The role of lipids in the pathogenesis of glomerulosclerosis.

Most patients with chronic renal impairment develop progressive glomerulosclerosis and eventually require dialysis. The pathogenesis of this process is poorly understood. This thesis addresses the possibility that hyperlipidaemia initiates and/or aggravates glomerulosclerosis. The handling of lipoproteins by human glomerular cells was studied by incubating cells cultured from isolated human glomeruli with fluorescent-labelled lipoproteins. It was demonstrated that all cells take up low density lipoproteins (LDL) by receptor- mediated endocytosis. Chemically modified LDL was taken up by macrophages, suggesting that human glomerular 'foam' cells are derived from monocytes rather than intrinsic mesangial cells. A series of experiments was performed in rats to investigate the effects of manipulating serum lipids on glomerular damage. Attempts to lower serum cholesterol with cholestyramine and synvinolin were unsuccessful. Dietary cholesterol supplementation caused hyper?lipoproteinaemia and glomerular lipid deposition, especially of cholesterol and cholesteryl esters. In rats made uraemic and hypertensive by 11/3 nephrectomy, the diet did not affect the severity of proteinuria or glomerulosclerosis over a 7 week period. However, when administered for 21 weeks following unilateral nephrectomy, proteinuria was increased. The number of bone marrow-derived glomerular macrophages was slightly but significantly increased and many became foam cells. These changes were not associated with glomerulosclerosis but there was a significant increase of glomerular size which is known to precede sclerosis. These results suggest that hyperlipidaemia and glomerular lipid deposition contribute to the development of glomerulosclerosis by stimulating an influx of macrophages which may cause glomerular hypertrophy and injury through the release of factors during phagocytosis. The magnitude of these changes indicates that the effect of lipids is likely to be low-grade and only of importance over a prolonged period of time.