Association of I/D angiotensin-converting enzyme genotype with erythropoietin stimulation in kidney failure
Keywords:
hemodialysis, hemoglobin, oral iron, IV iron, epoetin beta, ACE I/D genotypeAbstract
Angiotensin-converting enzyme (ACE)-gene polymorphism is a possible predisposing factor of erythropoietin response under hypoxic conditions. However, it is not completely clear whether the ACE insertion/deletion (I/D) genotype has an impact on anemia in patients with permanent kidney failure. A 9-month prospective trial was conducted on 53 patients on hemodialysis aimed at determining the beneficial effect of oral vs intravenous iron in anemia management with recombinant human erythropoietin (rHuEpo), and identifying a possible association of the ACE gene I/D polymorphism with the response to rHuEpo. Patients were randomly allocated to receive 50-100 mg daily of ferrous gluconate orally (N=26) or intravenously every two weeks (N=27), together with rHuEpo-beta (200 IU/kg) subcutaneously, to achieve a hemoglobin increase to 105 g/L; subsequently the rHuEpo dose was adjusted at one or two week intervals. In 34 patients who regularly received ACE-inhibitor (ACEi) medication, genotyping for ACE-gene I/D polymorphism was performed using PCR, gel analysis and appropriate restriction digestion. After prolonged rHuEpo treatment, 24.5% of patients attained the targeted 9th-month hemoglobin concentration (105 g/L). Of these, 6/26 of patients received elemental iron orally and 7/27 received it intravenously. We observed an association between homozygous DD (deletion) of the ACE gene and a remarkable early increase in blood hemoglobin (p=0.028), erythrocyte count (p=0.020) and hematocrit (p=0.043) after reduction of the dose of rHuEpo (F=3.95; p=0.029), irrespective of the iron repletion mode (p=0.960). This is the first report on DD genotype as a linkage marker for the optimization of rHuEpo dose for anemia management in hemodialysis patients.
Received: March 3, 2016; Revised: March 31, 2016; Accepted: April 5, 2016; Published online: May 18, 2016
How to cite this article: Savin M, Hadzibulic E, Damjanović T, Santric V, Stankovic S. Association of I/D angiotensin-converting enzyme genotype with erythropoietin stimulation in kidney failure. Arch Biol Sci. 2017;69(1):15-22.
Downloads
References
Kim YC, Mungunsukh O, McCart EA, Roehrich PJ, Yee DK, Day RM. Mechanism of erythropoietin regulation by angiotensin II. Mol Pharmacol. 2014; 85(6):898-908.
Vlahakos DV, Marathias KP, Madias NE. The role of the renin-angiotensin system in the regulation of erythropoiesis. Am J Kidney Dis. 2010;56(3):558-65.
Iodice C, Balletta MM, Minutolo R, Giannattasio P, Tuccillo S, Bellizzi V, D'Amora M, Rinaldi G, Signoriello G, Conte G, De Nicola L. Maximal suppression of renin-angiotensin system in nonproliferative glomerulonephritis. Kidney Int. 2003;63(6):2214-21.
Jacobsen P, Andersen S, Jensen BR, Parving HH. Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy. J Am Soc Nephrol. 2003;14(4):992-9.
Jeong K, Lee T, Ihm C, Lee S, Moon J. Polymorphisms in two genes, IL-1b and ACE, are associated with erythropoietin resistance in Korean patients on maintenance hemodialysis. Exp Mol Med. 2008;40(2):161-6.
KDIGO clinical practice guideline for anemia in chronic kidney disease. Kidney Int Suppl. 2012;2:279-335.
Tsuchida A, Paudyal B, Paudyal P, Ishii Y, Hiromura K, Nojima Y, Komai M. Effectiveness of oral iron to manage anemia in long-term hemodialysis patients with the use of ultrapure dialysate. Exp Therap Med. 2010;1:777-81.
Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16 (3):1215.
Macdougall IC, Tucker B, Thompson J, Tomson CR, Baker LR, Raine AE. A randomized controlled study of iron supplementation in patients treated with erythropoietin. Kidney Int. 1996;50:1694-9.
Fudin R, Jaichenko J, Shostak A, Bennett M, Gotloib L. Correction of uremic iron deficiency anemia in hemodialyzed patients: a prospective study. Nephron. 1998;79:299-305.
Wingard RL, Paeker RA, Nuhad I, Hakim RM. Efficacy of oral iron therapy in patients receiving recombinant human erythropoietin. Am J Kidney Dis. 1995;35(3):433-9.
Babitt JL, Lin HY. Molecular mechanisms of hepcidin regulation: implications for the anemia of CKD. Am J Kidney Dis. 2010;55:726-41.
National Kidney Foundation. K/DOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. Am J Kidney Dis.2006;47:S11-S145.
Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest. 1990;86(4):1343-6.
Seikaly MG, Arant BS, Seney FD. Endogenous angiotensin concentrations in specific intrarenal fluid compartments of the rat. J Clin Invest. 1990;86(4):1352-7.
Ingelfinger JR, Dzau VJ. Molecular biology of renal injury: Emphasis on the role of the renin-angiotensin system. J Am Soc Nephrol. 1991;2:S2-S20.
Zhou TB, Yin SS, Qin YH. Association between angiotensin-converting enzyme insertion/deletion gene polymorphism and end-stage renal disease susceptibility. J Renin Angiotensin Aldosterone Syst. 2014;15(1):22-31.
Savin M, Petronic V. The significance of angiotensin-converting enzyme inhibitors genotype for ACEi response in patients with chronic allograft nephropathy. Serb Arch Medicine. 2005; 133:194-8.
Vlahakos DV, Balodimos C, Papachristopoulos V, Vassilakos P, Hinari E, Vlachojannis JG. Renin-angiotensin system stimulates erythropoietin secretion in chronic hemodialysis patients. Clin Nephrol. 1995;43(1):53-9.
Varagunam M, McCloskey DJ, Sinnott PJ, Raftery MJ, Yaqoob MM. Angiotensin-converting enzyme gene polymorphism and erythropoietin requirement. Perit Dial Int 2003;23(2):111-5.
Sharples EJ, Varagunam M, Sinnott PJ, McCloskey DJ, Raftery MJ, Yaqoob MM. The effect of proinflammatory cytokine gene and angiotensin-converting enzyme polymorphisms on erythropoietin requirements in patients on continuous ambulatory peritoneal dialysis. Perit Dial Int. 2006;26(1):64-8.
Kiss Z, Ambrus C, Kulcsár I, Szegedi J, Kiss I. ACEgen-BB HU workgroup. Effect of angiotensin-converting enzyme gene insertion/deletion polymorphism and angiotensin-converting enzyme inhibition on erythropoiesis in patients on haemodialysis. J Renin Angiotensin Aldosterone Syst. 2015;16(4):1021-7.
Downloads
Published
How to Cite
Issue
Section
License
Authors grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution 4.0 International License that allows others to share the work with an acknowledgment of the work’s authorship and initial publication in this journal.
