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 Although cystatin C is a more sensitive marker for detecting the early stages of CKD than creatinine, especially in groups at risk for CKD, such as patients with diabetes mellitus and renal transplant recipients, it has some limitations. 32,33 High doses of glucocorticoids and hyperthyroidism may result in increased serum levels of cystatin C, whereas hypothyroidismmay result in a decrease. 34 Some factors, such as age, male gender, body weight, smoking, C-reactive protein, cancer, inflammatory processes and steroid therapy may also influence serum levels of cystatin C, limiting its assessment in clinical practice. 35 Renal weight and volume decrease gradually between the ages of 30 and 90 years, resulting in a natural decline of renal function with increasing age. 36 Thus, elderly patients have a lower GFR, which may be associated with higher levels of cystatin C and an increased risk of cardiovascular events. 28 As most of the studies that performed the multivariate regression analysis [66.66% (n = 4)] 15,17,18,23 included age in this analysis, and nonetheless found a significant association between high levels of cystatin C and the development of adverse outcomes, it is possible to conclude that this association is age-independent. It should be noted that the two studies 20,25 that were included in the meta-analysis are among these studies that included age in the multivariate regression analysis, indicating that the association between high levels of cystatin C and any cause-related mortality observed in meta‑analysis is age-independent. All selected studies have described the renal function of patients as being normal. The estimated GFR calculated by the MDRD formula, greater than 60 mL/min/1.73 m 2 , was used as a criterion for normal renal function in 66.67% of the studies, and 8.33% used serum creatinine levels below 115 μmol/L. The estimated GFR is a better marker for renal function evaluation than serum creatinine, because it undergoes interference of muscle mass, gender, age, physical activity and diet. Moreover, unlike GFR, serum creatinine is not able to detect the presence of chronic renal disease early because its levels increase only when renal disease is already at an advanced stage. 31 The inclusion of individuals with estimated GFR greater than 60 mL/min/1.73 m 2 by most studies, including studies of the meta-analysis, supports the information that the association between high levels of cystatin C and the risk of cardiovascular events or mortality is not dependent on the renal function of the patient evaluated by creatinine-based estimated GFR, which is a marker that has good sensitivity for the detection of renal dysfunction in the early stages. Immunonephelometry and immunoturbidimetry were the most commonly used methods [75% (n = 9)] for the laboratory dosage of cystatin C and were even used by the studies included in the meta-analysis. These methods have good precision, specificity, adequate time to result, and minimum amount of sample required, being the methods of choice for cystatin C 37,38 dosage. Therefore, the use of these methods by most of the studies included in the systematic review brings greater reliability to the results. The sample size of the studies ranged from 127 to 4,663 individuals, with most of them having more than 400 individuals [58.33% (n = 7)]. 8,15,17,18,20,23,24 The study 7 that obtained the smallest sample size still included more than 100 individuals, which can be considered a significant number if the follow-up is performed for an adequate time. 39 It should be noted that this study found a significant difference between patients who developed fatal or non-fatal cardiovascular events and those who did not develop these events. This systematic review had some limitations, such as the population studied, which varied widely among the studies. Only one study 24 included healthy elderly subjects, while the population of the other studies consisted of patients at risk for cardiovascular events, 15 with STEMI and NSTEMI, 7,16 with stable CAD, 17,18 SCA, 17 patients undergoing percutaneous coronary intervention, 19 with CHF, 20,21 with CHF who underwent coronary angiography, 8 with stable angina and AMI, 22 and with a history of AMI that had angiographic evidence of stenosis greater than 50%. 23 This variation may lead to bias in the results, because cardiovascular impairment varied among the populations at the beginning of the studies, which may influence cystatin C levels, since patients with CHF or AMI could present higher levels of cystatin C at the beginning of the study if compared to patients who only present risk of cardiovascular events. 23 Since most studies evaluated a population at risk of cardiovascular events or who already have some degree of cardiovascular impairment, it is possible to suggest that cystatin C is an interesting marker for assessing the risk of cardiovascular events or mortality in these population groups and may complement the currently available markers. In addition to the variation of the study population, follow‑up time, patient classification, and outcomes also varied widely across studies. The follow-up time ranged from six months to ten years, and three studies (25%) 7,16,22 followed the patients for less than 15 months and four studies (33.33%) 15,18,20,24 have followed formore thannine years. Theprevalent timeof follow‑up of the studies was three to six years [41.67% (n = 5)]. 8,17,19,21,23 The follow-up time should be adequate for the outcome to be observed, and should be greater for the detection of mortality than for cardiovascular events. The study 22 with shorter follow‑up (6 months) found higher levels of cystatin C among patients who developed fatal and non‑fatal cardiovascular events compared to patients who did not develop these outcomes, indicating that even shorter follow‑up time was sufficient for the detection of both outcomes and for the observation of a significant association with Cystatin C levels. Both studies included in the meta‑analysis assessed the outcome for all-cause mortality. One of them followed the patients for three years and the other for ten years, with these times being adequate for the evaluation of the outcome. Patients classification to carry out the statistical analysis also varied considerably among the studies. Only five studies (41.66%), 8,17,18,20,23 including the studies of the meta-analysis, classified patients according to quartiles of cystatin C, which is the best classification to establish a cutoff point above which the risk of developing cardiovascular events or mortality would be higher. Despite these study limitations, of the articles selected in this systematic review, 11 have excellent methodological quality and only one has good quality. 804