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Published in: BMC Nephrology 1/2020

01-12-2020 | Research article

Premature aging of circulating T cells predicts all-cause mortality in hemodialysis patients

Authors: Fangfang Xiang, Rongyi Chen, Xuesen Cao, Bo Shen, Xiaohong Chen, Xiaoqiang Ding, Jianzhou Zou

Published in: BMC Nephrology | Issue 1/2020

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Abstract

Background

Patients with end-stage renal disease (ESRD) exhibit a premature aging phenotype of immune system, which is recently concerned as a significant factor for increased risk of various morbidities. Nevertheless, there are few dates explicating the relevancy of T cell senescence to mortality. In this study, we prospectively studied the predictive value of T cell senescence for mortality in hemodialysis patients.

Methods

Patients who had been on hemodialysis treatment for at least 6 months were enrolled. T cell senescence determined by differentiation status was evaluated by flow cytometry. Survival outcomes were estimated using the Kaplan-Meier method. Univariate and multivariate analyses were performed to evaluate the prognostic impact of T cell premature aging and other clinical factors on all-cause mortality.

Results

A total of 466 patients (277 man and 169 women) were enrolled in this study. Decreased number of naïve T cell, as the most prominent feature of T cell senescence, did not change in parallel with age in these patients. Decreased absolute count of T cell, naïve T cell, CD4+ naïve T cell were independently associated with all-cause mortality. Decreased percentage of T cell and increased percentage of CD8+central-memory T cell were also independently associated with all-cause mortality. After including all the T cell parameters in one regression model, only decreased count of naïve T cell was significantly associated with increased mortality in these patients.

Conclusions

Aging-associated T cell changes are aggravated in ESRD patients. For the first time, our study demonstrates that naïve T cell depletion is a strong predictor of all-cause mortality in HD patients.
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Literature
1.
go back to reference Kooman JP, Kotanko P, Schols AM, Shiels PG, Stenvinkel P. Chronic kidney disease and premature ageing. NAT REV NEPHROL. 2014;10(12):732–42.PubMed Kooman JP, Kotanko P, Schols AM, Shiels PG, Stenvinkel P. Chronic kidney disease and premature ageing. NAT REV NEPHROL. 2014;10(12):732–42.PubMed
2.
go back to reference Stenvinkel P, Larsson TE. Chronic kidney disease: a clinical model of premature aging. Am J Kidney Dis. 2013;62(2):339–51.PubMed Stenvinkel P, Larsson TE. Chronic kidney disease: a clinical model of premature aging. Am J Kidney Dis. 2013;62(2):339–51.PubMed
3.
go back to reference Chiu YL, Tsai HH, Lai YJ, Tseng HY, Wu YW, Peng YS, Chiu CM, Chuang YF. Cognitive impairment in patients with end-stage renal disease: accelerated brain aging? J Formos Med Assoc. 2019;118(5):867–75.PubMed Chiu YL, Tsai HH, Lai YJ, Tseng HY, Wu YW, Peng YS, Chiu CM, Chuang YF. Cognitive impairment in patients with end-stage renal disease: accelerated brain aging? J Formos Med Assoc. 2019;118(5):867–75.PubMed
4.
go back to reference Goronzy JJ, Weyand CM. Understanding immunosenescence to improve responses to vaccines. Nat Immunol. 2013;14(5):428–36.PubMedPubMedCentral Goronzy JJ, Weyand CM. Understanding immunosenescence to improve responses to vaccines. Nat Immunol. 2013;14(5):428–36.PubMedPubMedCentral
5.
go back to reference Fülöp T, Dupuis G, Witkowski JM, Larbi A. The Role of Immunosenescence in the Development of Age-Related Diseases. Revista de investigacion clinica. 2016;68(2):84.PubMed Fülöp T, Dupuis G, Witkowski JM, Larbi A. The Role of Immunosenescence in the Development of Age-Related Diseases. Revista de investigacion clinica. 2016;68(2):84.PubMed
6.
go back to reference Betjes MG, Langerak AW, van der Spek A, de Wit EA, Litjens NH. Premature aging of circulating T cells in patients with end-stage renal disease. Kidney Int. 2011;80(2):208–17.PubMed Betjes MG, Langerak AW, van der Spek A, de Wit EA, Litjens NH. Premature aging of circulating T cells in patients with end-stage renal disease. Kidney Int. 2011;80(2):208–17.PubMed
7.
go back to reference Betjes MG. Immune cell dysfunction and inflammation in end-stage renal disease. NAT REV NEPHROL. 2013;9(5):255–65.PubMed Betjes MG. Immune cell dysfunction and inflammation in end-stage renal disease. NAT REV NEPHROL. 2013;9(5):255–65.PubMed
8.
go back to reference Betjes MGH, de Wit EEA, Weimar W, Litjens NHR. Circulating pro-inflammatory CD4posCD28null T cells are independently associated with cardiovascular disease in ESRD patients. Nephrol , Dial Transpl. 2010;25(11):3640–6. Betjes MGH, de Wit EEA, Weimar W, Litjens NHR. Circulating pro-inflammatory CD4posCD28null T cells are independently associated with cardiovascular disease in ESRD patients. Nephrol , Dial Transpl. 2010;25(11):3640–6.
9.
go back to reference Crépin T, Legendre M, Carron C, Vachey C, Courivaud C, Rebibou J, Ferrand C, Laheurte C, Vauchy C, Gaiffe E, et al. Uraemia-induced immune senescence and clinical outcomes in chronic kidney disease patients. Nephrol Dial Transpl. 2020;35(4):624–32. Crépin T, Legendre M, Carron C, Vachey C, Courivaud C, Rebibou J, Ferrand C, Laheurte C, Vauchy C, Gaiffe E, et al. Uraemia-induced immune senescence and clinical outcomes in chronic kidney disease patients. Nephrol Dial Transpl. 2020;35(4):624–32.
10.
go back to reference Ruud WMMG. T-cell ageing in end-stage renal disease patients: assessment and clinical relevance. World J Nephrol. 2014;3(4):268–76. Ruud WMMG. T-cell ageing in end-stage renal disease patients: assessment and clinical relevance. World J Nephrol. 2014;3(4):268–76.
11.
go back to reference Freitas GRR, Da Luz FM, Agena F, Jaluul O, Silva SC, Lemos FBC, Coelho V, Elias D, Galante NZ. Aging and end stage renal disease cause a decrease in absolute circulating lymphocyte counts with a shift to a memory profile and diverge in Treg population. Aging Dis. 2019;10(1):49–61.PubMedPubMedCentral Freitas GRR, Da Luz FM, Agena F, Jaluul O, Silva SC, Lemos FBC, Coelho V, Elias D, Galante NZ. Aging and end stage renal disease cause a decrease in absolute circulating lymphocyte counts with a shift to a memory profile and diverge in Treg population. Aging Dis. 2019;10(1):49–61.PubMedPubMedCentral
12.
go back to reference Chiu Y, Shu K, Yang F, Chou T, Chen P, Lay F, Pan S, Lin C, Litjens NHR, Betjes MGH, et al. A comprehensive characterization of aggravated aging-related changes in T lymphocytes and monocytes in end-stage renal disease: the iESRD study. Immun Ageing. 2018;15(1):27.PubMedPubMedCentral Chiu Y, Shu K, Yang F, Chou T, Chen P, Lay F, Pan S, Lin C, Litjens NHR, Betjes MGH, et al. A comprehensive characterization of aggravated aging-related changes in T lymphocytes and monocytes in end-stage renal disease: the iESRD study. Immun Ageing. 2018;15(1):27.PubMedPubMedCentral
13.
go back to reference Provinciali M, Moresi R, Donnini A, Lisa RM. Reference values for CD4+ and CD8+ T lymphocytes with Naïve or memory phenotype and their association with mortality in the elderly. GERONTOLOGY. 2009;55(3):314–21.PubMed Provinciali M, Moresi R, Donnini A, Lisa RM. Reference values for CD4+ and CD8+ T lymphocytes with Naïve or memory phenotype and their association with mortality in the elderly. GERONTOLOGY. 2009;55(3):314–21.PubMed
14.
go back to reference Nikolich-Zugich J. Aging of the T cell compartment in mice and humans: from no naive expectations to foggy memories. J Immunol. 2014;193(6):2622–9.PubMedPubMedCentral Nikolich-Zugich J. Aging of the T cell compartment in mice and humans: from no naive expectations to foggy memories. J Immunol. 2014;193(6):2622–9.PubMedPubMedCentral
15.
go back to reference Moskowitz DM, Zhang DW, Hu B, Le Saux S, Yanes RE, Ye Z, Buenrostro JD, Weyand CM, Greenleaf WJ, Goronzy JJ. Epigenomics of human CD8 T cell differentiation and aging. Sci Immunol. 2017;2(8):eaag0192. Moskowitz DM, Zhang DW, Hu B, Le Saux S, Yanes RE, Ye Z, Buenrostro JD, Weyand CM, Greenleaf WJ, Goronzy JJ. Epigenomics of human CD8 T cell differentiation and aging. Sci Immunol. 2017;2(8):eaag0192.
16.
go back to reference Sen DR, Kaminski J, Barnitz RA, Kurachi M, Gerdemann U, Yates KB, Tsao HW, Godec J, LaFleur MW, Brown FD, et al. The epigenetic landscape of T cell exhaustion. Science. 2016;354(6316):1165–9.PubMedPubMedCentral Sen DR, Kaminski J, Barnitz RA, Kurachi M, Gerdemann U, Yates KB, Tsao HW, Godec J, LaFleur MW, Brown FD, et al. The epigenetic landscape of T cell exhaustion. Science. 2016;354(6316):1165–9.PubMedPubMedCentral
18.
go back to reference Goronzy JJ, Fang F, Cavanagh MM, Qi Q, Weyand CM. Naive T cell maintenance and function in human aging. J Immunol. 2015;194(9):4073–80.PubMedPubMedCentral Goronzy JJ, Fang F, Cavanagh MM, Qi Q, Weyand CM. Naive T cell maintenance and function in human aging. J Immunol. 2015;194(9):4073–80.PubMedPubMedCentral
19.
go back to reference Levine S, Saltzman A. Are urea and creatinine uremic toxins in the rat? Ren Fail. 2001;23(1):53–9.PubMed Levine S, Saltzman A. Are urea and creatinine uremic toxins in the rat? Ren Fail. 2001;23(1):53–9.PubMed
20.
go back to reference Raskova J, Czerwinski DK, Shea SM, Raska JK. Cellular immunity and lymphocyte populations in developing uremia in the rat. J Exp Pathol. 1986;2(4):229.PubMed Raskova J, Czerwinski DK, Shea SM, Raska JK. Cellular immunity and lymphocyte populations in developing uremia in the rat. J Exp Pathol. 1986;2(4):229.PubMed
21.
go back to reference Iio K, Kabata D, Iio R, Imai Y, Hatanaka M, Omori H, Hoshida Y, Saeki Y, Shintani A, Hamano T, et al. Parathyroid hormone and premature thymus ageing in patients with chronic kidney disease. SCI REP UK. 2019;9(1):813–8. Iio K, Kabata D, Iio R, Imai Y, Hatanaka M, Omori H, Hoshida Y, Saeki Y, Shintani A, Hamano T, et al. Parathyroid hormone and premature thymus ageing in patients with chronic kidney disease. SCI REP UK. 2019;9(1):813–8.
22.
go back to reference Fry TJ, Mackall CL. The many faces of IL-7: from Lymphopoiesis to peripheral T cell maintenance. J Immunol. 2005;174(11):6571–6.PubMed Fry TJ, Mackall CL. The many faces of IL-7: from Lymphopoiesis to peripheral T cell maintenance. J Immunol. 2005;174(11):6571–6.PubMed
23.
go back to reference Litjens NHR, van Druningen CJ, Betjes MGH. Progressive loss of renal function is associated with activation and depletion of naive T lymphocytes. Clin Immunol. 2006;118(1):83–91.PubMed Litjens NHR, van Druningen CJ, Betjes MGH. Progressive loss of renal function is associated with activation and depletion of naive T lymphocytes. Clin Immunol. 2006;118(1):83–91.PubMed
24.
go back to reference Tsukamoto H, Clise-Dwyer K, Huston GE, Duso DK, Buck AL, Johnson LL, Haynes L, Swain SL. Age-associated increase in lifespan of Naïve CD4 T cells contributes to T-cell homeostasis but facilitates development of functional defects. P NATL ACAD SCI USA. 2009;106(43):18333–8. Tsukamoto H, Clise-Dwyer K, Huston GE, Duso DK, Buck AL, Johnson LL, Haynes L, Swain SL. Age-associated increase in lifespan of Naïve CD4 T cells contributes to T-cell homeostasis but facilitates development of functional defects. P NATL ACAD SCI USA. 2009;106(43):18333–8.
25.
go back to reference Čičin-Šain L, Messaoudi I, Park B, Currier N, Planer S, Fischer M, Tackitt S, Nikolich-Žugich D, Legasse A, Axthelm MK, et al. Dramatic Increase in Naïve T Cell Turnover Is Linked to Loss of Naïve T Cells from Old Primates. P NATL ACAD SCI USA. 2007;104(50):19960–5. Čičin-Šain L, Messaoudi I, Park B, Currier N, Planer S, Fischer M, Tackitt S, Nikolich-Žugich D, Legasse A, Axthelm MK, et al. Dramatic Increase in Naïve T Cell Turnover Is Linked to Loss of Naïve T Cells from Old Primates. P NATL ACAD SCI USA. 2007;104(50):19960–5.
26.
27.
go back to reference Cheng T, Rodrigues N, Shen H, Yang Y, Dombkowski D, Sykes M, Scadden DT. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. SCIENCE. 2000;287(5459):1804–8.PubMed Cheng T, Rodrigues N, Shen H, Yang Y, Dombkowski D, Sykes M, Scadden DT. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. SCIENCE. 2000;287(5459):1804–8.PubMed
28.
go back to reference Goronzy JJ, Li G, Yang Z, Weyand CM. The janus head of T cell aging - autoimmunity and immunodeficiency. Front Immunol. 2013;4:131.PubMedPubMedCentral Goronzy JJ, Li G, Yang Z, Weyand CM. The janus head of T cell aging - autoimmunity and immunodeficiency. Front Immunol. 2013;4:131.PubMedPubMedCentral
30.
go back to reference Stenvinkel P. Inflammation in end-stage renal failure: could it be treated? Nephrol Dial Transplant. 2002;17(Suppl 8):33–8 40.PubMed Stenvinkel P. Inflammation in end-stage renal failure: could it be treated? Nephrol Dial Transplant. 2002;17(Suppl 8):33–8 40.PubMed
31.
go back to reference Posnett DN, Sinha R, Kabak S, Russo C. Clonal populations of T cells in normal elderly humans: the T cell equivalent to "benign monoclonal gammapathy". J Exp Med. 1994;179(2):609–18.PubMed Posnett DN, Sinha R, Kabak S, Russo C. Clonal populations of T cells in normal elderly humans: the T cell equivalent to "benign monoclonal gammapathy". J Exp Med. 1994;179(2):609–18.PubMed
32.
go back to reference Goronzy JJ, Bartz-Bazzanella P, Hu W, Jendro MC, Walser-Kuntz DR, Weyand CM. Dominant clonotypes in the repertoire of peripheral CD4+ T cells in rheumatoid arthritis. J Clin Invest. 1994;94(5):2068–76.PubMedPubMedCentral Goronzy JJ, Bartz-Bazzanella P, Hu W, Jendro MC, Walser-Kuntz DR, Weyand CM. Dominant clonotypes in the repertoire of peripheral CD4+ T cells in rheumatoid arthritis. J Clin Invest. 1994;94(5):2068–76.PubMedPubMedCentral
33.
go back to reference Crawford DC, Bailey J, Miskimen K, Miron P, McCauley JL, Sedor JR, OToole JF, Bush WS. Somatic T-cell receptor diversity in a chronic kidney disease PatientPopulation linked to electronic health records. AMIA Jt Summits Transl Sci Proc. 2018;2017:63–71.PubMed Crawford DC, Bailey J, Miskimen K, Miron P, McCauley JL, Sedor JR, OToole JF, Bush WS. Somatic T-cell receptor diversity in a chronic kidney disease PatientPopulation linked to electronic health records. AMIA Jt Summits Transl Sci Proc. 2018;2017:63–71.PubMed
34.
go back to reference Huang L, Betjes MGH, Klepper M, Langerak AW, Baan CC, Litjens NHR. End-stage renal disease causes skewing in the TCR Vβ-repertoire primarily within CD8 + T cell subsets. Front Immunol. 2017;8:1826.PubMedPubMedCentral Huang L, Betjes MGH, Klepper M, Langerak AW, Baan CC, Litjens NHR. End-stage renal disease causes skewing in the TCR Vβ-repertoire primarily within CD8 + T cell subsets. Front Immunol. 2017;8:1826.PubMedPubMedCentral
35.
go back to reference Huang L, Litjens N, Kannegieter NM, Klepper M, Baan CC, Betjes M. pERK-dependent defective TCR-mediated activation of CD4(+) T cells in end-stage renal disease patients. Immun Ageing. 2017;14:14.PubMedPubMedCentral Huang L, Litjens N, Kannegieter NM, Klepper M, Baan CC, Betjes M. pERK-dependent defective TCR-mediated activation of CD4(+) T cells in end-stage renal disease patients. Immun Ageing. 2017;14:14.PubMedPubMedCentral
36.
go back to reference Fülöp T, Larbi A, Pawelec G. Human T cell aging and the impact of persistent viral infections. Front Immunol. 2013;4:271.PubMedPubMedCentral Fülöp T, Larbi A, Pawelec G. Human T cell aging and the impact of persistent viral infections. Front Immunol. 2013;4:271.PubMedPubMedCentral
37.
go back to reference Blankenberg S, Rupprecht HJ, Bickel C, Espinola-Klein C, Rippin G, Hafner G, Ossendorf M, Steinhagen K, Meyer J. Cytomegalovirus infection with interleukin-6 response predicts cardiac mortality in patients with coronary artery disease. Circulation. 2001;103(24):2915–21.PubMed Blankenberg S, Rupprecht HJ, Bickel C, Espinola-Klein C, Rippin G, Hafner G, Ossendorf M, Steinhagen K, Meyer J. Cytomegalovirus infection with interleukin-6 response predicts cardiac mortality in patients with coronary artery disease. Circulation. 2001;103(24):2915–21.PubMed
38.
go back to reference Betjes MG, Litjens NH, Zietse R. Seropositivity for cytomegalovirus in patients with end-stage renal disease is strongly associated with atherosclerotic disease. Nephrol Dial Transplant. 2007;22(11):3298–303.PubMed Betjes MG, Litjens NH, Zietse R. Seropositivity for cytomegalovirus in patients with end-stage renal disease is strongly associated with atherosclerotic disease. Nephrol Dial Transplant. 2007;22(11):3298–303.PubMed
39.
go back to reference Litjens N, Wit E, Betjes M. Differential effects of age, cytomegalovirus-seropositivity and end-stage renal disease (ESRD) on circulating T lymphocyte subsets. Immun Ageing. 2011;8(1):2.PubMedPubMedCentral Litjens N, Wit E, Betjes M. Differential effects of age, cytomegalovirus-seropositivity and end-stage renal disease (ESRD) on circulating T lymphocyte subsets. Immun Ageing. 2011;8(1):2.PubMedPubMedCentral
40.
go back to reference Meijers RW, Litjens NH, de Wit EA, Langerak AW, van der Spek A, Baan CC, Weimar W, Betjes MG. Cytomegalovirus contributes partly to uraemia-associated premature immunological ageing of the T cell compartment. Clin Exp Immunol. 2013;174(3):424–32.PubMedPubMedCentral Meijers RW, Litjens NH, de Wit EA, Langerak AW, van der Spek A, Baan CC, Weimar W, Betjes MG. Cytomegalovirus contributes partly to uraemia-associated premature immunological ageing of the T cell compartment. Clin Exp Immunol. 2013;174(3):424–32.PubMedPubMedCentral
41.
go back to reference Huang L, Langerak AW, Baan CC, Litjens NH, Betjes MG. Latency for cytomegalovirus impacts T cell ageing significantly in elderly end-stage renal disease patients. Clin Exp Immunol. 2016;186(2):239–48.PubMedPubMedCentral Huang L, Langerak AW, Baan CC, Litjens NH, Betjes MG. Latency for cytomegalovirus impacts T cell ageing significantly in elderly end-stage renal disease patients. Clin Exp Immunol. 2016;186(2):239–48.PubMedPubMedCentral
42.
go back to reference Yang F, Shu K, Chen H, Chen I, Lay F, Chuang Y, Wu C, Tsai W, Peng Y, Hsu S, et al. Anti-cytomegalovirus IgG antibody titer is positively associated with advanced T cell differentiation and coronary artery disease in end-stage renal disease. Immun Ageing. 2018;15(1):15.PubMedPubMedCentral Yang F, Shu K, Chen H, Chen I, Lay F, Chuang Y, Wu C, Tsai W, Peng Y, Hsu S, et al. Anti-cytomegalovirus IgG antibody titer is positively associated with advanced T cell differentiation and coronary artery disease in end-stage renal disease. Immun Ageing. 2018;15(1):15.PubMedPubMedCentral
43.
go back to reference Betjes MG, Huisman M, Weimar W, Litjens NH. Expansion of cytolytic CD4+CD28- T cells in end-stage renal disease. Kidney Int. 2008;74(6):760–7.PubMed Betjes MG, Huisman M, Weimar W, Litjens NH. Expansion of cytolytic CD4+CD28- T cells in end-stage renal disease. Kidney Int. 2008;74(6):760–7.PubMed
44.
go back to reference Meijers R, Litjens N, Wit E, Langerak A, Spek A, Baan C, Weimar W, Betjes M. Uremia causes premature ageing of the T cell compartment in end-stage renal disease patients. Immun Ageing. 2012;9(1):19.PubMedPubMedCentral Meijers R, Litjens N, Wit E, Langerak A, Spek A, Baan C, Weimar W, Betjes M. Uremia causes premature ageing of the T cell compartment in end-stage renal disease patients. Immun Ageing. 2012;9(1):19.PubMedPubMedCentral
45.
go back to reference Ducloux D, Legendre M, Bamoulid J, Rebibou JM, Saas P, Courivaud C, Crepin T. ESRD-associated immune phenotype depends on dialysis modality and iron status: clinical implications. Immun Ageing. 2018;15:16.PubMedPubMedCentral Ducloux D, Legendre M, Bamoulid J, Rebibou JM, Saas P, Courivaud C, Crepin T. ESRD-associated immune phenotype depends on dialysis modality and iron status: clinical implications. Immun Ageing. 2018;15:16.PubMedPubMedCentral
46.
go back to reference Meijers RWJ, Litjens NHR, Wit EA, Langerak AW, Baan CC, Betjes MGH. Uremia-associated immunological aging is stably imprinted in the T-cell system and not reversed by kidney transplantation. Transpl Int. 2014;27(12):1272–84.PubMed Meijers RWJ, Litjens NHR, Wit EA, Langerak AW, Baan CC, Betjes MGH. Uremia-associated immunological aging is stably imprinted in the T-cell system and not reversed by kidney transplantation. Transpl Int. 2014;27(12):1272–84.PubMed
Metadata
Title
Premature aging of circulating T cells predicts all-cause mortality in hemodialysis patients
Authors
Fangfang Xiang
Rongyi Chen
Xuesen Cao
Bo Shen
Xiaohong Chen
Xiaoqiang Ding
Jianzhou Zou
Publication date
01-12-2020
Publisher
BioMed Central
Published in
BMC Nephrology / Issue 1/2020
Electronic ISSN: 1471-2369
DOI
https://doi.org/10.1186/s12882-020-01920-8

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