Circulating angiopoietin-2 levels increase with progress of chronic kidney disease

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Abstract
Background. Angiopoietin-2 (Ang-2) is an antagonistic ligand of the endothelial-specific Tie2 receptor. Patients on dialysis have markedly elevated Ang-2 levels, and those correlate with their atherosclerotic burden. The aim of the current study was to investigate the relationship between the circulating levels of Ang-2 and renal function throughout all stages of chronic kidney disease (CKD). In addition, we aimed to detect a potential link between the nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine (ADMA) and the Ang-2 levels. Methods. Glomerular filtration rate (GFR) was assessed by the inulin clearance technique (iGFR) and compared to serum Ang-2 (immunoluminometric assay) and ADMA levels (liquid chromatography–electrospray tandem mass spectrometry) in 44 untreated non-smokers at the different stages of CKD 1–4. Ang-2 was also measured in 19 patients on dialysis (CKD stage 5). In addition, the Ang-2 and cGFR (cystatin C) measurements were taken in 15 healthy individuals before and 72 h after kidney donation. Results. The median Ang-2 levels steadily increased across the following groups: healthy controls: 0.77 (0.32–1.08) ng/mL; CKD 1: 0.83 (0.67–1.09) ng/mL; CKD 2: 0.93 (0.74–1.15) ng/mL; CKD 3: 1.13 (0.87–1.49) ng/mL; CKD 4: 1.75 (1.23–2.61) ng/mL; and CKD 5: 4.87 (3.22–7.59) ng/mL, respectively (non-parametric ANOVA P < 0.0001). Ang-2 was associated with the degree of CKD as evidenced by an inverse correlation with the iGFR (r = −0.509, P < 0.0001) and positive correlations with homocysteine (r = 0.365, P = 0.015) and phosphate (r = 0.53, P < 0.0001). Additionally, Ang-2 correlated with the ADMA levels (r = 0.35, P = 0.01). We detected a close inverse correlation between the mean changes in GFR and circulating Ang-2 at 72 h after kidney donation (r = −0.54, P = 0.03). Conclusions. Circulating Ang-2, a putative marker and potential mediator of accelerated atherosclerosis, is inversely related to GFR and increases with advanced CKD. The correlation between Ang-2 and ADMA points towards the hypothesis that the ADMA-driven NO deficiency might trigger Ang-2 release and account for the Ang-2 increase in CKD patients.

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