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1.
J Lipid Res ; 55(4): 747-57, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24534704

RESUMO

Oxidation of LDL by the myeloperoxidase (MPO)-H2O2-chloride system is a key event in the development of atherosclerosis. The present study aimed at investigating the interaction of MPO with native and modified LDL and at revealing posttranslational modifications on apoB-100 (the unique apolipoprotein of LDL) in vitro and in vivo. Using amperometry, we demonstrate that MPO activity increases up to 90% when it is adsorbed at the surface of LDL. This phenomenon is apparently reflected by local structural changes in MPO observed by circular dichroism. Using MS, we further analyzed in vitro modifications of apoB-100 by hypochlorous acid (HOCl) generated by the MPO-H2O2-chloride system or added as a reagent. A total of 97 peptides containing modified residues could be identified. Furthermore, differences were observed between LDL oxidized by reagent HOCl or HOCl generated by the MPO-H2O2-chloride system. Finally, LDL was isolated from patients with high cardiovascular risk to confirm that our in vitro findings are also relevant in vivo. We show that several HOCl-mediated modifications of apoB-100 identified in vitro were also present on LDL isolated from patients who have increased levels of plasma MPO and MPO-modified LDL. In conclusion, these data emphasize the specificity of MPO to oxidize LDL.


Assuntos
Apolipoproteína B-100/metabolismo , Lipoproteínas LDL/metabolismo , Peroxidase/metabolismo , Sequência de Aminoácidos , Apolipoproteína B-100/química , Estudos de Casos e Controles , Humanos , Peróxido de Hidrogênio/química , Hidrólise , Nefropatias/sangue , Nefropatias/terapia , Lipoproteínas LDL/química , Dados de Sequência Molecular , Oxirredução , Fragmentos de Peptídeos , Peroxidase/química , Processamento de Proteína Pós-Traducional , Diálise Renal
2.
Nephrol Dial Transplant ; 29(2): 463-6, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24275542

RESUMO

BACKGROUND: Patients undergoing kidney transplantation are sometimes being treated with antiplatelet agents such as ticlopidine or clopidogrel. Some teams refuse to wait-list these patients for fear of bleeding during transplant surgery. METHODS: We retrospectively reviewed the records of 702 adult patients with a kidney transplant alone between 2000 and 2010. Nineteen (2.7%) patients were taking clopidogrel or ticlopidine when called in for transplantation. Furthermore, 10 of these 19 patients were also taking low-dose aspirin (ASA). We compared the risk of bleeding peri- and postoperatively, and the occurrence of cardiovascular complications within 30 days after renal transplantation between 19 cases and 39 controls randomly selected within the cohort. RESULTS: Platelets were administered to 7 cases (37%) versus 0 controls (P<0.001). A single case (5.3%) presented with significant bleeding during surgery following an implantation biopsy, and required 4 red bood cell (RBC) units. During the first day, 3 of the 19 cases (16%) and 1 of the 39 controls required RBC (P=0.1). No reoperation was performed for bleeding. After the transplant, clopidogrel or ticlopidine was resumed in only two patients. The platelet count and haemoglobin were similar between cases and controls at Day 30. No cardiovascular event occurred in cases or controls during the first month post-transplantation. At 5 years, graft and patient survival was similar in cases and controls. CONCLUSIONS: Clopidogrel and ticlopidine, sometimes in combination with ASA, are associated with a low risk of bleeding during renal transplantation and does not seem to be a contraindication for renal transplant surgery.


Assuntos
Aspirina/administração & dosagem , Perda Sanguínea Cirúrgica/prevenção & controle , Falência Renal Crônica/cirurgia , Transplante de Rim , Complicações Pós-Operatórias/prevenção & controle , Ticlopidina/análogos & derivados , Ticlopidina/administração & dosagem , Estudos de Casos e Controles , Clopidogrel , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Seguimentos , Sobrevivência de Enxerto , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/administração & dosagem , Complicações Pós-Operatórias/epidemiologia , Prognóstico , Estudos Retrospectivos , Risco , Fatores de Risco , Taxa de Sobrevida/tendências , Fatores de Tempo
3.
Nephrol Dial Transplant ; 27(6): 2547-53, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22123748

RESUMO

BACKGROUND: Several studies suggest that the introduction of tacrolimus (TRL), mycophenolic acid (MPA) and interleukin 2 receptor antibodies (IL2Ra) as single drugs more than a decade ago has not increased the risk of malignancy after renal transplantation. However, only limited data are available on their carcinogenic effects when used in combination as a potent immunosuppressive regimen. METHODS: A retrospective single-centre cohort study on 929 adult renal transplant recipients. Investigation of the effect of two consecutive immunosuppressive regimens [1993-98, N = 405, anti-lymphocyte antibodies, cyclosporine and azathioprine (AZA); 1999-2007, N = 524, predominantly IL2Ra, TRL and MPA] on the incidence rate of skin cancer, solid tumours and post-transplant lymphoproliferative disease (PTLD). RESULTS: In total, 365 malignancies developed among 113 patients. As compared to the previous cyclosporine and AZA-based immunosuppression, the introduction of the new immunosuppressive regimen did not increase the incidence rate of skin cancer [rate ratio 0.84; 95% confidence interval (CI) 0.48-1.46], solid tumours (0.89; 95% CI 0.46-1.67) and PTLD (0.82; 95% CI 0.28-2.21). Patients treated with the more recent regimens less frequently developed multiple skin cancers and invasive squamous cell cancer. Skin cancer after transplantation was strongly associated with the development of solid tumours (odds ratio 5.2; P < 0.0001). The introduction of the new immunosuppressive drugs reduced the incidence of first year acute rejection from 34.8 to 13.2% (P < 0.0001). CONCLUSION: Although significantly more efficient in the prevention of acute rejection, the introduction of TRL, MPA and IL2Ra-based immunosuppression after kidney transplantation was not associated with an increased incidence of skin cancer, solid tumours or PTLD.


Assuntos
Anticorpos Anti-Idiotípicos/efeitos adversos , Transplante de Rim/efeitos adversos , Ácido Micofenólico/efeitos adversos , Neoplasias/etiologia , Neoplasias/mortalidade , Receptores de Interleucina-2/imunologia , Tacrolimo/efeitos adversos , Adulto , Antibióticos Antineoplásicos/efeitos adversos , Combinação de Medicamentos , Feminino , Seguimentos , Rejeição de Enxerto , Sobrevivência de Enxerto , Humanos , Imunossupressores/efeitos adversos , Falência Renal Crônica/mortalidade , Falência Renal Crônica/terapia , Transplante de Rim/mortalidade , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
4.
PLoS One ; 16(5): e0251793, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34015014

RESUMO

BACKGROUND: The efficacy and cost-effectiveness of prophylactic thrombolytic locks in hemodialysis patients at high-risk of thrombotic dialysis catheter dysfunction is uncertain. We investigated this question in a double-blinded randomized controlled study. METHODS: Prevalent hemodialysis patients from 8 Belgian hemodialysis units, with ≥2 separate episodes of thrombotic dysfunction of their tunneled cuffed catheter during the 6 months before inclusion, were randomized to either: taurolidine heparin locks thrice weekly (control arm) or the same locks twice a week combined with taurolidine urokinase locks once a week before the longest interval without HD (TaurolockU arm). The primary efficacy outcome was the incidence rate of catheter thrombotic dysfunction requiring thrombolytic locks to restore function. RESULTS: 68 hemodialysis patients (32 controls, 36 urokinase) were followed during 9875 catheter days between May 2015 and June 2017. Incidence rate of thrombotic catheter dysfunction was 4.8 in TaurolockU vs 12.1/1000 catheter days in control group (rate ratio 0.39; 95%CI 0.23-0.64). 15/36 (42%) catheters in the treatment group required at least one therapeutic urokinase lock vs 23/32 (72%) in the control group (P = 0.012). The two groups did not differ significantly in catheter-related bloodstream infection and combined cost of prophylactic and therapeutic catheter locks. The TaurolockU group had a numerically higher number of episodes of refractory thrombosis. CONCLUSIONS: Prophylactic use of urokinase locks is highly effective in reducing the number of thrombotic catheter dysfunctions in catheters with a history of recurring dysfunction. Prophylactic use of urokinase locks did not reduce the overall costs associated with catheter locks and was associated with a numerically higher number of episodes of refractory thrombosis. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02036255.


Assuntos
Cateterismo Venoso Central/efeitos adversos , Cateteres Venosos Centrais/efeitos adversos , Diálise Renal/efeitos adversos , Taurina/análogos & derivados , Tiadiazinas/administração & dosagem , Trombose/prevenção & controle , Ativador de Plasminogênio Tipo Uroquinase/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Taurina/administração & dosagem , Trombose/etiologia
5.
Talanta ; 99: 603-9, 2012 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-22967600

RESUMO

A high degree of uremia is common in patients with end-stage renal disease and has been linked to the development of chronic inflammation and cardiovascular diseases. In conditions where transplantation is not possible, uremia can be reduced by hemodialysis although the repeated interventions have been implicated in loss of renal function, partially as a result of chronic inflammation and/or oxidative stress processes. In this context, it has been suggested that myeloperoxidase (MPO) can contribute to the oxidative stress during hemodialysis and to the cardiovascular risk. Protein damages due to MPO activity have never been assessed during hemodialysis although two of its reaction products, 3-chlorotyrosine and homocitrulline, are of interest. Indeed, the first one is a specific product of MPO activity and the formation of the second one could be catalyzed by MPO. In order to analyze these products in plasma proteins, a total hydrolysis method followed by liquid chromatography mass spectrometry analysis was developed. Different conditions of hydrolysis were tested and the optimized procedure was assessed for complete hydrolysis and artifactual chlorination. Finally, the method was used for analyzing 3-chlorotyrosine and homocitrulline in plasma proteins during a hemodialysis session in fifteen patients and data were related to measurements of MPO concentration and activity. Both increases in MPO activity and protein-bound 3-chlorotyrosine were observed, highlighting the involvement of MPO in oxidative stress during hemodialysis and further demonstrating the link between hemodialysis and cardiovascular diseases.


Assuntos
Análise Química do Sangue/métodos , Proteínas Sanguíneas/metabolismo , Citrulina/análogos & derivados , Micro-Ondas , Peroxidase/metabolismo , Diálise Renal , Tirosina/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Animais , Cromatografia Líquida , Citrulina/sangue , Citrulina/metabolismo , Feminino , Humanos , Hidrólise , Lisina/sangue , Masculino , Pessoa de Meia-Idade , Peroxidase/sangue , Espectrometria de Massas em Tandem , Fatores de Tempo , Tirosina/sangue , Tirosina/metabolismo
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