Skip to main content
Log in

Can Serum Gdf-15 be Associated with Functional Iron Deficiency in Hemodialysis Patients?

  • Original Article
  • Published:
Indian Journal of Hematology and Blood Transfusion Aims and scope Submit manuscript

Abstract

Functional iron deficiency (FID) incidence is gradually increasing in hemodialysis (HD) patients. Recently, high levels of GDF-15 supressed the iron regulatory protein hepcidin and GDF-15 expression increased in iron-deficient patients. The relationship between FID, GDF-15, and hepcidin is currently unknown. The present study aimed to evaluate the association between GDF-15, hepcidin, and FID in chronic HD patients. Serum GDF-15 and hepcidin concentrations were measured in 105 HD patients and 40 controls. FID is defined as serum ferritin >800 ng/mL, TSAT <25 %, Hb levels <11 g/dL, and reticulocyte haemoglobin content (CHr) <29 pg. Serum GDF-15 and hepcidin levels were increased significantly in HD patients with FID, compared to HD patients without anemia and controls. GDF-15 correlated with ferritin, hepcidin, and CRP in the entire cohort. GDF-15 was related to ferritin and CRP in HD patients with FID. GDF-15 is better diagnostic marker than hepcidin for detection of FID [AUC = 0.982 (0.013) versus AUC = 0.921 (0.027); P = 0.0324]. GDF-15 appears to be a promising tool for detection of FID. High levels of ferritin and CRP correlated with GDF-15. Our results support GDF-15 as a new mediator of FID via hepcidin, chronic inflammation, or unknown pathways.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Drüeke T (2001) Hyporesponsiveness to recombinant human erythropoietin. Nephrol Dial Transplant 16:25–28

    Article  PubMed  Google Scholar 

  2. Gouva C, Nikolopoulos P, Ioannidis JP et al (2004) Treating anemia early in renal failure patients slows the decline of renal function: a randomized controlled trial. Kidney Int 66:753–760

    Article  PubMed  Google Scholar 

  3. Vlagopoulos, PT, Tighiouart H, Weiner DE et al (2005) Anemia as a risk factor for cardiovascular disease and all-cause mortality in diabetes: the impact of chronic kidney disease. J Am Soc Nephrol 16:3403–3410

    Article  PubMed  Google Scholar 

  4. Hörl WH (2013) Anaemia management and mortality risk in chronic kidney disease. Nat Rev Nephrol 9(5):291–301

    Article  PubMed  Google Scholar 

  5. Cavill I (1999) Iron status as measured by serum ferritin: the marker and its limitations. Am J Kidney Dis 34(Suppl 2):S12–S17

    Article  CAS  PubMed  Google Scholar 

  6. Lankhorst CE, Wish JB (2010) Anemia in renal disease: diagnosis and management. Blood Rev 24(1):39–47

    Article  CAS  PubMed  Google Scholar 

  7. Nakanishi T, Kuragano T, Kaibe S, Nagasawa Y, Hasuike Y (2012) Should we reconsider iron administration based on prevailing ferritin and hepcidin concentrations? Clin Exp Nephrol 16(6):819–826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. VanWyck DB, Bailie G, Aronoff G (2002) Just the FAQs: frequently asked questions about iron and anemia in patients with chronic kidney disease. Am J Kidney Dis 39:426–432

    Article  Google Scholar 

  9. Besarab A (2001) Evaluating iron sufficiency: a clearer view. Kidney Int 60:2412–2414

    Article  CAS  PubMed  Google Scholar 

  10. Unsicker K, Spittau B, Krieglstein K (2013) The multiple facets of the TGF-β family cytokine growth/differentiation factor-15/macrophage inhibitory cytokine-1. Cytokine Growth Factor Rev 24(4):373–384

    Article  CAS  PubMed  Google Scholar 

  11. Aw Yong KM, Zeng Y, Vindivich D, Phillip JM, Wu PH, Wirtz D, Getzenberg RH (2014) Morphological effects on expression of growth differentiation factor 15 (GDF15), a marker of metastasis. J Cell Physiol 229(3):362–373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Eggers KM, Kempf T, Lind L, Sundström J, Wallentin L, Wollert KC, Siegbahn A (2012) Relations of growth-differentiation factor-15 to biomarkers reflecting vascular pathologies in a population-based sample of elderly subjects. Scand J Clin Lab Invest 72(1):45–51

    Article  CAS  PubMed  Google Scholar 

  13. Kempf T, Eden M, Strelau J, Naguib M, Willenbockel C, Tongers J, Heineke J, Kotlarz D, Xu J, Molkentin JD, Niessen HW, Drexler H, Wollert KC (2006) The transforming growth factor-beta superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury. Circ Res 98(3):351–360

    Article  CAS  PubMed  Google Scholar 

  14. Johnen H, Lin S, Kuffner T, Brown DA, Tsai VW, Bauskin AR, Wu L, Pankhurst G, Jiang L, Junankar S, Hunter M, Fairlie WD, Lee NJ, Enriquez RF, Baldock PA, Corey E, Apple FS, Murakami MM, Lin EJ, Wang C, During MJ, Sainsbury A, Herzog H, Breit SN (2007) Tumor-induced anorexia and weight loss are mediated by the TGF-beta superfamily cytokine MIC-1. Nat Med 13(11):1333–1340

    Article  CAS  PubMed  Google Scholar 

  15. Tanno T, Bhanu NV, Oneal PA, Goh SH, Staker P, Lee YT, Moroney JW, Reed CH, Luban NL, Wang RH, Eling TE, Childs R, Ganz T, Leitman SF, Fucharoen S, Miller JL (2007) High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med 13:1096–1101

    Article  CAS  PubMed  Google Scholar 

  16. Tanno T, Miller JL (2011) GDF15 expression and iron overload in ineffective erythropoiesis. Rinsho Ketsueki 52(6):387–398

    PubMed  Google Scholar 

  17. Lakhal S, Talbot NP, Crosby A, Stoepker C, Townsend AR, Robbins PA, Pugh CW, Ratcliffe PJ, Mole DR (2009) Regulation of growth differentiation factor 15 expression by intracellular iron. Blood 113:1555–1563

    Article  CAS  PubMed  Google Scholar 

  18. Casanovas G, Spasic MV, Casu C, Rivella S, Strelau J, Unsicker K, Muckenthaler MU (2013) The murine growth differentiation factor 15 is not essential for systemic iron homeostasis in phlebotomized mice. Haematologica 98(3):444–447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hanley JA, McNeil BJ (1983) A method of comparing the areas under receiver operating characteristic curves derived from the same cases. Radiology 148:839–843

    Article  CAS  PubMed  Google Scholar 

  20. Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group (2012) KDIGO Clinical Practice Guideline for anemia in chronic kidney disease. Kidney Int 2 (Suppl):279–335

    Google Scholar 

  21. Tsubakihara Y, Nishi S, Akiba T, Hirakata H, Iseki K, Kubota M, Kuriyama S, Komatsu Y, Suzuki M, Nakai S, Hattori M, Babazono T, Hiramatsu M, Yamamoto H, Bessho M, Akizawa T (2010) 2008 Japanese Society for Dialysis Therapy: guidelines for renal anemia in chronic kidney disease. Ther Apher Dial 14(3):240–275

    Article  CAS  PubMed  Google Scholar 

  22. Nakanishi T, Kuragano T, Kaibe S, Nagasawa Y, Hasuike Y (2012) Should we reconsider iron administration based on prevailing ferritin and hepcidin concentrations? Clin Exp Nephrol 16(6):819–826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Thomas DW, Hinchliffe RF, Briggs C, Macdougall IC, Littlewood T, Cavill I (2013) British Committee for Standards in Haematology. Guideline for the laboratory diagnosis of functional iron deficiency. Br J Haematol 161(5):639–648

    Article  CAS  PubMed  Google Scholar 

  24. Małyszko J, Małyszko JS, Hryszko T, Pawlak K, Mysliwiec M (2005) Is hepcidin a link between anemia, inflammation and liver function in hemodialyzed patients? Am J Nephrol 25(6):586–590

    Article  PubMed  Google Scholar 

  25. Małyszko J, Koc-Żórawska E, Levin-Iaina N, Małyszko J, Koźmiński P, Kobus G, Myśliwiec M (2012) New parameters in iron metabolism and functional iron deficiency in patients on maintenance hemodialysis. Pol Arch Med Wewn 122(11):537–542

    PubMed  Google Scholar 

  26. Kempf T, Wollert KC (2009) Growth-differentiation factor-15 in heart failure. Heart Fail Clin 5:537–547

    Article  PubMed  Google Scholar 

  27. Goodnough LT (2012) Iron deficiency syndromes and iron-restricted erythropoiesis (CME). Transfusion 52(7):1584–1592

    Article  PubMed  Google Scholar 

  28. Ramirez JM, Schaad O, Durual S, Cossali D, Docquier M, Beris P, Descombes P, Matthes T (2009) Growth differentiation factor 15 production is necessary for normal erythroid differentiation and is increased in refractory anaemia with ring-sideroblasts. Br J Haematol 144:251–262

    Article  PubMed  Google Scholar 

  29. Malyszko J, Koc-Zorawska E, Malyszko JS, Glowinska I, Mysliwiec M, Macdougall IC (2013) GDF15 is related to anemia and hepcidin in kidney allograft recipients. Nephron Clin Pract 123(1–2):112–117

    Article  CAS  PubMed  Google Scholar 

  30. Jiang F, Yu WJ, Wang XH, Tang YT, Guo L, Jiao XY (2014) Regulation of hepcidin through GDF-15 in cancer-related anemia. Clin Chim Acta 428:14–19

    Article  CAS  PubMed  Google Scholar 

  31. Theurl I, Finkenstedt A, Schroll A, Nairz M, Sonnweber T, Bellmann-Weiler R, Theurl M, Seifert M, Wroblewski VJ, Murphy AT, Witcher D, Zoller H, Weiss G (2010) Growth differentiation factor 15 in anaemia of chronic disease, iron deficiency anaemia and mixed type anaemia. Br J Haematol 148(3):449–455

    Article  PubMed  Google Scholar 

  32. Tanno T, Noel P, Miller JL (2010) Growth differentiation factor 15 in erythroid health and disease. Curr Opin Hematol 17(3):184–190

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Fishbane S, Kalantar-Zadeh K, Nissenson AR (2004) Serum ferritin in chronic kidney disease: reconsidering the upper limit for iron treatment. Semin Dial 17:336–341

    Article  PubMed  Google Scholar 

  34. Kalantar-Zadeh K, Rodriguez RA, Humphreys MH (2004) Association between serum ferritin and measures of inflammation, nutrition and iron in hemodialysis patients. Nephrol Dial Transplant 19:141–149

    Article  CAS  PubMed  Google Scholar 

  35. Rambod M, Kovesdy CP, Kalantar-Zadeh K (2008) Combined high serum ferritin and low iron saturation in hemodialysis patients: the role of inflammation. Clin J Am Soc Nephrol 3(6):1691–1701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Stenvinkel P, Wanner C, Metzger T et al (2002) Inflammation and outcome in end-stage renal failure: does female gender constitute a survival advantage? Kidney Int 62:1791–1798

    Article  PubMed  Google Scholar 

  37. Wanner C, Richardson D, Fouque D, Stenvinkel P (2007) OPTA—Influence of inflammation/infection on anaemia therapy in haemodialysis patients. Nephrol Dial Transplant 22(Suppl 3):iii7–iii12

    CAS  Google Scholar 

  38. Nitta K, Akiba T, Takei T et al (2002) Inflammation and resistance to erythropoietin in hemodialysis patients. Acta Haematol 108:168–170

    Article  PubMed  Google Scholar 

  39. Weiss G, Goodnough LT (2005) Anemia of chronic disease. New Engl J Med 352:1011–1023

    Article  CAS  PubMed  Google Scholar 

  40. Ashby DR, Gale DP, Busbridge M et al (2009) Plasma hepcidin levels are elevated but responsive to erythropoietin therapy in renal disease. Kidney Int 75:976–981

    Article  CAS  PubMed  Google Scholar 

  41. Weiss G, Theurl I, Eder S et al (2009) Serum hepcidin concentration in chronic haemodialysis patients: associations and effects of dialysis, iron and erythropoietin therapy. Eur J Clin Invest 39:883–890

    Article  CAS  PubMed  Google Scholar 

  42. Kato A, Tsuji T, Luo J, Sakao Y, Yasuda H, Hishida A (2008) Association of prohepcidin and hepcidin-25 with erythropoietin response and ferritin in hemodialysis patients. Am J Nephrol 28:115–121

    Article  CAS  PubMed  Google Scholar 

  43. Ford BA, Eby CS, Scott MG, Coyne DW (2010) Intra-individual variability in serum hepcidin precludes its use as a marker of iron status in hemodialysis patients. Kidney Int 78:769–773

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

We have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hakki Yilmaz.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yilmaz, H., Cakmak, M., Darcin, T. et al. Can Serum Gdf-15 be Associated with Functional Iron Deficiency in Hemodialysis Patients?. Indian J Hematol Blood Transfus 32, 221–227 (2016). https://doi.org/10.1007/s12288-015-0551-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12288-015-0551-0

Keywords

Navigation