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.
Highlights
Since its discovery in 2001 [1, 2], the peptide hormone hepcidin has been identified as the principal regulator of iron availability in the body
Hepcidin levels are increased in the presence of chronic inflammation, such as in patients with chronic kidney disease (CKD) [5,6,7,8], contributing to the functional iron deficiency which is frequently observed in this patient population
During the 12-month study, a total of 10 patients received an alternative anemia therapy at some point (2 high ferritin ferric carboxymaltose (FCM), 2 low ferritin FCM, 6 oral iron), and in these patients subsequent hepcidin values were excluded from analysis since this could have affected hepcidin concentrations
Summary
Since its discovery in 2001 [1, 2], the peptide hormone hepcidin has been identified as the principal regulator of iron availability in the body. It maintains iron homeostasis by controlling intestinal absorption of dietary iron and release of iron from the liver and spleen [3]. Hepcidin levels rise in response to iron repletion such that iron absorption and release are reduced. Hepcidin levels are increased in the presence of chronic inflammation, such as in patients with chronic kidney disease (CKD) [5,6,7,8], contributing to the functional iron deficiency which is frequently observed in this patient population
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