eMedicine Specialties > Nephrology > Glomerular Diseases

Glomerulonephritis, Membranous

Abeera Mansur, MD, Consultant Nephrologist, Doctors Hospital and Medical Center, Pakistan

Updated: Dec 16, 2008

Introduction

Background

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.

Pathophysiology

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.

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.¹

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.

Frequency

United States

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.²

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

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

Membranous nephropathy has a predilection for males over females, with a male-to-female ratio of 2:1.

Age

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.

Clinical

History

Onset is insidious.
Approximately 80% of patients describe edema.
Patients may present with nonspecific complaints of anorexia, malaise, and fatigue.
Some patients may present with asymptomatic proteinuria.

Physical

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

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 DQ7.³

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.
- Systemic mastocytosis

Differential Diagnoses

Focal Segmental Glomerulosclerosis
Glomerulonephritis, Membranoproliferative
Minimal-Change Disease

Workup

Laboratory Studies

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.

Imaging Studies

Sonogram

Procedures

Renal biopsy: Definitive diagnosis is made based on findings from a renal biopsy.

Histologic Findings

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.

Treatment

Medical Care

Search for an underlying cause. Successful treatment of the underlying cause may be curative in secondary forms.

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.
NSAIDs help to decrease the proteinuria. These 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.
Hepatic 3-methylglutaryl coenzyme A reductase inhibitors help treat hypercholesterolemia.
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 thrombosis. Once found, anticoagulation is generally continued indefinitely.
In hepatitis-associated membranous nephropathy, antivirals may be useful.
Treat hypertension aggressively.
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 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
- Tubulointerstitial changes or focal sclerosis

Surgical Care

Transplantation is indicated if the patient progresses to ESRD. Some risk of recurrence in the allograft is recognized.

Diet

Institute a low-salt diet.
Protein restrictions may or may not be useful.

Activity

Activity can be performed as tolerated.

Medication

Corticosteroids alone are ineffective in the treatment of membranous nephropathy. Additionally, cyclophosphamide and chlorambucil should be reserved for patients who exhibit clinical features, such as severe or prolonged nephrosis, renal insufficiency, or hypertension.

Alternating monthly treatment with a combination of chlorambucil and steroids for 6 months has also 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 these patients showed complete remission in 9 out of 15 patients and partial remission in 4 out of 15 patients; 2 out 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%.⁴ Cyclophosphamide can be used as an alternative, and cyclosporine is indicated in those patients in whom the above cannot be used or in patients with a high risk of progression.

One review failed to show any long-term effects of immunosuppressive treatment on patient and/or renal survival. An increased number of discontinuations were because of adverse events in the immunosuppressive treatment groups. Within the class of alkylating agents, weak evidence supports the efficacy of cyclophosphamide as compared to chlorambucil. On the other hand, cyclophosphamide had fewer adverse effects leading to patient withdrawal than chlorambucil.

Recently, 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.⁵

Tacrolimus has also been used with some success. Monoclonal antibodies against the B cell surface antigen CD20 have been used to explore whether specific inhibition of B cells may help improve the outcome of idiopathic membranous nephropathy and may avoid the adverse effects of steroids and immunosuppressants. Promising results have recently been obtained with rituximab, a monoclonal antibody against the CD20 antigen of B lymphocytes that is able to deplete these cells.⁶

Titrating rituximab to circulating CD20 B cells may improve safety by avoiding hypersensitivity; it also may limit the costs of treatment while achieving similar results.⁷ However, it has not been possible to precisely predict which patients will respond to rituximab.⁸

In secondary membranous nephropathy associated with hepatitis B, in addition to interferon, lamivudine monotherapy may induce and maintain complete remission.⁹

Histology findings in idiopathic membranous nephropathy have been associated with the risk of renal failure, but whether they are independent of the clinical variables at the time of biopsy, predict rate of progression, or should guide therapy is uncertain. 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.¹⁰

Diuretics

Used to control volume overload.

Furosemide (Lasix)

Has a potent diuretic effect because it blocks sodium reabsorption in the thick ascending loop of Henle.

Dosing

Adult

20-80 mg/d PO; not to exceed 600 mg/d

Pediatric

1-2 mg/kg/dose PO; not to exceed 6 mg/kg/dose q6h

Interactions

Alcohol and CNS depressants may exacerbate orthostatic hypotension; effects are antagonized by indomethacin; may alter salicylate and lithium levels; hearing loss may occur with concurrent administration of aminoglycoside
Potentiates therapeutic effect of other antihypertensives; avoid ethacrynic acid because of the possibility for ototoxicity; antagonizes effect of tubocurarine and potentiates the action of succinylcholine

Contraindications

Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in renal or hepatic dysfunction, diabetes, and gout; monitor electrolytes and renal profile; potassium replacement may be needed
Adverse effects may include GI upset, dizziness, vertigo, paresthesias, orthostatic hypotension, hyperglycemia, jaundice, hyperuricemia, rash, photosensitivity, tinnitus, hearing loss, interstitial nephritis, and blood dyscrasias

Hepatic 3-methylglutaryl coenzyme A reductase inhibitors

Decrease the increased cholesterol associated with nephrotic syndrome.

Simvastatin (Zocor)

Decreases intracellular cholesterol pools and increases LDL receptors, which causes a decrease in LDL-C.

Dosing

Adult

10-40 mg/d PO

Pediatric

Not established

Interactions

Rifampin and nicotinic acid may decrease effects; clofibrate, itraconazole, erythromycin, cyclosporine, and niacin increase toxicity; coadministration with niacin or erythromycin associated with rhabdomyolysis; increases toxicity of anticoagulants and levothyroxine

Contraindications

Documented hypersensitivity; active liver disease; unexplained elevation of liver enzymes

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Monitor liver function and CK; suspend if a predisposition to development of renal failure secondary to rhabdomyolysis develops
Adverse effects include elevated serum transaminase levels, GI upset, headache, rash, pruritus, myalgia, dizziness, blurred vision, and rhabdomyolysis

Atorvastatin (Lipitor)

Inhibits 3-hydroxy-3-methylglutaryl coenzyme A, which, in turn, inhibits cholesterol synthesis and increases cholesterol metabolism.

Dosing

Adult

10 mg PO qd; titrate to a maximum of 80 mg/d prn

Pediatric

Not established

Interactions

Toxicity increases when coadministered with triazole antifungals, CNS depressants, macrolide antibiotics, and mibefradil

Contraindications

Documented hypersensitivity; significant hepatic impairment

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Do not exceed daily dose; caution in patients receiving drugs which prolong QRS or Q-T interval

Corticosteroids

Induce remission of proteinuria.

Prednisone (Deltasone, Meticorten, Orasone, Sterapred)

Exerts an anti-inflammatory effect via the inhibition of inflammatory mediator gene transcription.

Dosing

Adult

1 mg/kg/d PO on alternate days from cyclophosphamide

Pediatric

2 mg/kg/d PO on alternate days from cyclophosphamide

Interactions

Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and fungal or tubercular skin infections; GI disease

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Tuberculosis, ocular herpes simplex, peptic ulcer, hypertension, osteoporosis, and diabetes
Supplement with additional steroids in physiologic stress
Avoid abrupt cessation; alternate-day, intermittent, or single-day doses at 8 am minimize adrenal suppression; monitor weight, growth, and fluid and electrolyte balance
Adverse effects include HPA axis suppression, masking of infection, glaucoma, cataracts, secondary infections, hypokalemia, hypocalcemia, hypernatremia, hypertension, psychic disorders, myopathy, osteoporosis, peptic ulcer, dermal atrophy, increased intracranial pressure, and carbohydrate intolerance

Methylprednisolone (Adlone, Medrol, Solu-Medrol)

Exerts an anti-inflammatory effect via inhibition of inflammatory mediator gene transcription.

Dosing

Adult

1 mg/kg/d PO on alternate days from cyclophosphamide

Pediatric

2 mg/kg/d PO on alternate days from cyclophosphamide

Interactions

Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels; phenobarbital, phenytoin, and rifampin may decrease levels (adjust dose); monitor patients for hypokalemia when taking concurrently with diuretics

Contraindications

Documented hypersensitivity; viral, fungal, or tubercular skin infections

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Cyclophosphamide (Cytoxan, Neosar)

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.

Dosing

Adult

1.5 mg/kg/d PO; given on alternate day from prednisone

Pediatric

2.5-3 mg/kg/d PO (not to exceed 90 d) given on alternate day from prednisone

Interactions

Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones
Chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity of cyclophosphamide; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity

Contraindications

Documented hypersensitivity; severely depressed bone marrow function, breastfeeding

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis; caution in hepatic or renal impairment, leukopenia, and thrombocytopenia; adverse effects include CHF, secondary malignancies, leukopenia, renal tubular necrosis, poor wound healing, anorexia, nausea, vomiting, alopecia, thrombocytopenia, anemia, hemorrhagic and nonhemorrhagic cystitis, gonadal suppression, interstitial pulmonary fibrosis, pigmentation changes, dermatitis, and jaundice

Chlorambucil (Leukeran)

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

Dosing

Adult

0.2 mg/kg/d PO for 5-15 wk

Pediatric

0.1-0.2 mg/kg/d PO for 5-15 wk

Interactions

Myelosuppressives and radiotherapy potentiate antineoplastic effect; antigout agents are antagonized

Contraindications

Documented hypersensitivity; previous resistance to medication

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Compromised bone marrow function or seizure disorder; monitor blood counts weekly; adverse effects include bone marrow suppression, leukemia, seizures, hyperuricemia, oral ulcerations, fever, rash, urticaria, azoospermia, amenorrhea, sterility in prepubertal and pubertal males, bronchopulmonary dysplasia, and pulmonary fibrosis; impaired immune response to vaccines possible (infection after administration of live vaccines may occur)

Immunosuppressant agents

For remission of nephrotic syndrome.

Cyclosporine A (Sandimmune)

Inhibits production and release of IL-2, leading to inhibition of IL-2–mediated activation of T lymphocytes.

Dosing

Adult

4-6 mg/kg/d PO in 2 divided doses to keep trough level at 120-200 ng/mL

Pediatric

Not established

Interactions

Carbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase toxicity; acute renal failure, rhabdomyolysis, myositis, and myalgias increase when taken concurrently with lovastatin

Contraindications

Documented hypersensitivity; uncontrolled hypertension or malignancies; do not administer concomitantly with PUVA or UVB radiation in psoriasis because may increase risk of cancer

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Nephrotoxic; can raise blood pressure; caution in glaucoma, Tourette syndrome, infections, and lymphoma; use drug levels to monitor dose; airway and other supportive measures should be available for the treatment of anaphylaxis when giving an IV dose
Adverse effects include hypertension, hirsutism, gingival hypertrophy, hypomagnesemia, hyperkalemia, tremor, seizure, headache, nephrotoxicity, nausea, vomiting, leg cramps, hepatotoxicity, hyperlipidemia, glucose intolerance, increased immunologic and infectious complications, hyperuricemia, and increased incidence of thromboembolic events

Angiotensin-converting enzyme inhibitors

Control blood pressure and proteinuria.

Lisinopril (Zestril, Prinivil)

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.

Dosing

Adult

10-40 mg PO qd

Pediatric

0.5 mg/kg/dose PO in 2-4 divided doses, not to exceed 6 mg/kg/d

Interactions

May increase digoxin, lithium, and allopurinol levels; probenecid may increase levels; coadministration with diuretics increases hypotensive effects; hypotensive effects may be enhanced when given concurrently with diuretics and NSAIDs

Contraindications

Documented hypersensitivity; ACE-associated angioedema

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in aortic stenosis; monitor renal function and WBC count; monitor for hyperkalemia
Adverse effects include hypotension, headache, dysgeusia, rash, pruritus, dizziness, fatigue, cough, proteinuria, GI upset, hyperkalemia, hyponatremia, tachycardia, dry mouth, angioedema, jaundice, somnolence, sweating, sinusitis, impotence, and agranulocytosis

Enalapril (Vasotec)

Competitive inhibitor of ACE. Reduces angiotensin II levels, decreasing aldosterone secretion.

Dosing

Adult

2.5-5 mg/d PO (increase prn)
Dosing range: 10-40 mg/d PO in 1-2 divided doses; alternatively, 1.25 mg/dose IV over 5 min q6h

Pediatric

Not established

Interactions

NSAIDs may reduce hypotensive effects; ACE inhibitors may increase digoxin, lithium, and allopurinol levels; rifampin decreases levels; probenecid may increase levels; hypotensive effects of ACE inhibitors may be enhanced when given concurrently with diuretics

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in renal impairment, valvular stenosis, or severe congestive heart failure

Nonsteroidal anti-inflammatory drugs

Used to decrease proteinuria.

Ibuprofen (Motrin, Ibuprin)

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.

Dosing

Adult

400 mg PO q4-6h, 600 mg q6h, or 800 mg q8h while symptoms persist; not to exceed 3.2 g/d

Pediatric

20-70 mg/kg/d PO divided tid/qid; start at lower end of dosing range and titrate; not to exceed 2.4 g/d

Interactions

Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; monitor PT closely (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently

Contraindications

Documented hypersensitivity; peptic ulcer disease, recent GI bleeding or perforation, renal insufficiency, or high risk of bleeding

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Category D in third trimester of pregnancy; caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in anticoagulation abnormalities or during anticoagulant therapy

Naproxen (Anaprox, Naprelan, Naprosyn)

For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which is responsible for prostaglandin synthesis.

Dosing

Adult

250-500 mg PO bid; may increase to 1.5 g/d for limited periods

Pediatric

<2 years: Not established
>2 years: 2.5 mg/kg/dose PO; not to exceed 10 mg/kg/d

Interactions

Contraindications

Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Category D in third trimester of pregnancy; acute renal insufficiency, interstitial nephritis, hyperkalemia, hyponatremia, and renal papillary necrosis may occur; patients with preexisting renal disease or compromised renal perfusion risk acute renal failure; leukopenia occurs rarely, is transient, and usually returns to normal during therapy; persistent leukopenia, granulocytopenia, or thrombocytopenia warrants further evaluation and may require discontinuation of drug

Ketoprofen (Actron, Orudis, Oruvail)

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.

Dosing

Adult

25-50 mg PO q6-8h prn; not to exceed 300 mg/d

Pediatric

<3 months: Not established
3 months to 12 years: 0.1-1 mg/kg PO q6-8h
>12 years: Administer as in adults

Interactions

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Follow-up

Further Outpatient Care

Management is on an outpatient basis, with emphasis on controlling blood pressure. Observation for signs and symptoms of renal vein thrombosis, deep vein thrombosis, and pulmonary embolism is crucial in these patients.
Renal function, proteinuria (measured by the ratio of urinary protein to creatinine), and electrolytes need to be monitored at regular intervals.
Additional monitoring is indicated for pharmacologic interventions.

Complications

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.

Prognosis

The outcome depends on the renal function at the time of diagnosis and the amount of proteinuria, ranging from remission without medication to ESRD.

Patient Education

For excellent patient education resources, visit eMedicine's Hepatitis Center and Liver, Gallbladder, and Pancreas Center. Also, see eMedicine's patient education articles Liver Transplant, Hepatitis B, Hepatitis C, and Cirrhosis.

Miscellaneous

Medicolegal Pitfalls

Factors predicting a more aggressive disease should be taken into account before starting immunosuppressive therapy. Failure to diagnose renal vein thrombosis may result in potentially lethal pulmonary embolism; on the other hand, use of anticoagulation is fraught with risks, particularly in patients with nephrotic syndrome and renal insufficiency.

Special Concerns

The threshold to rule out thromboembolic phenomenon should be low.

References

Ronco P, Debiec H. New insights into the pathogenesis of membranous glomerulonephritis. Curr Opin Nephrol Hypertens. May 2006;15(3):258-63. [Medline].
Chen A, Frank R, Vento S, et al. Idiopathic membranous nephropathy in pediatric patients: presentation, response to therapy, and long-term outcome. BMC Nephrol. Aug 6 2007;8:11. [Medline].
El Kossi M, Harmer A, Goodwin J, et al. De novo membranous nephropathy associated with donor-specific alloantibody. Clin Transplant. Jan-Feb 2008;22(1):124-7. [Medline].
Polenakovic M, Grcevska L, Dzikova S. 20 years after methylprednisolone/chlorambucil treatment in idiopathic membranous nephropathy stage II-III with nephrotic syndrome. Prilozi. Dec 2006;27(2):5-12. [Medline].
Branten AJ, du Buf-Vereijken PW, Vervloet M, et al. Mycophenolate mofetil in idiopathic membranous nephropathy: a clinical trial with comparison to a historic control group treated with cyclophosphamide. Am J Kidney Dis. Aug 2007;50(2):248-56. [Medline].
Ruggenenti P, Cravedi P, Remuzzi G. Latest treatment strategies for membranous nephropathy. Expert Opin Pharmacother. Dec 2007;8(18):3159-71. [Medline].
Cravedi P, Ruggenenti P, Sghirlanzoni MC, et al. Titrating rituximab to circulating B cells to optimize lymphocytolytic therapy in idiopathic membranous nephropathy. Clin J Am Soc Nephrol. Sep 2007;2(5):932-7. [Medline].
Fervenza FC, Cosio FG, Erickson SB, et al. Rituximab treatment of idiopathic membranous nephropathy. Kidney Int. Jan 2008;73(1):117-25. [Medline].
Chuang TW, Hung CH, Huang SC, et al. Complete remission of nephrotic syndrome of hepatitis B virus-associated membranous glomerulopathy after lamivudine monotherapy. J Formos Med Assoc. Oct 2007;106(10):869-73. [Medline].
[Best Evidence] Troyanov S, Roasio L, Pandes M, et al. Renal pathology in idiopathic membranous nephropathy: a new perspective. Kidney Int. May 2006;69(9):1641-8. [Medline].
Cameron JS. The nephrotic syndrome and its complications. Am J Kidney Dis. Sep 1987;10(3):157-71. [Medline].
Choi MJ, Eustace JA, Gimenez LF, et al. Mycophenolate mofetil treatment for primary glomerular diseases. Kidney Int. Mar 2002;61(3):1098-114. [Medline].
Coupes B, Brenchley PE, Short CD, et al. Clinical aspects of C3dg and C5b-9 in human membranous nephropathy. Nephrol Dial Transplant. 1992;7 Suppl 1:32-4. [Medline].
Cunningham PN, Quigg RJ. Contrasting roles of complement activation and its regulation in membranous nephropathy. J Am Soc Nephrol. May 2005;16(5):1214-22. [Medline].
Haas M, Meehan SM, Karrison TG, et al. Changing etiologies of unexplained adult nephrotic syndrome: a comparison of renal biopsy findings from 1976-1979 and 1995-1997. Am J Kidney Dis. Nov 1997;30(5):621-31. [Medline].
Hogan SL, Muller KE, Jennette JC, et al. A review of therapeutic studies of idiopathic membranous glomerulopathy. Am J Kidney Dis. Jun 1995;25(6):862-75. [Medline].
Honkanen E, Tornroth T, Gronhagen-Riska C. Natural history, clinical course and morphological evolution of membranous nephropathy. Nephrol Dial Transplant. 1992;7 Suppl 1:35-41. [Medline].
Hunt LP. Statistical aspects of survival in membranous nephropathy. Nephrol Dial Transplant. 1992;7 Suppl 1:53-9. [Medline].
Kuroki A, Iyoda M, Shibata T, et al. Th2 cytokines increase and stimulate B cells to produce IgG4 in idiopathic membranous nephropathy. Kidney Int. Jul 2005;68(1):302-10. [Medline].
Lin CY. Treatment of hepatitis B virus-associated membranous nephropathy with recombinant alpha-interferon. Kidney Int. Jan 1995;47(1):225-30. [Medline].
Muirhead N. Management of idiopathic membranous nephropathy: evidence-based recommendations. Kidney Int Suppl. Jun 1999;70:S47-55. [Medline].
Nangaku M, Shankland SJ, Couser WG. Cellular response to injury in membranous nephropathy. J Am Soc Nephrol. May 2005;16(5):1195-204. [Medline].
Ponticelli C, Zucchelli P, Passerini P, et al. A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy. Kidney Int. Nov 1995;48(5):1600-4. [Medline].
Reichert LJ, Koene RA, Wetzels JF. Prognostic factors in idiopathic membranous nephropathy. Am J Kidney Dis. Jan 1998;31(1):1-11. [Medline].
Reichert LJ, Koene RA, Wetzels JF. Urinary excretion of beta 2-microglobulin predicts renal outcome in patients with idiopathic membranous nephropathy. J Am Soc Nephrol. Dec 1995;6(6):1666-9. [Medline].
Ruggenenti P, Chiurchiu C, Brusegan V, et al. Rituximab in idiopathic membranous nephropathy: a one-year prospective study. J Am Soc Nephrol. Jul 2003;14(7):1851-7. [Medline].
Schieppati A, Perna A, Zamora J, et al. Immunosuppressive treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome. Cochrane Database Syst Rev. Oct 18 2004;CD004293. [Medline].
Yokoyama H, Yoshimoto K, Wada T. [Membranous nephropathy]. Nippon Rinsho. Oct 2004;62(10):1856-60. [Medline].

Keywords

membranous glomerulonephritis, membranous nephropathy, nephrotic syndrome

Contributor Information and Disclosures

Author

Abeera Mansur, MD, Consultant Nephrologist, Doctors Hospital and Medical Center, Pakistan
Abeera Mansur, MD is a member of the following medical societies: American College of Physicians and American Society of Nephrology
Disclosure: Nothing to disclose.

Medical Editor

James H Sondheimer, MD, Director of Hemodialysis Unit, Harper Hospital; Associate Professor, Department of Internal Medicine, Division of Nephrology, Wayne State University School of Medicine
James H Sondheimer, MD is a member of the following medical societies: American College of Physicians and American Society of Nephrology
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Ajay K Singh, MB, MRCP, MBA, Associate Professor of Medicine, Director of Dialysis, Department of Medicine, Harvard Medical School; Clinical Chief of Renal Division, Brigham and Women's Hospital
Disclosure: Nothing to disclose.

CME Editor

Rebecca J Schmidt, DO, FACP, FASN, Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine
Rebecca J Schmidt, DO, FACP, FASN is a member of the following medical societies: American College of Osteopathic Internists, American College of Physicians, American Medical Association, American Society of Nephrology, International Society of Nephrology, National Kidney Foundation, Renal Physicians Association, and West Virginia State Medical Association
Disclosure: Abbott Grant/research funds Speaking and teaching; Genzyme Honoraria Consulting; Roche Honoraria Consulting

Chief Editor

Vecihi Batuman, MD, FACP, FASN, Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Medicine Service, Southeast Louisiana Veterans Health Care System
Vecihi Batuman, MD, FACP, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, and International Society of Nephrology
Disclosure: Nothing to disclose.

Further Reading

eMedicine Specialties > Nephrology > Glomerular Diseases

Glomerulonephritis, Membranous

Introduction

Background

Pathophysiology

Frequency

United States

International

Mortality/Morbidity

Race

Sex

Age

Clinical

History

Physical

Causes

Differential Diagnoses

Other Problems to Be Considered

Workup

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Treatment

Medical Care

Surgical Care

Diet

Activity

Medication

Diuretics

Furosemide (Lasix)

Dosing

Adult

Pediatric

Interactions

Contraindications

Precautions

Pregnancy

Precautions

Hepatic 3-methylglutaryl coenzyme A reductase inhibitors

Simvastatin (Zocor)

Dosing

Adult

Pediatric

Interactions

Contraindications

Precautions

Pregnancy

Precautions

Atorvastatin (Lipitor)

Dosing

Adult

Pediatric

Interactions

Contraindications

Precautions

Pregnancy

Precautions

Corticosteroids

Prednisone (Deltasone, Meticorten, Orasone, Sterapred)

Dosing

Adult

Pediatric

Interactions

Contraindications

Precautions

Pregnancy

Precautions

Methylprednisolone (Adlone, Medrol, Solu-Medrol)

Dosing

Adult

Pediatric

Interactions

Contraindications

Precautions

Pregnancy

Precautions

Cyclophosphamide (Cytoxan, Neosar)

Dosing

Adult