Anke Tönjes1, Annett Hoffmann1, Susan Kralisch1,2, Abdul Rashid Qureshi3, Nora Klöting2, Markus Scholz2,4, Dorit Schleinitz2, Anette Bachmann1, Jürgen Kratzsch5, Marcin Nowicki6, Sabine Paeschke6, Kerstin Wirkner4,7, Cornelia Enzenbach4,7, Ronny Baber5,7, Joachim Beige8,9, Matthias Anders10, Ingolf Bast10, Matthias Blüher1,11, Peter Kovacs1,2, Markus Löffler4,7, Ming-Zhi Zhang12,13, Raymond C Harris12,13, Peter Stenvinkel3, Michael Stumvoll1, Mathias Fasshauer1,2,14, Thomas Ebert1,2,3. 1. Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany. 2. Leipzig University Medical Center, IFB AdiposityDiseases, Leipzig, Germany. 3. Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden. 4. Institute of Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany. 5. Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Leipzig, Germany. 6. nstitute of Anatomy, University of Leipzig, Leipzig, Germany. 7. LIFE - Leipzig Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany. 8. Division of Nephrology and KfH Renal Unit, Hospital St. Georg, Leipzig, Germany. 9. Martin-Luther-University Halle/Wittenberg, Halle, Germany. 10. Outpatient Nephrology Care Unit, Leipzig, Germany. 11. Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig, Leipzig, Germany. 12. Department of Medicine, Division of Nephrology, Vanderbilt University School of Medicine, C3121 MCN, Nashville, Tennessee, USA. 13. Department of Medicine, Vanderbilt University School of Medicine, Nashville Veterans Affairs Hospital, Nashville, Tennessee, USA. 14. Institute of Nutritional Science, Justus-Liebig-University, Giessen, Germany.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Authors: Sam Hobson; Henriette de Loor; Karolina Kublickiene; Joachim Beige; Pieter Evenepoel; Peter Stenvinkel; Thomas Ebert Journal: Toxins (Basel) Date: 2022-06-16 Impact factor: 5.075