Immunological determinants of long-term kidney graft survival as therapeutic targets

  • M. Kolesnyk State Institution “O.O. Shalimov National Scientific Center of Surgery and Transplantology of the National Academy of Medical Science of Ukraine,” Kyiv, Ukraine https://orcid.org/0000-0001-6658-3729
  • L. Korol State Institution “O.O. Shalimov National Scientific Center of Surgery and Transplantology of the National Academy of Medical Science of Ukraine”, Kyiv, Ukraine https://orcid.org/0000-0002-5484-0326
  • I. Shifris State Institution “O.O. Shalimov National Scientific Center of Surgery and Transplantology of the National Academy of Medical Science of Ukraine,” Kyiv, Ukraine https://orcid.org/0000-0002-9413-7301
  • N. Stepanova State Institution “O.O. Shalimov National Scientific Center of Surgery and Transplantology of the National Academy of Medical Science of Ukraine,” Kyiv, Ukraine https://orcid.org/0000-0002-1070-3602
  • O. Voroniak State Institution “O.O. Shalimov National Scientific Center of Surgery and Transplantology of the National Academy of Medical Science of Ukraine”, Kyiv, Ukraine https://orcid.org/0000-0001-7188-5596
  • I. Shuba Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
DOI: https://doi.org/10.31450/ukrjnd.2(86).2025.10
Keywords: kidney transplantation, graft survival, immune response, donor-specific antibodies, graft rejection, acute rejection, chronic rejection, complement system proteins, biomarkers, artificial intelligence.

Abstract

This article analyzes current research on the mechanisms underlying acute and chronic rejection of kidney transplants (KT) to identify key immunological determinants of long-term graft survival.

According to contemporary understanding, both forms of allograft rejection are mediated by effector responses of the innate and adaptive immune systems.
Immune-mediated damage to the graft remains the leading cause of transplant loss, regardless of the post-transplantation period.

Advancements in methodology, including the use of novel biomarkers, allow for earlier diagnosis of rejection mechanisms, while artificial intelligence and genome/proteome-based monitoring provide tools for predicting the progression of alloimmune responses.

Several immunological determinants influencing kidney graft longevity have been identified as potential therapeutic targets to enhance transplant survival.

Downloads

Download data is not yet available.

References

Deng L, Guo S, Liu Y, Zhou Y, Liu Y, Zheng X, et al. Global, regional, and national burden of chronic kidney disease and its underlying etiologies from 1990 to 2021: a systematic analysis for the Global Burden of Disease Study 2021. BMC Public Health. 2025;25(1):636. doi: 10.1186/s12889-025-21851-z.

USRDS Browser [Internet]. Incidence, Prevalence, Patient Characteristics, and Treatment Modalities; 2020 Annual Report; [cited 2025 March 15]. Available from: https://usrds-adr.niddk.nih.gov/2020/end-stage-renal-disease/1-incidence-prevalence-patient-characteristics-and-treatment-modalities.

He YJ, Liu PL, Wei T, Liu T, Li YF, Yang J, Fan WX. Artificial intelligence in kidney transplantation: a 30-year bibliometric analysis of research trends, innovations, and future directions. Renal Failure, 2025. 47(1), 2458754. doi: 10.1080/0886022X.2025.2458754.

Boenink R, Bonthuis M, Boerstra BA, Astley ME, Montez de Sousa IR, Helve J, et al. The ERA Registry Annual Report 2022: Epidemiology of Kidney Replacement Therapy in Europe, with a focus on sex comparisons. Clin. Kidney J. 2024;18(2):sfae405. doi: 10.1093/ckj/sfae405.

Johansen KL, Chertow GM, Gilbertson DT, Ishani A, Israni A, Ku E, et al. US Renal Data System 2022 Annual Data Report: epidemiology of kidney disease in the United States. Am J Kidney Dis. 2023;81(3)(suppl 1): A8-A11. doi: 10.1053/j.ajkd.2022.12.001.

Xie Y, Bowe B, Mokdad AH, Xian H, Yan Y, Li T, et al. Analysis of the Global Burden of Disease study highlights the global, regional, and national trends of chronic kidney disease epidemiology from 1990 to 2016. Kidney Int. 2018; 94 (3):567-81. doi: 10.1016/j.kint.2018.04.011.

Tonelli M, Wiebe N, Knoll G, Bello A, Browne S, Jadhav D, et al. Systematic review: kidney transplantation compared with dialysis in clinically relevant outcomes. Am J Transplant.2011;11:2093-109. doi: 10.1111/j.1600-6143.2011.03686.x.

Organización Nacional de Trasplantes. Ministerio de Sanidad. Balance de actividad del 2021. Comunicado de Prensa, 2021 Gen, Madrid. Available online: https://www.ont.es/wp-content/uploads/2023/02/Balance-de-actividad-Donacion-y-Trasplante-2021_ONT.pdf

Beviá-Romero Á, Quereda-Flores F, Díaz-Carnicero J, Gómez F, Ramos-Cebrián M, Espinosa-Vañó J, et al. Kidney Transplant: Survival Analysis and Prognostic Factors after 10 Years of Follow-Up. Mathematics. 2023; 11(7):1640. doi:10.3390/math11071640.

Coemans M, Süsal C, Döhler B, Anglicheau D, Giral M, Bestard O, et al. Analyses of the short- and long-term graft survival after kidney transplantation in Europe between 1986 and 2015. Kidney Int. 2018;94(5):964-73. doi: 10.1016/j.kint.2018.05.018.

Bauer AC, Franco RF, Manfro RC. Immunosuppression in Kidney Transplantation: State of the Art and Current Protocols. Curr Pharm Des. 2020;26 (28):3440–50. doi: 10.2174/1381612826666200521142448.

Lentine KL, Smith JM, Miller JM, Bradbrook K, Larkin L, Weiss S, et al. OPTN/SRTR 2021 Annual Data Report: Kidney. Am J Transplant. 2023;23(2 Suppl 1):S21-S120. doi: 10.1016/j.ajt.2023.02.004.

Merzkani MA, Bentall AJ, Smith BH, Benavides Lopez X, D'Costa MR, Park WD, et al. Death with function and graft failure after kidney transplantation: risk factors at baseline suggest new approaches to management. Transplant Direct.2022;8:e1273. doi: 10.1097/TXD.0000000000001273.

Grothgar E, Goerlich N, Samans B, Skopnik CM, Metzke D, Klocke J, et al. Urinary CD8+HLA-DR+ T Cell Abundance Non-invasively Predicts Kidney Transplant Rejection. Front Med (Lausanne). 2022;9:928516. doi: 10.3389/fmed.2022.928516.

Agrawal A, Balakrishnan S, Gandhi MJ, Alexander MP, Cornell L, Bentall AJ, et al. Highly Sensitized Candidates Remain at Risk for Microvascular Inflammation Even When Donor-specific Antibody Is Avoided: A Matched Cohort Study. Transplantation. 2024 Sep 1;108(9):1986-93. doi: 10.1097/TP.0000000000005011.

Eikmans M, Gielis EM, Ledeganck KJ, Yang J, Abramowicz D, Claas FFJ. Non-invasive Biomarkers of Acute Rejection in Kidney Transplantation: Novel Targets and Strategies. Front Med (Lausanne). 2019;5:358. doi: 10.3389/fmed.2018.00358.

Loupy A, Aubert O, Orandi BJ, Naesens M, Bouatou Y, Raynaud M, et аl. Prediction system for risk of allograft loss in patients receiving kidney transplants: international derivation and validation study. BMJ. 2019;366:l4923. doi:10.1136/bmj.l4923.

Kolesnyk M, Stepanova N, Korol L, Shifris I, Zograbian R, Voronyak O. Non-immunological determinants of transplanted kidney function longevity. Ukr J Nephrol Dialys. 2025;1(85):81-96. doi: 10.31450/ukrjnd.1(85).2025.10.

Ning J, Wang Y, Tao Z. The complex role of immune cells in antigen presentation and regulation of T-cell responses in hepatocellular carcinoma: progress, challenges, and future directions. Front. Immunol. 2024;15:1483834. doi: 10.3389/fimmu.2024.1483834.

Yi SG, Gaber AO, Chen W. B-cell response in solid organ transplantation. Front. Immunol. 2022;13:895157. doi: 10.3389/fimmu.2022.895157.

Pontrelli P, Rascio F, Castellano G, Grandaliano G, Gesualdo L, Stallone G. The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation. Front Immunol. 2020;11:1454. doi: 10.3389/fimmu.2020.01454.

Lamarthée B, Callemeyn J, Van Herck Y, Antoranz A, Anglicheau D, Boada P, et al. Transcriptional and spatial profiling of the kidney allograft unravels a central role for Fc□RIII+ innate immune cells in rejection. Nat Commun. 2023;14(1):4359. doi: 10.1038/s41467-023-39859-7.

Hamada S, Dubois V, Koenig A, Thaunat O. Allograft recognition by recipient's natural killer cells: Molecular mechanisms and role in transplant rejection HLA. 2021;98(3):191-9. doi: 10.1111/tan.14332.

Buxeda A, Llinàs-Mallol L, Gimeno J, Redondo-Pachón D, Arias-Cabrales C, Burballa C, et al. Microvascular inflammation in the absence of human leukocyte antigen-donor-specific antibody and C4d: an orphan category in Banff classification with cytotoxic T and natural killer cell infiltration. Am J Transplant. 2023;23:464-74. doi: 10.1016/j.ajt.2022.12.018.

Liu W, Zhao J, Kang ZY, Xiao YL, Yang L, Liu C, Li DH. De novo donor-specific HLA antibodies reduce graft survival rates and increase the risk of kidney transplant rejection: A single-center retrospective study. Transpl Immunol. 2021;68:101430. doi: 10.1016/j.trim.2021.101430.

Wan SS, Chadban SJ, Watson N, Wyburn K. Development and outcomes of de novo donor-specific antibodies in low, moderate, and high immunological risk kidney transplant recipients. Am J Transplant. 2020;20(5):1351-64. doi: 10.1111/ajt.15754.

López del Moral C., Wu K., Naik M., Osmanodja B., Akifova A., Lachmann N, et al. Predictors of graft failure after first detection of de novo donor-specific HLA antibodies in kidney transplant recipients. Nephrology Dialysis Transplantation. 2024;39(1):84–94. doi: 10.1093/ndt/gfad149.

López del Moral C, Wu K, Naik M, Osmanodja B, Akifova A, Lachmann N, et al. The natural history of de novo donor-specific HLA antibodies after kidney transplantation. Front Med. 2022; 9:943502. doi: 10.3389/fmed.2022.943502.

Zhang R. Donor-Specific Antibodies in Kidney Transplant Recipients. Clin J Am Soc Nephrol. 2018;13(1):182-192. doi: 10.2215/CJN.00700117.

Novotný M, Kment M, Viklický O. Antibody-mediated rejection of renal allografts: diagnostic pitfalls and challenges. Physiol Res. 2021;70(Suppl4):S551-S565. doi: 10.33549/physiolres.934801.

Zhang H, Zheng C, Li X, Fu Q, Li J, Su Q, et al. Diagnostic Performance of Donor-Derived Plasma Cell-Free DNA Fraction for Antibody-Mediated Rejection in Post Renal Transplant Recipients: A Prospective Observational Study. Front Immunol. 2020;11:342. doi: 10.3389/fimmu.2020.00342.

Akifova A, Budde K, Oellerich M, Beck J, Bornemann-Kolatzki K, Schütz E, et al. Perspective for Donor-Derived Cell-Free DNA in Antibody-Mediated Rejection After Kidney Transplantation: Defining Context of Use and Clinical Implications. Transpl Int. 2024;37:13239. doi: 10.3389/ti.2024.13239.

Tian Y, Frischknecht L, Mallone A, Rössler F, Schachtner T, Nilsson J. Evaluation of de novo donor specific antibodies after kidney transplantation in the era of donor-derived cell-free DNA. Front Immunol. 2025;15:1530065. doi: 10.3389/fimmu.2024.1530065.

Callemeyn J, Lamarthée B, Koenig A, Koshy P, Thaunat O, Naesens M. Allorecognition and the spectrum of kidney transplant rejection. Kidney Int 2022;101:692-710. doi: 10.1016/j.kint.2021.11.029.

Loupy A, Haas M, Roufosse C, Naesens M, Adam B, Afrouzian M, et al. The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell– and antibody-mediated rejection. Am. J. Transplant.2020;20:2318–31. doi: 10.1111/ajt.15898.

O’Leary JG, Kaneku H, Banuelos N, Jennings LW, Klintmalm GB, Terasaki PI. Impact of IgG3 Subclass and C1q-Fixing Donor-Specific HLA Alloantibodies on Rejection and Survival in Liver Transplantation. Am J Transpl. 2015;15:1003−13. doi: 10.1111/ajt.13153.

Lefaucheur C, Viglietti D, Bentlejewski C, Duong van Huyen J-P, Vernerey D, Aubert O, et al. IgG Donor-Specific Anti-Human HLA Antibody Subclasses and Kidney Allograft Antibody-Mediated Injury. J Am Soc Nephrol.2016;27 (1):293−304. doi: 10.1681/ASN.2014111120.

Short S, Lewik G, Issa F. An Immune Atlas of T Cells in Transplant Rejection: Pathways and Therapeutic Opportunities. Transplantation. 2023;107(11):2341-2352. doi: 10.1097/TP.0000000000004572.

Krupickova L, Fialova M, Novotny M, Svachova V, Mezerova K, Cecrdlova E, et al. Chemokine Profiles Are Affected in Serum of Patients with Acute Rejection of Kidney Allograft. Mediators Inflamm. 2021;2021:5513690. doi: 10.1155/2021/5513690.

Zhang H, Li Z, Li W. M2 Macrophages Serve as Critical Executor of Innate Immunity in Chronic Allograft Rejection. Front Immunol. 2021;12:648539. doi: 10.3389/fimmu.2021.648539.

Pardali E, Sanchez-Duffhues G, Gomez-Puerto MC, Ten Dijke P. TGF-β-Induced Endothelial-Mesenchymal Transition in Fibrotic Diseases. Int J Mol Sci. 2017;18(10):2157. doi: 10.3390/ijms18102157.

Taniguchi R, Ohashi Y, Lee JS, Hu H, Gonzalez L, Zhang W, et al. Endothelial Cell TGF-β (Transforming Growth Factor-Beta) Signaling Regulates Venous Adaptive Remodeling to Improve Arteriovenous Fistula Patency. Arterioscler Thromb Vasc Biol. 2022;42(7):868-83. doi: 10.1161/ATVBAHA.122.317676.

Berger M, Baliker M, Van Gelder T, Böhmig GA, Mannon RB, Kumar D, et al. Chronic Active Antibody-mediated Rejection: Opportunity to Determine the Role of Interleukin-6 Blockade. Transplantation. 2024;108(5):1109-14. doi: 10.1097/TP.0000000000004822.

Jordan SC, Ammerman N, Huang E, Vo A. Importance of IL-6 inhibition in prevention and treatment of antibody-mediated rejection in kidney allografts. Am J Transplant. 2022;22:28–37. doi: 10.1111/ajt.17207.

Chandran S, Leung J, Hu C, Laszik ZG, Tang Q, Vincenti FG. Interleukin-6 blockade with tocilizumab increases Tregs and reduces T effector cytokines in renal graft inflammation: a randomized controlled trial. Am J Transplant. 2021;21(7):2543–54. doi: 10.1111/ajt.16459.

Eskandari SK, Gaya da Costa М, Faria B, Petr V, Azzi JR, Berger SP, et al. An interleukin 6-based genetic risk score strengthened with interleukin 10 polymorphisms associated with long-term kidney allograft outcomes. Am J Transplant. 2022;22 (Suppl 4):45–57. doi: 10.1111/ajt.17212.

Nicosia M, Fairchild RL, Valujskikh A. Memory T Cells in Transplantation: Old Challenges Define New Directions. Transplantation. 2020;104(10):2024-34. doi: 10.1097/TP.0000000000003169.

Novacescu D, Latcu SC, Bardan R, Daminescu L, Cumpanas AA. Contemporary Biomarkers for Renal Transplantation: A Narrative Overview. J Pers Med. 2023;13(8):1216. doi: 10.3390/jpm13081216.

Salvadori M, Rosati A, Rosso G. Evolving Biomarkers in Kidney Transplantation. Transplantology. 2024;5(3):116-128. doi: 10.3390/transplantology5030012.

Lazarou C, Moysidou E, Christodoulou M, Lioulios G, Sampani E, Dimitriadis C, et al. Non-Invasive Biomarkers for Early Diagnosis of Kidney Allograft Dysfunction: Current and Future Applications in the Era of Precision Medicine. Medicina (Kaunas). 2025; 61(2):262. doi: 10.3390/medicina61020262.

Guzzi F, Cirillo L, Buti E, Becherucci F, Errichiello C, Roperto RM, et al. Urinary Biomarkers for Diagnosis and Prediction of Acute Kidney Allograft Rejection: A Systematic Review. Int J Mol Sci.2020;21(18):6889. doi: 10.3390/ijms21186889.

Lim JH, Chung BH, Lee SH, Jung HY, Choi JY, Cho JH, et al. Omics-based biomarkers for diagnosis and prediction of kidney allograft rejection. Korean J Intern Med.2022;37:520-33. doi: 10.3904/kjim.2021.518.

Seo JW, Lee YH, Tae DH, Park SH, Moon JY, Jeong KH, et al. Non-Invasive Diagnosis for Acute Rejection Using Urinary mRNA Signature Reflecting Allograft Status in Kidney Transplantation. Front Immunol. 2021;12:656632. doi: 10.3389/fimmu.2021.656632. Erratum in: Front Immunol. 2022;12:825243. doi: 10.3389/fimmu.2021.825243.

Heng B, Ding H, Ren H, Shi L, Chen J, Wu X, et al. Diagnostic Performance of Fas Ligand mRNA Expression for Acute Rejection after Kidney Transplantation: A Systematic Review and Meta-Analysis. PLoS ONE.2016; 11(11):e0165628. doi: 10.1371/journal.pone.0165628.

Song Y, Wang Y, Wang W, Xie Y, Zhang J, Liu J, et al. Advancements in noninvasive techniques for transplant rejection: from biomarker detection to molecular imaging. J Transl Med. 2025;23(1):147. doi: 10.1186/s12967-024-05964-4.

Oellerich M, Sherwood K, Keown P, Schütz E, Beck J, Stegbauer J, et al. Liquid biopsies: donor-derived cell-free DNA for the detection of kidney allograft injury. Nat Rev Nephrol. 2021;17(9):591-603. doi: 10.1038/s41581-021-00428-0.

Suthanthiran M. Urine as liquid gold: the transcriptional landscape of acute rejection defined by urinary cell mRNA profiling of kidney allograft recipients. Curr Opin Organ Transplant. 2023;28(2):117-25. doi: 10.1097/MOT.0000000000001051.

O'Connell PJ, Zhang W, Menon MC, Yi Z, Schröppel B, Gallon L, et al. Biopsy Transcriptome Expression Profiling to Identify Kidney Transplants at Risk of Chronic Injury: A Multicentre, Prospective Study. Lancet. 2016;388:983-93. doi: 10.1016/S0140-6736(16)30826-1.

Shaw BI, Villani V, Kesseli SJ, Nobuhara C, Samoylova ML, et al. A Historical Cohort in Kidney Transplantation: 55-Year Follow-Up of 72 HLA-Identical, Donor-Recipient Pairs. J Clin Med. 2021;10(23):5505. doi: 10.3390/jcm10235505.

Leng Q, Ma M, Tang Z, Jiang W, Han F, Huang Z. Assessing donor kidney function: the role of CIRBP in predicting delayed graft function post-transplant. Front Immunol. 2025;15:1518279. doi: 10.3389/fimmu.2024.1518279.

Nusshag C, Benning L, Göth D, Mahler C, Kälble F, Speer C, et al. Proenkephalin A 119-159 as a Novel Biomarker for Early Detection of Delayed Graft Function After Kidney Transplantation: FR-OR66. J Am Soc Nephrol. 2023;34(11S): 47. doi: 10.1681/ASN.20233411S147c.

Koukoulaki M., Kitsiou V., Balaska A., Pistolas D., Loukopoulos I., V. Drakopoulos V, et al. Immunologic Prognostic Factors of Renal Allograft Survival. Transplantation Proceedings.2014;46(9):3175-8. doi: 10.1016/j.transproceed.2014.10.031.

Hart A, Schladt DP, Matas AJ, Itzler R, Israni AK, Kasiske BL. Incidence, risk factors, and long-term outcomes associated with antibody-mediated rejection - The long-term Deterioration of Kidney Allograft Function (DeKAF) prospective cohort study. Clin Transplant. 2021;35(7):e14337. doi: 10.1111/ctr.14337.

Paquette FX, Ghassemi A, Bukhtiyarova O, Cisse M, Gagnon N, Della Vecchia A, et al. Machine Learning Support for Decision-Making in Kidney Transplantation: Step-by-Step Development of a Technological Solution. JMIR Med Inform. 2022;10(6):e34554. doi: 10.2196/34554.

Мizera J, Pondel M, Kepinska M, Jerzak P, Banasik M. Advancements in Artificial Intelligence for Kidney Transplantology: A Comprehensive Review of Current Applications and Predictive Models. J Clin Med. 2025;14(3):975. doi: 10.3390/jcm14030975.

Naqvi SAA, Tennankore K, Vinson A, Roy PC, Abidi SSR. Predicting Kidney Graft Survival Using Machine Learning Methods: Prediction Model Development and Feature Significance Analysis Study. J Med Internet Res. 2021;23:e26843. doi: 10.2196/26843.

Heidt S, Kramer CSM, Haasnoot GW, Schmidt AH, Zoet YM, Claas FHJ, Vogelaar S. Introduction of the donor centre virtual crossmatch in Eurotransplant. HLA. 2024;104(2):e15653. doi: 10.1111/tan.15653.

Klein A, Kosinski L, Loupy A, Frey E, Stegall M, Helanterä I, Newell K, Meier-Kriesche HU, Mannon RB, Fitzsimmons WE; Transplant Therapeutics Consortium. Comparing the prognostic performance of iBOX and biopsy-proven acute rejection for long-term kidney graft survival. Am J Transplant. 2024;24(10):1784-1793. doi: 10.1016/j.ajt.2024.04.004.

Salaün A, Knight S, Wingfield L, Zhu T. Predicting graft and patient outcomes following kidney transplantation using interpretable machine learning models. Sci Rep. 2024 Jul 29;14(1):17356. doi: 10.1038/s41598-024-66976-0.

He J, Liu P, Cao L, Su F, Li Y, Liu T, Fan W. A machine learning-based nomogram for predicting graft survival in allograft kidney transplant recipients: a 20-year follow-up study. Front Med (Lausanne). 2025;12:1556374. doi: 10.3389/fmed.2025.1556374.

Bakar KS, Teixeira-Pinto A, Gately R, Boroumand F, Lim WH, Wong G. Dynamic prediction of kidney allograft and patient survival using post-transplant estimated glomerular filtration rate trajectory. Clin Kidney J. 2024;17(11):sfae314. doi: 10.1093/ckj/sfae314.

Erdoğmuş Ş, Şengül Ş. Immunologic Risk Assessment before Kidney Transplantation: An Update. Turk J Nephrol.2019;28(3):216-24. doi: 10.5152/turkjnephrol.2019.3513.

Pratschke J, Dragun D, Hauser IA, Horn S, Mueller TF, Schemmer P, et al. Immunological risk assessment: The key to individualized immunosuppression after kidney transplantation. Transplant Rev (Orlando).2016;30(2):77-84. doi 10.1016/j.trre.2016.02.002.


Abstract views: 537
PDF Downloads: 284
Published
2025-06-03
How to Cite
Kolesnyk, M., Korol, L., Shifris, I., Stepanova, N., Voroniak, O., & Shuba, I. (2025). Immunological determinants of long-term kidney graft survival as therapeutic targets. Ukrainian Journal of Nephrology and Dialysis, (2(86), 98-111. https://doi.org/10.31450/ukrjnd.2(86).2025.10
Issue
No 2(86) (2025): Ukrainian Journal of Nephrology and Dialysis
Section
Nephrology School

Copyright (c) 2025 Ukrainian Journal of Nephrology and Dialysis

Creative Commons License

This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.