Effect of Hemodialysis with Citrate on Vascular Calcification

Background: Medial arterial calcification (MAC) is a serious problem in hemodialysis (HD) patients that leads to poor outcomes. Citrate, which can inhibit calcium crystallization, is used in some HD solutions but its effect on vascular calcification is unknown. We have shown that MAC can be conveniently measured on standard mammograms (MGs) and correlates with MAC in other locations and with cardiovascular outcomes. Therefore, we used mammography to measure changes in MAC in female HD patients during HD with and without citrate. Methods: In this cross-over study in 4 outpatient units, patients with pre-existing MAC on MGs were recruited to 1 year periods of HD with and without citrate (Citrasate and Naturalyte, Fresenius) with MGs and measurements of serum Mg and ionized Ca (iCa), and plasma citrate every 6-months (NCT04956120). Lengths of calcified arteries were summed manually and the rate of change determined from the slope of values from the 3 MGs at the start, middle, and end of each arm. Data are means + SE with analysis by paired t-test, or medians (interquartile range) for MAC with analysis by Wilcoxon test. Results: 28 of 30 subjects have completed the study, 12 starting on the citrate arm. Durations of the arms did not differ (citrate: 383 + 8 days; no citrate 407 + 15). Dialysis adequacy, dialysate Ca, and pre-HD serum total Ca, iCa, and phosphorus did not differ between arms; pre-HD Mg was lower in the citrate arm (2.28 + 0.05 vs. 2.42 + 0.07 mg/dl, p=0.003. The change in serum Mg or iCa with HD did not differ significantly between arms. Pre-HD plasma citrate was similar (133 + 8 vs. 127 + 6 uM) but was substantially greater after HD with citrate (364 + 17 vs. 144 + 9 uM, p<0.001). The change in MAC was greater during citrate HD: 44 (21-121) mm/yr vs. 10 (-5-35), p=0.0002, or 35 (14-104) %/yr vs.12 (-3-23), p=0.002. 22 subjects had a greater change during citrate HD (median: 51 %/yr), while only 6 had a greater change without citrate (median: 14 %/yr). The change in MAC did not correlate with pre-HD serum iCa, P, or Mg. Conclusion: Citrate HD unexpectedly promoted vascular calcification, which was not explained by changes in mineral metabolism or dialysis adequacy. This result may be related to known effects of citrate to promote or stabilize bone mineralization. Further studies are needed to determine the underlying mechanism and whether this is associated with adverse clinical outcomes. Funding: Commercial Support - Fresenius Medical Care Renal Therapies Group