Longitudinal Pharmacokinetics of Everolimus When Combined With Low-level of Tacrolimus in Elderly Renal Transplant Recipients

David‐Neto, Elias; Agena, Fabiana; Ramos, Fernanda; Triboni, Ana Heloísa Kamada; Romano, Paschoalina; Ebner, Pérsio de Almeida Rezende; Coelho, Venceslau A; Galante, Nelson Zocoler; Lemos, Francisco José Alves

doi:10.1097/tp.0000000000001549

Cited by 15 publications

(10 citation statements)

References 26 publications

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“…Besides, these elderly patients may need lower IS exposure and doses [4, 5] to avoid both rejection and infection. Lower immunosuppression with relative regulatory sparing could take advantage of the elderly lymphocyte profile maintaining lower acute rejection rates and maybe lowering infection rates.…”

Section: Discussionmentioning

confidence: 99%

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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

Freitas¹,

Fernandes²,

Agena³

et al. 2019

Aging and disease

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There is a growing number of elderly kidney transplant (Ktx) recipients. Elderly recipients present lower acute rejection rates but higher incidence of infection and malignancies. Aging per se seems to result in a shift to memory profile and chronic kidney disease (CKD) in premature immunological aging. Understanding aging and CKD effects on the immune system can improve elderly Ktx immunosuppression. We analyzed the effects of aging and CKD in the immune system, comparing healthy adults (HAd) (n=14, 26±2y), healthy elderly (HEld) (n=15, 79±7y), end stage renal disease (ESRD) adults (EnAd) (n=18, 36±7y) and ESRD elderly (EnEld) (n=31, 65±3y) prior to Ktx regarding their naïve, memory and regulatory T and B peripheral lymphocytes. Aging and ESRD presented additive effect decreasing absolute numbers of B and T-lymphocytes, affecting memory, naive and regulatory subsets without synergic effect. Both resulted in higher percentages of T memory subsets and opposing effects on regulatory T (TREG) subsets, higher percentage in aging and lower in ESRD. Combined effect of aging and ESRD also resulted in higher regulatory B cell percentages. In addition to global lymphopenia and TCD4+ memory shift in both aging and ESRD, aging shifts to an immunoregulatory profile, inducing a increase in TREG percentages, contrasting with ESRD that decreases TREGs. Differential immunosuppression regimens for elderly Ktx may be required. (ClinicalTrials.gov number: NTC01631058).

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Section: Discussionmentioning

confidence: 99%

“…Although these events are often attributed to over-immunosuppression with lower clearance of drugs [4, 5], aging influences many aspects of the immune system, including lymphocyte counts, subset differentiation and function.…”

mentioning

confidence: 99%

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

Freitas¹,

Fernandes²,

Agena³

et al. 2019

Aging and disease

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“…mTOR Inhibitors Many studies evaluating mTORi pharmacokinetics included subgroup analyses of older patients and found no significant difference of drug clearance across age groups [82,[108][109][110][111]. A recent study assessed the pharmacokinetics of everolimus in 16 older kidney transplant recipients receiving everolimus with low-dose tacrolimus and corticosteroids [112]. The investigators demonstrated that older patients had stable everolimus pharmacokinetic parameters without significant changes in dose or exposure during the first 6 months after kidney transplantation.…”

Section: Age and The Pharmacology Of Immunosuppressive Drugsmentioning

confidence: 99%

Immunosuppression Considerations for Older Kidney Transplant Recipients

et al. 2021

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Purpose of Review While kidney transplantation improves the long-term survival of the majority of patients with end-stage kidney disease (ESKD), age-related immune dysfunction and associated comorbidities make older transplant recipients more susceptible to complications related to immunosuppression. In this review, we discuss appropriate management of immunosuppressive agents in older adults to minimize adverse events, avoid acute rejection, and maximize patient and graft survival. Recent Findings Physiological changes associated with senescence can impact drug metabolism and increase the risk of post-transplant infection and malignancy. Clinical trials assessing the safety and efficacy of immunosuppressive agents in older adults are lacking. Recent findings from U.S. transplant registry–based studies suggest that risk-adjusted death-censored graft failure is higher among older patients who received antimetabolite avoidance, mammalian target of rapamycin inhibitor (mTORi)–based, and cyclosporine-based regimens. Observational data suggest that risk-adjusted mortality may be increased in older patients who receive mTORi-based and cyclosporine-based regimens but lower in those managed with T cell induction and maintenance steroid avoidance/withdrawal. Summary Tailored immunosuppression management to improve patient and graft survival in older transplant recipients is an important goal of personalized medicine. Lower intensity immunosuppression, such as steroid-sparing regimens, appears beneficial whereas mTORi- and cyclosporine-based maintenance are associated with greater potential for adverse effects. Prospective clinical trials to assess the safety and efficacy of immunosuppression agents in older recipients are urgently needed.

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“…Resultados: Envelhecimento e doença renal crônica apresentaram efeito aditivo em reduzir os números de linfócitos T [AdS=1737(1446T [AdS=1737( -1933 vs. IdS=1172(934-1360) vs. AdDRC=1238(847-1599) vs. IdDRC= 718(484-993)cels/mm 3 , DRC p<0,001 e envelhecimento p<0,001], afetando populações memória, naive e reguladoras, mas sem efeito sinérgico. Envelhecimento [Linfócitos T memória central -AdS=6,7 (5)(6)(7)(8)5) vs. IdS=9,2 (6,(7)(8)(9)(10)(11)9) vs. AdDRC=5,9(3,[3][4][5][6][7][8]8) vs. IdDRC= 7,7(5,[2][3][4][5][6][7][8][9][10][11][12]4)%, DRC p=0,39 e envelhecimento p=0,02] e doença renal crônica [Linfócitos T memória efetora -AdS=28,2 (16,3) vs. IdS=31,2 (23,5) vs. AdDRC=34 (25,7) vs. IdDRC= 39,6(27,6)%, DRC p=0,03 e envelhecimento p=0,19] resultaram ...…”

Section: Lista De Abreviaturas Símbolos E Siglasunclassified

“…Although these events are often attributed to overimmunosuppression with lower clearance of drugs [4,5], aging influences many aspects of the immune system, including lymphocyte counts, subset differentiation and function.…”

Section: Postersmentioning

confidence: 99%

Efeitos do uso de globulina antitimócito e de everolimo nas subpopulações de linfócitos T e B do sangue periférico em receptores idosos de transplante renal

Freitas¹

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DedicatóriaDedico este manuscrito aos meus familiares, pelos momentos em que me apoiaram e pelos momentos em que me ausentei.Em especial dedico ao meu filho Enzo Rocha Freitas e à minha esposa Lucila Soares que estiveram sempre ao meu lado.Ainda dedico à minha mãe Americilda Rezende Ramos de Freitas e à minha sogra Ione Soares da Silva Rocha pelo auxilio nos cuidados de meu filho quando me ausentei. AgradecimentosComo todo trabalho científico, nada é realizado integralmente por um único indivíduo. Mas alguns membros da equipe de trabalho têm especial destaque.Agradeço especialmente à amiga Maria da Luz responsável pelo meu treinamento no laboratório e responsável pela análise de várias amostras avaliadas.Agradeço ao Dr. Nelson Zocoler Galante por me orientar em tema inédito em minha formação. A maior parte das concepções deste trabalho e de suas análises foram possíveis pela expertise do Dr. Nelson no tema.Agradeço à Dra. Verônica Coelho por disponibilizar seu laboratório e também por todas as segundas feiras à tarde em que nos encontramos para debater imunologia nestes anos. Agradeço ainda pela oportunidade de discutir a ciência em uma amplitude maior, discutindo temas por vezes, além da biologia.Agradeço à toda equipe do laboratório de imunologia do INCOR com que trabalhei estes anos. Aqui não irei nomear todos grandes colegas para não incorrer no risco de esquecer alguém.Agradeço ainda a equipe de pesquisa clínica da unidade de transplante renal do hospital das clínicas da USP e à equipe do ambulatório de idosos saudáveis do departamento de nefrologia da USP.Agradeço ao Dr. Elias pelo estímulo de todos participantes da unidade de transplante renal em realizarem trabalhos científicos e discussões científicas regulares, viabilizando vários projetos, dentre estes, a presente tese de doutorado. Normalização adotadaEsta dissertação ou tese está de acordo com as seguintes normas, em vigor no momento desta publicação:Referências: adaptado de Associação Brasileira de Normas Técnicas

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Longitudinal Pharmacokinetics of Everolimus When Combined With Low-level of Tacrolimus in Elderly Renal Transplant Recipients

Abstract: Our data indicate that elderly renal transplant recipients starting EVL 1 month after transplantation along with a steady-state TCL level, present stable EVL-PK parameters without significant changes in dose or exposure during the first 6 months after renal transplantation.

Cited by 15 publications

References 26 publications

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 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

Immunosuppression Considerations for Older Kidney Transplant Recipients

Efeitos do uso de globulina antitimócito e de everolimo nas subpopulações de linfócitos T e B do sangue periférico em receptores idosos de transplante renal

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