Skip to main content

Advertisement

SpringerLink
Log in

Chronic Kidney Disease and Premature Ageing of the Adaptive Immune Response

  • Kidney Diseases (G Ciancio, Section Editor)
  • Published:
Current Urology Reports Aims and scope Submit manuscript

Abstract

Los of renal function is associated with uremia-associated immune deficiency, which contributes significantly to the mortality and morbidity of end-stage renal disease (ESRD) patients. In this review, the effect of ESRD on the adaptive cellular immune system is discussed. Progressive loss of renal function causes a preferential loss of number and function of lymphoid cells. More in depth analysis of these changes reveals a loss of thymic function, attrition of telomeres, and expanded memory T cell population, which is compatible with the concept of premature immunological ageing. Latency for cytomegalovirus is associated with more profound changes and the expansion of a unique pro-inflammatory, cytotoxic subset of CD4-positive CD28null T cells. Epigenetically, modifications in hematopoietic stem cells may underlie uremia-associated immunological ageing, which is not reversed by kidney transplantation. Possible therapeutic options to reverse or halt uremia-associated immunological ageing are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Verkade MA, van de Wetering J, Klepper M, Vaessen LM, Weimar W, Betjes MG. Peripheral blood dendritic cells and GM-CSF as an adjuvant for hepatitis B vaccination in hemodialysis patients. Kidney Int. 2004;66:614–21.

    Article  CAS  PubMed  Google Scholar 

  2. Stewart JH, Vajdic CM, van Leeuwen MT, et al. The pattern of excess cancer in dialysis and transplantation. Nephrol Dial Transplant. 2009;24:3225–31.

    Article  PubMed  Google Scholar 

  3. Meier P, Golshayan D, Blanc E, Pascual M, Burnier M. Oxidized LDL modulates apoptosis of regulatory T cells in patients with ESRD. J Am Soc Nephrol. 2009;20:1368–84.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. The New England journal of medicine. 2004;351:1296–305.

    Article  CAS  PubMed  Google Scholar 

  5. 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;80:208–17. This study demonstrates significant premature immunological ageing of the T cell system in ESRD patients based on assesment of thymic function, telomere length and T cell differentiation.

    Article  PubMed  Google Scholar 

  6. Litjens NH, de Wit EA, Betjes MG. Differential effects of age, cytomegalovirus-seropositivity and end-stage renal disease (ESRD) on circulating T lymphocyte subsets. Immun Ageing. 2011;8:2.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Meijers RW, Litjens NH, de Wit EA, et al. Cytomegalovirus contributes partly to uraemia-associated premature immunological ageing of the T cell compartment. Clin Exp Immunol. 2013;174:424–32.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Steinman RM, Idoyaga J. Features of the dendritic cell lineage. Immunol Rev. 2010;234:5–17.

    Article  CAS  PubMed  Google Scholar 

  9. Litjens NH, van Druningen CJ, Betjes MG. Progressive loss of renal function is associated with activation and depletion of naive T lymphocytes. Clin Immunol. 2006;118:83–91.

    Article  CAS  PubMed  Google Scholar 

  10. Yoon JW, Gollapudi S, Pahl MV, Vaziri ND. Naive and central memory T-cell lymphopenia in end-stage renal disease. Kidney Int. 2006;70:371–6.

    Article  CAS  PubMed  Google Scholar 

  11. Litjens NH, Huisman M, van den Dorpel M, Betjes MG. Impaired immune responses and antigen-specific memory CD4+ T cells in hemodialysis patients. J Am Soc Nephrol. 2008;19:1483–90.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Betjes MG. Immune cell dysfunction and inflammation in end-stage renal disease. Nat Rev Nephrol. 2013;9:255–65. This review is an in-depth analysis of the current knowledge on the role of inflammation, oxidative stress and dysfunction of both the adaptive and innate immune response in ESRD patients.

    Article  CAS  PubMed  Google Scholar 

  13. Pahl MV, Gollapudi S, Sepassi L, Gollapudi P, Elahimehr R, Vaziri ND. Effect of end-stage renal disease on B-lymphocyte subpopulations, IL-7, BAFF and BAFF receptor expression. Nephrol Dial Transplant. 2010;25:205–12.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Lim WH, Kireta S, Thomson AW, Russ GR, Coates PT. Renal transplantation reverses functional deficiencies in circulating dendritic cell subsets in chronic renal failure patients. Transplantation. 2006;81:160–8.

    Article  PubMed  Google Scholar 

  15. Hesselink DA, Betjes MG, Verkade MA, Athanassopoulos P, Baan CC, Weimar W. The effects of chronic kidney disease and renal replacement therapy on circulating dendritic cells. Nephrol Dial Transplant. 2005;20:1868–73.

    Article  PubMed  Google Scholar 

  16. Agrawal S, Gollapudi P, Elahimehr R, Pahl MV, Vaziri ND. Effects of end-stage renal disease and haemodialysis on dendritic cell subsets and basal and LPS-stimulated cytokine production. Nephrol Dial Transplant. 2010;25:737–46.

    Article  CAS  PubMed  Google Scholar 

  17. Verkade MA, van Druningen CJ, Vaessen LM, Hesselink DA, Weimar W, Betjes MG. Functional impairment of monocyte-derived dendritic cells in patients with severe chronic kidney disease. Nephrol Dial Transplant. 2007;22:128–38.

    Article  CAS  PubMed  Google Scholar 

  18. Witko-Sarsat V, Friedlander M, Nguyen Khoa T, et al. Advanced oxidation protein products as novel mediators of inflammation and monocyte activation in chronic renal failure. J Immunol. 1998;161:2524–32.

    CAS  PubMed  Google Scholar 

  19. Vaziri ND. Oxidative stress in uremia: nature, mechanisms, and potential consequences. Semin Nephrol. 2004;24:469–73.

    Article  CAS  PubMed  Google Scholar 

  20. Akar H, Akar GC, Carrero JJ, Stenvinkel P, Lindholm B. Systemic consequences of poor oral health in chronic kidney disease patients. Clin J Am Soc Nephrol. 2011;6:218–26.

    Article  PubMed  Google Scholar 

  21. Anders HJ, Andersen K, Stecher B. The intestinal microbiota, a leaky gut, and abnormal immunity in kidney disease. Kidney Int. 2013;83:1010–6. This article describes a novel source of chronic inflammation, the leaky gut in uremic patients. The possible relation with abnormal immunity in these patients is discussed.

    Article  CAS  PubMed  Google Scholar 

  22. Betjes MG, de Wit EE, Weimar W, Litjens NH. Circulating pro-inflammatory CD4posCD28null T cells are independently associated with cardiovascular disease in ESRD patients. Nephrol Dial Transplant. 2010;25:3640–6.

    Article  CAS  PubMed  Google Scholar 

  23. McKay D, Jameson J. Kidney transplantation and the ageing immune system. Nat Rev Nephrol. 2012;8:700–8. This review describes the various aspects of the ageing immune system and the consequences thereof for immune suppressive therapy after kidney transplantation.

    Article  CAS  PubMed  Google Scholar 

  24. den Braber I, Mugwagwa T, Vrisekoop N, et al. Maintenance of peripheral naive T cells is sustained by thymus output in mice but not humans. Immunity. 2012;36:288–97. This article gives a thorough analysis of findings in mice and humans on the maintenance of peripheral naïve T cells. Based on elaborated cell labeling techniques and modelling it is clear that findings from mice studies cannot be extrapolated to explain T cell homeostasis in humans and vice versa.

    Article  Google Scholar 

  25. Westera L, Drylewicz J, den Braber I, et al. Closing the gap between T-cell life span estimates from stable isotope-labeling studies in mice and humans. Blood. 2013;122:2205–12.

    Article  CAS  PubMed  Google Scholar 

  26. Kohler S, Thiel A. Life after the thymus: CD31+ and CD31- human naive CD4+ T-cell subsets. Blood. 2009;113:769–74.

    Article  CAS  PubMed  Google Scholar 

  27. Meijers RW, Litjens NH, de Wit EA, et al. Uremia causes premature ageing of the T cell compartment in end-stage renal disease patients. Immun Ageing. 2012;9:19.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Betjes MG, Meijers RW, de Wit LE, Litjens NH. A killer on the road: circulating CD4(+)CD28null T cells as cardiovascular risk factor in ESRD patients. J Nephrol. 2012;25:183–91.

    Article  CAS  PubMed  Google Scholar 

  29. Betjes MG, Huisman M, Weimar W, Litjens NH. Expansion of cytolytic CD4 + CD28-T cells in end-stage renal disease. Kidney Int. 2008;74:760–7.

    Article  CAS  PubMed  Google Scholar 

  30. 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;22:3298–303.

    Article  PubMed  Google Scholar 

  31. Courivaud C, Bamoulid J, Chalopin JM, et al. Cytomegalovirus exposure and cardiovascular disease in kidney transplant recipients. J Infect Dis. 2013;207:1569–75. The authors show that cytomegalovirus infections in recently transplanted patients induces an increased risk for a vascular event. This finding supports the concept of the pro-atherogenic role of CMV infection in kidney transplantation patients.

    Article  PubMed  Google Scholar 

  32. van de Berg PJ, Heutinck KM, Raabe R, et al. Human cytomegalovirus induces systemic immune activation characterized by a type 1 cytokine signature. J Infect Dis. 2010;202:690–9.

    Article  PubMed  Google Scholar 

  33. van de Berg PJ, Griffiths SJ, Yong SL, et al. Cytomegalovirus infection reduces telomere length of the circulating T cell pool. J Immunol. 2010;184:3417–23.

    Article  PubMed  Google Scholar 

  34. Zawada AM, Rogacev KS, Hummel B, et al. SuperTAG Methylation-Specific Digital Karyotyping (SMSDK) Reveals Uremia Induced Epigenetic Dysregulation of Atherosclerosis-Related Genes. Circ Cardiovasc Genet. 2012;5:611–20.

  35. Scherberich JE, Nockher WA. CD14++ monocytes, CD14+/CD16+ subset and soluble CD14 as biological markers of inflammatory systemic diseases and monitoring immunosuppressive therapy. Clin Chem Lab Med. 1999;37:209–13.

    Article  CAS  PubMed  Google Scholar 

  36. Meijers RW, Litjens NH, de Wit EA, Langerak AW, Baan CC, Betjes MG. Uremia-associated immunological ageing is stably imprinted in the T-cell system and not reversed by kidney transplantation. Transpl Int 2014. This article describes that premature immunological ageing is not reversed in stable kidney transplant patients, irrespective of their age and renal allograft function. This is compatible with the concept of epigenetic imprinting.

  37. Betjes MG, Weimar W, Litjens NH. Circulating CD4(+)CD28null T Cells May Increase the Risk of an Atherosclerotic Vascular Event Shortly after Kidney Transplantation. J Transplant. 2013;2013:841430.

    PubMed Central  PubMed  Google Scholar 

  38. Betjes MG, Meijers RW, de Wit EA, Weimar W, Litjens NH. Terminally differentiated CD8+ Temra cells are associated with the risk for acute kidney allograft rejection. Transplantation. 2012;94:63–9.

    Article  CAS  PubMed  Google Scholar 

  39. Sportes C, Hakim FT, Memon SA, et al. Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets. J Exp Med. 2008;205:1701–14.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Ruiz S, Pergola PE, Zager RA, Vaziri ND. Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease. Kidney Int. 2013;83:1029–41.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

ᅟ

Conflict of Interest

Dr. Michiel G. H. Betjes and Dr. Nicolle H. R. Litjens each declare no potential conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus Medical Centre, P.O. Box 2040, 3000, CA, Rotterdam, The Netherlands

    Michiel GH Betjes & Nicolle HR Litjens

Authors
  1. Michiel GH Betjes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicolle HR Litjens
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michiel GH Betjes.

Additional information

This article is part of the Topical Collection on Kidney Diseases

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Betjes, M.G., Litjens, N.H. Chronic Kidney Disease and Premature Ageing of the Adaptive Immune Response. Curr Urol Rep 16, 471 (2015). https://doi.org/10.1007/s11934-014-0471-9

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11934-014-0471-9

Keywords

Search

Navigation