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1.
Transplant Proc ; 51(3): 722-728, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30979456

RESUMEN

TruGraf v1 is a laboratory-developed DNA microarray-based gene expression blood test to enable proactive noninvasive serial assessment of kidney transplant recipients with stable renal function. It has been previously validated in patients identified as Transplant eXcellence (TX: stable serum creatinine, normal biopsy results, indicative of immune quiescence), and not-TX (renal dysfunction and/or rejection on biopsy results). TruGraf v1 is intended for use in subjects with stable renal function to measure the immune status as an alternative to invasive, expensive, and risky surveillance biopsies. MATERIALS AND METHODS: In this study, simultaneous blood tests and clinical assessments were performed in 192 patients from 7 transplant centers to evaluate TruGraf v1. The molecular testing laboratory was blinded to renal function and biopsy results. RESULTS: Overall, TruGraf v1 accuracy (concordance between TruGraf v1 result and clinical and/or histologic assessment) was 74% (142/192), and a result of TX was accurate in 116 of 125 (93%). The negative predictive value for TruGraf v1 was 90%, with a sensitivity 74% and specificity of 73%. Results did not significantly differ in patients with a biopsy-confirmed diagnosis vs those without a biopsy. CONCLUSIONS: TruGraf v1 can potentially support a clinical decision enabling unnecessary surveillance biopsies with high confidence, making it an invaluable addition to the transplant physician's tool kit for managing patients. TruGraf v1 testing can potentially avoid painful and risky invasive biopsies, reduce health care costs, and enable frequent assessment of patients with stable renal function to confirm the presence of immune quiescence in the peripheral blood.


Asunto(s)
Perfilación de la Expresión Génica/métodos , Rechazo de Injerto/diagnóstico , Trasplante de Riñón , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Adulto , Biopsia , Femenino , Rechazo de Injerto/inmunología , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sensibilidad y Especificidad , Receptores de Trasplantes
2.
Pharmacogenomics J ; 18(3): 501-505, 2018 05 22.
Artículo en Inglés | MEDLINE | ID: mdl-29160300

RESUMEN

The immunosuppressant tacrolimus (TAC) is metabolized by both cytochrome P450 3A4 (CYP3A4) and CYP3A5 enzymes. It is common for European Americans (EA) to carry two CYP3A5 loss-of-function (LoF) variants that profoundly reduces TAC metabolism. Despite having two LoF alleles, there is still considerable variability in TAC troughs and identifying additional variants in genes outside of the CYP3A5 gene could provide insight into this variability. We analyzed TAC trough concentrations in 1345 adult EA recipients with two CYP3A5 LoF alleles in a genome-wide association study. Only CYP3A4*22 was identified and no additional variants were genome-wide significant. Additional high allele frequency genetic variants with strong genetic effects associated with TAC trough variability are unlikely to be associated with TAC variation in the EA population. These data suggest that low allele frequency variants, identified by DNA sequencing, should be evaluated and may identify additional variants that contribute to TAC pharmacokinetic variability.


Asunto(s)
Citocromo P-450 CYP3A/genética , Estudio de Asociación del Genoma Completo , Trasplante de Riñón , Tacrolimus/farmacocinética , Adulto , Femenino , Frecuencia de los Genes , Genotipo , Rechazo de Injerto/sangre , Rechazo de Injerto/genética , Rechazo de Injerto/patología , Humanos , Inmunosupresores/sangre , Inmunosupresores/farmacocinética , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Tacrolimus/sangre , Tacrolimus/uso terapéutico , Receptores de Trasplantes , Población Blanca/genética
3.
Am J Transplant ; 18(2): 293-307, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29243394

RESUMEN

The kidney sessions of the 2017 Banff Conference focused on 2 areas: clinical implications of inflammation in areas of interstitial fibrosis and tubular atrophy (i-IFTA) and its relationship to T cell-mediated rejection (TCMR), and the continued evolution of molecular diagnostics, particularly in the diagnosis of antibody-mediated rejection (ABMR). In confirmation of previous studies, it was independently demonstrated by 2 groups that i-IFTA is associated with reduced graft survival. Furthermore, these groups presented that i-IFTA, particularly when involving >25% of sclerotic cortex in association with tubulitis, is often a sequela of acute TCMR in association with underimmunosuppression. The classification was thus revised to include moderate i-IFTA plus moderate or severe tubulitis as diagnostic of chronic active TCMR. Other studies demonstrated that certain molecular classifiers improve diagnosis of ABMR beyond what is possible with histology, C4d, and detection of donor-specific antibodies (DSAs) and that both C4d and validated molecular assays can serve as potential alternatives and/or complements to DSAs in the diagnosis of ABMR. The Banff ABMR criteria are thus updated to include these alternatives. Finally, the present report paves the way for the Banff scheme to be part of an integrative approach for defining surrogate endpoints in next-generation clinical trials.


Asunto(s)
Rechazo de Injerto/diagnóstico , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Inflamación/diagnóstico , Isoanticuerpos/inmunología , Trasplante de Riñón/efectos adversos , Complicaciones Posoperatorias , Linfocitos T/inmunología , Rechazo de Injerto/etiología , Rechazo de Injerto/patología , Humanos , Inflamación/etiología , Inflamación/patología , Pronóstico , Informe de Investigación
4.
Am J Transplant ; 17(10): 2712-2719, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28556519

RESUMEN

The intent of this National Institutes of Health-sponsored study was to compare a belatacept-based immunosuppressive regimen with a maintenance regimen of tacrolimus and mycophenolate. Nineteen primary, Epstein-Barr virus-immune renal transplant recipients with a negative cross-match were randomized to one of three groups. All patient groups received perioperative steroids and maintenance mycophenolate mofetil. Patients in groups 1 and 2 were induced with alemtuzumab and maintained on tacrolimus or belatacept, respectively. Patients in group 3 were induced with basiliximab, received 3 mo of tacrolimus, and maintained on belatacept. There was one death with a functioning allograft due to endocarditis (group 1). There were three graft losses due to vascular thrombosis (all group 2) and one graft loss due to glomerular disease (group 1). Biopsy-proven acute cellular rejection was more frequent in the belatacept-treated groups, with 10 treated episodes in seven participants compared with one episode in group 1; however, estimated GFR was similar between groups at week 52. There were no episodes of posttransplant lymphoproliferative disorder or opportunistic infections in any group. Protocol enrollment was halted prematurely because of a high rate of serious adverse events. Such negative outcomes pose challenges to clinical investigators, who ultimately must weigh the risks and benefits in randomized trials.


Asunto(s)
Abatacept/uso terapéutico , Corticoesteroides/uso terapéutico , Inhibidores de la Calcineurina/uso terapéutico , Inmunosupresores/uso terapéutico , Trasplante de Riñón , Adolescente , Adulto , Anciano , Femenino , Tasa de Filtración Glomerular , Supervivencia de Injerto , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto Joven
5.
Am J Transplant ; 17(11): 2851-2862, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28449409

RESUMEN

The authors conducted a prospective trial to assess the feasibility of real time central molecular assessment of kidney transplant biopsy samples from 10 North American or European centers. Biopsy samples taken 1 day to 34 years posttransplantation were stabilized in RNAlater, sent via courier overnight at ambient temperature to the central laboratory, and processed (29 h workflow) using microarrays to assess T cell- and antibody-mediated rejection (TCMR and ABMR, respectively). Of 538 biopsy samples submitted, 519 (96%) were sufficient for microarray analysis (average length, 3 mm). Automated reports were generated without knowledge of histology and HLA antibody, with diagnoses assigned based on Molecular Microscope Diagnostic System (MMDx) classifier algorithms and signed out by one observer. Agreement between MMDx and histology (balanced accuracy) was 77% for TCMR, 77% for ABMR, and 76% for no rejection. A classification tree derived to provide automated sign-outs predicted the observer sign-outs with >90% accuracy. In 451 biopsy samples where feedback was obtained, clinicians indicated that MMDx more frequently agreed with clinical judgment (87%) than did histology (80%) (p = 0.0042). In 81% of feedback forms, clinicians reported that MMDx increased confidence in management compared with conventional assessment alone. The authors conclude that real time central molecular assessment is feasible and offers a useful new dimension in biopsy interpretation. ClinicalTrials.gov NCT#01299168.


Asunto(s)
Biomarcadores/metabolismo , Perfilación de la Expresión Génica , Rechazo de Injerto/diagnóstico , Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Rechazo de Injerto/etiología , Rechazo de Injerto/metabolismo , Supervivencia de Injerto , Humanos , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Factores de Riesgo , Adulto Joven
6.
Pharmacogenomics J ; 17(1): 61-68, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-26667830

RESUMEN

Tacrolimus is dependent on CYP3A5 enzyme for metabolism. Expression of the CYP3A5 enzyme is controlled by several alleles including CYP3A5*1, CYP3A5*3, CYP3A5*6 and CYP3A5*7. African Americans (AAs) have on average higher tacrolimus dose requirements than Caucasians; however, some have requirements similar to Caucasians. Studies in AAs have primarily evaluated the CYP3A5*3 variant; however, there are other common nonfunctional variants in AAs (CYP3A5*6 and CYP3A5*7) that do not occur in Caucasians. These variants are associated with lower dose requirements and may explain why some AAs are metabolically similar to Caucasians. We created a tacrolimus clearance model in 354 AAs using a development and validation cohort. Time after transplant, steroid and antiviral use, age and CYP3A5*1, *3, *6 and *7 alleles were significant toward clearance. This study is the first to develop an AA-specific genotype-guided tacrolimus dosing model to personalize therapy.


Asunto(s)
Negro o Afroamericano/genética , Inhibidores de la Calcineurina/administración & dosificación , Citocromo P-450 CYP3A/genética , Cálculo de Dosificación de Drogas , Inmunosupresores/administración & dosificación , Trasplante de Riñón , Variantes Farmacogenómicas , Tacrolimus/administración & dosificación , Receptores de Trasplantes , Adolescente , Adulto , Anciano , Inhibidores de la Calcineurina/efectos adversos , Inhibidores de la Calcineurina/farmacocinética , Canadá/epidemiología , Citocromo P-450 CYP3A/metabolismo , Femenino , Frecuencia de los Genes , Genotipo , Rechazo de Injerto/etnología , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Supervivencia de Injerto/efectos de los fármacos , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/farmacocinética , Trasplante de Riñón/efectos adversos , Masculino , Tasa de Depuración Metabólica/genética , Persona de Mediana Edad , Modelos Genéticos , Farmacogenética , Pruebas de Farmacogenómica , Fenotipo , Tacrolimus/efectos adversos , Tacrolimus/farmacocinética , Resultado del Tratamiento , Estados Unidos/epidemiología , Adulto Joven
7.
Am J Transplant ; 16(4): 1094-101, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26730885

RESUMEN

The development of new immunosuppressive drugs has slowed markedly over the past several years, and the outlook that improved therapy will be available to the next generation of transplant recipients is bleak. In this viewpoint, the authors outline some of important barriers to new drug development and suggest specific steps that the transplant community can take to overcome them.


Asunto(s)
Descubrimiento de Drogas , Rechazo de Injerto/prevención & control , Tolerancia Inmunológica/inmunología , Inmunosupresores/uso terapéutico , Trasplante de Órganos , Receptores de Trasplantes , Rechazo de Injerto/etiología , Humanos , Terapia de Inmunosupresión , Pronóstico
8.
Am J Transplant ; 16(2): 574-82, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26485092

RESUMEN

We previously reported that tacrolimus (TAC) trough blood concentrations for African American (AA) kidney allograft recipients were lower than those observed in white patients. Subtherapeutic TAC troughs may be associated with acute rejection (AR) and AR-associated allograft failure. This variation in TAC troughs is due, in part, to differences in the frequency of the cytochrome P450 CYP3A5*3 allele (rs776746, expresses nonfunctional enzyme) between white and AA recipients; however, even after accounting for this variant, variability in AA-associated troughs is significant. We conducted a genomewide association study of TAC troughs in AA kidney allograft recipients to search for additional genetic variation. We identified two additional CYP3A5 variants in AA recipients independently associated with TAC troughs: CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343). All three variants and clinical factors account for 53.9% of the observed variance in troughs, with 19.8% of the variance coming from demographic and clinical factors including recipient age, glomerular filtration rate, anticytomegalovirus drug use, simultaneous pancreas-kidney transplant and antibody induction. There was no evidence of common genetic variants in AA recipients significantly influencing TAC troughs aside from the CYP3A gene. These results reveal that additional and possibly rare functional variants exist that account for the additional variation.


Asunto(s)
Negro o Afroamericano/genética , Citocromo P-450 CYP3A/genética , Estudio de Asociación del Genoma Completo , Rechazo de Injerto/genética , Polimorfismo de Nucleótido Simple/genética , Complicaciones Posoperatorias/genética , Tacrolimus/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Niño , Preescolar , Femenino , Estudios de Seguimiento , Genotipo , Tasa de Filtración Glomerular , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/etnología , Supervivencia de Injerto , Humanos , Inmunosupresores/uso terapéutico , Lactante , Recién Nacido , Fallo Renal Crónico/genética , Fallo Renal Crónico/cirugía , Pruebas de Función Renal , Trasplante de Riñón/efectos adversos , Masculino , Persona de Mediana Edad , Pronóstico , Factores de Riesgo , Donantes de Tejidos , Receptores de Trasplantes , Población Blanca/genética , Adulto Joven
9.
Am J Transplant ; 15(11): 2970-7, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26484839

RESUMEN

Clostridium difficile infection (CDI) is a considerable health issue in the United States and represents the most common healthcare-associated infection. Solid organ transplant recipients are at increased risk of CDI, which can affect both graft and patient survival. However, little is known about the impact of CDI on health services utilization posttransplantation. We examined hospital-onset CDI from 2012 to 2014 among transplant recipients in the University HealthSystem Consortium, which includes academic medical center-affiliated hospitals in the United States. Infection was five times more common among transplant recipients than among general medicine inpatients (209 vs 40 per 10 000 discharges), and factors associated with CDI among transplant recipients included transplant type, risk of mortality, comorbidities, and inpatient complications. Institutional risk-standardized CDI varied more than 3-fold across high-volume hospitals (infection ratio 0.54-1.82, median 1.04, interquartile range 0.78-1.28). CDI was associated with increased 30-day readmission, transplant organ complications, cytomegalovirus infection, inpatient costs, and lengths of stay. Total observed inpatient days and direct costs for those with CDI were substantially higher than risk-standardized expected values (40 094 vs 22 843 days, costs $198 728 368 vs $154 020 528). Further efforts to detect, prevent, and manage CDI among solid organ transplant recipients are warranted.


Asunto(s)
Infecciones por Clostridium/epidemiología , Infección Hospitalaria/microbiología , Costos de Hospital , Mortalidad Hospitalaria , Trasplante de Órganos/efectos adversos , Receptores de Trasplantes/estadística & datos numéricos , Adulto , Clostridioides difficile/aislamiento & purificación , Infecciones por Clostridium/diagnóstico , Estudios de Cohortes , Infección Hospitalaria/epidemiología , Bases de Datos Factuales , Femenino , Estudios de Seguimiento , Rechazo de Injerto , Supervivencia de Injerto , Hospitales Universitarios , Humanos , Incidencia , Tiempo de Internación/economía , Modelos Lineales , Masculino , Persona de Mediana Edad , Trasplante de Órganos/métodos , Trasplante de Órganos/mortalidad , Estudios Retrospectivos , Medición de Riesgo , Tasa de Supervivencia , Resultado del Tratamiento , Estados Unidos
10.
Am J Transplant ; 15(8): 2096-104, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25773499

RESUMEN

Excellent outcomes among HIV+ kidney transplant (KT) recipients have been reported by the NIH consortium, but it is unclear if experience with HIV+ KT is required to achieve these outcomes. We studied associations between experience measures and outcomes in 499 HIV+ recipients (SRTR data 2004-2011). Experience measures examined included: (1) center-level participation in the NIH consortium; (2) KT experiential learning curve; and (3) transplant era (2004-2007 vs. 2008-2011). There was no difference in outcomes among centers early in their experience (first 5 HIV+ KT) compared to centers having performed >6 HIV+ KT (GS adjusted hazard ratio [aHR]: 1.05, 95% CI: 0.68-1.61, p = 0.82; PS aHR: 0.93; 95% CI: 0.56-1.53, p = 0.76), and participation in the NIH-study was not associated with any better outcomes (GS aHR: 1.08, 95% CI: 0.71-1.65, p = 0.71; PS aHR: 1.13; 95% CI: 0.68-1.89, p = 0.63). Transplant era was strongly associated with outcomes; HIV+ KTs performed in 2008-2011 had 38% lower risk of graft loss (aHR: 0.62; 95% CI: 0.42-0.92, p = 0.02) and 41% lower risk of death (aHR: 0.59; 95% CI: 0.39-0.90, p = 0.01) than that in 2004-2007. Outcomes after HIV+ KT have improved over time, but center-level experience or consortium participation is not necessary to achieve excellent outcomes, supporting continued expansion of HIV+ KT in the US.


Asunto(s)
Infecciones por VIH/cirugía , Trasplante de Riñón , Adolescente , Adulto , Anciano , Humanos , Persona de Mediana Edad , Estados Unidos , Adulto Joven
11.
Am J Transplant ; 14(6): 1236-48, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24840316

RESUMEN

The microbiota represents the complex collections of microbial communities that colonize a host. In health, the microbiota is essential for metabolism, protection against pathogens and maturation of the immune system. In return, the immune system determines the composition of the microbiota. Altered microbial composition (dysbiosis) has been correlated with a number of diseases in humans. The tight reciprocal immune/microbial interactions complicate determining whether dysbiosis is a cause and/or a consequence of immune dysregulation and disease initiation or progression. However, a number of studies in germ-free and antibiotic-treated animal models support causal roles for intestinal bacteria in disease susceptibility. The role of the microbiota in transplant recipients is only starting to be investigated and its study is further complicated by putative contributions of both recipient and donor microbiota. Moreover, both flora may be affected directly or indirectly by immunosuppressive drugs and antimicrobial prophylaxis taken by transplant patients, as well as by inflammatory processes secondary to ischemia/reperfusion and allorecognition, and the underlying cause of end-organ failure. Whether the ensuing dysbiosis affects alloresponses and whether therapies aimed at correcting dysbiosis should be considered in transplant patients constitutes an exciting new field of research.


Asunto(s)
Sistema Inmunológico/inmunología , Microbiota , Trasplante Autólogo , Homeostasis , Humanos
13.
Am J Transplant ; 13(7): 1891-7, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23802725

RESUMEN

Gene expression profiling of transplant recipient blood and urine can potentially be used to monitor graft function, but the multitude of protocols in use make sharing data and comparing results from different laboratories difficult. The goal of this study was to evaluate the performance of current methods of RNA isolation, reverse transcription and quantitative polymerase chain reaction (qPCR) and to test whether multiple centers using a standardized protocol can obtain the same results. Samples, reagents and detailed instructions were distributed to six participating sites that performed RNA isolation, reverse transcription and qPCR for 18S, PRF, GZB, IL8, CXCL9 and CXCL10 as instructed. All data were analyzed at a single site. All sites demonstrated proficiency in RNA isolation and qPCR analysis. Gene expression measurements for all targets and samples had correlations >0.938. The coefficient of variation of fold-changes between pairs of samples was less than 40%. All sites were able to accurately quantify a control sample of known concentration within a factor of 1.5. Collectively, we have formulated and validated detailed methods for measuring gene expression in blood and urine that can yield consistent results in multiple laboratories.


Asunto(s)
Perfilación de la Expresión Génica/normas , Regulación de la Expresión Génica , Trasplante de Riñón , ARN Mensajero/análisis , ADN Polimerasa Dirigida por ARN/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Perfilación de la Expresión Génica/métodos , Humanos , Límite de Detección , ARN Mensajero/genética , ADN Polimerasa Dirigida por ARN/genética , Sensibilidad y Especificidad , Trasplante Homólogo
14.
Am J Transplant ; 11(11): 2308-16, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21967066

RESUMEN

Breakthroughs in basic and clinical science in solid organ transplantation were presented at the American Transplant Congress 2011. Key areas of presentation included the pathogenesis of late allograft failure, immune regulation and tolerance, pathways in allograft injury, electing appropriate patients for transplantation, determining the best allocation schemes to maximize effective utilization, organ preservation, monitoring the alloimmune response and immunosuppressive management. In this review, we present highlights of the meeting. These presentations demonstrate the exciting promise in translating from the bench to affect patient care.


Asunto(s)
Trasplante de Órganos , Rechazo de Injerto/etiología , Humanos , Tolerancia Inmunológica/fisiología , Terapia de Inmunosupresión , Inmunosupresores/uso terapéutico , Preservación de Órganos , Donantes de Tejidos/provisión & distribución , Inmunología del Trasplante , Trasplante Homólogo , Insuficiencia del Tratamiento
15.
Transplant Proc ; 42(9): 3554-8, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21094814

RESUMEN

The recent availability of cinacalcet has provided a possible alternative to parathyroidectomy in kidney transplant patients with persistent hyperparathyroidism, but its effect on bone mass density (BMD) is unknown. From our database containing 163 kidney transplants performed at our center from 1999 to 2007, we compared recipients who received cinacalcet for persistent hypercalcemia and hyperparathyroidism following renal transplantation (n = 8) with up to two other posttransplant patients matched for age, sex, race, and graft function (n = 15). The outcome of the study was BMD changes from baseline to 12, 24, and 36 months post-renal transplantation. Repeated-measures mixed model was used to assess the difference of BMD change between two groups. Cinacalcet therapy was started at a median of 9 (range = 1 to 24) months posttransplant with a mean dose 56 ± 29 mg/d (mean duration = 1.6; range = 1 to 2.1 years). Cinacalcet therapy was associated with significant reduction of serum calcium compared to control. Cinacalcet therapy was associated with greater BMD increase at the hip over the 36-month posttransplant period. Cinacalcet was well tolerated. Our results suggest that cinacalcet may have a small but favorable effect on bone density following kidney transplantation.


Asunto(s)
Densidad Ósea/efectos de los fármacos , Calcimiméticos/uso terapéutico , Hipercalcemia/tratamiento farmacológico , Hiperparatiroidismo Secundario/tratamiento farmacológico , Trasplante de Riñón/efectos adversos , Naftalenos/uso terapéutico , Absorciometría de Fotón , Adulto , Huesos del Brazo/diagnóstico por imagen , Huesos del Brazo/efectos de los fármacos , Biomarcadores/sangre , Calcimiméticos/efectos adversos , Calcio/sangre , Estudios de Casos y Controles , Cinacalcet , Femenino , Articulación de la Cadera/diagnóstico por imagen , Articulación de la Cadera/efectos de los fármacos , Humanos , Hipercalcemia/sangre , Hipercalcemia/diagnóstico por imagen , Hipercalcemia/etiología , Hiperparatiroidismo Secundario/sangre , Hiperparatiroidismo Secundario/diagnóstico por imagen , Hiperparatiroidismo Secundario/etiología , Masculino , Persona de Mediana Edad , Naftalenos/efectos adversos , National Institutes of Health (U.S.) , Estudios Retrospectivos , Columna Vertebral/diagnóstico por imagen , Columna Vertebral/efectos de los fármacos , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos
16.
Am J Transplant ; 10(9): 2066-73, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20883541

RESUMEN

The Banff scoring schema provides a common ground to analyze kidney transplant biopsies. Interstitial inflammation (i) and tubulitis (t) in areas of viable tissue are features in scoring acute rejection, but are excluded in areas of tubular atrophy (TA). We studied inflammation and tubulitis in a cohort of kidney transplant recipients undergoing allograft biopsy for new-onset late graft dysfunction (N = 337). We found inflammation ('iatr') and tubulitis ('tatr') in regions of fibrosis and atrophy to be strongly correlated with each other (p < 0.0001). Moreover, iatr was strongly associated with death-censored graft failure when compared to recipients whose biopsies had no inflammation, even after adjusting for the presence of interstitial fibrosis (Hazard Ratio = 2.31, [1.10-4.83]; p = 0.0262) or TA (hazard ratio = 2.42, [1.16-5.08]; p = 0.191), serum creatinine at the time of biopsy, time to biopsy and i score. Further, these results did not qualitatively change after additional adjustments for C4d staining or donor specific antibody. Stepwise regression identified the most significant markers of graft failure which include iatr score. We propose that a more global assessment of inflammation in kidney allograft biopsies to include inflammation in atrophic areas may provide better prognostic information. Phenotypic characterization of these inflammatory cells and appropriate treatment may ameliorate late allograft failure.


Asunto(s)
Trasplante de Riñón/patología , Túbulos Renales/patología , Nefritis/patología , Atrofia , Biopsia , Estudios de Cohortes , Creatinina/sangre , Estudios Transversales , Femenino , Fibrosis , Rechazo de Injerto/mortalidad , Humanos , Técnicas In Vitro , Masculino , Nefritis/sangre , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Medición de Riesgo , Índice de Severidad de la Enfermedad , Trasplante Homólogo
18.
Am J Transplant ; 10(3): 464-71, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20121738

RESUMEN

The 10th Banff Conference on Allograft Pathology was held in Banff, Canada from August 9 to 14, 2009. A total of 263 transplant clinicians, pathologists, surgeons, immunologists and researchers discussed several aspects of solid organ transplants with a special focus on antibody mediated graft injury. The willingness of the Banff process to adapt continuously in response to new research and improve potential weaknesses, led to the implementation of six working groups on the following areas: isolated v-lesion, fibrosis scoring, glomerular lesions, molecular pathology, polyomavirus nephropathy and quality assurance. Banff working groups will conduct multicenter trials to evaluate the clinical relevance, practical feasibility and reproducibility of potential changes to the Banff classification. There were also sessions on quality improvement in biopsy reading and utilization of virtual microscopy for maintaining competence in transplant biopsy interpretation. In addition, compelling molecular research data led to the discussion of incorporation of omics-technologies and discovery of new tissue markers with the goal of combining histopathology and molecular parameters within the Banff working classification in the near future.


Asunto(s)
Anticuerpos/química , Trasplante de Órganos/métodos , Biopsia , Canadá , Complemento C4b/metabolismo , Fibrosis/patología , Humanos , Enfermedades Renales/diagnóstico , Enfermedades Renales/patología , Enfermedades Renales/virología , Trasplante de Riñón , Estudios Multicéntricos como Asunto , Fragmentos de Péptidos/metabolismo , Fenotipo , Infecciones por Polyomavirus/diagnóstico , Control de Calidad
19.
Am J Transplant ; 8(6): 1297-302, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18444933

RESUMEN

Valganciclovir is commonly used for cytomegalovirus (CMV) prophylaxis in renal transplant patients. A fixed dose of 900 mg daily is typically recommended, however, there has never been a formal pharmacokinetic study comparing various doses in renal transplant patients. We therefore compared the pharmacokinetic characteristics of intravenous ganciclovir (IV GCV) and oral ganciclovir (GCV) with two different doses of valganciclovir (VGCV) in an open-label crossover study. Ten adult kidney recipients participated in a four-phase crossover treatment schedule of IV GCV (2.5 mg/kg every 12 h), VGCV (900 mg daily), VGCV (450 mg daily) and oral GCV (1000 mg Q8 H). IV GCV and oral VGCV 900 mg daily achieved similar values for AUC(0-24) (median 60.63 vs. 62.86 microg/h/mL). Oral VGCV 450 mg achieved comparable AUC(0-24) values as oral GCV 1000 mg Q8 H (median AUC(0-24) 35.9 vs. 29.04 microg/h/mL). Oral VGCV 900 mg daily provided systemic GCV exposure similar to IV GCV and confirms PV 16 000 study results. Further, VGCV 450 mg daily provided comparable systemic exposure versus oral GCV. Due to its favorable pharmacokinetic profile, data herein suggest that VGCV can be used in the early post-kidney transplant period, and that 450 mg daily provides ample drug exposure for effective CMV prophylaxis in kidney transplant patients.


Asunto(s)
Antivirales/farmacocinética , Infecciones por Citomegalovirus/prevención & control , Ganciclovir/análogos & derivados , Trasplante de Riñón , Adulto , Antivirales/administración & dosificación , Estudios Cruzados , Infecciones por Citomegalovirus/etiología , Relación Dosis-Respuesta a Droga , Femenino , Ganciclovir/administración & dosificación , Ganciclovir/farmacocinética , Humanos , Trasplante de Riñón/efectos adversos , Masculino , Persona de Mediana Edad , Valganciclovir
20.
Am J Transplant ; 8(4): 753-60, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18294345

RESUMEN

The 9th Banff Conference on Allograft Pathology was held in La Coruna, Spain on June 23-29, 2007. A total of 235 pathologists, clinicians and scientists met to address unsolved issues in transplantation and adapt the Banff schema for renal allograft rejection in response to emerging data and technologies. The outcome of the consensus discussions on renal pathology is provided in this article. Major updates from the 2007 Banff Conference were: inclusion of peritubular capillaritis grading, C4d scoring, interpretation of C4d deposition without morphological evidence of active rejection, application of the Banff criteria to zero-time and protocol biopsies and introduction of a new scoring for total interstitial inflammation (ti-score). In addition, emerging research data led to the establishment of collaborative working groups addressing issues like isolated 'v' lesion and incorporation of omics-technologies, paving the way for future combination of graft biopsy and molecular parameters within the Banff process.


Asunto(s)
Trasplante de Riñón/patología , Biopsia , Ensayos Clínicos como Asunto , Complemento C4b/análisis , Rechazo de Injerto/patología , Rechazo de Injerto/prevención & control , Supervivencia de Injerto , Humanos , Inmunosupresores/uso terapéutico , Trasplante de Riñón/inmunología , Fragmentos de Péptidos/análisis , Trasplante Homólogo
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