A reduction in the effective glomerular capillary surface available for filtration by renal ablation or acquired renal disease results in functional and structural adaptations which lead to endothelial, mesangial and epithelial cell dysfunction. The structural lesions that ensue include capillary microthrombosis, mesangial expansion, microaneurysm formation, epithelial cell detachment with hyalin deposition, and basement membrane thickening. These alterations lead to segmental and eventually global glomerulosclerosis, closing the loop of a positive feedback mechanism that perpetuates and accelerates the microvascular damage. Dietary, hormonal, and as yet poorly identified constitutional factors can modulate the hemodynamic response to the original insult and offer an opportunity to influence this process therapeutically.