RENAL FUNCTIONS AND ERYTHROPOIETIN STATUS OF BETA THALASSEMIA PATIENTS
Main Article Content
Keywords
.
Abstract
Background
Thalassemias are heterogeneous group of hereditary disorders resulting from mutations that impact the synthesis of globin chains of hemoglobin. Evidence of both glomerular and proximal tubular damage is observed in β-TM patients. Erythropoietin (EPO) is one of the key regulators of erythropoiesis, promoting the proliferation of erythroid progenitor cells and increasing the production of red blood cells with recently discovered receptors in multiple organs. Inspired by studies proposing EPO as a part of the treatment in β-hemoglobinopathies and more studies with significant effects of EPO to reduce tubular dysfunction and glomerular injury, our study aimed to assess the tubular and glomerular renal functions of β-TM patients along with their EPO status.
Materials and methods
This prospective case-control study included a total of 71 TDT beta thalassemia patients and 22 healthy, age- and sex-matched controls. All patients were examined for their current weight and height, body mass index (BMI), z score, blood pressure, renal glomerular and tubular status and erythropoietin levels.
Results
There were 16 malnourished patients with VKI <18 and -2 SDS. Forty-eight patients (67,6% of patient group) had proteinuria and 16 (22,5%) had albuminuria. Twenty nine of β-TM (40,8%) patients had high fractional excretion of uric acid (FEUA). TmP/GFR was <2,8 in 22,5% (n=16) of patients demonstrating higher phosphate wasting. Thirty eight percent (n=27) of the patients showed hypercalciuria. Serum beta-2-microglobulin and urine β-2-MG were elevated in 80,3% (n=57) and 49,3% (n=35) of the patients respectively. Sixty four (90,1%) patients had elevated serum EPO.
Conclusion
Compared to healthy group, patient group had significantly higher levels of serum urea, proteinuria, albuminuria, hyperuricosuria, phosphaturia and significantly elevated eGFR, EPO, urine and serum β-2-MG. Both renal tubular and glomerular functions of a β-TM patient deteriorate beginning from childhood years. Routine follow-up of serum creatinine, eGFR, serum cystatin C, spot urine protein/creatinine, spot urine Ca/Cr, FENa and FEUA could fail to detect early renal damage but still essential to analyze as they may be discovered impaired.
References
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doi:10.1016/j.transci.2020.102746.
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21- Mokhtar GM, Gadallah M, El Sherif NH, Ali HT. Morbidities and mortality in transfusion-dependent Beta-thalassemia patients (single-center experience). Pediatr Hematol Oncol. 2013 Mar;30(2):93-103. doi: 10.3109/08880018.2012.752054.
22- Zhou XJ, Laszik Z, Wang XQ, Silva FG, Vaziri ND. Association of renal injury with increased oxygen free radical activity and altered nitric oxide metabolism in chronic experimental hemosiderosis. Lab Invest. 2000 Dec;80(12):1905-14. doi: 10.1038/labinvest.3780200.
23- Ponticelli C, Musallam KM, Cianciulli P, Cappellini MD. Renal complications in transfusion-dependent beta thalassaemia. Blood Rev. 2010 Nov;24(6):239-44. doi: 10.1016/j.blre.2010.08.004.
24- Sleiman J, Tarhini A, Taher AT. Renal Complications in Thalassemia. Thalassemia Reports. 2018; 8(1):7481. doi:10.4081/thal.2018.7481.
25- Davis LE, Hohimer AR. Hemodynamics and organ blood flow in fetal sheep subjected to chronic anemia. Am J Physiol. 1991 Dec;261(6 Pt 2):R1542-8. doi: 10.1152/ajpregu.1991.261.6.R1542.
26- Mohkam M, Shamsian BS, Gharib A, Nariman S, Arzanian MT. Early markers of renal dysfunction in patients with beta-thalassemia major. Pediatr Nephrol. 2008 Jun;23(6):971-6. doi: 10.1007/s00467-008-0753-x.
27- Smolkin V, Halevy R, Levin C, Mines M, Sakran W, Ilia K, Koren A. Renal function in children with beta-thalassemia major and thalassemia intermedia. Pediatr Nephrol. 2008 Oct;23(10):1847-51. doi: 10.1007/s00467-008-0897-8.
28- Aldudak B, Karabay Bayazit A, Noyan A, Ozel A, Anarat A, Sasmaz I, Kilinç Y, Gali E, Anarat R, Dikmen N. Renal function in pediatric patients with beta-thalassemia major. Pediatr Nephrol. 2000 Nov;15(1-2):109-12. doi: 10.1007/s004670000434.
29- Chaidos A, Makis A, Hatzimichael E, Tsiara S, Gouva M, Tzouvara E, Bourantas KL. Treatment of beta-thalassemia patients with recombinant human erythropoietin: effect on transfusion requirements and soluble adhesion molecules. Acta Haematol. 2004;111(4):189-95. doi: 10.1159/000077551.
30- Nisli G, Kavakli K, Aydinok Y, Oztop S, Cetingül N, Basak N. Recombinant erythropoietin trial in children with transfusion-dependent homozygous beta-thalassemia. Acta Haematol. 1997;98(4):199-203. doi: 10.1159/000203624.
31- Borgna-Pignatti C, Gamberini MR. Complications of thalassemia major and their treatment. Expert Rev Hematol. 2011 Jun;4(3):353-66. doi: 10.1586/ehm.11.29.
32- Ganz T, Nemeth E. Hepcidin and disorders of iron metabolism. Annu Rev Med. 2011;62:347-60. doi: 10.1146/annurev-med-050109-142444.
33- Chen JS, Lin KH, Wang ST, Tsao CJ, Yeh TF. Blunted serum erythropoietin response to anemia in patients polytransfused for beta-thalassemia major. J Pediatr Hematol Oncol. 1998 Mar-Apr;20(2):140-4. doi: 10.1097/00043426-199803000-00010.
34- Logar CM, Brinkkoetter PT, Krofft RD, Pippin JW, Shankland SJ. Darbepoetin alfa protects podocytes from apoptosis in vitro and in vivo. Kidney Int. 2007 Aug;72(4):489-98. doi: 10.1038/sj.ki.5002362.
35- Chaisiripoomkere W, Jootar S, Chanjarunee S, Ungkanont A. Serum erythropoietin levels in thalassemia major and intermedia. Southeast Asian J Trop Med Public Health. 1999 Dec;30(4):786-8.
36- Eckardt KU, Hartmann W, Vetter U, Pohlandt F, Burghardt R, Kurtz A. Serum immunoreactive erythropoietin of children in health and disease. Eur J Pediatr. 1990 Apr;149(7):459-64. doi: 10.1007/BF01959395.
37- Hellebostad M, Hågå P, Cotes PM. Serum immunoreactive erythropoietin in healthy normal children. Br J Haematol. 1988 Oct;70(2):247-50. doi: 10.1111/j.1365-2141.1988.tb02471.x.
38- Nişli G, Kavakli K, Aydinok Y, Oztop S, Cetingül N. Serum erythropoietin levels in patients with beta thalassemia major and intermedia. Pediatr Hematol Oncol. 1997 Mar-Apr;14(2):161-7. doi: 10.3109/08880019709030902.
39- Vesey DA, Cheung C, Pat B, Endre Z, Gobé G, Johnson DW. Erythropoietin protects against ischaemic acute renal injury. Nephrol Dial Transplant. 2004 Feb;19(2):348-55. doi: 10.1093/ndt/gfg547.
40- Fliser D, Bahlmann FH, Haller H. EPO: renoprotection beyond anemia correction. Pediatr Nephrol. 2006 Dec;21(12):1785-9. doi: 10.1007/s00467-006-0284-2.
41- Rossert J, McClellan WM, Roger SD, Verbeelen DL. Epoetin treatment: what are the arguments to expect a beneficial effect on renal disease progression? Nephrol Dial Transplant. 2002 Mar;17(3):359-62. doi: 10.1093/ndt/17.3.359.
42- Sharples EJ, Patel N, Brown P, Stewart K, Mota-Philipe H, Sheaff M, Kieswich J, Allen D, Harwood S, Raftery M, Thiemermann C, Yaqoob MM. Erythropoietin protects the kidney against the injury and dysfunction caused by ischemia-reperfusion. J Am Soc Nephrol. 2004 Aug;15(8):2115-24. doi: 10.1097/01.ASN.0000135059.67385.5D.
43- Kher K. K., Schnaper H.W., Greenbaum L. A. Clinical Pediatric Nephrology. Third Edition. CRC Press Taylor & Francis Group; 2017.
44- Tojo A, Kinugasa S. Mechanisms of glomerular albumin filtration and tubular reabsorption. Int J Nephrol. 2012;2012:481520. doi: 10.1155/2012/481520.
45- Bernier GM. beta 2-Microglobulin: structure, function and significance. Vox Sang. 1980 Jun;38(6):323-7. doi: 10.1111/j.1423-0410.1980.tb04500.x.
46- Piga A, Longo F, Origa R, Roggero S, Pinna F, Zappu A, Castiglioni C, Cappellini MD. Deferasirox for cardiac siderosis in β-thalassaemia major: a multicentre, open label, prospective study. Br J Haematol. 2014 Nov;167(3):423-6. doi: 10.1111/bjh.12987.
47- Dee CM, Cheuk DK, Ha SY, Chiang AK, Chan GC. Incidence of deferasirox-associated renal tubular dysfunction in children and young adults with beta-thalassaemia. Br J Haematol. 2014 Nov;167(3):434-6. doi: 10.1111/bjh.13002.
48- Yacobovich J, Stark P, Barzilai-Birenbaum S, Krause I, Pazgal I, Yaniv I, Tamary H. Acquired proximal renal tubular dysfunction in β-thalassemia patients treated with deferasirox. J Pediatr Hematol Oncol. 2010 Oct;32(7):564-7. doi: 10.1097/MPH.0b013e3181ec0c38.
49- Rheault MN, Bechtel H, Neglia JP, Kashtan CE. Reversible Fanconi syndrome in a pediatric patient on deferasirox. Pediatr Blood Cancer. 2011 Apr;56(4):674-6. doi: 10.1002/pbc.22711.
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2- Arman Bilir Ö, Kirkiz S, Fettah A, Ok Bozkaya İ, Kara A, Çakar N, Yaralı N. Renal function and the oxidative status among children with thalassemia major and healthy controls: A cross-sectional study. Transfus Apher Sci. 2020 Aug;59(4):102746.
doi:10.1016/j.transci.2020.102746.
3- Mahmoud AA, Elian DM, Abd El Hady NM, Abdallah HM, Abdelsattar S, Khalil FO, Abd El Naby SA. Assessment of Subclinical Renal Glomerular and Tubular Dysfunction in Children with Beta Thalassemia Major. Children (Basel). 2021 Feb 3;8(2):100. doi: 10.3390/children8020100.
4- Bakr A, Al-Tonbary Y, Osman G, El-Ashry R. Renal complications of beta-thalassemia major in children. Am J Blood Res. 2014 Sep 5;4(1):1-6. PMID: 25232499; PMCID: PMC4165117.
5- Tanous O, Azulay Y, Halevy R, Dujovny T, Swartz N, Colodner R, Koren A, Levin C. Renal function in β-thalassemia major patients treated with two different iron-chelation regimes. BMC Nephrol. 2021 Dec 20;22(1):418. doi: 10.1186/s12882-021-02630-5.
6- Uzun E, Balcı YI, Yüksel S, Aral YZ, Aybek H, Akdağ B. Glomerular and tubular functions in children with different forms of beta thalassemia. Ren Fail. 2015;37(9):1414-8. doi: 10.3109/0886022X.2015.1077314.
7- Grote Beverborg N, Verweij N, Klip IT, van der Wal HH, Voors AA, van Veldhuisen DJ, Gansevoort RT, Bakker SJ, van der Harst P, van der Meer P. Erythropoietin in the general population: reference ranges and clinical, biochemical and genetic correlates. PLoS One. 2015 Apr 27;10(4):e0125215. doi: 10.1371/journal.pone.0125215.
8- Fibach E, Rachmilewitz EA. Does erythropoietin have a role in the treatment of β-hemoglobinopathies? Hematol Oncol Clin North Am. 2014 Apr;28(2):249-63. doi: 10.1016/j.hoc.2013.11.002.
9- Sharples EJ, Yaqoob MM. Erythropoietin in experimental acute renal failure. Nephron Exp Nephrol. 2006;104(3):e83-8. doi: 10.1159/000094546.
10- Sturiale A, Campo S, Crascì E, Aloisi C, Buemi M. Experimental models of acute renal failure and erythropoietin: what evidence of a direct effect? Ren Fail. 2007;29(3):379-86. doi: 10.1080/08860220701193290.
11- Sharples EJ, Thiemermann C, Yaqoob MM. Mechanisms of disease: Cell death in acute renal failure and emerging evidence for a protective role of erythropoietin. Nat Clin Pract Nephrol. 2005 Dec;1(2):87-97. doi: 10.1038/ncpneph0042.
12- Geary D., Schaefer F. Pediatric Kidney Disease Second Edition. Springer;2008.
13- Dusunsel R., Bastug F. Nefroloji El Kitabı, Klinik Pratik Yaklaşımlar. Çocuk Nefroloji Derneği; 2018.
14- Sadeghi-Bojd S, Hashemi M, Karimi M. Renal tubular function in patients with beta-thalassaemia major in Zahedan, southeast Iran. Singapore Med J. 2008 May;49(5):410-2.
15- Murakami T, Kawakami H. Urine concentration adjustment with a dipstick is dispensable for urinary beta 2-microglobulin screening in children. Nihon Jinzo Gakkai Shi. 1992 Sep;34(9):993-6.
16- DeFreitas MJ, Seeherunvong W, Katsoufis CP, RamachandraRao S, Duara S, Yasin S, Zilleruelo G, Rodriguez MM, Abitbol CL. Longitudinal patterns of urine biomarkers in infants across gestational ages. Pediatr Nephrol. 2016 Jul;31(7):1179-88. doi: 10.1007/s00467-016-3327-3.
17- Tzvi-Behr S, Ivgi H, Frishberg Y, Ben Shalom E. First-week urine beta-2 microglobulin levels in term healthy neonates. Pediatr Nephrol. 2021 Jun;36(6):1511-1514. doi: 10.1007/s00467-020-04839-2.
18- Schwartz G.J., Haycock G.B., Edelmann C.M., Spitzer A. A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics. 1976 Aug; 58 (2): 259–263. 58 (2): 259–263. doi: 10.1542/peds.58.2.259.
19- Schwartz GJ, Muñoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL. New equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009 Mar;20(3):629-37. doi: 10.1681/ASN.2008030287.
20- Yaghobi M, Miri-Moghaddam E, Majid N, Bazi A, Navidian A, Kalkali A. Complications of Transfusion-Dependent β-Thalassemia Patients in Sistan and Baluchistan, South-East of Iran. Int J Hematol Oncol Stem Cell Res. 2017 Oct 1;11(4):268-272.
21- Mokhtar GM, Gadallah M, El Sherif NH, Ali HT. Morbidities and mortality in transfusion-dependent Beta-thalassemia patients (single-center experience). Pediatr Hematol Oncol. 2013 Mar;30(2):93-103. doi: 10.3109/08880018.2012.752054.
22- Zhou XJ, Laszik Z, Wang XQ, Silva FG, Vaziri ND. Association of renal injury with increased oxygen free radical activity and altered nitric oxide metabolism in chronic experimental hemosiderosis. Lab Invest. 2000 Dec;80(12):1905-14. doi: 10.1038/labinvest.3780200.
23- Ponticelli C, Musallam KM, Cianciulli P, Cappellini MD. Renal complications in transfusion-dependent beta thalassaemia. Blood Rev. 2010 Nov;24(6):239-44. doi: 10.1016/j.blre.2010.08.004.
24- Sleiman J, Tarhini A, Taher AT. Renal Complications in Thalassemia. Thalassemia Reports. 2018; 8(1):7481. doi:10.4081/thal.2018.7481.
25- Davis LE, Hohimer AR. Hemodynamics and organ blood flow in fetal sheep subjected to chronic anemia. Am J Physiol. 1991 Dec;261(6 Pt 2):R1542-8. doi: 10.1152/ajpregu.1991.261.6.R1542.
26- Mohkam M, Shamsian BS, Gharib A, Nariman S, Arzanian MT. Early markers of renal dysfunction in patients with beta-thalassemia major. Pediatr Nephrol. 2008 Jun;23(6):971-6. doi: 10.1007/s00467-008-0753-x.
27- Smolkin V, Halevy R, Levin C, Mines M, Sakran W, Ilia K, Koren A. Renal function in children with beta-thalassemia major and thalassemia intermedia. Pediatr Nephrol. 2008 Oct;23(10):1847-51. doi: 10.1007/s00467-008-0897-8.
28- Aldudak B, Karabay Bayazit A, Noyan A, Ozel A, Anarat A, Sasmaz I, Kilinç Y, Gali E, Anarat R, Dikmen N. Renal function in pediatric patients with beta-thalassemia major. Pediatr Nephrol. 2000 Nov;15(1-2):109-12. doi: 10.1007/s004670000434.
29- Chaidos A, Makis A, Hatzimichael E, Tsiara S, Gouva M, Tzouvara E, Bourantas KL. Treatment of beta-thalassemia patients with recombinant human erythropoietin: effect on transfusion requirements and soluble adhesion molecules. Acta Haematol. 2004;111(4):189-95. doi: 10.1159/000077551.
30- Nisli G, Kavakli K, Aydinok Y, Oztop S, Cetingül N, Basak N. Recombinant erythropoietin trial in children with transfusion-dependent homozygous beta-thalassemia. Acta Haematol. 1997;98(4):199-203. doi: 10.1159/000203624.
31- Borgna-Pignatti C, Gamberini MR. Complications of thalassemia major and their treatment. Expert Rev Hematol. 2011 Jun;4(3):353-66. doi: 10.1586/ehm.11.29.
32- Ganz T, Nemeth E. Hepcidin and disorders of iron metabolism. Annu Rev Med. 2011;62:347-60. doi: 10.1146/annurev-med-050109-142444.
33- Chen JS, Lin KH, Wang ST, Tsao CJ, Yeh TF. Blunted serum erythropoietin response to anemia in patients polytransfused for beta-thalassemia major. J Pediatr Hematol Oncol. 1998 Mar-Apr;20(2):140-4. doi: 10.1097/00043426-199803000-00010.
34- Logar CM, Brinkkoetter PT, Krofft RD, Pippin JW, Shankland SJ. Darbepoetin alfa protects podocytes from apoptosis in vitro and in vivo. Kidney Int. 2007 Aug;72(4):489-98. doi: 10.1038/sj.ki.5002362.
35- Chaisiripoomkere W, Jootar S, Chanjarunee S, Ungkanont A. Serum erythropoietin levels in thalassemia major and intermedia. Southeast Asian J Trop Med Public Health. 1999 Dec;30(4):786-8.
36- Eckardt KU, Hartmann W, Vetter U, Pohlandt F, Burghardt R, Kurtz A. Serum immunoreactive erythropoietin of children in health and disease. Eur J Pediatr. 1990 Apr;149(7):459-64. doi: 10.1007/BF01959395.
37- Hellebostad M, Hågå P, Cotes PM. Serum immunoreactive erythropoietin in healthy normal children. Br J Haematol. 1988 Oct;70(2):247-50. doi: 10.1111/j.1365-2141.1988.tb02471.x.
38- Nişli G, Kavakli K, Aydinok Y, Oztop S, Cetingül N. Serum erythropoietin levels in patients with beta thalassemia major and intermedia. Pediatr Hematol Oncol. 1997 Mar-Apr;14(2):161-7. doi: 10.3109/08880019709030902.
39- Vesey DA, Cheung C, Pat B, Endre Z, Gobé G, Johnson DW. Erythropoietin protects against ischaemic acute renal injury. Nephrol Dial Transplant. 2004 Feb;19(2):348-55. doi: 10.1093/ndt/gfg547.
40- Fliser D, Bahlmann FH, Haller H. EPO: renoprotection beyond anemia correction. Pediatr Nephrol. 2006 Dec;21(12):1785-9. doi: 10.1007/s00467-006-0284-2.
41- Rossert J, McClellan WM, Roger SD, Verbeelen DL. Epoetin treatment: what are the arguments to expect a beneficial effect on renal disease progression? Nephrol Dial Transplant. 2002 Mar;17(3):359-62. doi: 10.1093/ndt/17.3.359.
42- Sharples EJ, Patel N, Brown P, Stewart K, Mota-Philipe H, Sheaff M, Kieswich J, Allen D, Harwood S, Raftery M, Thiemermann C, Yaqoob MM. Erythropoietin protects the kidney against the injury and dysfunction caused by ischemia-reperfusion. J Am Soc Nephrol. 2004 Aug;15(8):2115-24. doi: 10.1097/01.ASN.0000135059.67385.5D.
43- Kher K. K., Schnaper H.W., Greenbaum L. A. Clinical Pediatric Nephrology. Third Edition. CRC Press Taylor & Francis Group; 2017.
44- Tojo A, Kinugasa S. Mechanisms of glomerular albumin filtration and tubular reabsorption. Int J Nephrol. 2012;2012:481520. doi: 10.1155/2012/481520.
45- Bernier GM. beta 2-Microglobulin: structure, function and significance. Vox Sang. 1980 Jun;38(6):323-7. doi: 10.1111/j.1423-0410.1980.tb04500.x.
46- Piga A, Longo F, Origa R, Roggero S, Pinna F, Zappu A, Castiglioni C, Cappellini MD. Deferasirox for cardiac siderosis in β-thalassaemia major: a multicentre, open label, prospective study. Br J Haematol. 2014 Nov;167(3):423-6. doi: 10.1111/bjh.12987.
47- Dee CM, Cheuk DK, Ha SY, Chiang AK, Chan GC. Incidence of deferasirox-associated renal tubular dysfunction in children and young adults with beta-thalassaemia. Br J Haematol. 2014 Nov;167(3):434-6. doi: 10.1111/bjh.13002.
48- Yacobovich J, Stark P, Barzilai-Birenbaum S, Krause I, Pazgal I, Yaniv I, Tamary H. Acquired proximal renal tubular dysfunction in β-thalassemia patients treated with deferasirox. J Pediatr Hematol Oncol. 2010 Oct;32(7):564-7. doi: 10.1097/MPH.0b013e3181ec0c38.
49- Rheault MN, Bechtel H, Neglia JP, Kashtan CE. Reversible Fanconi syndrome in a pediatric patient on deferasirox. Pediatr Blood Cancer. 2011 Apr;56(4):674-6. doi: 10.1002/pbc.22711.
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Published
Jul 16, 2023
Article Details
How to Cite
Berfin Uysal, & Elif Güler Kazancı. (2023). RENAL FUNCTIONS AND ERYTHROPOIETIN STATUS OF BETA THALASSEMIA PATIENTS. Journal of Population Therapeutics and Clinical Pharmacology, 30(12), 476-484. https://doi.org/10.53555/jptcp.v30i12.2841
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All articles published in JPTCP are licensed under Copyright Creative Commons Attribution-NonCommercial 4.0 International License.
Author Biographies
Berfin Uysal
MD, Division of Pediatric Nephrology, Bursa City Hospital, University of Health Sciences
ORCID number: 0000-0001-6267-0454
Elif Güler Kazancı
MD, Associate Professor, Division of Pediatric Hematology and Oncology, Bursa City Hospital, University of Health Sciences, ORCID number: 0000-0003-0910-1142
How to Cite
Berfin Uysal, & Elif Güler Kazancı. (2023). RENAL FUNCTIONS AND ERYTHROPOIETIN STATUS OF BETA THALASSEMIA PATIENTS. Journal of Population Therapeutics and Clinical Pharmacology, 30(12), 476-484. https://doi.org/10.53555/jptcp.v30i12.2841