The Relation of Hepcidin to Iron Disorders, Inflammation and Hemoglobin in Chronic Kidney Disease

The metabolism of hepcidin is profoundly modified in chronic kidney disease (CKD). We investigated its relation to iron disorders, inflammation and hemoglobin (Hb) level in 199 non-dialyzed, non-transplanted patients with CKD stages 1–5. All had their glomerular filtration rate measured by 51Cr-EDTA renal clearance (mGFR), as well as measurements of iron markers including hepcidin and of erythropoietin (EPO). Hepcidin varied from 0.2 to 193 ng/mL. The median increased from 23.3 ng/mL [8.8–28.7] to 36.1 ng/mL [14.1–92.3] when mGFR decreased from ≥60 to <15 mL/min/1.73 m2 (p = 0.02). Patients with absolute iron deficiency (transferrin saturation (TSAT) <20% and ferritin <40 ng/mL) had the lowest hepcidin levels (5.0 ng/mL [0.7–11.7]), and those with a normal iron profile (TSAT ≥20% and ferritin ≥40), the highest (34.5 ng/mL [23.7–51.6]). In multivariate analysis, absolute iron deficiency was associated with lower hepcidin values, and inflammation combined with a normal or functional iron profile with higher values, independent of other determinants of hepcidin concentration, including EPO, mGFR, and albuminemia. The hepcidin level, although it rose overall when mGFR declined, collapsed in patients with absolute iron deficiency. There was a significant interaction with iron status in the association between Hb and hepcidin. Except in absolute iron deficiency, hepcidin’s negative association with Hb level indicates that it is not down-regulated in CKD anemia.

[1]  Y. Le Marchand-Brustel,et al.  Increased adipose tissue expression of hepcidin in severe obesity is independent from diabetes and NASH. , 2006, Gastroenterology.

[2]  T. Ganz,et al.  Reduction of serum hepcidin by hemodialysis in pediatric and adult patients. , 2010, Clinical journal of the American Society of Nephrology : CJASN.

[3]  B. Stengel,et al.  Timing and determinants of erythropoietin deficiency in chronic kidney disease. , 2012, Clinical journal of the American Society of Nephrology : CJASN.

[4]  D. Swinkels,et al.  Serum hepcidin-25 levels in patients with chronic kidney disease are independent of glomerular filtration rate. , 2010, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[5]  M. Jadoul,et al.  Plasma hepcidin levels are elevated but responsive to erythropoietin therapy in renal disease. , 2009, Kidney international.

[6]  J. Małyszko,et al.  A possible role of hepcidin in the pathogenesis of anemia among kidney allograft recipients. , 2009, Transplantation proceedings.

[7]  L. Kiemeney,et al.  Serum hepcidin: reference ranges and biochemical correlates in the general population. , 2011, Blood.

[8]  L. N. Valenti,et al.  Hepcidin and HFE protein: Iron metabolism as a target for the anemia of chronic kidney disease. , 2012, World journal of nephrology.

[9]  C. Eby,et al.  Intra-individual variability in serum hepcidin precludes its use as a marker of iron status in hemodialysis patients. , 2010, Kidney international.

[10]  N. Akar,et al.  Serum Pro-Hepcidin Levels and Relationship with Ferritin in Healthy Non-Anaemic Infants , 2007, Acta Haematologica.

[11]  A. Nissenson,et al.  Hepcidin--a potential novel biomarker for iron status in chronic kidney disease. , 2009, Clinical journal of the American Society of Nephrology : CJASN.

[12]  D. Swinkels,et al.  High‐sensitive radioimmunoassay for human serum hepcidin , 2009, British journal of haematology.

[13]  H. Umehara,et al.  Detection of serum hepcidin in renal failure and inflammation by using ProteinChip System. , 2006, Blood.

[14]  T. Shiigai,et al.  High serum bicarbonate level within the normal range prevents the progression of chronic kidney disease in elderly chronic kidney disease patients , 2013, BMC Nephrology.

[15]  D. Swinkels,et al.  Hepcidin Serum Levels and Resistance to Recombinant Human Erythropoietin Therapy in Haemodialysis Patients , 2009, Acta Haematologica.

[16]  N. Andrews,et al.  Transferrin is a major determinant of hepcidin expression in hypotransferrinemic mice. , 2011, Blood.

[17]  D. Girelli,et al.  Hepcidin levels in chronic hemodialysis patients: a critical evaluation , 2014, Clinical chemistry and laboratory medicine.

[18]  H. Rakugi,et al.  Serum hepcidin-25 levels and anemia in non-dialysis chronic kidney disease patients: a cross-sectional study. , 2012, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[19]  D. Swinkels,et al.  Hepcidin-25 in Chronic Hemodialysis Patients Is Related to Residual Kidney Function and Not to Treatment with Erythropoiesis Stimulating Agents , 2012, PloS one.

[20]  E. Fung,et al.  A mouse model of anemia of inflammation: complex pathogenesis with partial dependence on hepcidin. , 2014, Blood.

[21]  K. Pantopoulos,et al.  Regulation of iron transport and the role of transferrin. , 2012, Biochimica et biophysica acta.

[22]  Olivier Moranne,et al.  Timing of onset of CKD-related metabolic complications. , 2009, Journal of the American Society of Nephrology : JASN.

[23]  C. Datz,et al.  Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications. , 2009, Blood.

[24]  J. Małyszko,et al.  Hyporesponsiveness to Erythropoietin Therapy in Hemodialyzed Patients: Potential Role of Prohepcidin, Hepcidin, and Inflammation , 2009, Renal failure.

[25]  L. Miranda,et al.  Development of a method for the sensitive and quantitative determination of hepcidin in human serum using LC-MS/MS. , 2009, Journal of pharmacological and toxicological methods.

[26]  D. Girelli,et al.  The A736V TMPRSS6 polymorphism influences hepcidin and iron metabolism in chronic hemodialysis patients: TMPRSS6 and hepcidin in hemodialysis , 2013, BMC Nephrology.

[27]  B. Stengel,et al.  A 3-Marker Index Improves the Identification of Iron Disorders in CKD Anaemia , 2014, PloS one.

[28]  J. Cook,et al.  A clinical evaluation of serum ferritin as an index of iron stores. , 1974, The New England journal of medicine.

[29]  D. Swinkels,et al.  Tubular reabsorption and local production of urine hepcidin-25 , 2013, BMC Nephrology.

[30]  J. McClung,et al.  Hepcidin: A Critical Regulator of Iron Metabolism during Hypoxia , 2011, Advances in hematology.

[31]  Jinghui Luo,et al.  Association of Prohepcidin and Hepcidin-25 with Erythropoietin Response and Ferritin in Hemodialysis Patients , 2007, American Journal of Nephrology.