Sequence variation in vitamin K epoxide reductase gene is associated with survival and progressive coronary calcification in chronic kidney disease.

OBJECTIVE: Sequence variations in the gene(s) encoding vitamin K epoxide reductase complex subunit 1 (VKORC1), the enzyme target of warfarin, have been associated with increased cardiovascular disease in the general population. Coronary artery calcification (CAC) is a prevalent form of cardiovascular disease in chronic kidney disease. We tested the hypothesis that the VKORC1 rs8050894 CC genotype would be associated with mortality and progression of CAC ≤ 4 years. APPROACH AND RESULTS: This study is an observational, prospective study of 167 individuals with stages 3 to 5 chronic kidney disease. Survival ≤ 4 years was assessed in all participants, and CAC progression was measured in a subset of 86 patients. Participants with the CG/GG genotype of VKORC1 had higher baseline CAC scores (median score, 112 versus 299; P=0.036). Of those 86 patients who had a 4-year CAC score, those with the CG/GG genotype had an increased risk of progressive CAC (adjusted for age, diabetes mellitus, estimated glomerular filtration rate, and hypertension) compared with those with the CC genotype. Four-year mortality risk was 4 times higher for individuals with the CG/GG genotypes compared with individuals with the CC genotype (odds ratio, 3.8; 95% confidence interval, 1.2-12.5; P=0.02), adjusted for age, sex, diabetes mellitus, estimated glomerular filtration rate, baseline CAC, and hypertension. CONCLUSIONS: Patients with the CG/GG genotype of VKORC1 had a higher risk of CAC progression and a poorer survival. These data provide new perspectives on the potential extrahepatic role of VKORC1 in individuals with chronic kidney disease.

Associations of epicardial fat with coronary calcification, insulin resistance, inflammation, and fibroblast growth factor-23 in stage 3-5 chronic kidney disease.

BACKGROUND: Epicardial fat, quantified in a single multi-slice computed tomography (MSCT) slice, is a reliable estimate of total epicardial fat volume (EFV). We sought to determine risk factors for EFV detected in a single-slice MSCT measurement (ssEFV) in pre-dialysis chronic kidney disease (CKD) patients. Our primary objective was to determine the association between ssEFV and coronary artery calcification (CAC). METHODS: 94 pre-dialysis stage 3-5 CKD patients underwent MSCT to measure ssEFV and CAC. ssEFV was quantified at the level of the left main coronary artery. Measures of inflammation, traditional and kidney-related cardiovascular disease risk factors were collected. RESULTS: Mean age: 63.7 ± 14 years, 56% male, 39% had diabetes, and mean eGFR: 25.1 ± 11.9 mL/min/1.73 m2. Mean ssEFV was 5.03 ± 2.4 cm3. By univariate analysis, body mass index (BMI) (r = 0.53; P = <0.0001), abdominal obesity (r = 0.51; P < 0.0001), high density lipoprotein (HDL) cholesterol (r = - 0.39; P = <0.0001), insulin resistance (log homeostasis model assessment of insulin resistance (log HOMA-IR)) (r = 0.38, P = 0.001), log interleukin-6 (IL-6) (r = 0.34; P = 0.001), and log urinary albumin to creatinine ratio (UACR) (r = 0.30, P = 0.004) demonstrated the strongest associations with ssEFV. Log coronary artery calcification (log CAC score) (r = 0.28, P = 0.006), and log fibroblast growth factor-23 (log FGF-23) (r = 0.23, P = 0.03) were also correlated with ssEFV. By linear regression, log CAC score (beta =0.40; 95% confidence interval (CI), 0.01-0.80; P = 0.045), increasing levels of IL-6 (beta = 0.99; 95% CI, 0.38 - 1.61; P = 0.002), abdominal obesity (beta = 1.86; 95% CI, 0.94 - 2.8; P < 0.0001), lower HDL cholesterol (beta = -2.30; 95% CI, - 3.68 to -0.83; P = 0.002) and albuminuria (log UACR, beta = 0.81; 95% CI, 0.2 to 1.4; P = 0.01) were risk factors for increased ssEFV. CONCLUSIONS: In stage 3-5 CKD, coronary calcification and IL-6 and were predictors of ssEFV. Further studies are needed to clarify the mechanism by which epicardial fat may contribute to the pathogenesis of coronary disease, particularly in the CKD population.

Statins are associated with a reduced risk of bone fracture in hemodialysis (HD) patients.

The Dialysis Outcomes and Practice Patterns Study reported a statistically non-significant protective effect of HMG-co reductase inhibitors (statins) on bone fracture risk in hemodialysis (HD) patients. We sought to determine whether statin exposure was associated with reduced risk of bone fracture in our HD population. This was a retrospective cohort study of 174 prevalent HD patients. Fracture data are abstracted from the medical record. Subjects were considered to be on a statin if they were exposed at any time since the date of dialysis initiation. The subjects were 174 HD patients (68.4% male) with a median age of 69.1 and age range from 25.2 to 96.3 years. The median age at initiation of HD was 62.5, ranging from 15.2 to 90.5 years. The mean (SD) dialysis vintage was 7.3 (4.5) years. Seventy-seven subjects (44.3%) had statin exposure. There were a total of 54 first bone fractures. There was a positive correlation between bone fracture and dialysis vintage (p=0.023) and a negative association between bone fracture and statin exposure (p=0.044). Those with statin exposure had a higher prevalence of CAD (p=0.030) compared with those not exposed. Logistic regression analysis (stepwise, alpha=0.05) was performed with dependent variable bone fracture and independent variables age at HD initiation (forced), dialysis vintage, gender (forced), prednisone use (forced), and statin exposure. The significant predictors of bone fracture (R2=0.14, p=0.004) were age at HD initiation (p=0.016), dialysis vintage (p=0.007), and absence of statin exposure (p=0.019). Statin exposure appears to be associated with a reduced frequency of bone fracture in HD patients. Future studies evaluating the potential anabolic effect of statins on bone are required.

Apolipoprotein(a) phenotype and lipoprotein(a) level predict peritoneal dialysis patient mortality.

OBJECTIVE: To examine the associations between lipoprotein(a) [Lp(a)] level, apolipoprotein(a) [apo(a)] phenotype, and patient mortality in peritoneal dialysis (PD) patients. DESIGN: Observational prospective study of prevalent PD patients. SETTING: Tertiary-care health sciences center. PATIENTS: 54 prevalent PD patients were followed prospectively for 24 months. MAIN OUTCOME MEASURES: The exposures were Lp(a) level and apo(a) phenotype, designated by the apo(a) isoform size (number of kringle 4 repeats). Outcome was death from any cause. RESULTS: There were 24 deaths in 77.9 patient-years' follow-up. The independent predictors of death in the multivariate survival analysis were age [relative risk (RR) = 1.03, p = 0.23], diabetes (RR = 3.00, p = 0.03), diastolic blood pressure < or = 70 mmHg (RR = 2.94, p = 0.03), serum albumin (RR = 0.87, p < 0.01), and Lp(a) level (RR = 1.004, p < 0.01). There was strong inverse correlation of Lp(a) with apo(a) isoform size (r = -0.62, p < 0.01). With Lp(a) removed from the model, apo(a) isoform size was a significant predictor of death (RR = 0.91, p = 0.0497). CONCLUSIONS: Lipoprotein(a) level and apo(a) phenotype are associated with PD patient mortality. Measurement of Lp(a) level and apo(a) phenotype may be useful in clinical practice to identify patients at high risk for cardiovascular disease. Large prospective studies are needed to determine if a reversal of the increase in Lp(a) level associated with renal disease and dialysis is feasible and beneficial in reducing the risk of cardiovascular disease and mortality.