MP353SUSTAINED PHOSPHATE CAUSES ENDOTHELIAL DYSFUNCTION AND INCREASES VASCULAR STIFFNESS IN CKD PATIENTS

Abstract

Introduction and Aims: Serum phosphate is linked with increased cardiovascular risk although the mechanism of action is unclear. The effect of sustained short term phosphate loading on endothelial function has not previously been studied. This study considers the effect of phosphate loading on endothelial function measured by flow mediated dilatation (FMD) and vascular stiffness measured by pulse wave velocity (PWV). Methods: Patients with CKD attended for a baseline and 2 subsequent visits. Blood was drawn for measures including bone biochemistry, vitamin D, FGF-23 and klotho. A 24-hour urine collection was performed prior to attendance and analysis included urinary cGMP and FGF-23 concentrations. PWV and FMD were recorded. Volunteers were randomized to take lanthanum carbonate (LC) or Phosphate Sandoz (PS) for 2 weeks prior to the next visit. After a wash out period, patients took the other drug and attended for a final visit. One individual, blinded to the order of drug ingestion, performed and analysed each FMD measure. Results: Of 8 participants, 6 were male. At baseline, mean age was 65.8±9.9 years, eGFR 36.4±14.8ml/min and serum phosphate 1.09±0.32mmol/L. Median FMD was 6.4% (IQR 4.9-8.2%) post cuff inflation. After PS, serum phosphate was significantly higher (1.4±0.46mmol/L, p =0.02), FGF-23 rose significantly compared to baseline (p<0.001) and FMD post cuff inflation reduced significantly (2.76% (IQR 2.27-5.13%), p<0.001). PWV, as a marker of arterial stiffness, was significantly increased (13.3±4.2 v 11.4±3.2 m/s; p<0.05). With LC, there was a non-significant trend towards a lower serum phosphate and no effect on FMD but PWV was reduced (10.6±2.2 v 11.4±3.2m/ s p<0.05). Randomization order had no effect. In a regression model, higher serum phosphate was an independent predictor of attenuated post cuff inflation FMD ( p<0.01). Urinary cGMP correlated negatively with serum phosphate (p=0.04). Conclusions: This is a small pilot study but it is the first to demonstrate that sustained phosphate loading impairs endothelial function and increases vascular stiffness. Urinary cGMP, as a marker of endothelial dysfunction negatively correlates with serum phosphate level. Lowering phosphate improves vascular compliance. This study demonstrates that phosphate increases cardiovascular risk both by impairing endothelial function, possibly via the nitric oxide pathway, and by increasing vascular stiffness. Sustained phosphate loading is directly detrimental to the vasculature even when serum phosphate is only marginally elevated.