title: The atherogenic lipoprotein phenotype in renal disease
Creators: name: Deighan, Christopher J.
Publisher: name: University of Glasgow
Year: 1999

description: Nephrotic range proteinuria and chronic renal failure are associated with both qualitative and quantitative changes in lipoproteins and increased cardiovascular risk. LDL exhibits heterogeneity with increased small dense LDL (LDLIII) associated with increased risk of coronary heart disease (CHD). In normal populations, production of small dense LDL is physiologically linked to mild hypertriglyceridaemia and low HDL, a combination that has been labelled 'the atherogenic lipoprotein phenotype'. This thesis aimed to explore abnormalities in the metabolism of triglyceride-rich lipoproteins in patients with chronic renal dysfunction, with particular reference to changes in LDL subfraction distribution and remnant lipoprotein particles. The main population investigated were patients with nephrotic range proteinuria secondary to primary glomerular disease, however this work was extended to examine changes in lipoproteins in patients with proteinuria secondary to diabetic nephropathy in type 2 diabetes, and also patients with end-stage renal failure. Our hypothesis was that in patients with proteinuria, hypertriglyceridaemia occurs as a result of impaired catabolism of VLDL. The consequence is the generation of small dense LDL (LDLIII) and remnant lipoproteins, both of which are pathogenic agents which may contribute to accelerated vascular disease and to the rate of progression of renal failure. Quantitative analysis of both LDLIII and remnant lipoproteins was performed in 27 patients with nephrotic range proteinuria and well preserved renal function. This revealed a marked increased in plasma LDLIII concentration, to levels that are noted to be atherogenic in normal populations. This increase primarily due to a shift in particle size towards smaller denser particles. Remnant lipoproteins (RLP) were V similarly increased in proteinuric patients. The excess of both of these atherogenic particles was independently related to the increase in plasma triglyceride prevalent in this population, an increase that previously been demonstrated to result in part, from delayed clearance of the VLDL1 subfraction of very-low density lipoprotein (VLDL). The 27 patients studied were found to have normal in vitro lipase activity, however marked abnormalities in the lipid and apolipoprotein content of the VLDLI particles was observed. Despite apparently normal plasma concentration of both apolipoprotein (apo) CII and apoCIII, the patients with proteinuria possessed VLDLI particles that were deficient in both of these apolipoproteins. This deficiency was accompanied by a relative deficiency in both plasma and VLDLI apoE. VLDLI particles were also found to be smaller than those in the control group with a higher surface ratio of free cholesterol: phospholipid. The presence of smaller, free cholesterol enriched, apolipoprotein deficient particles could easily account for the observed delay in clearance of VLDLI observed in this population. 12 patients with &gt;1.5g/24hrs of urinary albumin, hypercholesterolaemia and plasma triglyceride &gt;1.5mmol/l were studied in a randomised crossover trial comparing the effects of a statin (cerivastatin) and a fibrate (fenofibrate) on the concentration of LDLIII and remnant lipoproteins (RLP). Fenofibrate produced a significant reduction in both LDLIII and RLP. Cerivastatin reduced LDLIII but not RLP, moreover the reduction in LDLIII was greater on fenofibrate than following cerivastatin. The two treatments also differed in the manner in which plasma LDLIII was reduced, thus the reduction in LDLIII following fenofibrate correlated with plasma triglyceride reduction whilst the LDLIII reduction on cerivastatin was associated with LDL-C reduction. Therefore fenofibrate seemed to reduce LDLIII by removing the excess triglyceride essential for formation of small dense LDL, with cerivastatin reducing LDLIII by decreasing the total amount of LDL present. (Abstract shortened by ProQuest.).