In membranous nephropathy

Size selectivity is probably caused by the mesh of glomerular basement proteins, which effectively restricts the passage of larger proteins with molecular weight of more than 150 kDa. Loss of size selectivity is probably the main cause of nonselective proteinuria in membranous nephropathy (SI3). 

Podocyte damage in membranous nephropathy is probably caused by the local activation of complement with the formation of the membranolytic complex C5b-C9. Locally formed chemotactic fragments of complement (e.g., C5a) do not penetrate through the glomerular basement membrane, and that is why in membranous nephropathy glomeruli are not infiltrated with leukocytes. 

Proteinuria in membranous nephropathy is nonselective and it is believed to be caused by the loss of size selectivity (C4). 

Pathogenesis of foot process fusion in various human glomerulopathies may be different. On one hand, in membranous nephropathy, foot process fusion may be the consequence of complement-induced podocyte damage (Cl 1) on the other hand, in minimal change disease, proteinuria may be caused by direct damage to the slit diaphragm with consequent foot process fusion. In any case, foot process fusion results in the formation of large pores and proteinuria. 

Verroust PJ. Kinetics of immime deposits in membranous nephropathy. Kidney Int 1989 35(6) 1418-28. 

Bazzi C, Petrini C, Rizza V, Arrigo G. Beltrame A, Pisano E, D Amico G. Urinary excretion of IgG and P-1 -microglobulin predicts clinical course better than extent of proteinuria in membranous nephropathy. Am J Kidney Dis 2001 38 240-248. 

Nangaku M, Shankland SJ, Couser WG Cellular response to injury in membranous nephropathy. J Am Soc Nephrol 2005 16 1195-204. 

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 48 1600-1604. 

The ACE gene encodes two isozymes (somatic ACE isozyme and germinal ACE isozyme). ACE is a membrane-bound enzyme on the surface of vascular endothelial cells that also circulates in plasma and shows great individual variability determined by an I/D polymorphism in intron 16 of the ACE gene (ACE-I/D polymorphism). More than 160 ACE polymorphisms have been reported, 34 of which are located in coding regions, and 18 are missense mutations (606). ACE-related polymorphic variants have been associated with hypertension, atherosclerosis, stroke, left ventricular hypertrophy, chronic renal failure in IgA nephropathy, Henoch-Schonlein purpura nephritis, mechanical efficiency of skeletal muscle, intracranial aneurysms, susceptibility to myocardial infarction, diabetic nephropathy, AD, and longevity (12,606,607). 

Schieppati A, Perna A, Zamora J, Giuhano GA, Braun N, Remuzzi G. Immunosuppressive treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome. Cochrane Database Syst Rev 2004. 

The cytoplasmic part of nephrin interacts also with ZO-1 protein and actin (K10). Interaction of the antibody or toxin with the extracellular part of nephrin could thus also result in intracellular signaling (phophorylation of tyrosine residues in the cytoplasmic part of nephrin), change of the actin cytoskeleton, and foot process fusion. Indeed, increased levels of phosphotyrosine were demonstrated in renal biopsies of patients with minimal change disease and membranous nephropathy (B2). 

In the following we concentrate mainly on the pathogenesis of minimal change disease, focal and segmental glomerulosclerosis, and idiopathic membranous nephropathy. These three diseases are responsible for about 60-95% of nephrotic syndromes and their prevalence depends on age. 

Idiopathic membranous nephropathy is the commonest form of nephrotic syndrome in middle-aged and elderly patients. The glomerular capillary wall is thickened due to immune deposits (containing mosty immunoglobulin G, IgG)... 

The hypercoagulable state of nephrotic subjects is further worsened with immobilization, hemoconcentration in patients with decreased intravascular volume (usually due to diuretic therapy), and corticosteroid therapy. Prophylactic anticoagulant therapy should be administered to high-risk patients, for example, patients with membranous nephropathy with nephrotic proteinuria and serum albumin level below 20 g/L. 

C11. Cybulsky, A. V., Rennke, H. G., Feintzeig, I. D., and Salant, D. J., Complement-induced glomerular epithelial cell injury The role of the membrane attack complex in rat membranous nephropathy. J. Clin. Invest. 11, 1096-1107 (1986). 

Active Heymann nephritis (AHN), a model of human membranous nephropathy, induced in female Wistar rats by i.p. injection of proximal tubule brush border antigen (FxlA) brought about an increase of blood plasma TAC, beginning in week 9 and reaching maximum (134.9% of control) at week 15. After week 18, plasma TAC returned progressively to the control level (K14). 

TI. Takekoshi, Y., Tanaka, M., Shida, N., Satake, Y., Saheld, Y, and Matsumoto, S., Strong association between membranous nephropathy and hepatitis-B surface antigenaemia in Japanese children. Lancet 2, 1065-1068 (1978). 

Tamatani T, Miyasaka M (1990) Identification of monoclonal antibodies reactive with the rat homolog of ICAM-1 and evidence for differential involvement of ICAM-1 in the adherence of resting versus activated lymphocytes to high endothelial cells. Int Immunol 2 165-171 Thaiss F, Schoeppe W, Willaredt-Stoll JG et al. (1989) Cyclosporin A prevents proteinuria in an active model of membranous nephropathy in rats. Labor Invest 61 661-669... 

There is no y-GT activity in muscle, bone and erythrocytes. Despite high y-GT activity in kidneys, nephropathies do not result in y-GT elevations. During pregnancy, y-GT activity is normal or the serum values may show a declining tendency from the second trimester onwards. In the liver, y-GT is found in the membranes of hepatocytes and bile duct epithelia. The periphery of the liver lobule has the highest y-GT activity. Gamma-GT passes from the liver into the bile and is then excreted partly by the kidneys in the urine, (s. tabs. 5.4, 5.5)... 

Kawano M, Nomura H, Iwainaka Y, Nakashima A, Koni I, Tofuku Y, Takeda R. [Bucillamine-associated membranous nephropathy in a patient with rheumatoid arthritis.) Nippon Jinzo Gakkai Shi 1990 32(7) 817-21. 

Of 847 patients with different rheumatic diseases who took oxaprozin daily for up to 1 year, 6% developed significant rises in blood urea nitrogen or creatinine, but a severe adverse renal effect occurred in only one patient (SEDA-12, 87). Oxaprozin can cause membranous nephropathy with nephrotic syndrome (SEDA-21,106). 

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