Subclinical atherosclerosis burden predicts cardiovascular events in individuals with diabetes and chronic kidney disease

Background: Individuals with diabetes have remarkably high rates of cardiovascular morbidity and mortality. However, the incremental cardiovascular risk in diabetes is heterogeneous and has often been related to renal involvement. The purpose of this study was to analyse the prognostic value of subclinical atherosclerosis in determining the incidence of first cardiovascular events (CVEs) in individuals with diabetes and chronic kidney disease (CKD) compared to CKD individuals without diabetes. Methods: We included data from individuals with CKD with and without diabetes, free from pre-existing cardiovascular disease, from the NEFRONA cohort. Participants underwent baseline carotid and femoral ultrasound and were followed up for 4 years. All CVEs during follow-up were registered. Bivariate analysis and Fine-Gray competing risk models were used to perform the statistical analysis. Results: During the mean follow-up time of 48 months, a total of 203 CVE was registered. 107 CVE occurred among participants without diabetes (19.58 per 1000 person-years) and 96 CVE occurred among participants with diabetes (44.44 per 1000 person-years). Following the competing risk analysis, the variables predicting CVEs in CKD individuals without diabetes were the number of territories with plaque at baseline (HR 1.862, 95% CI [1.432;2.240]), age (HR 1.026, 95% CI [1.003;1.049]) and serum concentrations of 25-OH vitamin D (HR 0.963, 95% CI [0.933;0.094]). The only variable predicting CVEs among CKD participants with diabetes was the number of territories with plaque at baseline (HR 1.782, 95% CI [1.393, 2.278]). For both models, concordance (C) index yielded was over 0.7. Conclusions: The burden of subclinical atherosclerosis is the strongest predictor of future CVEs in diabetic individuals with CKD. Early detection of subclinical atherosclerotic burden by multiterritorial vascular ultrasound could improve CVE prediction in this population.Peer reviewe

Association of Candidate Gene Polymorphisms With Chronic Kidney Disease: Results of a Case-Control Analysis in the Nefrona Cohort

Chronic kidney disease (CKD) is a major risk factor for end-stage renal disease, cardiovascular disease and premature death. Despite classical clinical risk factors for CKD and some genetic risk factors have been identified, the residual risk observed in prediction models is still high. Therefore, new risk factors need to be identified in order to better predict the risk of CKD in the population. Here, we analyzed the genetic association of 79 SNPs of proteins associated with mineral metabolism disturbances with CKD in a cohort that includes 2, 445 CKD cases and 559 controls. Genotyping was performed with matrix assisted laser desorption ionizationtime of flight mass spectrometry. We used logistic regression models considering different genetic inheritance models to assess the association of the SNPs with the prevalence of CKD, adjusting for known risk factors. Eight SNPs (rs1126616, rs35068180, rs2238135, rs1800247, rs385564, rs4236, rs2248359, and rs1564858) were associated with CKD even after adjusting by sex, age and race. A model containing five of these SNPs (rs1126616, rs35068180, rs1800247, rs4236, and rs2248359), diabetes and hypertension showed better performance than models considering only clinical risk factors, significantly increasing the area under the curve of the model without polymorphisms. Furthermore, one of the SNPs (the rs2248359) showed an interaction with hypertension, being the risk genotype affecting only hypertensive patients. We conclude that 5 SNPs related to proteins implicated in mineral metabolism disturbances (Osteopontin, osteocalcin, matrix gla protein, matrix metalloprotease 3 and 24 hydroxylase) are associated to an increased risk of suffering CKD

Circulating CD5L is associated with cardiovascular events and all-cause mortality in individuals with chronic kidney disease

This study assessed the association of CD5L and soluble CD36 (sCD36) with the risk of a cardiovascular event (CVE), including CV death and all-cause mortality in CKD. We evaluated the association of CD5L and sCD36 with a predefined composite CV endpoint (unstable angina, myocardial infarction, transient ischemic attack, cerebrovascular accident, congestive heart failure, arrhythmia, peripheral arterial disease [PAD] or amputation by PAD, aortic aneurysm, or death from CV causes) and all-cause mortality using Cox proportional hazards regression, adjusted for CV risk factors. The analysis included 1,516 participants free from pre-existing CV disease followed up for 4 years. The median age was 62 years, 38.8% were female, and 26.8% had diabetes. There were 98 (6.5%) CVEs and 72 (4.8%) deaths, of which 26 (36.1%) were of CV origin. Higher baseline CD5L concentration was associated with increased risk of CVE (HR, 95% CI, 1.17, 1.0-1.36), and all-cause mortality (1.22, 1.01-1.48) after adjusting for age, sex, diabetes, systolic blood pressure, dyslipidemia, waist circumference, smoking, and CKD stage. sCD36 showed no association with adverse CV outcomes or mortality. Our study showed for the first time that higher concentrations of CD5L are associated with future CVE and all -cause mortality in individuals with CKD.Peer reviewe

Factors predicting cardiovascular events in chronic kidney disease patients. Role of subclinical atheromatosis extent assessed by vascular ultrasound

<div><p>Patients with chronic kidney disease (CKD) have an increased incidence of cardiovascular events (CVE). The contribution of subclinical atheromatosis extent, including femoral arteries, to CVE in CKD patients has not been investigated. In this paper, we examine the prognostic value of subclinical atheromatosis extent, assessed as the number of arterial territories with plaque, in predicting the incidence of major and minor CVE. The NEFRONA is a multicenter, prospective cohorts study that recruited 2445 CKD subjects and 559 controls, free from previous cardiovascular disease, in 81 medical centers across Spain. The presence of atheroma plaque was assessed by arterial ultrasound in ten arterial territories (carotid and femoral). The predictive power of the presence or absence of atheroma plaque in any territory was compared with the quantification of atheroma extent as the number of territories with plaque. During the median follow up of 48 months, 216 CVE were reported. Factors predicting the incidence of CVE in the whole cohort were being male, CKD patient, lower levels of 25(OH) vitamin D, higher levels of cholesterol and the extent of subclinical atheromatosis, yielding a higher concordance (C) index than the presence or absence of plaque. In stratified analysis including specific factors of CKD patients not on dialysis, the variables predicting CVE were the same as in the whole cohort, plus higher levels of potassium. Again, the inclusion of the information about atheromatosis as number of territories with plaque, presented a higher C index than the presence or absence of plaque. In the dialysis population, significant variables were older age, diabetes, dialysis vintage and higher levels of cholesterol and phosphate. In this case the higher C index was obtained with the information about plaque presence.</p><p>Subclinical atheromatosis extent, including femoral arteries, influences CVE in CKD and its detection could improve the prediction of cardiovascular events.</p></div

Bivariate analysis of the basal characteristics of the CKD patients not on dialysis in the NEFRONA cohort according to the incidence of CVE.

<p>Quantitative data are expressed as mean and standard deviation (SD) or median, (p25, p75) depending on the normality of the distribution. Qualitative variables are expressed as N (%). HR: Hazard ratio; CI95%: 95% confidence interval. SBP: systolic blood pressure; PP: pulse pressure; cIMT: intima media thickness; ABI: ankle-brachial index; hsCRP: high sensitivity C-reactive protein. Ref: Reference.</p

Multivariate competing risk regression to model the incidence of CVE.

<p>Results are expressed as Hazard Ratios (HR; *Exponential β for independent variables with interactions) and 95% Confidence interval (95% CI). The variables introduced to build multivariate models were all the significant variables listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0186665#pone.0186665.t001" target="_blank">Table 1</a> plus any potential confounder.</p

Bivariate analysis of the basal characteristics of the NEFRONA cohort according to the incidence of CVE.

<p>Quantitative data are expressed as mean and standard deviation (SD) or median, (p25, p75) depending on the normality of the distribution. Qualitative variables are expressed as N (%). HR: Hazard ratio; CI95%: 95% confidence interval. SBP: systolic blood pressure; PP: pulse pressure; cIMT: intima media thickness; ABI: ankle-brachial index; hsCRP: high sensitivity C-reactive protein. Ref: Reference.</p

Kaplan-Meier curve showing the unadjusted incidence of CVE along the follow up time (months) depending on (A) the presence or absence of atheroma plaque (p<0.000 Mantel-Haenzel) or (B) the number of arterial territories with atheroma plaque (p<0.000 Mantel-Haenzel linear trend).

<p>Kaplan-Meier curve showing the unadjusted incidence of CVE along the follow up time (months) depending on (A) the presence or absence of atheroma plaque (p<0.000 Mantel-Haenzel) or (B) the number of arterial territories with atheroma plaque (p<0.000 Mantel-Haenzel linear trend).</p

Bivariate analysis of the basal characteristics of the dialysis patients in the NEFRONA cohort according to the incidence of CVE.

<p>Quantitative data are expressed as mean and standard deviation (SD) or median, (p25, p75) depending on the normality of the distribution. Qualitative variables are expressed as N (%). HR: Hazard ratio; CI95%: 95% confidence interval. SBP: systolic blood pressure; PP: pulse pressure; cIMT: intima media thickness; ABI: ankle-brachial index; hsCRP: high sensitivity C-reactive protein. Ref: Reference.</p