Thomas Ebert, Denise Focke, David Petroff, Ulrike Wurst, Judit Richter, Anette Bachmann, Ulrike Lössner, Susan Kralisch, Jürgen Kratzsch, Joachim Beige, Ingolf Bast, Matthias Anders, Matthias Blüher, Michael Stumvoll and Mathias Fasshauer
Irisin has recently been introduced as a novel myokine which reverses visceral obesity and improves glucose metabolism in mice. However, regulation of irisin in humans in relation to renal and metabolic disease has not been comprehensively studied.
Design and methods
Serum irisin levels were quantified by ELISA and correlated with anthropometric and biochemical parameters of renal function, glucose and lipid metabolism, as well as inflammation, in 532 patients with stages 1–5 of chronic kidney disease (CKD).
Median serum irisin levels adjusted for age, gender, and BMI significantly decreased with increasing CKD stage and lowest concentrations were seen in patients with CKD stage 5. Furthermore, irisin concentrations were associated with facets of the metabolic syndrome including diastolic blood pressure, markers of impaired glucose tolerance, and dyslipidemia in univariate analysis. Moreover, markers of renal function, e.g. glomerular filtration rate, and insulin resistance, e.g. homeostasis model assessment of insulin resistance, remained independently associated with circulating irisin levels in robust multivariate analysis.
We show that irisin serum concentrations decrease with increasing CKD stage and are independently and positively predicted by renal function and insulin resistance. The physiological relevance of our findings, as well as the factors contributing to irisin regulation in humans, needs to be further defined in future experiments.
Anke Tönjes, Annett Hoffmann, Susan Kralisch, Abdul Rashid Qureshi, Nora Klöting, Markus Scholz, Dorit Schleinitz, Anette Bachmann, Jürgen Kratzsch, Marcin Nowicki, Sabine Paeschke, Kerstin Wirkner, Cornelia Enzenbach, Ronny Baber, Joachim Beige, Matthias Anders, Ingolf Bast, Matthias Blüher, Peter Kovacs, Markus Löffler, Ming-Zhi Zhang, Raymond C. Harris, Peter Stenvinkel, Michael Stumvoll, Mathias Fasshauer and Thomas Ebert
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.