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1.
Ann Transplant ; 25: e920224, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32029699

RESUMO

BACKGROUND ABO-incompatible (ABOi) living-donor kidney transplantation (KTx) is well established in developed countries, but not yet in China. MATERIAL AND METHODS We developed individualized preconditioning protocols for ABOi KTx based on initial ABO antibody titers. After propensity score matching of ABOi with ABO-compatible (ABOc) KTx, post-transplant outcomes were compared. RESULTS Between September 2014 and June 2018, 48 ABOi living-donor KTx candidates received individualized preconditioning, and all underwent subsequent KTx (median initial ABO titers: 16 for IgM and 16 for IgG). Thirty-one recipients (64.6%) were preconditioned with rituximab (median dose: 200 mg, range: 100-500 mg). Among 37 patients (77.1%) who received pre-transplant antibody removal, the median number of sessions of antibody removal required to achieve ABOi KTx was 2 (range: 1-5), which was conducted between days -10 and -1. Eleven ABOi recipients (22.9%) were preconditioned with oral immunosuppressants alone. Hyperacute rejection led to the loss of 2 grafts in the ABOi group. After a median follow-up of 27.6 months (ABOi group) and 29.8 months (ABOc group), there were no significant differences in graft/recipient survival, rejection, and infection. There were marginally higher rates of severe thrombocytopenia (<50×109/L) (P=0.073) and delayed wound healing (P=0.096) in ABOi recipients. CONCLUSIONS Our individualized preconditioning protocol evolved as our experience grew, and the short-term clinical outcomes of ABOi KTx did not differ from those of matched ABOc patients. ABOi KTx may be a major step forward in expanding the kidney living-donor pool in China.

2.
Clin Infect Dis ; 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32100025

RESUMO

BACKGROUND: Data on kidney transplantation (KTx) from hepatitis B surface antigen (HBsAg)+ donors to HBsAg- recipients [D(HBsAg+)/R(HBsAg-)] are limited. We aimed to report the outcomes of D(HBsAg+)/R(HBsAg-) KTx in recipients with or without hepatitis B surface antibody (HBsAb). METHODS: Eighty-three D(HBsAg+)/R(HBsAg-) living KTx cases were retrospectively identified. The 384 cases of KTx from hepatitis B core antibody (HBcAb)+ living donors to HBcAb- recipients [D(HBcAb+)/R(HBcAb-)] were used as the control group. Primary endpoint was post-transplant HBsAg -→+. RESULTS: Before KTx, 24 donors (28.9%) in the D(HBsAg+)/R(HBsAg-) group were hepatitis B virus (HBV) DNA+, and 20 recipients were HBsAb-. All eighty-three D(HBsAg+)/R(HBsAg-) recipients received HBV prophylaxis, while no D(HBcAb+)/R(HBcAb-) recipients received prophylaxis. After a median follow-up of 36 months (range 6-106) and 36 months (range 4-107) for the D(HBsAg+)/R(HBsAg-) and D(HBcAb+)/R(HBcAb-) groups, respectively, 2/83 (2.41%) D(HBsAg+)/R(HBsAg-) recipients and 1/384 (0.26%) D(HBcAb+)/R(HBcAb-) became HBsAg+, accompanied with HBV DNA+ (P=0.083). The three recipients with HBsAg-→+ were exclusively HBsAb-/HBcAb- before KTx. Recipient deaths were more frequent in the D(HBsAg+)/R(HBsAg-) group (6.02% vs. 1.04%, P=0.011), while liver and graft function, rejection, infection, and graft loss were not significantly different. In univariate analyses, pre-transplant HBsAb-/HBcAb- combination in the D(HBsAg+)/R(HBsAg-) recipients carried a significantly higher risk of HBsAg-→+, HBV DNA-→+, and death. CONCLUSIONS: Living D(HBsAg+)/R(HBsAg-) KTx in HBsAb+ recipients provides excellent graft and patient survivals without HBV transmission. HBV transmission risks should be more balanced with respect to benefits of D(HBsAg+)/R(HBsAg-) KTx in HBsAb-/HBcAb- candidates.

3.
Ann Transplant ; 24: 594-604, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31712547

RESUMO

BACKGROUND Tacrolimus is a widely used immunosuppressant in renal transplant recipients. It was demonstrated in rats and healthy volunteers that Wuzhi capsules could inhibit metabolism and maintain blood concentration of tacrolimus. However, there are no clinical studies of Wuzhi capsules in renal transplant recipients. This research aimed to assess the effect of Wuzhi capsules on the blood concentration of tacrolimus in renal transplant recipients. MATERIAL AND METHODS A total of 158 Chinese renal transplant recipients receiving tacrolimus with or without Wuzhi capsules were included in this retrospective study. The cohort study included 126 recipients, with 86 recipients receiving Wuzhi capsules (WZCs) and the other 40 recipients not receiving WZCs. Another 32 recipients were involved in a self-control study. RESULTS Dose- and body weight-adjusted trough concentrations (C0/D/W) of tacrolimus in the WZC group were found to be significantly higher than that in the non-WZC group (P<0.05). The improvement of C0/D/W by administration of Wuzhi capsules was more significant in CYP3A5 expressers than in non-expressers following subgroup analysis. Furthermore, the WZC group had a remarkably higher proportion of subjects who reached target tacrolimus concentration than in the non-WZC group, both in CYP3A5 expressers (P=0.01) and non-expressers (P<0.001). Multiple linear regression analysis and self-control analysis confirmed the positive impact of Wuzhi capsules on tacrolimus concentration (P<0.001). CONCLUSIONS Wuzhi capsules can increase tacrolimus trough concentration without adverse effects on allograft function, especially in CYP3A5 expressers. Efficient and convenient immunosuppressive effects on renal transplant recipients can be achieved by treatment including administration of Wuzhi capsules.

4.
BMC Nephrol ; 20(1): 291, 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375084

RESUMO

BACKGROUND: Neutrophil gelatinase-assoicated lipocalin (NGAL) appears to be a promising proximal tubular injury biomarker for early prediction of delayed graft function (DGF) in kidney transplant recipients. However, its predictive values in urine and blood were varied among different studies. Here, we performed the meta-analysis to compare the predictive values of urine NGAL (uNGAL) and blood NGAL (bNGAL) for DGF in adult kidney transplant recipients. METHODS: We systematically searched Medline, Cochrane library and Embase for relevant studies from inception to May 2018. The summary receiver operating characteristic (SROC) curves, the pooled sensitivity, specificity and diagnostic odds ratio (DOR) were used to evaluate the prognostic performance of uNGAL and bNGAL for the identification of DGF. RESULTS: A total of 1036 patients from 14 eligible studies were included in the analysis. 8 studies focused on NGAL in urine and 6 reported NGAL in serum or plasma. The composite area under the ROC (AUC) for 24 h uNGAL was 0.91 (95% CI, 0.89-0.94) and the overall DOR for 24 h uNGAL was 24.17(95% CI, 9.94-58.75) with a sensitivity of 0.88 (95% CI, 0.75-0.94) and a specificity of 0.81 (95% CI, 0.68-0.89). The composite AUC for 24 h bNGAL was 0.95 (95% CI, 0.93-0.97) and the overall DOR for 24 h bNGAL was 43.11 (95% CI, 16.43-113.12) with a sensitivity of 0.91 (95% CI, 0.81-0.96) and a specificity of 0.86 (95% CI, 0.78-0.92). CONCLUSIONS: Urine and serum/plasma NGAL were valuable biomarkers for early identification of DGF in kidney transplantation. In addition, the bNGAL was superior to uNGAL in early prediction of DGF.

5.
Int Immunopharmacol ; 75: 105803, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31401383

RESUMO

Infection remains a major cause of morbidity and mortality after kidney transplantation (KT). Reliable biomarkers to predict post-transplant infection are lacking. We investigated the predictive performance of pre- and post-transplant levels of T-cell immunoglobulin and mucin domain-3 (Tim-3) and Galectin-9 (Gal-9), two pleiotropic immunomodulatory molecules, in early identification of infection. Serum Tim-3 and Gal-9 were paired measured before and 30 days after transplantation (PTD 30) in 95 KT recipients (KTRs). The decline rates of Tim-3 and Gal-9 were calculated relative to pre-transplant levels. KTRs with infection history had significantly higher levels of PTD 30 Tim-3 and Gal-9, and slower decrease rates of Gal-9 compared to non-infected recipients, while no difference was observed between two groups regarding pre-transplant levels. The AUCs for predicting 1-year post-transplant infection were 0.653 and 0.711 for post-transplant Tim-3 and Gal-9, 0.664 and 0.670 for relative Tim-3 and Gal-9, respectively. After adjusting for potential confounders, PTD 30 Tim-3, Gal-9 and relative Gal-9 remained as independent risk factors for post-transplant infection. Our results suggested that PTD 30 Tim-3 and Gal-9 and relative decrease of Gal-9 were promising predictors for identifying KTRs with high risk of infection, while pre-transplant Tim-3 and Gal-9 showed no predictive power to infection.


Assuntos
Galectinas/sangue , Receptor Celular 2 do Vírus da Hepatite A/sangue , Transplante de Rim , Complicações Pós-Operatórias/sangue , Adulto , Feminino , Humanos , Masculino , Risco
6.
Medicine (Baltimore) ; 98(3): e14137, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30653146

RESUMO

The aim of this study was to investigate the correlation between CYP2C19 genotype and dose-adjusted voriconazole (VCZ) trough concentrations (C0/dose).We analyzed the correlation between CYP2C192(681G>A), CYP2C193(636G>A), and CYP2C1917(-806C>T) genetic polymorphisms and the dose-corrected pre-dose concentration (C0/dose) in 106 South-western Chinese Han patients.The frequencies of variant alleles of CYP2C192, 3, and 17 were 29.7%, 4.25%, and 0.92%. For 49.3% of the VCZ samples, the therapeutic window between 1.5 and 5.5 µg/ml was reached. Following the first dose VCZ measurement, in subsequent samples the proportion of VCZ C0 within the therapeutic window increased, suggesting effective therapeutic drug monitoring (TDM) (P = .001). The VCZ C0 was significantly different (P = .010) between patients with normal metabolism (NMs), intermediate metabolism (IMs), and poor metabolism (PMs). The VZC C0/dose was 12.2 (interquartile range (IQR), 8.33-18.2 µg·ml/kg·day), and 7.68 (IQR, 4.07-16.3 µg·ml/kg·day) in PMs and IMs patients, respectively, which was significantly higher than in NMs phenotype patients (4.68; IQR, 2.51-8.87 µg·ml/kg·day, P = .008 and P = .014).This study demonstrated that the VCZ C0/dose was significantly influenced by the CYP2C19 genotype in South-western Chinese Han patients. In this patient population, more over-exposure was observed in patients with a CYP2C19 genotype associated with poor or intermediate metabolism. CYP2C19 genotype-based dosing combined with TDM will support individualization of VCZ dosing, and potentially will minimize toxicity and maximize therapeutic efficacy.


Assuntos
Antifúngicos/administração & dosagem , Citocromo P-450 CYP2C19/genética , Monitoramento de Medicamentos/métodos , Infecções Fúngicas Invasivas/tratamento farmacológico , Voriconazol/administração & dosagem , Adulto , Alelos , Antifúngicos/sangue , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Coortes , Feminino , Genótipo , Humanos , Infecções Fúngicas Invasivas/genética , Masculino , Pessoa de Meia-Idade , Testes Farmacogenômicos , Fenótipo , Polimorfismo Genético , Estudos Retrospectivos , Voriconazol/sangue
7.
Ann Transplant ; 23: 300-309, 2018 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-29735966

RESUMO

BACKGROUND We investigated whether a low fixed Tac starting dose regimen could lead to a better achievement of Tac target concentrations, as well as an effective immunosuppressive treatment, in Chinese kidney transplant recipients (KTRs). MATERIAL AND METHODS We collected whole-blood and serum samples from 189 KTRs and the Tac starting dose was 2, 2.5, or 3 mg/day. Information on Tac C0, dose, body weight, body mass index (BMI), Scr, eGFR, and CYP3A5 genotypes were collected from a routine therapeutic drug monitoring database. The correlation between Tac C0 and body weight (or BMI) was investigated by calculating the goodness of fit. Multivariable logistic regression was performed to estimate the independent associated factors. RESULTS The patients with 3 mg per day of Tac had higher C0 at day 7 compared to those with 2 or 2.5 mg. For patients receiving the same Tac starting dose, no significant difference was found in Tac C0 at day 7 among different body weight or BMI groups. There was no significant difference in Scr or eGFR at 1 year after transplant, nor was there a significant difference in the rates of DGF or AR at post-transplant day 30 among different Tac starting dose groups or among the 3 Tac C0 range groups. CYP3A5 genotype and Tac initial dose were independently associated with Tac C0. CONCLUSIONS CYP3A5 genotype and Tac initial dose were independently associated with Tac C0 in renal transplant recipients. Our results suggest that a low Tac target C0 range (5-8 ng/ml) with a low fixed starting dose (3 mg/day) would be safe and effective among Chinese KTRs.


Assuntos
Imunossupressores/administração & dosagem , Transplante de Rim/métodos , Tacrolimo/administração & dosagem , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Peso Corporal , China , Citocromo P-450 CYP3A/genética , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Feminino , Rejeição de Enxerto , Humanos , Imunossupressores/sangue , Transplante de Rim/efeitos adversos , Modelos Logísticos , Masculino , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Tacrolimo/sangue , Transplantados , Adulto Jovem
8.
Int Immunopharmacol ; 55: 330-335, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29310109

RESUMO

BACKGROUND: T cell immunoglobulin mucin-3 (Tim-3) has been reported to participate in the regulation of immune response and the induction of allograft tolerance. However, the association between Tim-3 and renal allograft dysfunction is unclear. We studied the expression of cellular and soluble Tim-3 (sTim-3), soluble galectin-9 (sGal-9) and carcinoembryonic antigen-related cell adhesion molecule-1 (sCEACAM-1) in kidney transplantation recipients (KTRs) to explore their roles in allograft dysfunction. METHODS: 96 KTRs (53 with stable graft and 43 with graft dysfunction) and 30 healthy controls (HC) were enrolled. Among the KTRs, 55 used Tacrolimus (TAC) and 41 used Sirolimus (SRL). In the dysfunction group, 29 recipients have undergone graft biopsy and 14 were classified as biopsy-proven rejection (BPR). Cellular Tim-3 was determined by flow cytometry. sTim-3 was determined by ELISA. sGal-9 and sCEACAM-1 were determined by Bio-Plex® suspension array system. RESULTS: KTRs with renal dysfunction showed significantly higher levels of sTim-3 and sGal-9 but similar levels of cellular Tim-3 and sCEACAM-1 compared with stable recipients. Correlation analysis revealed that estimated glomerular filtration rate (eGFR) was negatively associated with sTim-3 and sGal-9. Both BPR and non-BPR groups showed comparable levels of Tim-3, Gal-9 and CEACAM-1. Moreover, SRL group showed significantly higher levels of sCEACAM-1 than TAC and HC groups. CONCLUSIONS: sTim-3 and sGal-9 were promising biomarkers for allograft dysfunction, but unable to differentiate allograft rejection from other causes of renal dysfunction in KTRs. Moreover, long-term administration of sirolimus would up-regulate sCEACAM-1 level, while exert similar regulatory effects on Tim-3 and Gal-9 compared to tacrolimus.


Assuntos
Biomarcadores/metabolismo , Proteínas Sanguíneas/metabolismo , Galectinas/metabolismo , Rejeição de Enxerto/diagnóstico , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Nefropatias/diagnóstico , Transplante de Rim , Adulto , Aloenxertos/imunologia , Antígenos CD/metabolismo , Moléculas de Adesão Celular/metabolismo , Estudos Transversais , Diagnóstico Diferencial , Feminino , Taxa de Filtração Glomerular , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Sirolimo/uso terapêutico , Tacrolimo/uso terapêutico
9.
Transpl Immunol ; 46: 1-7, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28974433

RESUMO

BACKGROUND: T follicular helper cells (Tfh) are recently revealed to be vital in antibody-mediated rejection (AMR) in kidney transplant recipients (KTRs). However, the impact of immunosuppressive drugs on Tfh cells is not fully understood. The purpose of this study was to investigate the variation of Tfh cells phenotypically and functionally in KTRs treated with different immunosuppression regimens. METHODS: We recruited 26 KTRs treated with tacrolimus (TAC) -based regimen, 13 with sirolimus (SRL) -based regimen and 10 healthy controls (HC) in this study. The percentage and absolute number of circulating Tfh cells and the co-expression of Tfh related molecules including inducible costimulatory molecule (ICOS), programmed cell death protein 1 (PD-1), interleukin-21 (IL-21) and signal transducer and activator of transcription 3 (STAT3) were analyzed by flow cytometry, while serum IL-6 was detected by electrochemiluminescence immunoassay. RESULTS: The percentage and absolute number of Tfh cells and the co-expression of PD-1, STAT3 in Tfh cells were significantly higher in TAC group than that in SRL group. While no difference was found in regard to IL-21 and ICOS co-expressed with Tfh cells among three groups. Multiple linear regression analysis results showed that pre-transplant PRA level was the significant confounder affecting the absolute numbers of Tfh and CD4+CXCR5+PD-1+ T cells. In addition, correlation analysis showed that CD4+CXCR5+STAT3+ T cells were positively correlated to Tfh cells. CONCLUSIONS: Our study indicates that sirolimus can suppress the quantity of Tfh cells more significantly than tacrolimus. The higher level of circulating Tfh cells in tacrolimus group might be related to STAT3 signaling.


Assuntos
Centro Germinativo/imunologia , Rejeição de Enxerto/imunologia , Imunossupressores/uso terapêutico , Transplante de Rim , Sirolimo/uso terapêutico , Linfócitos T Auxiliares-Indutores/imunologia , Tacrolimo/uso terapêutico , Adulto , Citotoxicidade Celular Dependente de Anticorpos , Feminino , Rejeição de Enxerto/prevenção & controle , Humanos , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Isoanticorpos/metabolismo , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Receptor de Morte Celular Programada 1/metabolismo , Receptores CXCR5/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
10.
Expert Opin Drug Metab Toxicol ; 13(12): 1225-1236, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29084469

RESUMO

INTRODUCTION: Tacrolimus (Tac) is the cornerstone of immunosuppressive therapy after solid organ transplantation and will probably remain so. Excluding belatacept, no new immunosuppressive drugs were registered for the prevention of acute rejection during the last decade. For several immunosuppressive drugs, clinical development halted because they weren't sufficiently effective or more toxic. Areas covered: Current methods of monitoring Tac treatment, focusing on traditional therapeutic drug monitoring (TDM), controversies surrounding TDM, novel matrices, pharmacogenetic and pharmacodynamic monitoring are discussed. Expert opinion: Due to a narrow therapeutic index and large interpatient pharmacokinetic variability, TDM has been implemented for individualization of Tac dose to maintain drug efficacy and minimize the consequences of overexposure. The relationship between predose concentrations and the occurrence of rejection or toxicity is controversial. Acute cellular rejection also occurs when the Tac concentration is within the target range, suggesting that Tac whole blood concentrations don't necessarily correlate with pharmacological effect. Intracellular Tac, the unbound fraction of Tac or pharmacodynamic monitoring could be better biomarkers/tools for adequate Tac exposure - research into this has been promising. Traditional TDM, perhaps following pre-emptive genotyping for Tac-metabolizing enzymes, must suffice for a few years before these strategies can be implemented in clinical practice.


Assuntos
Imunossupressores/farmacocinética , Transplante de Rim , Tacrolimo/farmacocinética , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Genótipo , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/administração & dosagem , Farmacogenética , Tacrolimo/administração & dosagem
11.
Medicine (Baltimore) ; 96(25): e7205, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28640108

RESUMO

Previous study has identified that the genetic variants in the human leukocyte antigen (HLA)-DP/DQ region were strongly associated with hepatitis B virus (HBV) infection. But their roles in liver function recovery after hepatic transplantation were still obscure. This study aimed to investigate whether HLA-DP/DQ polymorphisms were associated with post-transplant etiologies and prognosis in Chinese liver transplant recipients.A total of 144 liver transplant recipients were enrolled, which were divided into 2 groups according to the transplant etiology: HBV-related disease and non-HBV-related disease. HBV-related disease includes 3 subgroups: liver cirrhosis, hepatocellular carcinoma, and progressive HBV hepatitis. Three single-nucleotide polymorphisms HLA-DP (rs3077 and rs9277535) and HLA-DQ (rs7453920) were studied in all recipients by high-resolution melting curve analysis. Liver function indices (albumin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyltranspeptidase, direct bilirubin, total bilirubin) and coagulation indices (prothrombin time, platelet, international normalized ratio, fibrinogen) were routinely tested. After transplant, 10 recipients who were positive for HBsAg or with elevation in HBV virus load were regarded as HBV recurrence.No significant association of HLA-DP/DQ polymorphisms with HBV recurrence or transplant etiology was observed (P < .05). Recipients with HLA-DQ (rs7453920) AG and AA genotype had lower direct bilirubin levels than GG genotype individuals, especially on the 14th day after surgery (17.80 vs. 5.35, P  =  .038). Patients with A alleles displayed earlier liver function recovery than patients with G alleles (7 vs. 6 months). No significant correlation was shown in HLA-DP rs3077 and rs9277535 with HBV infection or liver function recovery (P < .05).Our study concluded that HLA-DP (rs3077 and rs9277535) and HLA-DQ (rs7453920) were not significantly associated with HBV recurrence or HBV susceptibility, but HLA-DQ rs7453920 was related to prognosis of liver transplant recipients. HLA-DQ rs7453920 A might be used as an indicator of earlier recovery and better prognosis after transplantation.


Assuntos
Antígenos HLA-DP/genética , Antígenos HLA-DQ/genética , Hepatopatias/genética , Hepatopatias/cirurgia , Transplante de Fígado , Polimorfismo de Nucleotídeo Único , Adulto , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Técnicas de Genotipagem , Hepatite B/genética , Hepatite B/cirurgia , Vírus da Hepatite B , Humanos , Hepatopatias/etiologia , Hepatopatias/virologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Carga Viral
12.
Pharmacogenet Genomics ; 27(1): 19-26, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27779570

RESUMO

OBJECTIVE: A genome-wide association study has identified several gene polymorphisms associated with loss of renal function. The effect of these variants on renal function in kidney transplant recipients receiving immunosuppressive treatment is unknown. MATERIALS AND METHODS: A cohort of 189 kidney transplant recipients and their living donors were recruited from West China Hospital of Sichuan University, on whom we assessed the association of five single nucleotide polymorphisms with renal function after kidney transplantation. RESULTS: Glomerular filtration rate estimated by serum creatinine was significantly higher in recipients carrying allograft with the A allele at rs17319721 in SHROOM3 (shroom family member 3) than those in the group with the GG genotype from month 1 to month 6 after transplantation (P=0.020). Covariate adjustment analysis showed that the variant at rs17319721 in SHROOM3 was an independent risk factor for renal dysfunction after the first month after transplantation (P=0.022). The estimated glomerular filtration rate was the lowest in recipients with allograft carrying both the A allele at rs17319721 in SHROOM3 and the CC genotype at rs1045642 in ABCB1 (P<0.05). CONCLUSION: The genetic variants in SHROOM3 and ABCB1 in donors were associated closely with renal function after kidney transplantation.


Assuntos
Creatinina/sangue , Imunossupressores/administração & dosagem , Rim/fisiopatologia , Proteínas dos Microfilamentos/genética , Polimorfismo de Nucleotídeo Único , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , China , Feminino , Genótipo , Taxa de Filtração Glomerular , Humanos , Imunossupressores/farmacologia , Transplante de Rim , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Variantes Farmacogenômicos , Adulto Jovem
13.
Pharmacogenomics ; 17(3): 249-57, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26784512

RESUMO

AIM: Determine the effect of genetic variants of donors and recipients on early renal function and tacrolimus pharmacokinetics in kidney transplant recipients. PATIENTS & METHODS: We measured CYP3A5 (6986A>G), ABCB1 (3435C>T, 2677G>T/A, 1236C>T) genetic polymorphisms in 120 renal transplant recipients and donors by high-resolution melting curve analysis. The renal function and tacrolimus trough concentrations were analyzed. RESULTS: The genotype of CYP3A5 (6986A>G) in recipients showed strong influence on tacrolimus pharmacokinetics. The ABCB1 3435 CC genotype in donor was significantly associated with lower estimated glomerular filtration in recipients within 1 month (p < 0.05) and correlated with delayed creatinine recovery (p = 0.007). CONCLUSIONS: ABCB1 3435 CC genotype in donor influences early renal function and creatinine recovery in tacrolimus-treated kidney transplant recipients.


Assuntos
Imunossupressores/farmacocinética , Transplante de Rim , Rim/efeitos dos fármacos , Doadores Vivos , Tacrolimo/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Creatinina/sangue , Citocromo P-450 CYP3A/genética , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Rim/fisiopatologia , Masculino , Polimorfismo de Nucleotídeo Único
14.
Transplant Rev (Orlando) ; 29(4): 224-30, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26048322

RESUMO

Elderly patients are a fast growing population among transplant recipients over the past decades. Both the innate and adaptive immune reactivity decrease with age, which is believed to contribute to the decreased incidence of acute rejection and increased infectious death rate in elderly transplant recipients. In contrast to recipient age, donor age is associated with a higher incidence of acute rejection. Pharmacokinetic studies in renal transplant recipients show that CNI troughs are >5% higher in elderly compared to younger patients given the same dose normalized by body weight. This may impact the starting dose of tacrolimus and cyclosporine. Possibly in elderly patients the intracellular (in lymphocyte) concentrations are relatively high in relation to the whole blood concentration, resulting in a stronger pharmacodynamic effect at the same whole blood trough concentration. For cyclosporine this has been shown, but it is not clear if the same is true for other immunosuppressive drugs. Pharmacodynamic studies have compared the inhibition of target enzymes, or more downstream effects of immunosuppressive drugs, in younger and older patients. Measurement of nuclear factor of activated T-cell (NFAT)-regulated gene expression (RGE), a pharmacodynamic read-out of CNI, is a promising biomarker of immunosuppression. Low levels of NFAT RGE are associated with increased risk of infection and non-melanoma skin cancer in elderly patients. Clinical trials to evaluate the safety and efficacy of immunosuppression regimens in this specific patient population, which is underrepresented in published trials, are lacking. More studies in elderly patients are needed to investigate the impact of age on the pharmacokinetics or pharmacodynamics of immunosuppressive drugs, and to decide on the optimal regimen and target levels for elderly transplant recipients.


Assuntos
Envelhecimento/metabolismo , Imunossupressores/farmacocinética , Transplante de Rim , Idoso , Biomarcadores/metabolismo , Monitoramento de Medicamentos , Humanos
15.
Anesthesiology ; 117(3): 475-86, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22846680

RESUMO

BACKGROUND: About one in four patients suffers from postoperative nausea and vomiting. Fortunately, risk scores have been developed to better manage this outcome in hospitalized patients, but there is currently no risk score for postdischarge nausea and vomiting (PDNV) in ambulatory surgical patients. METHODS: We conducted a prospective multicenter study of 2,170 adults undergoing general anesthesia at ambulatory surgery centers in the United States from 2007 to 2008. PDNV was assessed from discharge until the end of the second postoperative day. Logistic regression analysis was applied to a development dataset and the area under the receiver operating characteristic curve was calculated in a validation dataset. RESULTS: The overall incidence of PDNV was 37%. Logistic regression analysis of the development dataset (n=1,913) identified five independent predictors (odds ratio; 95% CI): female gender (1.54; 1.22 to 1.94), age less than 50 yr (2.17; 1.75 to 2.69), history of nausea and/or vomiting after previous anesthesia (1.50; 1.19 to 1.88), opioid administration in the postanesthesia care unit (1.93; 1.53 to 2.43), and nausea in the postanesthesia care unit (3.14; 2.44-4.04). In the validation dataset (n=257), zero, one, two, three, four, and five of these factors were associated with a PDNV incidence of 7%, 20%, 28%, 53%, 60%, and 89%, respectively, and an area under the receiver operating characteristic curve of 0.72 (0.69 to 0.73). CONCLUSIONS: PDNV affects a substantial number of patients after ambulatory surgery. We developed and validated a simplified risk score to identify patients who would benefit from long-acting prophylactic antiemetics at discharge from the ambulatory care center.


Assuntos
Procedimentos Cirúrgicos Ambulatórios , Náusea e Vômito Pós-Operatórios/etiologia , Adulto , Idoso , Antieméticos/uso terapêutico , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Alta do Paciente , Curva ROC , Fatores de Risco
16.
Rheumatol Int ; 32(9): 2731-6, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21809006

RESUMO

Proinflammatory Th17 cells and CD4(+)CD25(+) regulatory T (Treg) cells are two newly identified T lymphocyte subsets, which have opposite effects on autoimmunity and inflammation. To assess the Th17/Treg pattern and cytokine microenvironment in peripheral blood of patients with RA, we included 66 RA patients and 20 healthy volunteers. Of all these subjects, peripheral Th17 and Treg frequencies were analyzed by flow cytometry (FCM) and the plasma levels of interleukin (IL)-17, 23, 6, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-ß1 were detected by ELISA. The results demonstrated that RA patients revealed an obvious increase in peripheral Th17 frequencies and levels of Th17-related cytokines (IL-17, IL-23, IL-6, TNF-α) while a significant decrease in Treg frequencies and Treg-related cytokine (TGF-ß1) levels when compared with healthy people. Our study indicated that development of RA is associated with peripheral Th17/Treg imbalance and characterized by a proinflammatory cytokine microenvironment, which supports continuing generation of Th17 cells.


Assuntos
Artrite Reumatoide/patologia , Linfócitos T Reguladores/patologia , Células Th1/patologia , Adulto , Artrite Reumatoide/sangue , Estudos de Casos e Controles , Contagem de Células , Feminino , Humanos , Interleucina-17/sangue , Interleucina-23/sangue , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Fator de Crescimento Transformador beta1/sangue , Fator de Necrose Tumoral alfa/sangue
17.
Mol Biol Rep ; 38(8): 4913-9, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21181275

RESUMO

The aim of this study was to perform an association study between two single nucleotide polymorphisms (SNPs) rs2910164 G>C and rs3746444 T>C in pre-miRNA (hsa-mir-146a and hsa-mir-499) and rheumatoid arthritis (RA) in the Han Chinese population. 208 Han Chinese patients with RA and 240 healthy controls were recruited in this study. The SNPs was genotyped by polymerase chain reaction-restriction fragment length polymorphism. Anti-cyclic citrullinated peptide (anti-CCP) antibody was measured by enzyme linked immunosorbent assay and rheumatoid factor (RF) was measured by rate nephelometry. The genotype frequencies between cases and controls were compared by χ(2) analysis. No significant association between the SNPs (rs2910164 and rs3746444) and RA was observed (P = 0.631 and 0.775, respectively), and the SNPs did not show any association with the RF-positive (P = 0.631 and 0.775, respectively). However, there was a significant difference on the level of anti-CCP antibody between different genotypes in rs3746444 (P = 0.007). The heterozygote CT had significantly higher level of anti-CCP antibody compared with homozygote CC and TT (P = 0.054 and 0.003, respectively). We first investigated the association between the SNPs (rs2910164 G>C and rs3746444 T>C) in the pre-miRNA (hsa-mir-146a and hsa-mir-499) and RA in a Han Chinese population. We did not find a significant association between the SNPs and the susceptibility to RA, while the SNP rs3746444 may affect anti-CCP antibody production.


Assuntos
Artrite Reumatoide/genética , Grupo com Ancestrais do Continente Asiático/genética , Grupos Étnicos/genética , Predisposição Genética para Doença , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único/genética , Anticorpos/imunologia , Artrite Reumatoide/imunologia , Estudos de Casos e Controles , China , Feminino , Frequência do Gene/genética , Genética Populacional , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos Cíclicos/imunologia
18.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 40(3): 499-503, 2009 May.
Artigo em Chinês | MEDLINE | ID: mdl-19627014

RESUMO

OBJECTIVE: To establish a diagnostic model for systemic lupus erythematosus (SLE) using proteiomic fingerprint techology. METHODS: Blood samples were collected from 64 cases of SLE, 30 cases of rheumatoid arthritis (RA), 30 cases of Sjogren's syndrome (SS), 25 cases of systemic sclerosis (SSc), as well as 83 healthy controls. Proteomic spectra of these 232 serum samples were generated by proteomic fingerprint technology. Diagnostic model was established by a machine learning algorithm called decision boosting. The sensitivity and specificity of the diagnostic model was validated with a blinded testing set. RESULTS: Sixty differential protein peaks (P<0.05) between SLE and control subjects were indicated, 28 of them were up regulated and 32 were down regulated in SLE patients. The algorithm identified a cluster pattern segregating SLE from non-SLE with sensitivity of 91% and specificity of 92%. The discriminatory diagnostic pattern correctly identified SLE. A sensitivity of 78% and specificity of 96% for the blinded test were obtained when comparing SLE vs non-SLE. CONCLUSION: This diagnostic model using proteiomic fingerprint techology appears to be a promising tools with high sensitivity and specificity in diagnosis of SLE.


Assuntos
Proteínas Sanguíneas/análise , Lúpus Eritematoso Sistêmico/diagnóstico , Proteômica/métodos , Biomarcadores/análise , Proteínas Sanguíneas/genética , Feminino , Humanos , Lúpus Eritematoso Sistêmico/sangue , Masculino , Modelos Biológicos , Sensibilidade e Especificidade
19.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 40(3): 504-7, 512, 2009 May.
Artigo em Chinês | MEDLINE | ID: mdl-19627015

RESUMO

OBJECTIVE: To investigate the proteomic characteristics of systemic lupus erythematosus (SLE) in a SLE family from Sichuan, China which consisting of 7 members with 3 SLE cases, and to find the proteins correlated with the heredity of SLE. METHODS: A total of 153 serum samples were collected from 7 members including 3 SLE sisters in this SLE family, 63 individual SLE patients, as well as 83 healthy controls. The diagnosis of SLE is based on the American College of Rheumatology criteria (1997). All serum samples were analyzed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) combined with magnetic beads technology. Serum protein profiles were obtained by MALDI-TOF-MS combined with magnetic beads in order to identify predictive biomarkers of risk of suffering SLE. The resulting spectra were analyzed with Biomarker Wizard software 3.1.0. RESULTS: Four discriminative mass/charge (m/z) proteins serving as pathogenic biomarkers were identified on arrays for family SLE cases versus individual SLE and healthy controls. The protein level of peak intensities at m/z of 9342.23 was significantly greater in SLE family group compared with that in individual SLE patients and healthy controls (P<0.05), those of individual SLE patients were significantly greater compared with healthy controls (P<0.05); the proteins level of peak intensities at m/z of 4094.03, 5905.35 and 7973.53 in SLE family group were significantly lower compared with that in individual SLE patients and healthy controls (P<0.05), those of individual SLE patients were significantly lower compared with healthy controls (P<0.05). CONCLUSION: The proteins of m/z of 9342.23, 4094.03, 5905.35 and 7973.53 maybe play a great role in assemble pathogenesis of SLE and predict the risk of suffering SLE. The higher protein level of m/z of 9342.23 and the lower protein level of m/z of 4094.03, 5905.35 and 7973.53, the higher risk of sufferring with SLE.


Assuntos
Proteínas Sanguíneas/análise , Lúpus Eritematoso Sistêmico/genética , Proteômica/métodos , Adolescente , Adulto , Idoso , Biomarcadores/análise , Proteínas Sanguíneas/genética , China , Feminino , Humanos , Lúpus Eritematoso Sistêmico/sangue , Masculino , Pessoa de Meia-Idade , Linhagem , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Adulto Jovem
20.
Proc Natl Acad Sci U S A ; 103(33): 12335-40, 2006 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-16894153

RESUMO

Although the multilineage potential of human adipose-derived adult stromal cells (ADAS) has been well described, few published studies have investigated the biological and molecular mechanisms underlying osteogenic differentiation of mouse ADAS. We report here that significant osteogenesis, as determined by gene expression and histological analysis, is induced only when mouse ADAS are cultured in the presence of retinoic acid with or without recombinant human bone morphogenetic protein (BMP)-2 supplementation. Furthermore, a dynamic expression profile for the BMP receptor (BMPR) isoform IB was observed, with dramatic up-regulation during osteogenesis. Western blot analysis revealed that retinoic acid enhanced levels of BMPR-IB protein during the first 7 days of osteogenic differentiation and that RNAi-mediated suppression of BMPR-IB dramatically impaired the ability of ADAS to form bone in vitro. In contrast, absence of BMPR-IA did not significantly diminish ADAS osteogenesis. Our data therefore demonstrate that the osteogenic commitment of multipotent mouse ADAS requires retinoic acid, which enhances expression of the critical BMPR-IB isoform.


Assuntos
Tecido Adiposo/citologia , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/metabolismo , Diferenciação Celular/fisiologia , Osteogênese/fisiologia , Transdução de Sinais/fisiologia , Células Estromais/fisiologia , Tretinoína/metabolismo , Células 3T3 , Animais , Antineoplásicos/metabolismo , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/genética , Proliferação de Células , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Camundongos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Interferência de RNA , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Células Estromais/citologia
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