{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T17:17:04Z","timestamp":1793812624705,"version":"4.6.1"},"reference-count":110,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,4,3]],"date-time":"2020-04-03T00:00:00Z","timestamp":1585872000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Progressive loss of renal function is associated with a series of changes of the adaptive immune system which collectively constitute premature immunological ageing. This phenomenon contributes significantly to the mortality and morbidity of end-stage renal disease (ESRD) patients. In this review, the effect of ESRD on the T cell part of the adaptive immune system is highlighted. Na\u00efve T cell lymphopenia, in combination with the expansion of highly differentiated memory T cells, are the hallmarks of immunological ageing. The decreased production of newly formed T cells by the thymus is critically involved. This affects both the CD4 and CD8 T cell compartment and may contribute to the expansion of memory T cells. The expanding populations of memory T cells have a pro-inflammatory phenotype, add to low-grade inflammation already present in ESRD patients and destabilize atherosclerotic plaques. The effect of loss of renal function on the thymus is not reversed after restoring renal function by kidney transplantation and constitutes a long-term mortality risk factor. Promising results from animal experiments have shown that rejuvenation of the thymus is a possibility, although not yet applicable in humans.<\/jats:p>","DOI":"10.3390\/toxins12040224","type":"journal-article","created":{"date-parts":[[2020,4,9]],"date-time":"2020-04-09T14:42:03Z","timestamp":1586443323000},"page":"224","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["Uremia-Associated Ageing of the Thymus and Adaptive Immune Responses"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9435-6208","authenticated-orcid":false,"given":"Michiel GH","family":"Betjes","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus Medical Centre, Rg5, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/nrneph.2013.44","article-title":"Immune cell dysfunction and inflammation in end-stage renal disease","volume":"9","author":"Betjes","year":"2013","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.thorsurg.2018.12.001","article-title":"The Role of the Thymus in the Immune Response","volume":"29","author":"Thapa","year":"2019","journal-title":"Thorac. Surg. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/S0952-7915(00)00180-1","article-title":"The cell biology of antigen presentation in dendritic cells","volume":"13","author":"Thery","year":"2001","journal-title":"Curr. Opin. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1681\/ASN.2008070734","article-title":"Oxidized LDL modulates apoptosis of regulatory T cells in patients with ESRD","volume":"20","author":"Meier","year":"2009","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1159\/000356084","article-title":"Loss of renal function causes premature aging of the immune system","volume":"36","author":"Betjes","year":"2013","journal-title":"Blood Purif."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1007\/s11934-014-0471-9","article-title":"Chronic kidney disease and premature ageing of the adaptive immune response","volume":"16","author":"Betjes","year":"2015","journal-title":"Curr. Urol. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1038\/ki.2011.110","article-title":"Premature aging of circulating T cells in patients with end-stage renal disease","volume":"80","author":"Betjes","year":"2011","journal-title":"Kidney Int."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Crepin, T., Legendre, M., Carron, C., Vachey, C., Courivaud, C., Rebibou, J.M., Ferrand, C., Laheurte, C., Vauchy, C., and Gaiffe, E. (2018). Uraemia-induced immune senescence and clinical outcomes in chronic kidney disease patients. Nephrol. Dial. Transplant., 1\u20139.","DOI":"10.1093\/ndt\/gfy276"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1111\/j.1523-1755.2004.00781.x","article-title":"Peripheral blood dendritic cells and GM-CSF as an adjuvant for hepatitis B vaccination in hemodialysis patients","volume":"66","author":"Verkade","year":"2004","journal-title":"Kidney Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3225","DOI":"10.1093\/ndt\/gfp331","article-title":"The pattern of excess cancer in dialysis and transplantation","volume":"24","author":"Stewart","year":"2009","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1681\/ASN.2007090971","article-title":"Impaired immune responses and antigen-specific memory CD4+ T cells in hemodialysis patients","volume":"19","author":"Litjens","year":"2008","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"611","DOI":"10.14336\/AD.2016.1230","article-title":"Cancer and Aging\u2014The Inflammatory Connection","volume":"8","author":"Zinger","year":"2017","journal-title":"Aging Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.ebiom.2018.03.001","article-title":"Vaccines for Improved Cellular Immunity to Influenza","volume":"30","author":"Pawelec","year":"2018","journal-title":"EBioMedicine"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/s00281-018-0697-6","article-title":"Does patient age influence anti-cancer immunity?","volume":"41","author":"Pawelec","year":"2019","journal-title":"Semin. Immunopathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.exger.2017.10.024","article-title":"Age and immunity: What is \u201cimmunosenescence\u201d?","volume":"105","author":"Pawelec","year":"2018","journal-title":"Exp. Gerontol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41590-017-0006-x","article-title":"The twilight of immunity: Emerging concepts in aging of the immune system","volume":"19","year":"2018","journal-title":"Nat. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/1742-4933-3-2","article-title":"Age and immunity","volume":"3","author":"Vasto","year":"2006","journal-title":"Immun. Ageing"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1007\/s00262-005-0109-3","article-title":"Immunosenescence, suppression and tumour progression","volume":"55","author":"Pawelec","year":"2006","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s12979-019-0151-1","article-title":"Cytokines for evaluation of chronic inflammatory status in ageing research: Reliability and phenotypic characterisation","volume":"16","author":"Koelman","year":"2019","journal-title":"Immun. Ageing"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.mad.2006.11.016","article-title":"Inflammaging and anti-inflammaging: A systemic perspective on aging and longevity emerged from studies in humans","volume":"128","author":"Franceschi","year":"2007","journal-title":"Mech. Ageing Dev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1111\/j.0105-2896.2006.00348.x","article-title":"Central tolerance: Good but imperfect","volume":"209","author":"Gallegos","year":"2006","journal-title":"Immunol. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1038\/nature12079","article-title":"Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota","volume":"497","author":"Cebula","year":"2013","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1182\/blood-2008-02-139154","article-title":"Life after the thymus: CD31+ and CD31- human naive CD4+ T-cell subsets","volume":"113","author":"Kohler","year":"2009","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1002\/cyto.b.21341","article-title":"Thymic output: Assessment of CD4(+) recent thymic emigrants and T-Cell receptor excision circles in infants","volume":"92","author":"Ravkov","year":"2017","journal-title":"Cytom. B Clin. Cytom."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1111\/cei.12934","article-title":"Lymph node and circulating T cell characteristics are strongly correlated in end-stage renal disease patients, but highly differentiated T cells reside within the circulation","volume":"188","author":"Dedeoglu","year":"2017","journal-title":"Clin. Exp. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.clim.2005.09.007","article-title":"Progressive loss of renal function is associated with activation and depletion of naive T lymphocytes","volume":"118","author":"Litjens","year":"2006","journal-title":"Clin. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1159\/000334245","article-title":"Dendritic cells and damage-associated molecular patterns: Endogenous danger signals linking innate and adaptive immunity","volume":"4","author":"Nace","year":"2012","journal-title":"J. Innate. Immun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1146\/annurev.immunol.23.021704.115732","article-title":"Antigen-specific memory B cell development","volume":"23","year":"2005","journal-title":"Annu. Rev. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s12979-020-0173-8","article-title":"Contributions of Age-Related Thymic Involution to Immunosenescence and Inflammaging","volume":"17","author":"Thomas","year":"2020","journal-title":"Immun. Ageing"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Ou, X.L., Gao, J., Wang, H., Wang, H.S., Lu, H.L., and Sun, H.Y. (2012). Predicting human age with bloodstains by sjTREC quantification. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0042412"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/s41577-018-0001-y","article-title":"The full spectrum of human naive T cells","volume":"18","author":"Borghans","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.4049\/jimmunol.180.3.1499","article-title":"Homeostasis of the naive CD4+ T cell compartment during aging","volume":"180","author":"Kilpatrick","year":"2008","journal-title":"J. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2860","DOI":"10.1182\/blood.V95.9.2860.009k35_2860_2868","article-title":"Shortage of circulating naive CD8(+) T cells provides new insights on immunodeficiency in aging","volume":"95","author":"Fagnoni","year":"2000","journal-title":"Blood"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6739","DOI":"10.4049\/jimmunol.0904193","article-title":"Loss of naive T cells and repertoire constriction predict poor response to vaccination in old primates","volume":"184","author":"Currier","year":"2010","journal-title":"J. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5553","DOI":"10.1182\/blood-2007-11-123547","article-title":"A new mechanism for the aging of hematopoietic stem cells: Aging changes the clonal composition of the stem cell compartment but not individual stem cells","volume":"111","author":"Cho","year":"2008","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3900","DOI":"10.1182\/blood-2011-12-376749","article-title":"Stem cell heterogeneity: Implications for aging and regenerative medicine","volume":"119","author":"Sieburg","year":"2012","journal-title":"Blood"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"606","DOI":"10.18632\/aging.100487","article-title":"Aging induced decline in T-lymphopoiesis is primarily dependent on status of progenitor niches in the bone marrow and thymus","volume":"4","author":"Sun","year":"2012","journal-title":"Aging (Albany NY)"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"502","DOI":"10.3389\/fimmu.2016.00502","article-title":"Inflamm-Aging of Hematopoiesis, Hematopoietic Stem Cells, and the Bone Marrow Microenvironment","volume":"7","author":"Kovtonyuk","year":"2016","journal-title":"Front. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1111\/j.1474-9726.2007.00325.x","article-title":"Lymphohematopoietic progenitors do not have a synchronized defect with age-related thymic involution","volume":"6","author":"Zhu","year":"2007","journal-title":"Aging Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1093\/intimm\/dxm095","article-title":"The aged thymus shows normal recruitment of lymphohematopoietic progenitors but has defects in thymic epithelial cells","volume":"19","author":"Gui","year":"2007","journal-title":"Int. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.mad.2005.11.001","article-title":"Accumulation of memory T cells from childhood to old age: Central and effector memory cells in CD4(+) versus effector memory and terminally differentiated memory cells in CD8(+) compartment","volume":"127","author":"Saule","year":"2006","journal-title":"Mech. Ageing Dev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1046\/j.1365-2567.1996.d01-689.x","article-title":"Expansion of cytotoxic CD8+ CD28- T cells in healthy ageing people, including centenarians","volume":"88","author":"Fagnoni","year":"1996","journal-title":"Immunology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1111\/tri.12658","article-title":"Clinical consequences of circulating CD28-negative T cells for solid organ transplantation","volume":"29","author":"Betjes","year":"2016","journal-title":"Transpl. Int."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2645","DOI":"10.4049\/jimmunol.176.4.2645","article-title":"Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly","volume":"176","author":"Hadrup","year":"2006","journal-title":"J. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s12979-019-0161-z","article-title":"Peripheral antibody concentrations are associated with highly differentiated T cells and inflammatory processes in the human bone marrow","volume":"16","author":"Naismith","year":"2019","journal-title":"Immun. & Ageing"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.jcv.2007.10.016","article-title":"A fingerprint left by cytomegalovirus infection in the human T cell compartment","volume":"41","year":"2008","journal-title":"J. Clin. Virol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1038\/ki.2008.301","article-title":"Expansion of cytolytic CD4+CD28- T cells in end-stage renal disease","volume":"74","author":"Betjes","year":"2008","journal-title":"Kidney Int."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1086\/655472","article-title":"Human cytomegalovirus induces systemic immune activation characterized by a type 1 cytokine signature","volume":"202","author":"Heutinck","year":"2010","journal-title":"J. Infect. Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"183","DOI":"10.5301\/jn.5000057","article-title":"A killer on the road: Circulating CD4(+)CD28null T cells as cardiovascular risk factor in ESRD patients","volume":"25","author":"Betjes","year":"2012","journal-title":"J. Nephrol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"841430","DOI":"10.1155\/2013\/841430","article-title":"Circulating CD4(+)CD28null T Cells May Increase the Risk of an Atherosclerotic Vascular Event Shortly after Kidney Transplantation","volume":"2013","author":"Betjes","year":"2013","journal-title":"J. Transplant."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3640","DOI":"10.1093\/ndt\/gfq203","article-title":"Circulating pro-inflammatory CD4posCD28null T cells are independently associated with cardiovascular disease in ESRD patients","volume":"25","author":"Betjes","year":"2010","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1038\/sj.ki.5001550","article-title":"Naive and central memory T-cell lymphopenia in end-stage renal disease","volume":"70","author":"Yoon","year":"2006","journal-title":"Kidney Int."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s12979-018-0131-x","article-title":"A comprehensive characterization of aggravated aging-related changes in T lymphocytes and monocytes in end-stage renal disease: The iESRD study","volume":"15","author":"Chiu","year":"2018","journal-title":"Immun. Ageing"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s12979-020-00175-z","article-title":"A very low thymus function identifies patients with substantial increased risk for long-term mortality after kidney transplantation","volume":"17","author":"Betjes","year":"2020","journal-title":"Immun. & Ageing"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1189\/jlb.0108025","article-title":"Cytokines, leptin, and stress-induced thymic atrophy","volume":"84","author":"Gruver","year":"2008","journal-title":"J. Leukoc. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1093\/ndt\/gfr010","article-title":"CD4+CD28null cells are expanded and exhibit a cytolytic profile in end-stage renal disease patients on peritoneal dialysis","volume":"26","author":"Yadav","year":"2011","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2686","DOI":"10.1182\/blood-2002-08-2502","article-title":"Primary immune responses to human CMV: A critical role for IFN-gamma-producing CD4+ T cells in protection against CMV disease","volume":"101","author":"Gamadia","year":"2003","journal-title":"Blood"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"4342","DOI":"10.4049\/jimmunol.170.8.4342","article-title":"Frequencies of circulating cytolytic, CD45RA+CD27-, CD8+ T lymphocytes depend on infection with CMV","volume":"170","author":"Kuijpers","year":"2003","journal-title":"J. Immunol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.3389\/fimmu.2017.01137","article-title":"Protective Cytomegalovirus (CMV)-Specific T-Cell Immunity Is Frequent in Kidney Transplant Patients without Serum Anti-CMV Antibodies","volume":"8","author":"Litjens","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3143","DOI":"10.1111\/ajt.13396","article-title":"Primary Cytomegalovirus Infection Significantly Impacts Circulating T Cells in Kidney Transplant Recipients","volume":"15","author":"Meijers","year":"2015","journal-title":"Am. J. Transplant."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1","DOI":"10.12688\/f1000research.15753.1","article-title":"Cytomegalovirus infection and progressive differentiation of effector-memory T cells","volume":"7","author":"Pardieck","year":"2018","journal-title":"F1000Research"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1953","DOI":"10.3389\/fimmu.2017.01953","article-title":"The Contribution of Cytomegalovirus Infection to Immune Senescence Is Set by the Infectious Dose","volume":"8","author":"Redeker","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/1742-4933-8-2","article-title":"Differential effects of age, cytomegalovirus-seropositivity and end-stage renal disease (ESRD) on circulating T lymphocyte subsets","volume":"8","author":"Litjens","year":"2011","journal-title":"Immun. Ageing"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"268","DOI":"10.5527\/wjn.v3.i4.268","article-title":"T-cell ageing in end-stage renal disease patients: Assessment and clinical relevance","volume":"3","author":"Meijers","year":"2014","journal-title":"World J. Nephrol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/1742-4933-9-19","article-title":"Uremia causes premature ageing of the T cell compartment in end-stage renal disease patients","volume":"9","author":"Meijers","year":"2012","journal-title":"Immun. Ageing"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1111\/cei.12188","article-title":"Cytomegalovirus contributes partly to uraemia-associated premature immunological ageing of the T cell compartment","volume":"174","author":"Meijers","year":"2013","journal-title":"Clin. Exp. Immunol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.3389\/fimmu.2017.01826","article-title":"End-Stage Renal Disease Causes Skewing in the TCR Vbeta-Repertoire Primarily within CD8(+) T Cell Subsets","volume":"8","author":"Huang","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s12979-015-0055-7","article-title":"End stage renal disease patients have a skewed T cell receptor Vbeta repertoire","volume":"12","author":"Huang","year":"2015","journal-title":"Immun. Ageing"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s12979-017-0096-1","article-title":"pERK-dependent defective TCR-mediated activation of CD4(+) T cells in end-stage renal disease patients","volume":"14","author":"Huang","year":"2017","journal-title":"Immun. Ageing"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1093\/ndt\/gfp397","article-title":"Effect of end-stage renal disease on B-lymphocyte subpopulations, IL-7, BAFF and BAFF receptor expression","volume":"25","author":"Pahl","year":"2010","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1097\/01.tp.0000188620.72969.56","article-title":"Renal transplantation reverses functional deficiencies in circulating dendritic cell subsets in chronic renal failure patients","volume":"81","author":"Lim","year":"2006","journal-title":"Transplantation"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1868","DOI":"10.1093\/ndt\/gfh897","article-title":"The effects of chronic kidney disease and renal replacement therapy on circulating dendritic cells","volume":"20","author":"Hesselink","year":"2005","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1093\/ndt\/gfp580","article-title":"Effects of end-stage renal disease and haemodialysis on dendritic cell subsets and basal and LPS-stimulated cytokine production","volume":"25","author":"Agrawal","year":"2010","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1093\/ndt\/gfl519","article-title":"Functional impairment of monocyte-derived dendritic cells in patients with severe chronic kidney disease","volume":"22","author":"Verkade","year":"2007","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2524","DOI":"10.4049\/jimmunol.161.5.2524","article-title":"Advanced oxidation protein products as novel mediators of inflammation and monocyte activation in chronic renal failure","volume":"161","author":"Friedlander","year":"1998","journal-title":"J. Immunol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/j.semnephrol.2004.06.026","article-title":"Oxidative stress in uremia: Nature, mechanisms, and potential consequences","volume":"24","author":"Vaziri","year":"2004","journal-title":"Semin. Nephrol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"218","DOI":"10.2215\/CJN.05470610","article-title":"Systemic consequences of poor oral health in chronic kidney disease patients","volume":"6","author":"Akar","year":"2011","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1038\/ki.2012.440","article-title":"The intestinal microbiota, a leaky gut, and abnormal immunity in kidney disease","volume":"83","author":"Anders","year":"2013","journal-title":"Kidney Int."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.exger.2017.12.022","article-title":"Thymic stromal cells: Roles in atrophy and age-associated dysfunction of the thymus","volume":"105","author":"Cepeda","year":"2018","journal-title":"Exp. Gerontol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1111\/sji.12618","article-title":"Thymic Atrophy: Experimental Studies and Therapeutic Interventions","volume":"87","author":"Majumdar","year":"2018","journal-title":"Scand. J. Immunol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"5399","DOI":"10.4049\/jimmunol.163.10.5399","article-title":"Reactive oxygen intermediates during programmed cell death induced in the thymus of the Ts(1716)65Dn mouse, a murine model for human Down\u2019s syndrome","volume":"163","author":"Flores","year":"1999","journal-title":"J. Immunol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/nrneph.2017.165","article-title":"Advances in the understanding and treatment of sepsis-induced immunosuppression","volume":"14","author":"Venet","year":"2018","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.ccc.2017.08.007","article-title":"Management of Sepsis-Induced Immunosuppression","volume":"34","author":"Venet","year":"2018","journal-title":"Crit. Care Clin."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1111\/imm.13043","article-title":"Comparative analysis of thymic subpopulations during different modes of atrophy identifies the reactive oxygen species scavenger, N-acetyl cysteine, to increase the survival of thymocytes during infection-induced and lipopolysaccharide-induced thymic atrophy","volume":"157","author":"Majumdar","year":"2019","journal-title":"Immunology"},{"key":"ref_85","first-page":"229","article-title":"Cellular immunity and lymphocyte populations in developing uremia in the rat","volume":"2","author":"Raskova","year":"1986","journal-title":"J. Exp. Pathol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"138","DOI":"10.4049\/jimmunol.1602005","article-title":"Physiologic Thymic Involution Underlies Age-Dependent Accumulation of Senescence-Associated CD4(+) T Cells","volume":"199","author":"Sato","year":"2017","journal-title":"J. Immunol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"3070","DOI":"10.1172\/JCI39269","article-title":"Evidence of premature immune aging in patients thymectomized during early childhood","volume":"119","author":"Sauce","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2883","DOI":"10.1161\/01.CIR.101.25.2883","article-title":"Monoclonal T-Cell Proliferation and Plaque Instability in Acute Coronary Syndromes","volume":"101","author":"Liuzzo","year":"2000","journal-title":"Circulation"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1161\/01.CIR.100.21.2135","article-title":"Perturbation of the T-cell repertoire in patients with unstable angina","volume":"100","author":"Liuzzo","year":"1999","journal-title":"Circulation"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.atherosclerosis.2010.01.037","article-title":"Leukocyte telomere length is associated with measures of subclinical atherosclerosis","volume":"211","author":"Panayiotou","year":"2010","journal-title":"Atherosclerosis"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1161\/CIRCULATIONAHA.109.854299","article-title":"Accelerated Telomere Shortening in Leukocyte Subpopulations of Patients With Coronary Heart Disease: Role of Cytomegalovirus Seropositivity","volume":"120","author":"Spyridopoulos","year":"2009","journal-title":"Circulation"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1681\/ASN.2015030250","article-title":"CD8+ Immunosenescence Predicts Post-Transplant Cutaneous Squamous Cell Carcinoma in High-Risk Patients","volume":"27","author":"Bottomley","year":"2016","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Dedeoglu, B., Meijers, R.W., Klepper, M., Hesselink, D.A., Baan, C.C., Litjens, N.H., and Betjes, M.G. (2016). Loss of CD28 on Peripheral T Cells Decreases the Risk for Early Acute Rejection after Kidney Transplantation. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0150826"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1097\/TP.0b013e31825306ff","article-title":"Terminally differentiated CD8+ Temra cells are associated with the risk for acute kidney allograft rejection","volume":"94","author":"Betjes","year":"2012","journal-title":"Transplantation"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Betjes, M.G.H., and Litjens, N.H.R. (2020). High numbers of differentiated CD28null CD8+ T cells are associated with a lowered risk for late rejection and graft loss after kidney transplantation. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0228096"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.1111\/ajt.13759","article-title":"Uremia-Associated Premature Aging of T Cells Does Not Predict Infectious Complications After Renal Transplantation","volume":"16","author":"Dedeoglu","year":"2016","journal-title":"Am. J. Transplant."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"3391","DOI":"10.1093\/ndt\/gfr048","article-title":"Risk of Pneumocystis jiroveci pneumonia in patients long after renal transplantation","volume":"26","author":"Struijk","year":"2011","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1681\/ASN.2009090976","article-title":"Prolonged CD4 T cell lymphopenia increases morbidity and mortality after renal transplantation","volume":"21","author":"Ducloux","year":"2010","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/s10522-008-9138-6","article-title":"The immune risk profile is associated with age and gender: Findings from three Swedish population studies of individuals 20\u2013100 years of age","volume":"9","author":"Wikby","year":"2008","journal-title":"Biogerontology"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"5836","DOI":"10.1074\/jbc.M109.072124","article-title":"Postnatal tissue-specific disruption of transcription factor FoxN1 triggers acute thymic atrophy","volume":"285","author":"Cheng","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1111\/j.1474-9726.2010.00559.x","article-title":"Declining expression of a single epithelial cell-autonomous gene accelerates age-related thymic involution","volume":"9","author":"Sun","year":"2010","journal-title":"Aging Cell"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"5723","DOI":"10.1182\/blood-2011-03-342097","article-title":"Overexpression of Foxn1 attenuates age-associated thymic involution and prevents the expansion of peripheral CD4 memory T cells","volume":"118","author":"Zook","year":"2011","journal-title":"Blood"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1182\/blood-2003-10-3635","article-title":"Exogenous IL-7 increases recent thymic emigrants in peripheral lymphoid tissue without enhanced thymic function","volume":"104","author":"Chu","year":"2004","journal-title":"Blood"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1084\/jem.20071681","article-title":"Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets","volume":"205","author":"Sportes","year":"2008","journal-title":"J. Exp. Med."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"4112","DOI":"10.4049\/jimmunol.175.6.4112","article-title":"An IL-7 fusion protein that shows increased thymopoietic ability","volume":"175","author":"Henson","year":"2005","journal-title":"J. Immunol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1038\/ki.2012.439","article-title":"Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease","volume":"83","author":"Ruiz","year":"2013","journal-title":"Kidney Int."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1111\/tri.12416","article-title":"Uremia-associated immunological aging is stably imprinted in the T-cell system and not reversed by kidney transplantation","volume":"27","author":"Meijers","year":"2014","journal-title":"Transpl. Int."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"3803","DOI":"10.1182\/blood-2009-03-213595","article-title":"Obesity accelerates thymic aging","volume":"114","author":"Yang","year":"2009","journal-title":"Blood"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/s41577-019-0177-9","article-title":"Can physical activity ameliorate immunosenescence and thereby reduce age-related multi-morbidity?","volume":"19","author":"Duggal","year":"2019","journal-title":"Nat. Rev. Immunol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/acel.12750","article-title":"Major features of immunesenescence, including reduced thymic output, are ameliorated by high levels of physical activity in adulthood","volume":"17","author":"Duggal","year":"2018","journal-title":"Aging Cell"}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/12\/4\/224\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:15:10Z","timestamp":1760174110000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/12\/4\/224"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,3]]},"references-count":110,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["toxins12040224"],"URL":"https:\/\/doi.org\/10.3390\/toxins12040224","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,3]]}}}