*3.3. Cardiac Biomarkers*

Several cardiac biomarkers were investigated, mainly for establishing their role in CV and renal risk prediction in CKD patients. Cardiac troponins (high-sensitivity cardiac troponin (hs-cTnT)) and natriuretic peptides (N-terminal pro-B-type natriuretic peptide (NT-proBNP)) are largely used in CV medicine to diagnose coronary artery disease (CAD) and heart failure (HF), respectively. Both these biomarkers are, thus, an expression of subclinical abnormalities in the heart [54,55]. However, one major problem that makes their introduction in individual risk prediction difficult is that cardiac markers are an expression of both cardiac and kidney dysfunction and cannot discern these two conditions. Natriuretic peptides act by promoting the tubular natriuresis across the kidney and counteracting the effects of renin–angiotensin–aldosterone system, which is triggered by heart failure, as well as renal dysfunction [56]. Concerns about the interpretation of hs-cTnT and natriuretic peptides also derive from the evidence that these marker concentrations are influenced by kidney function levels [56,57]. So far, cardiac markers found more application in the context of prognostic estimation of cardiorenal syndromes (CRS), clinical disorders where an acute or chronic dysfunction of one organ may lead to an acute or chronic dysfunction of the other, thus testifying the strict relationship between the heart and the kidney [58]. In the general population, hs-cTnT and NT-proBNP were shown to be strong predictors for incident HF over time [59,60]. In the setting of CKD, an attempt to evaluate, with appropriate statistical tools, the contribution of cardiac markers to the development of CV events was made using the Atherosclerosis Risk in Communities study (ARIC) population. In this study, examining 7682 non-CKD and 970 patients with CKD stage 1–5, hs-cTnT and NT-proBNP were associated with the development of CV events (defined as the composite of coronary heart disease, stroke, and HF) independently of kidney measures (eGFR and albuminuria) [61]. The finding was confirmed for both CKD and non-CKD patients, as well as for patients with or without previous CV disease. However, the interpretation of these results should be done with caution since the ARIC cohort was stratified, for this analysis, by the presence/absence of CKD, thus limiting the influence of kidney measures on CV risk prediction [61]. Results of the association between cardiac markers and renal outcomes in CKD patients are even more conflicting. The CRIC investigators found, in a cohort of over 3000 CKD patients, that increased plasma levels of growth differentiation factor-15 (GDF-15, a member of the transforming growth factor (TGF)-β cytokine family), hs-cTnT, and NT-proBNP were associated with CKD progression. defined as the onset of ESKD or 50% eGFR decline [62]. However, when all these parameters were added to the prediction model including traditional CV risk factors, the model discrimination (i.e., the ability of the model to separate individuals who develop events from those who do not; see more details in Section 5) did not improve, meaning that their clinical utility was scarce. Moreover, in the Framingham cohort, hs-cTnT was not associated with a faster eGFR decline or with incident CKD [63]. There is, overall, a need for future work to assess the role of cardiac markers in CV and renal risk prediction [61–63].
