RESUMEN
BACKGROUND: Returning to dialysis after kidney graft loss (GL) is associated with a high risk of mortality, mainly in the first 3-6 months. The follow-up of patients with GL should be extended to better understand crude patient outcomes, mainly in emerging countries, where the transplantation activity has increased. METHODS: This is a historical single-center cohort study conducted in an emerging country (Brazil) that included 115 transplant patients with kidney allograft failure who were followed for 44.1 (21.4; 72.6) months after GL. The outcomes were death or retransplantation after GL calculated by Kaplan-Meier and log-rank tests. Proportional hazard ratios for death and retransplantation were assessed by Cox regression. RESULTS: The 5-year probability of retransplantation was 38.7% (95% CI: 26.1%-51.2%) and that of death was 37.7% (95% CI: 24.9%-50.5%); OR = 1.03 (95% CI: 0.71-1.70) and P = 0.66. The likelihood of retransplantation was higher in patients who resumed dialysis with higher levels of hemoglobin (HR = 1.22; 95% CI = 1.04-1.43; P = 0.01) and lower in blood type O patients (HR = 0.48; 95% CI = 0.25-0.93; P = 0.03), which was associated with a lower frequency of retransplantation with a subsequent living-donor kidney. On the other hand, the risk of death was significantly associated with Charlson comorbidity index (HR for each point = 1.37; 95% CI 1.19-1.50; P<0.001), and residual eGFR at the time when patients had resumed to dialysis (HR for each mL = 1.14; 95% CI = 1.05-1.25; P = 0.002). The trend toward a lower risk of death when patients had resumed to dialysis using AV fistula access was observed (HR = 0.50; 95% CI 0.25-1.02; P = 0.06), while a higher risk seems to be associated with the number of previous engraftment (HR = 2.01; 95% CI 0.99-4.07; P = 0.05). CONCLUSIONS: The 5-year probability of retransplantation was not less than that of death. Variables related to the probability of retransplantation were hemoglobin level before resuming dialysis and ABO blood type, while the risk of death was associated with comorbidities and residual eGFR.
Asunto(s)
Sistema del Grupo Sanguíneo ABO/sangre , Rechazo de Injerto , Trasplante de Riñón , Donadores Vivos , Adulto , Brasil/epidemiología , Femenino , Estudios de Seguimiento , Rechazo de Injerto/sangre , Rechazo de Injerto/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Cell-free DNA (cfDNA) exists in plasma and can be measured by several techniques. It is now possible to differentiate donor-derived cfDNA (ddcfDNA) from recipient cfDNA in the plasma or urine of solid organ transplant recipients in the absence of donor and recipient genotyping. The assessment of ddcfDNA is being increasingly studied as a noninvasive means of identifying acute rejection (AR) in solid organ transplants, including subclinical AR. We herein review the literature on the correlation of ddcfDNA with AR in kidney transplantation. There have been at least 15 observational studies that have assessed ddcfDNA in urine or plasma using various methodologies with various thresholds for abnormality. Overall, elevated ddcfDNA indicates allograft injury as may occur with AR, infection, or acute tubular injury but may also be found in clinically stable patients with normal histology. Sensitivity is greater for antibody-mediated AR than for cell-mediated AR, and normal levels do not preclude significant cell-mediated rejection. Measurement of ddcfDNA is not a replacement for biopsy that remains the gold standard for diagnosing AR. Serial monitoring of stable patients may allow earlier detection of subclinical AR, but the efficacy of this approach remains to be established. Normal levels should not preclude planned protocol biopsies. There may be roles for following ddcfDNA levels to assess the adequacy of treatment of AR and to guide the intensity of immunosuppression in the individual patient. Randomized controlled trials are necessary to validate the benefit and cost-effectiveness for these various uses. No firm recommendations can be made at this time.
Asunto(s)
Ácidos Nucleicos Libres de Células/sangre , Rechazo de Injerto/diagnóstico , Trasplante de Riñón , Monitoreo Fisiológico/métodos , Donantes de Tejidos , Biomarcadores/sangre , Rechazo de Injerto/sangre , Humanos , Receptores de Trasplantes , Trasplante HomólogoRESUMEN
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.
Asunto(s)
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
Cytokine polymorphisms can influence their plasma levels and thus affect the immune response in renal transplantation. A total of 146 renal transplant recipients (RTR) were classified into groups according to the estimated glomerular filtration rate (R1: < 60 and R2: ≥ 60 mL/min/1.73 m2) and time after transplantation (T1: 1 to 24, T2: 25 to 60, T3: 61 to 120, and T4: > 120 months after transplantation). The polymorphisms were genotyped by single specific primer-polymerase chain reaction. IL-10 was measured by ELISA and IL-6, and TNF levels were determined using Miliplex®. A higher frequency of the - 308G allele and the - 308G/G genotype, low-producer, was observed in the R1 group compared with R2. In addition, a higher frequency of the - 308A carriers, high-producer, was found in the R2 group. However, no significant difference was observed in cytokine levels when both groups were compared. Higher levels of IL-6 were observed in T1 compared with T2 and T4 groups. Lower IL-6 levels were found in T2 compared with T3 group. Lower levels of IL-10 were also found in T1 group in relation to T2, while higher levels of this cytokine were observed in T2 group compared with T3. The results suggest that the - 308G > A polymorphism in the TNF gene is associated with filtration function after renal transplantation, and IL-6 and IL-10 levels change according to the time after transplantation. Thus, the joint evaluation of - 308G > A polymorphism in TNF gene and IL-6 and IL-10 levels would provide a broader and effective view on the clinical monitoring of RTR.
Asunto(s)
Rechazo de Injerto/diagnóstico , Interleucina-10/sangre , Interleucina-6/sangre , Trasplante de Riñón/efectos adversos , Factor de Necrosis Tumoral alfa/genética , Adulto , Alelos , Aloinjertos/inmunología , Aloinjertos/fisiopatología , Biomarcadores/sangre , Brasil , Femenino , Frecuencia de los Genes , Tasa de Filtración Glomerular/fisiología , Rechazo de Injerto/sangre , Rechazo de Injerto/genética , Rechazo de Injerto/inmunología , Humanos , Interleucina-10/genética , Interleucina-6/genética , Riñón/inmunología , Riñón/fisiopatología , Fallo Renal Crónico/cirugía , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Periodo Posoperatorio , Factores de Tiempo , Factor de Necrosis Tumoral alfa/sangreRESUMEN
The majority of cells comprising the inflammatory infiltrates in kidney allografts undergoing acute and/or chronic rejection are typically T cells and monocyte/macrophages with B cells, plasma cells, and eosinophils accounting for <5%. In a significant minority of biopsies, B lineage cells (B cells and/or plasma cells) may be found more abundantly. Although plasma cell infiltrates tend to be more diffuse, B cells tend to aggregate into nodules that may mature into tertiary lymphoid organs. Given the ability to target B cells with anti-CD20 monoclonal antibodies and plasma cells with proteasome inhibitors and anti-CD38 monoclonal antibodies, it is increasingly important to determine the significance of such infiltrates. Both cell types are potential effectors of rejection, but both also have a tolerizing potential. B cell infiltrates have been associated with steroid resistance and reduced graft survival in some studies but not in others, and their presence should not prompt automatic depletional therapy. Plasma cell-rich infiltrates tend to occur later, may be associated with cell-mediated and/or antibody-mediated rejection, and portend an adverse outcome. Viral infection and malignancy must be ruled out. Randomized controlled trials are needed to determine the appropriateness of specific therapy when B cells and/or plasma cells are found. No strong therapeutic recommendations can be made at this time.
Asunto(s)
Linfocitos B/inmunología , Linaje de la Célula , Rechazo de Injerto/inmunología , Supervivencia de Injerto , Trasplante de Riñón , Células Plasmáticas/inmunología , Animales , Linfocitos B/efectos de los fármacos , Linfocitos B/metabolismo , Rechazo de Injerto/sangre , Rechazo de Injerto/prevención & control , Supervivencia de Injerto/efectos de los fármacos , Humanos , Inmunosupresores/uso terapéutico , Trasplante de Riñón/efectos adversos , Fenotipo , Células Plasmáticas/efectos de los fármacos , Células Plasmáticas/metabolismo , Resultado del TratamientoRESUMEN
BACKGROUND: The vigilance of tacrolimus (TAC) trough levels is an essential part of renal transplant follow up. Reduced TAC trough levels and high variability are related to adverse outcomes. The aim of this study was to evaluate the impact of brand changes on tacrolimus (TAC) subtherapeutic (SubT) trough levels, acute rejection (AR), and kidney function. METHODS: This is a prospective, observational cohort study of renal transplant recipients, between January 2016 and October 2018. Tacrolimus trough levels and brand used by the patient were both registered at every consult. Tacrolimus values ≤3.5 ng/mL were considered SubT. RESULTS: 445 patients were included. The median number of TAC brand changes was 2 (IQR, 1-4). Patients were grouped according to the number of brand changes: Group 1 = 0 (n = 107), Group 2 = 1-4 (n = 236), and Group 3 = ≥5 (n = 102). Patients with the greatest number of brand changes had a greater proportion and number of SubT TAC trough levels (Group 1 = 36.4%, average 0.53; Group 2 = 39.8%, average 0.65, Group 3 = 59.8%, average 1.17, P < .001) and AR (Group 1 = 0.9%, Group 2 = 11%, Group 3 = 14.7%, P < .001). On multivariate analysis, SubT levels and the number of brand changes were related to AR. CONCLUSIONS: In Mexico, changes in TAC brand are associated with an elevated frequency of SubT levels. Brand changes and SubT levels are independently associated with acute rejection. The supply policies on TAC brands in Mexico require revision to avoid changing brands as much as possible.
Asunto(s)
Rechazo de Injerto/etiología , Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Complicaciones Posoperatorias/etiología , Tacrolimus/efectos adversos , Tacrolimus/sangre , Receptores de Trasplantes/estadística & datos numéricos , Adulto , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Rechazo de Injerto/sangre , Rechazo de Injerto/patología , Supervivencia de Injerto , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/sangre , Pruebas de Función Renal , Masculino , Complicaciones Posoperatorias/sangre , Complicaciones Posoperatorias/patología , Pronóstico , Estudios Prospectivos , Factores de RiesgoRESUMEN
We determined peripheral blood (PB) and biopsy (Bx) RNA expression signatures in a Brazilian and US cohort of kidney transplant patients. Phenotypes assigned by precise histology were: acute rejection (AR), interstitial fibrosis/tubular atrophy/chronic rejection (CR), excellent functioning transplants (TX), and glomerulonephritis recurrence (GN). Samples were analyzed on microarrays and profiles from each cohort were cross-validated on the other cohort with similar phenotypes. We discovered signatures for each tissue: (1) AR vs TX, (2) CR vs TX, and (3) GN vs TX using the Random Forests algorithm. We validated biopsies signatures of AR vs TX (area under the curve [AUC] 0.97) and CR vs TX (AUC 0.87). We also validated both PB and Bx signatures of AR vs TX and CR vs TX with varying degrees of accuracy. Several biological pathways were shared between AR and CR, suggesting similar rejection mechanisms in these 2 clinical phenotypes. Thus, we identified gene expression signatures for AR and CR in transplant patients and validated them in independent cohorts of significantly different racial/ethnic backgrounds. These results reveal that there are strong unifying immune mechanisms driving transplant diseases and identified in the signatures discovered in each cohort, suggesting that molecular diagnostics across populations are feasible despite ethnic and environmental differences.
Asunto(s)
Biomarcadores/análisis , Etnicidad/genética , Rechazo de Injerto/diagnóstico , Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Leucocitos Mononucleares/metabolismo , Transcriptoma , Adolescente , Adulto , Anciano , Biopsia , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Perfilación de la Expresión Génica , Rechazo de Injerto/sangre , Rechazo de Injerto/etiología , Supervivencia de Injerto , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Adulto JovenRESUMEN
Tacrolimus is the cornerstone in pediatric liver transplant immunosuppression. Despite close monitoring, fluctuations in tacrolimus blood levels affect safety and efficacy of immunosuppressive treatments. Identifying the factors related to the variability in tacrolimus exposure may be helpful in tailoring the dose. The aim of the present study was to characterize the clinical, pharmacological, and genetic variables associated with systemic tacrolimus exposure in pediatric liver transplant patients. De novo transplant patients with a survival of more than 1 month were considered for inclusion and were genotyped for cytochrome P450 3A5 (CYP3A5). Peritransplant clinical factors and laboratory covariates were recorded retrospectively between 1 month and 2 years after transplant, including alanine aminotransferase (ALT), aspartate aminotransferase, hematocrit, and tacrolimus predose steady-state blood concentrations collected 12 hours after tacrolimus dosing. A linear mixed effect (LME) model was used to assess the association of these factors and the log-transformed tacrolimus dose-normalized trough concentration (logC0/D) levels. Bootstrapping was used to internally validate the final model. External validation was performed in an independent group of patients who matched the original population. The developed LME model described that logC0/D increases with increases in time after transplant (ß = 0.019, 95% confidence interval [CI], 0.010-0.028) and ALT values (ß = 0.00030, 95% CI, 0.00002-0.00056), whereas logC0/D is significantly lower in graft CYP3A5 expressers compared with nonexpressers (ß = -0.349, 95% CI, -0.631 to -0.062). In conclusion, donor CYP3A5 genotype, time after transplant, and ALT values are associated with tacrolimus disposition between 1 month and 2 years after transplant. A better understanding of tacrolimus exposure is essential to minimize the occurrence of an out-of-range therapeutic window that may lead to adverse drug reactions or acute rejection.
Asunto(s)
Citocromo P-450 CYP3A/genética , Rechazo de Injerto/prevención & control , Inmunosupresores/farmacocinética , Trasplante de Hígado/efectos adversos , Tacrolimus/farmacocinética , Administración Oral , Adolescente , Adulto , Alanina Transaminasa/sangre , Alanina Transaminasa/metabolismo , Aloinjertos/metabolismo , Argentina , Aspartato Aminotransferasas/sangre , Aspartato Aminotransferasas/metabolismo , Niño , Monitoreo de Drogas/métodos , Enfermedad Hepática en Estado Terminal/sangre , Enfermedad Hepática en Estado Terminal/cirugía , Femenino , Estudios de Seguimiento , Rechazo de Injerto/sangre , Rechazo de Injerto/inmunología , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Hígado/metabolismo , Masculino , Persona de Mediana Edad , Modelos Biológicos , Polimorfismo Genético , Estudios Retrospectivos , Tacrolimus/administración & dosificación , Tacrolimus/efectos adversos , Factores de TiempoRESUMEN
BACKGROUND: Belatacept could be the treatment of choice in renal-transplant recipients with renal dysfunction attributed to calcineurin inhibitor (CNI) nephrotoxicity. Few studies have described its use in patients with donor-specific antibody (DSA). METHODS: We retrospectively evaluated conversion from CNIs to belatacept in 29 human leukocyte antigen-immunized renal-transplant recipients. Data about acute rejection, DSA, and renal function were collected. These patients were compared with 42 nonimmunized patients treated with belatacept. RESULTS: Patients were converted from CNIs to belatacept a median of 444 days (interquartile range, 85-1200) after transplantation and were followed up after belatacept conversion, for a median of 308 days (interquartile range, 125-511). At conversion, 16 patients had DSA. Nineteen DSA were observed in these 16 patients, of which 11/19 were <1000 mean fluorescence intensity (MFI), 7/19 were between 1000 and 3000 MFI, and one was >3000 MFI. At last follow-up, preexisting DSA had decreased or stabilized. Seven patients still had DSA with a mean MFI of 1298 ± 930 at the last follow-up. No patient developed a de novo DSA in the DSA-positive group. In the nonimmunized group, one patient developed de novo DSA (A24-MFI 970; biopsy for cause did not show biopsy-proven acute rejection or microinflammation score). After belatacept conversion, one antibody-mediated rejection was diagnosed. The mean estimated glomerular filtration rate improved from 31.7 ± 14.2 mL/min/1.73 m to 40.7 ± 12.3 mL/min/1.73 m (P < 0.0001) at 12 months after conversion. We did not find any significant difference between groups in terms of renal function, proteinuria, or biopsy-proven acute rejection. CONCLUSIONS: We report on a safe conversion to belatacept in human leukocyte antigen-immunized patients with low DSA levels.
Asunto(s)
Abatacept/administración & dosificación , Inhibidores de la Calcineurina/efectos adversos , Rechazo de Injerto/tratamiento farmacológico , Isoanticuerpos/sangre , Trasplante de Riñón/efectos adversos , Insuficiencia Renal/prevención & control , Adulto , Anciano , Aloinjertos/efectos de los fármacos , Aloinjertos/inmunología , Aloinjertos/patología , Biopsia , Inhibidores de la Calcineurina/administración & dosificación , Sustitución de Medicamentos , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Tasa de Filtración Glomerular/inmunología , Rechazo de Injerto/sangre , Rechazo de Injerto/inmunología , Rechazo de Injerto/patología , Antígenos HLA/inmunología , Humanos , Isoanticuerpos/inmunología , Isoantígenos/inmunología , Riñón/efectos de los fármacos , Riñón/inmunología , Riñón/patología , Masculino , Persona de Mediana Edad , Insuficiencia Renal/inducido químicamente , Resultado del TratamientoRESUMEN
BACKGROUND: BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) is a consequence of BKPyV replication in the urinary tract in kidney transplant recipients (KTR). OBJECTIVES: The objectives were to determine the prevalence of BKPyV replication and BKPyVAN, risk factors associated to sustained viremia and BKPyVAN, and viremia cut-off that best predict the occurrence of sustained viremia and nephropathy in KTR of a single University Hospital Kidney Transplant Center. PATIENTS AND METHODS: All KTR undergoing transplantation from August 2010 to December 2011 were enrolled and monitored up to 2 years posttransplantation for BKPyV viruria by decoy cells shedding or polymerase chain reaction (PCR) and viremia by PCR. Kidney biopsy was indicated if sustained viremia (two or more viremia above 10 000 copies/mL) to confirm BKPyVAN diagnosis. RESULTS: In this study, 326 transplants were performed and 246 patients were included. Prevalence of viruria was 36.9%, viremia 22.3% and nephropathy 3.2%. Male gender was the only risk factor associated to sustained viremia or nephropathy. Cut-off value of viremia that best discriminates the progression to sustained viremia and to BKPyVAN was 37 488 and 44 956 copies/mL, respectively. CONCLUSIONS: Prevalence of viruria, viremia, and nephropathy were similar to those reported in literature but the cut-off value of viremia that best discriminates the risk of progression to nephropathy was greater than the value usually reported, which is 10 000 copies/mL.
Asunto(s)
Virus BK/aislamiento & purificación , Enfermedades Renales/epidemiología , Infecciones por Polyomavirus/epidemiología , Infecciones Tumorales por Virus/epidemiología , Viremia/diagnóstico , Adolescente , Adulto , Anciano , Virus BK/fisiología , Biopsia , ADN Viral/aislamiento & purificación , Progresión de la Enfermedad , Femenino , Rechazo de Injerto/sangre , Rechazo de Injerto/epidemiología , Rechazo de Injerto/patología , Rechazo de Injerto/virología , Humanos , Terapia de Inmunosupresión/efectos adversos , Terapia de Inmunosupresión/métodos , Riñón/patología , Riñón/virología , Enfermedades Renales/diagnóstico , Enfermedades Renales/patología , Enfermedades Renales/virología , Trasplante de Riñón/efectos adversos , Masculino , Persona de Mediana Edad , Selección de Paciente , Infecciones por Polyomavirus/diagnóstico , Infecciones por Polyomavirus/patología , Infecciones por Polyomavirus/virología , Valor Predictivo de las Pruebas , Prevalencia , Estudios Prospectivos , Factores de Riesgo , Infecciones Tumorales por Virus/diagnóstico , Infecciones Tumorales por Virus/patología , Infecciones Tumorales por Virus/virología , Viremia/epidemiología , Viremia/virología , Adulto JovenRESUMEN
The aim of the present study was to evaluate messenger RNA expression in kidney allograft recipients. Forty-four kidney transplant recipients were evaluated up to three months after grafting. After transplantation, peripheral blood samples were drawn sequentially for real-time polymerase chain reaction analyses of perforin and TIM-3 genes. Biopsies were obtained to evaluate acute graft dysfunction and interpreted according to the Banff classification. Eight patients presented episodes of acute rejection. Recipients with rejection had significantly higher levels of TIM-3 mRNA transcripts compared to those without rejection (median gene expression 191.2 and 36.9 mRNA relative units, respectively; P<0.0001). Also, perforin gene expression was higher in patients with rejection (median gene expression 362.0 and 52.8 mRNA relative units; P<0.001). Receiver operating characteristic curves showed that the area under the curve (AUC) for the TIM-3 gene was 0.749 (95%CI: 0.670-0.827). Perforin gene mRNA expression provided an AUC of 0.699 (95%CI: 0.599 to 0.799). Overall accuracy of gene expression was 67.9% for the TIM-3 gene and 63.6% for the perforin gene. Combined accuracy was 76.8%. Negative predictive values were 95.3% for the TIM-3 gene, 95.5% for the perforin gene, and 95.4% in the combined analyses. Gene expression was significantly modulated by rejection treatment decreasing 64.1% (TIM-3) and 90.9% (perforin) compared to the median of pre-rejection samples. In conclusion, the longitudinal approach showed that gene profiling evaluation might be useful in ruling out the diagnosis of acute rejection and perhaps evaluating the efficacy of treatment.
Asunto(s)
Rechazo de Injerto/sangre , Receptor 2 Celular del Virus de la Hepatitis A/sangre , Trasplante de Riñón/efectos adversos , Perforina/sangre , Adulto , Aloinjertos , Biomarcadores/sangre , Femenino , Expresión Génica , Rechazo de Injerto/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa , Transcripción GenéticaRESUMEN
BACKGROUND: Pretransplantation soluble CD30 (sCD30) has been shown to be a good predictor of acute rejection (AR) and graft loss. This study aimed to evaluate the effectiveness of sCD30 measured pretransplant and up to 6 months after transplantation as a predictor of AR, graft loss, and survival at 5 years post-transplantation. Subjects were patients receiving living donor renal transplants at Bonsucesso Federal Hospital (Rio de Janeiro) in 2006 and between August 2010 and May 2011. METHODS: sCD30 was analyzed in samples collected pretransplantation and 7, 14, and 21, 28 days and 3, 4, 5, and 6 months post-transplantation from 73 kidney recipients. RESULTS: Patients in the AR group did not present a positive correlation with the sCD30 levels pretransplant (P = .54); in the post-transplant period, the 7- to 14-day samples showed patients with AR had higher levels of this biomarker (P = .036). The graft survival in 5 years of follow-up was not different between groups. CONCLUSIONS: The best time to predict AR using sCD30 is the 7- to 14-day sample; however, identifying and following the decrease of this biomarker from pre- to post-transplant seems to be better than just 1 measurement. The sCD30 post-transplant is another tool that may be used in monitoring patients after renal transplantation.
Asunto(s)
Rechazo de Injerto/sangre , Supervivencia de Injerto/fisiología , Antígeno Ki-1/sangre , Trasplante de Riñón/efectos adversos , Adulto , Biomarcadores/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Periodo Posoperatorio , Valor Predictivo de las Pruebas , Periodo Preoperatorio , Factores de TiempoRESUMEN
INTRODUCTION: Kidney transplantation is considered the ideal treatment for end-stage renal disease. Acute rejection can influence graft survival. The aim of this study was to propose a classification system for acute rejection based on factor analysis. MATERIALS AND METHODS: Data were collected from kidney transplant recipients with acute rejection diagnosis based on standard histological variables, the presence of peritubular eosinophils, and immunolabeling for lysozyme and myeloperoxidase in kidney tissue. Factor analysis was employed for data reduction and generation of a new case classification, with orthogonal rotation as a strategy to simplify factors, and principal component analysis was used as an extraction method. RESULTS: Seventy-nine kidney biopsies were obtained from 74 patients. The total population was divided into humoral rejection (39.2%), cellular rejection (34.1%), and mixed acute rejection (26.7%). No significant differences were found between the three groups in clinical and biochemical variables. We extracted 4 factors using factor analysis. The 1st factor was characterized by the presence of capillaritis, plasma cells infiltration, tubulitis, and inflammation. The 2nd factor included positivity for lysozyme and myeloperoxidase, while the 3rd factor included the presence of eosinophils and glomerulitis. The 4th component consisted of the presence of C4d and endarteritis. The cases belonging to the 3rd factor showed the greatest increase in serum creatinine. The cases belonging to the 4th factor exhibited greater urinary excretion of proteins. CONCLUSIONS: This proposal of classification of acute rejection could contribute to evaluate the prognosis of kidney transplant recipients.
Asunto(s)
Técnicas de Apoyo para la Decisión , Rechazo de Injerto/diagnóstico , Trasplante de Riñón/efectos adversos , Riñón/inmunología , Enfermedad Aguda , Adolescente , Adulto , Albuminuria/clasificación , Albuminuria/diagnóstico , Biomarcadores/sangre , Biopsia , Análisis Factorial , Femenino , Rechazo de Injerto/sangre , Rechazo de Injerto/clasificación , Rechazo de Injerto/inmunología , Supervivencia de Injerto , Humanos , Inmunidad Celular , Inmunidad Humoral , Riñón/metabolismo , Riñón/patología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Análisis de Componente Principal , Pronóstico , Factores de Riesgo , Factores de Tiempo , Adulto JovenRESUMEN
The aim of the present study was to evaluate messenger RNA expression in kidney allograft recipients. Forty-four kidney transplant recipients were evaluated up to three months after grafting. After transplantation, peripheral blood samples were drawn sequentially for real-time polymerase chain reaction analyses of perforin and TIM-3 genes. Biopsies were obtained to evaluate acute graft dysfunction and interpreted according to the Banff classification. Eight patients presented episodes of acute rejection. Recipients with rejection had significantly higher levels of TIM-3 mRNA transcripts compared to those without rejection (median gene expression 191.2 and 36.9 mRNA relative units, respectively; P<0.0001). Also, perforin gene expression was higher in patients with rejection (median gene expression 362.0 and 52.8 mRNA relative units; P<0.001). Receiver operating characteristic curves showed that the area under the curve (AUC) for the TIM-3 gene was 0.749 (95%CI: 0.670-0.827). Perforin gene mRNA expression provided an AUC of 0.699 (95%CI: 0.599 to 0.799). Overall accuracy of gene expression was 67.9% for the TIM-3 gene and 63.6% for the perforin gene. Combined accuracy was 76.8%. Negative predictive values were 95.3% for the TIM-3 gene, 95.5% for the perforin gene, and 95.4% in the combined analyses. Gene expression was significantly modulated by rejection treatment decreasing 64.1% (TIM-3) and 90.9% (perforin) compared to the median of pre-rejection samples. In conclusion, the longitudinal approach showed that gene profiling evaluation might be useful in ruling out the diagnosis of acute rejection and perhaps evaluating the efficacy of treatment.
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Rechazo de Injerto/sangre , Receptor 2 Celular del Virus de la Hepatitis A/sangre , Trasplante de Riñón/efectos adversos , Perforina/sangre , Aloinjertos , Biomarcadores/sangre , Expresión Génica , Rechazo de Injerto/diagnóstico , Reacción en Cadena en Tiempo Real de la Polimerasa , Transcripción GenéticaRESUMEN
Mycophenolate mofetil (MMF) is a prodrug active only after its hydrolysis to mycophenolic acid (MPA). The UGT1A9 enzyme is of special interest since it is the main enzyme involved in the glucuronidation of MPA. Single nucleotide polymorphisms (SNPs) in the UGT1A9 gene may be responsible for individual differences in the pharmacokinetics of MMF. Expression levels and the activity of UGT1A9 may depend on the presence of some SNPs located in the gene promoter region (-2152C>T and -275T>A), as well as changes in the coding region (c.98T>C). The objective of this study was to evaluate the effect of allelic variants of the UGT1A9 c.98T>C polymorphism (rs72551330; g. 87289T>C) on MMF metabolism in renal transplant patients. MPA and MPA 7-O glucuronide (MPAG) levels were determined on plasma samples of kidney transplant patients (N = 39) by high-performance liquid chromatography using ultraviolet detection. DNA was isolated from leukocytes and stored at -20°C. The presence of SNPs was investigated using polymerase chain reaction, followed by amplicon sequencing. The analysis of the UGT1A9 c.98T>C polymorphism revealed that all study patients presented the TT genotype. Diverse MPA and MPAG plasma concentrations were detected, including therapeutic, subtherapeutic, and toxic levels. A standardized molecular method permitted identification of UGT1A9 c.98T>C polymorphism genotypes in the examined renal transplant patients. All individuals of the study group presented the same genotype (c.98TT) for that polymorphism. Thereby, no association between the c.98T>C polymorphism and MPA and MPAG plasma levels could be evaluated, despite different levels of these compounds being observed.
Asunto(s)
Glucurónidos/sangre , Glucuronosiltransferasa/genética , Rechazo de Injerto/sangre , Trasplante de Riñón/efectos adversos , Ácido Micofenólico/análogos & derivados , Polimorfismo de Nucleótido Simple , Adulto , Femenino , Glucurónidos/genética , Rechazo de Injerto/genética , Humanos , Masculino , Persona de Mediana Edad , Ácido Micofenólico/sangre , UDP Glucuronosiltransferasa 1A9RESUMEN
We analyzed microRNA (miR)-142-3p expression in leucocytes of the peripheral blood and urinary sediment cell samples obtained from kidney transplant recipients who developed graft dysfunction. Forty-one kidney transplant recipients with kidney graft dysfunction and 8 stable patients were included in the study. The groups were divided according to histological analysis into acute rejection group (n=23), acute tubular necrosis group (n=18) and stable patients group used as a control for gene expression (n=8). Percutaneous biopsies were performed and peripheral blood samples and urine samples were obtained. miR-142-3p was analyzed by real-time polymerase chain reaction. The group of patients with acute tubular necrosis presented significantly higher expressions in peripheral blood (P<0.05) and urine (P<0.001) compared to the stable patients group. Also, in the peripheral blood, miR-142-3p expression was significantly higher in the acute tubular necrosis group compared to the acute rejection group (P<0.05). Urine samples of the acute rejection group presented higher expression compared to the stable patients group (P<0.001) but the difference between acute tubular necrosis and acute rejection groups was not significant in the urinary analyzes (P=0.079). miR-142-3p expression has a distinct pattern of expression in the setting of post-operative acute tubular necrosis after kidney transplantation and may potentially be used as a non-invasive biomarker for renal graft dysfunction.
Asunto(s)
Rechazo de Injerto/patología , Trasplante de Riñón/efectos adversos , Necrosis Tubular Aguda/patología , MicroARNs/sangre , MicroARNs/orina , Regulación hacia Arriba/fisiología , Adulto , Anciano , Biomarcadores/sangre , Biomarcadores/orina , Femenino , Expresión Génica , Rechazo de Injerto/sangre , Rechazo de Injerto/orina , Humanos , Biopsia Guiada por Imagen , Riñón/patología , Necrosis Tubular Aguda/sangre , Necrosis Tubular Aguda/orina , Masculino , Persona de Mediana Edad , Disfunción Primaria del Injerto/sangre , Disfunción Primaria del Injerto/patología , Disfunción Primaria del Injerto/orina , Reacción en Cadena en Tiempo Real de la Polimerasa , Valores de Referencia , Sensibilidad y Especificidad , Estadísticas no Paramétricas , Receptores de Trasplantes , Resultado del TratamientoRESUMEN
BACKGROUND Late acute rejection (LAR) differs in its clinical and histological presentation and management from early acute rejection. This clinical entity is not completely understood; thus, we aimed to identify significant prognostic factors that can influence post-transplant survival in LAR patients. The purpose of this study was to evaluate the incidence and post-transplant survival of patients from a single center with a focus on late acute rejection. MATERIAL AND METHODS From January 2002 to June 2013, all liver biopsies from patients with rejection were scored using the Banff criteria. The groups were compared, and simple and multiple logistic regression and survival curves were created. RESULTS A total of 779 liver transplants were performed; 585 patients with no rejections and 194 patients with rejections were analyzed. The overall incidence of LAR was 6.7%, and there was a higher prevalence of early acute cellular rejection than LAR. The mean time to LAR was 564 days (median 214 days, range 91-2642). LAR had a more severe grade (35.3%) than early acute rejection (23.5%). The survival rates were similar between both modalities for the long-term period. Worse mortality rates were observed in liver re-transplantation (HR 4.77; p<0.0001); in hepatitis C virus patients with increased creatinine levels (HR 22.48; p=0.016); and in donors >41 years of age (OR 2.1; p=0.047) in a long-term analysis of LAR. CONCLUSIONS Liver re-transplantation, higher creatinine levels in hepatitis C virus patients, and donor age were predictors of mortality in this long-term analysis of late acute rejection in liver transplantation.
Asunto(s)
Creatinina/sangre , Rechazo de Injerto/mortalidad , Hepatitis C/cirugía , Trasplante de Hígado/mortalidad , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Femenino , Rechazo de Injerto/sangre , Hepatitis C/sangre , Hepatitis C/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Reoperación , Factores de Riesgo , Donantes de Tejidos , Adulto JovenRESUMEN
BACKGROUND: Recent literature has stressed the prominent role of antibodies in graft loss. This study was designed to assess a growing perception that T cell-mediated rejection (TCMR) is no longer clinically relevant. METHODS: Five hundred forty-five renal allograft recipients over a 3-year period were screened for biopsies with: (a) TCMR including borderline change (BL), (b) negative complement protein C4 degradation fragment, and (c) absence of donor-specific antibody at time of transplant, within 30 days of the biopsy, and up to 4 measurements at later time points. RESULTS: These stringent requirements identified 28 "pure" cases of late TCMR/BL. Low-grade glomerulitis, peritubular capillaritis, or chronic transplant glomerulopathy were found in 9/28 (32%) biopsies. Serum creatinine showed complete short-term remission in 7/10 (70%) BL and 9/18 (50%) TCMR patients 1 month postbiopsy. Yet, both treated and untreated patients demonstrated further decline in graft function as assessed by serum creatinine and estimated glomerular filtration rate. CONCLUSIONS: Late TCMR seen in 7.9% of biopsies can contribute to significant deterioration of graft function in patients in whom the dominant contribution of antibody-mediated injury has been reasonably excluded. Our data also reinforce existing literature showing that microvascular lesions do not have absolute specificity for a diagnosis of antibody-mediated rejection.
Asunto(s)
Complemento C4b/análisis , Rechazo de Injerto/inmunología , Antígenos HLA/inmunología , Inmunidad Celular , Isoanticuerpos/sangre , Trasplante de Riñón/efectos adversos , Riñón/inmunología , Fragmentos de Péptidos/análisis , Linfocitos T/inmunología , Adulto , Anciano , Aloinjertos , Biomarcadores/sangre , Biopsia , Estudios de Casos y Controles , Creatinina/sangre , Femenino , Fibrosis , Rechazo de Injerto/sangre , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/tratamiento farmacológico , Supervivencia de Injerto , Humanos , Inmunidad Celular/efectos de los fármacos , Inmunosupresores/uso terapéutico , Riñón/efectos de los fármacos , Riñón/patología , Riñón/fisiopatología , Masculino , Persona de Mediana Edad , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
The ability to noninvasively diagnose acute cellular rejection (ACR) with high specificity and sensitivity would significantly advance personalized liver transplant recipient care and management of immunosuppression. We performed microRNA (miRNA) profiling in 318 serum samples from 69 liver transplant recipients enrolled in the Immune Tolerance Network immunosuppression withdrawal (ITN030ST) and Clinical Trials in Organ Transplantation (CTOT-03) studies. We quantified serum miRNA at clinically indicated and/or protocol biopsy events (n = 130). The trajectory of ACR diagnostic miRNAs during immunosuppression withdrawal were also evaluated in sera taken at predetermined intervals during immunosuppression minimization before and at clinically indicated liver biopsy (n = 119). Levels of 31 miRNAs were significantly associated with ACR diagnosis with two miRNAs differentiating ACR from non-ACR (area under the receiver operating characteristic curve = 90%, 95% confidence interval = 82%-96%) and predicted ACR events up to 40 days before biopsy-proven rejection. The most differentially expressed miRNAs were low or absent in the blood of healthy individuals but highly expressed in liver tissue, indicating an ectopic origin from the liver allograft. Pathway analyses of rejection-associated miRNAs and their target messenger RNAs (mRNAs) showed induction of proinflammatory and cell death-related pathways. Integration of differentially expressed serum miRNA with concordant liver biopsy mRNA demonstrates interaction between molecules with a known role in transplant rejection. CONCLUSION: Distinct miRNA levels profiled from sera at the time of clinical allograft dysfunction can be used to noninvasively diagnose ACR. Predictive trajectories of the same profile during supervised immunosuppression minimization diagnosed rejection up to 40 days prior to clinical expression. The rejection-associated miRNAs in sera appear to be ectopically expressed liver and specific immune cell miRNAs that are biologically related, and the consequences of immune-mediated damage to the allograft. (Hepatology 2017;65:269-280).
Asunto(s)
Rechazo de Injerto/sangre , Rechazo de Injerto/diagnóstico , Trasplante de Hígado , MicroARNs/sangre , Expresión Génica Ectópica , Femenino , Rechazo de Injerto/genética , Humanos , Masculino , MicroARNs/biosíntesis , MicroARNs/genética , Persona de Mediana Edad , Pronóstico , Transcriptoma , Trasplante HomólogoRESUMEN
We analyzed microRNA (miR)-142-3p expression in leucocytes of the peripheral blood and urinary sediment cell samples obtained from kidney transplant recipients who developed graft dysfunction. Forty-one kidney transplant recipients with kidney graft dysfunction and 8 stable patients were included in the study. The groups were divided according to histological analysis into acute rejection group (n=23), acute tubular necrosis group (n=18) and stable patients group used as a control for gene expression (n=8). Percutaneous biopsies were performed and peripheral blood samples and urine samples were obtained. miR-142-3p was analyzed by real-time polymerase chain reaction. The group of patients with acute tubular necrosis presented significantly higher expressions in peripheral blood (P<0.05) and urine (P<0.001) compared to the stable patients group. Also, in the peripheral blood, miR-142-3p expression was significantly higher in the acute tubular necrosis group compared to the acute rejection group (P<0.05). Urine samples of the acute rejection group presented higher expression compared to the stable patients group (P<0.001) but the difference between acute tubular necrosis and acute rejection groups was not significant in the urinary analyzes (P=0.079). miR-142-3p expression has a distinct pattern of expression in the setting of post-operative acute tubular necrosis after kidney transplantation and may potentially be used as a non-invasive biomarker for renal graft dysfunction.