Assessment of Serum Bioactive Hepcidin-25, Soluble Transferrin Receptor and Their Ratio in Predialysis Patients: Correlation with the Response to Intravenous Ferric Carboxymaltose Administration
Authors: Drakou Athina , Poziopoulos Christos , Margeli Alexandra , Papassotiriou Ioannis , Vlahakos Demetrios 
Published: October 2019

Abstract
Background: No reliable biomarker exists to predict responsiveness to intravenous (IV) iron (Fe) in iron deficient patients with chronic kidney disease (CKD). Our aim was to investigate if Hepcidin-25 (Hepc25) and soluble Transferrin Receptor (sTfR) and their Ratio sTfR/Hepc25 ratio prior to treatment can make a distinction between those predialysis patients with and those without adequate erythropoiesis after administration of IV ferric carboxymaltose (FCM).
Patients and methods: In this prospective study we enrolled 78 stable stage III-IV CKD patients with iron deficiency (serum ferritin levels lower than 100µg/L) treated with IV FCM 1000mg/100ml NaCl-0.9% and infused over a period of 20min. Patients were divided in two groups according to hemoglobin (Hb) increase within a month after treatment. The responders (Group R, n=40), showed above 1g/dL increase in Hb concentration. The non-responders (Group NR, n=38) had no such a favorable reaction. Patient data, clinical information and blood samples were collected prior to IV iron administration. Hematologic analysis was performed using a hematogy analyzer. Blood chemistry, including measurements of renal, nutrition and inflammation markers along with measurements of Hepc25, IL-6 and sTfR were performed using appropriate techniques. Receiver Operating Curve (ROC) analysis was applied in order to evaluate the diagnostic potential of Hepc25 and sTfR/Hepc25 ratio and conclusions about the specificity and sensitivity were drawn.
Results: As shown in Table 1, there were no significant differences at baseline between responders and non-responders in demographic and clinical parameters. No significant differences were revealed for serum creatinine, e-GFR, folic acid (FA), vitamin B12, hs-CRP and IL-6, with the notable exception of ferritin and Hepc25 levels that were lower and sTfR and sTfR/Hepc25 ratio that were higher in the responders as compared to non-responders (Table 1). Diagnostic efficacy was analyzed by ROC analysis. Cut off point of 1.49 for Hepc25 had sensitivity 84% and specificity 48%, and cut off point of 1.21 for sTfR/Hepc25 ratio had sensitivity 82% and specificity 52% to predict correctly response to Fe therapy (Table 2).
Conclusions: These results suggest that lower Hepc25 and ferritin levels, as well as higher sTfR and sTfR/Hepc25 ratio were significant predictors of favorable hemoglobin response within a month after IV administration of FCM in CKD patients. Further in vitro and in vivo experiments and clinical studies in a larger population of patients are needed to better elucidate the role of Hepc25 and sTfR/Hepc25 ratio in iron deficiency anemia in CKD.
Table 1. Demographic, clinical and biochemical parameters in responders vs non-responders. Group R (n=40 Group NR (n=38) Age (years) 72.7±11.2 74.5±10.3 NS Gender (M /F) 27:13 25:13 NS Medications -RAS inhibitors 21(27%) 19(24%) NS rh EPO 1(27%) 20(26%) NS CCB 10(13%) ) 11(14% NS BMI (Κg/m2) 25.5±3.3 25.1±3.4 NS Comorbidities -Cardiovascular Disease 17(22%) 15(19%) NS -Μechanical valve heart 2(2%) 2(2%) NS -Diabetes Mellitus 20(26%) 17(22%) NS -Polycystic Kidney Disease 2(1%) 1(1%) NS Hemoglobin (g/dL) 10.9±1.6 11.1±1.3 NS Creatinine (mg/dL) 2.4±1.1 2.5±1.1 NS eGFR(mL/min/1.73 m2) 35.2±16.9 30.0±13.4 NS B12 (pg/mL) 512.0±369.0 655.0±414.0 NS hs-CRP (mg/L) 3.9±5.9 3.7± 4.9 NS IL-6 (pg/mL) 6.2±5.3 5.78±4.5 NS sTfR (mg/L) 2.27±0.99 1.76±0.76 0.014 Log (1+Hepc25) 0.552±0.343 0.728±0.348 0.027 sTfR/Hepc25 1.91±1.53 0.80±0.72 0.002
Table 2. Sensitivity and specificity of Hepcidin and sTfR/H as predictors of responsiveness to IV FCM AUC 95%C.I. P-value Cut-off Point Sensitivity Specificity Hepc25 0.648 0.52-0.77 0.025 1.49 84% 48% sTfR/Hepc25 0.680 0.56-0.80 0.006 1.21 82% 52%

Disclosures
No relevant conflicts of interest to declare.