HMG CoA reductase inhibition and endothelial function in children with chronic kidney disease (CKD) – a pilot study

Cardiovascular (CVS) death accounts for almost a quarter of paediatric and young adult end stage kidney disease deaths (1) and traditional CVS risk factors are often evident at an early age in children with chronic kidney disease (CKD). Endothelial dysfunction is a precursor of atherosclerosis (2) and it has been documented to be present by the first decade of life in children with CKD. (3). Given that endothelial dysfunction occurs very early in the timeline of atherosclerosis, it would seem to be an attractive target for therapeutic intervention (4). There is some evidence that statins may improve endothelial dysfunction in nephrotic syndrome (5), and in adults with raised (6,7) and borderline raised (8) lipid levels. We therefore designed an intervention trial in children with CKD to determine whether we could improve endothelial dysfunction by using an HMG CoA reductase inhibitor (statin). Patients were included if lipid levels were ‡50th percentile (rather than the more conventional 95th percentile) because the risk of hyperlipidaemia seems to be continuous, evidenced by an almost linear correlation between increasing lipid levels and decreasing arterial distensibility in normal children (9). The objective of this study was to assess the effect of statin-associated cholesterol lowering on endothelial function, lipoprotein levels, C reactive protein (CRP), blood pressure (BP) and renal function in mildly hyperlipidaemic children with CKD stages 3–4 [estimated glomerular filtration rate (GFR) (10) <60 mL ⁄ min ⁄ 1.73 m]. A prospective, randomized double-blinded placebo controlled, crossover trial of atorvastatin 10 mg daily for 8 weeks in children (5–17 years of age; n = 8) with serum lipoprotein levels >50th percentile was conducted (i.e. each patient was studied before and after 8 weeks of placebo and atorvastatin with a 4-week washout period between treatment arms). Seven of eight children were taking Angiotensin Converting Enzyme Inhibitors (ACE-inhibitors) for renoprotection (not hypertension). Endothelial function was measured non-invasively by studying brachial artery reactivity by vascular ultrasound (ATL HDI 5000 Phillips, Bothell, Washington, DC, USA) (11). Change in brachial artery endothelium-dependent flow-mediated dilatation (FMD) was the primary end-point. It was estimated that in a crossover design with scans before and after intervention, 10 patients would detect a significant change in FMD of 3.6% (11) to provide 80% power at the 5% significance level. Unfortunately, placebo expiry and recruitment difficulty led to only eight patients participating in a pilot study. Patients were recruited from the renal clinic of Sydney Children’s Hospital and South Eastern Area Health and Central Sydney Ethics Committees approved the study. Total cholesterol and LDL significantly decreased during treatment by a mean of 1.3 ± 0.3 mmol ⁄ L p < 0.0001 and 1.1 ± 0.3 mmol ⁄ L respectively p < 0.0001 (paired student t test) (Table 1). Baseline FMD was normal with a mean of 9.75 ± 0.39% (SEM) and did not significantly alter after 8 weeks of atorvastatin (8.04 ± 1.02% p = 0.18) (Table 2). No significant change was seen in creatinine, BP, CRP, liver function tests, or creatinine kinase levels with atorvastatin. There was no significant correlation (Pearson) between vascular reactivity studies and serum creatinine or estimated GFR. There was no correlation between lipid concentrations, BP, BMI and FMD or glyceryl trinitrate (GTN) studies. Atorvastatin therapy for 8 weeks did not alter endothelial function in children with CKD despite a dose which achieved a significant reduction in LDL cholesterol. We postulate this may be attributable to the FMD results that Acta Pædiatrica ISSN 0803–5253