Hyperlipidemia and glomerular sclerosis: an alternative viewpoint.

Clinical and experimental observations suggest an association between hypercholesterolemia and progressive glomerular injury. In the main, most investigators have assumed that hypercholesterolemia induces an atherosclerotic process in the renal microvasculature analogous to that well recognized in larger vessels. The evidence for this line of reasoning is well described in other papers in this symposium. It is our belief that hypercholesterolemia may also lead to glomerular injury by hemodynamic mechanisms. In support of this latter view, diet-induced hypercholesterolemia often raises blood pressure in experimental animals and markedly impairs endothelial cell-dependent vascular relaxation in vitro. A high cholesterol diet also increases renal vascular resistance and contributes to glomerular capillary hypertension, a hemodynamic maladaptation known to cause glomerular sclerosis. In addition, hypercholesterolemia results in hyperviscosity, a rheologic abnormality leading to increased efferent arteriolar resistance and glomerular hypertension. The similar glomerular hemodynamic responses to two hyperviscosity states, elevated hematocrit and hypercholesterolemia, implicate efferent arteriolar hyperviscosity as a potential mechanism of injury common to hyperviscosity states. It therefore seems likely that as in atherosclerosis, multiple risk factors act synergistically to initiate glomerular structural injury. Specifically, we suggest that hypercholesterolemia and glomerular hypertension act synergistically to initiate structural injury. Although modification of either risk factor may limit injury, it seems likely that therapy targeted to each of multiple risk factors may afford superior protection.