Abstract
Background and Aims
While being a GFR biomarker with comparable performance than serum creatinine (SCr), Serum cystatin C (ScysC) is a better predictor of morbi-mortalilty in the general as well as the CKD population. The mechanisms underlying the prognostic dimension of ScysC are unclear. Unlike SCr, ScysC is known to strongly and positively correlate to C Reactive Protein (CRP) and thereby could reflect autonomic nervous system (ANS) dysfunction. Transversal studies have underlined the association between the decline in autonomic nervous system (ANS) activity and all-cause mortality. ANS is thought to reflexively regulate the inflammatory response (« inflammatory reflex ») and autonomic dysfunction has been shown to be associated with deleterious sustained inflammatory stress.
The Proof study is a prospective observational cohort of 1011 individuals, all aged 65 years at baseline (i.e. 2001), that was designed to assess the prognostic values of the ASN activity and its decline for the cardiovascular morbidity and mortality. We took advantage of the Proof cohort to explore the relationship between ScysC and ANS activity.
Method
The PROOF Cohort Study (PROgnostic indicator OF cardiovascular and cerebrovascular events) is constituted of elderly subjects aged 65 years in 2001 recruited from the electoral list of Saint-Etienne, France. Three initial 2-year examination were scheduled (2001–2007) along with late events monitoring which is still ongoing. At each examination, ANS activity was evaluated (baroreflex sensitivity by TILT testing) along with clinical and biological cardiovascular risk factors. Individuals with diagnosed CKD, history of myocardial infarction or stroke, heart failure, insulin-dependent diabetes mellitus, and a severe disease that limited life expectancy to 5 years or less could not be included in the Proof cohort.
SCr and ScysC were measured from sera drawn at baseline and stored at -80°C, using IDMS-traceable enzymatic method and immunoturbidimetry calibrated method, respectively.
Relationhip between SCysC and baroreflex sensitivity was analysed by univariate linear and multivariate logistic regressions.
Results
SCr and ScysC were measured in 803 patients of the Proof Cohort (71% of men) follow up to December 2019. Mean (+/- SD) SCr was 77 (+/- 15) micromol/l. ScysC was significantly associated to 18 years - all cause mortality (OR=4.1, p=0.01) and baseline CRP (p= 0.002). In univariate analysis, ScysC was the covariate most strongly associated to impaired BRS (coeff=-1.62, p=0.02), followed by diabetes (coeff=-0.73, p=0;04), gender (coeff=-0.59, p=0.001), hypertension (coeff=-0;48, p=0.009), active smoking (-0.47, p=0.01), CRP (-0.03, p=0;04) and SCr (-0.01, p= 0;02). Dyslipidemia and age were not significantly associated to BRS. In multivariate analysis, ScysC and gender (male) were the 2 covariates that independently and significantly associated with BRS.
Conclusion
By reporting for the first time an association between ScysC and BRS, our data suggest a new mechanism by which ScysC could predict excess risk of morbi-mortality beyond its sole ability to predict GFR. ScysC could be an easy-to-monitor marker of the “inflammatory reflex”.
Autonomic nervous system activity (baroreflex sensitivity): prediction by polymorphism at the tyrosine hydroxylase (TH) locus, the rate-limiting enzyme in catecholamine biosynthesis
