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2.
BMJ Open ; 12(11): e066128, 2022 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-36368749

RESUMO

INTRODUCTION: Donor-derived modified immune cells (MIC) induced long-term specific immunosuppression against the allogeneic donor in preclinical models of transplantation. In a phase I clinical trial (TOL-1 Study), MIC treatment resulted in a cellular phenotype that was directly and indirectly suppressive to the recipient's immune system allowing for reduction of conventional immunosuppressive therapy. Here, we describe a protocol for a randomised controlled, multicentre phase-IIb clinical trial of individualised immunosuppression with intravenously administered donor MIC compared with standard-of-care (SoC) in living donor kidney transplantation (TOL-2 Study). METHODS AND ANALYSIS: Sixty-three living donor kidney transplant recipients from six German transplant centres are randomised 2:1 to treatment with MIC (MIC group, N=42) or no treatment with MIC (control arm, N=21). MIC are manufactured from donor peripheral blood mononuclear cells under Good Manufacturing Practice conditions. The primary objective of this trial is to determine the efficacy of MIC treatment together with reduced conventional immunosuppressive therapy in terms of achieving an operational tolerance-like phenotype compared with SoC 12 months after MIC administration. Key secondary endpoints are the number of patient-relevant infections as well as a composite of biopsy-proven acute rejection, graft loss, graft dysfunction or death. Immunosuppressive therapy of MIC-treated patients is reduced during follow-up under an extended immunological monitoring including human leucocyte antigen-antibody testing, and determination of lymphocyte subsets, for example, regulatory B lymphocytes (Breg) and antidonor T cell response. A Data Safety Monitoring Board has been established to allow an independent assessment of safety and efficacy. ETHICS AND DISSEMINATION: Ethical approval has been provided by the Ethics Committee of the Medical Faculty of the University of Heidelberg, Heidelberg, Germany (AFmu-580/2021, 17 March 2022) and from the Federal Institute for Vaccines and Biomedicines, Paul-Ehrlich-Institute, Langen, Germany (Vorlage-Nr. 4586/02, 21 March 2022). Written informed consent will be obtained from all patients and respective donors prior to enrolment in the study. The results from the TOL-2 Study will be published in peer-reviewed medical journals and will be presented at symposia and scientific meetings. TRIAL REGISTRATION NUMBER: NCT05365672.


Assuntos
Transplante de Rim , Humanos , Transplante de Rim/efeitos adversos , Doadores Vivos , Padrão de Cuidado , Leucócitos Mononucleares , Terapia de Imunossupressão , Imunossupressores/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como Assunto , Ensaios Clínicos Fase II como Assunto
3.
Clin Kidney J ; 12(4): 527-529, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31384444

RESUMO

Acute kidney injury (AKI) is a major complication in patients with cancer, associated with significant morbidity and mortality. Only two cases of kidney lymphangitic carcinomatosis associated with AKI have been reported, in gastric and colorectal adenocarcinoma. Here, we report on a 53-year-old man with pancreatic adenocarcinoma who developed AKI as a result of kidney lymphangitic carcinomatosis. The patient rapidly became anuric and required haemodialysis. Kidney lymphangitic carcinomatosis should be considered as a cause of AKI in patients with cancer and may become a more frequent clinical finding as patients with metastatic carcinoma survive for longer.

4.
J Am Soc Nephrol ; 22(4): 627-33, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21273381

RESUMO

Patients with CKD are at higher risk for major events after percutaneous coronary intervention (PCI) compared with subjects with normal renal function. The aims of this study were to evaluate responsiveness to clopidogrel in patients with CKD and to examine the effect of antiplatelet drug response on post-PCI outcome. We retrospectively evaluated a consecutive cohort of 1567 patients with symptomatic coronary artery disease undergoing PCI, 648 (41%) of whom had stage 3 to 5 CKD. We assessed responsiveness to clopidogrel by ADP-induced platelet aggregation after oral administration of a 600-mg clopidogrel loading dose and 100 mg of aspirin. In a multivariate survival analysis that included 1335 (85%) of the cohort, stage 3 to 5 CKD and low response to clopidogrel were independent predictors of the primary end point (composite of myocardial infarction, ischemic stroke, and death within 1 year). In summary, a low response to clopidogrel might be an additional risk factor for the poorer outcomes in patients with stage 3 to 5 CKD compared with patients with better renal function.


Assuntos
Angioplastia Coronária com Balão , Doença da Artéria Coronariana/terapia , Nefropatias/complicações , Inibidores da Agregação Plaquetária/uso terapêutico , Ticlopidina/análogos & derivados , Idoso , Aspirina/efeitos adversos , Aspirina/uso terapêutico , Doença Crônica , Clopidogrel , Estudos de Coortes , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Hemorragia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Ticlopidina/efeitos adversos , Ticlopidina/uso terapêutico , Resultado do Tratamento
5.
Immunol Invest ; 38(3-4): 255-67, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19811436

RESUMO

Data regarding polymorphisms of immunoregulatory genes in polyglandular autoimmunity (PGA) are lacking. We have analyzed whether the polymorphism of the proinflammatory cytokine gene TNF-alpha; -308 and mutations of the autoimmune regulator (AIRE) gene were associated with PGA in adults. Sixty-seven patients with PGA and 209 healthy controls were genotyped by multiplex minisequencing with capillary electrophoresis on an ABI PRISM-310 genetic analyzer. HLA DRB1 typing was performed using polymerase-chain-reaction-amplified DNA hybridized with sequence-specific-oligonucleotide probes (PCR-SSO). The TNF-alpha; -308*A allele occurred more frequently in patients (0.269) than in controls (0.163, P = 0.008, P(c) = 0.016). Also, TNF-alpha; -308*A carriers were more frequent in patients than controls (47.8% vs. 31.1%, OR = 1.89, 95%CI = 1.19-3.00). The frequency of the AA genotype was increased in PGA (P = 0.014, P(c) = 0.042). PGA patients with autoimmune thyroid disease and the TNF-alpha; -308 AA genotype showed the highest prevalence of thyroid autoantibodies (TPO, P = 0.04; Tg, P = 0.003). HLA-DRB1*03 and TNF-alpha; -308*A alleles were strongly associated in patients with PGA (87.5%, P(c) < 0.00001). The AIRE R257X and 13bpdel mutations were not observed in patients with PGA. The association of TNF-alpha; -308*A with PGA might be directly or indirectly due to the association with HLA-DRB1*03.


Assuntos
Predisposição Genética para Doença , Poliendocrinopatias Autoimunes/genética , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética , Fator de Necrose Tumoral alfa/genética , Adolescente , Adulto , Idoso , Eletroforese Capilar , Feminino , Genótipo , Antígenos HLA-DR/genética , Cadeias HLA-DRB1 , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto Jovem , Proteína AIRE
6.
Thromb Haemost ; 101(5): 911-5, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19404545

RESUMO

Platelets play a key role in the development of an acute coronary syndrome (ACS) and contribute to cardiovascular events. Platelet collagen receptor glycoprotein VI (GPVI) contributes significantly to platelet adhesion and thrombus formation in ACS. We consecutively investigated both the platelet count and the platelet surface expression of GPVI in 843 patients with a symptomatic coronary artery disease verified by coronary angiography. Four hundred fourteen patients presented with stable angina pectoris and 429 patients with ACS. Platelet surface expression of GPVI and CD62P was determined by flow cytometry and platelet count with a coulter counter, plasmatic soluble GPVI was measured by ELISA. Platelet GPVI expression in patients with ACS was compared to platelet count. Patients with ACS showed significantly elevated GPVI expression levels in the first and second quartiles of platelet count compared to patients with higher platelet count [mean fluorescence intensity (MFI) +/- standard deviation): 1(st) vs. 4(th): 20.44 +/- 6.1 vs. 18.62 +/- 3.7; p=0.012; 2(nd)vs.3(rd):21.2+/-8.5vs.18.76+/-3.7;P=0.03; 2(nd)vs.4(th): 21.2+/-8.5vs.18.62+/-3.7;P=0.004], which was paralleled in trend for the CD62P expression [MFI: 1(st) vs. 4(th): 11.2 +/- 6.8 vs. 12.3 +/- 9; p=0.057; 2(nd) vs. 3(rd): 16.3 +/- 16 vs.12.7 +/- 5.3; p=0.138; 2(nd) vs. 4(th): 16.3 +/- 16 vs.11 +/- 4.4; p=0.043]. In a subgroup of 48 patients with ACS, determination of soluble GPVI showed similar results [plasma GPVI (ng/ml): 1(st)vs.4(th): 1.6 +/- 0.6 vs. 1.2 +/- 0.4; p=0.046; 1(st) vs. 3(rd): 1.6 +/- 0.6 vs. 1.1 +/- 0.5; p=0.038; 2(nd) vs. 3(rd): 1.9 +/- 0.8 vs. 1.1 +/- 0.5; p=0.04; 2(nd) vs. 4(th): 1.9 +/- 0.8 vs. 1.2 +/- 0.4; p=0.056]. Thus, a lower platelet count comes along with a higher GPVI surface expression and plasma concentration in patients with ACS, which potentially reflects increased activation and enhanced recruitment of platelets to the site of vascular injury.


Assuntos
Síndrome Coronariana Aguda/sangue , Angina Pectoris/sangue , Antígenos CD36/sangue , Doença da Artéria Coronariana/sangue , Ativação Plaquetária , Contagem de Plaquetas , Síndrome Coronariana Aguda/diagnóstico por imagem , Síndrome Coronariana Aguda/etiologia , Síndrome Coronariana Aguda/mortalidade , Idoso , Angina Pectoris/diagnóstico por imagem , Angina Pectoris/etiologia , Angina Pectoris/mortalidade , Biomarcadores/sangue , Angiografia Coronária , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/etiologia , Selectina-P/sangue , Valor Preditivo dos Testes , Prognóstico , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/etiologia , Fatores de Tempo
7.
J Autoimmun ; 32(1): 7-13, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19022625

RESUMO

A deficiency in the DNase enzyme, and thereby, a failure to remove DNA from nuclear antigens promotes disease susceptibility to autoimmune disorders. This study examined in patients with autoimmune thyroid disease (AITD) whether a reduced DNase activity is associated with sequence variations in the DNASE1 gene. The study included 18 patients with AITD, their 10 relatives, and 111 unrelated healthy controls. Serum DNase activity was determined with a validated, standardized enzyme-linked-immunosorbent assay. The promoter and all nine exons of the DNASE1 gene were sequenced. Heat stability of DNase enzyme was tested. In patients with AITD, a novel mutation (1218G>A, exon 5) and multiple polymorphisms were identified in the DNASE1 gene. The allele frequency of the mutation was increased in patients vs controls (P=0.001). In contrast to controls, the novel mutation was present in all five members of a family with AITD showing decreased DNase activity. The mutation resulted in the replacement of highly conserved valine with methionine at amino acid position 89 of the DNase enzyme. It was related to lowered heat stability and lowered activity of the enzyme. The identified new mutation and numerous polymorphisms, noted for the first time in AITD patients, may alter transcription and translation of the DNASE1 gene, thereby decreasing the stability and activity of the corresponding enzyme.


Assuntos
Doenças Autoimunes/enzimologia , Doenças Autoimunes/genética , Desoxirribonuclease I/genética , Desoxirribonuclease I/metabolismo , Mutação de Sentido Incorreto/fisiologia , Doenças da Glândula Tireoide/enzimologia , Doenças da Glândula Tireoide/genética , Doença de Addison/complicações , Adolescente , Adulto , Doenças Autoimunes/sangue , Criança , Desoxirribonuclease I/sangue , Desoxirribonuclease I/química , Feminino , Frequência do Gene , Doença de Graves/sangue , Doença de Graves/genética , Doença de Hashimoto/sangue , Doença de Hashimoto/complicações , Doença de Hashimoto/genética , Temperatura Alta , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Estabilidade Proteica , Splicing de RNA/genética , Doenças da Glândula Tireoide/sangue , Adulto Jovem
8.
Pharmacogenomics ; 9(9): 1251-9, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18781853

RESUMO

AIMS: To investigate an association of responsiveness to clopidogrel loading dose with genotypes of cytochrome P450 (CYP) 2C19, other CYP isozymes and nongenetic factors in patients with coronary artery disease. MATERIALS & METHODS: Genotyping for CYP2C19 (*2, *3 and *17), CYP3A4*1B and CYP3A5*3 variants was performed in patients (n = 237) who underwent percutaneous coronary intervention. Adenosine diphosphate-induced platelet aggregation was determined after first administration of 600 mg clopidogrel. RESULTS: CYP2C19*2 carriers showed significantly increased residual platelet aggregation (RPA) (OR: 4.6; 95% CI: 2.5-8.7; p < 0.0001) compared with noncarriers. All other polymorphisms had no influence on RPA. For the development of a risk score for better prediction of RPA, CYP2C19*2 genotype and previously identified nongenetic risk factors (age >65 years, Type 2 diabetes mellitus, decreased left ventricular function, renal failure and acute coronary syndrome) were analyzed. Multivariable logistic regression analysis showed a significant correlation of the nongenetic factors (chi (2) = 5.32; p = 0.021) and CYP2C19*2 (chi (2) = 21.31; p < 0.0001) with high RPA, and an even higher association for the combination of both (chi (2) = 25.85; p < 0.0001). CONCLUSIONS: Prediction of responsiveness after clopidogrel loading dose may substantially be improved by adding CYP2C19*2 genotype to nongenetic risk factors.


Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Procedimentos Cirúrgicos Cardíacos/tendências , Stents , Ticlopidina/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Procedimentos Cirúrgicos Cardíacos/instrumentação , Clopidogrel , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/cirurgia , Citocromo P-450 CYP2C19 , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Fatores de Risco , Ticlopidina/administração & dosagem , Ticlopidina/sangue
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