Lipoprotein Metabolism in the Nephrotic Syndrome in Man

Warwick, Graham L (1991) Lipoprotein Metabolism in the Nephrotic Syndrome in Man. MD thesis, University of Glasgow.

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The aim of this thesis was to characterise the abnormalities of plasma lipoprotein metabolism which occur in the nephrotic syndrome in man. Both quantitative and qualitative changes in plasma lipoproteins were documented in a series of 45 consecutive patients with heavy proteinuria. Patients with proteinuria less than the nephrotic range (<3g/24 hours) did not have any significant elevations in cholesterol concentrations compared to controls but there was a relationship between urinary albumin loss and blood cholesterol. Primary hyperlipidaemia was not associated with increased urinary albumin losses. The duration and magnitude of postprandial lipaemia following an oral fat load were not significantly greater in a group of nephrotic subjects compared to controls. However, both groups showed a high degree of interindividual variation. The lipoproteins isolated in the d< 1.006g/mL fraction following an oral fat load did not differ in composition between the two groups. Post-heparin lipase activities were not significantly different. The transfer of apolipoprotein B along the delipidation cascade from very low to low density lipoproteins was investigated using radioiodinated lipoproteins. Overall, apoB synthesis in nephrotic syndrome was not greater than in controls although the range in the nephrotic group was wide (up to four times normal). There was a significant increase in the production of apoB into the smaller, triglyceride-poor VLDL2 density interval. Both VLDL1 and VLDL2 were cleared from the plasma at slower rates in the nephrotic syndrome. There was a modest increase in apoB transfer to LDL. Studies of LDL metabolism revealed a consistent defect in fractional catabolism of LDL by the receptor-mediated pathway. LDL production was closely related to proteinuria and only rose when this exceeded 10g/day. Inhibition of cholesterol synthesis with simvastatin produced dramatic falls in total and LDL-cholesterol in these subjects. Metabolic studies revealed a heterogeneous response with a majority of patients demonstrating increased catabolism of LDL but some showing reduced synthesis. Two serious and potentially worrying adverse events were witnessed during simvastatin therapy. Particles corresponding to both HDL and LDL were isolated form urine collected from nephrotic subjects. The significance of this is uncertain but justified the corrections made for urinary LDL losses in the metabolic studies and gives credence to the suggestion that filterd lipoproteins may be nephrotoxic. The results of these studies are compared with the relatively few previous reports of lipoprotein metabolism in human nephrotic syndrome and the extensive literature on animal work. In man, catabolic defects appear to be at least as important as increases in lipoprotein production in the genesis of the hyperlipidaemia. However, some of the data is difficult to reconcile. Reasons for conflicting observations are discussed and areas requiring further research are highlighted.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Keywords: Biochemistry
Date of Award: 1991
Depositing User: Enlighten Team
Unique ID: glathesis:1991-78299
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 28 Feb 2020 12:09
Last Modified: 28 Feb 2020 12:09

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