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1.
Am J Physiol Renal Physiol ; 312(3): F457-F464, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28031169

RESUMO

The hypoxanthine-xanthine oxidase (XO) axis is considered to be a key driver of transplantation-related ischemia-reperfusion (I/R) injury. Whereas interference with this axis effectively quenches I/R injury in preclinical models, there is limited efficacy of XO inhibitors in clinical trials. In this context, we considered clinical evaluation of a role for the hypoxanthine-XO axis in human I/R to be relevant. Patients undergoing renal allograft transplantation were included (n = 40) and classified based on duration of ischemia (short, intermediate, and prolonged). Purine metabolites excreted by the reperfused kidney (arteriovenous differences) were analyzed by the ultra performance liquid chromatography-tandem mass spectrometer (UPLCMS/MS) method and tissue XO activity was assessed by in situ enzymography. We confirmed progressive hypoxanthine accumulation (P < 0.006) during ischemia, using kidney transplantation as a clinical model of I/R. Yet, arteriovenous concentration differences of uric acid and in situ enzymography of XO did not indicate significant XO activity in ischemic and reperfused kidney grafts. Furthermore, we tested a putative association between hypoxanthine accumulation and renal oxidative stress by assessing renal malondialdehyde and isoprostane levels and allantoin formation during the reperfusion period. Absent release of these markers is not consistent with an association between ischemic hypoxanthine accumulation and postreperfusion oxidative stress. On basis of these data for the human kidney we hypothesize that the role for the hypoxanthine-XO axis in clinical I/R injury is less than commonly thought, and as such the data provide an explanation for the apparent limited clinical efficacy of XO inhibitors.


Assuntos
Função Retardada do Enxerto/enzimologia , Hipoxantina/metabolismo , Transplante de Rim/efeitos adversos , Rim/enzimologia , Rim/cirurgia , Traumatismo por Reperfusão/enzimologia , Xantina Oxidase/metabolismo , Adulto , Idoso , Biomarcadores/sangue , Cromatografia Líquida de Alta Pressão , Função Retardada do Enxerto/diagnóstico , Função Retardada do Enxerto/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Espécies Reativas de Oxigênio/sangue , Traumatismo por Reperfusão/diagnóstico , Traumatismo por Reperfusão/etiologia , Transdução de Sinais , Espectrometria de Massas em Tandem , Fatores de Tempo , Resultado do Tratamento , Ácido Úrico/sangue , Xantina Oxidase/sangue
2.
Kidney Int ; 90(1): 181-91, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27188504

RESUMO

Delayed graft function (DGF) following kidney transplantation affects long-term graft function and survival and is considered a manifestation of ischemia reperfusion injury. Preclinical studies characterize metabolic defects resulting from mitochondrial damage as primary driver of ischemia reperfusion injury. In a comprehensive approach that included sequential establishment of postreperfusion arteriovenous concentration differences over the human graft, metabolomic and genomic analysis in tissue biopsies taken before and after reperfusion, we tested whether the preclinical observations translate to the context of clinical DGF. This report is based on sequential studies of 66 eligible patients of which 22 experienced DGF. Grafts with no DGF immediately recovered aerobic respiration as indicated by prompt cessation of lactate release following reperfusion. In contrast, grafts with DGF failed to recover aerobic respiration and showed persistent adenosine triphosphate catabolism indicated by a significant persistently low post reperfusion tissue glucose-lactate ratio and continued significant post-reperfusion lactate and hypoxanthine release (net arteriovenous difference for lactate and hypoxanthine at 30 minutes). The metabolic data for the group with DGF point to a persistent post reperfusion mitochondrial defect, confirmed by functional (respirometry) and morphological analyses. The archetypical mitochondrial stabilizing peptide SS-31 significantly preserved mitochondrial function in human kidney biopsies following simulated ischemia reperfusion. Thus, development of DGF is preceded by a profound post-reperfusion metabolic deficit resulting from severe mitochondrial damage. Strategies aimed at preventing DGF should be focused on safeguarding a minimally required post-reperfusion metabolic competence.


Assuntos
Aloenxertos/patologia , Função Retardada do Enxerto/metabolismo , Sobrevivência de Enxerto , Transplante de Rim/efeitos adversos , Mitocôndrias/patologia , Traumatismo por Reperfusão/complicações , Aloenxertos/metabolismo , Biópsia , Estudos de Coortes , Função Retardada do Enxerto/epidemiologia , Função Retardada do Enxerto/etiologia , Função Retardada do Enxerto/patologia , Feminino , Humanos , Incidência , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Oligopeptídeos/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
3.
Clin Transplant ; 27(6): 799-808, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24127649

RESUMO

Kidney transplantation represents one of the medical achievements of the 20th century. However, its continued success is limited by the increasing shortage of donor grafts. As a result, more kidney grafts from marginal donors are being considered for transplantation, with concomitantly more initial graft injury and limited organ and patient survival. This has led to an increased need for interventions aiming to optimize and preserve graft quality. Interventions within the donor may protect against ischemia/reperfusion injury, and therefore, donor pre-treatment is a promising strategy to increase graft function and survival. During the last decade, diverse donor pre-treatment interventions have been explored in animal studies. Moreover, the first human trials concerning donor pre-treatment in kidney transplantation have provided encouraging results. Unfortunately, it remains difficult to determine how and where to intervene in the multifactorial and complex processes that affect the donor kidney. Moreover, ethical matters play a critical role in donor interventions, and pre-treatment should principally not have any potentially unfavorable effects on other organs to be transplanted or on the living donor. This review provides an overview of promising therapeutical strategies for donor pre-treatment in kidney transplantation and discusses the clinical trials that have been conducted thus far.


Assuntos
Rejeição de Enxerto/prevenção & controle , Transplante de Rim , Traumatismo por Reperfusão/prevenção & controle , Doadores de Tecidos/provisão & distribuição , Sobrevivência de Enxerto , Humanos
5.
Oxid Med Cell Longev ; 2018: 3704129, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30671169

RESUMO

Delayed graft function is an early complication following kidney transplantation with an unclear molecular mechanism. Here we determined whether impaired reactive aldehyde metabolism is associated with delayed graft function. Human kidney biopsies from grafts with delayed graft function were compared with grafts that did not develop delayed graft function by Ingenuity gene pathway analysis. A second series of grafts with delayed graft function (n = 10) were compared to grafts that did not develop delayed graft function (n = 10) by measuring reactive aldehyde metabolism, reactive aldehyde-induced protein adduct formation, and aldehyde dehydrogenase (ALDH) gene and protein expression. In the first series of kidney biopsies, several gene families known for metabolizing reactive aldehydes, such as aldehyde dehydrogenase (ALDH), aldo-keto reductase (AKR), and glutathione-S transferase (GSTA), were upregulated in kidneys that did not develop delayed graft function versus those that did. In the second series of kidney grafts, we focused on measuring aldehyde-induced protein adducts and ALDH enzymatic activity. The reactive aldehyde metabolism by ALDH enzymes was reduced in kidneys with delayed graft function compared to those that did not (37 ± 12∗ vs. 79 ± 5 µg/min/mg tissue, ∗ P < 0.005, respectively). ALDH enzymatic activity was also negatively correlated with length of hospital stay after a kidney transplant. Together, our study identifies a reduced ALDH enzymatic activity with kidneys developing delayed graft function compared to those that did not. Measuring ALDH enzymatic activity and reactive aldehyde-induced protein adducts can potentially be further developed as a biomarker to assess for delayed graft function and recovery from a kidney transplant.


Assuntos
Aldeído Desidrogenase/biossíntese , Aldeídos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Sobrevivência de Enxerto , Transplante de Rim , Rim/metabolismo , Regulação para Cima , Adulto , Aldo-Ceto Redutases/biossíntese , Feminino , Glutationa Transferase/biossíntese , Humanos , Rim/patologia , Masculino , Pessoa de Meia-Idade
6.
EClinicalMedicine ; 4-5: 25-31, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-31193600

RESUMO

BACKGROUND: Despite growing waiting lists for renal transplants, hesitations persist with regard to the use of deceased after cardiac death (DCD) renal grafts. We evaluated the outcomes of DCD donations in The Netherlands, the country with the highest proportion of DCD procedures (42.9%) to test whether these hesitations are justified. METHODS: This study included all procedures with grafts donated after brain death (DBD) (n = 3611) and cardiac death (n = 2711) performed between 2000 and 2017. Transplant outcomes were compared by Kaplan Meier and Cox regression analysis, and factors associated with short (within 90 days of transplantation) and long-term graft loss evaluated in multi-variable analyses. FINDINGS: Despite higher incidences of early graft loss (+ 50%) and delayed graft function (+ 250%) in DCD grafts, 10-year graft and recipient survival were similar for the two graft types (Combined 10-year graft survival: 73.9% (95% CI: 72.5-75.2), combined recipient survival: 64.5% (95 CI: 63.0-66.0%)). Long-term outcome equivalence was explained by a reduced impact of delayed graft function on DCD graft survival (RR: 0.69 (95% CI: 0.55-0.87), p < 0.001). Mid and long-term graft function (eGFR), and the impact of incident delayed graft function on eGFR were similar for DBD and DCD grafts. INTERPRETATION: Mid and long term outcomes for DCD grafts are equivalent to DBD kidneys. Poorer short term outcomes are offset by a lesser impact of delayed graft function on DCD graft survival. This nation-wide evaluation does not justify the reluctance to use of DCD renal grafts. A strong focus on short-term outcome neglects the superior recovery potential of DCD grafts.

8.
Antioxid Redox Signal ; 19(6): 535-45, 2013 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-23305329

RESUMO

AIMS: Ischemia/reperfusion (I/R) injury is a common clinical problem. Although the pathophysiological mechanisms underlying I/R injury are unclear, oxidative damage is considered a key factor in the initiation of I/R injury. Findings from preclinical studies consistently show that quenching reactive oxygen and nitrogen species (RONS), thus limiting oxidative damage, alleviates I/R injury. Results from clinical intervention studies on the other hand are largely inconclusive. In this study, we systematically evaluated the release of established biomarkers of oxidative and nitrosative damage during planned I/R of the kidney and heart in a wide range of clinical conditions. RESULTS: Sequential arteriovenous concentration differences allowed specific measurements over the reperfused organ in time. None of the biomarkers of oxidative and nitrosative damage (i.e., malondialdehyde, 15(S)-8-iso-prostaglandin F2α, nitrite, nitrate, and nitrotyrosine) were released upon reperfusion. Cumulative urinary measurements confirmed plasma findings. As of these negative findings, we tested for oxidative stress during I/R and found activation of the nuclear factor erythroid 2-related factor 2 (Nrf2), the master regulator of oxidative stress signaling. INNOVATION: This comprehensive, clinical study evaluates the role of RONS in I/R injury in two different human organs (kidney and heart). Results show oxidative stress, but do not provide evidence for oxidative damage during early reperfusion, thereby challenging the prevailing paradigm on RONS-mediated I/R injury. CONCLUSION: Findings from this study suggest that the contribution of oxidative damage to human I/R may be less than commonly thought and propose a re-evaluation of the mechanism of I/R.


Assuntos
Traumatismo por Reperfusão Miocárdica/metabolismo , Estresse Oxidativo , Adulto , Idoso , Biomarcadores/sangue , Dinoprosta/análogos & derivados , Dinoprosta/sangue , Dinoprostona/urina , Feminino , Expressão Gênica , Regulação da Expressão Gênica , Valvas Cardíacas/cirurgia , Humanos , Rim/metabolismo , Rim/cirurgia , Transplante de Rim , Masculino , Malondialdeído/sangue , Pessoa de Meia-Idade , Miocárdio/metabolismo , Miocárdio/patologia , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/metabolismo , Elementos de Resposta
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