Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany.
Leipzig University Medical Center, IFB AdiposityDiseases, Leipzig, Germany.
Eur J Endocrinol. 2020 Sep;183(3):233-244. doi: 10.1530/EJE-20-0087.
Patients with chronic kidney disease (CKD) have a high risk of premature cardiovascular diseases (CVD) and show increased mortality. Pro-neurotensin (Pro-NT) was associated with metabolic diseases and predicted incident CVD and mortality. However, Pro-NT regulation in CKD and its potential role linking CKD and mortality have not been investigated, so far.
In a central lab, circulating Pro-NT was quantified in three independent cohorts comprising 4715 participants (cohort 1: patients with CKD; cohort 2: general population study; and cohort 3: non-diabetic population study). Urinary Pro-NT was assessed in part of the patients from cohort 1. In a 4th independent cohort, serum Pro-NT was further related to mortality in patients with advanced CKD. Tissue-specific Nts expression was further investigated in two mouse models of diabetic CKD and compared to non-diabetic control mice.
Pro-NT significantly increased with deteriorating renal function (P < 0.001). In meta-analysis of cohorts 1-3, Pro-NT was significantly and independently associated with estimated glomerular filtration rate (P ≤ 0.002). Patients in the middle/high Pro-NT tertiles at baseline had a higher all-cause mortality compared to the low Pro-NT tertile (Hazard ratio: 2.11, P = 0.046). Mice with severe diabetic CKD did not show increased Nts mRNA expression in different tissues compared to control animals.
Circulating Pro-NT is associated with impaired renal function in independent cohorts comprising 4715 subjects and is related to all-cause mortality in patients with end-stage kidney disease. Our human and rodent data are in accordance with the hypotheses that Pro-NT is eliminated by the kidneys and could potentially contribute to increased mortality observed in patients with CKD.
患有慢性肾病 (CKD) 的患者有发生过早心血管疾病 (CVD) 的高风险，且死亡率增加。前神经降压素 (Pro-NT) 与代谢疾病相关，可预测 CVD 发病和死亡率。然而，迄今为止，CKD 中 Pro-NT 的调节及其潜在作用尚未得到研究，以将 CKD 与死亡率联系起来。
在一个中心实验室，在包含 4715 名参与者的三个独立队列中（队列 1：CKD 患者；队列 2：一般人群研究；和队列 3：非糖尿病人群研究）定量检测循环 Pro-NT。队列 1 中的部分患者评估了尿 Pro-NT。在第四个独立队列中，进一步研究了血清 Pro-NT 与晚期 CKD 患者死亡率的关系。还进一步在两种糖尿病 CKD 的小鼠模型中研究了组织特异性 Nts 表达，并与非糖尿病对照小鼠进行了比较。
Pro-NT 随着肾功能恶化而显著增加（P < 0.001）。在队列 1-3 的荟萃分析中，Pro-NT 与估算肾小球滤过率显著且独立相关（P ≤ 0.002）。与低 Pro-NT 三分位相比，基线时处于中/高 Pro-NT 三分位的患者全因死亡率更高（风险比：2.11，P = 0.046）。与对照动物相比，严重糖尿病 CKD 小鼠的不同组织中 Nts mRNA 表达并未增加。
在包含 4715 名受试者的独立队列中，循环 Pro-NT 与肾功能受损相关，与终末期肾病患者的全因死亡率相关。我们的人体和啮齿动物数据与 Pro-NT 由肾脏清除并可能导致 CKD 患者死亡率增加的假设一致。
