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BACKGROUND: Patients with bronchiectasis have frequent exacerbations that are thought to be related to neutrophilic inflammation. The activity and quantity of neutrophil serine proteases, including neutrophil elastase, are increased in the sputum of patients with bronchiectasis at baseline and increase further during exacerbations. Brensocatib (INS1007) is an oral reversible inhibitor of dipeptidyl peptidase 1 (DPP-1), an enzyme responsible for the activation of neutrophil serine proteases. METHODS: In a phase 2, randomized, double-blind, placebo-controlled trial, we randomly assigned, in a 1:1:1 ratio, patients with bronchiectasis who had had at least two exacerbations in the previous year to receive placebo, 10 mg of brensocatib, or 25 mg of brensocatib once daily for 24 weeks. The time to the first exacerbation (primary end point), the rate of exacerbations (secondary end point), sputum neutrophil elastase activity, and safety were assessed. RESULTS: Of 256 patients, 87 were assigned to receive placebo, 82 to receive 10 mg of brensocatib, and 87 to receive 25 mg of brensocatib. The 25th percentile of the time to the first exacerbation was 67 days in the placebo group, 134 days in the 10-mg brensocatib group, and 96 days in the 25-mg brensocatib group. Brensocatib treatment prolonged the time to the first exacerbation as compared with placebo (P = 0.03 for 10-mg brensocatib vs. placebo; P = 0.04 for 25-mg brensocatib vs. placebo). The adjusted hazard ratio for exacerbation in the comparison of brensocatib with placebo was 0.58 (95% confidence interval [CI], 0.35 to 0.95) in the 10-mg group (P = 0.03) and 0.62 (95% CI, 0.38 to 0.99) in the 25-mg group (P = 0.046). The incidence-rate ratio was 0.64 (95% CI, 0.42 to 0.98) in the 10-mg group, as compared with placebo (P = 0.04), and 0.75 (95% CI, 0.50 to 1.13) in the 25-mg group, as compared with placebo (P = 0.17). With both brensocatib doses, sputum neutrophil elastase activity was reduced from baseline over the 24-week treatment period. The incidence of dental and skin adverse events of special interest was higher with the 10-mg and 25-mg brensocatib doses, respectively, than with placebo. CONCLUSIONS: In this 24-week trial, reduction of neutrophil serine protease activity with brensocatib in patients with bronchiectasis was associated with improvements in bronchiectasis clinical outcomes. (Funded by Insmed; WILLOW ClinicalTrials.gov number, NCT03218917.).
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Benzoxazóis/administração & dosagem , Bronquiectasia/tratamento farmacológico , Dipeptidil Peptidases e Tripeptidil Peptidases/antagonistas & inibidores , Oxazepinas/administração & dosagem , Serina Proteases/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzoxazóis/efeitos adversos , Bronquiectasia/metabolismo , Progressão da Doença , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Volume Expiratório Forçado , Humanos , Elastase de Leucócito/metabolismo , Masculino , Pessoa de Meia-Idade , Oxazepinas/efeitos adversos , Escarro/metabolismoRESUMO
BACKGROUND: Brensocatib is an oral, selective, reversible inhibitor of dipeptidyl peptidase-1 (DPP-1), responsible for activating neutrophil serine proteases (NSPs) including neutrophil elastase (NE), proteinase 3 (PR3), and cathepsin G (CatG). In chronic inflammatory lung diseases such as non-cystic fibrosis bronchiectasis (NCFBE), neutrophils accumulate in the airways resulting in excess active NSPs that cause damaging inflammation and lung destruction. METHODS: The 24-week WILLOW trial (NCT03218917) was a randomized, double-blind, placebo-controlled, parallel-group trial in patients with NCFBE conducted at 116 sites across 14 countries. In this trial, treatment with brensocatib was associated with improvements in clinical outcomes including time to first exacerbation, reduction in exacerbation frequency and a reduction in NE activity in sputum. An exploratory analysis of NE activity in white blood cell (WBC) extracts and NE, PR3 and CatG activity in sputum was conducted to further characterize brensocatib's effect and identify potential correlated effects. RESULTS: NE, PR3 and CatG activities were reduced in sputum and NE activity was reduced in WBC extracts in a dose-dependent manner after four weeks of brensocatib treatment, with a return to baseline four weeks after the end of treatment. Brensocatib produced the greatest reduction in the sputum activity of CatG, followed by NE and then PR3. Positive correlations among the sputum NSPs were observed both at baseline and in response to treatment, with the strongest correlation among the sputum NSPs for NE and CatG. CONCLUSIONS: These results suggest a broad anti-inflammatory effect of brensocatib underlying its clinical efficacy observed in NCFBE patients. TRIAL REGISTRATION: The study was approved by the corresponding ethical review boards of all participating centers. The trial was approved by the Food and Drug Administration and registered at clinicaltrials.gov (NCT03218917) on July 17, 2017 and approved by the European Medicines Agency and registered at the European Union Clinical trials Register (EudraCT No. 2017-002533-32). An independent, external data and safety monitoring committee (comprising physicians with pulmonary expertise, a statistician experienced in the evaluation of clinical safety, and experts in periodontal disease and dermatology) reviewed all adverse events.
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Bronquiectasia , Fibrose Cística , Salix , Humanos , Serina Proteases/farmacologia , Serina Proteases/uso terapêutico , Neutrófilos , Bronquiectasia/diagnóstico , Bronquiectasia/tratamento farmacológico , Elastase de Leucócito , Mieloblastina , Dipeptidil Peptidases e Tripeptidil Peptidases/farmacologia , Dipeptidil Peptidases e Tripeptidil Peptidases/uso terapêuticoRESUMO
BACKGROUND: Mycobacterial time to positivity (TTP) in liquid culture media has predictive value for longer term outcomes in pulmonary tuberculosis, but has not been thoroughly studied in nontuberculous mycobacterial pulmonary disease. This study sought to evaluate for association between TTP and sputum culture conversion to negative in pulmonary disease caused by Mycobacterium avium complex (MAC). METHODS: Data from the CONVERT trial (NCT02344004) that evaluated efficacy of guideline-based-therapy with or without amikacin liposome inhalation suspension in adults with refractory MAC-PD (Mycobacterium avium complex pulmonary disease) were analyzed. We evaluated TTP measures for sputum obtained prior to study treatment initiation and at monthly visits, assessing reproducibility of measures as well as association of TTP with culture conversion on treatment. RESULTS: Data from 71 participants with at least one screening visit TTP value were analyzed. For participants who provided more than one sputum sample at a given visit, there was moderate between-sample reliability, with median intraclass correlation coefficient 0.62 (IQR 0.50, 0.70). Median TTP at screening was longer in those participants who subsequently achieved vs. did not achieve culture conversion (10.5 [IQR 9.4] days vs. 4.2 [IQR 2.8] days, p = 0.0002). Individuals with culture conversion by study treatment month 6 were more likely to have a screening TTP > 5 days compared to those who did not achieve culture conversion (OR 15.4, 95% CI 1.9, 716.7, p = 0.0037) and had increasing TTPs over time. CONCLUSIONS: TTP prior to and on treatment is associated with microbiological treatment response in patients with MAC-PD.
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Complexo Mycobacterium avium , Infecção por Mycobacterium avium-intracellulare , Adulto , Antibacterianos/uso terapêutico , Humanos , Infecção por Mycobacterium avium-intracellulare/diagnóstico , Infecção por Mycobacterium avium-intracellulare/tratamento farmacológico , Infecção por Mycobacterium avium-intracellulare/microbiologia , Reprodutibilidade dos Testes , Resultado do TratamentoRESUMO
Prospective data regarding the de novo use of everolimus following kidney transplantation in children are sparse. In a prospective, 12-month, single-arm, open-label study, pediatric kidney transplant patients received everolimus (target trough concentration ≥3 ng/mL) with reduced-exposure CsA and corticosteroids, with or without basiliximab induction. Sixteen of the 18 patients completed the study on-treatment. Age range was 2-16 yr (mean 10.9 yr); eight patients received a living donor graft. Mean (s.d.) everolimus level was 7.4 (3.1) ng/mL during the first 12 months post-transplant. There were no cases of BPAR, graft loss, or death during the study. Protocol biopsies were performed at month 12 in seven patients, with subclinical (untreated) acute rejection diagnosed in one case. Mean (s.d.) estimated GFR (Schwartz formula) was 98 (34) mL/min/1.73 m(2) at month 12. Three patients experienced one or more serious adverse events with a suspected relation to study medication. One patient discontinued study medication due to post-transplant lymphoproliferative disease (5.6%). Everolimus with reduced-dose CsA and corticosteroids achieved good efficacy and renal function and was well tolerated in this small cohort of pediatric kidney transplant patients. Controlled trials are required to answer remaining questions about the optimal use of everolimus in this setting.
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Ciclosporina/administração & dosagem , Imunossupressores/administração & dosagem , Transplante de Rim/métodos , Sirolimo/análogos & derivados , Adolescente , Corticosteroides/uso terapêutico , Biópsia , Criança , Pré-Escolar , Esquema de Medicação , Everolimo , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Estudos Prospectivos , Projetos de Pesquisa , Sirolimo/administração & dosagem , Resultado do TratamentoRESUMO
Marraset al. report a low number needed to treat and high number needed to harm supporting addition of amikacin liposome inhalation suspension to guideline-based treatments in patients with treatment-refractory Mycobacterium avium complex lung disease https://bit.ly/3tPFW7D.
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BACKGROUND AND OBJECTIVE: Brensocatib is an investigational, first-in-class, selective, and reversible dipeptidyl peptidase 1 inhibitor that blocks activation of neutrophil serine proteases (NSPs). The NSPs neutrophil elastase, cathepsin G, and proteinase 3 are believed to be central to the pathogenesis of several chronic inflammatory diseases, including bronchiectasis. In a phase II study, oral brensocatib 10 mg and 25 mg reduced sputum neutrophil elastase activity and prolonged the time to pulmonary exacerbation in patients with non-cystic fibrosis bronchiectasis (NCFBE). A population pharmacokinetic (PPK) model was developed to characterize brensocatib exposure, determine potential relationships between brensocatib exposure and efficacy and safety measures, and inform dose selection in clinical studies. METHODS: Pharmacokinetic (PK) data pooled from a phase I study of once-daily brensocatib (10, 25, and 40 mg) in healthy adults and a phase II study of once-daily brensocatib (10 mg and 25 mg) in adults with NCFBE were used to develop a PPK model and to evaluate potential covariate effects on brensocatib pharmacokinetics. PK-efficacy relationships for sputum neutrophil elastase below the level of quantification (BLQ) and reduction in pulmonary exacerbation and PK-safety relationships for adverse events of special interest (AESIs; periodontal disease, hyperkeratosis, and infections other than pulmonary infections) were evaluated based on model-predicted brensocatib exposure. A total of 1284 steady-state brensocatib concentrations from 225 individuals were included in the PPK data set; 241 patients with NCFBE from the phase II study were included in the pharmacodynamic (PD) population for the PK/PD analyses. RESULTS: The PPK model that best described the observed data consisted of two distributional compartments and linear clearance. Two significant covariates were found: age on volume of distribution and renal function on apparent oral clearance. PK-efficacy analysis revealed a threshold brensocatib exposure (area under the concentration-time curve) effect for attaining sputum neutrophil elastase BLQ and a strong relationship between sputum neutrophil elastase BLQ and reduction in pulmonary exacerbations. A PK-safety evaluation showed no noticeable trends between brensocatib exposure and the incidence of AESIs. Based on the predicted likelihood of clinical outcomes for sputum neutrophil elastase BLQ and pulmonary exacerbations, brensocatib doses of 10 mg and 25 mg once daily were selected for a phase III clinical trial in patients with NCFBE (ClinicalTrials.gov identifier: NCT04594369). CONCLUSIONS: PPK results revealed that age and renal function have a moderate effect on brensocatib exposure. However, this finding does not warrant dose adjustments based on age or in those with mild or moderate renal impairment. The PK/PD evaluation demonstrated the clinically meaningful relationship between suppression of neutrophil elastase activity and reduction in exacerbations in brensocatib-treated patients with NCFBE, supporting further development of brensocatib for bronchiectasis.
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Bronquiectasia , Fibrose Cística , Adulto , Benzoxazóis , Bronquiectasia/tratamento farmacológico , Catepsina G , Dipeptidil Peptidases e Tripeptidil Peptidases/uso terapêutico , Fibrose , Humanos , Elastase de Leucócito/uso terapêutico , Mieloblastina , Oxazepinas , Serina Proteases/uso terapêuticoRESUMO
BACKGROUND: Nontuberculous mycobacterial pulmonary disease (NTM-PD) is an uncommon mycobacterial infection characterized by worsening lung function and increased health care resource utilization; however, the overall risk for hospitalization among patients with NTM-PD remains unclear. RESEARCH QUESTION: What is the hospitalization risk among older adults with NTM-PD? STUDY DESIGN AND METHODS: A retrospective, nested, case-control study was conducted by using the Medicare claims database. Cases were defined as patients with ≥ 2 NTM-PD claims ≥ 30 days apart between January 1, 2007, and December 31, 2015. The study included individuals aged ≥ 65 years with ≥ 12 months of continuous enrollment in both Parts A and B before the first NTM-PD diagnosis. Cases were matched 1:2 to Medicare beneficiaries without NTM-PD (control subjects) according to age and sex. Hospitalizations following the first NTM-PD claim were compared between case and control subjects by using univariate and multivariate analyses. RESULTS: A total of 35,444 case subjects and 65,467 matched control subjects (mean age, 76.6 years; 70% female; ≥ 87% White) were identified. Baseline comorbidities, particularly pulmonary comorbidities, were more common in case subjects than in control subjects (81.1% vs 17.7% for COPD; 44.6% vs 0.6% for bronchiectasis). All-cause hospitalization was observed in 65.7% of case subjects and 44.9% of control subjects. Unadjusted annual hospitalization rates were significantly (P < .05) greater among case subjects than control subjects. Case subjects also had a significantly shorter time to hospitalization than control subjects. The increased burden due to hospitalization was reflected in multivariate analysis adjusting for baseline comorbidities. All-cause hospitalization in patients with NTM-PD relative to control subjects was 1.2 times more likely (relative risk, 1.23; 95% CI, 1.21-1.25; P < .0001) with a 46% greater hazard (hazard ratio, 1.46; 95% CI, 1.43-1.50; P < .0001). INTERPRETATION: Patients with NTM-PD were significantly more likely to be hospitalized, had greater annualized hospitalization rates, and had shorter time to hospitalization than age- and sex-matched control subjects without NTM-PD. These findings highlight the significantly increased burden of hospitalizations among patients with NTM-PD.
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Hospitalização/estatística & dados numéricos , Pneumopatias/epidemiologia , Pneumopatias/microbiologia , Infecções por Mycobacterium não Tuberculosas/epidemiologia , Risco , Idoso , Estudos de Casos e Controles , Comorbidade , Feminino , Humanos , Masculino , Medicare , Estudos Retrospectivos , Estados Unidos/epidemiologiaRESUMO
BACKGROUND AND OBJECTIVES: Use of parenteral amikacin to treat refractory nontuberculous mycobacterial (NTM) lung disease is limited by systemic toxicity. A population pharmacokinetic model was developed using data pooled from two randomized trials to evaluate the pharmacokinetic properties of once-daily amikacin liposome inhalation suspension (ALIS) in patients with treatment-refractory NTM lung disease. METHODS: In phase 2 (TR02-112) and phase 3 (CONVERT) studies, patients with sputum cultures positive for Mycobacterium avium complex (both studies) or M. abscessus (TR02-112) despite ≥ 6 months of guideline-based therapy were treated with once-daily ALIS 590 mg. RESULTS: Fifty-three patients (28 Japanese; 25 White) were assessed. At baseline and ≈ 6 months after daily dosing, median maximum concentration (Cmax) was < 2 mg/L and median area under the concentration-time curve (AUC0-24) was < 20 mg·h/L, suggesting low systemic exposure at both time points. Exposure estimates were similar between Japanese and White patients. The median unchanged amikacin fraction excreted in urine was < 10% of inhaled dose throughout the TR02-112 study, indicating that relatively small amounts reached systemic circulation. Median t1/2 was 5.5 h. Amikacin concentrations were much higher in sputum than in serum, demonstrating the ability to achieve higher drug concentration at the site of infection. Median sputum amikacin concentrations in the CONVERT study were high at 1-4 h postdose (range 242-426 µg/g) and decreased by 8 h (median 7 µg/g). CONCLUSIONS: Systemic exposure to amikacin in serum and urine following once-daily ALIS administration in patients with treatment-refractory NTM lung disease was notably lower than that previously reported for parenteral amikacin. TRIAL REGISTRATION: ClinicalTrials.gov NCT01315236 (registered March 15, 2011) and NCT02344004 (registered January 22, 2015).
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Amicacina/administração & dosagem , Antibacterianos/administração & dosagem , Pneumopatias/tratamento farmacológico , Infecção por Mycobacterium avium-intracellulare/tratamento farmacológico , Administração por Inalação , Adulto , Idoso , Idoso de 80 Anos ou mais , Amicacina/farmacocinética , Antibacterianos/farmacocinética , Área Sob a Curva , Método Duplo-Cego , Feminino , Humanos , Lipossomos , Pneumopatias/microbiologia , Masculino , Pessoa de Meia-Idade , Complexo Mycobacterium avium/isolamento & purificação , Infecção por Mycobacterium avium-intracellulare/microbiologia , Estudos Prospectivos , Fatores de Tempo , Distribuição Tecidual , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: In the CONVERT study, treatment with amikacin liposome inhalation suspension (ALIS) added to guideline-based therapy (GBT) met the primary end point of increased culture conversion by month 6 in patients with treatment-refractory Mycobacterium avium complex lung disease (ALIS plus GBT, 29% [65/224] vs GBT alone, 8.9% [10/112]; P < .0001). RESEARCH QUESTION: In patients who achieved culture conversion by month 6 in the CONVERT study, was conversion sustained (negative sputum culture results for 12 months with treatment) and durable (negative sputum culture results for 3 months after treatment) and were there any additional safety signals associated with a full treatment course of 12 months after conversion? STUDY DESIGN AND METHODS: Adults were randomized 2:1 to receive ALIS plus GBT or GBT alone. Patients achieving culture conversion by month 6 continued therapy for 12 months followed by off-treatment observation. RESULTS: More patients randomized to ALIS plus GBT (intention-to-treat population) achieved conversion that was both sustained and durable 3 months after treatment vs patients randomized to GBT alone (ALIS plus GBT, 16.1% [36/224] vs GBT alone, 0% [0/112]; P < .0001). Of the patients who achieved culture conversion by month 6, 55.4% of converters (36/65) in the ALIS plus GBT treated arm vs no converters (0/10) in the GBT alone arm achieved sustained and durable conversion (P = .0017). Relapse rates through 3 months after treatment were 9.2% (6/65) in the ALIS plus GBT arm and 30.0% (3/10) in the GBT alone arm. Common adverse events among ALIS plus GBT-treated patients (dysphonia, cough, dyspnea, hemoptysis) occurred mainly within the first 8 months of treatment. INTERPRETATION: In a refractory population, conversion was sustained and durable in more patients treated with ALIS plus GBT for 12 months after conversion than in those treated with GBT alone. No new safety signals were associated with 12 months of treatment after conversion. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02344004; URL: www.clinicaltrials.gov.
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Amicacina , Monitoramento de Medicamentos/métodos , Efeitos Adversos de Longa Duração , Pneumopatias , Complexo Mycobacterium avium/isolamento & purificação , Infecção por Mycobacterium avium-intracellulare , Administração por Inalação , Adulto , Amicacina/administração & dosagem , Amicacina/efeitos adversos , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Técnicas Bacteriológicas/métodos , Feminino , Humanos , Lipossomos , Efeitos Adversos de Longa Duração/classificação , Efeitos Adversos de Longa Duração/diagnóstico , Pneumopatias/diagnóstico , Pneumopatias/tratamento farmacológico , Pneumopatias/microbiologia , Masculino , Infecção por Mycobacterium avium-intracellulare/diagnóstico , Infecção por Mycobacterium avium-intracellulare/tratamento farmacológico , Infecção por Mycobacterium avium-intracellulare/fisiopatologia , Escarro/microbiologia , Resultado do TratamentoRESUMO
Rationale: Patients with refractory Mycobacterium avium complex (MAC) lung disease have limited treatment options. In the CONVERT study, amikacin liposome inhalation suspension (ALIS) added to guideline-based therapy (GBT) increased culture conversion rates versus GBT alone by Month 6. Limited data are available regarding >6-month treatment in a refractory population.Objectives: Evaluate 12-month safety, tolerability, and efficacy of ALIS+GBT.Methods: Adults with refractory MAC lung disease not achieving culture conversion by CONVERT Month 6 could enroll in this open-label extension (INS-312) to receive 590 mg once-daily ALIS+GBT for 12 months. Two cohorts enrolled: the "ALIS-naive" cohort included patients randomized to GBT alone in CONVERT, and the "prior-ALIS" cohort included those randomized to ALIS+GBT in CONVERT. Safety and tolerability of ALIS over 12 months (primary endpoint) and culture conversion by Months 6 and 12 were assessed.Results: In the ALIS-naive cohort, 83.3% of patients (n = 75/90) experienced respiratory treatment-emergent adverse events (TEAEs), and 35.6% (n = 32) had serious TEAEs; 26.7% (n = 24) achieved culture conversion by Month 6 and 33.3% (n = 30) by Month 12. In the prior-ALIS cohort, 46.6% of patients (n = 34/73) experienced respiratory TEAEs, and 27.4% (n = 20) had serious TEAEs; 9.6% (n = 7) achieved culture conversion by Month 6 (≤14 mo ALIS exposure) and 13.7% (n = 10) by Month 12 (≤20 mo ALIS exposure). Nephrotoxicity-related TEAEs and measured hearing decline were infrequent in both cohorts.Conclusions: In up to 20 months of ALIS use, respiratory TEAEs were common, nephrotoxicity and hearing decline were infrequent, and culture conversion continued beyond 6 months of therapy.Clinical trial registered with www.clinicaltrials.gov (NCT02628600).
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Pneumopatias , Infecção por Mycobacterium avium-intracellulare , Administração por Inalação , Adulto , Amicacina/efeitos adversos , Antibacterianos/efeitos adversos , Humanos , Lipossomos/uso terapêutico , Pneumopatias/tratamento farmacológico , Complexo Mycobacterium avium , Infecção por Mycobacterium avium-intracellulare/tratamento farmacológico , Resultado do TratamentoRESUMO
BACKGROUND: Failure to complete the medical evaluation for renal transplantation may impede access to transplantation and preclude the possibility of preemptive transplantation. We sought to (1) characterize completion rates of the transplantation medical evaluation and (2) determine factors associated with completion of the evaluation. We hypothesized that patients not on dialysis therapy complete the evaluation process more quickly than patients receiving dialysis. METHODS: Between September 2002 and September 2003, a total of 175 patients who were evaluated for renal transplantation at the Hospital of the University of Pennsylvania were enrolled in a prospective cohort study. Patients completed a self-administered questionnaire. The progress of patients' medical evaluations, including completion of requested tests and evaluations, was extracted from the electronic medical record. RESULTS: During follow-up, 100 patients (57.1%) completed the evaluation, including tests and evaluations requested by the transplant team, whereas 49 patients (28.0%) had tests still pending. The remaining patients died (2.3%), lost interest in transplantation (1.1%), or were immediately (7.4%) or later (4.0%) declared medically ineligible for transplantation. In the multivariable Cox proportional hazards model, black race (adjusted hazard ratio, 0.63; 95% confidence interval, 0.40 to 1.00; P = 0.05) was associated with time to completion of the transplantation evaluation, but receiving maintenance dialysis at the time of the initial transplantation evaluation was not (adjusted hazard ratio, 0.92; 95% confidence interval, 0.60 to 1.42; P = 0.72). CONCLUSION: Completion of the medical evaluation for transplantation is slower in blacks than nonblacks. We were unable to detect a significant difference between dialysis and nondialysis patients in rates of completion of the evaluation.
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Falência Renal Crônica/cirurgia , Transplante de Rim , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Cooperação do Paciente/estatística & dados numéricos , Cuidados Pré-Operatórios/estatística & dados numéricos , Diálise Renal , Inquéritos e Questionários , Adolescente , Adulto , Negro ou Afro-Americano/estatística & dados numéricos , Idoso , Estudos de Coortes , Escolaridade , Feminino , Hospitais Universitários/estatística & dados numéricos , Humanos , Falência Renal Crônica/psicologia , Falência Renal Crônica/terapia , Masculino , Sistemas Computadorizados de Registros Médicos , Pessoa de Meia-Idade , Seleção de Pacientes , Pennsylvania/epidemiologia , Modelos de Riscos Proporcionais , Estudos Prospectivos , Apoio Social , Fatores Socioeconômicos , Fatores de Tempo , Obtenção de Tecidos e Órgãos , Listas de EsperaRESUMO
BACKGROUND: Survival following liver transplantation for hepatitis C virus (HCV) is significantly poorer than for liver transplants performed for other causes of chronic liver disease. The factors responsible for the inferior outcome in HCV+ recipients, and whether they differ from factors associated with survival in HCV- recipients, are unknown. METHODS: The UNOS database was analyzed to identify factors associated with outcome in HCV+ and HCV- recipients. Kaplan-Meier graft and patient survival and Cox proportional hazards analysis were conducted on 13,026 liver transplants to identify the variables that were differentially associated with outcome survival in HCV- and HCV+ recipients. RESULTS: Of the 13,026 recipients, 7386 (56.7%) were HCV- and 5640 were HCV+. In HCV- and HCV+ recipient populations, five-year patient survival rates were 83.5% vs. 74.6% (P<0.00001) and five-year graft survival rates 80.6% vs. 69.9% (P<0.00001), respectively. In a multivariate regression model, donor age and recipient creatinine were observed to be significant covariates in both groups, while donor race, cold ischemia time (CIT), female to male transplants, and recipient albumin were independent predictors of survival of HCV- recipients. In the HCV+ cohort, recipient race, warm ischemia time (WIT), and diabetes also independently predicted graft survival. CONCLUSIONS: A number of parameters are differentially correlated with outcome in HCV- and HCV+ recipients of orthotopic liver transplantation. These findings may not only have practical implications in the selection and management of liver transplant patients, but also may shed new insight into the biology of HCV infection posttransplant.
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Hepatite C/cirurgia , Transplante de Fígado/fisiologia , Fatores Etários , Feminino , Sobrevivência de Enxerto/fisiologia , Teste de Histocompatibilidade , Humanos , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Grupos Raciais , Estudos Retrospectivos , Análise de Sobrevida , Doadores de Tecidos/estatística & dados numéricos , Quimeras de TransplanteRESUMO
BACKGROUND: Acute and chronic renal dysfunction (ARD, CRD) are common complications after liver transplantation and are associated with poor outcome. METHODS: We reviewed the results of 181 liver transplants performed in our institution between January 1, 1998 and December 31, 2000 in which the recipients were alive with good liver function at the end of the follow-up period (mean 2.7 years). Renal dysfunction was defined as a serum creatinine (Cr) greater than or equal to 2 mg/dL in both acute and chronic settings. RESULTS: The incidence of ARD during the first posttransplant week was 39.2% (n=71), whereas late CRD occurred in 6.0% (n=11) of the patients by the end of the follow-up period. Among the variables we examined for association with CRD, five factors were found to be statistically significant in univariate analysis: pretransplant diabetes (PRTDM) (0.000), Cr greater than or equal to 2 during the first postoperative week (0.003), posttransplant diabetes (POTDM) (0.014), age greater than 50 (0.025), and tacrolimus level greater than 15 ng/mL at postoperative day 15 (0.058). In binary logistic regression analysis, PRTDM (odds ratio [OR]=5.7, 95% confidence interval [CI]) and early postoperative ARD (OR=10.2 95% CI) remained consistently significant. Nine of 11 patients with CRD also had a history of ARD during the first postoperative week. These patients progressed to CRD despite the fact that seven of nine had normalized their renal function by day 90 posttransplant. CONCLUSION: We suggest that a combination of events during the first postoperative week after liver transplant serve as a physiologic "stress test" for the kidneys. Patients who fail the test (peak Cr >/=2 mg/dL during the first postoperative week) as well as the patients with diabetes mellitus are at increased risk of CRD. In such cases, conversion to a less nephrotoxic regimen may be beneficial.
Assuntos
Nefropatias/etiologia , Rim/fisiopatologia , Transplante de Fígado/efeitos adversos , Doença Aguda , Adulto , Idoso , Envelhecimento , Doença Crônica , Creatinina/sangue , Complicações do Diabetes , Relação Dose-Resposta a Droga , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Incidência , Nefropatias/sangue , Nefropatias/epidemiologia , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Prognóstico , Estudos Retrospectivos , Tacrolimo/administração & dosagem , Tacrolimo/efeitos adversosRESUMO
BACKGROUND: The Model for End-Stage Liver Disease (MELD) has been found to accurately predict pretransplant mortality and is a valuable system for ranking patients in greatest need of liver transplantation. It is unknown whether a higher MELD score also predicts decreased posttransplant survival. METHODS: We examined a cohort of patients from the United Network for Organ Sharing (UNOS) database for whom the critical pretransplant recipient values needed to calculate the MELD score were available (international normalized ratio of prothrombin time, total bilirubin, and creatinine). In these 2,565 patients, we analyzed whether the MELD score predicted graft and patient survival and length of posttransplant hospitalization. RESULTS: In contrast with its ability to predict survival in patients with chronic liver disease awaiting liver transplant, the MELD score was found to be poor at predicting posttransplant outcome except for patients with the highest 20% of MELD scores. We developed a model with four variables not included in MELD that had greater ability to predict 3-month posttransplant patient survival, with a c-statistic of 0.65, compared with 0.54 for the pretransplant MELD score. These pretransplant variables were recipient age, mechanical ventilation, dialysis, and retransplantation. Recipients with any two of the three latter variables showed a markedly diminished posttransplant survival rate. CONCLUSIONS: The MELD score is a relatively poor predictor of posttransplant outcome. In contrast, a model based on four pretransplant variables (recipient age, mechanical ventilation, dialysis, and retransplantation) had a better ability to predict outcome. Our results support the use of MELD for liver allocation and indicate that statistical modeling, such as reported in this article, can be used to identify futile cases in which expected outcome is too poor to justify transplantation.
Assuntos
Análise Discriminante , Falência Hepática/cirurgia , Transplante de Fígado , Modelos Teóricos , Adulto , Estudos de Coortes , Bases de Dados Factuais , Feminino , Sobrevivência de Enxerto , Recursos em Saúde/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Cuidados Pós-Operatórios , Prognóstico , Modelos de Riscos Proporcionais , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Preemptive renal transplantation (PRT) has been associated with improved allograft and patient survival rates and requires that the medical evaluation for suitability for transplantation occurs before the initiation of maintenance dialysis. The aim of this study was to understand the factors associated with the timing of evaluation for renal transplantation relative to the initiation of dialysis. METHODS: In a prospective study, patients who presented to the Renal Transplant Evaluation Clinic at the Hospital of the University of Pennsylvania completed a self-administered questionnaire. RESULTS: Of the 290 patients included in the analysis, 44.5% were not yet on dialysis. Non-dialysis-dependent persons had seen a nephrologist for a mean of 71.0 +/- 84.7 months before transplant evaluation, whereas persons who presented for nonpreemptive evaluation reported first seeing a nephrologist a mean of 25.0 +/- 42.8 months before dialysis initiation (P < 0.001). First learning about transplantation from somebody other than a nephrologist significantly increased the odds of undergoing nonpreemptive transplant evaluation (adjusted odds ratio [OR], 2.46; P = 0.01). The odds of nonpreemptive evaluation were decreased for every additional 3 months of chronic renal disease care by a nephrologist (adjusted OR, 0.96; P < 0.001) and significantly decreased if the patient reported having a spouse as a potential donor (adjusted OR, 0.41; P = 0.03). CONCLUSION: There is substantial opportunity for transplant evaluation before dialysis initiation that is not capitalized on and is affected by the duration of care provided by a nephrologist and the type of potential living donor.
Assuntos
Falência Renal Crônica/cirurgia , Transplante de Rim/normas , Seleção de Pacientes , Inquéritos e Questionários , Feminino , Sobrevivência de Enxerto , Humanos , Falência Renal Crônica/psicologia , Falência Renal Crônica/terapia , Transplante de Rim/psicologia , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Nefrologia , Razão de Chances , Educação de Pacientes como Assunto , Estudos Prospectivos , Diálise Renal/psicologia , Diálise Renal/normas , Fatores de TempoRESUMO
BACKGROUND: Pharmacokinetic modeling supports trough monitoring of everolimus, but prospective data comparing this approach versus mycophenolate mofetil (MMF) in de novo cardiac transplant recipients are currently unavailable. METHODS: In a 12-month multicenter open-label study, cardiac transplant patients received everolimus (trough level 3-8 ng/mL) with reduced cyclosporine A (CsA) or MMF (3 g/day) with standard CsA, both with corticosteroids+/-induction therapy. RESULTS: In total, 176 patients were randomized (everolimus 92, MMF 84). Mean creatinine clearance was 72.5+/-27.9 and 76.8+/-32.1 mL/min at baseline, 65.4+/-24.7 and 72.2+/-26.2 mL/min at month 6, and 68.7+/-27.7 and 71.8+/-29.8 mL/min at month 12 with everolimus and MMF, respectively. The primary endpoint was not met since calculated CrCl at month 6 posttransplant was 6.9 mL/min lower with everolimus, exceeding the predefined margin of 6 mL/min. However, by month 12 the between-group difference had narrowed versus baseline (3.1 mL/min). All efficacy endpoints were noninferior for everolimus versus MMF. The 12-month incidence of biopsy-proven acute rejection International Heart and Lung Transplantation grade more than or equal to 3A was 21 of 92 (22.8%) with everolimus and 25 of 84 (29.8%) with MMF. Adverse events were consistent with class effects including less-frequent cytomegalovirus infection with everolimus (4 [4.4%]) than MMF (14 [16.9%], P=0.01). CONCLUSION: Concentration-controlled everolimus with reduced CsA results in similar renal function and equivalent efficacy compared with MMF with standard CsA at 12 months after cardiac transplantation.
Assuntos
Ciclosporina/administração & dosagem , Rejeição de Enxerto/prevenção & controle , Transplante de Coração , Imunossupressores/administração & dosagem , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Ácido Micofenólico/análogos & derivados , Sirolimo/análogos & derivados , Corticosteroides/administração & dosagem , Adulto , Biópsia , Creatinina/sangue , Ciclosporina/efeitos adversos , Quimioterapia Combinada , Europa (Continente) , Everolimo , Feminino , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/patologia , Transplante de Coração/efeitos adversos , Humanos , Imunossupressores/efeitos adversos , Rim/fisiopatologia , Nefropatias/induzido quimicamente , Nefropatias/fisiopatologia , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/efeitos adversos , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
Since 1988 over 10 000 simultaneous cadaveric pancreas-kidney transplants (SPK) have been performed in the United States among patients with end-stage renal disease due to Type 1 diabetes (T1DM). The two aims of this study were to assess the impact on kidney allograft survival of (i) SPK versus transplantation of a kidney alone (KA), and (ii) SPK prior to versus after initiation of chronic dialysis. This retrospective, non-concurrent cohort study examined registry data collected from 8323 patients waitlisted in the United States for an SPK and transplanted with either an SPK or a KA during January 1, 1990 - October 31, 2002. SPK recipients had an adjusted hazard ratio for kidney allograft loss of 0.63 (95% CI: 0.51-0.77, p < 0.001) compared to transplantation without pancreas allograft. SPK recipients who received their allografts prior to beginning chronic dialysis had a lower rate of kidney allograft loss than SPK recipients who received their transplant after initiation of chronic dialysis (adjusted hazard rates (HR) = 0.83, 95% CI: 0.69-0.99, p = 0.042). Simultaneous transplantation of pancreas-kidney compared to kidney transplantation alone and SPK prior to the initiation of chronic dialysis compared to SPK after initiation of dialysis were both associated with longer kidney allograft survival.
Assuntos
Sobrevivência de Enxerto , Transplante de Rim , Transplante de Pâncreas , Adolescente , Adulto , Diabetes Mellitus Tipo 1/cirurgia , Feminino , Rejeição de Enxerto , Humanos , Falência Renal Crônica/cirurgia , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
Nonadherence to immunosuppressive medications may partly explain the worse allograft outcomes among black recipients of renal transplants. In a prospective cohort study of recipients of deceased donor renal transplants, microelectronic cap monitors were placed on bottles of one immunosuppressive medication to (1) measure average daily percentage adherence during the first posttransplantation year and (2) determine the factors associated with adherence. A total of 278 transplant recipients who provided sufficient microelectronic adherence data were grouped into four categories of average daily percentage adherence: 95 to 100% adherence (41.0% of patients), 80 to 95% adherence (32.4%), 50 to 80% adherence (12.9%), and 0 to 50% adherence (13.7%). In the unadjusted ordinal logistic regression model, black race was associated with decreased adherence (odds ratio [OR], 0.43; 95% confidence interval [CI], 0.26 to 0.72; P = 0.001). Cause of renal disease, Powerful Others health locus of control, transplant center, and dosing frequency were also associated with adherence. After adjustment for transplant center and dosing frequency, the association between black race and decreased adherence was substantially attenuated (OR, 0.65; 95% CI, 0.38 to 1.14, P = 0.13). Transplant center (P = 0.003) and increased dosing frequency (OR, 0.43; 95% CI, 0.22 to 0.86, for three or four times per day dosing; OR, 2.35; 95% CI, 1.01 to 5.45, for daily dosing; versus two times per day dosing; P = 0.003) remained independently associated with adherence. Other baseline demographic, socioeconomic, medical, surgical, and psychosocial characteristics were not associated with adherence. The transplant center and dosing frequencies of immunosuppressive medications are associated with adherence and explain a substantial proportion of the race-adherence relationship.
Assuntos
Negro ou Afro-Americano , Instalações de Saúde , Imunossupressores/uso terapêutico , Transplante de Rim , Recusa do Paciente ao Tratamento , Adulto , Esquema de Medicação , Feminino , Rejeição de Enxerto/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Dialysis has been the long-established initial choice of treatment for persons with end-stage renal disease. Transplantation before dialysis, or preemptive renal transplantation (PRT), has been controversial because of the paucity of clinical evidence that has clarified the benefits vs. risks of this approach. However, several recent observational analyses indicate that PRT is the optimal strategy to benefit patients requiring renal replacement therapy. This current review will discuss the advantages that are associated with PRT, and will summarize studies that have investigated the impact of the timing of transplantation on outcomes. We will also discuss the utility of PRT from various perspectives, and describe the challenges ahead in expanding the opportunity of PRT for more patients.