RESUMO
BACKGROUND: Deceased donor kidneys with acute kidney injury (AKI) are often discarded because of concerns about inferior transplant outcomes. A means of grading the quality of such kidneys is the performance of procurement biopsies. METHODS: This is a retrospective study of 221 brain death donors with marginal kidneys transplanted in 223 recipients in Germany. Marginal kidneys were defined as kidneys with procurement biopsies done exceptionally to assess suitability for transplantation in otherwise potentially discarded organs. The impact of deceased donor AKI on patient survival and death-censored graft survival at 1, 3 and 5 years and graft function at 1 and 3 years after transplantation was investigated. RESULTS: Recipients of kidneys with stage 3 AKI had a greater incidence of delayed graft function [DGF; ORStage 1: 1.435 (95% CI 0.438-0.702), ORStage 2: 2.463 (95% CI 0.656-9.245), ORStage 3: 4.784 (95% CI 1.421-16.101)] but a similar graft and patient survival compared to recipients of donors without AKI and with AKI stage 1 and 2 as well. The coexistence of recipient DGF and donor AKI was associated with the lowest graft survival and function rates. CONCLUSION: The transplantation of deceased donor marginal kidneys with AKI confers a higher risk for DGF but is associated with acceptable graft and patient outcomes, which do not differ in comparison with marginal donor kidneys without AKI. Graft prognosis is especially poor if donor AKI and recipient DGF concur. Donor AKI was a risk factor independent of the histological lesions of procurement biopsies.
Assuntos
Injúria Renal Aguda , Transplante de Rim , Obtenção de Tecidos e Órgãos , Humanos , Estudos Retrospectivos , Doadores de Tecidos , Rim , Sobrevivência de Enxerto , Biópsia , Função Retardada do Enxerto/epidemiologiaRESUMO
Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) comprises a group of multisystem disorders involving severe, systemic, small-vessel vasculitis with short- and long term serious and life-threating complications. Despite the simplification of treatment, fundamental aspects concerning assessment of its efficacy and its adaptation to encountered complications or to the relapsing/remitting/subclinical disease course remain still unknown. The pathogenesis of AAV is complex and unique, and despite the progress achieved in the last years, much has not to be learnt. Foremost, there is still no accurate marker enabling us to monitoring disease and guide therapy. Therefore, the disease management relays often on clinical judgment and follows a" trial and error approach". In the recent years, an increasing number of new molecules s have been explored and used for this purpose including genomics, B- and T-cell subpopulations, complement system factors, cytokines, metabolomics, biospectroscopy and components of our microbiome. The aim of this review is to discuss both the role of known historical and clinically established biomarkers of AAV, as well as to highlight potential new ones, which could be used for timely diagnosis and monitoring of this devastating disease, with the goal to improve the effectiveness and ameliorate the complications of its demanding therapy.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Metabolômica , Humanos , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , GenômicaRESUMO
INTRODUCTION: Predicting outcome after transplantation of marginal kidneys is a challenging task. Donor creatinine or estimated glomerular filtration rate (eGFR) are integral components of the respective risk scores. However, there is uncertainty on which of their values obtained successively during procurement is the most suitable. MATERIAL AND METHODS: This is a retrospective study of 221 adult brain death donors with marginal kidneys, transplanted in 223 recipients. We applied logistic regression analysis to investigate the association between initial (at hospital admission), nadir (lowest), zenith (highest) and terminal (at recovery) donor eGFR with primary non-function (PNF), delayed graft function (DGF), 3- and 12-month graft function and 1- and 3-year patient- and death-censored graft survival. RESULTS: In the multivariate analysis, admission, terminal, and the lowest donor eGFR could most accurately predict DGF. The respective ORs [95% CI] were: 0.875 [0.771-0.993], 0.818 [95% CI: 0.726-0.922] and 0.793 [0.689-0.900]. Although not being significant for DGF (OR 0.931 [95% CI: 0.817-1.106]), the highest eGFR was the best predictor of 3-month graft function (adjusted b coefficient 1.161 [95% CI: 0.355-1.968]). Analysis of primary nonfunction showed that determination of initial and the highest eGFR proved to be the best predictors. The respective ORs [95% CI] were: 0.804 [0.667-0.968] and 0.750 [0.611-0.919]. There were no differences in the risk associations of each of the four eGFR recordings with patient- and graft survival. CONCLUSION: The various eGFR recordings determined during the procurement process of marginal donors can predict PNF, DGF and 3- and 12-month graft function. Regarding short-term patient- and graft survival, there appears to be impacted by recipient factors rather than donor kidney function.
Assuntos
Transplante de Rim , Adulto , Humanos , Creatinina , Função Retardada do Enxerto/diagnóstico , Função Retardada do Enxerto/etiologia , Sobrevivência de Enxerto , Rim , Transplante de Rim/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Doadores de TecidosRESUMO
Human cytomegalovirus infections have a major negative effect on morbidity and mortality of immunosuppressed allograft recipients and indirectly on graft function and survival. The adoptive antiviral T-cell therapy is a novel therapeutic tool to restore immune competence after solid organ transplantation. Till now, the antiviral T-cell products mainly focused on cytotoxic CD8(+) T cells, whereas CD4(+) T cells played a minor role. Here, we demonstrate the importance of CD4(+) T cells within T-cell lines specific for human cytomegalovirus besides its essential support for the quality of CD8(+) T-cell memory. Virus-specific CD4(+) T cells elicit profound functionality after rechallenge (multicytokine secretors, CD137, CD154, and CD107a expression and killing of infected target cells). The CD4(+) T cells show predominantly a Th1 phenotype with cytolytic properties that is mainly perforin-dependent. The data demonstrate the significance of CD4(+) T cells within T-cell products to achieve a successful adoption with enhanced efficacy.
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Linfócitos T CD4-Positivos/imunologia , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/terapia , Citomegalovirus/imunologia , Imunoterapia Adotiva , Linfócitos T CD4-Positivos/transplante , Ligante de CD40/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/transplante , Terapia Baseada em Transplante de Células e Tecidos , Células Cultivadas , Infecções por Citomegalovirus/virologia , Humanos , Proteína 1 de Membrana Associada ao Lisossomo/metabolismo , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismoRESUMO
Effector memory T cells are effective in controlling acute infections, but central memory T cells play a key role in long-lasting protection against viruses and tumors. In vivo/in vitro challenge by Ag commonly supports the generation of effector memory T cells with limited longevity. To our knowledge, this study demonstrates for the first time in the human system and under rechallenge conditions that targeting IL-2R by partial mammalian target of rapamycin inhibition or blocking IL-2Rα enriches human CD4(+)/CD8(+) central memory T cells within the virus-specific T cell product associated with enhanced functionality (i.e., multicytokine secretors, including IL-2; enhanced CD137 and CD107a expression on CD8(+) and CD4(+) T cells, respectively; and killing infected target cells). Remarkably, the effects on CD8(+) T cells are mainly mediated via the enhancement of CD4(+) T cell function. The data reveal new insights into the role of CD4(+) T cell support for the quality of CD8(+) T cell memory, even under rechallenge conditions. Moreover, our method offers a new approach to improve the long-lasting efficacy of adoptive T cell therapy in patients.
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Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Infecções por Citomegalovirus/imunologia , Memória Imunológica , Subunidade alfa de Receptor de Interleucina-2/fisiologia , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/virologia , Linfócitos T CD4-Positivos/patologia , Células Cultivadas , Infecções por Citomegalovirus/metabolismo , Infecções por Citomegalovirus/patologia , Humanos , Subunidade alfa de Receptor de Interleucina-2/antagonistas & inibidores , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Subpopulações de Linfócitos T/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidoresRESUMO
After being activated by antigen, helper T lymphocytes switch from a resting state to clonal expansion. This switch requires inactivation of the transcription factor Foxo1, a suppressor of proliferation expressed in resting helper T lymphocytes. In the early antigen-dependent phase of expansion, Foxo1 is inactivated by antigen receptor-mediated post-translational modifications. Here we show that in the late phase of expansion, Foxo1 was no longer post-translationally regulated but was inhibited post-transcriptionally by the interleukin 2 (IL-2)-induced microRNA miR-182. Specific inhibition of miR-182 in helper T lymphocytes limited their population expansion in vitro and in vivo. Our results demonstrate a central role for miR-182 in the physiological regulation of IL-2-driven helper T cell-mediated immune responses and open new therapeutic possibilities.
Assuntos
Interleucina-2/imunologia , MicroRNAs/imunologia , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Artrite/imunologia , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: High-mobility group box-1 (HMGB-1) protein is released during "late sepsis" by activated monocytes. We investigated whether systemic HMGB-1 levels are associated with indices of monocytic activation/function in patients with sepsis-induced immunosuppression. METHODOLOGY: 36 patients (31 male, 64 +/- 14 years) with severe sepsis/septic shock and monocytic deactivation (reduced mHLA-DR expression and TNF-alpha release) were assessed in a subanalysis of a placebo-controlled immunostimulatory trial using GM-CSF. HMGB-1 levels were assessed over a 9-day treatment interval. Data were compared to standardized biomarkers of monocytic immunity (mHLA-DR expression, TNF-alpha release). PRINCIPLE FINDINGS: HMGB-1 levels were enhanced in sepsis but did not differ between treatment and placebo groups at baseline (14.6 +/- 13.5 versus 12.5 +/- 11.5 ng/ml, P = .62). When compared to controls, HMGB-1 level increased transiently in treated patients at day 5 (27.8 +/- 21.7 versus 11.0 +/- 14.9, P = .01). Between group differences were not noted at any other point of assessment. HMGB-1 levels were not associated with markers of monocytic function or clinical disease severity. CONCLUSIONS: GM-CSF treatment for sepsis-induced immunosuppression induces a moderate but only transient increase in systemic HMGB-1 levels. HMGB-1 levels should not be used for monitoring of monocytic function in immunostimulatory trials as they do not adequately portray contemporary changes in monocytic immunity.
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Proteína HMGB1/sangue , Tolerância Imunológica , Monócitos/fisiologia , Sepse/imunologia , Adulto , Idoso , Citocinas/sangue , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) controls tryptophan metabolism and is induced by pro-inflammatory stimuli. We investigated whether immunostimulatory treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF) influences IDO activity and tryptophan metabolism in sepsis. Thirty-six patients with severe sepsis/septic shock and sepsis-associated immunosuppression (assessed using monocytic human leukocyte antigen-DR (mHLA-DR) expression) were assessed in a controlled trial of GM-CSF or placebo treatment for 8 days. Using tandem mass spectrometry, levels of tryptophan, kynurenine, kynurenic acid, quinolinic acid, 5-hydroxytryptophan, serotonin, and estimated IDO activity were determined in a blinded fashion over a 9-day interval. At baseline, tryptophan and metabolite levels did not differ between the study groups. Although tryptophan levels were unchanged in both groups over the treatment interval (all p>0.8), IDO activity was markedly reduced after GM-CSF treatment (35.4 +/- 21.0 vs 21.6 +/-9.9 (baseline vs day 9), p = 0.02). IDO activity differed significantly between the 2 groups after therapy (p = 0.03). Metabolites downstream of IDO (kynurenine, quinolinic acid, kynurenic acid) were all induced in sepsis and declined in the GM-CSF group, but not in controls. Serotonin pathway metabolites remained unchanged in both groups (all p>0.15). Moreover, IDO activity correlated with procalcitonin (p< 0.0001, r = 0.56) and mHLA-DR levels (p = 0.005, r = -0.28) in the overall samples group. Thus, GM-CSF therapy is associated with decreased IDO activity and reduced kynurenine pathway catabolites in sepsis. This may be due to an improved antibacterial defence.