1. Causes of membranous nephropathy 신장내과 R 3 김경엽

2. Membranous nephropathy and focal glomerulosclerosis –Most common causes of the nephrotic syndrome in nondiabetic adults Membranous nephropathy [Term] –Basement membrane thickening with little or no cellular proliferation or infiltration on light microscopy Kyungyup Kim, M.D.

3. Normal glomerulus. The thickness of the glomerular capillary wall (long arrow) is similar to that of the tubular basement membranes (short arrow). Mesangial cells and matrix (arrows) Kyungyup Kim, M.D.

4. Diffuse thickening of the glomerular basement membrane (long arrows) Tubular basement membrane (short arrow) Mesangial expansion (asterisks) Kyungyup Kim, M.D.

5. Light micrograph silver stain of membranus nephropathy. Spike appearance (arrows). The spikes represent new basement membrane growing between the subepithelial immune deposits (visible on EM) Kyungyup Kim, M.D.

6. Immunofluorescence (IF) microscopy –Confirm of immune nature of deposits (IgG, other immunoglobulins, and complement) Kyungyup Kim, M.D.

7. Diffuse granular IgG deposition along the capillary walls Kyungyup Kim, M.D.

8. Generation of depositions –With cationic or low molecular weight antigens Easily cross the anionic charge barrier in the GBM –With circulating antibodies directed against endogenous antigens Megalin [gp330] in the experimental Heymann nephritis model of membranous nephropathy (not expressed in normal human glomeruli) Other antigens (e.g., neural endopeptidase) may play this role in human disease Kyungyup Kim, M.D.

9. Electron microscopy (EM) –Electron dense deposits across the GBM Kyungyup Kim, M.D.

10. Normal glomerulus. Fenerated endothelial cell (Endo), glomerular basement membrane (GBM), and the epithelial cells with its interdigitating foot processes (arrow) Kyungyup Kim, M.D.

11. Stage II membranous nephropathy. Electron dense deposits (D) are present in the subepithelial space across the GBM and under the epithelial cells (Ep). Kyungyup Kim, M.D.

12. Stage III membranous nephropathy. Subepithelial immune deposits (D) have a lucent, moth-eaten appearance and have been incorporated into the GBM as new GBM has grown around the deposits (arrows) Kyungyup Kim, M.D.

13. Membranous lupus nephritis. Subepithelial immune deposits (D) – characteristic of any form of membranous nephropathy. Intraendothelial tubuloreticular structures (arrow) strongly suggest underlying lupus Kyungyup Kim, M.D.

14. ETIOLOGY Kyungyup Kim, M.D.

15. Often not possible to distinguish on clinical ground between idiopathic and secondary membranous nephropathy (MN) Possible distinguishing characteristics on EM and IF –Idiopathic MN: usually induced by autoantibodies directed against antigens in the subepithelial space Ann Intern Med 1992; 116:672 electron dense deposits on EM – essentially limited to the subepithelial space Type of IgG is often IgG4 Kyungyup Kim, M.D.

16. –Secondary MN: concurrent presence of mesangial and subendothelial deposits Circulating antigens or antigen-antibody complexes as in lupus nephritis, hepatitis B virus-induced disease, or gold or penicillamine toxicity Kidney Int 1983; 24:377 Kidney Int Suppl 1991; 35:S34 Clin Nephrol 1994; 41:271 Type of IgG –IgG1 and 2 in malignancy-associated MN –IgG2 and 3 in lupus-associated MN (in lupus, IgG may coour in concert with C1q and other immunoglobulins [a ‘full house’] Am J Kidney Dis 1994; 23:358 Nephrol Dial Transplant 2004; 19:574 Kyungyup Kim, M.D.

17. Long-term prognosis –Patients with mesangial deposits > those with idiopathic MN limited to the subepithelial space Clin Nephrol 1994; 41:271 Kyungyup Kim, M.D.

18. Malignancy Up to 5 to 10 percent of cases MN in adults Risk being highest in patients over the age of 60 Am J Kidney Dis 1993; 22:5 Clin Nephrol 2003; 60:437 Malignancy occasionally presents some time after the diagnosis of MN is made Solid tumor (e.g., carcinoma of the lung or colon) or hematologic malignancy (e.g., chronic lymphocytic leukemia) – most often involved Am J Kidney Dis 1993; 22:5 Eur J Haematol 2001; 67:158 Kyungyup Kim, M.D.

19. Tumor antigens are deposited in the glomeruli Antibody deposition and complement activation Epithelial cell and basement membrane injury Proteinuria due to the associated increase in glomerular permeability Kyungyup Kim, M.D.

20. Systemic lupus erythematosus 10 ~ 20% of cases of lupus nephritis – MN picture –Some patients Present only with the renal disease No initial symptoms or serologic abnormalities suggestive of lupus Histologic findings that toward underlying lupus –Subendothelial as well as subepithelial immune deposits –Tubuloreticular structures in the glomerular endothelial cells Kidney Int 1983; 24:377 Am J Kidney Dis 1986; 7:115 Kyungyup Kim, M.D.

21. Membranous lupus nephritis. Subepithelial immune deposits (D) – characteristic of any form of membranous nephropathy. Intraendothelial tubuloreticular structures (arrow) strongly suggest underlying lupus Kyungyup Kim, M.D.

22. Hepatitis B Primarily occurs in children in endemic area Most asymptomatic carriers with no history of active hepatitis N Eng J Med 1991; 324:1457, Kidney Int 1990; 37:663, Clin Nephrol 1985; 23:28, Kidney Int 1991; 39:301 Serum transaminases –Normal or only mildly elevated Serology –Positive for HBs Ag, anti-HBc Ab, and usually HBe Ag Kyungyup Kim, M.D.

23. HBe Ag and cationic anti-HBe Ab –Primarily deposited in the glomeruli HBV infection, lupus –The only form of MN that may be associated with hypocomplementemia Clin Nephrol 1985; 23:28 Spontaneous resolution of the proteinuria –Common in children with MN associated with HBV infection –Not in adults, many of whom will have progressive disease N Eng J Med 1991; 324:1457 Kyungyup Kim, M.D.