Pro-Neurotensin depends on renal function and is related to all-cause mortality in chronic kidney disease

BACKGROUND Patients with chronic kidney disease (CKD) have a high risk of premature cardiovascular diseases (CVD) and show increased mortality. Pro-Neurotensin (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. METHODS In a central lab, circulating Pro-NT was quantified in three independent cohorts comprising 4,715 participants (cohort 1: patients with CKD; cohort 2: general population study; cohort 3: non-diabetic population study). Urinary Pro-NT was assessed in part of the patients from cohort 1. Serum Pro-NT was further related to mortality in patients with advanced CKD. Tissue-specific Nts expression was investigated in two mouse models of diabetic CKD and compared to non-diabetic control mice. RESULTS Pro-NT significantly increased with deteriorating renal function (p\textless0.001). In meta-analysis of cohorts 1-3, Pro-NT was significantly and independently associated with estimated glomerular filtration rate (p\leq0.002). 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. CONCLUSIONS Circulating Pro-NT is associated with impaired renal function in independent cohorts comprising 4,715 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.