Hyperphosphatemia is common in advanced chronic kidney disease (CKD) and end stage renal disease (ESRD) and strongly associated with cardiovascular events (CVE) and all-cause mortality. Evaluation of the mechanisms by which hyperphosphatemia causes CVE and mortality have focused almost exclusively on macrovascular complications including arterial calcification and stiffness. Recently, evidence has emerged suggesting that higher serum phosphate concentrations and greater dietary phosphate intake may lead to microvascular dysfunction, which may provide a new pathway through which phosphate contributes to cardiovascular disease. In this proposal we aim to characterize the effects of greater phosphate intake and greater serum phosphate concentration on microvascular function using novel measurements of the microvasculature. In the Maastricht Study approximately 3400 people underwent skin capillaroscopy, flicker heat-induced skin %-hyperemia (laser-Doppler flowmetry), and light-induced retinal arteriolar %-dilation, all to assess microvascular function in different vascular beds. I will use samples from the Maastricht Study cohort biorepository to measure serum phosphate concentrations and 24-hour urine phosphate and investigate associations with microvascular function. I am interested in extending these findings to advanced CKD, and to determine if manipulating phosphate status acutely influences microvascular function. Thus, I will also conduct a pilot study in which I will randomize 20 ESRD patients to lanthanum carbonate vs placebo in a crossover design. I will measure skin capillaroscopy and laser-Doppler flowmetry in order to understand the acute effects of phosphate changes on microvascular function. Through this proposal we will gain critical insights into the effects of phosphate on the microvasculature across the spectrum of CKD, develop new expertise in measures of microvascular function, and generate critical preliminary data to support my application for a career development award (K23).
Higher phosphate concentrations are a known risk factor for macrovascular complications in the general population and in chronic kidney disease. In this project we will use novel methods of evaluating the effects of higher serum phosphate concentrations and phosphate intake on microvascular function. This will allow nephrologists and other clinicians to better understand and manage hyperphosphatemia and prevent microvascular complications including retinopathy, progression of chronic kidney disease and development of coronary microvascular disease.
