Membranous nephropathy (MGN) is one of the more common forms of nephrotic syndrome in the adult population. It can be idiopathic or secondary (30%). The two can be distinguished by clinical, laboratory, and histological features (see Presentation and Workup).[1]
Successful treatment of the underlying cause may be curative in secondary forms. Immunosuppressive therapy may be appropriate for selected patients with idiopathic MGN (see Treatment and Medication).[2]
Membranous nephropathy is an immunologically mediated disease in which immune complexes deposit in the subepithelial space. The antigens associated with primary membranous nephropathy are not known. They may be located in the subepithelial space. Antigen-antibody complexes can develop by the production of immune complexes in situ or by deposition. In the experimental Heymann nephritis model of membranous nephropathy, the intrinsic antigen is a glycoprotein, megalin, synthesized by the glomerular visceral epithelial cells.[3]
Neutral endopeptidase, a podocyte antigen that can digest biologically active peptides, was recently identified as the target antigen of antibodies deposited in the subepithelial space of glomeruli in a subset of patients with antenatal membranous nephropathy.[4]
M-type phospholipase A2 receptor (PLA2R) has also been identified as a major target antigen in idiopathic membranous nephropathy in adults. Circulating autoantibodies against PLA2R have been found in 70-80% of patients with idiopathic membranous nephropathy. However, these antibodies are not found in patients with secondary membranous nephropathy.[5] However,detection of PLA2R antibodies in glomeruli but not in liver parenchyma is a common finding in patients with MGN associated with autoimmune liver disease, suggesting that these autoantibodies are not exclusively detected in idiopathic membranous nephropathy.[6]
Another minor antigen recently identified is thrombospondin type-1 domain–containing 7A (THSD7A). Patients who are positive for anti-THSD7A autoantibodies represent a distinct subgroup with this disease and make up approximately 2.5 to 5% of patients with idiopathic membranous nephropathy.[7, 8]
Hoxha et al report expression of THSD7A in a gallbladder carcinoma, in a patient who developed membranous nephropathy with anti-THSD7A antibodies, and subsequently found anti-THSD7A antibodies in six other patients with membranous nephropathy and malignant tumors, suggesting that THSD7A production by malignancies is a possible mechanism for membranous nephropathy.[9]
Debiec et al reported that four of nine patients with childhood membranous nephropathy had high levels of circulating anti–bovine serum albumin antibodies and circulating cationic bovine serum albumin. Bovine serum albumin was also seen in immune deposits. It is present in cow's milk and beef protein and can escape the intestinal barrier and cause antibody formation. Its cationic nature allows binding to the anionic glomerular capillary wall with resultant immune complex formation, a parallel to experimental models. This possible environmental trigger could lead to childhood membranous nephropathy, and improvement may be found by eliminating it from the diet.[10]
Many of the antigens associated with secondary membranous nephropathy are also not known. However, hepatitis B surface antigens and hepatitis E antigens have been identified in immune deposits, as have thyroid antigens in patients with thyroiditis.
The complement membrane attack complex (C5b-9) triggers the biosynthesis of oxygen radical–producing enzymes within the glomerular epithelial cells. The finding of urinary C5b-9 has been suggested as a diagnostic test for following disease activity.
C5b-9 in sublytic quantities stimulates podocytes to produce proteases, oxidants, prostanoids, extracellular matrix components, and cytokines, including transforming growth factor-beta (TGF-beta). C5b-9 also causes alterations of the cytoskeleton that lead to an abnormal distribution of slit diaphragm protein and detachment of viable podocytes that are shed into the Bowman space. These events result in disruption of the functional integrity of the glomerular basement membrane and the protein filtration barrier of podocytes with subsequent development of massive proteinuria.
In one study, a significant increase in the production of IgG4 in the presence of IL-4 was observed in the idiopathic membranous nephropathy group. These results indicate that the altered functions of T cells to produce Th2 cytokines and the increased production of IgG4 by B cells in response to these cytokines characterize the immune response in idiopathic membranous nephropathy.
In another study, the interstitial expression of CD20 mRNA was determined in 31 MGN patients and control subjects (tumor nephrectomies [n=4]), minimal-change disease (n=10), and focal segmental glomerulosclerosis (n=6). CD20 mRNA expression was significantly higher in patients with membranous nephropathy as compared to control subjects. B cell infiltration was confirmed by immunohistochemistry. These data suggest an involvement of B cells in the pathogenesis of membranous nephropathy, possibly as antigen-presenting cells.
Biopsy reveals an underlying glomerular lesion in 25% of adults with nephrotic syndrome. However, in patients older than 60 years, the incidence rate is 35%. Recently, the frequency of focal segmental glomerulosclerosis has exceeded that of membranous nephropathy. The variability of the relative distribution of pathologic causes of nephrotic syndrome is considerable among various centers, based on population and referral pattern factors.
In the pediatric population, membranous nephropathy is rare but serious. Membranous nephropathy accounts for approximately 3% of renal biopsies. Long-term prognosis is guarded because approximately 50% of patients may have evidence of progressive kidney disease.[11]
International
The frequency is the same as in the United States, although it is influenced by the prevalence of secondary causes.
Mortality/Morbidity
The course is variable, and patients may be divided into 3 groups of approximately equal size (ie, "rule of thirds"). Patients in the first and second category die from nonrenal causes.
Spontaneous complete remission: Renal function is normal, with or without subsequent relapse.
Persistent proteinuria of variable degree: Renal function is normal or impaired but stable.
Progressive disease, eventually leading to end-stage renal disease (ESRD): The incidence rate of ESRD is 14% at 5 years, 35% at 10 years, and 41% at 15 years.
Race
See the list below:
The incidence of secondary forms may be influenced by the prevalence of hepatitis and malaria in certain areas.
No increased incidence is reported in African Americans.
Sex
See the list below:
Membranous nephropathy has a predilection for males over females, with a male-to-female ratio of 2:1.
Age
See the list below:
The peak is around the fourth and fifth decades of life.
Onset outside the usual range is more likely to be a result of secondary causes.
The overwhelming majority of patients have edema or generalized anasarca. Hypertension may be present but is not characteristic of the disease in its early stages. This is unlike most other renal diseases, which are associated with significant hypertension.
Ascites and pericardial and pleural effusions are uncommon, unless the nephrotic syndrome is severe.
Causes of membranous nephropathy can be idiopathic or secondary. Often, distinguishing between idiopathic and secondary causes is not possible based on clinical evidence alone. In secondary membranous nephropathy, such as lupus and hepatitis, concomitant mesangial or subendothelial deposits may be present. De novo membranous glomerulopathy (DNMG) can develop post transplant. This can be in the context of a donor-specific alloantibody (DSA) directed against HLA DQ7.[12]
Autoimmune diseases
Ankylosing spondylitis
Dermatomyositis
Graves disease
Hashimoto disease
Mixed connective-tissue disease
Rheumatoid arthritis
Sjögren syndrome
Systemic lupus erythematosus: Of patients with lupus nephritis, 10-20% have membranous nephropathy.
Systemic sclerosis
Infectious diseases
Enterococcal endocarditis
Filariasis
Hepatitis B: This occurs in children in endemic areas.
Hepatitis C
Hydatid cyst
Leprosy
Malaria
Schistosomiasis
Syphilis
Malignancy: This is responsible for approximately 5-10% of cases of membranous nephropathy, with the higher risk occurring in patients older than 60 years.
Carcinoma (solid organ)
Leukemia
Lymphoma
Melanoma
Drugs
Captopril
Gold
Lithium
Mercury-containing compounds
Nonsteroidal anti-inflammatory drugs (NSAIDs): They are an uncommon cause; they are usually associated with minimal-change disease.
Penicillamine
Probenecid
Miscellaneous
De novo in renal allografts: The onset is delayed compared to recurrent disease. The rate of graft loss may be as high as 50%. Recurrence is infrequent, with rates of 3-7%. This can lead to loss of the graft. Membranous nephropathy recurs in 5-10% of patients.
Diabetes (uncommon)
Kimura disease
Sarcoidosis
Sickle cell disease: This is uncommon. It usually produces focal segmental glomerulosclerosis.
Urine microscopy: Urine sediment is typically nephrotic, with oval fat bodies and fatty casts; however, in mild cases, the urinalysis may reveal proteinuria without formed elements in the sediment.
Serum creatinine
Blood urea nitrogen
Serum albumin
Proteinuria (quantitative) with a 24-hour urine collection: A ratio of spot urine protein to creatinine is easier to obtain, and the findings may be sufficient for screening purposes.
Creatinine clearance
Antinuclear antibodies
Anti–double-strand DNA, if results from antinuclear antibody testing are positive
Hepatitis B serology (if positive, DNA quantitation)
Hepatitis C (if positive, RNA quantitation)
Syphilis serology
Complement levels
Cryoglobulin, particularly if hepatitis C and/or low levels of complement are found
Lipid profile
Urinary C5b-9
Urinary beta-2 microglobulin (worse prognosis with an increased level)
Malignancy workup: An exhaustive workup for malignancy is not recommended because most cases of membranous nephropathy are not associated with cancer. However, because some increase in the rate of occult malignancy is recognized in patients with newly diagnosed membranous nephropathy, (1) ensure that age-appropriate health screening (eg, mammography, sigmoidoscopy) has been performed, and (2) investigate any clues from the initial patient history and physical examination.
Pathologic features can be observed using light microscopy, immunofluorescence microscopy, and electron microscopy.
Light microscopy: The mesangium is normal, with no hypercellularity. All glomeruli are involved. The capillary walls are thickened with patent capillary lumina. Subepithelial deposits are seen; with trichrome stain, they are shown to have spikes.
Immunofluorescence microscopy: Use strong granular capillary wall staining for immunoglobulin G (IgG), with C3 and both kappa and lambda light chains.
Electron microscopy
A considerable diversity of prognosis is seen with idiopathic membranous nephropathy. In a study of 105 patients with idiopathic membranous nephropathy, 2 different groups were identified on the electron microscopic findings. In the homogeneous type, only 1 patient developed end-stage renal failure, and earlier remission occurred in this group. With regard to secondary outcome, increased age, focal segmental glomerular sclerosis, arteriolosclerosis, and heterogeneous type of electron microscopic findings were independent risk factors.
Stage 1: Features appear normal using light microscopy, but, with electron microscopy, a few electron-dense deposits are seen along the capillary walls.
Stage 2: Numerous and larger deposits with spikes are seen.
Stage 3: New extracellular material surrounds the deposits.
Stage 4: Initial electron-dense deposits become electron-lucent, and capillary walls become thickened.
Measurement of anti-PLA2R antibodies in serum and detection of PLA2R antigen in glomerular deposits can now be done routinely. Anti-PLA2R antibodies have high specificity (close to 100%), sensitivity (70-80%), and predictive value.[13]
Search for an underlying cause. Successful treatment of the underlying cause may be curative in secondary forms. In hepatitis-associated membranous nephropathy, antivirals may be useful.
Symptomatic treatment includes the following:
A low-salt diet is key to reducing anasarca. Protein restrictions may or may not be useful in reducing the rate of progression of chronic renal failure.
Diuretics help control edema. Loop diuretics are used most often.
Treat hypertension aggressively.
Statins help treat hypercholesterolemia.
Nonsteroidal anti-inflammatory drugs (NSAIDs) can help to decrease the proteinuria; however, NSAIDs have been largely supplanted by angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). ACE inhibitors decrease proteinuria and control hypertension; use ARBs for patients intolerant of ACE inhibitors.
Routine anticoagulation is controversial. However, the risk of renal vein thrombosis and other deep vein thromboses is significant, and the clinician must be vigilant in monitoring for signs of venous thromboembolism (VTE). Once VTE is found, anticoagulation is generally continued indefinitely. In a study of membranous nephropathy, the risk of developing VTE increased 3.9-fold with a reduction in serum albumin below the threshhold of 2.8g/dL and 5.8-fold with a serum albumin of less than 2.2 g/dL.[14]
Do not treat patients with asymptomatic nonnephrotic proteinuria with immunosuppressives. Patients who are asymptomatic and nephrotic may undergo remission, particularly if they have normal renal function and an early lesion. They may also be observed.
Therapy with immunosuppressive agents (see Medication) is indicated in those patients who have the following:
Increased creatinine level at presentation
Progressive disease
Severe symptomatic nephrotic syndrome
Persistent nephrotic syndrome
Thromboembolism
Persistent nephrotic syndrome, male sex, and age older than 50 years
Increased IgG excretion, HLA-DR3+/B8+, white race, and elevation of urinary excretion of complement activation products
Corticosteroids alone are ineffective in the treatment of membranous nephropathy. Alternating months of corticosteroid therapy and oral cytotoxic therapy with cyclophosphamide or chlorambucil has shown efficacy, but should be reserved for patients who exhibit clinical features such as severe or prolonged nephrosis, renal insufficiency, infections, thromboembolic events, or hypertension.
Alternating monthly treatment with a combination of chlorambucil and steroids for 6 months has been tried with some success, especially in patients with a creatinine level of less than 1.7 mg/dL. A 20-year follow-up of such cases showed complete remission in 9 of 15 patients and partial remission in 4 of 15 patients; 2 of 15 patients did not respond. The 10-year survival rate of the treated patients was 100%, whereas that of the untreated patients was 40%.[15]
Cyclophosphamide may be safer than chlorambucil in this setting, although data on this comparison are limited.[16] The Kidney Disease Improving Global Outcomes (KDIGO) guidelines suggest using cyclophosphamide rather than chlorambucil for initial therapy. As with chlorambucil, cyclophosphamide is given in alternating months with corticosteroids over 6 months, with adjustment of the cyclophosphamide dose according to the patient's age and estimated glomerular filtration rate. The goals are to achieve both total remission and preservation of renal function.[17]
Cyclical corticosteroid/alkylating agent therapy for idiopathic membranous nephropathy (IMN) (the Ponticelli regimen) is as follows:
Month 1: IV methylprednisolone (1 g) daily for 3 doses, then oral methylprednisolone (0.5 mg/kg/d) for 27 days
Month 2: Oral chlorambucil (0.15–0.2 mg/kg/d) or oral cyclophosphamide (2 mg/kg/d) for 30 days
Month 3: Repeat month 1
Month 4: Repeat month 2
Month 5: Repeat month 1
Month 6: Repeat month 2
Monitor every 2 weeks for 2 months, then every month for 6 months, with serum creatinine, urinary protein excretion, serum albumin, and white blood cell count. If the total leukocyte count falls to less than 3500/µL, hold chlorambucil or cyclophosphamide until recovery to 44000/µL.
KDIGO guidelines suggest conservative management for at least 6 months following the completion of this regimen before labelling the case as a treatment failure.[17]
Mycophenolate mofetil has been used with some success. A comparison of mycophenolate mofetil with cyclophosphamide showed decreased proteinuria and improved renal function in most patients, but mycophenolate mofetil did not appear as effective as or better tolerated than cyclophosphamide.[18] Although not recommended as initial therapy, it can be used in those patients who wish to avoid the toxicity of alkylating agents and for whom there is concern about the renal toxicity of calcineurin inhibitors.
Cyclosporine is indicated in those patients in whom the above cannot be used or in patients with a high risk of progression. In controlled trials, calcineurin inhibitors (CNIs), cyclosporine, and tacrolimus have also yielded increased remission rates of nephrotic syndrome and improved renal survival. These drugs can be used for at least 6 months in patients who meet the criteria for initial therapy but who choose not to or have contraindications to cyclical corticosteroid/alkylating agent regimen.
CNIs should be discontinued in patients who do not achieve complete or partial remission after 6 months of treatment. The dosage should be reduced at intervals of 4-8 weeks to a level of about 50% of the starting dosage once remission is maintained and continued for at least 12 months. Regimens are as follows:
Cyclosporine: 3.5–5.0 mg/kg/d given orally in 2 equally divided doses 12 hours apart, with prednisone 0.15 mg/kg/d, for 6 months
Tacrolimus: 0.05–0.075 mg/kg/d given orally in 2 divided doses 12 hours apart, without prednisone, for 6–12 months; levels should be monitored
It has been suggested that patients with IMN resistant to alkylating agent/steroid–based initial therapy be treated with a CNI and that patients with IMN resistant to CNI-based initial therapy be treated with an alkylating agent/steroid–based therapy. Relapses of nephrotic syndrome in IMN should be treated by reinstitution of the same therapy that resulted in the initial remission and should be repeated only once if a 6-month cyclical corticosteroid/alkylating agent regimen was used for initial therapy.
Despite these multiple therapeutic options, some patients with compelling indications for therapy fail to respond and need alternative therapy. Rituximab (a monoclonal antibody against CD20 antigen of B lymphocytes) and corticotropin have both been used in this situation, in the hope of improving the outcome of IMN and avoiding the adverse effects of steroids and immunosuppressants.[19]
Titration of rituximab to circulating CD20 B cell counts may improve safety by avoiding hypersensitivity; it also may limit the costs of treatment while achieving similar results.[20] However, it has not been possible to precisely predict which patients will respond to rituximab.[21] In a 2012 study, monthly rituximab was used in 100 patients, with varying results. In patients with long-standing membranous nephropathy resistant to immunosuppressants, rituximab did not produce sustained complete or partial remission. Thus, treating resistant membranous nephropathy may continue to be challenging. Using rituximab as first-line therapy may not be cost effective and may expose the patient to the risk of potential adverse effects.[22]
Some rituximab-treated patients show complete or partial remission of proteinuria and reduced levels of phospholipase A(2) receptor autoantibodies. In successful cases, rituximab therapy induces prolonged remission and enables discontinuation of other medications without substantially increasing the risk of infections and other serious adverse events.[23]
In the Membranous Nephropathy Trial of Rituximab (MENTOR) study, rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission up to 24 months.[24] In MENTOR,130 patients with proteinuria of more than 5 g, creatinine clearance of more than 40 ml/min, and renin-angiotensin system (RAS) blocker use for at least 3 months were randomized to rituximab or cyclosporine. At 12 months, rates of complete or partial remission were 60% in the rituximab group, compared with 52% in the cyclosporine group. The difference became more pronounced at 24 months, with 60% of patients treated with rituximab reaching the primary composite endpoint compared with 20% of those who received cyclosporine.
Corticotropin requires further study, as its mechanism of action remains unclear. It has some place in the treatment of those patients that have severe and resistant membranous nephropathy.[25]
In secondary membranous nephropathy associated with hepatitis B, in addition to int erferon, lamivudine monotherapy may induce and maintain complete remission.[26]
In patients with IMN, histology findings including interstitial fibrosis, tubular atrophy, and vascular sclerosis have been associated with the risk of renal failure, but it remains uncertain whether they are independent of the clinical variables at the time of biopsy, predict rate of progression, or should guide therapy. Although these histologic features were associated with a reduced renal survival rate, they did not predict this outcome independently of the baseline clinical variables, nor did they correlate with the rate of decline in function.[27]
Clinical Context:
Used for remission of nephrotic syndrome. Interferes with normal function of DNA by alkylation and cross-linking the strands of DNA and by possible protein modification.
Clinical Context:
For remission of proteinuria; given with prednisone (0.5 mg/kg/d) every other month. Steroids are given as 1 g methylprednisolone IV for 3 d. Interferes with DNA replication and RNA transcription by alkylation and cross-linking the strands of DNA
Clinical Context:
Inhibition of ACE leads to decreased plasma angiotensin II, which, in turn, leads to decreased vasopressor activity and decreased aldosterone secretion. ACE inhibitors minimize secondary intraglomerular hypertension and hypertrophy, leading to decreased proteinuria in idiopathic membranous nephropathy.
Clinical Context:
Exerts its effects by inhibiting both constitutive and inducible isoforms of cyclooxygenase, which produces a mild-to-moderate anti-inflammatory and analgesic effect. NSAIDs decrease intraglomerular pressure and decrease proteinuria.
Clinical Context:
For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which is responsible for prostaglandin synthesis.
Clinical Context:
For relief of mild to moderate pain and inflammation.
Small doses are initially indicated in small and elderly patients and in those with renal or liver disease. Doses >75 mg do not increase therapeutic effects. Administer high doses with caution and closely observe patient for response.
Most complications are associated with heavy proteinuria.
Serositis is a possible complication.
Hypovolemia, with the possibility of acute renal failure, may occur in patients who are overdiuresed. Hypovolemia exacerbates the adverse renal effects of ACE inhibitors, ARBs, and NSAIDs.
Increased incidence of infection may be present, even in patients not receiving immunosuppressives.
Hyperfibrinogenemia and erythrocytosis may lead to a hypercoagulable state, particularly renal vein thrombosis. Nephrotic syndrome may also result in loss of antithrombin III.
Lethargy and tiredness are complications.
An increased incidence of ischemic heart disease has not been proven.
Abeera Mansur, MD, Consultant Nephrologist, Doctors Hospital and Medical Center, Pakistan
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Ajay K Singh, MB, MRCP, MBA, Associate Professor of Medicine, Harvard Medical School; Director of Dialysis, Renal Division, Brigham and Women's Hospital; Director, Brigham/Falkner Dialysis Unit, Faulkner Hospital
Disclosure: Nothing to disclose.
Chief Editor
Vecihi Batuman, MD, FASN, Huberwald Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Renal Section, Southeast Louisiana Veterans Health Care System
Disclosure: Nothing to disclose.
Additional Contributors
James H Sondheimer, MD, FACP, FASN, Professor of Medicine, Division Chief, Nephrology and Hypertension, Department of Medicine, Wayne State University School of Medicine; Medical Director, DaVita Kresge Dialysis (Detroit)
[Guideline] Kidney Disease Improving Global Outcomes. KDIGO Clinical Practice Guidelines for Glomerulonephritis. Available at http://www.kdigo.org/clinical_practice_guidelines/pdf/KDIGO-GN-Guideline.pdf. Accessed: October 9, 2019.
