CYTOKINE PROFILE IN RENAL TRANSPLANT PATIENTS IN A LONG-TERM PERIOD AFTER SURGERY

Vladana Stojiljković, Nikola Stefanović, Katarina Danković, Branka Đorđević, Mina Cvetković, Nataša Stević, Stevan Vujić, Branka Mitić, Tatjana Cvetković

DOI Number
https://doi.org/10.22190/FUMB230406003S
First page
001
Last page
007

Abstract


In the long-term period after kidney transplantation, a certain level of tissue inflammation and therefore the production of proinflammatory cytokines, including TNF-α, IL-1β, IL-18 and IL-2 can be found. The aim of our study was to determine the concentrations of TNF-α, IL-1β, IL-18, IL-2 and its soluble receptor (IL-2R) in renal transplant patients, regarding the length of the postoperative period. The study involved 65 patients, transplanted at least 12 months prior to our investigation, divided into three groups, regarding the time passed since the transplantation (12-24, 24-48, and >48 months consecutively). Concentrations of the cytokines in the plasma of the subjects were measured using ELISA method. Group I showed significantly higher concentrations of IL-1b compared to the III (p<0.05), IL-18 compared to the II and III (p<0.05) and TNF-a compared to the II (p<0.05). Cytokine concentrations correlated with the time passed since the transplantation (p<0.05), except for TNF-a. Interleukin-2 correlated negatively with IL-18 and immunosuppressant dosage (p<0.05). Interleukin-1b, IL-18 and TNF-α measurements should be considered for monitoring and detecting potentially subclinical allograft damage in the second year after surgery. However, the dynamics of the change of cytokine concentration may also have been altered by the components of the immunosuppressive protocols used, such as tacrolimus, which is a link that is yet to be examined.


Keywords

TNF-α, IL-1β, IL-18, IL-2, IL-2 receptor, kidney transplantation

Full Text:

PDF

References


Ghelichi-Ghojogh M, Ghaem H, Mohammadizadeh F, et al. Graft and Patient Survival Rates in Kidney Transplantation, and Their Associated Factors: A Systematic Review and Meta-Analysis. Iran J Public Health 2021; 50(8):1555–63. https://pubmed.ncbi.nlm.nih.gov/34917526/

Hart A, Smith JM, Skeans MA, et al. OPTN/SRTR 2015 Annual Data Report: Kidney. Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg 2017; 17 Suppl 1(Suppl 1):21–116. https://pubmed.ncbi.nlm.nih.gov/28052609/

Lentine KL, Smith JM, Miller JM, et al. OPTN/SRTR 2021 Annual Data Report: Kidney. Am J Transplant 2023; 23(2):S21–120. https://pubmed.ncbi.nlm.nih.gov/35266618/

Rummo O, Carmellini M, Kamar N, et al. Long-term, prolonged-release tacrolimus-based immunosuppression in de novo kidney transplant recipients: 5-year prospective follow-up of the ADHERE study patients. Transpl Int 2020; 33(2):161–73. https://pubmed.ncbi.nlm.nih.gov/31536654/

Russell G, Graveley R, Seid J, al-Humidan AK, Skjodt H. Mechanisms of action of cyclosporine and effects on connective tissues. Semin Arthritis Rheum 1992; 21(6 Suppl 3):16–22. https://pubmed.ncbi.nlm.nih.gov/1502562/

Thomson AW, Bonham CA, Zeevi A. Mode of action of tacrolimus (FK506): molecular and cellular mechanisms. Ther Drug Monit 1995; 17(6):584–91. https://pubmed.ncbi.nlm.nih.gov/8588225/

Andrian T, Siriteanu L, Covic AS, et al. Non-Traditional Non-Immunological Risk Factors for Kidney Allograft Loss—Opinion. J Clin Med 2023; 12(6):2364. https://pubmed.ncbi.nlm.nih.gov/36983364/

Van Loon E, Bernards J, Van Craenenbroeck AH, Naesens M. The Causes of Kidney Allograft Failure: More Than Alloimmunity. A Viewpoint Article. Transplantation 2020; 104(2):e46. https://pubmed.ncbi.nlm.nih.gov/32000235/

Solez K, Colvin RB, Racusen LC, et al. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg 2008; 8(4):753–60. https://pubmed.ncbi.nlm.nih.gov/18294345/

Takada M, Nadeau KC, Shaw GD, Marquette KA, Tilney NL. The cytokine-adhesion molecule cascade in ischemia/reperfusion injury of the rat kidney. Inhibition by a soluble P-selectin ligand. J Clin Invest 1997; 99(11):2682–90. https://pubmed.ncbi.nlm.nih.gov/9169498/

Fernández AR, Sánchez-Tarjuelo R, Cravedi P, Ochando J, López-Hoyos M. Review: Ischemia Reperfusion Injury—A Translational Perspective in Organ Transplantation. Int J Mol Sci 2020; 21(22):8549. https://pubmed.ncbi.nlm.nih.gov/33202744/

Li Y, Yang J, Luo JH, Dedhar S, Liu Y. Tubular Epithelial Cell Dedifferentiation Is Driven by the Helix-Loop-Helix Transcriptional Inhibitor Id1. J Am Soc Nephrol 2007; 18(2):449. https://pubmed.ncbi.nlm.nih.gov/17202424/

Kooten C van, Daha MR, Es LA van. Tubular Epithelial Cells: A Critical Cell Type in the Regulation of Renal Inflammatory Processes. Nephron Exp Nephrol 1999; 7(5–6):429–37. https://pubmed.ncbi.nlm.nih.gov/10559641/

Smith SF, Hosgood SA, Nicholson ML. Ischemia-reperfusion injury in renal transplantation: 3 key signaling pathways in tubular epithelial cells. Kidney Int 2019; 95(1):50–6. https://pubmed.ncbi.nlm.nih.gov/30606429/

Hribova P, Kotsch K, Brabcova I, Vitko S, Volk HD, Lacha J. Cytokines and Chemokine Gene Expression in Human Kidney Transplantation. Transplant Proc 2005; 37(2):760–3. https://pubmed.ncbi.nlm.nih.gov/15848523/

Kaminska D, Tyran B, Mazanowska O, et al. Cytokine Gene Expression in Kidney Allograft Biopsies After Donor Brain Death and Ischemia-Reperfusion Injury Using In Situ Reverse-Transcription Polymerase Chain Reaction Analysis. Transplantation 2007; 84(9):1118. https://pubmed.ncbi.nlm.nih.gov/17998866/

Nguan CYC, Du C. Renal tubular epithelial cells as immunoregulatory cells in renal allograft rejection. Transplant Rev 2009; 23(3):129–38. https://pubmed.ncbi.nlm.nih.gov/19361977/

Alakulppi NS, Kyllönen LE, Jäntti VT, et al. Cytokine Gene Polymorphisms and Risks of Acute Rejection and Delayed Graft Function after Kidney Transplantation. Transplantation 2004; 78(10):1422. https://pubmed.ncbi.nlm.nih.gov/15599305/

Gandhi N, Goldman D, Kahan D, et al. Donor cytokine gene polymorphisms are associated with increased graft loss and dysfunction after transplant. Transplant Proc 2001; 33(1–2):827–8. https://pubmed.ncbi.nlm.nih.gov/11267084/

Timoshanko JR, Sedgwick JD, Holdsworth SR, Tipping PG. Intrinsic Renal Cells Are the Major Source of Tumor Necrosis Factor Contributing to Renal Injury in Murine Crescentic Glomerulonephritis. J Am Soc Nephrol 2003; 14(7):1785. https://pubmed.ncbi.nlm.nih.gov/12819238/

Sarhan M, von Mässenhausen A, Hugo C, Oberbauer R, Linkermann A. Immunological consequences of kidney cell death. Cell Death Dis 2018; 9(2):114. https://pubmed.ncbi.nlm.nih.gov/29371597/

Striz I, Krasna E, Eliska K, et al. Interleukin 18 (IL-18) upregulation in acute rejection of kidney allograft. Immunol Lett 2005; 99:30–5. https://pubmed.ncbi.nlm.nih.gov/15894108/

Krásná E, Kolesár L, Slavčev A, et al. IL-18 Receptor Expression on Epithelial Cells is Upregulated by TNF Alpha. Inflammation 2005; 29(1):33–7. https://pubmed.ncbi.nlm.nih.gov/16502344/

Park SJ, Yoon YC, Kang SW, et al. Impact of IL2 and IL2RB Genetic Polymorphisms in Kidney Transplantation. Transplant Proc 2011; 43(6):2383–7. https://pubmed.ncbi.nlm.nih.gov/21839273/

Fu MS, Lim SJ, Jalalonmuhali M, Ng KS, Lim SK, Ng KP. Clinical Significance of Renal Allograft Protocol Biopsies: A Single Tertiary Center Experience in Malaysia. J Transplant 2019; 2019:e9153875. https://pubmed.ncbi.nlm.nih.gov/31186948/

Sanjay S. Comparative study of once daily tacrolimus (extended-release capsule) versus conventional twice daily tacrolimus in renal transplant recipients. Int J Clin Virol 2022; 6(2):050–4. https://www.heighpubs.org/hjcv/ijcv-aid1050.php

Herrero-Fresneda I, Torras J, Cruzado JM, et al. Do Alloreactivity and Prolonged Cold Ischemia Cause Different Elementary Lesions in Chronic Allograft Nephropathy? Am J Pathol 2003; 162(1):127–37. https://pubmed.ncbi.nlm.nih.gov/12507896/

Shimizu A, Yamada K, Sachs DH, Colvin RB. Mechanisms of Chronic Renal Allograft Rejection. II. Progressive Allograft Glomerulopathy in Miniature Swine. Lab Invest 2002; 82(6):673–86. https://pubmed.ncbi.nlm.nih.gov/12065677/

Yang J, Reutzel-Selke A, Steier C, et al. Targeting of macrophage activity by adenovirus-mediated intragraft overexpression of TNFRp55-Ig, IL-12p40, and vIL-10 ameliorates adenovirus-mediated chronic graft injury, whereas stimulation of macrophages by overexpression of IFN-gamma accelerates chronic graft injury in a rat renal allograft model. J Am Soc Nephrol JASN 2003; 14(1):214–25. https://pubmed.ncbi.nlm.nih.gov/12506154/

Pilmore HL, Painter DM, Bishop GA, McCaughan GW, Eris JM. Early up-regulation of macrophages and myofibroblasts: a new marker for development of chronic renal allograft rejection. Transplantation 2000; 69(12):2658–62. https://pubmed.ncbi.nlm.nih.gov/10910290/

Savikko J, Taskinen E, Von Willebrand E. Chronic allograft nephropathy is prevented by inhibition of platelet-derived growth factor receptor: tyrosine kinase inhibitors as a potential therapy. Transplantation 2003; 75(8):1147–53. https://pubmed.ncbi.nlm.nih.gov/12717194/

Zhang H, Li Z, Li W. M2 Macrophages Serve as Critical Executor of Innate Immunity in Chronic Allograft Rejection. Front Immunol 2021; 12:648539. https://pubmed.ncbi.nlm.nih.gov/33815407/

Devraj VM, Kalidindi K, Guditi S, Uppin M, Taduri G. Macrophage polarization in kidney transplant patients. Transpl Immunol 2022; 75:101717. https://pubmed.ncbi.nlm.nih.gov/36130699/

Yazısız V, Yılmaz VT, Uçar İ, et al. The use of anti-interleukin-1 agents and tumor necrosis factor‐alpha inhibitors in renal transplant recipients. Arch Rheumatol 2021; 36(3):366–74. https://pubmed.ncbi.nlm.nih.gov/34870168/

Mulders-Manders CM, Baas MC, Molenaar FM, Simon A. Peri- and Postoperative Treatment with the Interleukin-1 Receptor Antagonist Anakinra Is Safe in Patients Undergoing Renal Transplantation: Case Series and Review of the Literature. Front Pharmacol 2017; 8:342. https://pubmed.ncbi.nlm.nih.gov/28620307/

Rowshani AT, Vereyken EJF. The Role of Macrophage Lineage Cells in Kidney Graft Rejection and Survival. Transplantation 2012; 94(4):309. https://pubmed.ncbi.nlm.nih.gov/22828735/

Wyburn KR, Jose MD, Wu H, Atkins RC, Chadban SJ. The Role of Macrophages in Allograft Rejection. Transplantation 2005; 80(12):1641. https://pubmed.ncbi.nlm.nih.gov/16378052/

Eloueyk AK, Alameddine RY, Osta BA, Awad DM. Correlations between serum inflammatory markers and comorbidities in patients with end-stage renal disease. J Taibah Univ Med Sci 2019; 14(6):547–52. https://pubmed.ncbi.nlm.nih.gov/31908643/

Hung AM, Ellis CD, Shintani A, Booker C, Ikizler TA. IL-1β Receptor Antagonist Reduces Inflammation in Hemodialysis Patients. J Am Soc Nephrol 2011; 22(3):437. https://pubmed.ncbi.nlm.nih.gov/21310819/

Herbelin A, Nguyen AT, Zingraff J, Ureña P, Descamps-Latscha B. Influence of uremia and hemodialysis on circulating interleukin-1 and tumor necrosis factor α. Kidney Int 1990; 37(1):116–25. https://pubmed.ncbi.nlm.nih.gov/2299797/

Squadrito F, Altavilla D, Squadrito G, et al. Tacrolimus suppresses tumour necrosis factor-α and protects against splanchnic artery occlusion shock. Br J Pharmacol 1999; 127(2):498–504. https://pubmed.ncbi.nlm.nih.gov/10385251/

Li J, Li C, Zhuang Q, et al. The Evolving Roles of Macrophages in Organ Transplantation. J Immunol Res 2019; 2019:e5763430. https://pubmed.ncbi.nlm.nih.gov/31179346/

Malek M, Nematbakhsh M. Renal ischemia/reperfusion injury; from pathophysiology to treatment. J Ren Inj Prev 2015; 4(2):20–7. https://pubmed.ncbi.nlm.nih.gov/26060833/

Li J, Nozaki Y, Akazawa H, Kishimoto K, Kinoshita K, Matsumura I. Deletion of Antigen-Presenting Cells in Lipopolysaccharide-Induced Acute Kidney Injury (AKI) Affects the Exacerbation and Repair in AKI. Curr Issues Mol Biol 2022; 44(11):5655–65. https://pubmed.ncbi.nlm.nih.gov/36421667/

Liang D, Liu HF, Yao CW, et al. Effects of interleukin 18 on injury and activation of human proximal tubular epithelial cells. Nephrology 2007; 12(1):53–61. https://pubmed.ncbi.nlm.nih.gov/17295661/

Thomas JM, Ling YH, Huuskes B, et al. IL-18 (Interleukin-18) Produced by Renal Tubular Epithelial Cells Promotes Renal Inflammation and Injury During Deoxycorticosterone/Salt-Induced Hypertension in Mice. Hypertension 2021; 78(5):1296–309. https://pubmed.ncbi.nlm.nih.gov/34488433/

Wyburn K, Wu H, Chen G, Yin J, Eris J, Chadban S. Interleukin-18 Affects Local Cytokine Expression But Does Not Impact on the Development of Kidney Allograft Rejection. Am J Transplant 2006; 6(11):2612–21. https://pubmed.ncbi.nlm.nih.gov/17049054/

Willoughby LM, Schnitzler MA, Brennan DC, et al. Early outcomes of thymoglobulin and basiliximab induction in kidney transplantation: Application of statistical approaches to reduce bias in observational comparisons. Transplantation 2009; 87(10):1520–9. https://pubmed.ncbi.nlm.nih.gov/19461489/

Lim WH, Chadban SJ, Campbell S, Dent H, Russ GR, Mcdonald SP. Interleukin-2 receptor antibody does not reduce rejection risk in low immunological risk or tacrolimus-treated intermediate immunological risk renal transplant recipients. Nephrology 2010; 15(3):368–76. https://pubmed.ncbi.nlm.nih.gov/19935375/

Tanriover B, Zhang S, MacConmara M, et al. Induction Therapies in Live Donor Kidney Transplantation on Tacrolimus and Mycophenolate With or Without Steroid Maintenance. Clin J Am Soc Nephrol 2015; 10(6):1041. https://pubmed.ncbi.nlm.nih.gov/25979971/

Ali H, Mohiuddin A, Sharma A, et al. Implication of interleukin-2 receptor antibody induction therapy in standard risk renal transplant in the tacrolimus era: a meta-analysis. Clin Kidney J 2019; 12(4):592–9. https://pubmed.ncbi.nlm.nih.gov/31384453/

Rodriguez-Galán MC, Bream JH, Farr A, Young HA. Synergistic Effect of IL-2, IL-12, and IL-18 on Thymocyte Apoptosis and Th1/Th2 Cytokine Expression12. J Immunol 2005; 174(5):2796–804. https://pubmed.ncbi.nlm.nih.gov/15728489/




DOI: https://doi.org/10.22190/FUMB230406003S

Refbacks

  • There are currently no refbacks.


© University of Niš, Serbia
Creative Commons licence CC BY-NC-ND
ISSN 0354-4699 (Print)
ISSN 2406-050X (Online)