Circulating angiopoietin-2 levels increase with progress of chronic kidney disease.
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 ((i)GFR) 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 (c)GFR (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 (i)GFR (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.
David
Sascha
S
Division of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany. david.sascha@web.de
Kümpers
Philipp
P
Lukasz
Alexander
A
Fliser
Danilo
D
Martens-Lobenhoffer
Jens
J
Bode-Böger
Stefanie M
SM
Kliem
Volker
V
Haller
Hermann
H
Kielstein
Jan T
JT
D000328:Adult; D000368:Aged; D042702:Angiopoietin-2 / Q000097:blood*; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000453:epidemiology; D016022:Case-Control Studies; D002908:Chronic Disease; D018450:Disease Progression; D005260:Female; D005919:Glomerular Filtration Rate / Q000502:physiology; D006801:Humans; D007674:Kidney Diseases / Q000097:blood* / Q000150:complications / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009392:Nephrectomy; D012307:Risk Factors; D014019:Tissue Donors
D042702:Angiopoietin-2; D015415:Biomarkers; C018524:N,N-dimethylarginine; D001120:Arginine