Assessment of Serum Bioactive Hepcidin-25, Soluble Transferrin Receptor and Their Ratio in Predialysis Patients: Correlation with the Response to Intravenous Ferric Carboxymaltose Administration

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%