjusted for sex and age) or evidence of secondary causes of MN, diabetes, or other atypical features, we perform a kidney biopsy, unless contraindicated. Although such patients most likely have a diagnosis of primary PLA2R-associated MN based upon serologic testing, a biopsy is obtained to exclude secondary causes of MN and superimposed disease (eg, crescentic glomerulonephritis) and to evaluate the chronicity of kidney damage (such as the extent of glomerulosclerosis, tubular atrophy, and interstitial fibrosis). The evaluation of the kidney biopsy and subsequent approach is the same as that discussed below for patients with a negative serum anti-PLA2R antibody test. (See 'Negative serum anti-PLA2R antibody test' below.)
Negative serum anti-PLA2R antibody test — In patients with a negative serum anti-phospholipase A2 receptor (PLA2R) antibody test (ELISA and IFA), we perform a kidney biopsy, unless contraindicated, to determine the cause of proteinuria and/or nephrotic syndrome (algorithm 1). If a kidney biopsy cannot be performed (due to patient preference, lack of availability, or contraindication to biopsy), we repeat serum anti-PLA2R antibody testing in three to four months since some patients with an initially negative serum antibody test may have delayed seroconversion [45,46]. If repeat serum anti-PLA2R testing is negative, a kidney biopsy should be performed, if possible.
Demonstration of the characteristic histologic features of MN on kidney biopsy confirms the diagnosis of MN (see 'Characteristic histologic features' above). In addition to routine light microscopy, immunofluorescence, and electron microscopy, staining for PLA2R should be performed:
●Positive staining for PLA2R – Nearly all patients with positive staining for PLA2R have a diagnosis consistent with primary PLA2R-associated MN. The rare exception is in patients with positive PLA2R staining and restriction to a single light chain subtype (kappa or lambda) by immunofluorescence; such patients do not have a diagnosis of primary PLA2R-associated MN but rather a diagnosis of MN associated with monoclonal antibodies toward PLA2R. (See "Diagnosis and treatment of monoclonal gammopathy of renal significance" and "Membranous nephropathy: Pathogenesis and etiology", section on 'MN with light chain–restricted deposits'.)
●Negative staining for PLA2R – Patients with negative staining for PLA2R may have either primary or secondary MN, and further diagnostic testing may be required. This field is rapidly evolving as additional target antigens or biomarkers are being identified in cases of PLA2R-negative MN [8]. However, there are only a handful of immunoassays for circulating antibodies against these antigens, and most kidney pathologists are limited in their ability to stain the biopsy tissue for antigens other than PLA2R.
Thus, when staining for PLA2R is negative, subsequent evaluation should be tailored according to which assays are most readily available (algorithm 2). Antibodies against NELL1, THSD7A, neural cell adhesion molecule 1 (NCAM1), semaphorin 3B (Sema3B), protocadherin 7 (PCDH7), exostosin 1 and 2 (EXT1/2), serine protease HTRA1, type III transforming growth factor beta receptor (TGFBR3), and netrin G1 (NTNG1) are commercially available; testing for some of these antigens is presently available in a few specialized pathology laboratories. It is important to note that in patients with de novo MN following kidney transplantation or MN associated with infections, medications, hematopoietic cell transplantation, or immunodeficiency, a known autoantigen may not be identified. Possible diagnostic approaches include the following:
•Antigen-based staining – Some centers proceed to stain the kidney biopsy sample for other more frequently encountered target antigens (such as NELL1 and THSD7A) or biomarkers (such as EXT2). Positive staining for NELL1 or THSD7A may represent primary MN, but due to an increased association with malignancy, more frequent age- and risk-appropriate screening for cancer may be indicated if MN is determined to be associated with these antigens (see 'Screening for malignancy' below). The presence of EXT2 is often associated with systemic autoimmune disease such as SLE. Specialized kidney pathology centers may be able to stain for additional antigens or perform mass spectrometry of the kidney biopsy tissue to identify the enriched antigen.
•Immunoglobulin subclass staining – Other centers will determine the relative intensities of the IgG subclasses (IgG1, 2, 3, 4) within the immune deposits by immunostaining. A predominance or codominance of IgG4 suggests primary MN and can be seen in THSD7A-, HTRA1-, PCDH7-, and NTNG1-associated MN [47]. Predominance of IgG1 is more common with NELL1-, Sema3B-, EXT1/2-, and NCAM1-associated MN. The IgG subclass pattern in TGFBR3-associated MN is variable but can lack IgG4.
Patients with negative staining of PLA2R and negative staining for IgG and its subclasses may have a diagnosis of "masked" MN. This diagnosis should be suspected when there is evidence of subepithelial deposits on electron microscopy resembling those in MN. In such patients, antigen retrieval methods (eg, pronase digestion) should be performed to determine if masked IgG deposits are present. Positive staining for serum amyloid P within the deposits may also support the diagnosis of this type of membranous-like nephropathy [48].
•Staining guided by clinical and pathologic features – Another approach is to use the patient's clinical and pathologic features to guide additional staining of the kidney biopsy:
-History of autoimmune disease – For patients with a positive ANA or history of autoimmune disease, staining for EXT1/2, TGFBR3, or NCAM1 can detect approximately 40 percent of cases of MN that are secondary to autoimmune disease or lupus membranous nephropathy. In patients with chronic inflammatory demyelinating polyneuropathy, staining for contactin 1 (CNTN1) may identify cases of CNTN1-associated MN [49]. (See "Membranous nephropathy: Pathogenesis and etiology", section on 'Systemic lupus erythematosus and other autoimmune disorders' and "Membranous nephropathy: Pathogenesis and etiology", section on 'Other antigens' and "Membranous nephropathy: Pathogenesis and etiology", section on 'Target antigens and autoantibodies'.)
-Age – MN is rare in children. Staining for Sema3B may identify approximately 10 percent of pediatric cases of MN [15]. One study demonstrated that PLA2R and EXT1/2 were the most common antigens enriched in cases of pediatric MN, whereas one-third of patients did not have an identifiable antigen [4]. PLA2R-associated MN is more often seen in adolescents and is rare in individuals under the age of 10. (See "Membranous nephropathy: Pathogenesis and etiology", section on 'Other antigens'.)
-Atypical biopsy features – Most patients with MN have diffuse and global distribution of immune deposits, which likely represents normal podocyte expression of the target protein. However, certain types of MN may exhibit a segmental pattern of immune deposits. This is most common with NELL1-associated MN [7] but can also rarely be seen with HTRA1-, EXT1/2-, NCAM1-, and TGFBR3-associated MN [8].
Lack of staining for C3 on immunofluorescence can be observed with PCDH7-associated MN [9].
•Mass spectroscopy – Mass spectroscopic analysis of the tissue deposits is an emerging alternative to immunostaining and may soon be available as a clinical test at specialized centers to determine the subtype of MN in cases that are anti-PLA2R, anti-THSD7A, and anti-NELL1 negative.
Screening for malignancy — Patients should have age- and risk-appropriate cancer screening, whether or not they are diagnosed with MN. (See "Overview of preventive care in adults", section on 'Cancer screening'.)
Some patients with MN will have an underlying malignancy, either overt or covert; however, such malignancies may not necessarily be causally related to the MN. In most patients, the cancer has already been diagnosed or is clinically apparent (overt) when the patient presents with proteinuria. Uncommonly, the diagnosis of MN precedes that of the malignancy [50]. (See "Membranous nephropathy: Pathogenesis and etiology", section on 'Malignancy'.)
Thus, patients without known cancer who are diagnosed with MN should undergo age- and risk-appropriate cancer screening, if not already performed. A diagnosis of MN should not prompt an extensive search for occult malignancy in the absence of some suggestive finding such an extensive smoking history, guaiac-positive stools, or unexplained anemia or weight loss. Although microscopic hematuria is common in MN, cystoscopy is indicated among patients with risk factors for bladder cancer. (See "Etiology and evaluation of hematuria in adults", section on 'Risk factors for malignancy' and "Overview of preventive care in adults", section on 'Cancer screening'.)
A positive test for anti-PLA2R also makes it much less likely that the patient has cancer-associated MN [29]. Patients with a positive anti-PLA2R antibody test and/or those whose kidney histology is consistent with primary MN therefore only require cancer screening at the same frequency as the general population.
However, if the anti-PLA2R antibody test is negative or the kidney histology is consistent with secondary MN and if there is no other clear cause of secondary MN, then such patients require, in our opinion, more frequent age- and risk-appropriate screening for malignancy. In one study of patients with biopsy-proven MN, a negative test for serum anti-PLA2R conferred a nearly 10-fold higher risk of malignancy [29]. Increased frequency of cancer screening should continue for a period of 5 to 10 years after the diagnosis of MN since cancers associated with MN are typically diagnosed within this time frame. (See "Overview of preventive care in adults", section on 'Cancer screening'.)
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 AND RECOMMENDATIONS
●Overview – Membranous nephropathy (MN) is among the most common causes of the nephrotic syndrome in adults without diabetes.
●Clinical manifestations – Most patients with MN present with the nephrotic syndrome, but some have only asymptomatic sub-nephrotic-range proteinuria. The serum creatinine is generally normal or near normal on initial presentation, and the majority of patients are normotensive. (See 'Clinical manifestations' above.)
●Pathology – MN is characterized pathologically by diffuse thickening of the glomerular basement membrane (GBM) on light microscopy; "spikes" on silver stain; diffuse, granular IgG and complement deposition on immunofluorescence; and subepithelial dense deposits on electron microscopy (picture 1A-E). (See 'Pathology' above.)
●Diagnosis – MN should be suspected in all adult patients who present with features of the nephrotic syndrome.
•Initial evaluation – In all patients suspected of having MN, we obtain a thorough history to assess for any potential secondary causes of MN and obtain selected laboratory and radiological studies as detailed above. All patients should be tested for autoantibodies against the phospholipase A2 receptor (PLA2R), the major antigen in primary MN. (See 'Evaluation for secondary causes' above and 'Anti-PLA2R antibody testing' above.)
•Establishing the diagnosis – Historically, a kidney biopsy was required to establish the diagnosis of MN; however, due to the identification of target antigens and the specificity of serologic assays for anti-PLA2R antibodies, many clinicians elect to begin with a serologic-based diagnostic approach, particularly if there are relative contraindications to performing a biopsy (algorithm 1 and algorithm 2). A serologic-based approach may obviate the need for a kidney biopsy in patients with positive anti-PLA2R serology, normal kidney function, no history of diabetes, and no evidence of secondary causes of MN. (See 'Establishing the diagnosis' above.)
•Screening for malignancy – Patients with MN should have age- and risk-appropriate cancer screening if it has not already been performed. The frequency of cancer screening after a diagnosis of MN depends, in part, upon whether or not the disease is primary or secondary and, if secondary, whether or not there is another clear cause of secondary MN. (See 'Screening for malignancy' above.)
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