Endothelial dysfunction in children with chronic renal failure : causes and therapies
Premature death from cardiovascular disease is common amongst adult patients with chronic renal failure (CRF). The implication for paediatric patients, the majority of whom now survive into adulthood, is that they maybe similarly affected but at an earlier age. Children with CRF already show signs of arterial disease in the absence of classical risk factors. The aim of this research was to develop ways of improving the outcome for children with CRF by investigating the effect of interventions on vascular function. Vascular endothelial function, which is dependent on nitric oxide (NO) (an antiatherogenic substance) can be measured using a non-invasive technique of high resolution ultrasound. Abnormal responses represent the earliest change in the pathogenesis of vascular disease and may be reversible. Bioavailability of NO may be reduced in CRF due to low levels of precursors, increased levels of inhibitors and increased oxidant stresses. The hypotheses examined were: 1) Dietary supplementation with L-arginine (the substrate for NO synthetase) improves large vessel endothelium-dependent vasodilatation and NO bioavailability. 2) Dietary supplementation with folic acid reduces homocysteine levels and improves large vessel endothelium-dependent dilatation. 3) Haemodialysis improves large vessel endothelium-dependent dilatation by lowering homocysteine levels, removing inhibitors of NO synthesis, reducing oxidative stress and/or removing free radicals. Methodology was double blinded, randomized and placebo controlled in children with stable CRF in the absence of classical risk factors for atherosclerosis. Endothelial function was measured in the brachial artery. Biochemical measures of NO activity and oxidant stress were also measured, along with the acute effect of haemodialysis on endothelial function. We demonstrated that L-arginine was not beneficial as a therapeutic agent. Folic acid improved vascular function and is now used routinely in all children with CRF at Gt Ormond St Hospital. Haemodialysis had an adverse effect on vascular function-an observation that needs further study as the process in itself may contribute to the development of atherosclerosis.