RESUMEN
BACKGROUND: Antibody-mediated rejection following liver transplantation (LT) has been increasingly recognized, particularly with respect to the emergence of de novo donor-specific antibodies (DSAs) and their impact on graft longevity. While substantial evidence for adult populations exists, research focusing on pediatric LT outcomes remains limited. AIM: To investigate the prevalence of human leukocyte antigen (HLA) mismatches and DSA and evaluate their association with rejection episodes after pediatric LT. METHODS: A cohort of pediatric LT recipients underwent HLA testing at Santa Casa de Porto Alegre, Brazil, between December 2013 and December 2023. Only patients who survived for > 30 days after LT with at least one DSA analysis were included. DSA classes I and II and cross-matches were analyzed. The presence of de novo DSA (dnDSA) was evaluated at least 3 months after LT using the Luminex® single antigen bead method, with a positive reaction threshold set at 1000 MFI. Rejection episodes were confirmed by liver biopsy. RESULTS: Overall, 67 transplanted children were analyzed; 61 received grafts from living donors, 85% of whom were related to recipients. Pre-transplant DSA (class I or II) was detected in 28.3% of patients, and dnDSA was detected in 48.4%. The median time to DSA detection after LT was 19.7 [interquartile range (IQR): 4.3-35.6] months. Biopsy-proven rejection occurred in 13 patients at follow-up, with C4d positivity observed in 5/13 Liver biopsies. The median time to rejection was 7.8 (IQR: 5.7-12.8) months. The presence of dnDSA was significantly associated with rejection (36% vs 3%, P < 0.001). The rejection-free survival rates at 12 and 24 months were 76% vs 100% and 58% vs 95% for patients with dnDSA anti-DQ vs those without, respectively. CONCLUSION: Our findings highlight the importance of incorporating DSA assessment into pre- and post-transplantation protocols for pediatric LT recipients. Future implications may include immunosuppression minimization strategies based on this analysis in pediatric LT recipients.
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Rechazo de Injerto , Supervivencia de Injerto , Antígenos HLA , Prueba de Histocompatibilidad , Isoanticuerpos , Trasplante de Hígado , Humanos , Trasplante de Hígado/efectos adversos , Masculino , Rechazo de Injerto/inmunología , Rechazo de Injerto/epidemiología , Femenino , Niño , Antígenos HLA/inmunología , Isoanticuerpos/sangre , Isoanticuerpos/inmunología , Brasil/epidemiología , Preescolar , Supervivencia de Injerto/inmunología , Prueba de Histocompatibilidad/métodos , Incidencia , Lactante , Adolescente , Hígado/inmunología , Hígado/patología , Biopsia , Estudios Retrospectivos , Donadores Vivos , Receptores de Trasplantes/estadística & datos numéricosRESUMEN
Background: Despite the growing number of elderly kidney transplant (Ktx) recipients, few studies have examined the effects of immunosuppression on their lymphocyte profiles. Methods: We evaluated the early conversion from mycophenolate sodium (MPS) to everolimus (EVL) after rabbit antithymocyte globulin (rATG) 2 mg/kg induction in elderly kidney recipients. Three groups of KTx patients were compared: (a) Young (n=20, 36 ± 7 y) receiving standard immunosuppression (Group A1) (prednisone, tacrolimus, and MPS), (b) Elderly (n=35, 65 ± 3 y) receiving standard immunosuppression (Group B1), and (c) Elderly (n=16, 65 ± 3 y) with early (mean 30 d) conversion from MPS to EVL (Group B2). Naive, memory, and regulatory peripheral blood TCD4+ lymphocytes were quantified at 0, 30, and 365 d. Results: Results are reported as [mean(p25-p75)]. Young recipients had higher lymphocyte counts at baseline [2,100(1,630-2,400) vs. 1,310 (1,000-1,600)/mm3, p<0.0001] maintained higher counts within 365 d [1,850(1,590-2,120) vs. 1,130(460-1,325)/mm3, p=0.018 and vs. 1,410(805-1,895)/mm3, p=0.268]. Elderly recipients showed a decrease in lymphocytes within 30 d [1,310(1,000-1,600) vs. 910(700-1,198)/mm3, p=0.0012] with recovery within 365 d. The same pattern was observed in total lymphocytes and TCD4+ counts. Rabbit antithymocyte globulin induced a reduction in central memory T-cell percentages at 30 d in both young recipients [6.2(3.77-10.8) vs. 5.32(2.49-7.28)% of CD4+, p=0.036] and in elderly recipients [8.17(5.28-12.88) vs. 6.74(4.36-11)% of CD4+, p=0.05] on standard immunosuppression, returning to baseline at 365 d in elderly recipients but not in young recipients. Regulatory T CD39+ cells (Treg) percentages decreased at 30 d in elderly recipients [2.1(1.23-3.51) vs. 1.69(0.8-2.66)% of CD4+, p=0.0028] and in young recipients [1.29(0.45-1.85) vs. 0.84(0.18-1.82)% of CD4+, p=0.0038], returning to baseline at 365 d in elderly recipients [2.1(1.23-3.51) vs. 2.042(0.88-2.42)% of CD4+], but not in young recipients [1.29(0.45-1.85) vs. 0.86(0.7-1.34) % of CD4+]. The elderly everolimus conversion group did not show significant changes in cell profile over time or compared to elderly recipients with standard immunosuppression. Conclusion: Aging favored the maintenance of Treg during the late transplantation period despite ongoing immunosuppression. Lymphocyte depletion due to rATG was more prominent in elderly recipients and affected memory subsets with a temporary reduction in central memory T cells. However, conversion to everolimus did not impact Treg profile. Reducing the dose of rATG in elderly recipients seems necessary for the expected lymphocyte changes with EVL to occur. Clinical trial registration: nEverOld Trial, identifier NTC01631058.
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Inmunosupresores , Trasplante de Riñón , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Edad , Suero Antilinfocítico/uso terapéutico , Everolimus , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Terapia de Inmunosupresión/métodos , Inmunosupresores/uso terapéutico , Recuento de Linfocitos , Ácido Micofenólico/administración & dosificación , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/metabolismo , Tacrolimus/administración & dosificación , Tacrolimus/uso terapéutico , Receptores de TrasplantesRESUMEN
INTRODUCTION: The scarcity of suitable donor organs has led to the inclusion of Expanded Criteria Donor (ECD) kidneys to augment the donor pool, despite potential concerns regarding post-transplant outcomes. METHODS: This retrospective study analyzed the clinical outcomes of a cohort of 317 kidney transplant recipients from deceased donors at a single center between 2008 and 2018. Patients were categorized into ECD and Standard Criteria Donor (SCD) groups, with primary nonfunctioning grafts excluded. Comprehensive laboratory evaluations were conducted, including HLA typing and serum creatinine levels. Immunosuppressive regimens were standardized, and statistical analyses were performed using the SPSS program. RESULTS: The sample consisted of 83 (26.18%) patients who received kidney transplants from ECDs and 234 (73.82%) from SCDs. The ECD group showed a longer cold ischemia time (p = 0.019) and a higher rate of delayed graft function (DGF) compared with the SCD group. No significant differences were observed in graft survival (p = 0.370) or patient survival (p = 0.993) between the ECD and SCD groups. However, differences in graft survival were noted between the groups when stratified by DGF status: ECD with DGF vs. ECD without DGF (p = 0.029), ECD with DGF vs. SCD with DGF (p = 0.188), ECD with DGF vs. SCD without DGF (p = 0.022), ECD without DGF vs. SCD with DGF (p = 0.014), ECD without DGF vs. SCD without DGF (p = 0.340), and SCD with DGF vs. SCD without DGF (p = 0.195). No differences in patient survival rates were observed among these groups for all pairwise comparisons (p > 0.05) when stratified by donor criteria and DGF status. CONCLUSIONS: Graft and patient survival rates were comparable between ECD and SCD kidney transplant recipients.
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Supervivencia de Injerto , Trasplante de Riñón , Donantes de Tejidos , Humanos , Femenino , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Adulto , Funcionamiento Retardado del Injerto , Rechazo de Injerto/mortalidad , Rechazo de Injerto/inmunología , Resultado del Tratamiento , Selección de Donante , Tasa de SupervivenciaRESUMEN
Pediatric solid organ transplant (SOT) recipients face a challenging balance between immunosuppression and graft rejection. While Epstein-Barr Virus (EBV) and cytomegalovirus (HCMV) are known contributors to post-transplant lymphoproliferative disease and graft rejection, respectively, the roles of herpesvirus 6 and 7 (HHV6 and HHV7) and the impact of these herpesviruses on cytokine levels remain unclear, leading to gaps in clinical practice. In this associative study, we measured 17 cytokines using a Bio-Plex assay in a meticulously curated plasma sample pool (N = 158) from pediatric kidney and liver transplant recipients over a one-year follow-up period. The samples included virus-negative and virus-positive cases, either individually or in combination, along with episodes of graft rejection. We observed that the elevation of IL-4, IL-8, and IL-10 correlated with graft rejection. These cytokines were elevated in samples where HCMV or HHV6 were detected alone or where EBV and HHV7 were co-detected. Interestingly, latent EBV, when detected independently, exhibited an immunomodulatory effect by downregulating cytokine levels. However, in co-detection scenarios with ß-herpesviruses, EBV transitioned to a lytic state, also associating with heightened cytokinemia and graft rejection. These findings highlight the complex interactions between the immune response and herpesviruses in transplant recipients. The study advocates for enhanced monitoring of not only EBV and HCMV but also HHV6 and HHV7, providing valuable insights for improved risk assessment and targeted interventions in pediatric SOT recipients.
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Citocinas , Citomegalovirus , Rechazo de Injerto , Herpesvirus Humano 6 , Herpesvirus Humano 7 , Trasplante de Riñón , Trasplante de Hígado , Humanos , Trasplante de Riñón/efectos adversos , Citocinas/sangre , Citocinas/metabolismo , Niño , Herpesvirus Humano 6/inmunología , Masculino , Femenino , Preescolar , Trasplante de Hígado/efectos adversos , Citomegalovirus/inmunología , Rechazo de Injerto/virología , Rechazo de Injerto/inmunología , Herpesvirus Humano 4/inmunología , Adolescente , Lactante , Infecciones por Herpesviridae/virología , Infecciones por Herpesviridae/inmunología , Receptores de Trasplantes , Infecciones por Virus de Epstein-Barr/virología , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Citomegalovirus/virología , Infecciones por Citomegalovirus/inmunología , HerpesviridaeRESUMEN
INTRODUCTION: Obesity is frequent among organ transplant recipients, increasing the risk of acute graft rejection and overall morbimortality. Laparoscopic sleeve gastrectomy (LSG) effectively improves graft survival and associated comorbidities. We first compared 30-d outcomes between chronic immunosuppressed (CI) and nonchronic immunosuppressed (non-CI) patients. Then, between organ transplant and non-organ transplant CI patients who underwent LSG. METHODS: Patients who underwent LSG within the metabolic and bariatric surgery accreditation and quality improvement program 2017-2019 were included. Using 1:1 and 1:4 propensity score matching analysis, the cohorts were matched for 30 characteristics. We then compared 30-d outcomes between CI and non-CI (analysis 1) and between organ transplant and non-organ transplant CI patients who underwent LSG (analysis 2). RESULTS: A total of 486,576 patients were included. The matched cohorts in analysis 1 (n = 8978) and analysis 2 (n = 1152, n = 371) had similar preoperative characteristics. Propensity score matching in analysis 1 showed that patients in the CI group had significantly higher rates of renal complications (0.4% versus 0.2%, P = 0.006), unplanned intensive care unit admission (1.1% versus 0.7%, P = 0.003), blood transfusions (1.1% versus 0.7%, P = 0.003), readmissions (4.6% versus 3.5%, P < 0.001), reoperations (1.4% versus 1.0%, P = 0.033), interventions (1.3% versus 1.0%, P = 0.026), and postoperative bleeding (0.6% versus 0.4%, P = 0.013). In analysis 2, patients with organ transplant CI had a higher rate of pulmonary complications (1.1% versus 0.3%, P = 0.043), renal complications (2.4% versus 0.2%, P < 0.001), blood transfusions (6.5% versus 1.3%, P < 0.001), and readmissions (10.0% versus 4.6%, P < 0.001). CONCLUSIONS: Patients with transplant-related CI who underwent LSG have higher 30-d postoperative complication rates compared to nontransplant-related CI patients; however, there were no differences in terms of mortality, intensive care unit admissions, staple line leaks, or bleeding. LSG is safe and feasible in this high-risk population.
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Gastrectomía , Trasplante de Órganos , Complicaciones Posoperatorias , Humanos , Masculino , Femenino , Gastrectomía/efectos adversos , Persona de Mediana Edad , Adulto , Estudios Retrospectivos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Trasplante de Órganos/efectos adversos , Puntaje de Propensión , Resultado del Tratamiento , Laparoscopía/efectos adversos , Terapia de Inmunosupresión/efectos adversos , Supervivencia de Injerto , Rechazo de Injerto/epidemiología , Rechazo de Injerto/inmunología , Rechazo de Injerto/etiologíaAsunto(s)
Everolimus , Inmunosupresores , Trasplante de Riñón , Ácido Micofenólico , Sirolimus , Tacrolimus , Humanos , Everolimus/uso terapéutico , Inmunosupresores/uso terapéutico , Inmunosupresores/efectos adversos , Tacrolimus/uso terapéutico , Ácido Micofenólico/uso terapéutico , Ácido Micofenólico/efectos adversos , Sirolimus/uso terapéutico , Sirolimus/efectos adversos , Rechazo de Injerto/prevención & control , Rechazo de Injerto/inmunología , Resultado del Tratamiento , Persona de Mediana Edad , Femenino , Factores de Tiempo , Masculino , Quimioterapia Combinada , AdultoRESUMEN
Regulatory T cells play a crucial role in the homeostasis of the immune response. Regulatory T cells are mainly generated in the thymus and are characterized by the expression of Foxp3, which is considered the regulatory T-cell master transcription factor. In addition, regulatory T cells can be induced from naive CD4+ T cells to express Foxp3 under specific conditions both in vivo (peripheral regulatory T cells) and in vitro (induced regulatory T cells). Both subsets of thymic regulatory T cells and peripheral regulatory T cells are necessary for the establishment of immune tolerance to self and non-self antigens. Although it has been postulated that induced regulatory T cells may be less stable compared to regulatory T cells, mainly due to epigenetic differences, accumulating evidence in animal models shows that induced regulatory T cells are stable in vivo and can be used for the treatment of inflammatory disorders, including autoimmune diseases and allogeneic transplant rejection. In this review, we describe the biological characteristics of induced regulatory T cells, as well as the key factors involved in induced regulatory T-cell transcriptional, metabolic, and epigenetic regulation, and discuss recent advances for de novo generation of stable regulatory T cells and their use as immunotherapeutic tools in different experimental models. Moreover, we discuss the challenges and considerations for the application of induced regulatory T cells in clinical trials and describe the new approaches proposed to achieve in vivo stability, including functional or metabolic reprogramming and epigenetic editing.
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Autoinmunidad , Linfocitos T Reguladores , Linfocitos T Reguladores/inmunología , Humanos , Animales , Inmunoterapia/métodos , Trasplante Homólogo , Epigénesis Genética , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/terapia , Rechazo de Injerto/inmunología , Factores de Transcripción Forkhead/metabolismoRESUMEN
BACKGROUND: The self-administered Kidney AlloTransplant Immunosuppressive Therapy Adherence (KATITA-25) questionnaire is a multidimensional scale for use in the pretransplant setting that evaluates the predisposition to nonadherence of patients who are candidates to kidney transplant. The scale has shown adequate internal consistency and test-retest reliability. This study presents the results of an external validation study of the KATITA-25 scale. METHODS: Patients >18 y old scheduled for kidney transplant were included in this multicenter study. The KATITA-25 scale was administered before surgery and then at 3-mo posttransplantation for evaluation of scale sensitivity to change. At this time, 2 validated medication adherence scales were applied for assessment of concurrent validity. For evaluation of predictive validity, nonadherence to immunosuppressive medication was assessed at 6 and 12 mo after transplantation by 3 independent methods: patient self-report of nonadherence using the Morisky-Green-Levine Medication Assessment Questionnaire scale, serum trough levels of immunosuppressants, and pharmacy refills. RESULTS: Three twenty-two patients were available for evaluation of concurrent validity and 311 patients of predictive validity. After kidney transplant, the median KATITA-25 score decreased from 20 to 8 ( P â <â 0.001), demonstrating scale sensitivity to change, and the KATITA-25 score showed correlation with the Basel Assessment of Adherence to Immunosuppressive Medication Scale score (Spearman's ρ 0.18, P â =â 0.002) and the Cuestionario para la Evaluación de la Adhesión al Tratamiento Antiretroviral scores (ρ -0.17, P â =â 0.002), confirming concurrent validity. The nonadherence rate was 57.6%. The scale predictive validity was demonstrated by the area under the receiver operating characteristics curve (0.68), sensitivity (59.8%), specificity (68.2%), and positive predictive value (71.8%). CONCLUSIONS: This external validation study of KATITA-25 scale provided evidence of sensitivity to change, and structural, criterion, and predictive validity.
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Inmunosupresores , Trasplante de Riñón , Cumplimiento de la Medicación , Humanos , Inmunosupresores/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Cumplimiento de la Medicación/estadística & datos numéricos , Reproducibilidad de los Resultados , Adulto , Encuestas y Cuestionarios/estadística & datos numéricos , Anciano , Autoinforme , Resultado del Tratamiento , Rechazo de Injerto/prevención & control , Rechazo de Injerto/inmunología , Factores de TiempoRESUMEN
Resumen El trasplante pulmonar implica una serie de desafíos, que como lo ha demostrado la historia, no sólo depende de un adecuado desarrollo de técnicas quirúrgicas, sino también de la comprensión de una serie de complejas interacciones inmunológicas celulares y humorales que serán las responsables del tipo de respuesta (innata y/o adquirida) fisiológica y que pudiesen desencadenar las complicaciones asociadas al trasplante (rechazo hiperagudo, agudo o crónico). Cada una de las cuales tiene su potencial prevención y/o tratamiento. El poder conocer esta serie de respuestas, permite al clínico anticiparse a algunos de estos eventos y evitar de mejor forma el daño y las consecuencias que pueden producir en los casos de trasplante pulmonar.
Lung transplantation involves a series of challenges, which as history has shown, depends not only on an adequate development of surgical techniques, but also on the understanding of a series of complex cellular and humoral immunological interactions that will be responsible for the type of physiological response (innate - acquired) and that could trigger the complications associated with transplantation (hyperacute, acute or chronic rejection). Each of which has its potential prevention and treatment. Being able to know this series of responses, allows the clinician to anticipate some of these events and to avoid in a better way the damage and the consequences that can occur in cases of lung transplantation.
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Humanos , Inmunología del Trasplante/inmunología , Trasplante de Pulmón , Rechazo de Injerto/inmunología , Linfocitos T/inmunología , Autoinmunidad , Proteína del Factor Nuclear 45 , Rechazo de Injerto/prevención & control , Inmunidad Celular , Inmunidad Innata , InmunosupresoresRESUMEN
Brain death is characterized by a generalized inflammatory response that results in multiorgan damage. This process is mainly mediated through cytokines, which amplify graft immunogenicity. We investigated the immunological response in a brain death liver donor model and analysed the effects of thalidomide, a drug with powerful immunomodulatory properties. Brain death was induced in male Lewis rats. We studied three groups: Control (sham-operated rats in which trepanation was performed without inserting the balloon catheter), BD (rats subjected to brain death by increasing intracranial pressure) and BD + Thalid (BD rats receiving thalidomide after brain death). After 6 h, serum levels of AST, ALT, LDH, and ALP as well as systemic and hepatic levels of TNF-α, IL1-ß, IL-6, and IL-10 were analysed. We also determined the mRNA expression of MHC Class I and Class II, NF-κB, and macrophage infiltration. NF-κB was also examined by electrophoretic mobility shift assay. Thalidomide treatment significantly reduced serum levels of hepatic enzymes and TNF-α, IL-1-ß, and IL-6. These cytokines were evaluated at either the mRNA expression or protein level in liver tissue. In addition, thalidomide administration resulted in a significant reduction in macrophages, MHC Class I and Class II, and NF-κB activation. This study reveals that thalidomide significantly inhibited the immunologic response and graft immunogenicity, possibly through suppression of NF-κB activation.
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Muerte Encefálica/inmunología , Rechazo de Injerto/prevención & control , Trasplante de Hígado/efectos adversos , Talidomida/administración & dosificación , Recolección de Tejidos y Órganos/métodos , Aloinjertos/efectos de los fármacos , Aloinjertos/inmunología , Animales , Modelos Animales de Enfermedad , Rechazo de Injerto/inmunología , Humanos , Hígado/efectos de los fármacos , Hígado/inmunología , Trasplante de Hígado/métodos , Masculino , Ratas , Ratas Endogámicas LewRESUMEN
Optimizing antithymocyte globulin (rATG) dosage is critical for high immunological risk patients undergoing a repeat kidney transplant. This natural retrospective cohort study compared clinical outcomes of two successive cohorts of consecutive recipients of retransplants receiving 5 x 1 mg/kg (rATG-5, n = 100) or a single 3 mg/kg (rATG-3, n = 110) dose of rATG induction therapy. All patients had negative complement-dependent cytotoxicity crossmatch and no anti-HLA A, B, DR donor-specific antibodies (DSA). The primary endpoint was efficacy failure (first biopsy-proven acute rejection, graft loss, or death) at 12 months. There was no difference in the cumulative incidence of efficacy failure (18.0% vs. 21.8%, HR = 1.22, 95% CI 0.66-2.25), respectively. There were no differences in 3-years freedom from biopsy proven acute rejection, and patient, graft, and death-censored graft survivals. There were no differences in the incidence of surgical complications (25.0% vs. 18.2%; p 0.151), early hospital readmission (27.8% vs. 29.5%; p = 0.877) and CMV infections (49% vs. 40%; p = 0.190). There were also no differences in the incidence (59.6% vs. 58.7%, p = 0.897) and duration of delayed graft function but a stable difference in estimate glomerular filtration rate was observed from month 1 (54.7±28.8 vs. 44.1±25.3 ml/min/1.73 m2, p = 0.005) to month 36 (51.1±27.7 vs. 42.5±24.5, p = 0.019). Mean urinary protein concentration (month 36: 0.38±0.81 vs. 0.70±2.40 g/ml, p = 0.008) and mean chronic glomerular Banff score in for cause biopsies (months 4-36: 0.0±0.0 vs. 0.04±0.26, p = 0.044) were higher in the rATG-3 group. This cohort analysis did not detect differences in the incidence of efficacy failure and in safety outcomes at 12 months among recipients of kidney retransplants without A, B, and DR DSA, receiving induction therapy with a single 3 mg/kg rATG dose or the traditional 5 mg/kg rATG.
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Suero Antilinfocítico/administración & dosificación , Suero Antilinfocítico/uso terapéutico , Trasplante de Riñón/métodos , Adulto , Anticuerpos Monoclonales Humanizados/uso terapéutico , Brasil , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Femenino , Rechazo de Injerto/inmunología , Supervivencia de Injerto , Humanos , Inmunosupresores/uso terapéutico , Riñón/citología , Masculino , Persona de Mediana Edad , Reoperación/métodos , Estudios RetrospectivosRESUMEN
BACKGROUND: The presence of donor-specific antibodies (DSAs) against HLA-DQB1 is considered a significant barrier to good outcome and allograft survival in kidney transplantation (KT). This study aimed to assess the impact of induction immunotherapy on the outcome and allograft survival in KT patients with HLA-DQB1-DSA. METHODOLOGY: Thirty-two patients who had undergone KT and found to be positive for HLA-DQB1-DSA were monitored at least one to 10 years. They were allocated into two groups of patients: G1 received induction immunotherapy (n = 14 patients; 43.75%), and G2 did not (n = 18 patients; 56.25%). RESULTS: In G1, 6 (42.86%) patients experienced rejection episodes (RE), 2 (14.29%) due to antibody-mediated rejection (ABMR) and 4 (28.57%) due to T-cell-mediated rejection (TCMR). In G2, 13 (72.22%) patients experienced RE, 3 (16.67%) due to ABMR, and 10 (55.56%) due to TCMR. Graft loss occurred in 4 patients from G1, 2 (14.29%) due to ABMR and 2 (14.29%) due to non-immunological causes. In G2, 9 (50.00%) patients lost their grafts, 2 (11.11%) due to TCMR, 2 (11.11%) due to ABMR, and 5 (27.78%) due to non-immunological causes. The graft survival rate was 64.29% in G1 and 45.83% in G2. Glomerulitis and peritubular capillaritis were observed in 3 and C4d-positive patients with/or without induction who lost their grafts by ABMR by HLA-DQ DSA. Two patients from G2 lost their graft by TCMR due to interstitial lymphocytic infiltrate (i1), foci of mild tubulitis (t2), interstitial edema, moderate interstitial fibrosis and tubular atrophy. Better graft survival rates were shown in patients from G1 who received induction immunotherapy. CONCLUSION: Our study suggests that patients with an immunological profile of HLA-DQ+ DSA+ treated by immunotherapy induction have a decreased risk of ABMR and increased allograft survival, and the presence of anti-HLA-DQB1 DSA+ detected before and after KT were associated with ABMR episodes and failure.
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Rechazo de Injerto , Supervivencia de Injerto/inmunología , Cadenas beta de HLA-DQ/inmunología , Isoanticuerpos/inmunología , Trasplante de Riñón , Adulto , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Rechazo de Injerto/inmunología , Rechazo de Injerto/mortalidad , Rechazo de Injerto/prevención & control , Humanos , Inmunoterapia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Regulatory T cell (Treg) therapy is a promising approach to amelioration of allograft rejection and promotion of organ transplant tolerance. However, the fate of infused Treg, and how this relates to their therapeutic efficacy using different immunosuppressive regimens is poorly understood. Our aim was to analyze the tissue distribution, persistence, replicative activity and phenotypic stability of autologous, donor antigen alloreactive Treg (darTreg) in anti-thymocyte globulin (ATG)-lymphodepleted, heart-allografted cynomolgus monkeys. METHODS: darTreg were expanded ex vivo from flow-sorted, circulating Treg using activated donor B cells and infused posttransplant into recipients of major histocompatibility complex-mismatched heart allografts. Fluorochrome-labeled darTreg were identified and characterized in peripheral blood, lymphoid, and nonlymphoid tissues and the graft by flow cytometric analysis. RESULTS: darTreg selectively suppressed autologous T cell responses to donor antigens in vitro. However, following their adoptive transfer after transplantation, graft survival was not prolonged. Early (within 2 wk posttransplant; under ATG, tacrolimus, and anti-IL-6R) or delayed (6-8 wk posttransplant; under rapamycin) darTreg infusion resulted in a rapid decline in transferred darTreg in peripheral blood. Following their early or delayed infusion, labeled cells were evident in lymphoid and nonlymphoid organs and the graft at low percentages (<4% CD4+ T cells). Notably, infused darTreg showed reduced expression of immunoregulatory molecules (Foxp3 and CTLA4), Helios, the proliferative marker Ki67 and antiapoptotic Bcl2, compared with preinfusion darTreg and endogenous CD4+CD25hi Treg. CONCLUSIONS: Lack of therapeutic efficacy of infused darTreg in lymphodepleted heart graft recipients appears to reflect loss of a regulatory signature and proliferative and survival capacity shortly after infusion.
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Traslado Adoptivo , Suero Antilinfocítico/farmacología , Proteínas Reguladoras de la Apoptosis/metabolismo , Apoptosis , Proliferación Celular , Rechazo de Injerto/prevención & control , Supervivencia de Injerto , Trasplante de Corazón , Activación de Linfocitos , Depleción Linfocítica , Linfocitos T Reguladores/trasplante , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Rechazo de Injerto/inmunología , Rechazo de Injerto/metabolismo , Trasplante de Corazón/efectos adversos , Macaca fascicularis , Masculino , Fenotipo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Factores de TiempoRESUMEN
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
BACKGROUND: HLA molecular mismatch (MM) is a risk factor for de novo donor-specific antibody (dnDSA) development in solid organ transplantation. HLA expression differences have also been associated with adverse outcomes in hematopoietic cell transplantation. We sought to study both MM and expression in assessing dnDSA risk. METHODS: One hundred three HLA-DP-mismatched solid organ transplantation pairs were retrospectively analyzed. MM was computed using amino acids (aa), eplets, and, supplementarily, Grantham/Epstein scores. DPB1 alleles were classified as rs9277534-A (low-expression) or rs9277534-G (high-expression) linked. To determine the associations between risk factors and dnDSA, logistic regression, linkage disequilibrium (LD), and population-based analyses were performed. RESULTS: A high-risk AA:GX (recipient:donor) expression combination (X = A or G) demonstrated strong association with HLA-DP dnDSA (P = 0.001). MM was also associated with HLA-DP dnDSA when evaluated by itself (eplet P = 0.007, aa P = 0.003, Grantham P = 0.005, Epstein P = 0.004). When attempting to determine the relative individual effects of the risk factors in multivariable analysis, only AA:GX expression status retained a strong association (relative risk = 18.6, P = 0.007 with eplet; relative risk = 15.8, P = 0.02 with aa), while MM was no longer significant (eplet P = 0.56, aa P = 0.51). Importantly, these risk factors are correlated, due to LD between the expression-tagging single-nucleotide polymorphism and polymorphisms along HLA-DPB1. CONCLUSIONS: The MM and expression risk factors each appear to be strong predictors of HLA-DP dnDSA and to possess clinical utility; however, these two risk factors are closely correlated. These metrics may represent distinct ways of characterizing a common overlapping dnDSA risk profile, but they are not independent. Further, we demonstrate the importance and detailed implications of LD effects in dnDSA risk assessment and possibly transplantation overall.
Asunto(s)
Rechazo de Injerto/inmunología , Cadenas beta de HLA-DP/biosíntesis , Isoanticuerpos/inmunología , Trasplante de Riñón/efectos adversos , Donantes de Tejidos , Estudios de Seguimiento , Cadenas beta de HLA-DP/inmunología , Trasplante de Células Madre Hematopoyéticas/métodos , Prueba de Histocompatibilidad , Humanos , Desequilibrio de Ligamiento , Estudios RetrospectivosRESUMEN
BACKGROUND: There are only a few reports evaluating the applicability of endothelial-damage markers analysis by immunohistochemistry (IHC) in kidney allograft samples. This study analyzed the expression of Caveolin-1 (Cav), von Willebrand factor (Vwf), and T-cadherin (Cad) in kidney biopsies and their association with antibody-mediated injury. METHODS: In this retrospective study, 114 cases with antibody-mediated changes (Banff, 2020) and 72 with interstitial fibrosis/tubular atrophy were selected. IHC for Cav, Vwf and Cad was performed and evaluated according to their qualitative expression in peritubular capillaries. The cases were grouped according to the presence of microvascular inflammation (MVI), donor-specific antibodies (DSA), C4d positivity and antibody-mediated rejection (AMR). A level of significance < 0.05 was adopted. RESULTS: Vwf expression was associated with MVI (p < 0.001), DSA (p = 0.016), C4d (p < 0.001) and AMR (p < 0.001), and was higher in DSA+/C4d+ cases despite MVI (p < 0.001). The expression of Cad correlated with MVI (p = 0.015), C4d (p = 0.005) and AMR (p = < 0.001). Cad was more expressed in chronic AMR compared with acute/active cases (p = 0.001). Cav expression was associated with MVI (p = 0.029) and AMR (p = 0.016) and was also higher in chronic AMR (p = 0.049). A combined score of Vwf and Cad was higher in AMR when compared with C4d without rejection and IF/TA cases (p < 0.001). CONCLUSION: Vwf, Cad and Cav expression shows association with antibody-mediated injury and may be helpful to support AMR diagnosis.
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Cadherinas/análisis , Caveolina 1/análisis , Rechazo de Injerto/metabolismo , Inmunohistoquímica , Isoanticuerpos/análisis , Trasplante de Riñón/efectos adversos , Riñón/química , Factor de von Willebrand/análisis , Adulto , Biomarcadores/análisis , Biopsia , Femenino , Rechazo de Injerto/inmunología , Rechazo de Injerto/patología , Humanos , Riñón/inmunología , Riñón/patología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Adulto JovenRESUMEN
Defined as histologic evidence of rejection on a protocol biopsy in the absence of kidney dysfunction, subclinical rejection has garnered attention since the 1990s. The major focus of much of this research, however, has been subclinical T cell-mediated rejection (TCMR). Herein, we review the literature on subclinical antibody-mediated rejection (AMR), which may occur with either preexisting donor-specific antibodies (DSA) or upon the development of de novo DSA (dnDSA). In both situations, subsequent kidney function and graft survival are compromised. Thus, we recommend protocol biopsy routinely within the first year with preexisting DSA and at the initial detection of dnDSA. In those with positive biopsies, baseline immunosuppression should be maximized, any associated TCMR treated, and adherence stressed, but it remains uncertain if antibody-reduction treatment should be initiated. Less invasive testing of blood for donor DNA or gene profiling may have a role in follow-up of those with negative initial biopsies. If a protocol biopsy is positive in the absence of detectable HLA-DSA, it also remains to be determined whether non-HLA-DSA should be screened for either in particular or on a genome-wide basis and how these patients should be treated. Randomized controlled trials are clearly needed.
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Rechazo de Injerto/inmunología , Antígenos HLA/inmunología , Histocompatibilidad , Isoanticuerpos/sangre , Trasplante de Riñón/efectos adversos , Animales , Rechazo de Injerto/sangre , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/patología , Humanos , Inmunosupresores/uso terapéutico , 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.
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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
Graft damage is a process that starts at the moment of transplantation, due to comorbidities of receptor, donor status, ischemia time, ischemia-reperfusion phenomenon, among others, those induce metabolic and immune factors that ultimately trigger clinical manifestations of graft dysfunction. However, the preclinical progression between the time of transplantation and the appearance of signs and symptoms of graft damage can take weeks to years. Therefore, the implementation of rational monitoring approaches during the post-transplantation period is critical and should include not only the clinical follow-up but also anticipate immunological graft damage. In the present essay, we propose an immunological monitoring algorithm for the post-renal transplantation period.
El daño del injerto es un proceso multifactorial que se inicia tempranamente después de la mayoría de los trasplantes de donantes sin HLA idéntico. Puede deberse a las comorbilidades del receptor, al estado del donante, al tiempo de isquemia, y al fenómeno de isquemia y reperfusión, entre otros, condiciones que inducen factores metabólicos e inmunológicos que finalmente desembocan en la disfunción del injerto. Sin embargo, entre el momento del trasplante y la aparición de los signos y síntomas existe un periodo que puede tardar semanas o años. Por ello, después del trasplante renal, es importante hacer un seguimiento racional que incluya la evaluación clínica y permita anticiparse al daño inmunológico del injerto. En este ensayo se propone un algoritmo de seguimiento del injerto renal después del trasplante.
Asunto(s)
Cuidados Posteriores/métodos , Algoritmos , Rechazo de Injerto/inmunología , Trasplante de Riñón , Enfermedad Aguda , Especificidad de Anticuerpos , Colombia , Diagnóstico Tardío , Diagnóstico Precoz , Estudios de Seguimiento , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/patología , Histocompatibilidad/inmunología , Humanos , Factores de TiempoRESUMEN
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.