ABC | Volume 111, Nº6, December 2018

Original Article Einwoegerer & Domingueti Cystatin C and cardiovascular event or mortality Arq Bras Cardiol. 2018; 111(6):796-807 Table 5 – Evaluation of study quality according to Newcastle-Ottawa Scale Author/Year Selection 1 2 3 4 Comparability 5 Outcomes 6 7 8 Total score Sai et al ., 2016 19 * * * - ** * * * 8 Bansal et al., 2016 15 * * * - ** * * * 8 Abid et al., 2016 7 * * * - * * * * 7 Woitas et al ., 2013 18 * * * - ** * * * 8 Dupont et al., 2012 8 * * * - * * * * 7 Gao et al., 2011 21 * * - - ** * * * 7 Keller et al ., 2009 17 * * * - ** * * * 8 Gao et al., 2009 22 * * - - * * - * 5 Alehagen et al., 2009 20 * * * - * * * * 7 Acuna et al., 2009 16 * * * - * * * * 7 Koenig et al ., 2007 24 * * - * * * * * 7 Ix et al., 2007 23 * * * - ** * * * 9 1 - Representativeness of the exposed cohort: all the studies received one star, because the exposed cohort was a little representative of the average in the community; 2 - Selection of the unexposed cohort: all studies received one star, because the unexposed cohort was obtained in the same community of the exposed cohort; 3- Determination of exposure: only studies that dosed cystatin C using the immunonephelometry or immunoturbidimetry methods received a star; 4 - Demonstration that the outcome of interest was not present at the beginning of the study: studies in which patients did not present any cardiovascular disease at the beginning of the study received one star; 5 - Cohort comparability based on design and analysis: studies that performed multivariate regression analysis of Cox proportional hazards and defined normal renal function as GFR > 60 mL/min/1.73 m 2 received 2 stars. Studies that only defined normal renal function as GFR > 60 mL/min/1.73 m 2 but did not perform multivariate regression analysis of Cox proportional hazards received 1 star. 6 - Determination of outcome: all studies received one star, because the evaluation of the outcome was performed by the physicians independently; 7 - Adequate follow-up period for the occurrence of outcome (s): studies in which patients were followed for at least six months received one star, and studies in which patients were followed for less than six months did not receive a star; 8 - Adequacy of the follow-up period of the cohort: studies in which at least 90% of the patients were followed to the end or who did not comment if there were significant loss of patients during follow-up received one star. indicate that there is a significant association between high levels of cystatin C and the development of cardiovascular events or mortality in subjects with normal renal function assessed by serum creatinine-based GFR. A possible mechanism for the association between high levels of cystatin C and the development of cardiovascular events is related to the atherogenic process. The development of lesions in the arteries endothelium results in the accumulation of cholesterol in the artery wall, and in the development of the atherosclerotic plaque. 25 It has been suggested that lysosomal cathepsins, whose production is stimulated by inflammatory cytokines, may contribute to the degradation of the atherosclerotic plaque. As cystatin C is able to inhibit lysosomal cathepsins, it is possible to suggest that elevated levels of cystatin C may contribute to non‑degradation of atherosclerotic plaque, resulting in increased risk of cardiovascular events. 26,27 Another possible mechanism is related to the fact that cystatin C presents a greater sensitivity for the detection of the initial stages of renal dysfunction than serum creatinine or creatinine-based GFR. 28,29 Several authors have already demonstrated that renal dysfunction is associated with an increased risk of cardiovascular events. 30,31 Thus, it is possible to suggest that patients who have normal renal function assessed by GFR based on creatinine or serum creatinine but who have high levels of cystatin C may present with renal dysfunction at an earlier stage, which could be associated with an increased risk of cardiovascular events. 1.281 0.718 0.346 0.166 18.7% 81.3% 100.0% 3.60 [1.83, 7.09] 2.05 [1.48, 2.84] 0.01 0.1 1 10 100 Favours [experimental] Favours [control] Ix et al., 2007 Woitas et al., 2013 Total (95% Cl) Heterogeneity: Chi 2 = 2.15, df = 1 (p = 0.14); I 2 = 54% Test for overall effect: Z = 5.50 (p < 0.00001) Study or Subgroup log[Hazard Ratio] SE Weight IV, Fixed, 95% Cl IV, Fixed, 95% Cl Hazard Ratio Hazard Ratio Figure 2 – Metanalysis of studies evaluating the association between high levels of cystatin C and the risk of mortality from any cause through the comparison between the fourth and first quartiles of cystatin C. 803