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membranous glomerulonephritis; mesangiocapillary glomerulonephritis (membranous nephropathy)

Etiology: 1) autoimmune (primary) - 75-85% with PLA2R antibody [6] 2) secondary to systemic disease a) connective tissue disease 1] systemic lupus erythematosus 2] Sjogren's syndrome b) sarcoidosis c) malignancy (1.5% of cases) - lung cancer - breast cancer - gastric cancer - pancreatic cancer - colon cancer - bladder cancer - sarcomas - lymphomas, leukemias - carcinoid - malignancies occur at 5 times the expected rate in patients with membranous glomerulonephritis d) infections - hepatitis B, hepatitis C - quartan malaria - syphilis - HIV1 infection e) sickle cell disease f) pharmacologic agents 1] gold 2] D-penicillamine 3] captopril 4] probenecid 5] some NSAIDs 6] TNF-alpha inhibitors 7] tiopronin g) heavy metals - mercury, gold h) thyroid disease Epidemiology: 1) primary cause of idiopathic nephrotic syndrome in white adults (50%) & in patients > 70 years of age - 18-41% of total nephrotic syndrome [3] 2) mean age of onset is 35 years Pathology: 1) deposition of cationic antigens in subepithelial space 2) 'spike & dome' epithelial deposits of basement membrane material 3) thickening of glomerular capillary wall 4) immunofluorescence shows subepithelial granular deposits of IgG4 & C3 (PLA2R antibody) [11] 5) electron miscroscopy shows podocyte foot process effacement consistent with protein leakage through the glomeruli [3] Genetics: - implicated genes: LRPAP1 (p39RAP) Clinical manifestations: 1) typically presents with nephrotic syndrome with preserved GFR - see nephrotic syndrome 2) onset may be abrupt 3) slow progression with spontaneous remissions & exacerbations 4) hypertension (40%) 5) end-stage renal disease (20%) Laboratory: 1) 24 hour urine: protein generally > 3.5 g (75%) 2) creatinine clearance & glomerular filtration rates are generally near normal 3) urinalysis a) microscopy: urine sediment generally unremarkable b) microscopic hematuria common c) erythrocyte casts absent [3] 4) serum complement levels are normal [3] 5) hepatitis serology 6) antinuclear antibody 7) PLA2R antibody in serum (phospholipase A2 receptor antibody) [6] - ~100% specific for primary membranous glomerulonephropathy - obviates need for renal biopsy if no evidence of other pathology [3] 8) lipid panel 9) renal biopsy needed for diagnosis [6] * also see ARUP consult [7] Special laboratory: 1) renal ultrasound with doppler (rule out renal vein thrombosis) - CT angiography is preferred procedure 2) renal biopsy confirms diagnosis 3) colonoscopy (rule out colon cancer) Radiology: 1) CT angiography to rule out renal vein thrombosis 2) mammography (rule out breast cancer) 3) chest X-ray or low-dose non-contrast chest CT (rule out lung cancer) Complications: 1) renal vein thrombosis (25-50%) - may cause acute renal failure - membranous nephropathy is most likely cause of nephrotic syndrome to result in renal vein thrombosis [3] 2) systemic venous thromboembolism - pulmonary embolism, deep vein thrombosis 3) progression to end-stage renal disease - risk factors - male > 50 years of age - low GFR - hypertension - secondary glomerulosclerosis & chronic tubulointerstitial nephritis on renal biopsy - nephrotic syndrome Management: 1) not all patients require treatment; without therapy a) 25-30% of patients will have complete remission within 1 year [3] b) 50% of patients will have partial remission c) 20% of patients will progress to end-stage renal disease d) observe for 6-12 months to allow time for spontaneous remission prior to initiating immunosuppressive therapy [3] 2) nephrotic syndrome - supportive therapy, unless complications such as acute renal failure, anasarca, deep vein thrombosis [3] - loop diuretic for edema. add metolazone as needed [3] 2) immunosuppressive therapy should be reserved for patients with high risk of progression to end-stage renal disease, nephrotic syndrome a) high dose alternate day glucocorticoids b) combination of cytotoxic agent & glucocorticoids 1] cyclosporine (Sandimmune) 2] mycophenolate (Cellcept) 3] tacrolimus [3] 4] other cytotoxic agents a] cyclophosphamide (Cytoxan) b] azathiaprine (Imuran) c] chlorambucil (Leukeran) c) rituximab may be a 1st-line treatment option in selected patients [14] d) calcineurin inhibitors [3] 3) ACE inhibitors may diminish the degree of proteinuria 4) control hypertension 5) treat underlying disorder - lamivudine may benefit nephropathy in patients with hepatitis B [3] 6) optimal therapy not established 7) screening for cancer (see etiology) determined by additional risk factors (if any) - extensive screening not indicated [3]

Interactions

disease interactions

Related

nephrotic syndrome renal vein thrombosis systemic lupus erythematosus

General

glomerulonephritis (GN, nephritic syndrome)

References

  1. Manual of Medical Therapeutics, 28th ed, Ewald & McKenzie (eds), Little, Brown & Co, Boston, 1995, pg 269
  2. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 608
  3. Medical Knowledge Self Assessment Program (MKSAP) 11, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2009, 2012, 2015, 2018, 2021 - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  4. Harrison's Principles of Internal Medicine, 13th ed. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1994, pg 1298, 1301
  5. Cattran D. Management of membranous nephropathy: when and what for treatment. J Am Soc Nephrol. 2005 May;16(5):1188-94. PMID: 15800117
  6. Young K, Sadoughi S, Hefner JE Physician's First Watch, June 2 2014 David G. Fairchild, MD, MPH, Editor-in-Chief Massachusetts Medical Society http://www.jwatch.org - FDA News Release. May 29, 2014 FDA allows marketing of first non-invasive test to help in identifying cause of certain kidney disease. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm399327.htm
  7. ARUP consult: Primary Membranous Nephropathy - Membranous Glomerulonephritis The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/primary-membranous-nephropathy
  8. Hazar DB, Eneanya ND, Kilcoyne A, Rosales IA. Case Records of the Massachusetts General Hospital. Case 35-2015: A 72-Year-Old Woman with Proteinuria and a Kidney Mass. N Engl J Med. 2015 Nov 12;373(20):1958-67. PMID: 26559575 http://www.nejm.org/doi/full/10.1056/NEJMcpc1505527
  9. Qin W, Beck LH Jr, Zeng C et al Anti-phospholipase A2 receptor antibody in membranous nephropathy. J Am Soc Nephrol. 2011 Jun;22(6):1137-43. PMID: 21566055 Free PMC Article
  10. Waldman M, Austin HA 3rd. Treatment of idiopathic membranous nephropathy. J Am Soc Nephrol. 2012 Oct;23(10):1617-30. Review. PMID: 22859855 Free PMC Article
  11. Morris CA, Patel MJ, Fenves AZ, Masia R. Case 17-2018: A 40-Year-Old Woman with Leg Swelling and Abdominal Distension and Pain. N Engl J Med 2018; 378:2124-2132. May 31, 2018 PMID: 29847754 https://www.nejm.org/doi/full/10.1056/NEJMcpc1712228
  12. Couser WG. Primary Membranous Nephropathy. Clin J Am Soc Nephrol. 2017 Jun 7;12(6):983-997. Review. PMID: 28550082 Free PMC Article
  13. Leeaphorn N, Kue-A-Pai P, Thamcharoen N et al Prevalence of cancer in membranous nephropathy: a systematic review and meta-analysis of observational studies. Am J Nephrol. 2014;40(1):29-35. Review. PMID: 24993974 Free Article
  14. Fervenza FC, Appel GB, Barbour SJ et al. Rituximab or cyclosporine in the treatment of membranous nephropathy. N Engl J Med 2019 Jul 4; 381:36-46. PMID: 31269364 - Ruggenenti P, Remuzzi G. A first step toward a new approach to treating membranous nephropathy. N Engl J Med 2019 Jul 4; 381:86-88. PMID: 31269372