Effects of pre‐ vs. intra‐dialysis folic acid on arterial wave reflections and endothelial function in patients with end‐stage renal disease

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Endothelial dysfunction and increased arterial wave reflection increase the risk of cardiovascular morbidity and mortality in patients with end‐stage renal disease on haemodialysis. • Folic acid enhances endothelial function, but its effects in end‐stage renal disease are controversial. • Haemodialysis is associated with a significant reduction in the serum concentrations of folic acid as well as other biochemical factors impairing endothelial function. WHAT THIS STUDY ADDS • Preventing folic acid loss during haemodialysis is associated with a reduction in arterial wave reflection but no significant changes in endothelial‐dependent vasodilation. • Given the prognostic significance of arterial wave reflections in end‐stage renal disease, the timing of folic acid may be important when designing interventional trials. The rapid replenishment of folic acid levels depleted during haemodialysis would ensure higher serum folic acid concentrations between haemodialysis sessions. BACKGROUND Haemodialysis (HD) is associated with the acute loss through the dialysis membrane of biochemical factors either enhancing [folic acid (F)] or impairing [asymmetric dimethylarginine (ADMA)] arterial function. Changes in these opposing factors might explain the absence of significant modifications in arterial function during HD. We speculated that intra‐HD, instead of pre‐HD, F administration would provide beneficial effects on arterial wave reflections and endothelial function by preventing HD‐induced F loss. METHODS Arterial wave reflections [augmentation index (AIx), pulse‐wave analysis], endothelium‐dependent vasodilation (salbutamol‐mediated changes in AIx) and plasma concentrations of F and ADMA were measured pre‐HD and end‐HD in 10 patients (age 67.7 ± 10.3 years). Each subject received F 5 mg either pre‐HD or intra‐HD in two separate studies 2–4 weeks apart, in an open‐label randomized cross‐over trial. RESULTS Pre‐HD F administration did not prevent significant reductions in F during HD (end‐HD vs. pre‐HD, −865 ± 465 nmol l −1 , P  < 0.001), but no significant changes in AIx (+1.4 ± 5.7%) or salbutamol‐mediated AIx modifications (+0.4 ± 5.5%) were observed. By contrast, intra‐HD F administration was associated with significant increases in F (+298 ± 283 nmol l −1 , P  = 0.010) and a significant reduction of AIx (−4.7 ± 7.2%, P  = 0.013), but no effects on salbutamol‐mediated AIx changes (+1.5 ± 4.4%). There was a trend towards greater HD‐induced reductions in plasma ADMA concentrations with intra‐HD F administration ( P  = 0.066). CONCLUSIONS Intra‐HD F administration reduces arterial wave reflections but not endothelial function during HD. Given the prognostic significance of arterial wave reflections in HD patients, the timing of F administration is important in the design of interventional trials in this cohort.