RESUMEN
This study evaluated the current practices of selecting cold storage preservation solutions in Brazil and their impact on delayed graft function (DGF) incidence and 1-year outcomes in kidney transplant recipients. A retrospective cohort study was conducted, including 3,134 brain-dead deceased donor kidney transplants performed between 2014 and 2015 in 18 Brazilian centers. The most commonly used preservation solution was Euro-collins (EC, 55.4%), followed by Histidine-tryptophan-ketoglutarate (HTK, 30%) and Institut Georges Lopez (IGL-1, 14.6%). The incidence of DGF was 54.4%, with 11.7% of patients requiring dialysis for more than 14 days, indicating prolonged DGF. Upon adjusting for confounding variables, HTK demonstrated a significantly lower risk of DGF than EC (OR 0.7350.82500.926), as did IGL-1 (OR 0.6050.7120.837). Similar protective effects were observed for prolonged DGF when comparing HTK (OR 0.4780.5990.749) and IGL-1 (OR 0.4780.6810.749) against EC. No significant association was found between preservation solutions and 1-year death-censored graft survival. In conclusion, EC was the most frequently used cold storage perfusion solution, demonstrating a higher incidence and duration of DGF compared with HTK and IGL-1, but with no impact on 1-year graft survival.
Asunto(s)
Funcionamiento Retardado del Injerto , Trasplante de Riñón , Soluciones Preservantes de Órganos , Preservación de Órganos , Trasplante de Riñón/métodos , Humanos , Brasil/epidemiología , Femenino , Masculino , Estudios Retrospectivos , Adulto , Persona de Mediana Edad , Preservación de Órganos/métodos , Funcionamiento Retardado del Injerto/epidemiología , Supervivencia de Injerto/efectos de los fármacosRESUMEN
The induction of antigen (Ag)-specific tolerance and replacement of islet ß-cells are major ongoing goals for the treatment of type 1 diabetes (T1D). Our group previously showed that a hybrid insulin peptide (2.5HIP) is a critical autoantigen for diabetogenic CD4+ T cells in the NOD mouse model. In this study, we investigated whether induction of Ag-specific tolerance using 2.5HIP-coupled tolerogenic nanoparticles (NPs) could protect diabetic NOD mice from disease recurrence upon syngeneic islet transplantation. Islet graft survival was significantly prolonged in mice treated with 2.5HIP NPs, but not NPs containing the insulin B chain peptide 9-23. Protection in 2.5HIP NP-treated mice was attributed both to the simultaneous induction of anergy in 2.5HIP-specific effector T cells and the expansion of Foxp3+ regulatory T cells specific for the same Ag. Notably, our results indicate that effector function of graft-infiltrating CD4+ and CD8+ T cells specific for other ß-cell epitopes was significantly impaired, suggesting a novel mechanism of therapeutically induced linked suppression. This work establishes that tolerance induction with an HIP can delay recurrent autoimmunity in NOD mice, which could inform the development of an Ag-specific therapy for T1D.
Asunto(s)
Diabetes Mellitus Tipo 1/terapia , Supervivencia de Injerto/efectos de los fármacos , Insulina/administración & dosificación , Trasplante de Islotes Pancreáticos/métodos , Fragmentos de Péptidos/administración & dosificación , Animales , Autoantígenos/inmunología , Autoinmunidad/inmunología , Linfocitos T CD4-Positivos/inmunología , Diabetes Mellitus Tipo 1/prevención & control , Femenino , Islotes Pancreáticos/inmunología , Ratones , Ratones Endogámicos NOD , Nanopartículas/administración & dosificación , RecurrenciaRESUMEN
BACKGROUND: Immunosuppressive nonadherence is a risk factor for worse outcomes after kidney transplantation (KT). Brazil, having the world's largest public, fully covered transplantation system and the second-highest KT volume worldwide, provides a unique setting for studying multilevel correlates of nonadherence (patient, healthcare provider, transplant center, and healthcare system levels) independent of patients' financial burden. METHODS: By applying a multistage sampling approach, we included 1105 patients from 20 KT centers. Nonadherence to immunosuppressives (implementation phase) was defined as any deviation in taking or timing adherence and dose reduction assessed by the Basel Assessment of Adherence to Immunosuppressive Medications Scale. Based on Bronfenbrenner's ecological model, we assessed multilevel factors using established instruments and measures specifically developed for this study and analyzed their independent contribution to nonadherence by performing sequential logistic regression analysis. RESULTS: The nonadherence prevalence rate was 39.7%. The following factors were independently associated with nonadherence: Patient level-having a stable partner (odds ratio [OR]: 0.75; confidence interval [CI]: 0.58-0.97), nonadherence to appointments (OR: 2.98; CI: 2.03-4.39), and nonadherence to physical activity recommendations (OR: 1.84; CI: 1.38-2.46); and transplant center level-satisfaction with the waiting room structure (OR: 0.54; CI: 0.42-0.71), consultation >30 minutes (OR: 1.60; CI: 1.19-2.14), adequacy of the consultation frequency (OR: 0.62; CI: 0.43-0.90), and centers with >500 beds (OR: 0.58; CI: 0.46-0.73). CONCLUSIONS: As the first multicenter study assessing multilevel correlates of nonadherence in KT, our findings point to the need for multilevel interventions beyond the patient level, targeting transplant center practice patterns as an approach to tackle nonadherence.
Asunto(s)
Rechazo de Injerto/prevención & control , Supervivencia de Injerto/efectos de los fármacos , Inmunosupresores/uso terapéutico , Trasplante de Riñón , Cumplimiento de la Medicación , Adulto , Brasil , Estudios Transversales , Atención a la Salud , Femenino , Rechazo de Injerto/inmunología , Humanos , Inmunosupresores/efectos adversos , Trasplante de Riñón/efectos adversos , Masculino , Persona de Mediana Edad , Pautas de la Práctica en Medicina , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVES: Pediatric patients are at higher risk of nonadherence to immunosuppressive medication after kidney transplant and the resulting adverse outcomes. Factors associated with nonadherence vary, which follow an epidemiological framework and according to health system patterns. The Brazilian public health system covers all costs of kidney transplant, including immunosuppressive medications. We aimed to assess the prevalence and correlates of nonadherence to immunosuppressive medications in a pediatric kidney transplant population who received free access to immunosuppressive medications within the health care system. MATERIALS AND METHODS: In this single-center crosssectional study, we studied a convenience sample of 156 outpatients (< 18 years old) who were a minimum of 4 weeks posttransplant. Implementation nonadherence to immunosuppressive medications was measured by the 4 questions of the Basel Assessment of Adherence to Immunosuppressive Medications Scale. Multilevel correlates to non - adherence (patient, micro, and macro levels) were assessed. RESULTS: In our patient population, 61% were males, mean age was 13.6 ± 3.1 years, 77% were adolescents, and 84% received organs from deceased donors. We found that 33% were nonadherent to immuno - suppressive medications, mainly in timing (25%) and taking (10.9%) dimensions. Being an adolescent (odds ratio: 2.66; CI, 1.02-6.96), religion other than Catholic or Protestant (odds ratio: 4.33; CI, 1.13-16.67), and family income higher than 4 reference wages (odds ratio: 3.50; CI, 1.14-10.75) were factors associated with nonadherence. CONCLUSIONS: In our patient population of mostly adolescents, one-third displayed nonadherence to immunosuppressants. Unexpectedly, a higher economic profile, potentially representing better previous access to health care, was independently associated with nonadherence. This result highlights the need for identifying specific correlates to non - adherence before designing interventions.
Asunto(s)
Rechazo de Injerto/prevención & control , Supervivencia de Injerto/efectos de los fármacos , Inmunosupresores/uso terapéutico , Trasplante de Riñón , Cumplimiento de la Medicación , Adolescente , Conducta del Adolescente , Factores de Edad , Brasil , Niño , Conducta Infantil , Preescolar , Estudios Transversales , Costos de los Medicamentos , Femenino , Rechazo de Injerto/economía , Rechazo de Injerto/inmunología , Conocimientos, Actitudes y Práctica en Salud , Accesibilidad a los Servicios de Salud/economía , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/economía , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/economía , Masculino , Factores Socioeconómicos , Factores de Tiempo , Resultado del TratamientoRESUMEN
INTRODUCTION AND AIM: The interleukin-2 receptor antagonist; basiliximab is used to allow delayed introduction of Calcineurin inhibitors (CNI) after liver transplantation and thus delay their renal insult. However, there is only little evidence for the safety and the efficacy of this regimen. This study aimed to evaluate the effectiveness and safety of basiliximab induction in liver transplantation. MATERIALS AND METHODS: This study included 89 patients who were classified into two groups: standard triple immunosuppression (IS) regimen of steroid, tacrolimus (TAC) and mycophenolate mofetil (MMF) (n = 47) and induction IS regimen of basiliximab, low dose steroids and MMF with delayed introduction of CNI (n = 42). All patients were followed after liver transplantation for at least six months or until death. RESULTS: There were no significant differences in patient survival, graft dysfunction, infection rate or type, or wound healing between both groups. The acute rejection rate was equivalent in both groups. Renal dysfunction in the first six months post-transplant was less in the basiliximab group in comparison to the other group (7.1% and 19.1% respectively). CONCLUSION: Basiliximab-induced IS protocol is a safe regimen that reduces medium-term renal dysfunction and achieves similar survival without increasing the acute rejection or infection rate in liver transplantation recipients.
Asunto(s)
Basiliximab/uso terapéutico , Rechazo de Injerto/prevención & control , Supervivencia de Injerto/efectos de los fármacos , Inmunosupresores/uso terapéutico , Trasplante de Hígado , Adulto , Basiliximab/efectos adversos , Inhibidores de la Calcineurina/uso terapéutico , Quimioterapia Combinada , Egipto , Femenino , Rechazo de Injerto/inmunología , Rechazo de Injerto/mortalidad , Humanos , Inmunosupresores/efectos adversos , Trasplante de Hígado/efectos adversos , Trasplante de Hígado/mortalidad , Masculino , Persona de Mediana Edad , Ácido Micofenólico/uso terapéutico , Esteroides/uso terapéutico , Tacrolimus/uso terapéutico , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVE: Melatonin has anti-inflammatory and antioxidant properties that can influence tissue growth and apoptosis. This aspect may influence the success of organ transplantation. To evaluate the relationship between melatonin and organ transplantation. METHODS: A systematic review was performed in PubMed databases using the search terms: "melatonin physiology" or "melatonin therapy" and "transplant pharmacology" or "transplant physiology" or "transplant therapy" or "Transplant therapy". Experiments on the organs of the reproductive system were not included. After analysis, five articles were selected after reading the title and abstract of 50 manuscripts. The works were divided into two aspects: a) analysis of the influence of the organ transplantation procedure on melatonin production; b) action of melatonin on organ transplantation. RESULTS: The cardiac transplantation surgical procedure, immunosuppression, and graft did not influence melatonin secretion in rodents, but there was a significant reduction of melatonin in the renal transplantation procedure in patients with renal insufficiency. Melatonin administration in experimental models decreased rejection and improved transplant success. CONCLUSION: Studies show that melatonin can reduce organ and species dependence, and the use of melatonin decreases graft rejection.
Asunto(s)
Antioxidantes/administración & dosificación , Rechazo de Injerto/prevención & control , Melatonina/administración & dosificación , Trasplante de Órganos , Animales , Supervivencia de Injerto/efectos de los fármacos , Trasplante de Corazón , Humanos , Terapia de Inmunosupresión , Trasplante de Riñón , Melatonina/fisiología , RatasRESUMEN
BACKGROUND: Tacrolimus (TAC) is the most important agent for maintenance immunosuppression and prevention of immunologic injury to the renal allograft, yet there remains no consensus on how best to monitor drug therapy. Both high TAC intrapatient variability and low TAC time in therapeutic range (TTR) have been associated with risk of de novo donor-specific antibodies (dnDSA). In this study, we hypothesized that the risk associated with high TAC coefficient of variation (CV) is a result of low TAC TTR rather than the variability itself. METHODS: We analyzed the risk of dnDSA, acute rejection, or death-censored graft loss by non-dosed-corrected TAC CV and TAC TTR during the first posttransplant year in a cohort of 538 patients with a median follow-up period of 4.1 years. RESULTS: Patients with CV >44.2% and TTR <40% (high intrapatient variability and low TTR) had a high risk of dnDSA (adjusted OR = 4.93, 95% confidence interval = 2.02-12.06, P < 0.001) and death-censored graft loss by 5 years (adjusted HR = 4.00, 95% confidence interval = 1.31-12.24, P = 0.015) when compared with patients with CV >44.2% and TTR ≥40% (high intrapatient variability and optimal TTR), while the latter patients had similar risk to patients with CV <44.2% (lower intrapatient variability). CONCLUSIONS: These data suggest that previously reported immunologic risk associated with high TAC intrapatient variability is due to time outside of therapeutic range rather than variability in and of itself when evaluating absolute non-dose-corrected TAC levels irrespective of reason or indication.
Asunto(s)
Inhibidores de la Calcineurina/uso terapéutico , Monitoreo de Drogas , Rechazo de Injerto/prevención & control , Antígenos HLA/inmunología , Inmunosupresores/uso terapéutico , Isoanticuerpos/sangre , Trasplante de Riñón , Tacrolimus/uso terapéutico , Adulto , Biomarcadores/sangre , Inhibidores de la Calcineurina/efectos adversos , Inhibidores de la Calcineurina/sangre , Femenino , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/inmunología , Rechazo de Injerto/mortalidad , Supervivencia de Injerto/efectos de los fármacos , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/sangre , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/mortalidad , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Tacrolimus/efectos adversos , Tacrolimus/sangre , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Pancreas transplant is an effective treatment for insulin-dependent diabetic individuals with end-stage renal disease, yet immunosuppression-associated adverse events may adversely affect patient and graft survival. The aim of the study was to document whether mammalian target of rapamycin inhibitors (mTORi) are safe and effective as a second-line drug after pancreas transplant. METHODOLOGY: An observational single-center study was performed in a cohort of 490 simultaneous pancreas-kidney transplant and 45 pancreas-after-kidney transplant individuals after conversion to mTORi (n = 13) owing to adverse events of either tacrolimus or mycophenolate. RESULTS: mTORi conversion was performed 11.5 ± 10.1 (range, 1-28) months after pancreas transplant, mainly owing to cytomegalovirus infection and gastrointestinal intolerance. We frequently observed clinical complications after mTORi conversion, yet creatinine, eGFR, proteinuria, fasting plasma glucose, HbA1c, and C-peptide remained stable throughout the study (mean follow-up 8.2 ± 5, range 1-17) years, as did the lipid profile (P > .05). However, graft loss occurred in almost 20% of patients owing to chronic alterations. LIMITATIONS: The small number of patients and a single-center cohort were limitations of the study. CONCLUSIONS: Late mTORi conversion is a safe and effective approach when tacrolimus or mycophenolate-mediated adverse events occur after pancreas transplant.
Asunto(s)
Everolimus/uso terapéutico , Inmunosupresores/uso terapéutico , Trasplante de Páncreas/métodos , Sirolimus/uso terapéutico , Adulto , Sustitución de Medicamentos/métodos , Femenino , Rechazo de Injerto/prevención & control , Supervivencia de Injerto/efectos de los fármacos , Humanos , Terapia de Inmunosupresión/métodos , Trasplante de Riñón , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
SUMMARY Melatonin has anti-inflammatory and antioxidant properties that can influence tissue growth and apoptosis. This aspect may influence the success of organ transplantation. OBJECTIVE To evaluate the relationship between melatonin and organ transplantation. METHODS A systematic review was performed in PubMed databases using the search terms: "melatonin physiology" or "melatonin therapy" and "transplant pharmacology" or "transplant physiology" or "transplant therapy" or "Transplant therapy". Experiments on the organs of the reproductive system were not included. After analysis, five articles were selected after reading the title and abstract of 50 manuscripts. The works were divided into two aspects: a) analysis of the influence of the organ transplantation procedure on melatonin production; b) action of melatonin on organ transplantation. RESULTS The cardiac transplantation surgical procedure, immunosuppression, and graft did not influence melatonin secretion in rodents, but there was a significant reduction of melatonin in the renal transplantation procedure in patients with renal insufficiency. Melatonin administration in experimental models decreased rejection and improved transplant success. CONCLUSION Studies show that melatonin can reduce organ and species dependence, and the use of melatonin decreases graft rejection.
RESUMO A melatonina tem propriedades anti-inflamatórias e antioxidantes que podem influenciar o crescimento e a apoptose dos tecidos. Esse aspecto pode influenciar o sucesso do transplante de órgãos. OBJETIVO Avaliar a relação entre a melatonina e o transplante de órgãos. MÉTODO A revisão sistemática foi realizada nas bases de dados do PubMed, usando os termos de pesquisa: "fisiologia da melatonina" ou "terapêutica da melatonina" e "farmacologia do transplante" ou "fisiologia do transplante" ou "terapêutica do transplante" ou "terapia do transplante". Não foram incluídos os experimentos sobre os órgãos do sistema reprodutivo. Após análise, cinco artigos foram selecionados após a leitura do título e do resumo de 50 manuscritos. Os trabalhos foram divididos em duas vertentes: a) análise da influência do procedimento de transplante de órgão na produção de melatonina; b) ação da melatonina sobre o transplante de órgãos. RESULTADOS O procedimento cirúrgico do transplante cardíaco, a imunossupressão e o enxerto não influenciaram a secreção de melatonina em roedores, mas houve redução significante da melatonina nos casos do procedimento de transplante renal em pacientes com insuficiência renal. A ministração de melatonina em modelos experimentais diminuiu a rejeição e melhorou o sucesso de transplante. CONCLUSÃO Os estudos mostram que a melatonina pode reduzir a dependência da espécie e do órgão e que o emprego da melatonina diminui a rejeição do órgão.
Asunto(s)
Humanos , Animales , Ratas , Trasplante de Órganos , Rechazo de Injerto/prevención & control , Melatonina/administración & dosificación , Antioxidantes/administración & dosificación , Trasplante de Corazón , Terapia de Inmunosupresión , Trasplante de Riñón , Supervivencia de Injerto/efectos de los fármacos , Melatonina/fisiologíaRESUMEN
The majority of cells comprising the inflammatory infiltrates in kidney allografts undergoing acute and/or chronic rejection are typically T cells and monocyte/macrophages with B cells, plasma cells, and eosinophils accounting for <5%. In a significant minority of biopsies, B lineage cells (B cells and/or plasma cells) may be found more abundantly. Although plasma cell infiltrates tend to be more diffuse, B cells tend to aggregate into nodules that may mature into tertiary lymphoid organs. Given the ability to target B cells with anti-CD20 monoclonal antibodies and plasma cells with proteasome inhibitors and anti-CD38 monoclonal antibodies, it is increasingly important to determine the significance of such infiltrates. Both cell types are potential effectors of rejection, but both also have a tolerizing potential. B cell infiltrates have been associated with steroid resistance and reduced graft survival in some studies but not in others, and their presence should not prompt automatic depletional therapy. Plasma cell-rich infiltrates tend to occur later, may be associated with cell-mediated and/or antibody-mediated rejection, and portend an adverse outcome. Viral infection and malignancy must be ruled out. Randomized controlled trials are needed to determine the appropriateness of specific therapy when B cells and/or plasma cells are found. No strong therapeutic recommendations can be made at this time.
Asunto(s)
Linfocitos B/inmunología , Linaje de la Célula , Rechazo de Injerto/inmunología , Supervivencia de Injerto , Trasplante de Riñón , Células Plasmáticas/inmunología , Animales , Linfocitos B/efectos de los fármacos , Linfocitos B/metabolismo , Rechazo de Injerto/sangre , Rechazo de Injerto/prevención & control , Supervivencia de Injerto/efectos de los fármacos , Humanos , Inmunosupresores/uso terapéutico , Trasplante de Riñón/efectos adversos , Fenotipo , Células Plasmáticas/efectos de los fármacos , Células Plasmáticas/metabolismo , Resultado del TratamientoRESUMEN
BACKGROUND AND OBJECTIVES: FSGS recurrence after kidney transplantation is a major risk factor for graft loss. However, the natural history, clinical predictors, and response to treatment remain unclear because of small sample sizes and poor generalizability of single-center studies, and disease misclassification in registry-based studies. We therefore aimed to determine the incidence, predictors, and treatment response of recurrent FSGS in a large cohort of kidney transplant recipients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Post-Transplant Glomerular Disease (TANGO) project is an observational, multicenter, international cohort study that aims to investigate glomerular disease recurrence post-transplantation. Transplant recipients were screened for the diagnosis of idiopathic FSGS between 2005 and 2015 and details were recorded about the transplant, clinical outcomes, treatments, and other risk factors. RESULTS: Among 11,742 kidney transplant recipients screened for FSGS, 176 had a diagnosis of idiopathic FSGS and were included. FSGS recurred in 57 patients (32%; 95% confidence interval [95% CI], 25% to 39%) and 39% of them lost their graft over a median of 5 (interquartile range, 3.0-8.1) years. Multivariable Cox regression revealed a higher risk for recurrence with older age at native kidney disease onset (hazard ratio [HR], 1.37 per decade; 95% CI, 1.09 to 1.56). Other predictors were white race (HR, 2.14; 95% CI, 1.08 to 4.22), body mass index at transplant (HR, 0.89 per kg/m2; 95% CI, 0.83 to 0.95), and native kidney nephrectomies (HR, 2.76; 95% CI, 1.16 to 6.57). Plasmapheresis and rituximab were the most frequent treatments (81%). Partial or complete remission occurred in 57% of patients and was associated with better graft survival. CONCLUSIONS: Idiopathic FSGS recurs post-transplant in one third of cases and is associated with a five-fold higher risk of graft loss. Response to treatment is associated with significantly better outcomes but is achieved in only half of the cases.
Asunto(s)
Glomeruloesclerosis Focal y Segmentaria/cirugía , Supervivencia de Injerto , Trasplante de Riñón/efectos adversos , Adulto , Brasil , Europa (Continente) , Femenino , Glomeruloesclerosis Focal y Segmentaria/diagnóstico , Glomeruloesclerosis Focal y Segmentaria/fisiopatología , Supervivencia de Injerto/efectos de los fármacos , Humanos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Plasmaféresis , Recurrencia , Retratamiento , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Rituximab/uso terapéutico , Factores de Tiempo , Resultado del Tratamiento , Estados UnidosRESUMEN
Host cell competition is a major barrier to engraftment after in utero hematopoietic cell transplantation (IUHCT). Here we describe a cell-engineering strategy using glycogen synthase kinase-3 (GSK3) inhibitor-loaded nanoparticles conjugated to the surface of donor hematopoietic cells to enhance their proliferation kinetics and ability to compete against their fetal host equivalents. With this approach, we achieved remarkable levels of stable, long-term hematopoietic engraftment for up to 24 weeks post-IUHCT. We also show that the salutary effects of the nanoparticle-released GSK3 inhibitor are specific to donor progenitor/stem cells and achieved by a pseudoautocrine mechanism. These results establish that IUHCT of hematopoietic cells decorated with GSK3 inhibitor-loaded nanoparticles can produce therapeutic levels of long-term engraftment and could therefore allow single-step prenatal treatment of congenital hematological disorders.
Asunto(s)
Comunicación Autocrina , Ingeniería Celular , Inhibidores Enzimáticos , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Supervivencia de Injerto/efectos de los fármacos , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/metabolismo , Nanopartículas/química , Animales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Femenino , Ratones , Ratones Endogámicos BALB CRESUMEN
OBJECTIVES: To describe the incidence of cytomegalovirus (CMV) infection/disease in kidney transplant recipients receiving an mTOR-inhibitor-containing immunosuppressive regimen without prophylactic CMV treatment. METHODS: This single-center retrospective cohort analysis included all de novo kidney transplant recipients (09/15/2015-07/31/2017) receiving 3 mg/kg single dose of rabbit antithymocyte globulin induction, tacrolimus, everolimus, and prednisone. Preemptive therapy was initiated only in patients deemed at higher risk for CMV infection: (a) D+/R- CMV patients; (b) after treatment for acute rejection (ARt); and (c) after everolimus discontinuation (EVRd). RESULTS: Of 230 patients, there were no episodes of CMV disease among 217 (94%) without criteria to initiate preemptive therapy. Of 77 (33.5%) patients initiating preemptive therapy, 13 were D+/R-, 30 were ARt, and 34 were EVRd. The overall incidence of first CMV infection/disease was 6% (46.1% in D+/R-, 13.3% ARt [all patients had also discontinued everolimus], and 11.8% after early [<90 days] EVRd). The incidence of biopsy-proven acute rejection was 5.6%, and median glomerular filtration rate at month 12 was 47 mL/min/1.73m2 . One-year patient and death-censored graft survivals were 97.4% and 98.1%. CONCLUSION: This study suggests that everolimus-containing immunosuppressive regimen reduces the need for preventive strategies for CMV infection in the majority of kidney transplant recipients, reducing antiviral drug-associated toxicities and healthcare-related expenditures.
Asunto(s)
Infecciones por Citomegalovirus/tratamiento farmacológico , Citomegalovirus/aislamiento & purificación , Rechazo de Injerto/tratamiento farmacológico , Supervivencia de Injerto/efectos de los fármacos , Inmunosupresores/administración & dosificación , Trasplante de Riñón/efectos adversos , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Adulto , Suero Antilinfocítico/administración & dosificación , Brasil/epidemiología , Infecciones por Citomegalovirus/epidemiología , Infecciones por Citomegalovirus/microbiología , Everolimus/administración & dosificación , Femenino , Estudios de Seguimiento , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/etiología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias , Prednisona/administración & dosificación , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Tacrolimus/administración & dosificaciónRESUMEN
Complement plays important roles in both ischemia-reperfusion injury (IRI) and antibody-mediated rejection (AMR) of solid organ allografts. One approach to possibly improve outcomes after transplantation is the use of C1 inhibitor (C1-INH), which blocks the first step in both the classical and lectin pathways of complement activation and also inhibits the contact, coagulation, and kinin systems. C1-INH can also directly block leukocyte-endothelial cell adhesion. C1-INH contrasts with eculizumab and other distal inhibitors, which do not affect C4b or C3b deposition or noncomplement pathways. Authors of reports on trials in kidney transplant recipients have suggested that C1-INH treatment may reduce IRI and delayed graft function, based on decreased requirements for dialysis in the first month after transplantation. This effect was particularly marked with grafts with Kidney Disease Profile Index ≥ 85. Other clinical studies and models suggest that C1-INH may decrease sensitization and donor-specific antibody production and might improve outcomes in AMR, including in patients who are refractory to other modalities. However, the studies have been small and often only single-center. This article reviews clinical data and ongoing trials with C1-INH in transplant recipients, compares the results with those of other complement inhibitors, and summarizes potentially productive directions for future research.
Asunto(s)
Activación de Complemento/efectos de los fármacos , Proteína Inhibidora del Complemento C1/uso terapéutico , Complemento C1s/antagonistas & inhibidores , Inactivadores del Complemento/uso terapéutico , Funcionamiento Retardado del Injerto/prevención & control , Rechazo de Injerto/prevención & control , Trasplante de Órganos , Daño por Reperfusión/prevención & control , Aloinjertos , Animales , Proteína Inhibidora del Complemento C1/efectos adversos , Complemento C1s/inmunología , Inactivadores del Complemento/efectos adversos , Funcionamiento Retardado del Injerto/inmunología , Rechazo de Injerto/inmunología , Supervivencia de Injerto/efectos de los fármacos , Humanos , Trasplante de Órganos/efectos adversos , Daño por Reperfusión/inmunología , Factores de Riesgo , Resultado del TratamientoRESUMEN
Previously, we found a substantial number of regulatory T cells (Tregs ) and fewer senescent and T helper type 17 (Th17) and a decrease in interstitial fibrosis (IF) in 12-month graft biopsies in belatacept versus cyclosporin (CNI)-treated patients [Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT) study]. Seven years after kidney transplantation (KT), mean estimated glomerular filtration rate (eGFR), patient and graft survival were significantly higher with belatacept versus CNI treatment. The aim of this study was to determine whether the immunophenotypes of inflammatory and regulatory cell subsets infiltrating the grafts contribute to the BENEFIT's clinical findings a decade after KT. Twenty-three adult patients with functionally stable KT treated with belatacept and 10 treated with CNI were enrolled. Biopsies were analyzed by histomorphometry and immunohistochemistry for proliferation, senescence, apoptosis, inflammatory and regulatory cell markers in a blinded manner. Significantly lower percentages of inflammatory/fibrogenic cells [interleukin (IL)-22+ /Th17/Th2/M1 macrophages] were observed in patients treated with belatacept than in patients treated with CNI. By contrast, remarkably higher percentages of regulatory cells [Tregs /Bregs / plasmacytoid dendritic regulatory cells (pDCregs )/M2] were found in belatacept-treated patients than in CNI-treated patients. Conspicuously lower percentages of apoptosis and senescence and higher proliferation markers were found in belatacept-treated patients than in CNI-treated patients. Consequently, there was significantly more inflammation in the microvascular compartments as well as increased tubular atrophy and IF in CNI-treated patients. These findings strongly suggest that regulatory mechanisms, along with the absence of deleterious effects of CNI, contribute to the long-term graft histology and function stability in patients treated with belatacept.
Asunto(s)
Abatacept/uso terapéutico , Ciclosporinas/uso terapéutico , Supervivencia de Injerto/efectos de los fármacos , Inmunosupresores/uso terapéutico , Trasplante de Riñón/métodos , Adulto , Recuento de Linfocito CD4 , Senescencia Celular/efectos de los fármacos , Femenino , Tasa de Filtración Glomerular/fisiología , Humanos , Inmunofenotipificación , Masculino , México , Linfocitos T Reguladores/inmunología , Tacrolimus/uso terapéutico , Células Th17/inmunologíaRESUMEN
BACKGROUND: The safety profiles of standard therapy versus everolimus with reduced-exposure calcineurin inhibitor (CNI) therapy using contemporary protocols in de novo kidney transplant recipients have not been compared in detail. METHODS: TRANSFORM was a randomized, international trial in which de novo kidney transplant patients were randomized to everolimus with reduced-exposure CNI (N = 1014) or mycophenolic acid (MPA) with standard-exposure CNI (N = 1012), both with induction and corticosteroids. RESULTS: Within the safety population (everolimus 1014, MPA 1012), adverse events with a suspected relation to study drug occurred in 62.9% versus 59.2% of patients given everolimus or MPA, respectively (P = 0.085). Hyperlipidemia, interstitial lung disease, peripheral edema, proteinuria, stomatitis/mouth ulceration, thrombocytopenia, and wound healing complications were more frequent with everolimus, whereas diarrhea, nausea, vomiting, leukopenia, tremor, and insomnia were more frequent in the MPA group. The incidence of viral infections (17.2% versus 29.2%; P < 0.001), cytomegalovirus (CMV) infections (8.1% versus 20.1%; P < 0.001), CMV syndrome (13.6% versus 23.0%, P = 0.044), and BK virus (BKV) infections (4.3% versus 8.0%, P < 0.001) were less frequent with everolimus. CMV infection was less common with everolimus versus MPA after adjusting for prophylaxis therapy in the D+/R- subgroup (P < 0.001). Study drug was discontinued more frequently due to rejection or impaired healing with everolimus, and more often due to BKV infection or BKV nephropathy with MPA. CONCLUSIONS: De novo everolimus with reduced-exposure CNI yielded a comparable incidence, though a distinctly different pattern, of adverse events versus current standard of care. Both regimens are safe and effective, yet their distinct profiles may enable tailoring for individual kidney transplant recipients.
Asunto(s)
Inhibidores de la Calcineurina/administración & dosificación , Ciclosporina/administración & dosificación , Everolimus/administración & dosificación , Rechazo de Injerto/prevención & control , Supervivencia de Injerto/efectos de los fármacos , Inmunosupresores/administración & dosificación , Trasplante de Riñón , Tacrolimus/administración & dosificación , Adulto , Inhibidores de la Calcineurina/efectos adversos , Ciclosporina/efectos adversos , Quimioterapia Combinada , Everolimus/efectos adversos , Rechazo de Injerto/inmunología , Rechazo de Injerto/mortalidad , Humanos , Inmunosupresores/efectos adversos , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/mortalidad , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Factores de Riesgo , Tacrolimus/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
While calcineurin inhibitors (CNIs) are effective for preventing acute rejection in kidney transplant recipients, long-term use may cause chronic kidney injury and is associated with increased risks of cardiovascular events, cancer, and infection-associated death. Immunosuppression strategies are needed to balance risks of acute and subclinical rejection with long-term benefits of improved kidney function. Sirolimus, an inhibitor of mammalian target of rapamycin, is used for immunosuppression in kidney transplantation. Its clinical utility has evolved, over more than 15 years, including de novo sirolimus with and without concomitant CNIs and conversion from CNI-based regimens to sirolimus. Sirolimus-containing regimens are associated with preservation of good renal function, with promising characteristics for improving long-term graft and patient survival, including antiviral and anticancer effects. Based on clinical evidence, use of low-dose sirolimus in a de novo approach with tacrolimus/steroids in the immediate posttransplantation period is appropriate. A feasible alternative is a long term, CNI-free combination with mycophenolate mofetil (following CNI-to-sirolimus conversion at 3-6 months). These strategies are appropriate for a broad range of patients with various levels of immunologic risk, including those receiving expanded criteria donor kidneys or at increased risk of delayed graft function, particular challenges in Latin America and other global regions.
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Rechazo de Injerto/tratamiento farmacológico , Supervivencia de Injerto/efectos de los fármacos , Inmunosupresores/administración & dosificación , Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Sirolimus/administración & dosificación , Rechazo de Injerto/etiología , Humanos , PronósticoRESUMEN
Background Kidney transplant recipients (KTR) receive fixed daily doses of mycophenolate sodium as part of the immunosuppressive regimen. Dose reductions occur primarily due to adverse events and may be associated with an increased risk of acute rejection and graft loss. Objectives To evaluate the tolerability of mycophenolate in kidney transplant recipients receiving tacrolimus and prednisone. Setting The study was performed at Hospital do Rim, Federal University of São Paulo in Brazil. Method This was a retrospective cohort study including 506 patients. Tolerability of mycophenolate sodium was classified into the following groups: Temporary reduction (TR), definitive reduction (DR), temporary interruption (TI), permanent discontinuation (PD) and without modification (WM). Main outcome measure The cause of mycophenolate dose change and its influence on rejection-free survival during the first 3 years after transplantation. Results The cumulative incidence of dose change was 51.2% (11%TR, 44%DR, 24%TI, and 21%PD). Gastrointestinal (45.3%), infection (31.9%) and hematological (14.9%) systems accounted for most of the dose changes. The adverse events with higher incidence were diarrhea, cytomegalovirus (CMV) infection and leukopenia. Changes in dose of mycophenole were associated with reduced acute rejection-free survival compared with patients WM group (71.4%TR, 58.9%DR, 56.7%TI, 53.7%PD vs. 74.2%WM, p = 0.020). Only patients with PD showed inferior patient (59.3% vs. 94.4%, p = 0.001) and death-censored graft (83.3% vs. 92.5%, p = 0.074) survivals compared to patients WM. Conclusion In this cohort, changes in the dose of mycophenolate were associated with increased risk of acute rejection and permanent discontinuation was associated with inferior patient and graft survival.
Asunto(s)
Inmunosupresores/efectos adversos , Trasplante de Riñón , Ácido Micofenólico/efectos adversos , Adulto , Anciano , Estudios de Cohortes , Femenino , Rechazo de Injerto/epidemiología , Rechazo de Injerto/mortalidad , Rechazo de Injerto/prevención & control , Supervivencia de Injerto/efectos de los fármacos , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/uso terapéutico , Incidencia , Masculino , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Ácido Micofenólico/uso terapéutico , Estudios Retrospectivos , Factores de RiesgoRESUMEN
The indirect effects of cytomegalovirus (CMV) viremia can be related to chronic changes in renal allograft structure, but its real impact in early and late graft function remains speculative. A total of 159 patients undergoing renal transplantation using a preemptive therapeutic strategy to prevent CMV disease were included in the present study. The patients were prospectively followed, with serial measurements of urinary retinol-binding protein (uRBP), a marker of proximal tubule injury. uRBP levels and their dynamic performance were compared according to CMV viremia and the 5-year estimated glomerular filtration rate (eGFR), as measured with the modification of diet in renal disease (MDRD) equation. CMV viremia was detected in 79.9% of the patients, with high uRBP levels being detected in 76.0% of these patients (compared with 40.7% in CMV-, P=0.005). High uRBP was associated with male recipients (P=0.02), the number of mismatches (P=0.02) and CMV infection (P=0.001). Five-year eGFR was worse in patients with high uRBP levels (50.3 ± 25.8 compared with 59.8 ± 26.4 ml/min, P=0.04). In a multivariate model, eGFR <60 ml/min was associated with donor age (P<0.001), the number of mismatches (P=0.04), thymoglobulin dose (P=0.02), the presence of and time with delayed graft function (DGF) (P=0.005 and P=0.04), 1-month tacrolimus levels (P=0.03), and uRBP levels after CMV treatment (P=0.01). Patients with CMV viremia in whom uRBP levels were normalized up to 3 months after treatment showed significantly better 5-year eGFR than those in whom uRBP remained high: 61.0 ± 24.2 compared with 42.3 ± 23.9 ml/min, P<0.001. CMV viremia was associated with high uRBP levels, which represent a profile of proximal tubule injury, and the dynamic performance of uRBP after treatment was associated with long-term kidney graft function.
Asunto(s)
Infecciones por Citomegalovirus/orina , Trasplante de Riñón/métodos , Proteínas de Unión al Retinol/orina , Viremia/orina , Adulto , Antivirales/uso terapéutico , Biomarcadores/orina , Infecciones por Citomegalovirus/prevención & control , Infecciones por Citomegalovirus/virología , Femenino , Ganciclovir/uso terapéutico , Tasa de Filtración Glomerular/efectos de los fármacos , Supervivencia de Injerto/efectos de los fármacos , Humanos , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/patología , Masculino , Persona de Mediana Edad , Factores de Tiempo , Viremia/prevención & control , Viremia/virologíaRESUMEN
There is no evidence of whether everolimus (EVR) reduces cytomegalovirus (CMV) events in patients receiving steroid-free regimens. Besides, studies evaluating a tacrolimus (TAC) and EVR regimen are limited to 1-year follow-up. In this single-center prospective randomized trial, the incidence of CMV and 3-year efficacy and safety outcomes of EVR were compared to those of mycophenolate sodium (MPS) in a steroid-free regimen based on low-exposure TAC. Both groups received rabbit anti-thymocyte globulin (r-ATG) induction (6 mg/kg) and the steroids were withdrawn at day 7. Maintenance immunosuppression consisted of TAC (4-7 ng/ml until month 3 and 2-4 ng/ml thereafter) plus EVR (3-8 ng/ml) in the EVR group (n = 59); and TAC (4-7 ng/ml during all follow-up) plus MPS (1440 mg) in the MPS group (n = 56). The EVR group presented with a lower incidence of CMV events (18.6% vs. 50%, P = 0.001). No differences were observed in biopsy-proven acute rejection (6.8% vs. 3.6%, P = 0.680),graft loss (0.0% vs. 1.8%, P = 0.487),death (6.8% vs. 1.8%, P = 0.365), or estimated glomerular filtration rate at 36 months (61.1 ± 25.4 vs. 66.3 ± 24 ml/min/1.73 m2 , P = 0.369). A higher proportion of patients discontinued MPS treatment (8.5% vs. 26.8%, P = 0.013) for safety issues. In conclusion, EVR was associated with lower rates of CMV events in patients induced with standard dose r-ATG and a maintenance steroid-free regimen based on TAC. This regimen effectively prevented acute rejection and demonstrated a more favorable safety profile. (ClinicalTrials.gov:NCT02084446).