Subclinical atherosclerosis in chronic kidney disease and diabetes

Abstract

BACKGROUND Cardiovascular disease is the leading cause of morbidity and mortality worldwide. Individuals with diabetes and chronic kidney disease (CKD) have remarkably high rates of cardiovascular disease risk. Moreover, incremental cardiovascular risk in diabetes is heterogeneous and has been often related to concomitant CKD. On the other hand, typically used risk equations based on traditional cardiovascular risk factors fail to accurately predict cardiovascular risk not only in the general population but also in these subsets of the population. Multi-territorial ultrasonography to assess subclinical atherosclerosis has emerged as a valid tool to refine cardiovascular risk assessment beyond traditional risk factors. The purpose of this thesis was to analyse the prevalence, distribution, and progression of subclinical atherosclerosis, as well as the associated cardiovascular risk factors in a large cohort of CKD subjects with and without diabetes, free from known cardiovascular disease, using multi-territorial ultrasonography. Subsequently, we further evaluated the prognostic value of subclinical atherosclerosis in determining the incidence of first cardiovascular events in this high-risk population. METHODS First, we included the data from CKD subjects with and without diabetes and free from previous cardiovascular events from the NEFRONA cohort, that were recruited at baseline, and that attended a follow-up visit 24 months later. Participants underwent a physical examination, fasting blood test, and carotid and femoral ultrasound examinations (including a total of 10 vascular territories: internal, bulb and common carotid, and common and superficial femoral arteries; right and left) at baseline and at 24-month follow-up. Plaque progression was defined as an increase in the number of territories with plaque(s) compared to the baseline examination. Multivariable models were used to assess the contribution of diabetes to the presence and progression of plaques. Other risk factors associated with the prevalence and progression of arterial disease were also evaluated using multivariate model analyses. We also conducted another study including data from the NEFRONA cohort subjects with and without diabetes that were recruited initially. All of the participants underwent a physical examination, fasting blood test, and carotid and femoral ultrasound examination (including all the 10 vascular territories described above) at baseline and were followed-up for 48 months. During the follow-up period, all cardiovascular events were registered. Bivariate analysis and Fine-Gray competing risk models were used to perform the statistical analysis. Concordance Index (C-statistics) was estimated for the strongest resulting risk models for CKD subjects with diabetes as well as for CKD subjects without diabetes. RESULTS With regards to the first study: a total of 419 individuals with diabetes and 1129 without diabetes were included. Individuals with diabetes were older, had a higher body mass index, and had a higher frequency of hypertension and dyslipidaemia. At baseline, the proportion of subjects with plaque at any of the examined territories was higher among diabetic individuals (81.4% vs 64.1%, p < 0.001). Diabetic subjects more frequently had more than two vascular territories with plaque (64.4% vs 48.4%, p < 0.001). During a 24-month follow-up period, plaque progression occurred in 72.2% individuals with diabetes whereas, among individuals without diabetes, plaque progression occurred in 55.8%. Multivariable analysis indicated that plaque at baseline was significantly associated with age, male gender, smoking, and renal replacement therapy in the non-diabetic subjects, while only age and male gender were associated with plaque presence in diabetic subjects. Plaque progression was significantly associated with age, the number of territories with basal plaque, smoking, and renal replacement therapy in both groups. Regarding the second study, during a mean follow-up time of 48 months, a total of 203 cardiovascular events was registered. One-hundred-seven cardiovascular events occurred among participants without diabetes (19.58 per 1000 person-years), and 96 cardiovascular events occurred among participants with diabetes (44.44 per 1000 person-years). After competing risk analyses and model selection, those variables that better predicted cardiovascular events 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]). Among CKD participants with diabetes, the strongest model predicting incident cardiovascular events had only one variable: the number of territories with a plaque at baseline (HR 1.782, 95% CI [1.393, 2.278]). For both models, the concordance (C) index score was greater than 0.7 at both 24 and 48 months. CONCLUSIONS Subclinical atherosclerosis is more prevalent, carries a higher plaque burden, and is more progressive in CKD subjects with diabetes than in subjects without diabetes. In these individuals, diabetes outweighs other described risk factors associated with the presence of subclinical atherosclerosis. The burden of subclinical atherosclerosis is the strongest predictor of future cardiovascular events in diabetic individuals with CKD. Early detection of the subclinical atherosclerotic burden by multi-territorial vascular ultrasound could improve cardiovascular events prediction in this population.