The Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) Study: Objectives,Design, and Methodology

Background and objectives: Children and adolescents with chronic kidney disease (CKD) are at high risk for cardiovascular morbidity and mortality. A systemic arteriopathy and cardiomyopathy has been characterized in pediatric dialysis patients by the presence of morphologic and functional abnormalities.Design, setting, participants, & measurements: The Cardiovascular Comorbidity in Children with CKD (4C) Study is a multicenter, prospective, observational study aiming to recruit more than 600 children, aged 6 to 17 years, with initial GFR of 10 to 45 ml/min per 1.73 m². The prevalence, degree, and progression of cardiovascular comorbidity as well as its association with CKD progression will be explored through longitudinal follow-up. The morphology and function of the heart and large arteries will be monitored by sensitive noninvasive methods and compared with aged-matched healthy controls. Multiple clinical, anthropometric, biochemical, and pharmacologic risk factors will be monitored prospectively and related to the cardiovascular status. A whole-genome association study will be performed to identify common genetic variants associated with progression of cardiovascular alterations and/or renal failure. Monitoring will be continued as patients reach end-stage renal disease and undergo different renal replacement therapies.Results: While cardiovascular morbidity in adults is related to older age and additional risk factor load (e.g., diabetes), the role of CKD-specific factors in the initiation and progression of cardiac and vascular disease are likely to be characterized with greater sensitivity in the pediatric age group.Conclusions: The 4C study is expected to provide innovative insight into cardiovascular and renal disease progression in CKD.Children and adolescents with chronic kidney disease (CKD) are at high risk for cardiovascular events (1). In young adults with end-stage renal disease, cardiovascular mortality is increased 500- to 1000-fold compared with the general population (2).Young CKD patients usually do not present with clinical symptoms of cardiovascular disease (CVD). Ischemic heart disease and myocardial infarction are very rare in childhood. However, even children may present with subclinical CVD, and significant structural and functional changes of the heart and the large arteries can be detected by sensitive methods (3,4).Recently, noninvasive measurements of vascular morphology and function such as carotid artery intima-media thickness (cIMT), pulse wave velocity (PWV), and the pulse wave augmentation index (AI) have been established as valid surrogate markers of arteriopathy in adult CKD patients (5). Similar to echocardiographic findings (6), these surrogate markers are highly predictive for future cardiovascular events.The pediatric population appears uniquely suited to study the effects of CKD on the cardiovascular system due to the virtual absence of vascular morbidity related to aging, diabetes, and smoking. However, the factors underlying early cardiovascular morbidity in CKD and their relative contribution are poorly understood. Moreover, the natural evolution of cardiovascular lesions and their relationship to kidney disease progression are largely unknown due a lack of prospective observational studies in a sufficiently large cohort of pediatric CKD patients.To improve our understanding of the causes and consequences of cardiovascular comorbidity in children with CKD, a consortium of pediatric nephrologists in Europe has joined to perform a long-term prospective observational study monitoring the cardiovascular health of children as they advance through successive stages of CKD. The Cardiovascular Comorbidity in Children with CKD (4C) Study will follow up to 625 patients in more than 50 pediatric nephrology units in 14 European countries (http://www.4c-study.org).