Lipids and progressive renal failure.

Experimental evidence suggests that lipids may modulate progressive renal injury. The inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase have demonstrated beneficial effects in different models of progressive renal failure. Recent experimental data suggests that these agents also may have glomerular protective effects independent of reduction in circulating lipids. Monocyte infiltration, mesangial cell proliferation and mesangial matrix expansion have been shown to be early events in the process of glomerulosclerosis that can be lessened by HMG-CoA reductase inhibition. In vitro, HMG-CoA reductase inhibitors have been shown to inhibit mesangial cell proliferation, as well as the production of chemokines involved in macrophage biology. These effects appear to be related to a reduction in cell production of cholesterol precursors, the so-called nonsterol isoprenoids. The isoprenoids are an important class of lipids necessary for isoprenylation of proteins such Ras, which are involved in cell signaling for various growth-promoting cytokines. We have also shown that interference with this signaling pathway results in marked reduction in the activation of nuclear transcription factors. Thus, it would appear that the HMG-CoA reductase inhibitors have the potential of modifying mesangial cell biology independent 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 evident in the diabetic patient at the onset of microalbuminuria. In diabetic and nondiabetic patients, preliminary studies have suggested that interventions with these agents may have salutary effects on the progression of renal disease. Recently, experimental and clinical studies have also suggested that HMG-CoA reductase inhibitors may also reduce the severity of chronic vascular rejection.