Primary renal disease of immunologic or nonimmunologic mechanisms induces loss of substantial nephron population. It is presumed that the initial loss of functioning nephrons causes alterations of function and metabolism in remnant nephrons, which per se are self-inflictive, leading to further loss of nephrons. The ultimate outcome of this vicious cycle is the end-stage kidney. The potential role of various pathophysiologic mechanisms has been explored. These studies have shown a tight link between glomerular hypertrophy and sclerosis. Analysis of individual glomeruli show a biphasic pattern of these two parameters. Early development of glomerular sclerosis takes place along with the hypertrophy of the glomerulus, and further advancement of sclerosis occurs with shrinkage in glomerular size. Thus, we propose that, after initial nephron loss, the remnant glomeruli are exposed to increased growth-promoting factors, which are self-inflictive in nature due to their capacity to produce excessive amounts of extracellular matrix in the mesangial area. When the excessive matrix obliterates the glomerular capillary lumen, a typical sclerotic lesion appears. This is a vicious and accelerating process, since sclerosis induces further reduction in the nephron population, thereby imposing greater influence of growth-promoting factors even on glomeruli that are initially resistant.