AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Membranous nephropathy 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. 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.

The antigens associated with primary membranous nephropathy are not known. They may be located in the subepithelial space. 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-C9 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 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 (MCD, n=10), and focal segmental glomerulosclerosis (n=6). CD20 mRNA expression was significantly higher in MGN patients as compared to control subjects. B cell infiltration was confirmed by immunohistochemistry. These data suggest an involvement of B cells in the pathogenesis of MGN, 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.

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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

• 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): These 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

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Secondary causes of membranous nephropathy

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab 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 MN. In a study of 105 patients with idiopathic MN, 2 different groups were identified on the electron microscopic (EM) 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 EM 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

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Search for an underlying cause. Successful treatment of the underlying cause may be curative in secondary forms. Try interferon therapy in patients with hepatitis. Cyclosporine does not protect in the development of de novo or recurrent membranous nephropathy.

• 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 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

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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. 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 due to 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. Monoclonal antibodies against the B cell surface antigen CD20 have been employed to explore whether specific inhibition of B cells may help improve the outcome of idiopathic membranous nephropathy (IMN) and may avoid the adverse effects of steroids and immunosuppressants.

Drug Category: Diuretics

Used to control volume overload.

Drug Category: Hepatic 3-methylglutaryl coenzyme A reductase inhibitors

Decrease the increased cholesterol associated with nephrotic syndrome.

Drug Category: Corticosteroids

Induce remission of proteinuria.

Drug Category: Immunosuppressant agents

For remission of nephrotic syndrome.

Drug Category: Angiotensin-converting enzyme inhibitors

Control blood pressure and proteinuria.

Drug Category: Nonsteroidal anti-inflammatory drugs

Used to decrease proteinuria.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal 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

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Cameron JS. The nephrotic syndrome and its complications. Am J of Kid Dis. 1987;X:157-171. [Medline].
• Choi MJ, Eustace JA, Gimenez LF. Mycophenolate mofetil treatment for primary glomerular diseases. Kidney Int. Mar 2002;61(3):1098-114. [Medline].
• Coupes B, Brenchley PE, Short CD, Mallick NP. 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, Spargo BH. 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, Falk RJ. A review of therapeutic studies of idiopathic membranous glomerulopathy. ALYSIS. 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. 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. 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].
• Reichert LJ, Koene RA, Wetzels JF. Prognostic factors in idiopathic membranous nephropathy. Am J Kidney Dis. Jan 1998;31(1):1-11. [Medline].
• Ruggenenti P, Chiurchiu C, Brusegan V. 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. Immunosuppressive treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome. Cochrane Database Syst Rev. 2004;CD004293. [Medline].
• Yokoyama H, Yoshimoto K, Wada T. Membranous nephropathy. Nippon Rinsho. Oct 2004;62(10):1856-60. [Medline].

Article Last Updated: May 16, 2006