RESUMEN
The Eurotransplant Senior Program (ESP) has expedited the chance for elderly patients with kidney failure to receive a timely transplant. This current study evaluated survival parameters of kidneys donated after brain death with or without matching for HLA-DR antigens. This cohort study evaluated the period within ESP with paired allocation of 675 kidneys from donors 65 years and older to transplant candidates 65 years and older, the first kidney to 341 patients within the Eurotransplant Senior DR-compatible Program and 334 contralateral kidneys without (ESP) HLA-DR antigen matching. We used Kaplan-Meier estimates and competing risk analysis to assess all cause mortality and kidney graft failure, respectively. The log-rank test and Cox proportional hazards regression were used for comparisons. Within ESP, matching for HLA-DR antigens was associated with a significantly lower five-year risk of mortality (hazard ratio 0.71; 95% confidence interval 0.53-0.95) and significantly lower cause-specific hazards for kidney graft failure and return to dialysis at one year (0.55; 0.35-0.87) and five years (0.73; 0.53-0.99) post-transplant. Allocation based on HLA-DR matching resulted in longer cold ischemia (mean difference 1.00 hours; 95% confidence interval: 0.32-1.68) and kidney offers with a significantly shorter median dialysis vintage of 2.4 versus 4.1 yrs. in ESP without matching. Thus, our allocation based on HLA-DR matching improved five-year patient and kidney allograft survival. Hence, our paired allocation study suggests a superior outcome of HLA-DR matching in the context of old-for-old kidney transplantation.
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Trasplante de Riñón , Obtención de Tejidos y Órganos , Humanos , Anciano , Trasplante de Riñón/efectos adversos , Estudios de Cohortes , Antígenos HLA-DR , Riñón , Donantes de Tejidos , Prueba de Histocompatibilidad , Supervivencia de InjertoRESUMEN
Dendritic cells are key players in renal allograft rejection and have been identified as an intrinsic part of the kidney. Here we quantified and phenotyped the dendritic cell populations in well-defined biopsies of 102 patients with acute renal allograft rejection in comparison with 78 available pretransplant biopsies. There was a strong increase in BDCA-1(+) and DC-SIGN(+) myeloid, BDCA-2(+) plasmacytoid, and DC-LAMP(+) mature dendritic cells in rejection biopsies compared with the corresponding pretransplant tissue. Mature dendritic cells were mostly found in clusters of lymphoid infiltrate and showed a strong correlation with the Banff infiltrate score. The presence of both myeloid and plasmacytoid dendritic cell subsets in the kidney during acute rejection correlated with interstitial fibrosis and tubular atrophy. Importantly, the myeloid dendritic cell density at the time of acute rejection was an independent risk factor for loss of renal function after the first year. Thus, acute renal allograft rejection is characterized by an influx of myeloid and plasmacytoid dendritic cells, strongly associated with local damage in the graft. Hence, the density of myeloid dendritic cells during acute rejection could be an important risk factor for the long-term development of chronic changes and loss of graft function.
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Células Dendríticas/patología , Rechazo de Injerto/patología , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/patología , Enfermedad Aguda , Adulto , Antígenos CD1 , Antígenos de Superficie/metabolismo , Atrofia , Moléculas de Adhesión Celular/metabolismo , Diferenciación Celular , Células Dendríticas/clasificación , Células Dendríticas/metabolismo , Femenino , Fibrosis , Glicoproteínas , Humanos , Lectinas Tipo C/metabolismo , Proteína 3 de la Membrana Asociada a Lisosoma/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Persona de Mediana Edad , Pronóstico , Receptores de Superficie Celular/metabolismo , Receptores Inmunológicos/metabolismo , Factores de RiesgoRESUMEN
There is an unmet need for noninvasive tools for diagnosis of rejection after kidney transplantation. The aim of this study was to determine the discriminative value of a combined cellular and molecular biomarker platform in urine for the detection of rejection. METHODS: First, microRNA (miR) molecules were screened in transplant biopsies and urine sediments of patients with acute rejection and patients without rejection and stable graft function. Second, the expression of 15 selected miRs was quantified in an independent set of 115 urine sediments of patients with rejection and 55 urine sediments of patients without histological signs of rejection on protocol biopsy. Additionally, CXCL-9 and CXCL-10 protein levels were quantified in the urine supernatant. RESULTS: Levels of miR-155-5p (5.7-fold), miR-126-3p (4.2-fold), miR-21-5p (3.7-fold), miR-25-3p (2.5-fold), and miR-615-3p (0.4-fold) were significantly different between rejection and no-rejection urine sediments. CXCL-9 and CXCL-10 levels were significantly elevated in urine from recipients with rejection. In a multivariable model (sensitivity: 89.1%, specificity: 75.6%, area under the curve: 0.94, P < 0.001), miR-155-5p, miR-615-3p, and CXCL-9 levels were independent predictors of rejection. Stratified 10-fold cross validation of the model resulted in an area under the curve of 0.92. CONCLUSIONS: A combined urinary microRNA and chemokine profile discriminates kidney transplant rejection from stable graft conditions.
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BACKGROUND: Proteinuria predicts progressive renal failure. Next to being a progression marker, non-selective proteinuria itself is thought to be toxic to the tubulointerstitium. In proteinuric states, activation of filtered or locally produced complement is toxic for renal tubular cells and likely contributes to the progression of renal failure. Recent experimental evidence suggests an important role for properdin in promoting intrarenal complement activation. We measured properdin in proteinuric urine and assessed its relation with urinary SC5b-9 levels, the soluble form of the effector phase of complement activation. METHODS: Seventy patients with renal disease of different origin but all with a protein excretion of at least 1 g/day were studied. Urinary properdin and SC5b-9 levels were measured using an ELISA technique. RESULTS: Properdin was detectable in the urine of 37 patients (53%). These subjects had higher urinary SC5b-9 levels {median 0.50 U/ml [interquartile range (IQR) 0.13-1.81] versus 0.049 U/ml (IQR 0.024-0.089), P < 0.001}. When adjusted for proteinuria and renal function, properdin excretion was strongly associated with increased urinary SC5b-9 levels (odds ratio 16.2, 95% confidence interval 3.6-74.4). Properdin excretion was associated with worse renal function. CONCLUSION: Our results suggest that urinary properdin excretion enhances intrarenal complement activation and thus may contribute to the progression of renal damage in proteinuric states.
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Biomarcadores/orina , Complejo de Ataque a Membrana del Sistema Complemento/orina , Enfermedades Renales/orina , Properdina/orina , Proteinuria/orina , Activación de Complemento , Ensayo de Inmunoadsorción Enzimática , Humanos , Enfermedades Renales/patología , Pruebas de Función Renal , Persona de Mediana Edad , PronósticoRESUMEN
OBJECTIVE: In patients with type 1 diabetes and end-stage renal disease, it is controversial whether a simultaneous pancreas-kidney (SPK) transplantation improves survival compared with kidney transplantation alone. We compared long-term survival in SPK and living- or deceased-donor kidney transplant recipients. RESEARCH DESIGN AND METHODS: We included all 2,796 patients with type 1 diabetes in the Netherlands who started renal replacement therapy between 1986 and 2016. We used multivariable Cox regression analyses adjusted for recipient age and sex, dialysis modality and vintage, transplantation era, and donor age to compare all-cause mortality between deceased- or living-donor kidney and SPK transplant recipients. Separately, we analyzed mortality between regions where SPK transplant was the preferred intervention (80% SPK) versus regions where a kidney transplant alone was favored (30% SPK). RESULTS: Of 996 transplanted patients, 42%, 16%, and 42% received a deceased- or living-donor kidney or SPK transplant, respectively. Mean (SD) age at transplantation was 50 (11), 48 (11), and 42 (8) years, respectively. Median (95% CI) survival time was 7.3 (6.2; 8.3), 10.5 (7.2; 13.7), and 16.5 (15.1; 17.9) years, respectively. SPK recipients with a functioning pancreas graft at 1 year (91%) had the highest survival (median 17.4 years). Compared with deceased-donor kidney transplant recipients, adjusted hazard ratios (95% CI) for 10- and 20-year all-cause mortality were 0.79 (0.49; 1.29) and 0.98 (0.69; 1.39) for living-donor kidney and 0.67 (0.46; 0.98) and 0.79 (0.60; 1.05) for SPK recipients, respectively. A treatment strategy favoring SPK over kidney transplantation alone showed 10- and 20-year mortality hazard ratios of 0.56 (0.40; 0.78) and 0.69 (0.52; 0.90), respectively. CONCLUSIONS: Compared with living- or deceased-donor kidney transplantation, SPK transplant was associated with improved patient survival, especially in recipients with a long-term functioning pancreatic graft, and resulted in an almost twofold lower 10-year mortality rate.
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Diabetes Mellitus Tipo 1/mortalidad , Diabetes Mellitus Tipo 1/terapia , Fallo Renal Crónico/mortalidad , Trasplante de Riñón/mortalidad , Trasplante de Páncreas/mortalidad , Adulto , Anciano , Estudios de Cohortes , Terapia Combinada/mortalidad , Diabetes Mellitus Tipo 1/complicaciones , Nefropatías Diabéticas/mortalidad , Nefropatías Diabéticas/terapia , Femenino , Estudios de Seguimiento , Supervivencia de Injerto/fisiología , Humanos , Fallo Renal Crónico/terapia , Trasplante de Riñón/métodos , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Trasplante de Páncreas/métodos , Diálisis Renal , Análisis de Supervivencia , Sobrevivientes/estadística & datos numéricosRESUMEN
BACKGROUND: Mannose-binding lectin (MBL) is a recognition molecule of the lectin pathway of complement activation, and its serum levels are largely determined by frequently occurring polymorphisms of the MBL gene. We questioned whether MBL deficiency influences infectious complications in patients after simultaneous pancreas-kidney transplantation (SPKT). METHODS: Infectious complications in the first year after transplantation were scored retrospectively in 152 consecutive SPKT patients who received their transplant at our center between 1990 and 2005. Pretransplant serum MBL levels were determined with enzyme-linked immunosorbent assay. RESULTS: Every 500 ng/mL increase in baseline MBL was associated with an odds ratio of 0.83 (P=0.045) for urinary tract infections and an odds ratio of 0.68 (P=0.029) for urosepsis. Urosepsis was significantly more common in patients with low baseline MBL (<400 ng/mL) compared with those with greater MBL levels (22.7% vs. 8.3%, P=0.015). No significant influence of MBL on the occurrence of wound infections and cytomegalovirus disease could be demonstrated. CONCLUSIONS: With the current study, we show that high levels of serum MBL are associated with protection against urinary tract infections and, more specifically, against urosepsis after SPKT. These data indicate an important role for the lectin pathway of complement activation in antimicrobial defense in these transplant recipients.
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Activación de Complemento/fisiología , Trasplante de Riñón/efectos adversos , Lectina de Unión a Manosa/fisiología , Trasplante de Páncreas/efectos adversos , Sepsis/etiología , Infecciones Urinarias/etiología , Adulto , Biomarcadores/sangre , Activación de Complemento/inmunología , Susceptibilidad a Enfermedades , Femenino , Supervivencia de Injerto/inmunología , Humanos , Inmunidad Innata/inmunología , Trasplante de Riñón/inmunología , Masculino , Lectina de Unión a Manosa/sangre , Persona de Mediana Edad , Análisis Multivariante , Trasplante de Páncreas/inmunología , Estudios Retrospectivos , Factores de Riesgo , Sepsis/sangre , Infecciones Urinarias/sangreRESUMEN
BACKGROUND: Molecules of the innate immune response are increasingly recognized as important mediators in allograft injury during and after kidney transplantation. We therefore aimed to establish the relationship between the expression of these genes at implantation, during an acute rejection (AR) and on graft outcome. METHODS: A total of 19 genes, including Toll like receptors (TLRs), complement components and regulators, and apoptosis-related genes were analyzed at the mRNA level by qPCR in 123 biopsies with acute rejection and paired pre-transplantation tissue (nâ¯=â¯75). RESULTS: Before transplantation, relative mRNA expression of BAX:BCL2 ratio (apoptosis marker) and several complement genes was significantly higher in tissue samples from deceased donors compared to living donors. During AR, TLRs and complement genes showed an increased expression compared to pre-transplant conditions, whereas complement regulators were decreased. A relatively high TLR4 expression level and BAX:BCL2 ratio during AR in the deceased donor group was associated with adverse graft outcome, independently of clinical risk factors. CONCLUSIONS: Complement- and apoptosis-related gene expression is elevated in deceased donor transplants before transplantation. High BAX:BCL2 ratio and TLR4 expression during AR may reflect enhanced intragraft cell death and immunogenic danger signals, and pose a risk factor for adverse graft outcome.
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Aloinjertos/metabolismo , Rechazo de Injerto/genética , Trasplante de Riñón , Riñón/metabolismo , Receptor Toll-Like 4/metabolismo , Enfermedad Aguda , Aloinjertos/patología , Apoptosis/genética , Proteínas del Sistema Complemento/genética , Femenino , Rechazo de Injerto/inmunología , Humanos , Inmunidad Innata/genética , Riñón/patología , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , ARN Mensajero/genética , Receptor Toll-Like 4/genética , Receptores Toll-Like/genética , Trasplante Homólogo , Proteína X Asociada a bcl-2/metabolismoRESUMEN
BACKGROUND: The introduction of human leukocyte antigen (HLA)-matching in nonliving kidney transplantation has resulted into a better graft outcome, but also in an increase of waiting time, especially for patients with rare HLA phenotypes. We addressed the question of the differential influence of HLA-DR-matching versus HLA-A,B in clinical kidney transplantation. METHODS: We used Kaplan-Meier product limit method to estimate survival rates, and Cox proportional hazard regression for the estimation of relative risks (Hazard-ratios) for different variables. RESULTS: A single center study (n=456 transplants, performed between 1985 and 1999) showed that full HLA-DR compatibility leads to a lower incidence of biopsy confirmed acute rejections in the first 180 posttransplantation days. These results were substantiated using the Eurotransplant database (n=39,205 transplants performed between 1985 and 2005) where graft survival in the full HLA-DR compatible group was significantly better than in the incompatible. An additional positive effect of HLA-A,B matching was only found in the full HLA-DR compatible group. In both studies, the introduction of a single HLA-DR incompatibility eliminates the HLA-A,B matching effect. CONCLUSIONS: We propose to allocate postmortem kidneys only to patients with full HLA-DR compatibility, and use HLA-A,B compatibility as an additional selection criterion. All patients, irrespective of their ethnic origin, will profit since the polymorphism of HLA-DR is by far lower than that of HLA-A,B. Excessive kidney travel and cold ischemia time will be significantly reduced.
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Antígenos HLA-DR/sangre , Asignación de Recursos para la Atención de Salud , Histocompatibilidad , Trasplante de Riñón , Donantes de Tejidos , Obtención de Tejidos y Órganos , Enfermedad Aguda , Cadáver , Bases de Datos Factuales , Femenino , Rechazo de Injerto/epidemiología , Supervivencia de Injerto , Antígenos HLA-A/sangre , Antígenos HLA-B/sangre , Prueba de Histocompatibilidad , Humanos , Incidencia , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Riesgo , Factores de TiempoRESUMEN
BACKGROUND: Acute rejection (AR) of kidney transplants is associated with the loss of endothelial integrity, microvascular rarefaction and, ultimately, graft dysfunction. Circulating angiogenic microRNAs (miRNAs) may serve as markers for microvascular injury. Here, we investigated the short- and long-term effects of AR after kidney transplantation on systemic vascular injury and the associated circulating miRNA profile. METHODS: Systemic vascular injury was determined by measuring capillary tortuosity and density within the oral mucosa as well as by assessing circulating levels of angiopoietin-2/angiopoietin-1 ratio, vascular endothelial growth factor and soluble thrombomodulin. After a pilot study, we selected 48 miRNAs to assess the AR- and microvascular injury associated circulating miRNAs. RESULTS: In stable transplant recipients (n = 25) and patients with AR (n = 13), which were also studied longitudinally (1, 6, and 12 months post-AR), we found an AR-associated increase in markers of systemic vascular injury, of which vascular endothelial growth factor and soluble thrombomodulin normalized within 1 year after AR. Of the 48 selected miRNAs, 8 were either decreased (miR-135a, miR-199a-3p, and miR-15a) or increased (miR-17, miR-140-3p, miR-130b, miR-122 and miR-192) in AR. Of these, miR-130b, miR-199a, and miR-192 associated with markers of vascular injury, whereas miR-140-3p, miR-130b, miR-122, and miR-192 normalized within 1 year after AR. CONCLUSIONS: AR after kidney transplantation is characterized by systemic microvascular injury and associates with specific circulating miRNA levels.
RESUMEN
BACKGROUND: The optimal immunosuppressive regimen in simultaneous pancreas-kidney transplant (SPKT) recipients that prevents acute rejection episodes (AREs) and allows optimal outcome remains elusive. METHODS: This cohort study assessed incidence and time to AREs in 73 consecutive SPKT recipients receiving alemtuzumab induction and steroid-free maintenance with tacrolimus and mycophenolate mofetil. A cohort with single high-dose antithymocyte globulin (ATG; n = 85) and triple therapy served as controls. In addition, we provided mechanistic insights in AREs after alemtuzumab depletion, including composition and alloreactivity of lymphocytes (flow cytometry and mixed lymphocyte reaction) plasma alemtuzumab levels (enzyme-linked immunosorbent assay), and maintenance drug exposure. RESULTS: Overall number of AREs at 3 years was significantly lower with alemtuzumab versus ATG induction (26.0% vs 43.5%; adjusted hazard ratio, 0.38; P = 0.029). Most AREs (94.6%) with ATG occurred within the first month, whereas 84.2% of AREs with alemtuzumab occurred beyond 3 months. Patients with and without an ARE in the steroid-free alemtuzumab group showed no differences in composition of lymphocytes, or in alemtuzumab levels. Of note, more than two thirds of these AREs were preceded by empiric tacrolimus and/or mycophenolate mofetil dose adjustments due to viral infections, leukopenia, or gastrointestinal symptoms. CONCLUSIONS: Alemtuzumab induction resulted in a significant lower incidence of AREs. Empiric dose adjustments beyond 3 months in the absence of steroids carry a significant risk for subsequent rejection in SPKT recipients.
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BACKGROUND: Glucocorticoid (GC)-refractory acute rejection (AR) is a risk factor for inferior renal allograft outcome. We investigated genetic predisposition to the response to steroid treatment of acute allograft rejection. METHODS: Single nucleotide polymorphisms of genes involved in GC signaling (GR, GLCCI1) and drug metabolism and transport (CYP3A5, ABCB1, and PXR) were analyzed in kidney transplant recipients (1995-2005, Leiden cohort, n = 153) treated with methylprednisolone. Significant associations were verified in a second cohort (Berlin cohort, n = 66). RESULTS: Patients who received a CYP3A5*1 allele expressing allograft had a lower risk of resistance to methylprednisolone during AR (odds ratio, 0.29; 95% confidence interval, 0.11-0.79; P = 0.016 in combined cohorts analysis). No differences were observed for GC signaling or other drug metabolism/transport-related genes. Both before transplantation (n = 69) and at time of AR (n = 88), tissue CYP3A5 mRNA expression was significantly higher in CYP3A5*1 allele expressing donor kidneys than in CYP3A5*3/*3 allografts (P < 0.00001). Moreover, steroid-responsive patients (n = 64) expressed significantly higher intragraft CYP3A5 mRNA levels compared to steroid-refractory patients (n = 42) in AR (P = 0.006). CONCLUSIONS: CYP3A5 protein expression was detected in tubular epithelial cells and inflammatory cells within the grafts. Our findings show that steroid resistance during AR is associated with donor genotype and intragraft expression levels of CYP3A5.
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Citocromo P-450 CYP3A/genética , Glucocorticoides/uso terapéutico , Rechazo de Injerto/tratamiento farmacológico , Trasplante de Riñón/efectos adversos , Riñón/efectos de los fármacos , Riñón/cirugía , Metilprednisolona/uso terapéutico , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Donantes de Tejidos , Enfermedad Aguda , Aloinjertos , Distribución de Chi-Cuadrado , Citocromo P-450 CYP3A/metabolismo , Resistencia a Medicamentos/genética , Femenino , Frecuencia de los Genes , Genotipo , Alemania , Glucocorticoides/metabolismo , Rechazo de Injerto/enzimología , Rechazo de Injerto/genética , Rechazo de Injerto/inmunología , Humanos , Estimación de Kaplan-Meier , Riñón/enzimología , Modelos Logísticos , Masculino , Metilprednisolona/metabolismo , Persona de Mediana Edad , Países Bajos , Oportunidad Relativa , Farmacogenética , Pruebas de Farmacogenómica , Fenotipo , Modelos de Riesgos Proporcionales , ARN Mensajero/genética , Factores de Riesgo , Resultado del TratamientoRESUMEN
BACKGROUND: Delayed graft function (DGF) occurs in up to 50% of renal transplants. Hypercalcemia and hyperparathyroidism are associated with impaired renal function. Little is known on the effects of serum calcium levels on DGF. This issue was addressed in the current study. METHODS: Patients receiving a cadaveric renal transplant between 1986 and 1996 were studied. Data on calcium metabolism and histologic characteristics of nephrocalcinosis, acute tubular necrosis (ATN), and acute rejection in biopsies taken within the first week were related to the occurrence of DGF. RESULTS: The incidence of DGF in a cohort of 585 cadaveric transplants was 31%. DGF correlated independently with serum calcium levels (odds ratio [OR] 1.14 [95% confidence interval (CI) 1.04-1.26] per 0.1 mmol/L). The use of calcium channel blockers before transplantation protected against DGF (OR 0.5 [95% CI 0.29- 0.87]). In this selected group, we found an association with histologic signs of ATN and DGF. However, most of the biopsies also had features of acute rejection or nephrocalcinosis. Nephrocalcinosis was found in 12 of 71 biopsies and was not associated with serum calcium levels or the occurrence of DGF. CONCLUSIONS: In this study, serum calcium levels were independently associated with DGF. This could not be explained by the presence of microscopic nephrocalcinosis. Therefore, DGF is attributed to high intracellular calcium levels. Because calcium supplementation and vitamin D analogues are commonly used in dialysis practice, hypercalcemia influences long-term graft outcome by its effect on DGF. The pretransplant use of calcium channel blockers has a protective effect on the occurrence of DGF.
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Calcio/sangre , Rechazo de Injerto/epidemiología , Trasplante de Riñón/fisiología , Adulto , Albuminuria , Biomarcadores/sangre , Cadáver , Calcinosis/patología , Estudios de Cohortes , Femenino , Humanos , Trasplante de Riñón/patología , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Hormona Paratiroidea/sangre , Fosfatos/sangre , Complicaciones Posoperatorias/sangre , Estudios Retrospectivos , Donantes de TejidosRESUMEN
BACKGROUND: Acute rejection is a major complication after renal transplantation and the most important risk factor for chronic rejection. We investigated whether the timing of the last treated acute rejection episode (ARE) influences long-term outcome and compared the risk profiles of early versus late ARE. METHODS: A cohort of 654 patients who underwent cadaveric renal transplants (1983-1997) that functioned for more than 6 months was studied. In 384 of 654 transplant recipients, one or more treated AREs were documented; the last ARE occurred in 297 of 384 transplant recipients within 3 months and in 87 of 384 after 3 months. Applying multivariate logistic regression analysis, we compared the predictor variables of the two groups with transplants without AREs. RESULTS: Ten-year graft survival rates censored for causes of graft loss other than chronic rejection were 94%, 86%, and 45% for patients without ARE, with early ARE, and with late ARE, respectively. Delayed graft function, odds ratio (OR) 2.37 (1.55-3.62), and major histocompatibility complex (MHC) class II incompatibility, OR 2.28 (1.62-3.20) per human leukocyte antigen (HLA)-DR mismatch, were independent risk factors for early ARE. In contrast, recipient age, OR 0.75 (0.61-0.93) per 10-year increase, donor age, OR 1.28 (1.07-1.53) per 10-year increase, female donor gender, OR 1.74 (1.03-2.94), and MHC class I incompatibility, OR 1.35 (1.07-1.72) per mismatch of cross reactive groups, were associated with late ARE. CONCLUSIONS: Late ARE has a detrimental impact on long-term graft survival and is associated with MHC class I incompatibility, whereas early ARE is correlated with HLA-DR mismatches and has a better prognosis. These data are consistent with the role of direct and indirect allorecognition in the pathophysiology of early and late ARE, respectively.
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Rechazo de Injerto , Trasplante de Riñón/inmunología , Enfermedad Aguda , Adulto , Anciano , Femenino , Supervivencia de Injerto , Antígenos HLA-DR/inmunología , Humanos , Masculino , Persona de Mediana EdadAsunto(s)
Transfusión Sanguínea/métodos , Rechazo de Injerto/prevención & control , Trasplante de Riñón/métodos , Trasplante de Páncreas/métodos , Cuidados Preoperatorios/métodos , Enfermedad Aguda , Adulto , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/cirugía , Femenino , Estudios de Seguimiento , Rechazo de Injerto/patología , Humanos , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/cirugía , Masculino , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Calcineurin inhibitors (CNIs) have an unfavorable cardiovascular risk profile in renal transplant recipients. The aim of this substudy was to assess the effects of late CNI or mycophenolate mofetil (MMF) withdrawal on ambulatory blood pressure monitoring and carotid intima media thickness. METHODS: A total of 119 stable renal transplant recipients on triple regimen with steroids, a CNI and MMF were randomized into either the concentration-controlled CNI or MMF withdrawal groups. Patients were treated for traditional cardiovascular risk factors according to predefined targets. Ambulatory blood pressure monitoring and measurements of intima media thickness were performed at baseline and after 1, 2, and 3 years after randomization. RESULTS: CNI withdrawal resulted in a significant decline in both ambulatory day- and nighttime blood pressures (daytime: systolic blood pressure, -1.6 mm Hg/y, P=0.018; diastolic blood pressure, -1.3 mm Hg/y, P=0.002; nighttime systolic blood pressure: -1.9 mm Hg/y, P=0.008; diastolic blood pressure: -1.3 mm Hg/y, P=0.014), which was not observed after MMF withdrawal. There was no difference in the proportion of nocturnal nondippers (both groups, 69%, P=0.95). Despite the reduction in ambulatory blood pressure, no effect of CNI withdrawal on carotid intima media thickness was found. CONCLUSION: In stable renal transplant recipients, late CNI withdrawal from a triple drug regimen decreased blood pressure in comparison with MMF withdrawal but had no specific impact on carotid intima media thickness. Considering the high prevalence of hypertension in patients on CNI therapy, most stable renal transplant recipients may benefit from late CNI withdrawal by improved blood pressure control.
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Presión Sanguínea/efectos de los fármacos , Inhibidores de la Calcineurina , Grosor Intima-Media Carotídeo , Inhibidores Enzimáticos/administración & dosificación , Rechazo de Injerto/tratamiento farmacológico , Trasplante de Riñón , Adulto , Anciano , Monitoreo Ambulatorio de la Presión Arterial , Ciclosporina/administración & dosificación , Ciclosporina/efectos adversos , Inhibidores Enzimáticos/efectos adversos , Femenino , Estudios de Seguimiento , Rechazo de Injerto/epidemiología , Rechazo de Injerto/fisiopatología , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Masculino , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Ácido Micofenólico/efectos adversos , Ácido Micofenólico/análogos & derivados , Factores de Riesgo , Esteroides/administración & dosificación , Síndrome de Abstinencia a Sustancias/epidemiología , Síndrome de Abstinencia a Sustancias/fisiopatología , Tacrolimus/administración & dosificación , Tacrolimus/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: Daclizumab and antithymocyte globulin (ATG) have been shown to reduce allograft rejection. We assessed the safety and efficacy of daclizumab or ATG prophylaxis in combination with triple immunotherapy in simultaneous pancreas-kidney transplant (SPKT) recipients. METHODS: Thirty-nine type 1 diabetic patients scheduled for primary SPKT were randomized to receive prophylactic therapy with either daclizumab or ATG. A group of 27 patients without prophylactic antibodies was used for retrospective comparison. All patients received cyclosporine and mycophenolate mofetil and gradually tapered prednisone. Autoantibodies and cellular autoreactivity were measured to assess recurrent autoreactive responses. RESULTS: Baseline and transplant characteristics were comparable among groups. Both daclizumab and ATG therapy resulted in a significant reduction in acute rejection episodes. The incidence of rejection episodes was significantly higher in pretransplantation GAD autoantibody-positive daclizumab-treated recipients compared with GAD autoantibody-negative or ATG-treated recipients. IA-2 islet autoantibodies showed no association with rejection. There were no significant differences between the groups for in vitro autoreactivity, clinical outcome, or functional parameters. CONCLUSIONS: Daclizumab or ATG combined with a maintenance immunosuppressive regime consisting of cyclosporine, mycophenolate mofetil, and prednisolone were well tolerated and equally effective in reducing the incidence of acute rejection episodes in SPKT recipients. Up to 3 years, no adverse sequelae of the immunoprophylaxis or clinical and ex vivo recurrent autoimmunity were observed. We propose that the pretransplantation existence of GAD65 autoantibodies serves as a marker guiding the choice for prophylactic therapy in pancreas transplantation.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Suero Antilinfocítico/administración & dosificación , Autoanticuerpos/sangre , Rechazo de Injerto/tratamiento farmacológico , Inmunoglobulina G/administración & dosificación , Trasplante de Riñón , Trasplante de Páncreas , Enfermedad Aguda , Adulto , Daclizumab , Diabetes Mellitus Tipo 1/cirugía , Femenino , Glutamato Descarboxilasa/inmunología , Rechazo de Injerto/epidemiología , Rechazo de Injerto/inmunología , Humanos , Inmunosupresores/administración & dosificación , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Estudios Retrospectivos , Factores de Riesgo , Trasplante Homólogo , Adulto JovenRESUMEN
BACKGROUND: Early calcineurin inhibitor (CNI) withdrawal with mycophenolate mofetil (MMF) has not become routine practice, due to concerns about excess acute rejection. Therapeutic drug monitoring may be advantageous when the CNI or MMF is withdrawn. METHODS: This prospective, randomized, concentration-controlled withdrawal study enrolled 177 stable renal transplant recipients on maintenance CNI-based immunosuppression, combined with steroids and MMF. After the feasibility phase of the study, patients were randomized to MMF-withdrawal (target area under the time-concentration curve-cyclosporine: 3250 ng·hr/mL or tacrolimus: 120 ng·hr/mL) or CNI-withdrawal (target area under the time-concentration curve-mycophenolic acid: 75 µg·hr/mL). RESULTS: The estimated glomerular filtration rate (modification of diet in renal disease) remained significantly better after CNI elimination (59.5±2.1 mL/min vs. 51.1±2.1 mL/min, P = 0.006) up to 3 years and resulted in less functional decline, including the subgroup with an estimated glomerular filtration rate less than 50 mL/min at baseline (P = 0.03). At 6 months, one patient in the MMF-withdrawal group (1.3%) and three in the CNI-withdrawal group (3.8%) experienced acute rejection (P = 0.62). The defined higher mycophenolic acid exposure was well tolerated. CONCLUSION: These data indicate that with time the large majority of stable renal transplant recipients can be safely reduced to dual therapy with MMF or CNIs, applying concentration-controlled dosing. CNI-free patients, including those with moderate renal allograft dysfunction, have the benefit of improved renal function, whereas the risk of acute rejection after late withdrawal is low.
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Inhibidores de la Calcineurina , Rechazo de Injerto/tratamiento farmacológico , Trasplante de Riñón , Ácido Micofenólico/análogos & derivados , Enfermedad Aguda , Biopsia , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Rechazo de Injerto/metabolismo , Rechazo de Injerto/fisiopatología , Supervivencia de Injerto , Humanos , Fallo Renal Crónico/fisiopatología , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Estudios Prospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Calcineurin inhibitor (CNI)-based therapy is associated with adverse cardiovascular effects. We examined the effects of late CNI or mycophenolate mofetil (MMF) withdrawal on echocardiographic parameters. METHODS: This study was conducted as a substudy of a randomized trial in stable renal transplant recipients who were on a triple CNI-based regimen with prednisone and MMF that evaluated late concentration-controlled withdrawal of CNI or MMF on renal function. A total of 108 patients (age, 52.3±11.5 years; 67% male; at a median of 2.0 years post-transplantation, (interquartile range 1.3-3.3 years); estimated glomerular filtration rate, 57±16 mL/min/1.73 m; 66% on cyclosporine and 34% on tacrolimus) entered the cardiovascular substudy examining echocardiographic parameters at baseline and 2 years after randomization. In all patients, traditional cardiovascular risk factors were treated according to predefined targets. RESULTS: Late CNI withdrawal prevented progressive development of left ventricular (LV) diastolic dysfunction, as assessed by markers of LV diastolic function (mitral deceleration time and mitral annular e' velocity). Conversely, in the MMF-withdrawal group, the left atrial volume index (an indicator of chronic LV diastolic dysfunction) was significantly increased at 2 years (from 24.1±6.7 to 27.0±7.0 mL/m, P<0.05). In addition, CNI withdrawal resulted in a higher proportion of patients achieving the predefined blood pressure targets (<130/85 mm Hg: 41.5% vs. 12.7%, P=0.001) at 2 years while requiring less antihypertensive drugs. Changes in the left atrial volume index were significantly associated with treatment arm (P=0.03) and changes in systolic (P=0.005) and diastolic (P=0.005) blood pressure. CONCLUSIONS: Late CNI withdrawal, from a triple-drug regimen in stable renal transplant recipients, prevented progressive deterioration of LV diastolic function and facilitated better blood pressure control.
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Inhibidores de la Calcineurina , Ciclosporina/administración & dosificación , Diástole/efectos de los fármacos , Inmunosupresores/administración & dosificación , Trasplante de Riñón , Tacrolimus/administración & dosificación , Disfunción Ventricular Izquierda/prevención & control , Función Ventricular Izquierda/efectos de los fármacos , Adulto , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Distribución de Chi-Cuadrado , Esquema de Medicación , Quimioterapia Combinada , Ecocardiografía Doppler de Pulso , Femenino , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/fisiopatología , Humanos , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/inmunología , Modelos Lineales , Masculino , Persona de Mediana Edad , Válvula Mitral/efectos de los fármacos , Válvula Mitral/fisiopatología , Ácido Micofenólico/administración & dosificación , Ácido Micofenólico/análogos & derivados , Países Bajos , Valor Predictivo de las Pruebas , Prednisona/administración & dosificación , Estudios Prospectivos , Factores de Tiempo , Resultado del Tratamiento , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
BACKGROUND: Steroid-resistant acute rejection is a risk factor for inferior renal allograft outcome. METHODS: From 873 kidney transplant recipients (1995-2005), 108 patients with a first rejection episode were selected for study using strict inclusion criteria and clinical endpoint definition. We aimed to predict response to corticosteroid treatment using gene expression of 65 transcripts. These reflect cytokines, chemokines, and surface and activation markers of various cell types including T cells, macrophages, B cells, and granulocytes. Steroid resistance (40% of the patients) was defined as requirement for antithymocyte globulin treatment within 2 weeks after corticosteroid treatment. RESULTS: None of the clinical and histomorphologic parameters showed a significant association with response to treatment. Univariate logistic regression analysis resulted in 11 messenger RNA markers, including T-cell-related transcripts CD25, lymphocyte activation gene-3, Granzyme B, and interleukin-10, and macrophage-specific transcripts mannose receptor and S100 calcium-binding protein A9, which significantly discriminated steroid resistant from steroid-responsive rejections (P<0.05). In multivariate logistic regression, the combination of T-cell activation markers CD25:CD3e ratio (odds ratio, 8.7; confidence interval, 2.4-31.2) and lymphocyte activation gene-3 (odds ratio, 3.3; confidence interval, 1.4-7.7) represented the best predictive model for steroid response (P<0.0001). Specificity and sensitivity were 78% and 60%, respectively. After internal stratified 10-fold cross-validation, the model remained significant. Inclusion of clinical variables into the model with molecular variables did not enhance prediction. CONCLUSIONS: Differences in intragraft expression profiles reflect variability in the response to antirejection treatment. In acute rejection, molecular markers, particularly those reflecting T-cell activation, offer superior prognostic value compared with conventional parameters.
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Corticoesteroides/uso terapéutico , Marcadores Genéticos , Rechazo de Injerto/prevención & control , Supervivencia de Injerto/efectos de los fármacos , Inmunosupresores/uso terapéutico , Trasplante de Riñón/inmunología , Reacción en Cadena en Tiempo Real de la Polimerasa , Enfermedad Aguda , Biopsia , Resistencia a Medicamentos/genética , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Rechazo de Injerto/genética , Rechazo de Injerto/inmunología , Supervivencia de Injerto/genética , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Países Bajos , Oportunidad Relativa , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Innate immunity plays a role in controlling adaptive immune responses. METHODS: We investigated the clinical relevance of single nucleotide polymorphisms in 22 genes encoding innate, secreted, and signaling pattern recognition receptors in a total of 520 donor-recipient pairs of postmortem, human leukocyte antigen-DR-compatible kidney transplantations. Associations with rejection incidence were tested in an a priori randomized training set and validation set. RESULTS: Polymorphisms in TLR-3 (rs3775296) in the recipients and in ficolin-2 (rs7851696; Ala258Ser) and C1qR1 (rs7492) in the donors showed the strongest association with severe rejection. In multivariate analysis, presence of the ficolin-2 Ala258Ser variant in the donor predicted lower incidence of severe rejection (odds ratio=0.3; 95% confidence interval, 0.1-0.9; P=0.024) and of graft loss (hazard ratio=0.5; 95% confidence interval, 0.2-1.0; P=0.046) independently of clinical risk factors. Ficolin-2 messenger RNA expression was detected in pretransplantation biopsies from 69 donor grafts. Serum and tissue ficolin-2 levels were unaffected by genotype. Ficolin-2 protein, which bound to dying cells, was detected in donor kidneys in a passenger leukocyte-like pattern. Indeed, monocytes, monocyte-derived macrophages, and peripheral blood mononuclear cells expressed ficolin-2. Donor grafts with the ficolin-2 Ala258Ser variant contained significantly elevated expression of interleukin 6, having ascribed cytoprotective effects. It has been described that Ala258Ser leads to increased binding capacity of ficolin-2 to N-acetylglucosamine. CONCLUSIONS: Presence of the ficolin-2 Ala258Ser polymorphism in the donor independently predicts improved graft outcome. Based on mechanistic data, we propose that this functional polymorphism leads to more efficient handling of injured cells by phagocytozing cells, resulting in decreased intragraft exposure to danger signals and dampened alloimmune responses.