The atherogenic lipoprotein phenotype in renal disease

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 >1.5g/24hrs of urinary albumin, hypercholesterolaemia and plasma triglyceride >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.)

Obstetric and long-term kidney outcomes in renal transplant recipients: a 40 year single-centre study

Female renal transplant recipients of childbearing age may ask what the outcomes are for pregnancy and whether pregnancy will affect graft function. We analyzed obstetric and transplant outcomes among renal transplant recipients in our center who have been pregnant between 1973 and 2013. A case−cohort study was performed identifying 83 pairs of pregnant and non-pregnant controls matched for sex, age, transplant vintage, and creatinine. There were 138 pregnancies reported from 89 renal transplant recipients. There were live births in 74% of pregnancies with high prevalence of prematurity (61%), low birth weight (52%), and pre-eclampsia (14%). Lower eGFR (OR 0.98; p = 0.05) and higher uPCR (OR 1.86; p = 0.02) at conception were independent predictors for poor composite obstetric outcome. Lower eGFR (OR 0.98; p = 0.04), higher uPCR (OR 1.50; p = 0.04), and live organ donation (OR 0.35; p = 0.02) were predictors of ≥20% loss of eGFR between immediately pre-pregnancy and one yr after delivery. There was no difference in eGFR at one, five, and 10 yr in pregnant women compared with non-pregnant controls and a pregnancy was not associated with poorer 10-yr transplant or 20-yr patient survival. Despite high rates of obstetric complications, most women had successful pregnancies with good long-term transplant function

Mosaic: A Satellite Constellation to Enable Groundbreaking Mars Climate System Science and Prepare for Human Exploration

The Martian climate system has been revealed to rival the complexity of Earth\u27s. Over the last 20 yr, a fragmented and incomplete picture has emerged of its structure and variability; we remain largely ignorant of many of the physical processes driving matter and energy flow between and within Mars\u27 diverse climate domains. Mars Orbiters for Surface, Atmosphere, and Ionosphere Connections (MOSAIC) is a constellation of ten platforms focused on understanding these climate connections, with orbits and instruments tailored to observe the Martian climate system from three complementary perspectives. First, low-circular near-polar Sun-synchronous orbits (a large mothership and three smallsats spaced in local time) enable vertical profiling of wind, aerosols, water, and temperature, as well as mapping of surface and subsurface ice. Second, elliptical orbits sampling all of Mars\u27 plasma regions enable multipoint measurements necessary to understand mass/energy transport and ion-driven escape, also enabling, with the polar orbiters, dense radio occultation coverage. Last, longitudinally spaced areostationary orbits enable synoptic views of the lower atmosphere necessary to understand global and mesoscale dynamics, global views of the hydrogen and oxygen exospheres, and upstream measurements of space weather conditions. MOSAIC will characterize climate system variability diurnally and seasonally, on meso-, regional, and global scales, targeting the shallow subsurface all the way out to the solar wind, making many first-of-their-kind measurements. Importantly, these measurements will also prepare for human exploration and habitation of Mars by providing water resource prospecting, operational forecasting of dust and radiation hazards, and ionospheric communication/positioning disruptions

Omega-3 fatty acids improve postprandial lipaemia in patients with nephrotic range proteinuria

<b>Background</b>: Patients with nephrotic range proteinuria have a marked increase in the risk of cardiovascular disease. Qualitative and quantitative changes in lipids and lipoproteins contribute to this increased risk with an abundance of atherogenic triglyceride (TG) rich apolipoprotein B containing lipoproteins. TG rich lipoproteins predominate postprandially and are associated with increased risk of coronary heart disease (CHD). Omega-3 fatty acids derived from fish oils have been shown to have beneficial effects on lipids and lipoproteins in patients without proteinuria. <b>Methods</b>: 17 patients with nephrotic range proteinuria and 17 age and sex matched controls were studied. Postprandial lipaemia was assessed in patients and controls, before and after 8 weeks treatment with 4 g daily of omega-3 fatty acids (Omacor). A standard fat load (90 g) was administered and blood sampling was performed in the fasting state and at 2, 4, 6 and 8 h after the fat load. Chylomicrons and VLDL1 density fraction was isolated from plasma by density ultracentrifugation. Postprandial chylomicron and VLDL1 triglyceride concentrations were measured and quantified using the incremental area under the curve (AUC) method. <b>Results</b>: Baseline postprandial chylomicron TG AUC was greater in patients compared with controls: median 18.5 mmol/l h (interquartile range 8.9–32.6) vs 9.3 mmol/l h (4.8–14.4) p = 0.05. Following treatment patient chylomicron AUC fell [mean reduction 6.8 mmol/l h (95% CI 0.1–13.6) p = 0.05]. No significant reduction in chylomicron AUC was observed in the controls [mean reduction 3.9 mmol/l h (95% CI −3.6 to 11.5)]. As a result, following 8 weeks treatment with omega-3 fatty acids, patient and control chylomicron AUC were no longer significantly different [patients 13.5 mmol/l h (7.4–22.9), controls 7.2 mmol/l h (4.6–14.5) both median and IQR, p = nsd]. VLDL1 TG AUC did not differ at baseline between patients and controls. Furthermore, there was no significant effect on VLDL1 AUC following treatment in either group. <b>Conclusions</b>: We have shown that there is an excess of postprandial chylomicron density fraction in patients with nephrotic range proteinuria, which is reduced by treatment with omega-3 fatty acids. We suggest that this would be an ideal therapy in combination with statins for this high risk group of patients