Abstract
Cardiovascular disease (CVD) is increasingly recognised as a complication of childhood chronic kidney disease (CKD) even in the absence of diabetes and hypertension. We hypothesized that an alteration in angiopoietin-1 and -2, growth factors which regulate endothelial and vascular function could be involved. We report that the endothelial survival factor, angiopoietin-1 is low in children with pre-dialysis CKD whereas the pro-inflammatory angiopoietin-2 is elevated in children on dialysis. In dialysis patients, angiopoietin-2 positively correlated with time on dialysis, systolic blood pressure, and carotid artery intima media thickness. Elevated angiopoietin-2 levels in dialysis versus pre-dialysis CKD patients were also associated with an anti-angiogenic (high soluble VEGFR-1 and low VEGF-A) and pro-inflammatory (high urate, E-selectin, P-selectin and VCAM-1) milieu. Ang-2 was immunodetected in arterial biopsy samples whilst the expression of VEGF-A was significantly downregulated in dialysis patients. Serum urate correlated with angiopoietin-2 levels in dialysis patients and addition of uric acid was able to induce rapid release of angiopoietin-2 from cultured endothelial cells. Thus, angiopoietin-2 is a marker for cardiovascular disease in children on chronic dialysis and may act as an anti-angiogenic and pro-inflammatory effector in this context. The possibility that the release of angiopoietin-2 from endothelia is mediated by urate should be explored further.
Highlights
Our study demonstrated that circulating Ang-2 levels were markedly elevated in dialysis patients compared with healthy controls and pre-dialysis chronic kidney disease (CKD) individuals
Ang-2 positively correlated with time on dialysis, systolic blood pressure and carotid artery intima media thickness (cIMT), but not pulse wave velocity (PWV)
Previous studies have demonstrated that in the more compliant vessels of children with CKD structural changes precede functional alterations with increases in cIMT observed before alterations in PWV
Summary
Children with chronic kidney disease (CKD) develop early onset cardiovascular disease (CVD). [1] Manifestations of CVD in childhood CKD include arterial stiffening [2] and calcification, [3] premature atherosclerosis, [4] and left ventricular hypertrophy. [5] Over time, CKD developing in children is associated with increased cardiovascular mortality that markedly accelerates once dialysis is initiated. [6,7]One of the earliest signs of CVD in individuals with CKD is endothelial damage and dysfunction, [8] and this has been shown even in children with pre-dialysis CKD. [9] In this context, potential causes of endothelial damage and aberrant repair are disturbances in growth factors involved in the formation of vascular networks. [10] Angiopoietin-1 (Ang-1) binds and activates the Tie-2 receptor on endothelia where it promotes cell survival and decreases vascular permeability. [11] As such, Ang-1 is usually considered beneficial for endothelial cell function. [5] Over time, CKD developing in children is associated with increased cardiovascular mortality that markedly accelerates once dialysis is initiated. One of the earliest signs of CVD in individuals with CKD is endothelial damage and dysfunction, [8] and this has been shown even in children with pre-dialysis CKD. Two other studies reported that Ang-2 levels were elevated in adults on hemodialysis (HD) or peritoneal dialysis (PD) compared with healthy controls. No clinical studies have examined angiopoietins in childhood CKD, despite the latter having similar cardiovascular complications as adults with CKD, but at a proportionately earlier age. We hypothesized that an imbalance of angiopoietin vascular growth factors, which would be detrimental to endothelial structure and function, might be present in children with CKD. We predicted that childhood CKD would be associated with elevated Ang-2 and that it would correlate with inflammatory markers
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