Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.548
Filtrar
1.
Am J Cardiol ; 125(3): 436-440, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31812226

RESUMO

This retrospective study analyzed glycemic trends, incidence of post-transplant diabetes mellitus (PTDM) incidence and associated risk factors in a cohort of patients who underwent first-time heart transplantation (HT). Univariate analyses compared patient with and without pretransplant diabetes mellitus (DM). Multivariate regression analyses were conducted to determine association between PTDM and different risk factors. Finally, trends in glucometrics and other outcomes are described across follow-up time points. There were 152 patients who underwent HT between 2010 and 2015, 109 of whom had no pretransplant history of DM. PTDM incidence was 38% by the 1-year follow-up. Pretransplant body mass index (odds ratio [OR] 1.12, 95% confidence interval [CI] 1.01 to 1.23, p = 0.03), insulin use during the final 24 hours of inpatient stay (OR 4.26, 95% CI 1.72 to 10.56, p <0.01), mean inpatient glucose (OR 2.21, 95% CI 1.33 to 3.69, p <0.01), and mean glucose in the final 24 hours before discharge (OR 1.29, 95% CI 1.03 to 1.60, p = 0.03) were associated with increased odds of PTDM at 1 year. In patients on insulin before discharge, blood glucose values were significantly higher compared with those who were not (136 mg/dl vs 114 mg/dl at 1 to 3 months, 112 vs 100 at 4 to 6 months, 109 vs 98 at 8 to 12 months, all p <0.01). This analysis improves understanding of PTDM incidence, glucometric trends, and risk differences by DM status in the HT population. Similar to liver and kidney patients, inpatient glucometrics may be informative of PTDM risk in HT patients. Guidelines for this population should be developed to account for risk heterogeneity and need for differential management.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus/epidemiologia , Hemoglobina A Glicada/metabolismo , Rejeição de Enxerto/complicações , Transplante de Coração/efeitos adversos , Medição de Risco/métodos , Biomarcadores/sangue , Diabetes Mellitus/sangue , Diabetes Mellitus/etiologia , Feminino , Seguimentos , Rejeição de Enxerto/sangue , Humanos , Incidência , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Fatores de Risco , Estados Unidos/epidemiologia
2.
Artif Organs ; 44(1): 100-105, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31429943

RESUMO

Rejection with severe hemodynamic compromise is a significant source of morbidity and mortality for pediatric heart transplant patients. Traditionally, treatment for these patients includes inotropes and escalation to extracorporeal membrane oxygenation (ECMO) when necessary. There is increasing interest in using percutaneous ventricular assistive devices in the pediatric population as a less invasive alternative to ECMO. We report the largest case series to date of biventricular support using percutaneous Impella devices. Retrospective case series was performed by chart review. Hemodynamics, left ventricular ejection fraction (LVEF), and indices of end organ function were collected before and after Impella placement. A 14-year-old male, 18-year-old male, and 19-year-old female, all status post heart transplant, presented with severely decreased biventricular function due to presumed clinical rejection, requiring maximal inotropic support without improvement. In all the three cases, simultaneous Impella CP and RP devices were placed percutaneously. Prior to implantation, LVEFs were 40%, 23%, and 25%, respectively. Hemodynamics measured invasively prior to device placement showed elevated filling pressures. Adverse events while on support included bleeding, hemolysis, and right femoral arterial dissection during implantation. All patients were successfully weaned from the devices and survived to discharge. The average time of right-sided support and total support was 11 days and 13 days, respectively. After device removal, right-sided pressures and echocardiographic measurements showed improvement in all patients. Bilateral Impella configuration (BiPella) is a viable option for temporary mechanical circulatory support in pediatric patients with significant graft dysfunction.


Assuntos
Transplante de Coração , Ventrículos do Coração/fisiopatologia , Coração Auxiliar , Adolescente , Adulto , Remoção de Dispositivo , Feminino , Rejeição de Enxerto/sangue , Rejeição de Enxerto/fisiopatologia , Transplante de Coração/efeitos adversos , Coração Auxiliar/efeitos adversos , Hemodinâmica , Humanos , Masculino , Estudos Retrospectivos , Adulto Jovem
3.
Ren Fail ; 42(1): 40-47, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31875761

RESUMO

Background: De novo Donor Specific Antibodies (DSA) are considered as a risk factor for the kidney allograft outcomes in recipients after simultaneous liver-kidney transplantation (SLKT). We hypothesized that length of hospital stay (LOS) might be associated with de novo DSA development of due to the increased likelihood of receiving blood transfusions with reduced immunosuppressive regimens.Methods: This study is a single-center, retrospective cohort study consisting of 85 recipients who underwent SLKT from 2009 to 2018 in our hospital. We divided the patients into two groups according to LOS [long hospital stay (L) group (LOS >14 days) and short hospital stay (S) group (LOS ≤14 days)]. Propensity score (PS) has been created using logistic regression to predict LOS greater than median of 14 days. The association between the presence of de novo DSA and LOS was assessed by logistic regression models adjusted for PS.Results: The mean age at transplantation of the entire cohort was 55.5 ± 10.1 years. Sixty percent of the recipients were male and Caucasian. Median LOS in (L) group was three-fold longer than (S) group [L: median 30 days (IQR: 21-52), S: median 8.5 days (IQR: 7-11)]. Eight patients developed de novo DSA after SLKT (9.4%), all of them were in (L) group. Longer LOS was significantly associated with higher risk of development of de novo DSA in unadjusted (OR+ each 5 days: 1.09, 95% CI:1.02-1.16) and PS adjusted (OR+ each 5 days: 1.11, 95% CI:1.02-1.21) analysis.Conclusion: Longer hospitalization is significantly associated with the development of de novo DSA in SLKT.


Assuntos
Rejeição de Enxerto/epidemiologia , Isoanticorpos/sangue , Transplante de Rim/efeitos adversos , Tempo de Internação/estatística & dados numéricos , Transplante de Fígado/efeitos adversos , Adulto , Idoso , Aloenxertos/imunologia , Transfusão de Sangue/estatística & dados numéricos , Feminino , Rejeição de Enxerto/sangue , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/administração & dosagem , Incidência , Isoanticorpos/imunologia , Isoantígenos/imunologia , Rim/imunologia , Fígado/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo
4.
PLoS One ; 14(12): e0226369, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31821367

RESUMO

BACKGROUND: This study was performed to determine the association between the ratio of C-reactive protein to albumin (CRP/ALB) and the risk of early allograft dysfunction (EAD) in patients undergoing living donor liver transplantation (LDLT). PATIENTS AND METHODS: A total of 588 adult patients undergoing LDLT were retrospectively investigated, after 22 were excluded because of signs of overt infection or history of ALB infusion. The study population was classified into high and low CRP/ALB ratio groups according to EAD. All laboratory variables, including CRP and ALB, had been collected on the day before surgery. A percentage value for the CRP/ALB ratio (%) was calculated as CRP/ALB × 100. RESULTS: After LDLT, 83 patients (14.1%) suffered EAD occurrence. A higher CRP/ALB ratio was independently associated with risk of EAD, Model for End-stage Liver Disease score, fresh frozen plasma transfusion, and donor age. Based on a cutoff CRP/ALB ratio (i.e., > 20%), the probability of EAD was significantly (2-fold) higher in the high versus low CRP/ALB group. The predictive utility of CRP/ALB ratio for EAD was greater than those of other inflammatory markers. In addition, patients with a high CRP/ALB ratio had poorer survival than those with a low CRP/ALB ratio during the follow-up period. CONCLUSIONS: The easily calculated CRP/ALB ratio may allow estimation of the risk of EAD after LDLT and can provide additional information that may facilitate the estimation of a patient's overall condition.


Assuntos
Albuminas/análise , Aloenxertos , Proteína C-Reativa/análise , Rejeição de Enxerto/sangue , Infecções/sangue , Transplante de Fígado/efeitos adversos , Fígado/cirurgia , Biomarcadores/sangue , Feminino , Humanos , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
6.
Transplant Proc ; 51(8): 2671-2675, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31477419

RESUMO

OBJECTIVE: Delta neutrophil index (DNI), representing an elevated fraction of circulating immature granulocyte in acute infection, has been reported as a useful, predictable marker for mortality in patients with sepsis. We have hypothesized that an increased recipient DNI is associated with poor prognosis in cadaver donor kidney transplantation. METHODS: We investigated patients undergoing kidney transplantation from cadaver donors from March 2013 to January 2018. Rejection was diagnosed by kidney biopsy with Banff classification and excluded subclinical rejection. RESULTS: In a total of 73 patients undergoing cadaver kidney transplantation, 25 (34.2%) patients were diagnosed with rejection based on the Banff classification. Among them, 11 patients were diagnosed with early rejection. The recipients' postoperative DNI (%) was different between patients with early rejection and patients without rejection (0.18 vs 1.21, P < .001). In the univariate logistic regression analysis, cold ischemic time, donor preoperative last creatinine level, postoperative DNI level, and perioperative infection were predictive of early rejection. However, in a multivariate adjusted logistic regression test, only a high level of DNI (odds ratio 12.307, 95% confidence interval [CI] 1.22-129.82) was associated with early rejection. The C-statistic was 0.777 (95% CI 0.604-0.951, P = .004) for DNI. In multivariate Cox regression analysis, the donor's last creatinine level (hazard ratio 2.25, 95% CI 1.26-4.13) and preoperative DNI (hazard ratio 14.02 95% CI 2.62-75.26) were predictors of renal survival. CONCLUSIONS: Increased DNI in cadaver donor kidney transplantation recipients might be one of the predictive values of early kidney rejection and prognosis.


Assuntos
Rejeição de Enxerto/sangue , Transplante de Rim , Neutrófilos/citologia , Neutrófilos/imunologia , Adulto , Cadáver , Feminino , Rejeição de Enxerto/imunologia , Humanos , Transplante de Rim/métodos , Transplante de Rim/mortalidade , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Doadores de Tecidos
7.
Transplant Proc ; 51(8): 2750-2754, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31563245

RESUMO

BACKGROUND AND AIMS: Postoperative hypoalbuminemia, especially following liver transplantation, can lead to adverse multisystem effects and even death. We investigated the relationship between postoperative albumin levels and organ failure (assessed using Sequential Organ Failure Assessment [SOFA] scores). METHODS: Sixty liver transplant recipients admitted to the intensive care unit (ICU) from 2012 to 2015 were retrospectively divided into 2 groups: lower albumin (LA) (n=28) and higher albumin (HA) (n=32), using whether serum albumin level fell below 3.0 g/dL during the first postoperative week as the stratifying factor. The SOFA scores (primary endpoint) and associated complications (ascites amount, rejection, re-intubation, abdominal re-operation, thrombosis), additional treatment (dialysis, pleural effusion drainage), and duration of ICU stay (secondary endpoints) of the 2 groups were compared. RESULTS: Average serum albumin levels were significantly different between HA and LA groups (3.6 [3.4-3.8] vs 3.1 [2.9-3.3], respectively, P<.05), although the amounts of albumin infused in the 2 groups during the first postoperative week were not different (HA vs LA: 42 [30-71] vs 40 [30-58], respectively, P=.37). Mean daily SOFA scores were not significantly different between the HA and LA groups (8.3 [6.6-9.0] vs 7.2 [6.3-8.6], P=.73), although the HA group had lower mean cardiovascular SOFA sub-scores than the LA group (0.1 [0-0.4] vs 0.4 [0-1.3], P=.032). There were no significant differences between the groups with regard to complication rates and duration of ICU and hospital stays. CONCLUSIONS: Serum albumin level might not influence cumulative organ function, but it decreases the amount of hemodynamic support required in liver transplant recipients.


Assuntos
Rejeição de Enxerto/sangue , Transplante de Fígado , Albumina Sérica/análise , Adulto , Feminino , Sobrevivência de Enxerto/fisiologia , Humanos , Hipoalbuminemia/etiologia , Transplante de Fígado/efeitos adversos , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Período Pós-Operatório , Estudos Retrospectivos
8.
J Pharm Biomed Anal ; 176: 112799, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31394306

RESUMO

Electrochemistry (EC) coupled with liquid chromatography and tandem mass spectrometry (HPLC/ESI-MS/MS) was used to study the oxidation products of cyclosporine A (CYC), everolimus (EWE), mycophenolic acid (MFA), sirolimus (SIR) and tacrolimus (TAK). Mimicry of the oxidative phase I and II metabolism was achieved in a thin-layer cell equipped with a boron doped diamond (BDD) working electrode. Structures of the electrochemically generated products were elucidated on the basis of MS/MS experiments. Additionally, a sensitive, specific and rapid HPLC-MS/MS method has been developed and validated for the quantification of selected drugs and their metabolites in human serum. Sample preparation was accomplished through microextraction by packed sorbent (MEPS) process. Finally, the identification of electrochemical products was done and results were compared with known metabolites of studied immunosuppressant drugs. Electrochemical conversion of target compounds has appeared as a new pseudo-in vitro instrumental technology for the prediction of potential metabolites, since the oxidation products have also been identified in serum samples.


Assuntos
Monitoramento de Medicamentos/métodos , Técnicas Eletroquímicas/métodos , Rejeição de Enxerto/sangue , Imunossupressores/sangue , Idoso , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Monitoramento de Medicamentos/instrumentação , Técnicas Eletroquímicas/instrumentação , Eletrodos , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/isolamento & purificação , Imunossupressores/metabolismo , Pessoa de Meia-Idade , Transplante de Órgãos/efeitos adversos , Oxirredução , Sensibilidade e Especificidade , Espectrometria de Massas por Ionização por Electrospray/instrumentação , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/instrumentação , Espectrometria de Massas em Tandem/métodos
9.
Transplant Proc ; 51(6): 1699-1705, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31399160

RESUMO

BACKGROUND: Rejection and infection are 2 major complications affecting the health and survival of patients receiving an allograft organ transplantation. We describe a diagnostic assay that simultaneously monitors for rejection and infection in recipients of kidney transplant by sequencing of cell-free DNA (cfDNA) in plasma. METHODS: By using cfDNA in plasma, we established a noninvasive method that simultaneously monitors rejection and infection in patients with a history of organ transplant. A total of 6200 single-nucleotide polymorphisms were captured by liquid hybridization and sequenced by next-generation sequencing. The donor-derived cfDNA (ddcfDNA) level was calculated based on maximum likelihood estimation, without relying on the donor's genotype. We also analyzed the nonhuman cfDNA to test for infections in the patients' plasma. RESULTS: Artificial ddcfDNA levels quantified by a donor-dependent and donor-independent algorithm were significantly correlated, with the multivariate coefficient of determination, or R2 value, of 0.999. This technique was applied on 30 patients (32 samples) after kidney transplantation, and a significant difference was observed on the ddcfdNA levels between nonrejection and rejection. Furthermore, 1 BK virus infection and 1 cytomegalovirus infection were revealed by this method, and the enrichment efficiency of the viral sequences was 114 and 489 times, respectively, which are consistent with clinical results. CONCLUSION: This method can be used to simultaneously monitor for acute rejection as well as a broad spectrum of infections for patients of allograft organ transplant because it provides comprehensive information for clinicians to optimize immunosuppression therapy.


Assuntos
Ácidos Nucleicos Livres/sangue , Rejeição de Enxerto/diagnóstico , Infecções/diagnóstico , Transplante de Órgãos/efeitos adversos , Complicações Pós-Operatórias/diagnóstico , Adulto , Algoritmos , Feminino , Rejeição de Enxerto/sangue , Humanos , Hospedeiro Imunocomprometido , Infecções/sangue , Infecções/imunologia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/sangue
10.
J Cancer Res Clin Oncol ; 145(11): 2779-2791, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31446489

RESUMO

PURPOSE: To evaluate serum procalcitonin (PCT) and C-reactive protein (CRP) as diagnostic biomarkers of transplant-related adverse events (TRAE) in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT). METHODS: This study analyzed PCT and CRP levels of 214 pediatric patients with a median age of 8.5 years (0.4-17.8 years) undergoing allogeneic HSCT with respect to major TRAE. RESULTS: 26 patients (12.1%) did not experience TRAE (control group), and 188 (87.9%) experienced median 2 (range 1-4) TRAE. Median CRP and PCT were highly and significantly increased during sepsis/SIRS and bacteremia (17.24 mg/dl | 6.30 ng/ml; p < 0.0001 vs. prior values), graft rejection (14.73 mg/dl | 3.20 ng/ml; p < 0.0001), and liver GvHD (6.88 mg/dl | 2.29 ng/ml; p < 0.01). Strong CRP increases and slight/minimal/no PCT increases occurred during fungemia (8.85 mg/dl | 0.72 ng/ml; p < 0.001), intestinal GvHD (8.73 mg/dl | 1.06 ng/ml; p < 0.0001), VOD (10.84 mg/dl | 0.59 ng/ml; p < 0.01), mucositis (8.84 mg/dl | 0.81 ng/ml; p < 0.0001), and viremia (3.62 mg/dl; p < 0.0001 | 0.43 ng/ml; below normal limit). During skin GvHD, CRP and PCT were slightly increased (2.03 mg/dl | 0.93 ng/ml; p < 0.0001). CONCLUSIONS: CRP and PCT did not show congruent changes during TRAE. PCT was a clinically relevant marker for the early detection and differentiation of severe mucositis and sepsis/SIRS and bacteremia during the critical neutropenic period after HSCT. PCT helped to discriminate acute intestinal GvHD from adenovirus viremia and liver GvHD from hepatic VOD. Thus, PCT may be a valuable parameter to enable a prompt and appropriate treatment during these complications, improving patient outcomes.


Assuntos
Bacteriemia/diagnóstico , Proteína C-Reativa/análise , Rejeição de Enxerto/diagnóstico , Doença Enxerto-Hospedeiro/diagnóstico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Pró-Calcitonina/sangue , Sepse/diagnóstico , Adolescente , Bacteriemia/sangue , Bacteriemia/etiologia , Biomarcadores/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Diagnóstico Precoce , Feminino , Seguimentos , Rejeição de Enxerto/sangue , Rejeição de Enxerto/etiologia , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/terapia , Humanos , Lactente , Masculino , Prognóstico , Estudos Retrospectivos , Sepse/sangue , Sepse/etiologia , Transplante Homólogo
11.
EBioMedicine ; 46: 463-472, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31378695

RESUMO

BACKGROUND: Antibody-mediated rejection, a leading cause of renal allograft graft failure, is diagnosed by histological assessment of invasive allograft biopsies. Accurate non-invasive biomarkers are not available. METHODS: In the multicentre, prospective BIOMARGIN study, blood samples were prospectively collected at time of renal allograft biopsies between June 2011 and August 2016 and analyzed in three phases. The discovery and derivation phases of the study (N = 117 and N = 183 respectively) followed a case-control design and included whole genome transcriptomics and targeted mRNA expression analysis to construct and lock a multigene model. The primary end point was the diagnostic accuracy of the locked multigene assay for antibody-mediated rejection in a third validation cohort of serially collected blood samples (N = 387). This trial is registered with ClinicalTrials.gov, number NCT02832661. FINDINGS: We identified and locked an 8-gene assay (CXCL10, FCGR1A, FCGR1B, GBP1, GBP4, IL15, KLRC1, TIMP1) in blood samples from the discovery and derivation phases for discrimination between cases with (N = 49) and without (N = 134) antibody-mediated rejection. In the validation cohort, this 8-gene assay discriminated between cases with (N = 41) and without antibody-mediated rejection (N = 346) with good diagnostic accuracy (ROC AUC 79·9%; 95% CI 72·6 to 87·2, p < 0·0001). The diagnostic accuracy of the 8-gene assay was retained both at time of stable graft function and of graft dysfunction, within the first year and also later after transplantation. The 8-gene assay is correlated with microvascular inflammation and transplant glomerulopathy, but not with the histological lesions of T-cell mediated rejection. INTERPRETATION: We identified and validated a novel 8-gene expression assay that can be used for non-invasive diagnosis of antibody-mediated rejection. FUNDING: The Seventh Framework Programme (FP7) of the European Commission.


Assuntos
Anticorpos/imunologia , Biomarcadores , Ácidos Nucleicos Livres , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/etiologia , Transplante de Rim/efeitos adversos , RNA Mensageiro/genética , Adulto , Feminino , Rejeição de Enxerto/sangue , Humanos , Biópsia Líquida , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , RNA Mensageiro/sangue , Curva ROC , Reprodutibilidade dos Testes , Transplante Homólogo
12.
Ther Drug Monit ; 41(4): 528-532, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31259882

RESUMO

BACKGROUND: There are inconsistent findings regarding the relationship between trough whole blood tacrolimus concentration (TAC C0) and acute kidney rejection in recipients undergoing TAC therapeutic drug monitoring (TDM). However, studies have not always assessed TAC C0 at the time of rejection or accounted for variability in hematocrit. Therefore, this study aimed to investigate the temporal relationship between TAC C0 and acute rejection, including when accounting for variation in hematocrit. METHODS: For 38 recipients who developed biopsy-proven acute rejection (BPAR) in the first 14 days after kidney transplantation, daily TAC C0 from TDM and hematocrit was collected from case notes. Differences in log10-transformed TAC C0 between the day of BPAR (log Cr), 1 day before BPAR (log Cr-1), and 2 days before BPAR (log Cr-2) and the combined median concentrations for the days preceding these (log Cprior) were examined by repeated-measures analysis of variance with Dunnett post hoc testing. Generalized linear mixed-effects regression (glmer) examined the ability of TAC C0 to predict acute rejection episodes with and without controlling for hematocrit. RESULTS: Log Cr-1 [mean difference (95% confidence interval) = -0.13 (-0.21 to -0.048), post hoc P = 0.002] and log Cr [-0.13 (-0.24 to -0.025), post hoc P = 0.013] were significantly lower than log Cprior. TAC C0 was a significant (P = 0.0078) predictor of rejection episodes (area under the receiver operating characteristic curve = 0.79) only in glmer models accounting for variability in hematocrit. CONCLUSIONS: In recipients who developed BPAR, there was a significant temporal relationship between TAC C0 and BPAR incidence under TAC TDM that may not be detected in cross-sectional studies, especially if variability in hematocrit is not addressed. This supports a TAC C0-rejection relationship, which differs between recipients, and may explain why some recipients do or do not experience rejection within or below the TDM range, respectively. However, studies with larger sample sizes are needed to confirm this finding.


Assuntos
Rejeição de Enxerto/sangue , Imunossupressores/sangue , Tacrolimo/sangue , Monitoramento de Medicamentos/métodos , Humanos , Transplante de Rim , Fatores de Tempo
13.
J Thorac Cardiovasc Surg ; 157(5): 2096-2106, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31288367

RESUMO

OBJECTIVE: Lung transplantation is therapeutic for end-stage lung disease, but survival is limited due to bronchiolitis obliterans syndrome and restrictive chronic lung allograft dysfunction. We sought a common denominator in lung transplant recipients, analyzing risk factors that trigger immune responses that lead to bronchiolitis obliterans syndrome. METHODS: We collected blood from patients who underwent lung transplant at our institution. Exosomes were isolated from the sera of recipients with risk factors for chronic rejection and from stable recipients. Exosomes were analyzed with western blot, using antibodies to lung self-antigens K alpha 1 tubulin and collagen-V, costimulatory molecules (costimulatory molecule 80, costimulatory molecule 86), transcription factors (nuclear factor kappa-light-chain-enhancer of activated B cells, hypoxia-inducible factor 1α, Class II Major Histocompatibility Complex Transactivator), and 20S proteasome. RESULTS: Of the 90 patients included, we identified 5 with grade 3 primary graft dysfunction, 5 without, 15 with respiratory viral infection, 10 with acute rejection, 10 with donor-specific antibodies (DSA), 5 without DSA, and 10 who were stable for exosome isolation. Recipients with grade 3 primary graft dysfunction, respiratory viral infection, acute rejection, and DSA had exosomes containing self-antigens; exosomes from stable recipients did not. Exosomes from recipients with grade 3 primary graft dysfunction, acute rejection, and DSA also demonstrated costimulatory molecule 80, costimulatory molecule 86, major histocompatibility complex class II, transcription factor, and 20S proteasome. CONCLUSIONS: Transplanted lungs with grade 3 primary graft dysfunction, symptomatic respiratory viral infection, acute rejection, and immune responses induce exosomes that contain self-antigens, costimulatory molecules, major histocompatibility complex class II, transcription factors, and 20S proteasome. Release of circulating exosomes post-transplant from the aforementioned stress-inducing insults augment immunity and may play an important role in the pathogenesis of bronchiolitis obliterans syndrome.


Assuntos
Bronquiolite Obliterante/imunologia , Exossomos/imunologia , Rejeição de Enxerto/imunologia , Transplante de Pulmão/efeitos adversos , Disfunção Primária do Enxerto/imunologia , Infecções Respiratórias/imunologia , Doença Aguda , Adulto , Idoso , Autoantígenos/sangue , Autoantígenos/imunologia , Antígenos B7/sangue , Antígenos B7/imunologia , Biomarcadores/sangue , Bronquiolite Obliterante/sangue , Bronquiolite Obliterante/diagnóstico , Estudos de Casos e Controles , Linhagem Celular , Feminino , Rejeição de Enxerto/sangue , Rejeição de Enxerto/diagnóstico , Antígenos de Histocompatibilidade Classe II/sangue , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Disfunção Primária do Enxerto/sangue , Disfunção Primária do Enxerto/diagnóstico , Complexo de Endopeptidases do Proteassoma/sangue , Complexo de Endopeptidases do Proteassoma/imunologia , Infecções Respiratórias/sangue , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/virologia , Fatores de Risco , Fatores de Tempo , Fatores de Transcrição/sangue , Fatores de Transcrição/imunologia , Resultado do Tratamento
14.
J Am Soc Nephrol ; 30(8): 1481-1494, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31278196

RESUMO

BACKGROUND: In kidney transplant recipients, surveillance biopsies can reveal, despite stable graft function, histologic features of acute rejection and borderline changes that are associated with undesirable graft outcomes. Noninvasive biomarkers of subclinical acute rejection are needed to avoid the risks and costs associated with repeated biopsies. METHODS: We examined subclinical histologic and functional changes in kidney transplant recipients from the prospective Genomics of Chronic Allograft Rejection (GoCAR) study who underwent surveillance biopsies over 2 years, identifying those with subclinical or borderline acute cellular rejection (ACR) at 3 months (ACR-3) post-transplant. We performed RNA sequencing on whole blood collected from 88 individuals at the time of 3-month surveillance biopsy to identify transcripts associated with ACR-3, developed a novel sequencing-based targeted expression assay, and validated this gene signature in an independent cohort. RESULTS: Study participants with ACR-3 had significantly higher risk than those without ACR-3 of subsequent clinical acute rejection at 12 and 24 months, faster decline in graft function, and decreased graft survival in adjusted Cox analysis. We identified a 17-gene signature in peripheral blood that accurately diagnosed ACR-3, and validated it using microarray expression profiles of blood samples from 65 transplant recipients in the GoCAR cohort and three public microarray datasets. In an independent cohort of 110 transplant recipients, tests of the targeted expression assay on the basis of the 17-gene set showed that it identified individuals at higher risk of ongoing acute rejection and future graft loss. CONCLUSIONS: Our targeted expression assay enabled noninvasive diagnosis of subclinical acute rejection and inflammation in the graft and may represent a useful tool to risk-stratify kidney transplant recipients.


Assuntos
Perfilação da Expressão Gênica , Rejeição de Enxerto/sangue , Rejeição de Enxerto/diagnóstico , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Adulto , Idoso , Biomarcadores/metabolismo , Biópsia , Feminino , Genômica , Sobrevivência de Enxerto , Humanos , Imunossupressores/uso terapêutico , Inflamação , Estimativa de Kaplan-Meier , Falência Renal Crônica/sangue , Falência Renal Crônica/mortalidade , Transplante de Rim/mortalidade , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Estudos Prospectivos , Fatores de Risco , Análise de Sequência de RNA
15.
Clin Chim Acta ; 495: 590-597, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31175849

RESUMO

BACKGROUND: Considerable effort has been exerted to develop noninvasive diagnostic biomarkers that might replace or reduce the need to perform endomyocardial biopsies. In this context, graft DNA circulating on transplant recipients has been proposed as a potential biomarker of organ rejection or cellular graft injury. METHODS: We propose a digital PCR (dPCR) method based on the amplification of ten specific InDels sufficiently sensitive to detect small amounts of specific donor circulating DNA diluted on the host cell free DNA (cfDNA). We obtained 23 informative mismatches from 30 host and donor organ biopsy pairs. RESULTS: Patients without heart-related complications showed a high increase in the specific genomic marker levels during the first 24 h after transplantation that dropped to the basal levels on days 3-4 post-surgery. In contrast, patients with complications presented a significantly lagged decay pattern from day one after transplantation. A specific donor cfDNA increase was detected in one patient two days before rejection diagnosis, diminishing the basal levels after successful immunotherapy. A cfDNA increase was also observed during graft injury due to heart damage. CONCLUSION: These results suggest that cfDNA monitoring of transplanted patients may be a useful tool to detect and probably anticipate graft rejection.


Assuntos
Ácidos Nucleicos Livres/sangue , Rejeição de Enxerto/sangue , Rejeição de Enxerto/genética , Transplante de Coração/efeitos adversos , Doadores de Tecidos , Adulto , Idoso , Biomarcadores/sangue , Ácidos Nucleicos Livres/genética , Feminino , Rejeição de Enxerto/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Reação em Cadeia da Polimerase
17.
Transplant Proc ; 51(4): 1074-1077, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31101173

RESUMO

AIM: End-stage renal disease is a disease in which the kidney is not able to perform its functions. Kidney transplantation is the most effective treatment and cost-effective modality of renal replacement therapy for patients with end-stage renal disease. However, the most important problem in end-stage renal disease patients is the unpredictability of immunologic response after transplants. In this study, it was aimed to investigate the possible association between the interleukin 2 (IL-2) expression level and an organ rejection or rejection episode. MATERIALS AND METHODS: Lymphocytes were isolated from peripheral blood obtained from 21 end-stage renal disease-diagnosed patients prior to transplant and at the sixth month after transplant. CD4+ T cells were separated from lymphocytes by the magnetic cell-sorting method. The purity of these cells were controlled by a flow cytometer. After total RNA isolation from CD4+ T cells, IL-2 was examined by the real-time polymerase chain reaction (RT-PCR) method. RESULTS: Among nonrejection patients (n = 18), the IL-2 expression level decreased in 12 patients in post-transplant time, and 3 of these were statistically significant (P < .05). The level was the same in 1 of 18 patients; it increased in 5 patients, and 1 of them was significant (P < .05). The IL-2 expression level also increased in 3 patients who had a rejection episode, and the increase was statistically significant in 2 samples (P < .05). CONCLUSION: When the patients were evaluated individually, it was observed that there might be a relationship between IL-2 expression levels in CD4+ T cells and rejection episodes. The clinical data of the patients, the immunosuppressive therapies, and post-transplant evaluation of cytokines should be considered together.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Rejeição de Enxerto/imunologia , Interleucina-2/sangue , Transplante de Rim , Adulto , Biomarcadores/sangue , Feminino , Rejeição de Enxerto/sangue , Humanos , Interleucina-2/imunologia , Falência Renal Crônica/cirurgia , Masculino , Pessoa de Meia-Idade
18.
Transplant Proc ; 51(4): 1078-1081, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31101174

RESUMO

INTRODUCTION: Early diagnosis of rejection in kidney transplant (KTx) recipients is of paramount importance for long-term graft survival. Cytokines play an important role in rejection via activating T cells. Neutrophil accumulation in the graft indicates cell-mediated rejection. Cellular infiltration is mediated through chemoattractant factors. The aim of this study was to investigate the relationship between graft function and serum levels of interleukin 2 (IL-2) and interleukin 8 (IL-8) in KTx. METHOD: Sixty-five patients undergoing KTx were enrolled in the study. Serum samples of IL-2 and IL-8 were collected the day before the operation, on postoperative days 1 and 7 day, and during the first and third month after the onset of rejection. The enzyme-linked immunosorbent assay method was used to determine the IL-2 and IL-8 values. RESULTS: A total of 9 (13.8%) patients had rejection documented on biopsy samples. Fifty-six patients had stable graft function (SGF). IL-2 and IL-8 values before KTx of both the rejected and SGF patients were not statistically different. Univariate analysis revealed that IL-2 and IL-8 were correlated with rejection (P = .046, P = .015). IL-8 levels were higher in the rejection group compared to the SGF group on the seventh day and first month postoperatively (P = .023, P = .038). The rejection group maintained higher levels of IL-8 for 11 days (range: 7-30) compared to the SGF group (P = .002) and the IL-8 levels correlated with serum creatinine levels (r = 0.621, P = .001). IL-2 levels were higher in the rejection group on days 1 and 7 compared to the SGF group (P = .042, P = .031). IL-2 and IL-8 levels were correlated with low eGFR in the third month in the rejection group (r = 0.421, P = .037; r = 0.518, P = .008). CONCLUSION: Determining the cytokine levels in the early post-KTx period may be helpful in tailoring immunosuppressive regimens in patients with a risk of rejection.


Assuntos
Biomarcadores/sangue , Rejeição de Enxerto/sangue , Interleucina-2/sangue , Interleucina-8/sangue , Transplante de Rim , Adulto , Feminino , Rejeição de Enxerto/imunologia , Humanos , Interleucina-2/imunologia , Interleucina-8/imunologia , Doadores Vivos , Masculino , Pessoa de Meia-Idade
19.
Curr Opin Organ Transplant ; 24(4): 411-415, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31145158

RESUMO

PURPOSE OF REVIEW: A key aspect of posttransplant management is to identify and treat graft injury before it becomes irreversible. The gold-standard for detection is histology, but biopsy is uncomfortable for the patient and carries a risk of complications. Detection of changes at a molecular level may preempt histological injury, and thereby identify injury earlier. RECENT FINDINGS: Indicators of immune system activation, such as candidate chemokines CXCL9 and CXCL10, and by-products of neutrophil activity, have been related to acute rejection and early allograft function. Transcriptomic studies of multiple-gene panels have identified candidate combinations that have proven very promising in risk-stratification and prediction of acute rejection, as well as diagnosis of both T-cell-mediated and antibody-mediated rejection. Serum and urine cell-free DNA is also a promising area of investigation, particularly in antibody-mediated rejection. SUMMARY: Noninvasive, rapid, and accurate tests for risk-prediction and diagnosis in renal transplant allografts are urgently required. The ideal candidate is one that can be measured in either urine or blood, is cheap, and is both sensitive and specific for the condition of interest. Numerous strategies have been proposed, with varying degrees of clinical and preclinical success. A few that meet the essential criteria have been evaluated; a few have made it as far as clinical testing.


Assuntos
Aloenxertos/fisiopatologia , Biomarcadores/sangue , Rejeição de Enxerto/sangue , Transplante de Rim/métodos , Humanos
20.
Xenotransplantation ; 26(4): e12522, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31077480

RESUMO

Monitoring for immune rejection is crucial for long-term survival of pig xenografts. Circulating DNA is a promising non-invasive biomarker for either organ injury or response to therapy. In this study, circulating pig-specific DNA (cpsDNA) was monitored during xenograft rejection. Potential targets of cpsDNA were selected by in silico analysis, and species specificity of selected primers was confirmed by PCR. Subsequently, cpsDNA as a biomarker was evaluated using a complement-dependent cytotoxicity (CDC) assay in vitro. Then, early diagnosis and response to rapamycin were assessed by an in vivo imaging model of pig-to-mouse cell transplantation. Finally, cpsDNA was monitored in a pig-to-monkey artery patch transplantation model. The results showed that (a) a method of cpsDNA quantitation was established for application in mouse and nonhuman primate models; (b) cpsDNA reflected CDC in vitro; (c) cpsDNA in vivo mirrored xenograft rejection, and correlated with xenograft loss in pig-to-mouse cell transplantation; (d) cpsDNA was significantly reduced when rapamycin was administered; and (e) dynamic cpsDNA was detectable in pig-to-monkey artery patch transplantation. In conclusion, measurement of cpsDNA could prove to be a less invasive, but more specific and sensitive low-cost biomarker enabling monitoring of xenograft rejection and the response to immunosuppressive therapy.


Assuntos
DNA/sangue , Rejeição de Enxerto/sangue , Porco Miniatura/genética , Animais , Anticorpos Heterófilos/sangue , Biomarcadores , Células Cultivadas , Primers do DNA , Células Endoteliais/transplante , Feminino , Genes Reporter , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/patologia , Xenoenxertos , Humanos , Artéria Ilíaca/citologia , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sirolimo/uso terapêutico , Especificidade da Espécie , Suínos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA