ABC | Volume 111, Nº6, December 2018

Original Article Association Between Increased Levels of Cystatin C and the Development of Cardiovascular Events or Mortality: A Systematic Review and Meta-Analysis Caroline Fuchs Einwoegerer and Caroline Pereira Domingueti Universidade Federal de São João del-Rei, Divinópolis, MG - Brazil Mailing Address: Caroline Pereira Domingueti • Universidade Federal de São João del-Rei – Campus Centro Oeste Dona Lindu Rua Sebastião Gonçalves Coelho, 400. CEP 35501-296, Chanadour, Divinópolis, MG – Brazil E-mail: caroldomingueti@ufsj.edu.br , caroldomingueti@yahoo.com.br Manuscript received April 02, 2018, revised manuscript May 25, 2018, accepted June 27, 2018 DOI: 10.5935/abc.20180171 Abstract Background: Cystatin C seems promising for evaluating the risk of cardiovascular events and mortality. Objective: To evaluate the association between high levels of cystatin C and the development of cardiovascular events or mortality. Methods: The articles were selected in the Medline/PubMed, Web of Science, and Scielo databases. The eligibility criteria were prospective cohort observational trials that assessed the association of high serum levels of cystatin C with the development of cardiovascular events or mortality in individuals with normal renal function. Only studies that evaluated the mortality outcome compared the fourth with the first quartile of cystatin C and performed multivariate Cox’s proportional hazard regression analysis were included in the meta-analysis. A p value < 0,05 was considered significant. Results: Among the 647 articles found, 12 were included in the systematic review and two in the meta-analysis. The risk of development of adverse outcomes was assessed by eight studies using the hazard ratio. Among them, six studies found an increased risk of cardiovascular events or mortality. The multivariate regression analysis was performed by six studies, and the risk of developing adverse outcomes remained significant after the analysis in four of these studies. The result of the meta-analysis [HR = 2.28 (1.70-3.05), p < 0.001] indicated that there is a significant association between high levels of cystatin C and the risk of mortality in individuals with normal renal function. Conclusion: There is a significant association between high levels of cystatin C and the development of cardiovascular events or mortality in individuals with normal renal function. (Arq Bras Cardiol. 2018; 111(6):796-807) Keywords: Cardiovascular Diseases/mortality; Cystatin C; Coronary Artery Disease; Myocardial Infarction; Renal Insufficiency, Chronic; Meta-Analysis as Topic. Introduction Cardiovascular diseases are the leading cause of death in the world, accounting for 31% of all deaths. In 2015, an estimated 17.7 million people died from cardiovascular diseases, mainly coronary heart disease, cerebrovascular disease, and peripheral arterial disease. 1 In addition to high mortality, cardiovascular diseases are also associated with high morbidity, contributing to a significant share of public expenditure on health. 2 Chronic kidney disease is an important risk factor for the development of cardiovascular events, and is also responsible for increased morbidity and mortality in patients with cardiovascular disease 3 . Cystatin C consists of a marker of renal dysfunction that has been shown to be more sensitive than serum creatinine to assess the early stages of renal failure 4 . It consists of a relatively stable cysteine protease inhibitor, produced in all nucleated cells at a constant rate. 5 Because of the greater sensitivity of cystatin C for detecting the early and milder stages of renal dysfunction, the evaluation of serum levels has been shown to be promising for assessing the risk of cardiovascular events and mortality in individuals with apparently normal renal function. In recent years, some studies have demonstrated an association between serum cystatin C levels and the development of AMI. 6 In addition, cystatin C has been shown to be useful for prognostic stratification in patients with ACS. 7 However, there is a divergence between the results of studies performed to date on the clinical utility of cystatin C to assess the risk of cardiovascular events and mortality in individuals with normal renal function. 3,7,8 Although some meta-analyses. 9-12 have been published on the subject, the population of the studies selected did not consist only of patients with normal renal function. Therefore, the objective of this systematic review and meta-analysis was to evaluate the association between high levels of cystatin C and the development of cardiovascular events or mortality in subjects with normal renal function. 796