The effect of CAPD treatment on lipoprotein metabolism: kinetics and biochemical analysis
Mortality rates due to cardiovascular diseases (CVD) are high in patients with end stage renal disease (ESRD) and continuous ambulatory peritoneal dialysis (CAPD). Although there is consensus about plasma levels of several lipo(proteins) in these patients (low albumin, high fibrinogen, high VLDL-1 apoB100, VLDL-2 apoB100 and IDL apoB100 but normal LDL apoB100), the mechanism(s) behind the disturbed plasma levels are often unknown. The final concentration of each protein is dependent upon the net changes in its rate of synthesis and catabolism and upon urinary loss that occur following the onset of proteinuria as seen in several renal patients and/or peritoneal loss in CAPD patients. Since quantitative information regarding synthesis and catabolism of proteins is essential to understand their metabolism in health and disease, we developed several protocols to investigate synthesis rates and catabolic rates in a wide spectrum of proteins.
For this purpose, we use innovative stable isotope approaches. The procedure for studying protein kinetics, involves administration of a priming dose of the stable isotope labeled amino acid (13C valine) followed by a constant intravenous infusion of the same isotope. The priming dose was given to allow a rapid establishment of an isotopic steady state in plasma. The fact that kinetics of several proteins can be investigated simultaneously makes endogenous labeling procedures a powerful tool. The duration of the infusion and the used dose is not only protein-dependent, but also patient-dependent. For analysis of the kinetic data, generated from the primed/constant infusion studies, a linear regression model, a mono-exponential model or a multicompartmental model (SAAM II) can be used.
Furthermore, another objective of the project is to study the exact mechanisms of dyslipidemia in renal disease. Uremic patients have also been reported to be insulin resistant. This, in turn, may be accompanied by an increase in free fatty acids (FFA) fluxes, which are the main determinants for hepatic VLDL apoB100 production. Interestingly, dyslipidemia may deteriorate upon initiation of CAPD. CAPD treatment leads to peritoneal absorption of considerable amounts of glucose. This increased glucose delivery may stimulate de novo lipogenesis and hepatic FFA availability. De novo lipogenesis (fatty acid synthesis) is determined from the incorporation of [1-13C]-acetate into palmitate of VLDL-triglycerides as measured by GC-MS, using Mass Isotopomer Distribution Analysis (MIDA). To determine lipolysis in adipose tissue, [D2]-palmitate complexed with human serum albumin is infused to measure the rate of appearance (Ra) of free fatty acids. Measurements will be performed in patients with ESRD just before initiation of CAPD treatment (basal), in CAPD treatment patients and in matched control subjects. The obtained results will be of importance for understanding the pathophysiology of the lipo(protein) metabolism in these patients.
On 17 june 2003 Dr. Berthil Prinsen defended his thesis titled ‘Regulation of human lipoprotein metabolism in health and renal disease’. Anyone who is interested can receive a thesis by sending an email to: Dr. Berthil Prinsen;
b.prinsen@umcutrecht.nl In vivo cardiovascular and renal risk factors in patients with proteinuria
Information for this project can be obtained from: Dr. Monique de Sain;
m.g.desain@umcutrecht.nl last update: 20 april 2004