Anemia is more prevalent in renal transplant recipients than in GFR-matched chronic kidney disease patients. Hepcidin is a small defensin-like peptide whose production by hepatocytes is modulated in response to anemia, hypoxia or inflammation. Growth differentiation factor 15 (GDF15) was recently identified as a hepcidin-suppression factor that is expressed at high levels in patients with ineffective erythropoiesis. The aim of the study was to assess GDF15 levels with relation to iron parameters in 62 stable kidney allograft recipients maintained on triple immunosuppressive therapy. Methods: Complete blood count, urea, creatinine, and iron status were assessed by standard methods. We measured GDF15, hepcidin, hemojuvelin, IL-6 and NGAL with commercially available assays. Results: Mean levels of GDF15, NGAL, hepcidin and hemojuvelin were significantly higher in kidney allograft recipients when compared to the control group (p < 0.001 for all). GDF15 was significantly higher in patients with anemia according to the WHO definition when compared to their nonanemic counterparts (p < 0.05). GDF15 levels were not dependent on the type of immunosuppressive therapy. In univariate analysis GDF15 was related to kidney function (creatinine r = 0.39, p < 0.01, eGFR by MDRD r = -0.37, p < 0.01), urea (r = 0.39, p < 0.01), uric acid (r = 0.42, p < 0.01), hepcidin (r = -0.32, p < 0.01), IL-6 (r = 0.28, p < 0.05), hemoglobin (r = -0.32, p < 0.05), and NGAL (r = -0.35, p < 0.01). GDF15 was not related to serum iron, or ferritin. In multivariate analysis, hepcidin was found to be a predictor of GDF15. In conclusion, our preliminary data may suggest possible mutual relations between GDF15 and hepcidin in patients with kidney disease and that GDF15 might be involved in the pathogenesis of anemia in kidney allograft recipients. However, the role of inflammation should be also elucidated.

Keywords:
Anemia, Growth differentiation factor 15Kidney transplantation, Hepcidin, Iron
1.
Hsu CY, McCulloch CE, Curhan GC: Epidemiology of anemia associated with chronic renal insufficiency among adults in the United States: results from the Third National Health and Nutrition Examination Survey. J Am Soc Nephrol 2002;13:504-510.
2.
World Health Organization: Nutritional anaemias: report of a WHO Scientific Group. World Health Organ Tech Rep Ser 1968;405:5-37.
3.
Kasiske BL, Cangro CB, Hariharan S, Hricik DE, Kerman RH, Roth D, Rush DN, Vazquez MA, Weir MR, American Society of Transplantation: The evaluation of renal transplantation candidates: clinical practice guidelines. Am J Transplant 2001;1(suppl 2):3-95.
4.
Eschbach JW, Adamson JW: Anaemia of end-stage renal disease (ESRD). Kidney Int 1985;28:1-5.
5.
Przybylowski P, Malyszko J, Glowinska I, Malyszko J, Kozlowska S, Mysliwiec M: Prevalence of iron deficiency in heart and kidney allograft recipients. Transplant Proc 2011;43:3885-3887.
6.
Przybylowski P, Malyszko J, Malyszko JS, Koc-Zorawska E, Sadowski J, Mysliwiec M: Anemia in heart and kidney allograft recipients: is there a role for hepcidin? Transplant Proc 2010;42:4255-4258.
7.
Ganz T: Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 2003;102:783-788.
8.
Yang J, Goetz D, Li JY, Wang W, Mori K, Setlik D, Du T, Erdjument-Bromage H, Tempst P, Strong R, Barasch J: An iron delivery pathway mediated by a lipocalin. Mol Cell. 2002;10:1045-1056.
9.
Hunter HN, Fulton DB, Ganz T, Vogel HJ: The solution structure of human hepcidin, a peptide-hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis J Biol Chem 2002;277:37597-37603.
10.
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: High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med 2007;13:1096-1101.
11.
Lakhal S, Talbot NP, Crosby A, Stoepker C, Townsend AR, Robbins PA, Pugh CW, Ratcliffe PJ, Mole DR: Regulation of growth differentiation factor 15 expression by intracellular iron. Blood 2009;113:1555-1563.
12.
Levey AS, Berg RL, Gassman JJ, Hall PM, Walker WG: Creatinine filtration, secretion and excretion during progressive renal disease. Modification of Diet in Renal Disease (MDRD) Study Group. Kidney Int Suppl 1989;27:S73-S80.
13.
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J, CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration): A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:604-612.
14.
Andriopoulos B Jr, Corradini E, Xia Y, Faasse SA, Chen S, Grgurevic L, Knutson MD, Pietrangelo A, Vukicevic S, Lin HY, Babitt JL: BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet 2009;41:482-487.
15.
Tanno T, Rabel A, Lee YT, Yau YY, Leitman SF, Miller JL: Expression of growth differentiation factor 15 is not elevated in individuals with iron deficiency secondary to volunteer blood donation. Transfusion 2010;50:1532-1535.
16.
Finkenstedt A, Widschwendter A, Brasse-Lagnel CG, Theurl I, Hubalek M, Dieplinger H, Tselepis C, Ward DG, Vogel W, Zoller H. Hepcidin is correlated tosoluble hemojuvelin but not to increased GDF15 during pregnancy. Blood Cells Mol Dis 2012;48:233-237.
17.
Bartnikas TB, Fleming MD: Hemojuvelin is essential for transferrin-dependent and transferrin-independent hepcidin expression in mice. Haematologica 2012;97:189-192.
18.
Tamary H, Shalev H, Perez-Avraham G, Zoldan M, Levi I, Swinkels DW, Tanno T, Miller JL: Elevated growth differentiation factor 15 expression in patients with congenital dyserythropoietic anemia type I. Blood 2008;112:5241-5244.
19.
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: Growth differentiation factor 15 in anaemia of chronic disease, iron deficiency anaemia and mixed type anaemia. Br J Haematol 2010;148:449-455.
20.
Liu Q, Davidoff O, Niss K, Haase VH. Hypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis. J Clin Invest 2012;122:4635-4644.
21.
Peyssonnaux C, Zinkernagel AS, Schuepbach RA, Rankin E, Vaulont S, Haase VH, Nizet V, Johnson RS: Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin Invest 2007;117:1926-1932.
22.
Kapitsinou PP, Liu Q, Unger TL, Rha J, Davidoff O, Keith B, Epstein JA, Moores SL, Erickson-Miller CL, Haase VH: Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia. Blood 2010;116:3039-3048.
23.
Rankin EB, Biju MP, Liu Q, Unger TL, Rha J, Johnson RS, Simon MC, Keith B, Haase VH: Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo. J Clin Invest 2007;117:1068-1077.
24.
Mastrogiannaki M, Matak P, Mathieu JR, Delga S, Mayeux P, Vaulont S, Peyssonnaux C: Hepatic HIF-2 down-regulates hepcidin expression in mice through epo-mediated increase in erythropoiesis. Haematologica 2012;97:827-834.
25.
Ramirez JM, Schaad O, Durual S, Cossali D, Docquier M, Beris P, Descombes P, Matthes T: Growth differentiation factor 15 production is necessary for normal erythroid differentiation and is increased in refractory anaemia with ring-sideroblasts. Br J Haematol 2009;144:251-262.
26.
Waalen J, von Löhneysen K, Lee P, Xu X, Friedman JS: Erythropoietin, GDF15, IL6, hepcidin and testosterone levels in a large cohort of elderly individuals with anaemia of known and unknown cause. Eur J Haematol 2011;87:107-116.
27.
Mast AE, Foster TM, Pinder HL, Beczkiewicz CA, Bellissimo DB, Murphy AT, Kovacevic S, Wroblewski VJ, Witcher DR: Behavioral, biochemical, and genetic analysis of iron metabolism in high-intensity blood donors. Transfusion 2008;48:2197-2204.
28.
Malyszko J, Malyszko JS, Kozminski P, Koc-Zorawska E, Mysliwiec M, Macdougall I: Possible relationship between neutrophil gelatinase-associated lipocalin, hepcidin, and inflammation in haemodialysed patients. Nephron Clin Pract 2010;115:c268-c275.
29.
Malyszko J, Bachorzewska-Gajewska H, Poniatowski B, Malyszko JS, Dobrzycki S: Urinary and serum biomarkers after cardiac catheterization in diabetic patients with stable angina and without severe chronic kidney disease. Ren Fail. 2009;31:910-919.
30.
Malyszko J, Tesar V, Macdougall IC: Neutrophil gelatinase-associated lipocalin and hepcidin: what do they have in common and is there a potential interaction? Kidney Blood Press Res 2010;33:157-165.
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2013
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