Membranous Glomerulonephritis

Membranous Glomerulonephritis

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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.

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. [11]

International

The frequency is the same as in the United States, although it is influenced by the prevalence of secondary causes.

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.

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.

See the list below:

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

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.

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Tran TH, J Hughes G, Greenfeld C, Pham JT. Overview of current and alternative therapies for idiopathic membranous nephropathy. Pharmacotherapy. 2015 Apr. 35 (4):396-411. [Medline].

Ronco P, Debiec H. Target antigens and nephritogenic antibodies in membranous nephropathy: of rats and men. Semin Immunopathol. 2007 Nov. 29 (4):445-58. [Medline].

Ronco P, Debiec H. New insights into the pathogenesis of membranous glomerulonephritis. Curr Opin Nephrol Hypertens. 2006 May. 15(3):258-63. [Medline].

Beck LH Jr, Bonegio RG, Lambeau G, Beck DM, Powell DW, Cummins TD, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009 Jul 2. 361(1):11-21. [Medline]. [Full Text].

Dauvergne M, Moktefi A, Rabant M, et al. Membranous Nephropathy Associated With Immunological Disorder-Related Liver Disease: A Retrospective Study of 10 Cases. Medicine (Baltimore). 2015 Jul. 94 (30):e1243. [Medline]. [Full Text].

Tomas NM, Beck LH Jr, Meyer-Schwesinger C, Seitz-Polski B, Ma H, Zahner G, et al. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. N Engl J Med. 2014 Dec 11. 371 (24):2277-87. [Medline]. [Full Text].

Iwakura T, Ohashi N, Kato A, Baba S, Yasuda H. Prevalence of Enhanced Granular Expression of Thrombospondin Type-1 Domain-Containing 7A in the Glomeruli of Japanese Patients with Idiopathic Membranous Nephropathy. PLoS One. 2015. 10 (9):e0138841. [Medline]. [Full Text].

Hoxha E, Wiech T, Stahl PR, Zahner G, Tomas NM, Meyer-Schwesinger C, et al. A Mechanism for Cancer-Associated Membranous Nephropathy. N Engl J Med. 2016 May 19. 374 (20):1995-6. [Medline]. [Full Text].

Debiec H, Lefeu F, Kemper MJ, Niaudet P, Deschênes G, Remuzzi G, et al. Early-childhood membranous nephropathy due to cationic bovine serum albumin. N Engl J Med. 2011 Jun 2. 364(22):2101-10. [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. 2007 Aug 6. 8:11. [Medline].

El Kossi M, Harmer A, Goodwin J, et al. De novo membranous nephropathy associated with donor-specific alloantibody. Clin Transplant. 2008 Jan-Feb. 22(1):124-7. [Medline].

Ronco P, Debiec H. Pathophysiological advances in membranous nephropathy: time for a shift in patient’s care. Lancet. 2015 May 16. 385 (9981):1983-92. [Medline].

Lionaki S, Derebail VK, Hogan SL, Barbour S, Lee T, Hladunewich M, et al. Venous thromboembolism in patients with membranous nephropathy. Clin J Am Soc Nephrol. 2012 Jan. 7(1):43-51. [Medline]. [Full Text].

Polenakovic M, Grcevska L, Dzikova S. 20 years after methylprednisolone/chlorambucil treatment in idiopathic membranous nephropathy stage II-III with nephrotic syndrome. Prilozi. 2006 Dec. 27(2):5-12. [Medline].

Chen Y, Schieppati A, Chen X, Cai G, Zamora J, Giuliano GA, et al. Immunosuppressive treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome. Cochrane Database Syst Rev. 2014 Oct 16. CD004293. [Medline].

[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: January 6, 2014.

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. 2007 Aug. 50(2):248-56. [Medline].

Ruggenenti P, Cravedi P, Remuzzi G. Latest treatment strategies for membranous nephropathy. Expert Opin Pharmacother. 2007 Dec. 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. 2007 Sep. 2(5):932-7. [Medline].

Fervenza FC, Cosio FG, Erickson SB, et al. Rituximab treatment of idiopathic membranous nephropathy. Kidney Int. 2008 Jan. 73(1):117-25. [Medline].

Ruggenenti P, Cravedi P, Chianca A, Perna A, Ruggiero B, Gaspari F, et al. Rituximab in idiopathic membranous nephropathy. J Am Soc Nephrol. 2012 Aug. 23(8):1416-25. [Medline]. [Full Text].

Sinha A, Bagga A. Rituximab therapy in nephrotic syndrome: implications for patients’ management. Nat Rev Nephrol. 2013 Mar. 9(3):154-69. [Medline].

Hogan J, Mohan P, Appel GB. Diagnostic Tests and Treatment Options in Glomerular Disease: 2014 Update. Am J Kidney Dis. 2013 Nov 14. [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. 2007 Oct. 106(10):869-73. [Medline].

Troyanov S, Roasio L, Pandes M, et al. Renal pathology in idiopathic membranous nephropathy: a new perspective. Kidney Int. 2006 May. 69(9):1641-8. [Medline].

Choi MJ, Eustace JA, Gimenez LF, et al. Mycophenolate mofetil treatment for primary glomerular diseases. Kidney Int. 2002 Mar. 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. 2005 May. 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. 1997 Nov. 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. 1995 Jun. 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. 2005 Jul. 68(1):302-10. [Medline].

Lin CY. Treatment of hepatitis B virus-associated membranous nephropathy with recombinant alpha-interferon. Kidney Int. 1995 Jan. 47(1):225-30. [Medline].

Nangaku M, Shankland SJ, Couser WG. Cellular response to injury in membranous nephropathy. J Am Soc Nephrol. 2005 May. 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. 1995 Nov. 48(5):1600-4. [Medline].

Reichert LJ, Koene RA, Wetzels JF. Prognostic factors in idiopathic membranous nephropathy. Am J Kidney Dis. 1998 Jan. 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. 1995 Dec. 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. 2003 Jul. 14(7):1851-7. [Medline].

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, American Society of Nephrology

Disclosure: Nothing to disclose.

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.

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

Vecihi Batuman, MD, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, International Society of Nephrology, Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

James H Sondheimer, MD, FACP, FASN Associate Professor of Medicine, Wayne State University School of Medicine; Medical Director of Hemodialysis, Harper University Hospital at Detroit Medical Center; Medical Director, DaVita Greenview Dialysis (Southfield)

James H Sondheimer, MD, FACP, FASN is a member of the following medical societies: American College of Physicians, American Society of Nephrology

Disclosure: Nothing to disclose.

Membranous Glomerulonephritis

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