A14(T)
IMBALANCE OF GROWTH FACTORS FAVOURING ANTI-ANGIOGENESIS IN
CHILDREN WITH SEVERE CHRONIC KIDNEY DISEASE
Long, D1, Price, K, 1, Kolatsi-Joannou, M1, Gullet, A1, Woolf, A2, Rees, L1, Shroff, R1
1
Nephro-Urology Unit, UCL Institute of Child Health, 2Developmental and Regenerative
Medicine Research Group, University of Manchester
Young adults with chronic renal disease as children suffer from accelerated cardiovascular
disease (CVD). Endothelial damage and dysfunction is one of the earliest events in the
development of CVD and an unexplored potential cause of endothelial aberrations in such
children is a disturbance of vascular growth factors. Angiopoietin-1 (Ang-1) promotes
endothelial survival and vessel stabilisation, whereas Ang-2 is an endogenous Ang-1
antagonist. When ambient vascular endothelial growth factor-A (VEGF-A) levels are low,
Ang-2 causes endothelial death and vessel regression; in addition Ang-2 can promote
inflammatory responses. We examined local expression of Ang and VEGF-A in arteries of
children with CKD stage V (pre-dialysis and dialysis) and age-matched controls. As assessed
by immunohistochemistry, Ang-1 and VEGF-A were downregulated in patients’ peripheral
arterial smooth muscle, whereas Ang-2 was unchanged. We next measured circulating Ang-2
in pre-dialysis (n=20) and dialysis (n=30) CKD children. Ang-2 levels were markedly
elevated in dialysis-dependent individuals versus those not yet on dialysis (respectively
10.5±1.3 and 2.6±0.2 ng/ml, p<0.001) and, using paired samples, we established that Ang-2
was not cleared by haemodialysis itself. Ang-2 significantly and positively correlated with
elevated levels of soluble P-selectin and soluble VCAM-1, both endothelial activation
markers. Thus, severe childhood CKD is accompanied by an anti-angiogenic milieu within
arterial walls as evidenced by Ang-1 and VEGF-depletion. Endothelial damage is accentuated
in children treated by haemodialysis and this insult is accompanied by increased circulating
Ang-2. Thus, vascular growth factors could constitute important biomarkers and therapeutic
targets in children with CKD.