V7 CVv

Figure 2.2. Immunofluorescence showing diffuse fine granular distribution pattern of immunoglobulin G (IgG) along the GBM in membranous glomerulopathy.

Figure 2.3. Electron microscopy showing subepithelial electron dense deposits, spike formation of GBM and obliteration of visceral epithelial cell pedicles in membranous glomerulopathy.

house"), suspicion of lupus membranous glomerulopathy should arise (22).

Electron Microscopy

At electron microscopy the spikes can most often be found in different stages of development, between and around the electron dense deposits (Fig. 2.3). As described, the immune deposits in membranous nephropathy are localized subepithelially and sometimes intramembranously. The subepithelial deposits are in contact with the glomerular epithelial cells. In these cells the cytoplasm close to the deposits often shows fibrillary condensation, while there is extensive obliteration of the pedicles. The epithelial cells may also show reabsorption droplets and microvillous transformation. The electron dense deposits show most often a finely granular ultrastructure. The surrounding spikes vary in size and shape, suggesting a certain sequence of events. With increasing basement membrane pathology the immunopathologic evidence for the presence of immune complexes decreases, as does the protein secretion. The size of the electron dense deposits and the thickness of the basement membranes are significantly correlated with clinical parameters such as proteinuria, serum creatinine, and creatinine clearance, and with prognosis (23,24).


Membranous glomerulopathy is a morphologic diagnosis. It describes a disease characterized by a spectrum of changes in the glomerular capillary wall, initiated by the formation of subepithelial immune complexes. It is assumed that immunologic pathogenetic mechanisms underlie membranous glomerulopathy, as reviewed extensively elsewhere (6,25-29). Membranous glomerulopathy is an immune complex disease associated with a T-helper 2 (Th2) nephritogenic immune response and overproduction of interleukin-4 (IL-4), a principal Th2 cytokine (30). Observations from animal models and some in humans suggest that the production of antibodies directed at glycoproteins occurring on the visceral epithelial cell surface results in in situ formation of subepithelial immune complexes and glo-merular damage (7,25,29,31-33). As discussed in more detail in the paragraph on membranous lupus nephritis, (Chapter 8), the purely subepithelial location of the immune complexes in membranous nephropathy leads to complement activation, but not to chemotaxis and activation of inflammatory cells with subsequent glomerular cell proliferation, since inflammatory cells cannot pass the glomerular basement membrane. Indeed, glomerular proliferation and influx of inflammatory cells are usually absent in membranous glomerulopathy. For this reason, the term membranous glomerulonephritis is regarded by some as a misnomer that should be replaced by the term membranous glomerulopathy. Subepithelial formation of immune complexes leads to podocyte damage with compensatory alterations in the expression of podocyte-associated molecules such as nephrin (34). In experimental membranous glomerulopathy, the onset of proteinuria is coincident with complement-dependent alterations in the association of nephrin with the actin cytoskeleton and loss of podocyte slit-diaphragm integrity (35). This leads to foot process broadening and depression of the single-nephron ultrafiltration coefficient and decrease of the GFR early in the course of the disease (36). Subepithelial deposits in membranous nephropathy drive glomerular epithelial cells to diminish their expression of vascular endothelial growth factor (VEGF), a presumably protective cytokine (37), and increase that of transforming growth factor-pi (TGF-pi). In turn, TGF-pi dysregulates the expression of matrix genes, leading to production of quantitatively and qualitatively abnormal basement membrane matrix by the glomerular visceral epithelial cells (38). This would somehow lead to both increased permeability of the glomerular basement membrane and ensuing nephrotic syndrome, and to the formation of spikes that contain predominantly laminin (20). Indeed, proteinuria in membranous glomerulopathy seems to result mainly from a loss of size selectivity of the glomerular capillary walls, in contrast to the defect in, for example, minimal change glomerulopathy, which results mainly from a loss of charge selectivity (2). In those patients with membranous nephropathy who develop chronic renal failure with further depression of GFR, hypofiltration is the consequence of a biphasic loss of glomerular ultrafiltration capacity, initially owing to impaired hydraulic permeability that is later exacerbated by a superimposed loss of functioning glomeruli and of filtration surface area (13). Severe proteinuria seems to be the main factor responsible for the upregulation of fibrogenic cytokines in tubular epithelial cells (39).

Clinicopathologic Correlations

The natural history of the untreated disease is variable. Complete or partial spontaneous remissions of proteinuria eventually occur in 40% to 50% of patients, usually accompanied by stable renal function (21). The remainder slowly progress to end-stage renal disease or die of complications or from unrelated disorder after 5 to 15 years (21). Factors influencing the progression of membranous glomerulopathy are numerous and include age, renal function, and albuminuria at the onset, and interactions between gene polymorphisms, such as those of nitric oxide synthase and the renin-angiotensin system (21,40). Membranous glomerulopathy may be complicated by focal and segmental glomerulosclerosis including the collapsing variant, also in HIV-negative patients (41).

The treatment of membranous glomerulopathy remains both controversial and suboptimal. For those patients who have persistent nephrotic pro-teinuria or manifest loss of renal function, steroids and immunosuppressive drugs are used (42). Angiotensin II inhibition may slow progression by controlling proteinuria (42). Alternative therapies and future intervention modalities include vaccines, inhibitors of plasminogen activator, humanized monoclonal antibodies, mycophenolate mofetil, and pentoxifylline (43). Treatment of secondary membranous glomerulopathy generally targets the primary diseases rather than the renal lesion (44). Recent data obtained from animal models suggest that antibody binding in membranous glomerulopathy depends on the conformation of the antigenic target sequence, and that interference with the immunologic basis of the disease by use of synthetic peptides should be possible (45-47).

The sequence of events occurring during the development of membranous glomerulopathy is so constant that its course can be divided into several stages (48). In stage I light microscopic changes are absent, but immunofluorescence shows granular aggregates of immunoglobulins. In stage II spikes are present, which in stage III embrace the subepithelial aggregates. This is accompanied by obliteration of pedicles. Stage IV is characterized by variation in electron density of the deposits and severe thickening and deformation of the glomerular basement membrane. In general, a relation exists between the morphologic stage of the disease and the clinical severity and duration. Interestingly, in patients in remission reversibility of the morphologic lesion has been reported (49). Of note, novel molecular biologic techniques may allow further subclassification as well as more accurate determination of the prognosis (50,51).


1. Lewis EJ. Management of the nephrotic syndrome in adults. In: Cameron JS, Glassock RJ, eds. The Nephrotic Syndrome. New York: Marcel Dekker, 1988:461-521.

Orth SR, Ritz E. The nephrotic syndrome. N Engl J Med 338:1202-1211, 1998.

Haas M, Spargo BH, Coventry S. Increasing incidence of focal-segmental glomerulosclerosis among adult nephropathies: a 20-year renal biopsy study. Am J Kidney Dis 26:740-750, 1995.

D'Agati V. The many masks of focal segmental glomerulosclerosis. Kidney Int 46:1223-1241, 1994.

Braden GL, Mulhern JG, O'Shea MH, Nash SV, Ucci AA, Germain MJ. Changing incidence of glomerular diseases in adults. Am J Kidney Dis 35:878-883, 2000.

Hricik DE, Chung-Park M, Sedor JR. Glomerulonephritis. N Engl J Med 339:888-900, 1998.

Schwartz MM. Membranous glomerulonephritis. In: Jennette JC, Olson JL, Schwartz MM, Silva FG, eds. Heptinstall's Pathology of the Kidney, 5th ed. Philadelphia: Lippincott, 1998:259-308.

Luyckx C, Van DB, Vanrenterghem Y, Maes B. Carcinoid tumor and membranous glomerulonephritis: coincidence or malignancy-associated glomerulonephritis? Clin Nephrol 57:80-84, 2002.

Nagahama K, Matsushita H, Hara M, Ubara Y, Hara S, Yamada A. Bucilla-mine induces membranous glomerulonephritis. Am J Kidney Dis 39:706-712, 2002.

Strippoli GF, Manno C, Rossini M, Occhiogrosso G, Maiorano E, Schena FP. Primary cerebral lymphoma and membranous nephropathy: a still unreported association. Am J Kidney Dis 39:E22, 2002.

Haas M, Zikos D. Membranous nephropathy. Distinction of latent membranous lupus nephritis from idiopathic membranous nephropathy on renal biopsy. Pathol Case Rev 3:175-179, 1998.

Schwartz MM. Membranous glomerulonephritis. In: Heptinstall RH, ed. Pathology of the Kidney, 4th ed. Boston, Little, Brown, 1992:559-626. Squarer A, Lemley KV, Ambalavanan S, et al. Mechanisms of progressive glomerular injury in membranous nephropathy. J Am Soc Nephrol 9:13891398, 1998.

Polenakovik MH, Grcevska L. Treatment and long-term follow-up of patients with stage II to III idiopathic membranous nephropathy. Am J Kidney Dis 34:911-917, 1999.

Ruggenenti P, Mosconi L, Vendramin G, et al. ACE inhibition improves glomerular size selectivity in patients with idiopathic membranous nephro-pathy and persistent nephrotic syndrome. Am J Kidney Dis 35:381-391, 2000.

Geddes CC, Cattran DC. The treatment of idiopathic membranous nephro-pathy. Semin Nephrol 20:299-308, 2000.

Branten AJW, Wetzels JFM. Short- and long-term efficacy of oral cyclophosphamide and steroids in patients with membranous nephropathy and renal insufficiency. Clin Nephrol 56:1-9, 2001.

Remuzzi G, Chiurchiu C, Abbate M, Brusegan V, Bontempelli M, Ruggenenti P. Rituximab for idiopathic membranous nephropathy. Lancet 360:923-924, 2002.

Cattran DC. Membranous nephropathy: quo vadis? Kidney Int 61:349-350, 2002.

20. Fukatsu A, Matsuo S, Killen PD, Martin GR, Andres GA, Brentjens JR. The glomerular distribution of type IV collagen and laminin in human membranous glomerulonephritis. Hum Pathol 19:64-68, 1990.

21. Glassock RJ. Diagnosis and natural course of membranous nephropathy. Semin Nephrol 23:324-332, 2003.

22. Picken MM. The role of kidney biopsy in the management of patients with systemic lupus erythematosus. Pathol Case Rev 3:204-209, 1998.

23. Toth T, Takebayashi S. Idiopathic membranous glomerulonephritis: a clinico-pathologic and quantitative morphometric study. Clin Nephrol 38:14-19,


24. Yoshimoto K, Yokoyama H, Wada T, et al. Pathologic findings of initial biopsies reflect the outcomes of membranous nephropathy. Kidney Int 65:148-153, 2004.

25. Bruijn JA, Hoedemaeker PJ. Nephritogenic immune reactions involving native renal antigens. In: Massry SG, Glassock RJ, eds. Textbook of Nephrology, 3rd ed. Baltimore: Williams & Wilkins, 1995:627-631.

26. Bruijn JA, de Heer E, Hoedemaeker PJ. Immune mechanisms in injury to glomeruli and tubulo-interstitial tissue. In: Jones TC, ed. Monographs on Pathology of Laboratory Animals. Urinary System, 2nd ed. New York: Springer-Verlag, 1998:199-224.

27. de Heer E, Bruijn JA, Hoedemaeker PJ. Heymann nephritis revisited. New insights into the pathogenesis of experimental membranous glomerulonephri-tis. Clin Exp Immunol 94:393-394, 1993.

28. Maruyama S, Cantu E, Demartino C, et al. Membranous glomerulonephritis induced in the pig by antibody to angiotensin-converting enzyme: considerations on its relevance to the pathogenesis of human idiopathic membranous glomerulonephritis. J Am Soc Nephrol 10:2102-2108, 1999.

29. Cattran DC. Idiopathic membranous glomerulonephritis. Kidney Int 59: 1983-1994, 2001.

30. Masutani K, Taniguchi M, Nakashima H, et al. Up-regulated interleukin-4 production by peripheral T-helper cells in idiopathic membranous nephro-pathy. Nephrol Dial Transplant 19:580-586, 2004.

31. Van Leer EHG, de Roo GM, Bruijn JA, Hoedemaeker PJ, de Heer E. Synergistic effects of anti-gp330 and anti-dipeptidyl peptidase type IV antibodies in the induction of glomerular damage. Exp Nephrol 1:292-300,


32. Oleinikov AV, Feliz BJ, Makker SP. A small N-terminal 60-kD fragment of gp600 (Megalin), the major autoantigen of active Heymann nephritis, can indiuce a full-blown disease. J Am Soc Nephrol 11:57-64, 2000.

33. Debiec H, Guigonis V, Mougenot B, et al. Antenatal membranous glomerulo-nephritis due to anti-neutral endopeptidase antibodies. N Engl J Med 346: 2053-2060, 2002.

34. Koop K, Eikmans M, Baelde HJ, et al. Expression of podocyte-associated molecules in acquired human kidney diseases. J Am Soc Nephrol 14:20632071, 2003.

35. Saran AM, Yuan H, Takeuchi E, McLaughlin M, Salant DJ. Complement mediates nephrin redistribution and actin dissociation in experimental membranous nephropathy. Kidney Int 64:2072-2078, 2003.

36. Hladunewich MA, Lemley KV, Blouch KL, Myers BD. Determinants of GFR depression in early membranous nephropathy. Am J Physiol Renal Physiol 284:F1014-F1022, 2003.

37. Honkanen E, von Willebrand E, Koskinen P, et al. Decreased expression of vascular endothelial growth factor in idiopathic membranous glomerulonephritis: relationships to clinical course. Am J Kidney Dis 42:1139-1148,


38. Kim TS, Kim JY, Hong HK, Lee HS. mRNA expression of glomerular basement membrane proteins and TGF-ß1 in human membranous nephropathy. J Pathol 189:425-430, 1999.

39. Mezzano SA, Droguett MA, Burgos ME, et al. Overexpression of chemokines, fibrogenic cytokines, and myofibroblasts in human membranous nephropathy. Kidney Int 57:147-158, 2000.

40. Stratta P, Bermond F, Guarrera S, et al. Interaction between gene polymorphisms of nitric oxide synthase and renin-angiotensin system in the progression of membranos glomerulonephritis. Nephrol Dial Transplant 19:587-595,


41. Al-Shamari A, Yeung K, Levin A, Taylor P, Magil A. Collapsing glomerulopathy coexisting with membranous glomerulonephritis in native kidney biopsies: a report of 3 HIV-negative patients. Am J Kidney Dis 42:591-595, 2003.

42. Schieppati A, Ruggenenti P, Perna A, Remuzzi G. Nonimmunosuppressive therapy of membranous nephropathy. Semin Nephrol 23:333-339, 2003.

43. Kshirsagar AV, Nachman PH, Falk RJ. Alternative therapies and future intervention for treatment of membranous nephropathy. Semin Nephrol 23:362372, 2003.

44. Jefferson JA, Couser WG. Therapy of membranous nephropathy associated with malignancy and secondary causes. Semin Nephrol 23:400-405, 2003.

45. Luca ME, Van der Wal A, Paul L, Bruijn JA, de Heer E. Treatment with mycophenolate mofetil attenuates the development of Heymann nephritis. Exp Nephrol 8:77-83, 2000.

46. Luca ME, de Geus B, Sahali D, Bruijn JA, Verroust P, de Heer E. Isolation of cDNAs encoding immunogenic regions of gp330, the autoantigen involved in Heymann nephritis. Clin Exp Immunol 104:312-317, 1996.

47. Kerjaschki D, Ullrich R, Exner M, Orlando RA, Farquhar MG. Induction of passive Heymann nephritis with antibodies specific for a synthetic peptide derived from the receptor-associated protein. J Exp Med 183:2007-2015, 1996.

48. Ehrenreich T, Churg J. Pathology of membranous nephropathy. In: Sommers SC, ed. Pathology Annual 1968, vol 3. New York: Appleton-Century-Crofts, 1968:145-154.

49. Gonzalo A, Mampaso F, Barcena R, Gallego N, Ortuno J. Membranous nephropathy associated with hepatitis B virus infection: long-term clinical and histological outcome. Nephrol Dial Transplant 14:416-418, 1999.

50. Eikmans M, Baelde JJ, de Heer E, Bruijn JA. RNA expression profiling as prognostic tool in renal patients: toward nephrogenomics. Kidney Int 62:11251135, 2002.

51. Eikmans M, Baelde HJ, Hagen EC, et al. Renal mRNA levels as prognostic tools in kidney diseases. J Am Soc Nephrol 14:899-907, 2003.

Diabetes Sustenance

Diabetes Sustenance

Get All The Support And Guidance You Need To Be A Success At Dealing With Diabetes The Healthy Way. This Book Is One Of The Most Valuable Resources In The World When It Comes To Learning How Nutritional Supplements Can Control Sugar Levels.

Get My Free Ebook

Post a comment