Serum and Urinary Netrin-1 as Biomarkers for Kidney Injury in Adults with Transfusion-Dependent Beta-Thalassemia

Asmaa El-Shemy; Aly Elkholy; Sara Abdou; Kholoud Adel Alsawy; Doaa Mohamed Salah El-Din

doi:10.46310/tjim.1839890

Serum and Urinary Netrin-1 as Biomarkers for Kidney Injury in Adults with Transfusion-Dependent Beta-Thalassemia

Abstract

Objective: Kidney disease in transfusion-dependent β thalassemia (TDBT) patients is more common and is associated with prolonged patient survival.

Methods: This was a case‒control study that included 44 adult patients with TDBT and evidence of kidney disease (impaired renal function, microalbuminuria, or macroalbuminuria) without other obvious causes of kidney disease who were recruited from the Hematology Unit. Kidney injury was predicted by measuring the serum and urinary netrin 1 (NTN 1) levels via ELISA. Routine tests, such as hemoglobin, ferritin, serum albumin, and creatinine, were also performed on the patients and controls.

Results: The results revealed statistically significant increases in S. urea, S. creatinine, S. ferritin, S. NTN-1, and urinary NTN-1 (P value <0.05). A significant positive correlation was found between S. NTN-1 and urea, creatinine, and the albumin‒creatinine ratio, and urinary Netrin-1 was positively correlated with urea, creatinine, the albumin‒creatinine ratio, and the serum ferritin level (P value <0.05). S. NTN-1 is a predictor of kidney injury among TDBT patients, with an AUC (95% CI) = 0.841, and at a cutoff value ≥ 564.5 pg/ml, its sensitivity and specificity were 81% and 72%, respectively. The urinary NTN-1 AUC (95% CI) was 0.993, and at a cutoff value of ≥ 645 pg/mg creatinine, its sensitivity and specificity were 96% and 89%, respectively.

Conclusion: Serum and urinary NTN-1 may be promising potential biomarkers for the early detection of renal dysfunction in β-TM patients, with promising sensitivity and specificity.

Keywords

References

1. Andani CN, Aman AK, Hariman H, Lubis B. Cytogenetic mutation in a family with sickle-cell beta-thalassemia in North Sumatera, Medan, Indonesia: a preliminary study. Bali Med J. 2019;8(2):532-36. doi:10.15562/BMJ. V8I2.1417.
2. Yesilipek MA. Stem cell transplantation in hemoglobinopathies. Hemoglobin. 2007;31(2):251-6. doi:10.1080/03630260701297196.
3. Rivella S. β-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies. Haematologica. 2015;100(4):418-30. doi:10.3324/haematol.2014.114827.
4. Cunningham MJ. Update on thalassemia: clinical care and complications. Hematol Oncol Clin North Am. 2010;24(1):215-27. doi:10.1016/j.hoc.2009.11.006.
5. Shah FT, Sayani F, Trompeter S, Drasar E, Piga A. Challenges of blood transfusions in β-thalassemia. Blood Rev. 2019;37:100588. doi:10.1016/j.blre.2019.100588.
6. Romadhon PZ, Ashariati A, Bintoro SUY, Thaha M, Suryantoro SD, Windradi C, et al. Markers of renal complications in beta thalassemia patients with iron overload receiving chelation agent therapy: a systematic review. J Blood Med. 2022;13:725-38. doi:10.2147/JBM.S387416.
7. Motta I, Mancarella M, Marcon A, Vicenzi M, Cappellini MD. Management of age-associated medical complications in patients with β-thalassemia. Expert Rev Hematol. 2020;13(1):85-94. doi:10.1080/17474086. 2020.1686354.
8. Tantawy AAG, El Bablawy N, Adly AAM, Ebeid FSE. Early predictors of renal dysfunction in Egyptian patients with β-thalassemia major and intermedia. Mediterr J Hematol Infect Dis. 2014;6(1):e2014057. doi:10.4084/ MJHID.2014.057.

9. Mallat NS, Mallat SG, Musallam KM, Taher AT. Potential mechanisms for renal damage in beta-thalassemia. J Nephrol. 2013;26(5):821-8. doi:10.5301/JN.5000253.
10. Ong-ajyooth L, Malasit P, Ong-ajyooth S, Fucharoen S, Pootrakul P, Vasuvattakul S, et al. Renal function in adult beta-thalassemia/Hb E disease. Nephron. 1998;78(2):156-61. doi:10.1159/000044904.
11. Ahmadzadeh A, Jalali A, Assar S, Khalilian H, Zandian K, Pedram M. Renal tubular dysfunction in pediatric patients with beta-thalassemia major. Saudi J Kidney Dis Transpl. 2011;22:497-500.
12. Sadeghi-Bojd S, Hashemi M, Karimi M. Renal tubular function in patients with beta-thalassaemia major in Zahedan, southeast Iran. Singapore Med J. 2008;49:410-2.
13. Sumboonnanonda A, Sanpakit K, Piyaphanee N. Renal tubule function in beta-thalassemia after hematopoietic stem cell transplantation. Pediatr Nephrol. 2009;24:183-7. doi:10.1007/S00467-008-0949-0.
14. Demosthenous C, Vlachaki E, Apostolou C, Eleftheriou P, Kotsiafti A, Vetsiou E, et al. Beta-thalassemia: renal complications and mechanisms: a narrative review. Hematology. 2019;24(1):426-38. doi:10.1080/16078454.20 19.1599096.
15. Smolkin V, Halevy R, Levin C, Mines M, Sakran W, Ilia K, et al. Renal function in children with β-thalassemia major and thalassemia intermedia. Pediatr Nephrol. 2008;23:1847-51. doi:10.1007/S00467-008-0897-8.
16. Kassab-Chekir A, Laradi S, Ferchichi S, Haj Khelil A, Feki M, Amri F, et al. Oxidant, antioxidant status and metabolic data in patients with beta-thalassemia. Clin Chim Acta. 2003;338(1-2):79-86. doi:10.1016/J. CCCN.2003.07.010.
17. Cianciulli P, Sollecito D, Sorrentino F, Forte L, Gilardi E, Massa A, et al. Early detection of nephrotoxic effects in thalassemic patients receiving desferrioxamine therapy. Kidney Int. 1994;46(2):467-70. doi:10.1038/ki.1994.295.
18. Vichinsky E. Clinical application of deferasirox: practical patient management. Am J Hematol. 2008;83(5):398-402. doi:10.1002/AJH.21119.
19. Şen V, Ece A, Uluca Ü, Söker M, Güneş A, Kaplan I, et al. Urinary early kidney injury molecules in children with beta-thalassemia major. Ren Fail. 2015;37(4):607-13. doi:10.3109/0886022X.2015.1007871.
20. Patsaoura A, Tatsi E, Margeli A, Kanavaki I, Delaporta P, Kyriakopoulou D, et al. Plasma neutrophil gelatinaseassociated lipocalin levels are markedly increased in patients with non-transfusion-dependent thalassemia: lack of association with markers of erythropoiesis, iron metabolism and renal function. Clin Biochem. 2014;47(12):1060-4. doi:10.1016/J.CLINBIOCHEM.2014.03.017.
21. Xia X, Hu Z, Wang S, Yin K. Netrin-1: an emerging player in inflammatory diseases. Cytokine Growth Factor Rev. 2022;64:46-56. doi:10.1016/j.cytogfr.2022.01.003.
22. Abd El-Khalik SR, Sharaby RM, Nasif E, Hamza MB, Ibrahim RR. Netrin-1 and clusterin: innovative potential diagnostic biomarkers for early renal damage in β-thalassemia major children. IUBMB Life. 2021;73(5):800-10. doi:10.1002/IUB.2464.
23. Kattamis A, Kwiatkowski JL, Aydinok Y. Thalassaemia. Lancet. 2022;399(10343):2310-24. doi:10.1016/S0140- 6736(22)00536-0.
24. Trougakos IP, Gonos ES. Regulation of clusterin/apolipoprotein J, a functional homologue to the small heat shock proteins, by oxidative stress in ageing and age-related diseases. Free Radic Res. 2006;40(12):1324-34. doi:10.1080/10715760600902310.
25. Tanous O, Azulay Y, Halevy R, Dujovny T, Swartz N, Colodner R, et al. Renal function in β-thalassemia major patients treated with two different iron-chelation regimes. BMC Nephrol. 2021;22:418. doi:10.1186/S12882- 021-02630-5.
26. Shwayel AJ, Jewad AM, Abdulsattar MQ. Evaluation of serum cystatin-C and netrin-1 as predictive biomarkers for renal injury in children with beta-thalassemia major. J Appl Hematol. 2023;14(3):236-41. doi:10.4103/JOAH.JOAH_29_23.
27. Aldudak B, Bayazit AK, Noyan A, Özel A, Anarat A, Sasmaz I, et al. Renal function in pediatric patients with β-thalassemia major. Pediatr Nephrol. 2000;15:109-12. doi:10.1007/S004670000434.
28. Milo G, Nevo RFG, Pazgal I, Gafter-Gvili A, Shpilberg O, Gafter U, et al. GFR in patients with β-thalassemia major. Clin J Am Soc Nephrol. 2015;10(8):1350-6. doi:10.2215/CJN.12181214.
29. Quinn CT, Johnson VL, Kim HY, Trachtenberg F, Vogiatzi MG, Kwiatkowski JL, et al. Renal dysfunction in patients with thalassaemia. Br J Haematol. 2011;153(1):111-7. doi:10.1111/J.1365-2141.2010.08477.X.
30. Mahmoud AA, Elian DM, Abd El Hady NMS, Abdallah HM, Abdelsattar S, Khalil FO, et al. Assessment of subclinical renal glomerular and tubular dysfunction in children with beta thalassemia major. Children (Basel). 2021;8(2):100. doi:10.3390/CHILDREN8020100.
31. Economou M, Printza N, Teli A, Tzimouli V, Tsatra I, Papachristou F, et al. Renal dysfunction in patients with betathalassemia major receiving iron chelation therapy either with deferoxamine and deferiprone or with deferasirox. Acta Haematol. 2010;123(3):148-52. doi:10.1159/000287238.
32. Bekhit OE, El Dash HH, Ahmed MS. Early detection of kidney dysfunction in Egyptian patients with betathalassemia major. Egypt Pediatr Assoc Gaz. 2017;65(3):85-9. doi:10.1016/J.EPAG.2017.02.002.
33. Lai ME, Spiga A, Vacquer S, Carta MP, Corrias C, Ponticelli C. Renal function in patients with β-thalassaemia major: a long-term follow-up study. Nephrol Dial Transplant. 2012;27(9):3547-51. doi:10.1093/NDT/GFS169.
34. Hashemieh M. Early detection of renal dysfunction in β thalassemia with focus on novel biomarkers. Iran J Pediatr Hematol Oncol. 2020;10(1):57-68. doi:10.18502/IJPHO.V10I1.2170.
35. Elbedewy T, Gawaly A, Abd El-Naby A. Serum cystatin-C and urinary N-acetyl-β-d-glucosaminidase as biomarkers for early renal dysfunction in adult Egyptian patients with β-thalassemia major. Tanta Med J. 2015;43(1):28-35. doi:10.4103/1110-1415.154563.
36. Karaman K, Şahin S, Geylan H, Yaşar AŞ, Çetin M, Kömüroğlu AU, et al. Evaluation of renal function disorder with urinary neutrophil gelatinase-associated lipocalin level in patients with β-thalassemia major. J Pediatr Hematol Oncol. 2019;41(7):507-10. doi:10.1097/MPH.0000000000001577.
37. Bhowad S, Samant P, Seth B. Biochemical assessment of renal function and its correlation with iron overloading in different variants of thalassemia. J Appl Nat Sci. 2022;14(3):1016-21. doi:10.31018/JANS.V14I3.3718.
38. Lafferty HM, Anderson S, Brenner BM. Anemia: a potent modulator of renal hemodynamics in models of progressive renal disease. Am J Kidney Dis. 1991;17(5 Suppl 1):2-7.
39. Nangaku M. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol. 2006;17(1):17-25. doi:10.1681/ASN.2005070757.
40. Ramesh G, Krawczeski CD, Woo JG, Wang Y, Devarajan P. Urinary netrin-1 is an early predictive biomarker of acute kidney injury after cardiac surgery. Clin J Am Soc Nephrol. 2010;5(3):395-401. doi:10.2215/CJN.05140709.
41. Ucaktürk SA, Mengen E, Elmaoğullarl S, Yücel Ç, Yllmaz AA, Çifci A. Evaluation of the relationship between short-term glycemic control and netrin-1, a urinary proximal tubular injury marker in children with type 1 diabetes. J Pediatr Endocrinol Metab. 2019;32(8):851-6. doi:10.1515/JPEM-2018-0373.
42. Liu C, Li Q, Feng X, Li Q. Elevated levels of netrin-1 in the serum of patients with diabetic nephropathy: relationship with renal function and inflammation. Eur J Inflamm. 2018;16:1-6. doi:10.1177/2058739218809288.
43. Rajasundari A, Pays L, Mehlen P, Ramesh G. Netrin-1 overexpression in kidney proximal tubular epithelium ameliorates cisplatin nephrotoxicity. Lab Investig. 2011;91(12):1717-26. doi:10.1038/labinvest.2011.126.

Details

Primary Language

English

Subjects

Cardiovascular Medicine and Haematology (Other) , Internal Diseases , Nefroloji

Journal Section

Research Article

Authors

Asmaa El-Shemy
0000-0002-8040-1589
Egypt

Aly Elkholy ^*
0000-0001-9927-7277
Egypt

Sara Abdou
0000-0001-8712-5751
Egypt

Kholoud Adel Alsawy
0000-0002-7845-2010
Egypt

Doaa Mohamed Salah El-Din
Egypt

Publication Date

April 1, 2026

Submission Date

December 10, 2025

Acceptance Date

March 9, 2026

Published in Issue

Year 2026 Volume: 8

DOI

https://doi.org/10.46310/tjim.1839890

IZ

https://izlik.org/JA62XK98BA

Cite

RIS / Bibtex

APA

El-Shemy, A., Elkholy, A., Abdou, S., Adel Alsawy, K., & Mohamed Salah El-Din, D. (2026). Serum and Urinary Netrin-1 as Biomarkers for Kidney Injury in Adults with Transfusion-Dependent Beta-Thalassemia. Turkish Journal of Internal Medicine, 8, 47-59. https://doi.org/10.46310/tjim.1839890

AMA

1.El-Shemy A, Elkholy A, Abdou S, Adel Alsawy K, Mohamed Salah El-Din D. Serum and Urinary Netrin-1 as Biomarkers for Kidney Injury in Adults with Transfusion-Dependent Beta-Thalassemia. Turk J Int Med. 2026;8:47-59. doi:10.46310/tjim.1839890

Chicago

El-Shemy, Asmaa, Aly Elkholy, Sara Abdou, Kholoud Adel Alsawy, and Doaa Mohamed Salah El-Din. 2026. “Serum and Urinary Netrin-1 As Biomarkers for Kidney Injury in Adults With Transfusion-Dependent Beta-Thalassemia”. Turkish Journal of Internal Medicine 8 (April): 47-59. https://doi.org/10.46310/tjim.1839890.

EndNote

El-Shemy A, Elkholy A, Abdou S, Adel Alsawy K, Mohamed Salah El-Din D (April 1, 2026) Serum and Urinary Netrin-1 as Biomarkers for Kidney Injury in Adults with Transfusion-Dependent Beta-Thalassemia. Turkish Journal of Internal Medicine 8 47–59.

IEEE

[1]A. El-Shemy, A. Elkholy, S. Abdou, K. Adel Alsawy, and D. Mohamed Salah El-Din, “Serum and Urinary Netrin-1 as Biomarkers for Kidney Injury in Adults with Transfusion-Dependent Beta-Thalassemia”, Turk J Int Med, vol. 8, pp. 47–59, Apr. 2026, doi: 10.46310/tjim.1839890.

ISNAD

El-Shemy, Asmaa - Elkholy, Aly - Abdou, Sara - Adel Alsawy, Kholoud - Mohamed Salah El-Din, Doaa. “Serum and Urinary Netrin-1 As Biomarkers for Kidney Injury in Adults With Transfusion-Dependent Beta-Thalassemia”. Turkish Journal of Internal Medicine 8 (April 1, 2026): 47-59. https://doi.org/10.46310/tjim.1839890.

JAMA

1.El-Shemy A, Elkholy A, Abdou S, Adel Alsawy K, Mohamed Salah El-Din D. Serum and Urinary Netrin-1 as Biomarkers for Kidney Injury in Adults with Transfusion-Dependent Beta-Thalassemia. Turk J Int Med. 2026;8:47–59.

MLA

El-Shemy, Asmaa, et al. “Serum and Urinary Netrin-1 As Biomarkers for Kidney Injury in Adults With Transfusion-Dependent Beta-Thalassemia”. Turkish Journal of Internal Medicine, vol. 8, Apr. 2026, pp. 47-59, doi:10.46310/tjim.1839890.

Vancouver

1.Asmaa El-Shemy, Aly Elkholy, Sara Abdou, Kholoud Adel Alsawy, Doaa Mohamed Salah El-Din. Serum and Urinary Netrin-1 as Biomarkers for Kidney Injury in Adults with Transfusion-Dependent Beta-Thalassemia. Turk J Int Med. 2026 Apr. 1;8:47-59. doi:10.46310/tjim.1839890