脑啡肽原，阿片系统替代物，作为心力衰竭的新型全面肾功能标志物。

Proenkephalin, an Opioid System Surrogate, as a Novel Comprehensive Renal Marker in Heart Failure.

机构信息

Department of Cardiology, University of Groningen, University Medical Center Groningen, The Netherlands (J.E.E., J.M.t.M., K. Damman, D.J.v.V., R.A.d.B., I.E.S., K.W.S., A.A.V.).

Sphingotec GmbH, Hennigsdorf, Germany (J.S., A.B.).

出版信息

Circ Heart Fail. 2019 May;12(5):e005544. doi: 10.1161/CIRCHEARTFAILURE.118.005544.

DOI:10.1161/CIRCHEARTFAILURE.118.005544

PMID:31091993

Abstract

BACKGROUND

PENK (proenkephalin) is a stable surrogate for enkephalins, endogenous opioid peptides, which exert cardiodepressive effects and improve renal function. PENK has been associated with heart failure (HF) severity and renal dysfunction. We therefore hypothesized that PENK could be associated with deterioration of kidney function and could have a role as a novel renal marker in HF.

METHODS AND RESULTS

In 2180 patients with HF of a large multicenter cohort (BIOSTAT-CHF [A Systems Biology Study to Tailored Treatment in Chronic Heart Failure]), the relationship between PENK and clinical variables, plasma and urinary biomarkers, and clinical end points was established. Data were validated in a separate cohort of 1703 patients with HF. PENK was elevated (>80 pmol/L, 99th percentile) in 1245 (57%) patients. Higher PENK was associated with more advanced HF and glomerular and tubular dysfunction. The strongest independent predictor of PENK was estimated glomerular filtration rate. Others were plasma NGAL (neutrophil gelatinase-associated lipocalin) and NT-proBNP (N-terminal pro-B-type natriuretic peptide; all P<0.001). Using correlation heatmaps and hierarchical cluster analyses, PENK clustered with estimated glomerular filtration rate, creatinine, NGAL, galectin-3, and urea. Higher PENK was independently associated with increased risk of deterioration of kidney function between baseline and 9 months (odds ratio, 1.29 [1.02-1.65] per PENK doubling; P=0.038; defined as >25% decrease in estimated glomerular filtration rate) and mortality (hazard ratio, 1.23 [1.07-1.43] per doubling; P=0.004). Analyses in the validation cohort yielded comparable findings.

CONCLUSIONS

Higher PENK levels are associated with more severe HF, with glomerular and tubular renal dysfunction, with incidence of a deterioration of kidney function, and with mortality. These findings suggest that the opioid system might be involved in deteriorating kidney function in HF.

摘要

背景

PENK（前啡肽原）是内啡肽（内源性阿片肽）的稳定替代物，具有心脏抑制作用，并能改善肾功能。PENK 与心力衰竭（HF）的严重程度和肾功能障碍有关。因此，我们假设 PENK 可能与肾功能恶化有关，并可能成为 HF 的一种新的肾脏标志物。

方法和结果

在一个大型多中心队列（BIOSTAT-CHF [慢性心力衰竭个体化治疗的系统生物学研究]）的 2180 例 HF 患者中，确定了 PENK 与临床变量、血浆和尿液生物标志物以及临床终点之间的关系。数据在另一个包含 1703 例 HF 患者的队列中进行了验证。在 1245 例（57%）患者中 PENK 升高（>80pmol/L，第 99 百分位数）。较高的 PENK 与更严重的 HF 以及肾小球和肾小管功能障碍相关。PENK 的最强独立预测因子是估算肾小球滤过率。其他预测因子为血浆 NGAL（中性粒细胞明胶酶相关脂质运载蛋白）和 NT-proBNP（N 末端 pro-B 型利钠肽；均 P<0.001）。使用相关热图和层次聚类分析，PENK 与估算肾小球滤过率、肌酐、NGAL、半乳糖凝集素-3 和尿素聚类。较高的 PENK 与基线至 9 个月期间肾功能恶化的风险增加独立相关（每 PENK 翻倍的比值比为 1.29[1.02-1.65]；P=0.038；定义为估算肾小球滤过率下降>25%）和死亡率（每翻倍的风险比为 1.23[1.07-1.43]；P=0.004）。验证队列中的分析得出了类似的结果。