FGF-23 and vascular dysfunction in patients with stage 3 and 4 chronic kidney disease

Studies in animals show that fibroblast growth factor (FGF)-23 interferes with vascular reactivity induced by the nitric oxide (NO) system. To investigate the relationship between circulating FGF-23 levels and the response of forearm blood flow to ischemia (flow-mediated vasodilatation, FMD) and nitroglycerin, we tested 183 patients with stage 3–4 chronic kidney disease (CKD). None of them had cardiovascular complications or were taking drugs interfering with vascular function. Patients with FGF-23 levels above the median had significantly lower glomerular filtration rate, FMD, and fetuin-A levels (an anti-inflammatory molecule and potent inhibitor of calcification). They also had higher proteinuria and phosphate levels when compared to patients whose FGF-23 levels were below the median. The response to nitroglycerin was not different between the two groups. Multiple regression analysis showed that the relationship between FGF-23 and FMD was only modestly sensitive to adjustment for classical risk factors, biomarkers of bone mineral metabolism, high-sensitivity C-reactive protein, and homeostatic model assessment index. Adjustment for asymmetrical dimethyl arginine (ADMA) weakened the strength of this link; however, it remained highly significant. There was no independent association between FGF-23 and nitroglycerin. Thus, attenuation of FMD by ADMA suggests that this endogenous inhibitor of NO synthase may, in part, mediate the vascular effects of FGF-23 in patients with CKD.