RESUMEN
Allosensitization is prevalent in heart transplant candidates and is associated with prolonged waiting times and poor outcomes following transplantation. We analyzed the efficacy of a desensitization regimen consisting of plasma exchange, intravenous immunoglobulin, and bortezomib among 25 consecutive sensitized waitlisted candidates at our center from 2016 to 2021. Following desensitization therapies, all C1q negative antibodies were removed from a candidate's unacceptable antigen list. There was a significant decrease in the median number of human leukocyte antigen (HLA) class I (21-15, p = .001) but not class II antibodies (7-6.5, p = .07). There was a significant corresponding decrease in median calculated panel reactive antibodies for class I (90%-74%, p = .004) but not class II (74.5%-75.5%, p = .30). Following desensitization, 76% of patients were transplanted at a median of 91 days. One-year survival following transplant was 89% with a 33% rate of antibody-mediated rejection (AMR). In conclusion, a bortezomib desensitization protocol was modestly effective for class I antibodies and allowed successful transplant in most cases when combined with selective crossing of C1q negative antigens.
Asunto(s)
Complemento C1q , Trasplante de Corazón , Humanos , Bortezomib/uso terapéutico , Anticuerpos , Inmunoglobulinas Intravenosas/uso terapéutico , Antígenos HLA , Desensibilización Inmunológica/métodos , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/etiología , IsoanticuerposRESUMEN
Pediatric and adolescent and young adult (AYA) patients who receive many blood product transfusions, such as individuals with sickle cell disease (SCD), severe aplastic anemia (SAA) or indolent hematologic malignancies, are at high risk for developing donor-specific antibodies (DSA). DSAs with mean fluorescence intensity (MFI) greater than 5000 have been associated with significant graft failure, but lower MFI values between 2000 and 5000 may result in poor graft function after hematopoietic cell transplant (HCT). Desensitization strategies have been developed to reduce the DSA burden in HCT recipients before graft infusion, but the experience with these strategies in the pediatric and AYA populations is not well described in the literature. Here, we describe our experience with successful desensitization by using a combination of treatment strategies in five pediatric and AYA patients, including a novel use of daratumumab in a young adult patient who had refractory DSAs and had suffered serious side effects from conventional desensitization strategies. The presence of elevated DSAs in pediatric and AYA recipients of a human leukocyte antigen (HLA)-mismatched haploidentical HCT can be overcome by a multipronged treatment strategy.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Adulto Joven , Adolescente , Humanos , Niño , Supervivencia de Injerto , Antígenos HLA , Donantes de Tejidos , Acondicionamiento Pretrasplante , Anticuerpos , Rechazo de InjertoRESUMEN
INTRODUCTION AND OBJECTIVE: The impact of pretransplant donor-specific antibodies (DSAs), especially class II DSAs, on kidney allograft outcomes remains unclear in simultaneous liver-kidney transplantation (SLKT) recipients. METHODS: We examined 85 recipients who consecutively underwent SLKT between 2009 and 2018 in our center. Associations between pretransplant DSA and worsening kidney function (WKF), kidney allograft loss, composite kidney outcome (WKF and/or antibody-mediated rejection and/or death-censored kidney allograft loss), death with functioning graft, and overall mortality were examined in survival analysis. WKF was defined as an eGFR decrease of 30% or greater from baseline, or 2 or more episodes of proteinuria, at least 90 days apart from each other. RESULTS: The mean age at SLKT was 56 ± 10 years, and 62% of the recipients were male. More than one quarter (26%) of our recipients were African American. The 2 major causes of end-stage liver disease were hepatitis C (28%) and alcoholic hepatitis (26%). Nineteen recipients (22%) had pretransplant DSAs at the time of SLKT. The DSA(+) group and DSA(-) group had similar risk of WKF (unadjusted model: hazard ratio [HR] = 0.77, 95% confidence interval [CI]: 0.29-2.05 and adjusted model: HR = 0.36, 95% CI: 0.12-1.08); similar risk of composite kidney outcome (unadjusted model: HR = 1.04, 95% CI: 0.45-2.43 and adjusted model: HR = 0.53, 95% CI: 0.20-1.39); and similar risk of overall death (unadjusted model: HR = 1.23, 95% CI: 0.45-3.36 and adjusted model: HR = 1.28, 95% CI: 0.42-3.87). We found similar results when comparing different DSA subclasses (class I and II DSAs) with recipients without DSAs. CONCLUSIONS: The presence of pretransplant DSAs was not associated with worse kidney allograft outcomes from our single-center experience. Further prospective larger studies are strongly warranted.
Asunto(s)
Suero Antilinfocítico/farmacología , Antígenos de Histocompatibilidad Clase II/inmunología , Isoanticuerpos/inmunología , Trasplante de Riñón/efectos adversos , Trasplante de Hígado , Adulto , Anciano , Aloinjertos , Femenino , Rechazo de Injerto/etiología , Humanos , Trasplante de Riñón/mortalidad , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Donantes de TejidosRESUMEN
Background: De novo Donor Specific Antibodies (DSA) are considered as a risk factor for the kidney allograft outcomes in recipients after simultaneous liver-kidney transplantation (SLKT). We hypothesized that length of hospital stay (LOS) might be associated with de novo DSA development of due to the increased likelihood of receiving blood transfusions with reduced immunosuppressive regimens.Methods: This study is a single-center, retrospective cohort study consisting of 85 recipients who underwent SLKT from 2009 to 2018 in our hospital. We divided the patients into two groups according to LOS [long hospital stay (L) group (LOS >14 days) and short hospital stay (S) group (LOS ≤14 days)]. Propensity score (PS) has been created using logistic regression to predict LOS greater than median of 14 days. The association between the presence of de novo DSA and LOS was assessed by logistic regression models adjusted for PS.Results: The mean age at transplantation of the entire cohort was 55.5 ± 10.1 years. Sixty percent of the recipients were male and Caucasian. Median LOS in (L) group was three-fold longer than (S) group [L: median 30 days (IQR: 21-52), S: median 8.5 days (IQR: 7-11)]. Eight patients developed de novo DSA after SLKT (9.4%), all of them were in (L) group. Longer LOS was significantly associated with higher risk of development of de novo DSA in unadjusted (OR+ each 5 days: 1.09, 95% CI:1.02-1.16) and PS adjusted (OR+ each 5 days: 1.11, 95% CI:1.02-1.21) analysis.Conclusion: Longer hospitalization is significantly associated with the development of de novo DSA in SLKT.
Asunto(s)
Rechazo de Injerto/epidemiología , Isoanticuerpos/sangre , Trasplante de Riñón/efectos adversos , Tiempo de Internación/estadística & datos numéricos , Trasplante de Hígado/efectos adversos , Adulto , Anciano , Aloinjertos/inmunología , Transfusión Sanguínea/estadística & datos numéricos , Femenino , Rechazo de Injerto/sangre , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Humanos , Inmunosupresores/administración & dosificación , Incidencia , Isoanticuerpos/inmunología , Isoantígenos/inmunología , Riñón/inmunología , Hígado/inmunología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Factores de TiempoRESUMEN
There is a dearth of published data regarding the presence of post-transplant donor-specific antibodies (DSA), especially C1q-binding DSA (C1q+DSA), and patient and kidney allograft outcomes in simultaneous liver-kidney transplant (SLKT) recipients. We conducted a retrospective cohort study consisted of 85 consecutive SLKT patients between 2009 and 2018 in our center. Associations between presence of post-transplant DSA, including persistent and/or newly developed DSA and C1q+DSA, and all-cause mortality and the composite outcome of mortality, allograft kidney loss, and antibody-mediated rejection were examined using unadjusted and age and sex-adjusted Cox proportional hazards and time-dependent regression models. The mean age at SLKT was 56 years and 60% of the patients were male. Twelve patients (14%) had post-transplant DSA and seven patients (8%) had C1q+DSA. The presence of post-transplant DSA was significantly associated with increased risk of mortality (unadjusted model: Hazard Ratio (HR) = 2.72, 95% confidence interval (CI): 1.06-6.98 and adjusted model: HR = 3.20, 95% CI: 1.11-9.22) and the composite outcome (unadjusted model: HR = 3.18, 95% CI: 1.31-7.68 and adjusted model: HR = 3.93, 95% CI: 1.39-11.10). There was also higher risk for outcomes in recipients with C1q+DSA compared the ones without C1q+DSA. Post-transplant DSA is significantly associated with worse patient and kidney allograft outcomes in SLKT. Further prospective and large cohort studies are warranted to better assess these associations.
Asunto(s)
Isoanticuerpos/inmunología , Trasplante de Riñón , Trasplante de Hígado , Receptores de Trasplantes , Complemento C1q/inmunología , Femenino , Rechazo de Injerto , Supervivencia de Injerto , Humanos , Riñón , Hígado , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Donantes de TejidosRESUMEN
DSA after HTx may have adverse effects on patient survival. The aim of this study was to assess risk factors for the development of DSA after pediatric HTx. All HTx recipients at our center with serial monitoring of DSA were identified. Cox proportional hazards model was used to estimate donor and recipient characteristics associated with the development of DSA. De novo DSA were detected in 40 (33%) of 121 HTx recipients. Characteristics associated with de novo DSA included older age, African American race, prior operations, prior ECMO, PRA > 10%, longer bypass time, mechanical support at transplant, and donor death from GSW. In a multivariable model, mechanical support (HR 3.23, 95% CI [1.02, 8.87]), African American race (HR 3.36, 95% CI [1.68, 7.32]), and donor death from GSW (HR 4.76, 95% CI [1.62, 14.01]) were significantly associated with DSA. Multiple factors appear to play a role in the development of DSA, knowledge of which may guide the frequency of post-transplant monitoring. DSA develop more frequently in those with prior sensitizing events, suggesting the possibility that these exposures predispose the immune system to respond to donor antigens, even in the presence of a negative cross-match.
Asunto(s)
Rechazo de Injerto/inmunología , Trasplante de Corazón , Isoanticuerpos/sangre , Adolescente , Biomarcadores/sangre , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Estudios de Seguimiento , Rechazo de Injerto/sangre , Humanos , Lactante , Recién Nacido , Estimación de Kaplan-Meier , Masculino , Modelos de Riesgos Proporcionales , Factores de Riesgo , Donantes de TejidosRESUMEN
Multiple sclerosis is a demyelinating disease of the central nervous system with a presumed autoimmune etiology. Previous microarray analyses identified conserved gene expression signatures in peripheral blood mononuclear cells of patients with autoimmune diseases. We used quantitative real-time polymerase chain reaction analysis to identify a minimum number of genes of which transcript levels discriminated multiple sclerosis patients from patients with other chronic diseases and from controls. We used a computer program to search quantitative transcript levels to identify optimum ratios that distinguished among the different categories. A combination of a 4-ratio equation using expression levels of five genes segregated the multiple sclerosis cohort (n=55) from the control cohort (n=49) with a sensitivity of 91% and specificity of 98%. When autoimmune and other chronic disease groups were included (n=78), this discriminator still performed with a sensitivity of 79% and a specificity of 87%. This approach may have diagnostic utility not only for multiple sclerosis but also for other clinically complex autoimmune diseases.
Asunto(s)
Pruebas Genéticas/métodos , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/genética , Transcripción Genética/genética , Adulto , Anciano , Biomarcadores , Análisis Discriminante , Femenino , Humanos , Masculino , Persona de Mediana Edad , ARN Mensajero/análisis , ARN Mensajero/genética , Curva ROC , Sensibilidad y Especificidad , Programas InformáticosRESUMEN
BACKGROUND: Quantitative real-time PCR has become the predominant molecular technique to monitor BCRABL levels in response to treatment in Ph(+) leukemia patients. However, without some form of standardized methodology between laboratories, the correlation of results is difficult. METHODS: Using TaqMan-based assays, parallel quantitative real-time PCR analysis was performed on 70 clinical specimens at Vanderbilt University Medical Center and Virginia Commonwealth University. While the same positive control cell line (K562) and quality control gene (BCR) were used, the RNA isolation technique, cDNA synthesis, BCR control cell line, and PCR primer and probe sequences were different. RESULTS: The detection of BCRABL-positive results spanned a dynamic range from 10(0) to 10(5)/100,000 cells. Forty-three samples were negative at both facilities. A Spearman rank correlation analysis was performed for the 22 BCRABL-positive paired results. The correlation coefficient, r(s), was 0.9435 (p < 0.00001), suggesting a strong correlation of the results. One discordant result was obtained for consecutive samples from one patient with a low BCRABL copy number as a result of a minimal RNA yield at one laboratory. CONCLUSIONS: These results suggest that quantitative real-time PCR assays for BCRABL detection can be comparable between laboratories despite significant differences in methodologies if the same positive control cell line and quality control gene are used. It is imperative that some level of assay standardization be adopted between laboratories, not only for patients who are monitored at different facilities, but also for larger investigative studies in which hematologic, cytogenetic and molecular responses are to be compared.