Serial troponin measurements to monitor risk and response to endothelin A antagonism in chronic kidney disease

Chronic kidney disease (CKD) is a global epidemic, but efforts to reduce its burden have been less effective than for other noncommunicable diseases. Between 1990 and 2017, the global age-standardized mortality rate fell by 41.3% for chronic obstructive pulmonary disease, 30.4% for cardiovascular disease, 14.9% for cancer, but by only 2.8% for CKD [1]. Importantly, CKD is an independent risk factor for cardiovascular disease (CVD), which is its most common endpoint [2]. Indeed, in a recent analysis, almost 7% of global CVD burden was attributed to impaired kidney function [3]. Identifying cardiovascular risk early in CKD and assessing its response to treatments are key unmet clinical challenges. Circulating cardiac troponin is a strong independent predictor of cardiovascular morbidity and mortality in individuals with and without CVD [4]. We recently demonstrated that cardiac troponin concentrations are reduced by statin therapy and, importantly, the magnitude of this reduction is an independent predictor of future coronary events [5]. This was the first description of a biomarker that can dynamically track cardiovascular risk with time and raises the possibility that serial testing may have a role in assessing response to a range of therapies. Given increased troponin concentrations are associated with higher blood pressure (BP) [6], a common feature of CKD [7], we hypothesized that in those with CKD, troponin concentrations may also be modified by BP-lowering therapies, a cornerstone of CKD management. To explore this, we performed a post hoc analysis of a previously reported randomized, doubleblind, placebo-controlled study that examined the systemic cardiovascular and renal effects of a selective endothelin A (ETA) receptor antagonist [8]. Endothelin receptor antagonism is a potential novel therapy for CKD currently being studied for its BP-, lipidand proteinuria-lowering effects [9] as well as its ability to improve patient outcomes [10]. In a randomized, double-blind, three-way crossover study, 27 participants with optimally managed and stable nondiabetic proteinuric CKD received the selective ETA receptor antagonist sitaxentan, nifedipine once daily or a matched placebo for 6 weeks in addition to their usual medications. There was a minimum 2-week washout period between phases. All subjects completed all three phases of the study. Patient diagnoses were immunoglobulin-A (IgA) nephropathy (n1⁄4 14), focal and segmental glomerulosclerosis (n1⁄4 6), membranous nephropathy (n1⁄4 3), hypertensive nephrosclerosis (n1⁄4 2), reflux nephropathy, microhematuria of presumed glomerular origin (n1⁄4 1 for both) and one subject with an unknown cause for their CKD. The mean age was 48 6 12 years, mean body mass index was 29.3 6 4.6 kg/m and 23 participants were male. The mean estimated glomerular filtration rate was 54 6 26 mL/min/ 1.73 m and mean proteinuria was 2.0 6 1.7 g/day. Eighteen (67%) participants were on statins and 24 (89%) were on either an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker. High-sensitivity cardiac troponin I concentrations (Abbott Laboratories, Abbott Park, IL, USA) were measured in stored plasma at baseline and at 3 and 6 weeks during each phase (limit of detection 1.2 ng/L, interassay coefficient of variation (CV) <10% at 4.7 ng/L) [11]. Low-density lipoprotein (LDL) cholesterol was measured by a direct method using an enzymatic colorimetric assay; the limit of detection was 1.0 mg/dL with an intraand interassay CV of 1.4% and 2.2%, respectively. Approval for the study was granted by the local ethics review board and participants provided informed consent. The study was performed in keeping with the principles outlined in the Declaration of Helsinki. At baseline, the median troponin concentration was 2.3 ng/L (interquartile range 1.6–4.4), the mean systolic BP was 125 6 12 mmHg and the LDL cholesterol concentration was 103 6 32 mg/dL. There were no differences in any of these parameters at the start of each phase (P> 0.05 for all). Whereas placebo and nifedipine did not affect cardiac troponin, selective ETA antagonism reduced troponin concentrations by 1.6 6 0.5 ng/L (27 6 19%) (P1⁄4 0.01 versus both placebo and