Doris T. Chan

Very Low Density Lipoprotein Metabolism and Plasma Adiponectin as Predictors of High-Density Lipoprotein Apolipoprotein A-I Kinetics in Obese and Nonobese Men

CONTEXT Hypercatabolism of high-density lipoprotein (HDL) apolipoprotein (apo) A-I results in low plasma apoA-I concentration. The mechanisms regulating apoA-I catabolism may relate to alterations in very low density lipoprotein (VLDL) metabolism and plasma adiponectin and serum amyloid A protein (SAA) concentrations. OBJECTIVE We examined the associations between the fractional catabolic rate (FCR) of HDL-apoA-I and VLDL kinetics, plasma adiponectin, and SAA concentrations. STUDY DESIGN The kinetics of HDL-apoA-I and VLDL-apoB were measured in 50 obese and 37 nonobese men using stable isotopic techniques. RESULTS In the obese group, HDL-apoA-I FCR was positively correlated with insulin, homeostasis model of assessment for insulin resistance (HOMA-IR) score, triglycerides, VLDL-apoB, and VLDL-apoB production rate (PR). In the nonobese group, HDL-apoA-I FCR was positively correlated with triglycerides, apoC-III, VLDL-apoB, and VLDL-apoB PR and negatively correlated with plasma adiponectin. Plasma SAA was not associated with HDL-apoA-I FCR in either group. In multiple regression analyses, VLDL-apoB PR and HOMA-IR score, and VLDL-apoB PR and adiponectin were independently predictive of HDL-apoA-I FCR in the obese and nonobese groups, respectively. HDL-apoA-I FCR was positively and strongly associated with HDL-apoA-I PR in both groups. CONCLUSIONS Variation in VLDL-apoB production, and hence plasma triglyceride concentrations, exerts a major effect on the catabolism of HDL-apoA-I. Insulin resistance and adiponectin may also contribute to the variation in HDL-apoA-I catabolism in obese and nonobese subjects, respectively. We also hypothesize that apoA-I PR determines a steady-state, lowered plasma of apoA-I, which may reflect a compensatory response to a primary defect in the catabolism of HDL-apoA-I due to altered VLDL metabolism.

Efficacy and safety of oral versus intravenous ascorbic acid for anaemia in haemodialysis patients.

Background:  Intravenous (i.v.) ascorbic acid (AA) improves anaemia in iron‐overloaded, erythropoietin (rEPO) hyporesponsive haemodialysis patients. While oral AA is readily attainable, the efficacy and safety of oral versus i.v. AA has not been examined.

Plasma apolipoprotein C-III metabolism in patients with chronic kidney disease

Moderate chronic kidney disease (CKD) (defined by an estimated glomerular filtration rate of 30–60 ml/min) is associated with mild hypertriglyceridemia related to delayed catabolism of triglyceride-rich lipoprotein particles. Altered apolipoprotein C-III (apoC-III) metabolism may contribute to dyslipidemia in CKD. To further characterize the dyslipidemia of CKD, we investigated the kinetics of plasma apoC-III in 7 nonobese, nondiabetic, non-nephrotic CKD subjects and 7 age- and sex-matched healthy controls, using deuterated leucine ([5, 5, 5, 2H3]leucine), gas chromatography-mass spectrometry, and multicompartmental modeling. Compared with controls, CKD subjects had higher concentrations of plasma and VLDL triglycerides and plasma and VLDL apoC-III (P < 0.05). The increased plasma apoC-III concentration was associated with a decreased apoC-III fractional catabolic rate (FCR) (1.21 ± 0.15 vs. 0.74 ± 0.12 pools/day, P = 0.03). There were no differences between apoC-III production rates of controls and those of CKD subjects. In CKD subjects, plasma apoC-III concentration was significantly and negatively correlated with apoC-III FCR (r = −0.749, P = 0.05) but not with apoC-III production rate. Plasma apoC-III concentration was positively correlated with plasma and VLDL triglycerides and VLDL apoB concentrations and negatively correlated with VLDL apoB FCR (P < 0.05 for all). ApoC-III FCR was negatively correlated with plasma and VLDL triglycerides and VLDL apoB concentration and positively correlated with VLDL apoB FCR (P < 0.05 for all). Altered plasma apoC-III metabolism is a feature of dyslipidemia in moderate CKD. Modification of apoC-III catabolism may be an important therapeutic target for reducing cardiovascular disease risk in moderate CKD.

Chronic kidney disease delays VLDL-apoB-100 particle catabolism: potential role of apolipoprotein C-III

To determine the relative contribution of obesity and/or insulin resistance (IR) in the development of dyslipidemia in chronic kidney disease (CKD), we investigated the transport of apolipoprotein (apo) B-100 in nonobese, nondiabetic, nonnephrotic CKD subjects and healthy controls (HC). We determined total VLDL, VLDL1, VLDL2, intermediate density lipoprotein (IDL), and LDL-apoB-100 using intravenous D3-leucine, GC-MS, and multicompartmental modeling. Plasma apoC-III and apoB-48 were immunoassayed. In this case control study, we report higher plasma triglyceride, IDL-, VLDL-, VLDL1-, and VLDL2-apoB-100 concentrations in CKD compared with HC (P < 0.05). This was associated with decreased fractional catabolic rates [FCRs (pools/day)] [IDL:CKD 3.4 (1.6) vs. HC 5.0 (3.2), P < 0.0001; VLDL:CKD 4.8 (5.2) vs. HC 7.8 (4.8), P = 0.038; VLDL1:CKD 10.1 (8.5) vs. HC 29.5 (45.1), P = 0.007; VLDL2:CKD 5.4 (4.6) vs. HC 10.4 (3.4), P = 0.001] with no difference in production rates. Plasma apoC-III and apoB-48 were significantly higher in CKD (P < 0.001) and both correlated with impaired FCRs of VLDL, VLDL1, and VLDL2 apoB-100 (P < 0.05). In CKD, apoC-III concentration was the only independent predictor of clearance defects in VLDL and its subfractions. Moderate CKD in the absence of central adiposity and IR is associated with mild hypertriglyceridemia due to delayed catabolism of triglyceride rich lipoproteins, IDL, and VLDL, without changes in production rate. Altered apoC-III metabolism may contribute to dyslipidemia in CKD, and this requires further investigation.

Rosiglitazone does not improve vascular function in subjects with chronic kidney disease

BACKGROUND Thiazolidinediones such as rosiglitazone (RSG) are insulin-sensitizing agents, which may improve inflammation and vascular function, and thus potentially lower cardiovascular risk in patients with chronic kidney disease (CKD). However, there is growing concern about the adverse cardiovascular effects of RSG in diabetic patients without CKD, and the data in patients with CKD remain conflicting. This study examines the effect of RSG on vascular function in patients with CKD. METHODS A randomized, double-blind placebo-controlled study comparing RSG 4 mg daily (n = 35) with placebo (n = 35) for 8 weeks was performed in CKD subjects. Primary outcome measures were flow-mediated dilatation (FMD), systemic arterial compliance (SAC) and augmentation index (AIx). Secondary outcomes included glyceryl trinitrate-mediated dilatation (GTN-MD), pulse-wave velocity (PWV), lipids, blood pressure, homoeostasis model assessment (HOMA), adiponectin, high-sensitivity C-reactive protein (hs-CRP) and high-sensitivity interleukin 6 (hs-IL-6) and in vivo marker of endothelial function [von Willebrand Factor (vWF)]. RESULTS RSG lowered HOMA score [RSG geometric mean 1.7 (95% confidence interval 1.3-2.3); placebo 1.9 (1.4-2.5), P = 0.04], hs-CRP [RSG 1.2 (0.9-1.7) mg/L; placebo 1.6 (1.2-2.3), P = 0.04] and vWF [RSG mean 126.1 ± SD 45.7%; placebo 132.7 ± 41.7, P = 0.01] but not hs-IL-6. RSG did not significantly change arterial function (FMD, GTN-MD, SAC), arterial stiffness (AIx, PWV) or blood pressure. RSG increased triglyceride concentration [RSG 1.8 (1.3-1.9) mmol/L; placebo 1.5 (1.3-1.9), P = 0.01] without affecting other lipid and lipoprotein concentrations. CONCLUSION Short-term RSG therapy reduced insulin resistance, in vivo markers of inflammation and abnormal endothelial function but had no effect on arterial function and stiffness in patients with CKD.

Interleukin-12 is associated with arterial stiffness in healthy individuals

BACKGROUND Atherosclerotic cardiovascular disease (CVD) is a chronic inflammatory disease mediated by the proinflammatory cytokines interleukin-12 (IL-12) and interleukin-18 (IL-18). Evidence suggests that IL-12 is dominant in early atherosclerosis, while IL-18 is critical in advanced atherosclerosis. In this study, we explore the association between IL-12 and IL-18 and arterial stiffness in healthy individuals. METHODS We performed a cross-sectional study examining pulse wave velocity (PWV), augmentation index (AIx), IL-12, and IL-18 in healthy individuals (N = 53) without CVD risk factors. RESULTS In multivariate regression, age (P < 0.01), systolic blood pressure (P = 0.05), and IL-12 (P < 0.01) were positively associated with PWV, and high-density lipoprotein (P = 0.04) was negatively associated with PWV (model R (2) = 0.476, P < 0.01). CONCLUSIONS IL-12, but not IL-18, is associated with PWV in healthy individuals without clinical CVD, supporting a role for IL-12 in early atherosclerosis as suggested by animal studies.

Insulin Resistance and the Metabolic Syndrome Are Associated With Arterial Stiffness in Patients With Chronic Kidney Disease

BACKGROUND Insulin resistance (IR) and the metabolic syndrome (MetS) may contribute to cardiovascular risk in chronic kidney disease (CKD). We examine the association between IR and vascular function in CKD. Furthermore, we define the prevalence of MetS and examine the association between defining MetS and vascular function. METHODS This cross-sectional study of 71 stage 3-4 CKD subjects assessed arterial stiffness (pulse wave velocity (PWV) and endothelial dysfunction (ED). IR was assessed using Homeostasis Model Assessment-IR (HOMA-IR). MetS was defined by the unified International Diabetes Federation and American Heart Association/National Heart Lung and Blood Institute criteria. RESULTS CKD subjects with HOMA-IR score above the median had significantly higher body mass index and waist circumference. They also had higher PWV, higher triglycerides with lower high-density lipoprotein concentration (P < 0.05). Age, systolic blood pressure, and HOMA-IR were independently associated with PWV, even after exclusion of diabetic subjects (n = 16) (P ≤ 0.05). MetS was more prevalent in CKD (78.9%) than controls (2.5%). MetS in CKD was associated with increased PWV (MetS(+) geometric mean = 9.5 m/s, 95% confidence interval (95% CI) = 8.9-10.2 m/s; vs. MetS(-) 8.1 m/s, 95% CI = 7.1-9.3 m/s; P = 0.03) but not ED. In a multiple logistic regression analysis, PWV higher than the median was independently associated with dysglycemia. CONCLUSIONS IR is independently associated with arterial stiffness, even in nondiabetic CKD. MetS is common and identified a subgroup of CKD patients with increased arterial stiffness, which is associated with dysglycemia.

Apolipoprotein A-II and adiponectin as determinants of very low-density lipoprotein apolipoprotein B-100 metabolism in nonobese men

Data from cellular systems and transgenic animal models suggest a role of apolipoprotein (apo) A-II in the regulation of very low-density lipoprotein (VLDL) metabolism. However, the precise mechanism whereby apoA-II regulates VLDL metabolism remains to be elucidated in humans. In this study, we examined the associations between the kinetics of high-density lipoprotein (HDL)-apoA-II and VLDL-apoB-100 kinetics, and plasma adiponectin concentrations. The kinetics of HDL-apoA-II and VLDL-apoB-100 were measured in 37 nonobese men using stable isotope techniques. Plasma adiponectin concentration was measured using immunoassays. Total plasma apoA-II concentration was positively associated with HDL-apoA-II production rate (PR) (r = 0.734, P < .01); both were positively associated with plasma triglyceride concentration (r = 0.360 and 0.369, respectively) and VLDL-apoB-100 PR (r = 0.406 and 0.427, respectively), and inversely associated with plasma adiponectin concentration (r = -0.449 and -0.375, respectively). Plasma adiponectin was inversely associated with plasma triglyceride concentration (r = -0.327), VLDL-apoB-100 concentration (r = -0.337), and VLDL-apoB-100 PR (r = -0.373). In multiple regression models including waist circumference and plasma insulin, plasma adiponectin concentration was an independent determinant of total plasma apoA-II concentration (β-coefficient = -0.508, P = .001) and HDL-apoA-II PR (β-coefficient = -0.374, P = .03). Conversely, total plasma apoA-II concentration (β-coefficient = 0.348, P = .047) and HDL-apoA-II PR (β-coefficient = -0.350, P = .035) were both independent determinants of VLDL-apoB-100 PR. However, these associations were not independent of plasma adiponectin. Variation in HDL apoA-II production, and hence total plasma apoA-II concentration, may exert a major effect on VLDL-apoB-100 production. Plasma adiponectin may also contribute to the variation in VLDL-apoB-100 production partly by regulating apoA-II transport.

The Impact of Chronic Kidney Disease and Short-Term Treatment with Rosiglitazone on Plasma Cell-Free DNA Levels

Patients with chronic kidney disease (CKD) are at increased risk of cardiovascular disease. Circulating free nucleic acids, known as cell-free DNA (cfDNA), have been proposed as a novel biomarker of cardiovascular risk. The impact of renal impairment on cfDNA levels and whether cfDNA is associated with endothelial dysfunction and inflammation in CKD has not been systematically studied. We analysed cfDNA concentrations from patients with varying degrees of CKD. In addition, to determine whether there is a relationship between cfDNA, inflammation, and endothelial dysfunction in CKD, levels of proinflammatory cytokines and von Willebrand Factor (vWF) were measured in patients treated with the peroxisome proliferator-activated receptor gamma agonist rosiglitazone or placebo for 8 weeks. cfDNA levels were not increased with renal impairment or associated with the degree of renal dysfunction (P = 0.5). Treatment with rosiglitazone for 8 weeks, but not placebo, was more likely to lead to a reduction in cfDNA levels (P = 0.046); however, the absolute changes in cfDNA concentrations during treatment were not statistically significant (P > 0.05). cfDNA levels correlated with markers of endothelial dysfunction (hsCRP P = 0.0497) and vWF (P = 0.0005). In conclusion, cell-free DNA levels are not influenced by renal impairment but do reflect endothelial dysfunction in patients with CKD.

Myeloma Renal Disease: Presentation and Outcome

Background: Renal disease can be the first presentation of multiple myeloma (MM) or develop during the disease process. Aim: To define the mode of presentation of MM to nephrologists and determine the association with patient characteristics and outcome. Methods: MM patients referred to a tertiary renal unit were studied retrospectively. Group I presented to nephrologists prior to MM diagnosis (n = 36); group II was referred to nephrology after diagnosis (n = 27), and group III was known only to haematology and never referred (n = 91). Age at presentation, gender, paraprotein type, need for dialysis, haematological and biochemical parameters, and survival were examined. Results: Of the 154 MM patients, 23.4% presented with renal impairment (group I), 17.5% were referred to nephrology after MM diagnosis (group II) and 59.1% did not receive renal input (group III). On presentation, group I had a median serum creatinine (sCr) of 700 (range 341–1,023) µmol/l and 80% required dialysis. Although the median sCr on presentation for group II was 131 (range 103–373) µmol/l, median sCr on renal referral was 554 (range 181–807) µmol/l and 57% needed dialysis. In contrast, the median sCr on presentation for group III was only 99 (range 85–117) µmol/l. Group I was more anaemic (p < 0.001) and had higher β2-microglobulin levels (p < 0.0001) on presentation compared to groups II and III. For groups I and II, the median survival after diagnosis (10.2 vs. 24.7 months, p = 0.11) and renal referral (10.5 vs. 20.0 months, p = 0.68) was not significantly different. Conclusion: Survival in myeloma renal disease remains poor regardless of the mode of presentation to nephrologists.