Jaffe, Allan S.

Abstract Background The assessment of kidney function and detection of acute kidney injury (AKI) remain cumbersome. On the one hand, because of limited accuracy of established tests: The most widely used methods are creatinine based, which lack in sensitivity, as creatinine is not purely filtrated by the kidney and rises relatively late after onset of AKI. On the other hand, because of labor-intensiveness: Gold standard inulin clearance and comparable methods involve intravenous compound infusion, blood sampling at several time points, and have error-sensitive determination methods. In recent years, several biomarkers have been put forward (e.g., NGAL, KIM-1, TIMP-2*IGFBP-7), but clinical implementation is limited up to now. Content Proenkephalin (PENK) represents a new candidate to determine kidney function. This peptide is cleaved from the precursor peptide preproenkephalin A alongside enkephalins (endogenous opioids) and is filtrated in the glomerulus. PENK plasma concentration appears to accurately represent glomerular filtration rate in patients diagnosed with sepsis or cardiac diseases. Moreover, increased PENK concentration is found to be associated with longer-term outcome concerning AKI and cardiac diseases. Lastly, the predominant receptor of enkephalins, the δ-opioid receptor, is expressed with the highest density in the kidney, suggesting that enkephalins could also exert a direct effect on kidney function. Summary In this review, we present an overview of enkephalins and the assessment of kidney function using this possible new functional biomarker PENK and compare it with established and novel biomarkers.

Objective— Ceramides are sphingolipids involved with cellular signaling. Synthesis of ceramides occurs in all tissues. Ceramides accumulate within tissues and the blood plasma during metabolic dysfunction, dyslipidemia, and inflammation. Elevations of ceramides are predictive of cardiovascular mortality. We sought to verify the utility of plasma concentrations of 4 ceramides: N-palmitoyl-sphingosine [Cer(16:0)], N-stearoyl-sphingosine [Cer(18:0)], N-nervonoyl-sphingosine [Cer(24:1)], and N-lignoceroyl-sphingosine [Cer(24:0)] in predicting major adverse cardiovascular events in a diverse patient population referred for coronary angiography. Approach and Results— Plasma ceramides were measured in 495 participants before nonurgent coronary angiography. Coronary artery disease, defined as >50% stenosis in ≥1 coronary artery, was identified 265 (54%) cases. Ceramides were not significantly associated with coronary artery disease. Patients were followed for a combined primary end point of myocardial infarction, percutaneous intervention, coronary artery bypass, stroke, or death within 4 years. Ceramides were significantly predictive of outcomes after adjusting for age, sex, body mass index, hypertension, smoking, LDL (low-density lipoprotein) cholesterol, HDL (high-density lipoprotein) cholesterol, triglycerides, serum glucose, and family history of coronary artery disease. The fully adjusted per SD hazard ratios (95% confidence interval) were 1.50 (1.16–1.93) for Cer(16:0), 1.42 (1.11–1.83) for Cer(18:0), 1.43 (1.08–1.89) for Cer(24:1), and 1.58 (1.22–2.04) for the ceramide risk score. Conclusions— Elevated plasma concentrations of ceramides are independently associated with major adverse cardiovascular events in patients with and without coronary artery disease.

AbstractBACKGROUNDIncreased cardiac troponin I or T detected by high-sensitivity assays (hs-cTnI or hs-cTnT) confers an increased risk of adverse prognosis. We determined whether patients presenting with putatively normal, detectable cTn concentrations [> limit of detection and < upper reference limit (URL)] have increased risk of major adverse cardiovascular events (MACE) or all-cause mortality.METHODSA prospective 5-year follow-up of patients recruited in the emergency department with possible acute coronary syndrome (ACS) and cTn concentrations measured with hs-cTnI (Abbott) and hs-cTnT (Roche) assays. Cox regression models were generated with adjustment for covariates in those without MACE on presentation. Hazard ratios (HRs) for hs-cTn were calculated relative to the HRs at the median concentration.RESULTSOf 1113 patients, 836 were without presentation MACE. Of these, 138 incurred a MACE and 169 died during a median 5.8-year follow-up. HRs for MACE at the URLs were 2.3 (95% CI, 1.7–3.2) for hs-cTnI and 1.8 (95% CI, 1.3–2.4) for hs-cTnT. Corresponding HRs for mortality were 1.7 (95% CI, 1.2–2.2) for hs-cTnI and 2.3 (95 % CI, 1.7–3.1) for hs-cTnT. The HR for MACE increased with increasing hs-cTn concentration similarly for both assays, but the HR for mortality increased at approximately twice the rate for hs-cTnT than hs-cTnI. Patients with hs-cTnI ≥10 ng/L or hs-cTnT ≥16 ng/L had the same percentage of MACE at 5-year follow-up (33%) as patients with presentation MACE.CONCLUSIONSMany patients with ACS ruled out and putatively normal but detectable hs-cTnI concentrations are at similar long-term risk as those with MACE. hs-cTnT concentrations are more strongly associated with 5-year mortality than hs-cTnI.

Background: Copeptin in combination with troponin has been shown to have incremental value for the early rule-out of myocardial infarction, but its performance in Black patients specifically has never been examined. In light of a potential for wider use, data on copeptin in different relevant cohorts are needed. This is the first study to determine whether copeptin is equally effective at ruling out myocardial infarction in Black and Caucasian races. Methods: This analysis of the CHOPIN trial included 792 Black and 1075 Caucasian patients who presented to the emergency department with chest pain and had troponin-I and copeptin levels drawn. Results: One hundred and forty-nine patients were diagnosed with myocardial infarction (54 Black and 95 Caucasian). The negative predictive value of copeptin at a cut-off of 14 pmol/l (as in the CHOPIN study) for myocardial infarction was higher in Blacks (98.0%, 95% confidence interval (CI) 96.2–99.1%) than Caucasians (94.1%, 95% CI 92.1–95.7%). The sensitivity at 14 pmol/l was higher in Blacks (83.3%, 95% CI 70.7–92.1%) than Caucasians (53.7%, 95% CI 43.2–64.0%). After controlling for age, hypertension, heart failure, chronic kidney disease and body mass index in a logistic regression model, the interaction term had a P value of 0.03. A cut-off of 6 pmol/l showed similar sensitivity in Caucasians as 14 pmol/l in Blacks. Conclusions: This is the first study to identify a difference in the performance of copeptin to rule out myocardial infarction between Blacks and Caucasians, with increased negative predictive value and sensitivity in the Black population at a cut-off of 14 pmol/l. This also holds true for non-ST-segment elevation myocardial infarction and, although numbers were small, similar trends exist in the normal troponin population. This may have significant implications for early rule-out strategies using copeptin.