Glomerulosclerosis

In the kidney, ANG II reduces renal blood flow and constricts preferentially the efferent arteriole of the glomerulus with the result of increased glomerular filtration pressure. ANG II further enhances renal sodium and water reabsorption at the proximal tubulus. ACE inhibitors thus increase renal blood flow and decrease sodium and water retention. Furthermore, ACE inhibitors are nephroprotective, delaying the progression of glomerulosclerosis. This also appears to be a result of reduced ANG II levels and is at least partially independent from pressure reduction. On the other hand, ACE inhibitors decrease glomerular filtration pressure due to the lack of ANG II-mediated constriction of the efferent arterioles. Thus, one important undesired effect of ACE inhibitors is impaired glomerular filtration rate and impaired kidney function. 

In the interstitium, angiotensin II induces proliferation of mesangial cells and fibroblasts and the synthesis of collagen and other matrix molecules by these cells via the ATI receptor. Moreover, by the concomitant stimulation of chemoattractant cytokines, inflammation is induced. These processes are mediated by endothelin, transforming growth factor(3, and reactive oxygen species, and finally lead to interstitial fibrosis and glomerulosclerosis observed in hypertension and diabetes. 

Minimal-change disease is more common in children than in adults. It is rare in black children and adults of sub-Saharan Africa. Minimal-change responds well to steroids. However, it may recur after prednisone is decreased or discontinued. In such cases, the addition of cyclophosphamide or chlorambucil may produce a response. The GFR is normal. Progression to renal failure does not occur unless focal glomerulosclerosis is present. 

Ichikawa, I., and Fogo, A. (1996). Focal segmental glomerulosclerosis. Pediatr. Nephrol. 10, 374-391. 

Michaud, J. L., Lemieux, L. I., Dube, M., Vanderhyden, B. C., Robertson, S. J., and Kennedy, C. R. (2003). Focal and segmental glomerulosclerosis in mice with podocyte-specific expression of mutant alpha aclinin-1. J. Am. Soc. Nephrol. 14, 1200-1211. 

Shirato, I., Hosser, H., Kimura, K., Sakai, T., Tomino, Y., and Kriz, W. (1996). The development of focal segmental glomerulosclerosis in masugi nephritis is based on progressive podocyte damage. Virchows Arch. 429, 255—273. 

H16. Hurd, E. R., and Ziff, M., Quantitative studies of immunoglobulin deposition in the kidney, glomerular cell proliferation and glomerulosclerosis in NZB/NZW FI hybrid mice. Clin. Exp. Immunol. 26, 261—268 (1976). 

Besides congenital nephrotic syndrome of the Finnish type (T6), nephrotic syndrome (with histologic appearance of focal segmental glomerulosclerosis) may result from mutations of other podocyte proteins (T7, K4) (Table 1). 

Nephrotic syndrome may complicate the course of many primary and secondary glomerulopathies. Diabetic nephropathy is the most common cause of nephrotic proteinuria (not always accompanied by full-blown nephrotic syndrome). Lupus nephritis and renal amyloidosis are much rarer secondary glomerulopathies resulting in nephrotic syndrome. The prevalence of primary glomerulopathies differs between Blacks and Whites (focal segmental glomerulosclerosis is more common... 

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. 

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