RESUMO
BACKGROUND: The molecular dynamics is an approach to obtain kinetic and thermodynamic characteristics of biomolecular structures. The molecular dynamics simulation softwares are very useful, however, most of them are used in command line form and continue with the same common implementation difficulties that plague researchers who are not computer specialists. RESULTS: Here, we have developed the VisualDynamics-a WEB tool developed to automate biological simulations performed in Gromacs using a graphical interface to make molecular dynamics simulation user-friendly task. In this new application the researcher can submit a simulation of the protein in the free form or complexed with a ligand. Can also download the graphics analysis and log files at the end of the simulation. CONCLUSIONS: VisualDynamics is a tool that will accelerate implementations and learning in the area of molecular dynamics simulation. Freely available at https://visualdynamics.fiocruz.br/login , is supported by all major web browsers. VisualDynamics was developed with Flask, which is a Python-based free and open-source framework for web development. The code is freely available for download at GitHub https://github.com/LABIOQUIM/visualdynamics .
Assuntos
Simulação de Dinâmica Molecular , Software , Proteínas/química , Cinética , NavegadorRESUMO
BACKGROUND: Histoplasmosis is a major AIDS-defining illness in Latin America. Liposomal amphotericin B (L-AmB) is the drug of choice for treatment, but access is restricted due to the high drug and hospitalization costs of the conventional long regimens. METHODS: Prospective randomized multicenter open-label trial of 1- or 2-dose induction therapy with L-AmB versus control for disseminated histoplasmosis in AIDS, followed by oral itraconazole therapy. We randomized subjects to: (i) single dose 10 mg/kg of L-AmB; (ii) 10 mg/kg of L-AmB on D1, and 5 mg/kg of L-AmB on D3; (iii) 3 mg/kg of L-AmB daily for 2 weeks (control). The primary outcome was clinical response (resolution of fever and signs/symptoms attributable to histoplasmosis) at day 14. RESULTS: A total of 118 subjects were randomized, and median CD4+ counts, and clinical presentations were similar between arms. Infusion-related toxicity, kidney toxicity at multiple time-points, and frequency of anemia, hypokalemia, hypomagnesemia, and liver toxicity were similar. Day 14 clinical response was 84% for single-dose L-AmB, 69% 2-dose L-AmB, and 74% for control arm (P = .69). Overall survival on D14 was 89.0% (34/38) for single-dose L-AmB, 78.0% (29/37) for 2-dose L-AmB, and 92.1% (35/38) for control arm (P = .82). CONCLUSIONS: One day induction therapy with 10 mg/kg of L-AmB in AIDS-related histoplasmosis was safe. Although clinical response may be non-inferior to standard L-AmB therapy, a confirmatory phase III clinical trial is needed. A single induction dose would markedly reduce drug-acquisition costs (>4-fold) and markedly shorten and simplify treatment, which are key points in terms of increased access.
Assuntos
Síndrome da Imunodeficiência Adquirida , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Histoplasmose , Humanos , Histoplasmose/tratamento farmacológico , Antifúngicos/efeitos adversos , HIV , Estudos Prospectivos , Síndrome da Imunodeficiência Adquirida/tratamento farmacológicoRESUMO
INTRODUCTION: The aim of this study was to analyze the waiting list for kidney transplantation in our hospital according to candidate's panel reactive antibodies (cPRA) and its outcomes. METHODS: One thousand six hundred forty patients who were on the waiting list between 2015 and 2019 were included. For the analysis, hazard ratios (HR) for transplant were estimated by Fine and Gray's regression model according to panel reactivity and HR for graft loss and death after transplantation. RESULTS: The mean age was 45.39 ± 18.22 years. Male gender was predominant (61.2%), but the proportion decreased linearly with the increase in cPRA (p < 0.001). The distribution of patients according to panels were: 0% (n = 390), 1% - 49% (n = 517), 50% - 84% (n = 269), and ≥ 85% (n = 226). Transplantation was achieved in 85.5% of the sample within a median time of 8 months (CI 95%: 6.9 - 9.1). The estimated HRs for transplantation during the follow-up were 2.84 (95% CI: 2.51 - 3.34), 2.41(95%CI: 2.07 - 2.80), and 2.45(95%CI: 2.08 - 2.90) in the cPRA range of 0%, 1%-49%, and 50%-84%, respectively, compared to cPRA ≥ 85 (p < 0.001). After transplantation, the HR for graft loss was similar in the different cPRA groups, but the HR for death (0.46 95% CI 0.24-0.89 p = 0.022) was lower in the 0% cPRA group when adjusted for age, gender, and presence of donor specific antibodies (DSA). CONCLUSION: Patients with cPRA below 85% are more than twice as likely to receive a kidney transplantation with a shorter waiting time. The risk of graft loss after transplantation was similar in the different cPRA groups, and the adjusted risk of death was lower in nonsensitized recipients.
Assuntos
Transplante de Rim , Obtenção de Tecidos e Órgãos , Humanos , Masculino , Adulto , Pessoa de Meia-Idade , Listas de Espera , Brasil , AnticorposRESUMO
OBJECTIVE: Kidney shortage for pediatric kidney transplantation (PKT) entails the need to use low-weight and age donors, despite the apprehension. The aim of this study was to analyze the pediatric deceased donor kidney transplantations (pDDKT) outcomes in the first year after the procedure, stratified by donor age. METHOD: Retrospective cohort of pDDKTs carried out between January 2013, and January 2018, at a PKT reference hospital in Southern Brazil. Donors were divided into group 1 (≤ 6 years), and group 2 (> 6 years); the analysis of the outcomes was carried out in the same period. RESULTS: There were 143 pDDKTs; 51 (35.66%) in group 1; and 92 (64.34%) in group 2. In both groups there were 17 graft losses (11.8%), with vascular thrombosis as the main cause (group 1: 5; group 2: 4). Among the complications, renal artery stenosis (RAS) with indication for angioplasty and stenting was more frequent in group 1 (7.8%; group 2: 2.2%). The 1-year Renal Transplant Recipients' and graft survival did not show significant differences between the groups, (p = = 0.95). However, the Glomerular Filtration Rate analysis was higher in group 2, reaching, in the 12th month, 79.3 mL/min/1,73m2, compared to 69.7 mL/min/1,73m2 in group 1(p = = 0.033). CONCLUSIONS: Small donors can be considered for pDDKTs, as long as there is an expert team to perform the transplantation.
Assuntos
Transplante de Rim , Humanos , Criança , Estudos Retrospectivos , Rejeição de Enxerto/etiologia , Doadores de Tecidos , Rim , Sobrevivência de Enxerto , Resultado do TratamentoRESUMO
BACKGROUND: Bioimpedance analysis (BIA) has been demonstrated to add accuracy to nutritional and volume status assessments in dialysis (HD) patients. AIM: to describe a sample of dialysis patients from a single center on their demographics and BIA of volume distribution and nutritional status, and mortality during 12-month follow-up. METHODS: prospective observational cohort study to evaluate vintage HD patients with single-frequency BIA. RESULTS: we evaluated 82 patients, 29% over 65 years old. Elderly patients had higher ECW/TBW (0.51 vs. 0.44, p < 0.0001), and narrower phase angle (PhA) (4.9 vs. 6.4º, p < 0.0001). Fifteen patients (18.2%) died during follow-up, eight (53%) were elderly. Death was associated with age (62.6 vs. 50.2 years, p = 0.012), post-HD PhA (4.8 vs. 6.2º, p = 0.0001), and post-HD ECW/TBW (0.50 vs. 0.45, p = 0.015). The ROC curve analysis to predict mortality found ECW/TBW ≥ 0.47 and PhA ≤ 5.5º to have the best sensitivity and specificity. One-year patient survival was lower with post-HD ECW/TBW ≥ 0.47 (69.5% vs. 90.6%, p = 0.019), age ≥ 65 years (64.2%, vs. 86.2%, p = 0.029), and PhA ≤ 5.5º (68.2 vs. 91.0%, p = 0.002). Cox regression analysis demonstrated that PhA [HR 5.04 (95%CI 1.60-15.86), p = 0.006] remained associated with death after adjusting for age and ECW/TBW. CONCLUSION: BIA is useful in assessing volume distribution and nutrition in HD patients, and combined with clinical judgement, may help determine dry weight, especially in elderly patients. Narrower PhA and higher ECW/TBW after HD were associated with poorer one-year survival.
Assuntos
Estado Nutricional , Diálise Renal , Humanos , Idoso , Estudos Prospectivos , Água CorporalRESUMO
Direct-acting antivirals are the gold-standard treatment for chronic HCV infections, but few studies have investigated their use on kidney and liver transplant recipients. We conducted a real-world study to evaluate the rates of sustained virological response with direct-acting antivirals in kidney and liver transplant recipients. Moreover, it also aimed to evaluate direct-acting antivirals (DAAs) interference with immunosuppressant levels and to describe the frequency of adverse events. As part of this retrospective observational cohort, we included adult patients that had undergone a kidney transplant (KT) or liver transplant (LT) at our center, had a chronic HCV infection, and were treated with DAAs from June 2016 to December 2021. A total of 165 patients were included in the analysis, divided in 108 KT and 57 LT recipients. HCV genotype 1 was more frequent in KT (58.4%), and genotype 3 was more prevalent in LT (57.9%) patients. Sustained virological response was achieved in 89.6% of patients. Adverse effects were reported by 36% of patients. There were significant interactions with immunosuppressants requiring dose adjustments. A total of three episodes of rejection were reported in KT recipients. In conclusion, DAA treatment resulted in high rates of SVR and was well tolerated in both kidney and liver transplant patients. Adverse events were frequent but not severe in most patients, with low treatment drop-out rates. Interactions with immunosuppressants need monitoring since dose adjustments may be required. Reporting real-life experiences is important to help build evidence for patient management in non-controlled environments.
Assuntos
Hepatite C Crônica , Hepatite C , Transplante de Fígado , Adulto , Humanos , Antivirais/efeitos adversos , Hepacivirus/genética , Estudos Retrospectivos , Brasil , Hepatite C Crônica/tratamento farmacológico , Imunossupressores/efeitos adversos , Rim , Resultado do TratamentoRESUMO
OBJECTIVE: To determine the role of urine cytology for 'decoy cells' as a screening tool for polyomavirus type BK (BKV) infection in renal transplant recipients. STUDY DESIGN: This was a prospective cohort study of patients undergoing renal transplantation between 2006 and 2010. RESULTS: A total of 442 patients underwent urine cytology for decoy cells, 27.8% underwent 1 examination only and 72.2% more than one. Of the 1,713 examinations reviewed, 426 (24.9%) were positive and 785 (45.8%) were negative for 'decoy' cells, 380 (22.2%) showed degenerated tubular cells and 122 (7.1%) were unsatisfactory for analysis. Urine cytology was found to have a specificity of 68.5%, a sensitivity of 84.6%, a positive predictive value of 21.2%, a negative predictive value of 97.8% and an overall accuracy of 69.9%. The incidence of polyomavirus nephropathy among the patients investigated was 11.8%. Of the 442 patients, 32 (7.2%) had graft loss, which was attributed to BKV nephropathy in 2 (6.2% of the 32). CONCLUSIONS: Urine cytology is an effective screening method for monitoring renal transplant patients, with high sensitivity and a high negative predictive value, and can therefore be used routinely in the follow-up of renal transplant patients.
Assuntos
Nefropatias/urina , Transplante de Rim/métodos , Infecções por Polyomavirus/urina , Infecções Tumorais por Vírus/urina , Vírus BK/fisiologia , Citodiagnóstico/métodos , Feminino , Humanos , Nefropatias/diagnóstico , Nefropatias/virologia , Transplante de Rim/efeitos adversos , Masculino , Programas de Rastreamento/métodos , Infecções por Polyomavirus/diagnóstico , Infecções por Polyomavirus/virologia , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/urina , Complicações Pós-Operatórias/virologia , Estudos Prospectivos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Infecções Tumorais por Vírus/diagnóstico , Infecções Tumorais por Vírus/virologiaRESUMO
INTRODUCTION: Cytomegalovirus (CMV) is one of the most common agents of infection in solid organ transplant patients, with significant morbidity and mortality. OBJECTIVE: This study aimed to establish a threshold for initiation of preemptive treatment. In addition, the study compared the performance of antigenemia with qPCR results. STUDY DESIGN: This was a prospective cohort study conducted in 2017 in a single kidney transplant center in Brazil. Clinical validation was performed by comparing in-house qPCR results, against standard of care at that time (Pp65 CMV Antigenemia). ROC curve analysis was performed to determine the ideal threshold for initiation of preemptive therapy based on the qPCR test results. RESULTS: Two hundred and thirty two samples from 30 patients were tested with both antigenemia and qPCR, from which 163 (70.26%) were concordant (Kappa coefficient: 0.435, p<0.001; Spearman correlation: 0.663). PCR allowed for early diagnoses. The median number of days for the first positive result was 50 (range, 24-105) for antigenemia and 42 (range, 24-74) for qPCR (p<0.001). ROC curve analysis revealed that at a threshold of 3,430 IU/mL (Log 3.54), qPCR had a sensitivity of 97.06% and a specificity of 74.24% (AUC 0.92617 ± 0.0185, p<0.001), in the prediction of 10 cells/105 leukocytes by antigenemia and physician's decision to treat. CONCLUSIONS: CMV Pp65 antigenemia and CMV qPCR showed fair agreement and a moderate correlation in this study. The in-house qPCR was revealed to be an accurate method to determine CMV DNAemia in kidney transplant patients, resulting in positive results weeks before antigenemia.
Assuntos
Infecções por Citomegalovirus , Transplante de Rim , Antígenos Virais , Infecções por Citomegalovirus/diagnóstico , DNA Viral , Humanos , Estudos Prospectivos , Reação em Cadeia da Polimerase em Tempo Real , Carga Viral , Organização Mundial da SaúdeRESUMO
BACKGROUND: Atypical Hemolytic Uremic Syndrome (aHUS) is an ultra-rare disease that potentially leads to kidney graft failure due to ongoing Thrombotic Microangiopathy (TMA). The aim was evaluating the frequency of TMA after kidney transplantation in patients with aHUS in a Brazilian cohort stratified by the use of the specific complement-inhibitor eculizumab. METHODS: This was a multicenter retrospective cohort study including kidney transplant patients diagnosed with aHUS. We collected data from 118 transplant centers in Brazil concerning aHUS transplanted patients between 01/01/2007 and 12/31/2019. Patients were stratified into three groups: no use of eculizumab (No Eculizumab Group), use of eculizumab for treatment of after transplantation TMA (Therapeutic Group), and use of eculizumab for prophylaxis of aHUS recurrence (Prophylactic Group). RESULTS: Thirty-eight patients with aHUS who received kidney transplantation were enrolled in the study. Patients' mean age was 30 years (24-40), and the majority of participants was women (63% of cases). In the No Eculizumab Group (n = 11), there was a 91% graft loss due to the TMA. The hazard ratio of TMA graft loss was 0.07 [0.01-0.55], p = 0.012 in the eculizumab Prophylactic Group and 0.04 [0.00-0.28], p = 0.002 in the eculizumab Therapeutic Group. CONCLUSION: The TMA graft loss in the absence of a specific complement-inhibitor was higher among the Brazilian cohort of kidney transplant patients. This finding reinforces the need of eculizumab use for treatment of aHUS kidney transplant patients. Cost optimization analysis and the early access to C5 inhibitors are suggested, especially in low-medium income countries.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Transplante de Rim/efeitos adversos , Microangiopatias Trombóticas/tratamento farmacológico , Adulto , Síndrome Hemolítico-Urêmica Atípica/complicações , Síndrome Hemolítico-Urêmica Atípica/patologia , Brasil/epidemiologia , Inativadores do Complemento/administração & dosagem , Feminino , Rejeição de Enxerto/complicações , Rejeição de Enxerto/patologia , Humanos , Masculino , Estudos Retrospectivos , Microangiopatias Trombóticas/induzido quimicamente , Microangiopatias Trombóticas/complicações , Microangiopatias Trombóticas/patologia , Adulto JovemRESUMO
INTRODUCTION: Kidney Donor Profile Index (KDPI) has been incorporated in the United States to improve the kidney transplant allocation system. OBJECTIVES: To evaluate deceased kidney donors' profile using KDPI and compare to the previous United Network for Organ Sharing (UNOS) definition of expanded criteria donors (ECD) and assess the KDPI applicability to predict five-year graft survival and renal function in our sample. METHODS: Retrospective cohort of 589 kidney transplants from deceased donors performed from January 2009 to May 2013 with follow-up until May 2018. RESULTS: In 589 kidney transplants, 36.6% of donors were classified as ECD and 28.8% had KDPI ≥ 85%. Mean KDPI was 63.1 (95%CI: 60.8-65.3). There was an overlap of standard and ECD in KDPI between 60 and 95 and a significantly lower death-censored graft survival in KDPI ≥ 85% (78.6%); KDPI 0-20: 89.8%, KDPI 21-59: 91.6%, and KDPI 60-84: 83.0%; p = 0.006. The AUC-ROC was 0.577 (95%CI: 0.514-0.641; p = 0.027). Renal function at 5 years was significantly lower according to the incremental KDPI (p < 0.002). KDPI (HR 1.011; 95%CI 1.001-1.020; p = 0.008), donor-specific antibodies (HR 2.77; 95%CI 1.69-4.54; p < 0.001), acute rejection episode (HR 1.73; 95%CI 1.04-2.86; p = 0.034) were independent and significant risk factors for death-censored graft loss at 5 years. CONCLUSION: In our study, 36.6% were classified as ECD and 28.8% had KDPI ≥ 85%. KDPI score showed a moderate power to predict graft survival at 5 years. Renal function was significantly lower in patients with higher KDPI.
Assuntos
Sobrevivência de Enxerto/fisiologia , Transplante de Rim/efeitos adversos , Doadores de Tecidos/classificação , Doadores de Tecidos/estatística & dados numéricos , Transplantados/estatística & dados numéricos , Adulto , Idoso , Brasil/epidemiologia , Estudos de Coortes , Feminino , Seguimentos , Taxa de Filtração Glomerular/fisiologia , Humanos , Testes de Função Renal/estatística & dados numéricos , Testes de Função Renal/tendências , Transplante de Rim/mortalidade , Transplante de Rim/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes/ética , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco , Doadores de Tecidos/provisão & distribuiçãoRESUMO
INTRODUCTION: Acute kidney injury (AKI) occurs in about 22% of the patients undergoing cardiac surgery and 2.3% requires renal replacement therapy (RRT). The current diagnostic criteria for AKI by increased serum creatinine levels have limitations and new biomarkers are being tested. Urine sediment may be considered a biomarker and it can help to differentiate pre-renal (functional) from renal (intrinsic) AKI. AIMS: To investigate the microscopic urinalysis in the AKI diagnosis in patients undergoing cardiac surgery with cardiopulmonary bypass. METHODS: One hundred and fourteen patients, mean age 62.3 years, 67.5 % male, with creatinine 0.91 mg/dL (SD 0.22) had a urine sample examined in the first 24 h after the surgery. We looked for renal tubular epithelial cells (RTEC) and granular casts (GC) and associated the results with AKI development as defined by KDIGO criteria. RESULTS: Twenty three patients (20.17 %) developed AKI according to the serum creatinine criterion and 76 (66.67 %) by the urine output criterion. Four patients required RRT. Mortality was 3.51 %. The use of urine creatinine criterion to predict AKI showed a sensitivity of 34.78 % and specificity of 86.81 %, positive likelihood ratio of 2.64 and negative likelihood ratio of 0.75, AUC-ROC of 0.584 (95%CI: 0.445-0.723). For the urine output criterion sensitivity was 23.68 % and specificity 92.11 %, AUC-ROC was 0.573 (95%CI: 0.465-0.680). CONCLUSION: RTEC and GC in urine sample detected by microscopy is a highly specific biomarker for early AKI diagnosis after cardiac surgery.
Assuntos
Injúria Renal Aguda/etiologia , Injúria Renal Aguda/urina , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Ponte Cardiopulmonar/efeitos adversos , Células Epiteliais/patologia , Túbulos Renais/patologia , Complicações Pós-Operatórias/urina , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/epidemiologia , Idoso , Biomarcadores/urina , Procedimentos Cirúrgicos Cardíacos/métodos , Creatinina/sangue , Creatinina/urina , Diagnóstico Precoce , Feminino , Humanos , Testes de Função Renal , Masculino , Microscopia de Contraste de Fase/métodos , Pessoa de Meia-Idade , Portugal/epidemiologia , Complicações Pós-Operatórias/diagnóstico , Estudos ProspectivosRESUMO
INTRODUCTION: Cytomegalovirus may cause severe disease in immunocompromised patients. Nowadays, quantitative polymerase chain reaction is the gold-standard for both diagnosis and monitoring of cytomegalovirus infection. Most of these assays use cytomegalovirus automated molecular kits which are expensive and therefore not an option for small laboratories, particularly in the developing world. OBJECTIVE: This study aimed to optimize and validate an in-house cytomegalovirus quantitative polymerase chain reaction test calibrated using the World Health Organization Standards, and to perform a cost-minimization analysis, in comparison to a commercial cytomegalovirus quantitative polymerase chain reaction test. STUDY DESIGN: The methodology consisted of determining: optimization, analytical sensitivity, analytical specificity, precision, curve variability analysis, and inter-laboratorial reproducibility. Patients (n=30) with known results for cytomegalovirus tested with m2000 RealTime System (Abbott Laboratories, BR) were tested with the in-house assay, as well as patients infected with other human herpes virus, in addition to BK virus. A cost-minimization analysis was performed, from a perspective of the laboratory, assuming diagnostic equivalence of the methodologies applied in the study. RESULTS: The in-house assay had a limit of detection and quantification of 60.3IU/mL, with no cross-reactivity with the other viral agents tested. Moreover, the test was precise and had a R2 of 0.954 when compared with the m2000 equipment. The cost analysis showed that the assay was economically advantageous costing a median value of 37.8% and 82.2% in comparison to the molecular test in use at the hospital and the m2000 equipment, respectively. CONCLUSIONS: These results demonstrated that in-house quantitative polymerase chain reaction testing is an attractive alternative in comparison to automated molecular platforms, being considerably less expensive and as efficacious as the commercial methods.
Assuntos
Infecções por Citomegalovirus/diagnóstico , Citomegalovirus , Kit de Reagentes para Diagnóstico , Custos e Análise de Custo , DNA Viral , Humanos , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Carga ViralRESUMO
ABSTRACT Introduction: The aim of this study was to analyze the waiting list for kidney transplantation in our hospital according to candidate's panel reactive antibodies (cPRA) and its outcomes. Methods: One thousand six hundred forty patients who were on the waiting list between 2015 and 2019 were included. For the analysis, hazard ratios (HR) for transplant were estimated by Fine and Gray's regression model according to panel reactivity and HR for graft loss and death after transplantation. Results: The mean age was 45.39 ± 18.22 years. Male gender was predominant (61.2%), but the proportion decreased linearly with the increase in cPRA (p < 0.001). The distribution of patients according to panels were: 0% (n = 390), 1% - 49% (n = 517), 50% - 84% (n = 269), and ≥ 85% (n = 226). Transplantation was achieved in 85.5% of the sample within a median time of 8 months (CI 95%: 6.9 - 9.1). The estimated HRs for transplantation during the follow-up were 2.84 (95% CI: 2.51 - 3.34), 2.41(95%CI: 2.07 - 2.80), and 2.45(95%CI: 2.08 - 2.90) in the cPRA range of 0%, 1%-49%, and 50%-84%, respectively, compared to cPRA ≥ 85 (p < 0.001). After transplantation, the HR for graft loss was similar in the different cPRA groups, but the HR for death (0.46 95% CI 0.24-0.89 p = 0.022) was lower in the 0% cPRA group when adjusted for age, gender, and presence of donor specific antibodies (DSA). Conclusion: Patients with cPRA below 85% are more than twice as likely to receive a kidney transplantation with a shorter waiting time. The risk of graft loss after transplantation was similar in the different cPRA groups, and the adjusted risk of death was lower in nonsensitized recipients.
RESUMO Introdução: O objetivo foi analisar a lista de espera para transplante renal em nosso hospital segundo o painel de reatividade de anticorpos (PRAc) do candidato e seus desfechos. Métodos: Incluímos 1.640 pacientes em lista de espera entre 2015 e 2019. Para a análise, estimou-se a razão de risco (HR) para transplante pelo modelo de regressão de Fine e Gray conforme o painel de reatividade e HR para perda do enxerto e óbito após o transplante. Resultados: A idade média foi 45,39 ± 18,22 anos. Sexo masculino foi predominante (61,2%), mas a proporção diminuiu linearmente com o aumento do PRAc (p < 0,001). A distribuição de pacientes conforme os painéis foi: 0% (n = 390), 1% - 49% (n = 517), 50% - 84% (n = 269), e ≥85% (n = 226). O transplante foi realizado em 85,5% da amostra em tempo mediano de 8 meses (IC 95%: 6,9 - 9,1). As HRs estimadas para transplante durante o acompanhamento foram 2,84 (IC 95%: 2,51 - 3,34), 2,41 (IC 95%: 2,07 - 2,80) e 2,45 (IC 95%: 2,08 - 2,90) no intervalo de PRAc de 0%, 1%-49% e 50%-84%, respectivamente, comparadas com PRAc ≥ 85 (p < 0,001). Após o transplante, a HR para perda do enxerto foi semelhante nos diferentes grupos de PRAc, mas HR para óbito (0,46 IC 95% 0,24-0,89 p = 0,022) foi menor no grupo PRAc 0% quando ajustada para idade, sexo e presença de anticorpos doador específico (DSA). Conclusão: Pacientes com PRAc abaixo de 85% têm mais que o dobro de probabilidade de receber transplante renal com tempo de espera menor. Risco de perda do enxerto após o transplante foi semelhante nos diferentes grupos PRAc, e risco ajustado de óbito foi menor em receptores não sensibilizados.
RESUMO
Abstract Objective Kidney shortage for pediatric kidney transplantation (PKT) entails the need to use low-weight and age donors, despite the apprehension. The aim of this study was to analyze the pediatric deceased donor kidney transplantations (pDDKT) outcomes in the first year after the procedure, stratified by donor age. Method Retrospective cohort of pDDKTs carried out between January 2013, and January 2018, at a PKT reference hospital in Southern Brazil. Donors were divided into group 1 (≤ 6 years), and group 2 (> 6 years); the analysis of the outcomes was carried out in the same period. Results There were 143 pDDKTs; 51 (35.66%) in group 1; and 92 (64.34%) in group 2. In both groups there were 17 graft losses (11.8%), with vascular thrombosis as the main cause (group 1: 5; group 2: 4). Among the complications, renal artery stenosis (RAS) with indication for angioplasty and stenting was more frequent in group 1 (7.8%; group 2: 2.2%). The 1-year Renal Transplant Recipients' and graft survival did not show significant differences between the groups, (p= = 0.95). However, the Glomerular Filtration Rate analysis was higher in group 2, reaching, in the 12th month, 79.3 mL/min/1,73m2, compared to 69.7 mL/min/1,73m2 in group 1(p= = 0.033). Conclusions Small donors can be considered for pDDKTs, as long as there is an expert team to perform the transplantation.
RESUMO
The PI3K/Akt/mTOR pathway is an important intracellular signaling pathway in cell cycle regulation and its dysregulation is associated with various types of diseases. mTOR (mechanistic or mammalian target of rapamycin) is the main enzyme that performs intermediate control of the signaling pathway through a phosphotransfer process. The classical inhibition of the mTOR pathway is effected by rapamycin and its analogous blocking allosterically the catalytic phosphorylation site, avoiding the deleterious side effects induced by ATP-competitive inhibitors. We employed ligand-based drug design strategies such as pharmacophore searching and analysis, molecular docking, absorption, distribution, metabolism, excretion and toxicity (ADMETox) properties filtering, and molecular dynamics to select potential molecules to become non-ATP competitive inhibitors of the mTOR complex. According to our findings, we propose eight novel potential mTOR inhibitors with similar or better properties than the classic inhibitor complex, rapamycin.
Assuntos
Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/química , Serina-Treonina Quinases TOR/química , Sítios de Ligação , Desenho de Fármacos , Humanos , Ligantes , Conformação Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Relação Quantitativa Estrutura-Atividade , Reprodutibilidade dos Testes , Serina-Treonina Quinases TOR/antagonistas & inibidoresRESUMO
ABSTRACT Background: Bioimpedance analysis (BIA) has been demonstrated to add accuracy to nutritional and volume status assessments in dialysis (HD) patients. Aim: to describe a sample of dialysis patients from a single center on their demographics and BIA of volume distribution and nutritional status, and mortality during 12-month follow-up. Methods: prospective observational cohort study to evaluate vintage HD patients with single-frequency BIA. Results: we evaluated 82 patients, 29% over 65 years old. Elderly patients had higher ECW/TBW (0.51 vs. 0.44, p < 0.0001), and narrower phase angle (PhA) (4.9 vs. 6.4º, p < 0.0001). Fifteen patients (18.2%) died during follow-up, eight (53%) were elderly. Death was associated with age (62.6 vs. 50.2 years, p = 0.012), post-HD PhA (4.8 vs. 6.2º, p = 0.0001), and post-HD ECW/TBW (0.50 vs. 0.45, p = 0.015). The ROC curve analysis to predict mortality found ECW/TBW ≥ 0.47 and PhA ≤ 5.5º to have the best sensitivity and specificity. One-year patient survival was lower with post-HD ECW/TBW ≥ 0.47 (69.5% vs. 90.6%, p = 0.019), age ≥ 65 years (64.2%, vs. 86.2%, p = 0.029), and PhA ≤ 5.5º (68.2 vs. 91.0%, p = 0.002). Cox regression analysis demonstrated that PhA [HR 5.04 (95%CI 1.60-15.86), p = 0.006] remained associated with death after adjusting for age and ECW/TBW. Conclusion: BIA is useful in assessing volume distribution and nutrition in HD patients, and combined with clinical judgement, may help determine dry weight, especially in elderly patients. Narrower PhA and higher ECW/TBW after HD were associated with poorer one-year survival.
RESUMO Antecedentes: Análise de bioimpedância (BIA) demonstrou adicionar acurácia às avaliações de estado nutricional e de volume em pacientes em diálise (HD). Objetivo: descrever amostra de pacientes em diálise de um único centro quanto aos aspectos demográficos e BIA na distribuição de volume e no estado nutricional, e a mortalidade em 12 meses de acompanhamento. Métodos: estudo de coorte observacional prospectivo para avaliar pacientes prevalentes em HD com BIA de frequência única. Resultados: avaliamos 82 pacientes, 29% acima de 65 anos. Pacientes idosos apresentaram maior AEC/ACT (0,51 vs. 0,44; p < 0,0001), e ângulo de fase mais estreito (PhA) (4,9 vs. 6,4º; p < 0,0001). Quinze pacientes (18,2%) foram a óbito durante acompanhamento, oito (53%) eram idosos. Óbito foi associado à idade (62,6 vs. 50,2 anos, p = 0,012), PhA pós-HD (4,8 vs. 6,2º; p = 0,0001), e AEC/ACT pós-HD (0,50 vs. 0,45, p = 0,015). A análise da curva ROC para prever mortalidade constatou que AEC/ACT ≥ 0,47 e PhA ≤ 5,5º apresentam melhor sensibilidade e especificidade. Sobrevida do paciente em um ano foi menor com AEC/ACT pós-HD ≥ 0,47 (69,5% vs. 90,6%; p = 0,019), idade ≥ 65 anos (64,2% vs. 86,2%; p = 0,029), e PhA ≤ 5,5º (68,2 vs. 91,0%; p = 0,002). A análise de regressão de Cox demonstrou que PhA [HR 5,04 (IC 95% 1,60-15,86); p = 0,006] permaneceu associado ao óbito após ajuste para idade e AEC/ACT. Conclusão: BIA é útil ao avaliar distribuição de volume e nutrição em pacientes em HD, e juntamente com julgamento clínico, pode ajudar a determinar o peso seco, principalmente em pacientes idosos. PhA mais estreito e maior AEC/ACT pós-HD foram associados a pior sobrevida em um ano.
RESUMO
ABSTRACT Direct-acting antivirals are the gold-standard treatment for chronic HCV infections, but few studies have investigated their use on kidney and liver transplant recipients. We conducted a real-world study to evaluate the rates of sustained virological response with direct-acting antivirals in kidney and liver transplant recipients. Moreover, it also aimed to evaluate direct-acting antivirals (DAAs) interference with immunosuppressant levels and to describe the frequency of adverse events. As part of this retrospective observational cohort, we included adult patients that had undergone a kidney transplant (KT) or liver transplant (LT) at our center, had a chronic HCV infection, and were treated with DAAs from June 2016 to December 2021. A total of 165 patients were included in the analysis, divided in 108 KT and 57 LT recipients. HCV genotype 1 was more frequent in KT (58.4%), and genotype 3 was more prevalent in LT (57.9%) patients. Sustained virological response was achieved in 89.6% of patients. Adverse effects were reported by 36% of patients. There were significant interactions with immunosuppressants requiring dose adjustments. A total of three episodes of rejection were reported in KT recipients. In conclusion, DAA treatment resulted in high rates of SVR and was well tolerated in both kidney and liver transplant patients. Adverse events were frequent but not severe in most patients, with low treatment drop-out rates. Interactions with immunosuppressants need monitoring since dose adjustments may be required. Reporting real-life experiences is important to help build evidence for patient management in non-controlled environments.
RESUMO
The mTOR (mammalian or mechanistic Target Of Rapamycin), a complex metabolic pathway that involves multiple steps and regulators, is a major human metabolic pathway responsible for cell growth control in response to multiple factors and that is dysregulated in various types of cancer. The classical inhibition of the mTOR pathway is performed by rapamycin and its analogs (rapalogs). Considering that rapamycin binds to an allosteric site and performs a crucial role in the inhibition of the mTOR complex without causing the deleterious side effects common to ATP-competitive inhibitors, we employ ligand-based drug design strategies, such as virtual screening methodology, computational determination of ADME/Tox properties of selected molecules, and molecular dynamics in order to select molecules with the potential to become non-ATP-competitive inhibitors of the mTOR enzymatic complex. Our findings suggest five novel potential mTOR inhibitors, with similar or better properties than the classic inhibitor complex, rapamycin.
Assuntos
Trifosfato de Adenosina/química , Antibióticos Antineoplásicos/química , Inibidores de Proteínas Quinases/química , Sirolimo/química , Serina-Treonina Quinases TOR/química , Sítio Alostérico , Desenho de Fármacos , Humanos , Cinética , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Relação Estrutura-Atividade , Especificidade por Substrato , Serina-Treonina Quinases TOR/antagonistas & inibidores , Termodinâmica , Interface Usuário-ComputadorRESUMO
Abstract Introduction: Cytomegalovirus (CMV) is one of the most common agents of infection in solid organ transplant patients, with significant morbidity and mortality. Objective: This study aimed to establish a threshold for initiation of preemptive treatment. In addition, the study compared the performance of antigenemia with qPCR results. Study design: This was a prospective cohort study conducted in 2017 in a single kidney transplant center in Brazil. Clinical validation was performed by comparing in-house qPCR results, against standard of care at that time (Pp65 CMV Antigenemia). ROC curve analysis was performed to determine the ideal threshold for initiation of preemptive therapy based on the qPCR test results. Results: Two hundred and thirty two samples from 30 patients were tested with both antigenemia and qPCR, from which 163 (70.26%) were concordant (Kappa coefficient: 0.435, p<0.001; Spearman correlation: 0.663). PCR allowed for early diagnoses. The median number of days for the first positive result was 50 (range, 24-105) for antigenemia and 42 (range, 24-74) for qPCR (p<0.001). ROC curve analysis revealed that at a threshold of 3,430 IU/mL (Log 3.54), qPCR had a sensitivity of 97.06% and a specificity of 74.24% (AUC 0.92617 ± 0.0185, p<0.001), in the prediction of 10 cells/105 leukocytes by antigenemia and physician's decision to treat. Conclusions: CMV Pp65 antigenemia and CMV qPCR showed fair agreement and a moderate correlation in this study. The in-house qPCR was revealed to be an accurate method to determine CMV DNAemia in kidney transplant patients, resulting in positive results weeks before antigenemia.
Resumo Introdução: Citomegalovírus (CMV) é um dos agentes infecciosos mais comuns em pacientes com transplante de órgãos sólidos, com morbidade e mortalidade significativas. Objetivo: Este estudo visou estabelecer um limite para o início do tratamento preemptivo. Além disso, comparou o desempenho da antigenemia com os resultados da qPCR in house. Desenho do estudo: Este foi um estudo de coorte prospectivo realizado em 2017 em um centro único de transplante renal no Brasil. A validação clínica foi realizada comparando resultados de qPCR in house, com o padrão de atendimento na época (Antigenemia para CMV Pp65). A análise da curva ROC foi realizada para determinar o limite ideal para o início da terapia preemptiva baseado nos resultados do teste qPCR in house. Resultados: 232 amostras de 30 pacientes foram testadas com antigenemia e qPCR, das quais 163 (70,26%) foram concordantes (Coeficiente Kappa: 0,435, p<0,001; Correlação Spearman: 0,663). PCR permitiu diagnósticos precoces. O número médio de dias para o primeiro resultado positivo foi 50 (intervalo, 24-105) para antigenemia e 42 (intervalo, 24-74) para qPCR (p<0,001). A análise da curva ROC revelou que em um limite de 3.430 UI/mL (Log 3,54), qPCR teve sensibilidade de 97,06% e especificidade de 74,24% (AUC 0,92617 ± 0,0185, p<0,001), na previsão de 10 células/10(5) leucócitos por antigenemia e na decisão do médico de tratar. Conclusões: Antigenemia para CMV Pp65 e qPCR para CMV mostraram uma concordância aceitável e uma correlação moderada neste estudo. qPCR in house revelou-se um método preciso para determinar DNAemia do CMV em pacientes transplantados renais, obtendo resultados positivos semanas antes da antigenemia.
Assuntos
Humanos , Transplante de Rim , Infecções por Citomegalovirus/diagnóstico , Organização Mundial da Saúde , DNA Viral , Estudos Prospectivos , Carga Viral , Reação em Cadeia da Polimerase em Tempo Real , Antígenos ViraisRESUMO
Abstract Introduction: Acute kidney injury (AKI) occurs in about 22% of the patients undergoing cardiac surgery and 2.3% requires renal replacement therapy (RRT). The current diagnostic criteria for AKI by increased serum creatinine levels have limitations and new biomarkers are being tested. Urine sediment may be considered a biomarker and it can help to differentiate pre-renal (functional) from renal (intrinsic) AKI. Aims: To investigate the microscopic urinalysis in the AKI diagnosis in patients undergoing cardiac surgery with cardiopulmonary bypass. Methods: One hundred and fourteen patients, mean age 62.3 years, 67.5 % male, with creatinine 0.91 mg/dL (SD 0.22) had a urine sample examined in the first 24 h after the surgery. We looked for renal tubular epithelial cells (RTEC) and granular casts (GC) and associated the results with AKI development as defined by KDIGO criteria. Results: Twenty three patients (20.17 %) developed AKI according to the serum creatinine criterion and 76 (66.67 %) by the urine output criterion. Four patients required RRT. Mortality was 3.51 %. The use of urine creatinine criterion to predict AKI showed a sensitivity of 34.78 % and specificity of 86.81 %, positive likelihood ratio of 2.64 and negative likelihood ratio of 0.75, AUC-ROC of 0.584 (95%CI: 0.445-0.723). For the urine output criterion sensitivity was 23.68 % and specificity 92.11 %, AUC-ROC was 0.573 (95%CI: 0.465-0.680). Conclusion: RTEC and GC in urine sample detected by microscopy is a highly specific biomarker for early AKI diagnosis after cardiac surgery.
Resumo Introdução: Lesão renal aguda (LRA) ocorre em cerca de 22% dos pacientes submetidos a cirurgia cardíaca e 2,3% necessitam de terapia renal substitutiva (TRS). Os atuais critérios diagnósticos para LRA fundamentados no aumento dos níveis de creatinina sérica apresentam limitações e novos biomarcadores estão sendo testados. O sedimento urinário é um biomarcador que pode ajudar a diferenciar a LRA pré-renal (funcional) da LRA renal (intrínseca). Objetivos: Investigar a urinálise microscópica no diagnóstico de LRA em pacientes submetidos a cirurgia cardíaca com circulação extracorpórea. Métodos: Um total de 114 pacientes com idade média de 62,3 anos, 67,5% do sexo masculino e níveis médios de creatinina de 0,91 mg/dL (DP 0,22) tiveram amostras de urina examinadas nas primeiras 24 horas após a cirurgia. A identificação de células epiteliais tubulares renais (CETR) e cilindros granulares (CG) foi associada a desfechos de desenvolvimento de LRA conforme os critérios do KDIGO. Resultados: Vinte e três pacientes (20,17%) desenvolveram LRA pelo critério de creatinina sérica e 76 (66,67%) pelo critério de diurese. Quatro pacientes necessitaram de TRS. A mortalidade foi de 3,51%. O uso da creatinina urinária como critério preditivo para LRA mostrou sensibilidade de 34,78% e especificidade de 86,81%; razão de verossimilhança positiva de 2,64 e razão de verossimilhança negativa de 0,75; e ASC-COR de 0,584 (IC 95%: 0,445-0,723). Para o critério de diurese, a sensibilidade foi de 23,68% e a especificidade 92,11%; a ASC-COR foi 0,573 (IC 95%: 0,465-0,680). Conclusão: A identificação de CETR e CG em amostras de urina por microscopia representa um biomarcador altamente específico para o diagnóstico precoce de LRA após cirurgia cardíaca.