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A Contraindication for Transplantation? Consequences of Frailty on Immunity and Immunosuppression

  • Yeqi Nian
  • Ryoichi Maenosono
  • Jasper Iske
  • Abdallah Elkhal
  • Stefan G. TulliusEmail author
Frailty and Gerontology (MM Demarco, Section Editor)
  • 12 Downloads
Part of the following topical collections:
  1. Topical Collection on Frailty and Gerontology

Abstract

Purpose of Review

Frailty has gained clinical relevance. While the condition may negatively impact outcomes, organ transplantation may also improve frailty. Notably, available assessment tools are broad and have not allowed for a detailed analysis or prognosis.

Recent Findings

Frailty has been linked to adverse surgical outcomes while imparting on immune competency. Immunosuppressive treatment may therefore require modifications in frail patients, and effects on drug metabolism may need consideration. Moreover, cognitive impairment may impact compliance. Here, we provide a comprehensive update on clinical features, diagnostics, consequences on immunity and immunosuppression, and clinical outcomes.

Summary

Clinical studies have shown promising outcomes for some frail transplant recipients. Relevant open questions include patient selection, adaptation of immunosuppression, potential to improve frailty, compliance, and transplant outcomes.

Keywords

Frailty Kidney transplantation Immunosuppression Risk assessment Patient selection Follow-up 

Abbreviations

CCR5

CC receptor 5

CKD

Chronic kidney disease

CMV

Cytomegalovirus

CNIs

Calcineurin inhibitors

CVD

Cardiovascular disease

CRP

C-reactive protein

CYP450

Cytochrome P450

DGF

Delayed graft function

EHR

Early hospital readmission

EPTS

Expected post-transplant survival

ESRD

End-stage renal disease

MDR

MMF-dose reduction

MMF

Mycophenolate mofetil

NODAT

New-onset diabetes after transplantation

PCT

Procalcitonin

PK/PD

Pharmacokinetic and pharmacodynamic

SASP

Senescence-associated secretory phenotype

sTNF-RII

Soluble TNF-receptor-II

TAC

Tacrolimus

Notes

Funding Information

This work has been supported by grants from the National Institutes of Health (R56/R01AGO39449). Y.N. was supported by a grant from China Scholarship Council (201606370196). R.M. was supported by the Osaka Medical Foundation. J.I. was supported by the Biomedical Education Program and The German Academic Exchange Service.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict 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.

References

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

  1. 1.
    Abecassis M, Bartlett ST, Collins AJ, Davis CL, Delmonico FL, Friedewald JJ, et al. Kidney transplantation as primary therapy for end-stage renal disease: a National Kidney Foundation/Kidney Disease Outcomes Quality Initiative (NKF/KDOQITM) conference. Clin J Am Soc Nephrol. 2008;3(2):471–80.  https://doi.org/10.2215/CJN.05021107.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Sorensen VR, Heaf J, Wehberg S, Sorensen SS. Survival benefit in renal transplantation despite high comorbidity. Transplantation. 2016;100(10):2160–7.  https://doi.org/10.1097/TP.0000000000001002.CrossRefPubMedGoogle Scholar
  3. 3.
    Ducloux D, Legendre M, Bamoulid J, Rebibou JM, Saas P, Courivaud C, et al. ESRD-associated immune phenotype depends on dialysis modality and iron status: clinical implications. Immun Ageing. 2018;15:16.  https://doi.org/10.1186/s12979-018-0121-z.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    McHugh D, Gil J. Senescence and aging: causes, consequences, and therapeutic avenues. J Cell Biol. 2018;217(1):65–77.  https://doi.org/10.1083/jcb.201708092.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    LeBrasseur NK, Tchkonia T, Kirkland JL. Cellular senescence and the biology of aging, disease, and frailty. Nestle Nutr Inst Workshop Ser. 2015;83:11–8.  https://doi.org/10.1159/000382054.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Kan WC, Wang JJ, Wang SY, Sun YM, Hung CY, Chu CC, et al. The new comorbidity index for predicting survival in elderly dialysis patients: a long-term population-based study. PLoS One. 2013;8(8):e68748.  https://doi.org/10.1371/journal.pone.0068748.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Huang E, Segev DL, Rabb H. Kidney transplantation in the elderly. Semin Nephrol. 2009;29(6):621–35.  https://doi.org/10.1016/j.semnephrol.2009.07.011.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    •• Tullius SG, Milford E. Kidney allocation and the aging immune response. N Engl J Med. 2011;364(14):1369–70.  https://doi.org/10.1056/NEJMc1103007 This study reports the impact of aging on both donors and recipients. CrossRefPubMedGoogle Scholar
  9. 9.
    Oberhuber R, Heinbokel T, Cetina Biefer HR, Boenisch O, Hock K, Bronson RT, et al. CD11c+ dendritic cells accelerate the rejection of older cardiac transplants via interleukin-17A. Circulation. 2015;132(2):122–31.  https://doi.org/10.1161/CIRCULATIONAHA.114.014917.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Yao X, Li H, Leng SX. Inflammation and immune system alterations in frailty. Clin Geriatr Med. 2011;27(1):79–87.  https://doi.org/10.1016/j.cger.2010.08.002.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56(3):M146–56.CrossRefGoogle Scholar
  12. 12.
    Bandeen-Roche K, Seplaki CL, Huang J, Buta B, Kalyani RR, Varadhan R, et al. Frailty in older adults: a nationally representative profile in the United States. J Gerontol A Biol Sci Med Sci. 2015;70(11):1427–34.  https://doi.org/10.1093/gerona/glv133.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    McAdams-DeMarco MA, Ying H, Olorundare I, King EA, Haugen C, Buta B, et al. Individual frailty components and mortality in kidney transplant recipients. Transplantation. 2017;101(9):2126–32.  https://doi.org/10.1097/TP.0000000000001546.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Exterkate L, Slegtenhorst BR, Kelm M, Seyda M, Schuitenmaker JM, Quante M, et al. Frailty and transplantation. Transplantation. 2016;100(4):727–33.  https://doi.org/10.1097/TP.0000000000001003.CrossRefPubMedGoogle Scholar
  15. 15.
    Andreux PA, van Diemen MPJ, Heezen MR, Auwerx J, Rinsch C, Jan Groeneveld G, et al. Mitochondrial function is impaired in the skeletal muscle of pre-frail elderly. Sci Rep. 2018;8(1):8548.  https://doi.org/10.1038/s41598-018-26944-x.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Xu M, Pirtskhalava T, Farr JN, Weigand BM, Palmer AK, Weivoda MM, et al. Senolytics improve physical function and increase lifespan in old age. Nat Med. 2018;24(8):1246–56.  https://doi.org/10.1038/s41591-018-0092-9.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Muller M. Cellular senescence: molecular mechanisms, in vivo significance, and redox considerations. Antioxid Redox Signal. 2009;11(1):59–98.  https://doi.org/10.1089/ars.2008.2104.CrossRefPubMedGoogle Scholar
  18. 18.
    Sharpless NE, DePinho RA. Telomeres, stem cells, senescence, and cancer. J Clin Invest. 2004;113(2):160–8.  https://doi.org/10.1172/JCI20761.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Solana R, Tarazona R, Gayoso I, Lesur O, Dupuis G, Fulop T. Innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans. Semin Immunol. 2012;24(5):331–41.  https://doi.org/10.1016/j.smim.2012.04.008.CrossRefPubMedGoogle Scholar
  20. 20.
    Rodier F, Coppe JP, Patil CK, Hoeijmakers WA, Munoz DP, Raza SR, et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol. 2009;11(8):973–9.  https://doi.org/10.1038/ncb1909.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Rodier F, Campisi J. Four faces of cellular senescence. J Cell Biol. 2011;192(4):547–56.  https://doi.org/10.1083/jcb.201009094.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Childs BG, Baker DJ, Kirkland JL, Campisi J, van Deursen JM. Senescence and apoptosis: dueling or complementary cell fates? EMBO Rep. 2014;15(11):1139–53.  https://doi.org/10.15252/embr.201439245.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Rao SG, Jackson JG. SASP: tumor suppressor or promoter? Yes! Trends Cancer. 2016;2(11):676–87.  https://doi.org/10.1016/j.trecan.2016.10.001.CrossRefPubMedGoogle Scholar
  24. 24.
    Fedarko NS. The biology of aging and frailty. Clin Geriatr Med. 2011;27(1):27–37.  https://doi.org/10.1016/j.cger.2010.08.006.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Bandeen-Roche K, Xue QL, Ferrucci L, Walston J, Guralnik JM, Chaves P, et al. Phenotype of frailty: characterization in the women’s health and aging studies. J Gerontol A Biol Sci Med Sci. 2006;61(3):262–6.CrossRefGoogle Scholar
  26. 26.
    Dent E, Kowal P, Hoogendijk EO. Frailty measurement in research and clinical practice: a review. Eur J Intern Med. 2016;31:3–10.  https://doi.org/10.1016/j.ejim.2016.03.007.CrossRefPubMedGoogle Scholar
  27. 27.
    Rothman MD, Leo-Summers L, Gill TM. Prognostic significance of potential frailty criteria. J Am Geriatr Soc. 2008;56(12):2211–6.  https://doi.org/10.1111/j.1532-5415.2008.02008.x.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Marcos-Perez D, Sanchez-Flores M, Maseda A, Lorenzo-Lopez L, Millan-Calenti JC, Gostner JM, et al. Frailty in older adults is associated with plasma concentrations of inflammatory mediators but not with lymphocyte subpopulations. Front Immunol. 2018;9:1056.  https://doi.org/10.3389/fimmu.2018.01056.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Mahmoud RA, El-Gendi HI, Ahmed HH. Serum neopterin, tumor necrosis factor-alpha and soluble tumor necrosis factor receptor II (p75) levels and disease activity in Egyptian female patients with systemic lupus erythematosus. Clin Biochem. 2005;38(2):134–41.  https://doi.org/10.1016/j.clinbiochem.2004.11.002.CrossRefPubMedGoogle Scholar
  30. 30.
    Wang B, Fujisawa H, Zhuang L, Kondo S, Shivji GM, Kim CS, et al. Depressed Langerhans cell migration and reduced contact hypersensitivity response in mice lacking TNF receptor p75. J Immunol. 1997;159(12):6148–55.PubMedGoogle Scholar
  31. 31.
    McAdams-DeMarco MA, Ying H, Thomas AG, Warsame F, Shaffer AA, Haugen CE, et al. Frailty, inflammatory markers, and waitlist mortality among patients with end-stage renal disease in a prospective cohort study. Transplantation. 2018;102(10):1740–6.  https://doi.org/10.1097/TP.0000000000002213.CrossRefPubMedGoogle Scholar
  32. 32.
    Yang Y, Hao Q, Flaherty JH, Cao L, Zhou J, Su L, et al. Comparison of procalcitonin, a potentially new inflammatory biomarker of frailty, to interleukin-6 and C-reactive protein among older Chinese hospitalized patients. Aging Clin Exp Res. 2018;30:1459–64.  https://doi.org/10.1007/s40520-018-0964-3.CrossRefPubMedGoogle Scholar
  33. 33.
    Rietman ML, Spijkerman AMW, Wong A, van Steeg H, Burkle A, Moreno-Villanueva M, et al. Antioxidants linked with physical, cognitive and psychological frailty: analysis of candidate biomarkers and markers derived from the MARK-AGE study. Mech Ageing Dev. 2018;177:135–43.  https://doi.org/10.1016/j.mad.2018.04.007.CrossRefPubMedGoogle Scholar
  34. 34.
    Garonzik-Wang JM, Govindan P, Grinnan JW, Liu M, Ali HM, Chakraborty A, et al. Frailty and delayed graft function in kidney transplant recipients. Arch Surg. 2012;147(2):190–3.  https://doi.org/10.1001/archsurg.2011.1229.CrossRefPubMedGoogle Scholar
  35. 35.
    McAdams-DeMarco MA, Law A, Salter ML, Chow E, Grams M, Walston J, et al. Frailty and early hospital readmission after kidney transplantation. Am J Transplant. 2013;13(8):2091–5.  https://doi.org/10.1111/ajt.12300.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    McAdams-DeMarco MA, King EA, Luo X, Haugen C, DiBrito S, Shaffer A, et al. Frailty, length of stay, and mortality in kidney transplant recipients: a National Registry and Prospective Cohort Study. Ann Surg. 2017;266(6):1084–90.  https://doi.org/10.1097/SLA.0000000000002025.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Haugen CE, Mountford A, Warsame F, Berkowitz R, Bae S, Thomas AG, et al. Incidence, risk factors, and sequelae of post-kidney transplant delirium. J Am Soc Nephrol. 2018;29(6):1752–9.  https://doi.org/10.1681/ASN.2018010064.CrossRefPubMedGoogle Scholar
  38. 38.
    Sundermann SH, Dademasch A, Seifert B, Rodriguez Cetina Biefer H, Emmert MY, Walther T, et al. Frailty is a predictor of short- and mid-term mortality after elective cardiac surgery independently of age. Interact Cardiovasc Thorac Surg. 2014;18(5):580–5.  https://doi.org/10.1093/icvts/ivu006.CrossRefPubMedGoogle Scholar
  39. 39.
    •• Bao Y, Dalrymple L, Chertow GM, Kaysen GA, Johansen KL. Frailty, dialysis initiation, and mortality in end-stage renal disease. Arch Intern Med. 2012;172(14):1071–7.  https://doi.org/10.1001/archinternmed.2012.3020 This study reports the mortality rates of frail patients on dialysis as high as 44%. CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Ommundsen N, Wyller TB, Nesbakken A, Jordhoy MS, Bakka A, Skovlund E, et al. Frailty is an independent predictor of survival in older patients with colorectal cancer. Oncologist. 2014;19(12):1268–75.  https://doi.org/10.1634/theoncologist.2014-0237.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Kim SW, Han HS, Jung HW, Kim KI, Hwang DW, Kang SB, et al. Multidimensional frailty score for the prediction of postoperative mortality risk. JAMA Surg. 2014;149(7):633–40.  https://doi.org/10.1001/jamasurg.2014.241.CrossRefPubMedGoogle Scholar
  42. 42.
    Rolland Y, Abellan van Kan G, Benetos A, Blain H, Bonnefoy M, Chassagne P, et al. Frailty, osteoporosis and hip fracture: causes, consequences and therapeutic perspectives. J Nutr Health Aging. 2008;12(5):335–46.CrossRefGoogle Scholar
  43. 43.
    Afilalo J. Frailty in patients with cardiovascular disease: why, when, and how to measure. Curr Cardiovasc Risk Rep. 2011;5(5):467–72.  https://doi.org/10.1007/s12170-011-0186-0.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    McAdams-DeMarco MA, Isaacs K, Darko L, Salter ML, Gupta N, King EA, et al. Changes in frailty after kidney transplantation. J Am Geriatr Soc. 2015;63(10):2152–7.  https://doi.org/10.1111/jgs.13657.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    McAdams-DeMarco MA, Olorundare IO, Ying H, Warsame F, Haugen CE, Hall R, et al. Frailty and postkidney transplant health-related quality of life. Transplantation. 2018;102(2):291–9.  https://doi.org/10.1097/TP.0000000000001943.CrossRefPubMedGoogle Scholar
  46. 46.
    Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, et al. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev. 2007;128(1):92–105.  https://doi.org/10.1016/j.mad.2006.11.016.CrossRefPubMedGoogle Scholar
  47. 47.
    Leng S, Chaves P, Koenig K, Walston J. Serum interleukin-6 and hemoglobin as physiological correlates in the geriatric syndrome of frailty: a pilot study. J Am Geriatr Soc. 2002;50(7):1268–71.CrossRefGoogle Scholar
  48. 48.
    Ershler WB, Keller ET. Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med. 2000;51:245–70.  https://doi.org/10.1146/annurev.med.51.1.245.CrossRefPubMedGoogle Scholar
  49. 49.
    Leng SX, Xue QL, Huang Y, Ferrucci L, Fried LP, Walston JD. Baseline total and specific differential white blood cell counts and 5-year all-cause mortality in community-dwelling older women. Exp Gerontol. 2005;40(12):982–7.  https://doi.org/10.1016/j.exger.2005.08.006.CrossRefPubMedGoogle Scholar
  50. 50.
    Leng SX, Xue QL, Tian J, Walston JD, Fried LP. Inflammation and frailty in older women. J Am Geriatr Soc. 2007;55(6):864–71.  https://doi.org/10.1111/j.1532-5415.2007.01186.x.CrossRefPubMedGoogle Scholar
  51. 51.
    Wang GC, Kao WH, Murakami P, Xue QL, Chiou RB, Detrick B, et al. Cytomegalovirus infection and the risk of mortality and frailty in older women: a prospective observational cohort study. Am J Epidemiol. 2010;171(10):1144–52.  https://doi.org/10.1093/aje/kwq062.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Leng SX, Tian X, Matteini A, Li H, Hughes J, Jain A, et al. IL-6-independent association of elevated serum neopterin levels with prevalent frailty in community-dwelling older adults. Age Ageing. 2011;40(4):475–81.  https://doi.org/10.1093/ageing/afr047.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Parker DC, Mielke MM, Yu Q, Rosenberg PB, Jain A, Lyketsos CG, et al. Plasma neopterin level as a marker of peripheral immune activation in amnestic mild cognitive impairment and Alzheimer's disease. Int J Geriatr Psychiatry. 2013;28(2):149–54.  https://doi.org/10.1002/gps.3802.CrossRefPubMedGoogle Scholar
  54. 54.
    Semba RD, Margolick JB, Leng S, Walston J, Ricks MO, Fried LP. T cell subsets and mortality in older community-dwelling women. Exp Gerontol. 2005;40(1–2):81–7.  https://doi.org/10.1016/j.exger.2004.09.006.CrossRefPubMedGoogle Scholar
  55. 55.
    De Fanis U, Wang GC, Fedarko NS, Walston JD, Casolaro V, Leng SX. T-lymphocytes expressing CC chemokine receptor-5 are increased in frail older adults. J Am Geriatr Soc. 2008;56(5):904–8.  https://doi.org/10.1111/j.1532-5415.2008.01673.x.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Mathes T, Grosspietsch K, Neugebauer EAM, Pieper D. Interventions to increase adherence in patients taking immunosuppressive drugs after kidney transplantation: a systematic review of controlled trials. Syst Rev. 2017;6(1):236.  https://doi.org/10.1186/s13643-017-0633-1.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Butler JA, Roderick P, Mullee M, Mason JC, Peveler RC. Frequency and impact of nonadherence to immunosuppressants after renal transplantation: a systematic review. Transplantation. 2004;77(5):769–76.CrossRefGoogle Scholar
  58. 58.
    Jankowska-Polanska B, Dudek K, Szymanska-Chabowska A, Uchmanowicz I. The influence of frailty syndrome on medication adherence among elderly patients with hypertension. Clin Interv Aging. 2016;11:1781–90.  https://doi.org/10.2147/CIA.S113994.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Davies EA, O'Mahony MS. Adverse drug reactions in special populations - the elderly. Br J Clin Pharmacol. 2015;80(4):796–807.  https://doi.org/10.1111/bcp.12596.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Boyle PA, Buchman AS, Wilson RS, Leurgans SE, Bennett DA. Physical frailty is associated with incident mild cognitive impairment in community-based older persons. J Am Geriatr Soc. 2010;58(2):248–55.  https://doi.org/10.1111/j.1532-5415.2009.02671.x.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    McAdams-DeMarco MA, Tan J, Salter ML, Gross A, Meoni LA, Jaar BG, et al. Frailty and cognitive function in incident hemodialysis patients. Clin J Am Soc Nephrol. 2015;10(12):2181–9.  https://doi.org/10.2215/CJN.01960215.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Jankowska-Polanska B, Zameta K, Uchmanowicz I, Szymanska-Chabowska A, Morisky D, Mazur G. Adherence to pharmacological and non-pharmacological treatment of frail hypertensive patients. J Geriatr Cardiol. 2018;15(2):153–61.  https://doi.org/10.11909/j.issn.1671-5411.2018.02.002.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Knoll GA, MacDonald I, Khan A, Van Walraven C. Mycophenolate mofetil dose reduction and the risk of acute rejection after renal transplantation. J Am Soc Nephrol. 2003;14(9):2381–6.CrossRefGoogle Scholar
  64. 64.
    Kahu J, Kyllonen L, Salmela K. Impact of mycophenolate mofetil intolerance on early results of kidney transplantation. Transplant Proc. 2005;37(8):3276–9.  https://doi.org/10.1016/j.transproceed.2005.09.014.CrossRefPubMedGoogle Scholar
  65. 65.
    McAdams-DeMarco MA, Law A, Tan J, Delp C, King EA, Orandi B, et al. Frailty, mycophenolate reduction, and graft loss in kidney transplant recipients. Transplantation. 2015;99(4):805–10.  https://doi.org/10.1097/TP.0000000000000444.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Pham PT, Pham PC, Lipshutz GS, Wilkinson AH. New onset diabetes mellitus after solid organ transplantation. Endocrinol Metab Clin N Am. 2007;36(4):873–90; vii.  https://doi.org/10.1016/j.ecl.2007.07.007.CrossRefGoogle Scholar
  67. 67.
    Kesiraju S, Paritala P, Rao Ch UM, Sahariah S. New onset of diabetes after transplantation - an overview of epidemiology, mechanism of development and diagnosis. Transpl Immunol. 2014;30(1):52–8.  https://doi.org/10.1016/j.trim.2013.10.006.CrossRefPubMedGoogle Scholar
  68. 68.
    Sinclair AJ, Sinclair H, Bellary S, Rodriguez-Manas L. The emergence of frailty and sarcopaenia in diabetes mellitus: description of inter-relationships and clinical importance. Cardiovasc Endocrinol Metab. 2016;5(2):40–50.  https://doi.org/10.1097/xce.0000000000000075.CrossRefGoogle Scholar
  69. 69.
    Calvo M, Martinez E. Update on metabolic issues in HIV patients. Curr Opin HIV AIDS. 2014;9(4):332–9.  https://doi.org/10.1097/COH.0000000000000075.CrossRefPubMedGoogle Scholar
  70. 70.
    Jacobson PA, Schladt D, Oetting WS, Leduc R, Guan W, Matas AJ, et al. Lower calcineurin inhibitor doses in older compared to younger kidney transplant recipients yield similar troughs. Am J Transplant. 2012;12(12):3326–36.  https://doi.org/10.1111/j.1600-6143.2012.04232.x.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Warrington JS, Greenblatt DJ, von Moltke LL. Age-related differences in CYP3A expression and activity in the rat liver, intestine, and kidney. J Pharmacol Exp Ther. 2004;309(2):720–9.  https://doi.org/10.1124/jpet.103.061077.CrossRefPubMedGoogle Scholar
  72. 72.
    • Krenzien F, Quante M, Heinbokel T, Seyda M, Minami K, Uehara H, et al. Age-dependent metabolic and immunosuppressive effects of tacrolimus. Am J Transplant. 2017;17(5):1242–54.  https://doi.org/10.1111/ajt.14087 This study reports the age-specific effect of immunosuppressant. CrossRefPubMedGoogle Scholar
  73. 73.
    Colvin MM, Smith CA, Tullius SG, Goldstein DR. Aging and the immune response to organ transplantation. J Clin Invest. 2017;127(7):2523–9.  https://doi.org/10.1172/JCI90601.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Johnston C, Hilmer SN, McLachlan AJ, Matthews ST, Carroll PR, Kirkpatrick CM. The impact of frailty on pharmacokinetics in older people: using gentamicin population pharmacokinetic modeling to investigate changes in renal drug clearance by glomerular filtration. Eur J Clin Pharmacol. 2014;70(5):549–55.  https://doi.org/10.1007/s00228-014-1652-7.CrossRefPubMedGoogle Scholar
  75. 75.
    Hubbard RE, O’Mahony MS, Calver BL, Woodhouse KW. Plasma esterases and inflammation in ageing and frailty. Eur J Clin Pharmacol. 2008;64(9):895–900.  https://doi.org/10.1007/s00228-008-0499-1.CrossRefPubMedGoogle Scholar
  76. 76.
    Opdam FL, Modak AS, Mooijaart SP, Louwerens M, de Waal MW, Gelderblom H, et al. CYP2D6 metabolism in frail elderly compared to non-frail elderly: a pilot feasibility study. Drugs Aging. 2015;32(12):1019–27.  https://doi.org/10.1007/s40266-015-0319-0.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Krenzien F, ElKhal A, Quante M, Rodriguez Cetina Biefer H, Hirofumi U, Gabardi S, et al. A rationale for age-adapted immunosuppression in organ transplantation. Transplantation. 2015;99(11):2258–68.  https://doi.org/10.1097/TP.0000000000000842.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Liu CK, Fielding RA. Exercise as an intervention for frailty. Clin Geriatr Med. 2011;27(1):101–10.  https://doi.org/10.1016/j.cger.2010.08.001.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Waters DL, Baumgartner RN, Garry PJ, Vellas B. Advantages of dietary, exercise-related, and therapeutic interventions to prevent and treat sarcopenia in adult patients: an update. Clin Interv Aging. 2010;5:259–70.CrossRefGoogle Scholar
  80. 80.
    Anawalt BD, Hotaling JM, Walsh TJ, Matsumoto AM. Performance of total testosterone measurement to predict free testosterone for the biochemical evaluation of male hypogonadism. J Urol. 2012;187(4):1369–73.  https://doi.org/10.1016/j.juro.2011.11.095.CrossRefPubMedGoogle Scholar
  81. 81.
    Ho CC, Tong SF, Low WY, Ng CJ, Khoo EM, Lee VK, et al. A randomized, double-blind, placebo-controlled trial on the effect of long-acting testosterone treatment as assessed by the aging male symptoms scale. BJU Int. 2012;110(2):260–5.  https://doi.org/10.1111/j.1464-410X.2011.10755.x.CrossRefPubMedGoogle Scholar
  82. 82.
    Legros JJ, Meuleman EJ, Elbers JM, Geurts TB, Kaspers MJ, Bouloux PM, et al. Oral testosterone replacement in symptomatic late-onset hypogonadism: effects on rating scales and general safety in a randomized, placebo-controlled study. Eur J Endocrinol. 2009;160(5):821–31.  https://doi.org/10.1530/EJE-08-0634.CrossRefPubMedGoogle Scholar
  83. 83.
    Srinivas-Shankar U, Roberts SA, Connolly MJ, O'Connell MD, Adams JE, Oldham JA, et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2010;95(2):639–50.  https://doi.org/10.1210/jc.2009-1251.CrossRefPubMedGoogle Scholar
  84. 84.
    Nian Y, Ding M, Hu S, He H, Cheng S, Yi L, et al. Testosterone replacement therapy improves health-related quality of life for patients with late-onset hypogonadism: a meta-analysis of randomized controlled trials. Andrologia. 2017;49(4).  https://doi.org/10.1111/and.12630.
  85. 85.
    •• Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015;14(4):644–58.  https://doi.org/10.1111/acel.12344 Suggests that clean up of senescent cells could reverse the phenotype of aging and frailty. CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Baar MP, Brandt RMC, Putavet DA, Klein JDD, Derks KWJ, Bourgeois BRM, et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell. 2017;169(1):132–47 e16.  https://doi.org/10.1016/j.cell.2017.02.031.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Kirkland JL, Tchkonia T, Zhu Y, Niedernhofer LJ, Robbins PD. The clinical potential of Senolytic drugs. J Am Geriatr Soc. 2017;65(10):2297–301.  https://doi.org/10.1111/jgs.14969.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Yeqi Nian
    • 1
    • 2
  • Ryoichi Maenosono
    • 1
    • 3
  • Jasper Iske
    • 1
    • 4
  • Abdallah Elkhal
    • 1
  • Stefan G. Tullius
    • 1
    Email author
  1. 1.Division of Transplant Surgery and Transplant Surgery Research Laboratory, Harvard Medical SchoolBrigham and Women’s HospitalBostonUSA
  2. 2.Department of UrologyThe Second Xiangya Hospital, Central South UniversityChangshaChina
  3. 3.Department of UrologyOsaka Medical CollegeOsakaJapan
  4. 4.Institute of Transplant Immunology, Hannover Medical SchoolHannoverGermany

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