Hepcidin Response to Iron Therapy in Patients with Non-Dialysis Dependent CKD: An Analysis of the FIND-CKD Trial

PLoS One. 2016 Jun 8;11(6):e0157063. doi: 10.1371/journal.pone.0157063. eCollection 2016.

Abstract

Hepcidin is the key regulator of iron homeostasis but data are limited regarding its temporal response to iron therapy, and response to intravenous versus oral iron. In the 56-week, open-label, multicenter, prospective, randomized FIND-CKD study, 626 anemic patients with non-dialysis dependent chronic kidney disease (ND-CKD) and iron deficiency not receiving an erythropoiesis stimulating agent were randomized (1:1:2) to intravenous ferric carboxymaltose (FCM), targeting higher (400-600μg/L) or lower (100-200μg/L) ferritin, or to oral iron. Serum hepcidin levels were measured centrally in a subset of 61 patients. Mean (SD) baseline hepcidin level was 4.0(3.5), 7.3(6.4) and 6.5(5.6) ng/mL in the high ferritin FCM (n = 17), low ferritin FCM (n = 16) and oral iron group (n = 28). The mean (SD) endpoint value (i.e. the last post-baseline value) was 26.0(9.1),15.7(7.7) and 16.3(11.0) ng/mL, respectively. The increase in hepcidin from baseline was significantly smaller with low ferritin FCM or oral iron vs high ferritin FCM at all time points up to week 52. Significant correlations were found between absolute hepcidin and ferritin values (r = 0.65, p<0.001) and between final post-baseline increases in both parameters (r = 0.70, p<0.001). The increase in hepcidin levels over the 12-month study generally mirrored the cumulative iron dose in each group. Hepcidin and transferrin saturation (TSAT) absolute values showed no correlation, although there was an association between final post-baseline increases (r = 0.42, p<0.001). Absolute values (r = 0.36, p = 0.004) and final post-baseline increases of hepcidin and hemoglobin (p = 0.30, p = 0.030) correlated weakly. Baseline hepcidin levels were not predictive of a hematopoietic response to iron therapy. In conclusion, hepcidin levels rose in response to either intravenous or oral iron therapy, but the speed and extent of the rise was greatest with intravenous iron targeting a higher ferritin level. However neither the baseline level nor the change in hepcidin was able to predict response to therapy in this cohort.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Administration, Intravenous
  • Aged
  • Aged, 80 and over
  • Anemia, Iron-Deficiency* / blood
  • Anemia, Iron-Deficiency* / drug therapy
  • Anemia, Iron-Deficiency* / etiology
  • Female
  • Ferric Compounds / administration & dosage*
  • Ferritins / blood
  • Hepcidins / blood*
  • Humans
  • Iron / administration & dosage
  • Male
  • Maltose / administration & dosage
  • Maltose / analogs & derivatives*
  • Middle Aged
  • Prospective Studies
  • Renal Insufficiency, Chronic* / blood
  • Renal Insufficiency, Chronic* / complications
  • Renal Insufficiency, Chronic* / drug therapy
  • Time Factors

Substances

  • Ferric Compounds
  • HAMP protein, human
  • Hepcidins
  • ferric carboxymaltose
  • Maltose
  • Ferritins
  • Iron

Grant support

The FIND-CKD study was funded by Vifor Pharma, Glattbrugg, Switzerland. Medical writing supported was provided by a freelance medical writer funded by Vifor Pharma (C Dunstall). MC, YM, and SL are employed by Vifor Pharma Ltd. Vifor Pharma Ltd provided support in the form of salaries for MC, YM, and SL, and contributed to the study design and data analysis, and these authors reviewed the manucript prior to publication. The specific roles of these authors are articulated in the ‘author contributions’ section. DBVW is employed by Davita Healthcare Partners. Davita Healthcare Partners provided support in the form of salary for author DBVW, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the ‘author contributions’ section.