Can We Save the Kidneys by Protecting the Heart?

• cardiovascular disease
• heart failure
• renal dysfunction

It is of utmost importance to improve detection at an early stage of disease to prevent the development of overt disease. Over the past several decades, we have gained significant pathophysiologic insights into specific disease processes using a combination of circulating biomarkers of subclinical abnormalities and risk prediction models. From a cardiac standpoint, two clinically available biomarkers have emerged, because they are specifically released from cardiac myocytes in response to myocardial stress and injury. As biomarkers of myocardial stress, B-type natriuretic peptide (BNP) and the inactive amino terminus of its prohormone (NT-proBNP) are synthesized mainly from the ventricles in response to pressure and/or volume overload. Hence, increased BNP production signals the counter-regulatory responses to adverse neurohormonal effects on the cardiovascular system. Beyond their intended cardiovascular diagnostic uses in heart failure, natriuretic peptides have been shown to provide consistent risk stratification across the spectrum of cardiovascular diseases (1) and in the general population (2). Meanwhile, cardiac troponins (cTns) are intracellular structural proteins involved in regulation of contraction and relaxation of cardiomyocytes. Detection of circulating cTn levels represents an indicator of myocardial injury. However, low levels of circulating cTn have been detected in heart failure as well as other conditions indicative of subclinical myonecrosis (3), and they may portend adverse consequences in the nonacute setting (4). The availability of highly sensitive assays of cTn with a detection limit that is 10-fold lower than conventional assays has further expanded the ability of cTn to risk stratify. For example, detectable circulating cTn was found in 25% of the general population with low to moderate cardiovascular risk (5) and 66% in the Cardiovascular Health Study with participants who are elderly and without heart failure (6). Levels of circulating cTn have a graded association with subclinical cardiac abnormalities, such as left ventricular mass, left ventricular ejection fraction, coronary artery calcium score, and CKD (5). Furthermore, detectable cTn has been independently associated with all-cause mortality, cardiovascular mortality, and incident heart failure (5–7).

The study by Bansal et al. (8) published in this issue of CJASN extends the risk prediction use of NT-proBNP and cTn measured by a highly sensitive assay for the decline in kidney function in an elderly population at risk of developing progressive CKD. Not surprisingly, participants with higher NT-proBNP and cTn were older and had more cardiovascular comorbidities and/or pathology as well as lower eGFR. However, after extensive adjustments for cardiac and renal factors, both biomarkers had a significantly graded association with decline in kidney function and incident CKD over the median follow-up of 6 years (8). Bansal et al. (8) provided extensive statistical demonstrations to solidify their hypothesis that subclinical myocardial dysfunction as detected by these sensitive cardiac-specific biomarkers may serve as an indicator of heightened risk for adverse kidney outcomes in a nonheart failure population.

The burning question becomes as follows: can protecting the vulnerable heart save the kidneys? Whether these observed associations can support the evolving concept of cardiorenal syndrome (the complex pathophysiologic interconnections between cardiac and renal dysfunctions) remains to be determined. Nevertheless, both disease processes share common pathophysiologic feedback pathways, including activation of the renin-angiotensin-aldosterone and adrenergic systems leading to inflammation, oxidative stress, and endothelial dysfunction. Hence, this is an attractive concept, with a dysfunctional heart driving a vicious cycle leading to further damage and dysfunction of both the heart and the kidneys. It is also important to point out that both NT-proBNP and cTn are primarily cleared by the kidneys, because they are frequently elevated in patients with CKD and inversely correlated with eGFR (9,10). Furthermore, both biomarkers were independently and strongly associated with mortality, cardiovascular events, and incident heart failure in the CKD population, even after adjusting for demographic variables, traditional cardiovascular risks, and indices of kidney disease (11,12). Therefore, it is conceivable that, as an alternative explanation, elevated cardiac biomarkers may represent a more sensitive measure of underlying renal insufficiency (potentially beyond mechanisms detectable by cystatin C), thereby independently associating with subsequent kidney function decline. Regardless of the mechanisms of their accumulation, elevated cardiac biomarkers portend poor prognosis likely with or without progressive renal dysfunction.

How do these results translate into clinical practice? First, it is important to recognize that the end points used in this study were not hard end points (e.g., incident development of ESRD or mortality associated with renal diseases) but surrogate measures of kidney function decline on the basis of changes in eGFR that were arbitrarily defined (8). Therefore, routine assessment of these cardiac biomarkers to guide therapy with the intention to alter the natural history of CKD remains unproven. Regardless of the renal consequences, it is still important to recognize (although beyond the findings of this paper) that detecting elevated cardiac biomarkers represents a valuable opportunity to investigate and intervene on potential underlying cardiac vulnerabilities in patients with CKD, whereas the lack of such biomarker elevations can be prognostically reassuring (8). Second, the key to achieving meaningful use of such clinical biomarkers demands the ability for their levels to indicate a change in therapeutic approaches. Indeed, there have been promising data to support the use of cardioprotective drug regimens, such as angiotensin-converting enzyme inhibitors and β-adrenergic blockers, for delaying progression of cardiac dysfunction in the setting of elevated BNP levels in the general practice setting (13) as well as the setting of elevated cTn in patients receiving high-dose chemotherapy (14). It may, therefore, be prudent to explore future interventional studies that use cardiac biomarkers to better define indications for guideline-directed medical therapy that are not routinely used in the CKD population (e.g., β-blockers) in the prevention of heart failure and cardiovascular diseases above the reliance of cardiac imaging information and beyond the concept of renoprotection. After all, heart disease remains the major cause of death for patients with CKD; thus, protecting the heart may even save more than the kidneys.

• Copyright © 2015 by the American Society of Nephrology