LIPIDS AND PROGRESSIVE RENAL-FAILURE

Experimental evidence suggests that lipids may modulate progressive re nal injury. The inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (H MG-CoA) reductase have demonstrated beneficial effects in different mo dels of progressive renal failure. Recent experimental data suggests t hat these agents also may have glomerular protective effects independe nt of reduction in circulating lipids. Monocyte infiltration: mesangia l cell proliferation and mesangial matrix expansion have been shown to be early events in the process of glomerulosclerosis that can be less ened by HMG-CoA reductase inhibition. In vitro, HMG-CoA reductase inhi bitors have been shown to inhibit mesangial cell proliferation, as wel l as the production of chemokines involved in macrophage biology. Thes e effects appear to be related to a reduction in cell production of ch olesterol precursors, the so-called nonsterol isoprenoids. The isopren oids are an important class of lipids necessary for isoprenylation of proteins such Ras, which are involved in for various growth-promoting cytokines. We have also shown that interference with this signaling pa thway results in marked reduction in the activation of nuclear transcr iption factors. Thus, it would appear that the HMG-CoA reductase inhib itors have the potential of modifying mesangial cell biology independe nt of any lipid-lowering effect. Clinically, a number of studies have shown that increased lipids are associated with an accelerated rate of progression of renal disease. Indeed, these lipid abnormalities are e vident in the diabetic patient at the onset of microalbuminuria. In di abetic and nondiabetic patients, preliminary studies have suggested th at interventions with these agents may have salutary effects on thr pr ogression of renal disease. Recently, experimental and clinical studie s have also suggested that HMG-CoA reductase inhibitors may also reduc e the severity of chronic vascular rejection.