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 2 – Method of dosing cystatin C and criteria for the definition of normal renal function in the selected studies Author/Year Method of dosing cystatin C Criteria used to define normal renal function Sai et al., 2016 19 Immunoturbimetry GFR calculated using the MDRD equation > 60 mL/min/1.73m 2 Bansal et al., 2016 15 Immunonephelometry GFR based on cystatin C using the equation CKD-EPI > 60 mL/min/1.73 m 2 and normal albuminuria Abid et al., 2016 7 Immunoturbimetry GFR calculated using the MDRD equation > 60 mL/min/1.73 m 2 Woitas et al., 2013 18 Immunonephelometry GFR calculated using the MDRD equation > 60 mL/min/1.73 m 2 Dupont et al., 2012 8 Immunoturbimetry GFR calculated using the MDRD equation > 60 mL/min/1.73 m 2 Gao et al., 2011 21 NI NI Keller et al., 2009 17 Immunonephelometry GFR calculated using the MDRD equation > 60 mL/min/1.73 m 2 Gao et al., 2009 22 Enzyme immunoassay NI Alehagen et al., 2009 20 Immunoturbimetry Creatinine < 115 μmol/L Acuna et al., 2009 16 Immunonephelometry GFR calculated using the MDRD equation > 60 mL/min/1.73 m 2 Koenig et al., 2007 24 NI GFR calculated using the MDRD equation > 60 mL/min/1.73 m 2 Ix et al., 2007 23 Immunonephelometry GFR calculated using the MDRD equation > 60 mL/min/1.73 m 2 MDRD: Modification of diet in renal disease; NI: Not informed; GFR: Glomerular filtration rate. a study (8.33%) 22 classified the patients into four groups: stable angina, unstable angina, AMI and healthy control group; another study (8.33%) 15 classified patients according to theGFR estimated by the CKD‑EPI equation based on cystatin C: between 60 and 75 mL/min/1.73 m 2 ; between 76 and 90 mL/min/1.73 m 2 ; and above 90mL/min/1.73m 2 ; two other studies (16.66%) 7,16 further divided patients into two groups according to cystatin C levels above or below 0.95 mg/L and above and below 1.2 mg/L; and one study 24 divided them according to high or low levels of cystatin C without mentioning the cutoff point. Studies results Among the included studies, two (16.66%) 16,19 analyzed the difference between the proportion of patients with high levels of cystatinCwhodeveloped fatal or non-fatal cardiovascular events, 19 cardiovascular death, 16 and CHF 16 compared with the proportion of patients with reduced levels of Cystatin C that developed these events, and all of them found a significant difference. A study (8.33%) 24 further observed that patients with high levels of cystatin C had more adverse cardiovascular events than those with reduced levels of cystatin C. The difference between cystatin C levels inpatients whodeveloped fatal or non-fatal cardiovascular events, and thosewho did not develop these events was evaluated by four studies (33.33%), 7,17,19,21 and all found significantly higher levels of cystatin C in the group of patients who developed the events. A study (8.33%) 18 also found that cystatinC levels inpatients withCADwere higher than in the control group and another study (8.33%) 22 observed that cystatinC levels in patients withAMI were higher than in patients with unstable angina, stable angina, and control group, and that cystatin C levels in patients with unstable angina were higher than in those with stable angina and control group. Another study (8.33%) 7 found a higher survival rate in patients with lower levels of cystatin C. The risk of developing adverse outcomes was assessed by eight studies (66.66%) 15,17-21,23,24 calculating the hazard ratio. Among these, two studies (22,22%) 19,21 found an increased risk of fatal or non-fatal cardiovascular events in patients with higher levels of cystatin C; one study (11.11%) 18 observed a higher risk of death from any cause and non-fatal cardiovascular events; another study found an increased risk of cardiovascular death and death from any cause; two studies (22.22%) 17,20 found an increased risk of cardiovascular death; one study (11.11%) 23 found an increased risk of death from any cause, cardiovascular events and CHF; and one study (11.11%) 15 still observed a higher risk of left ventricular hypertrophy. Finally, one study 24 found that each increase of 0.18 mg/L of cystatin C was associated with an increased risk of cardiovascular death, death from any cause, HF, stroke and AMI. The multivariate regression analysis was performed by six (50%) 15,17-19,21,23 of these studies, with the risk of developing evaluated adverse outcomes remaining significant after the performance of this analysis in four of these studies. 18,19,21,23 Methodological quality The results of the evaluation of the methodological quality of the studies included in this review are shown in Table 5, and the detailed description of the criteria used for the distribution of the stars is presented in the legend. After the quality analysis, a study (8.33%) 22 was found to have good methodological quality and 11 studies (91.66%) had excellent methodological quality. Meta-analysis Only two studies evaluated the outcome of all-cause mortality, compared the fourth quartile of cystatin C with the first quartile, and performed a multivariate regression analysis of Cox proportional hazards and were therefore included in the meta-analysis, the result of which is shown in Figure 2. Homogeneity was observed among the studies (I 2 = 53,423 and p = 0,14); therefore, the fixed-effect model was used to calculate the hazard ratio. The result of the meta-analysis [HR = 2.28 (1.70 - 3.05), p < 0.001] indicates that there is a significant association between high levels of cystatin C and the risk of all-cause mortality in individuals with normal renal function. A symmetric distribution of the articles included in the meta-analysis was observed in the funnel plot , indicating that there is no publication bias. 800