RESUMEN

Introduction The United States Department of Veterans Affairs (VA) National Transplant Program has made efforts to improve access by introducing Web-based referrals and telehealth. The aims of this study were to describe the programmatic implementation and evaluate the effectiveness of new technology on the timeliness to kidney transplant evaluation at a VA medical centre. Methods Between 1 January 2009 and 31 May 2016, 835 patients were approved for evaluation. Monthly data were summarized as: number of applications, median days to evaluation, and median percentage of evaluations that occurred within 30 days. Temporal trends were analysed using non-parametric comparisons of medians between three eras: Pre Web-based submission, Web-based submission, and Web-based submission with videoconference (VC) telehealth. Results The number of applications did not vary between eras ( p = 0.353). The median time to evaluation and the median percentage of patients with appointments within 30 days improved significantly in the Web-based submission with VC era when compared with the Web-based and Pre Web-based eras (37 vs. 260 and 116 days, respectively, p < 0.001; 100% vs. 8% and 0%, respectively, p < 0.001). Discussion We have been able to markedly improve the timeliness to kidney transplant waitlist evaluation with the addition of telehealth.

Asunto(s)

Trasplante de Riñón , Calidad de la Atención de Salud/organización & administración , Derivación y Consulta/estadística & datos numéricos , Telemedicina/métodos , Listas de Espera , Femenino , Humanos , Masculino , Persona de Mediana Edad , Cuidados Preoperatorios , Estados Unidos , United States Department of Veterans Affairs

RESUMEN

BACKGROUND: There have been limited publications on telehealth utilization in transplantation with no prior reports of telehealth-related costs for pretransplant evaluations. The aim of this study is to compare costs throughout the evaluation process for those patients assessed initially by telehealth with those seen in-person. METHODS: All patients approved for kidney transplant waitlist evaluation at our center from March 2013 thru May 2016 with decisions were included in this study. Patients approved for evaluation were scheduled for either an initial telehealth or in-person visit, partly based on patient factors. Clinically related and travel-related costs were calculated. Time estimates for patient time needed to complete visit, time from application approval to initial visit, and time from application approval to decision were obtained. Comparisons were made using t tests. RESULTS: Thirty-nine months were included for 302 patients. All categories of clinically or travel-related costs were significantly less for the telehealth cohort (P < 0.0001). Total mean cost per patient was US $656.11 versus US $1108.91 for the cohort initially evaluated by telehealth versus in-person (P < 0.001). The time needed to complete an evaluation (1.7 vs 2.4 days, P < 0.001) and the time to initial evaluation (51.4 vs 87.9.0 days, P < 0.001) were significantly less in the telehealth cohort. The cohort seen by telehealth was older with increased comorbidities (<0.001). CONCLUSIONS: As telemedicine applications continue to proliferate, we present our experience with telehealth for initial kidney transplant waitlist evaluations with associated reductions in cost and time which may also improve access to transplantation.

Asunto(s)

Costos de la Atención en Salud , Trasplante de Riñón , Telemedicina/economía , Listas de Espera , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Telemedicina/estadística & datos numéricos

RESUMEN

OBJECTIVES: We previously showed that management with a novel vaginal bowel control system was efficacious in women with moderate to severe fecal incontinence. The objective of this secondary analysis was to evaluate the clinical characteristics associated with device-fitting success. METHODS: This is a secondary analysis of an institutional review board-approved, multicenter, prospective, open-label clinical study of women aged 19 to 75 years with 4 or more episodes of fecal incontinence recorded on a 2-week baseline bowel diary. Those successfully fitted with the vaginal bowel control device entered a 1-month treatment period, and efficacy was assessed with a repeat bowel diary. Demographic data, medical and surgical history, and pelvic examination findings were compared across women with successful and unsuccessful completion of the fitting period. Multivariate logistic regression analysis was performed. RESULTS: Six clinical sites in the United States recruited from August 2012 through October 2013. Overall, 110 women underwent attempted fitting, of which 61 (55.5%) of 110 were successful and entered the treatment portion of the study. Multivariate logistic regression analysis revealed that previous prolapse surgery (P = 0.007) and shorter vaginal length (P = 0.041) were independently associated with unsuccessful fitting. Women who have not undergone previous prolapse surgery had 4.7 times the odds (95% confidence interval [CI], 1.53-14.53) of a successful fit. In addition, for every additional centimeter of vaginal length, women had 1.49 times the odds (95% CI, 1.02-2.17) of a successful fit. CONCLUSIONS: Shorter vaginal length and previous prolapse surgery were associated with an increased risk of fitting failure. These findings may be used to inform patients regarding their expectation of successful fitting.

Asunto(s)

Incontinencia Fecal/terapia , Prótesis e Implantes , Anciano , Femenino , Humanos , Persona de Mediana Edad , Ensayos Clínicos Controlados no Aleatorios como Asunto , Estudios Prospectivos , Vagina

RESUMEN

BACKGROUND: Hyperlipidemia is a common adverse effect of sirolimus (SRL). We previously showed significant associations of ABCB1 3435C>T and IL-10 -1082G>A with log-transformed SRL dose-adjusted weighted-normalized trough. We further examined to see whether these polymorphisms were also associated with SRL-induced dyslipidemia. METHODS: Genotyping was performed for ABCB1 1236C>T, 2677 G>T/A, and 3435C>T; CYP3A4 -392A>G; CYP3A5 6986A>G and 14690G>A; IL-10 -1082G>A; TNF -308G>A; and ApoE ε2, ε3, and ε4 alleles. The longitudinal changes of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels after SRL treatment before statin therapy were analyzed by a linear mixed-effects model, with adjustments for selected covariates for each lipid. RESULTS: Under the dominant genetic model, ABCB1 3435C>T was associated with TC (P=0.0001) and LDL-C (P<0.0001) values after SRL administration. Mean TC and LDL-C levels were 26.9 and 24.9 mg/dL higher, respectively, in ABCB1 3435T carriers than 3435CC homozygotes at an average SRL trough concentration of 4 ng/mL without concomitant medication. ABCB1 1236C>T under the recessive model and IL-10 -1082G>A under the dominant model were associated with log-transformed TG values (P=0.0051 and 0.0436, respectively). Mean TG value was 25.1% higher in ABCB1 1236TT homozygotes compared with ABCB1 1236C carriers and was 12.4% higher in IL-10 -1082AA homozygotes than -1082G carriers. CONCLUSIONS: ABCB1 polymorphisms were found to be associated with lipid responses to SRL treatment, confirming the role of ABCB1 gene in SRL pharmacokinetics and pharmacodynamics. Further studies are necessary to define the role of ABCB1 and IL-10 polymorphisms on SRL-induced dyslipidemia in renal transplantation.

Asunto(s)

Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Dislipidemias/inducido químicamente , Dislipidemias/genética , Interleucina-10/genética , Trasplante de Riñón/inmunología , Polimorfismo de Nucleótido Simple/genética , Sirolimus/efectos adversos , Subfamilia B de Transportador de Casetes de Unión a ATP , Adulto , Anciano , LDL-Colesterol/sangre , Relación Dosis-Respuesta a Droga , Dislipidemias/epidemiología , Femenino , Genotipo , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/farmacocinética , Inmunosupresores/uso terapéutico , Modelos Lineales , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Farmacogenética , Estudios Retrospectivos , Sirolimus/farmacocinética , Sirolimus/uso terapéutico , Triglicéridos/sangre

RESUMEN

BACKGROUNDS: Sirolimus (SRL) absorption and metabolism are affected by p-glycoprotein-mediated transport and CYP3A enzyme activity, which are further under the influences of cytokine concentrations. This retrospective study determined the associations of adenosine triphosphate-binding cassette, subfamily B, member 1 (ABCB1) 1236C>T, 2677 G>T/A, and 3435C>T, cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) -392A>G, cytochrome P450, family 3, subfamily A, polypeptide 5 (CYP3A5) 6986A>G and 14690G>A, interleukin (IL)-10 -1082G>A, and tumor necrosis factor (TNF) -308G>A polymorphisms with SRL dose-adjusted, weight-normalized trough concentrations (C/D) at 7 days, and at 1, 3, 6, and 12 months after initiation of SRL. METHODS: Genotypes for 86 renal transplant patients who received SRL-based maintenance immunosuppressive therapy were determined using polymerase chain reaction followed by chip-based mass spectrometry. The changes of log-transformed C/D over the days posttransplantation were analyzed using a linear mixed-effects model, with adjustments for body mass index and weight-normalized doses of tacrolimus, prednisone, clotrimazole, and statins. RESULTS: ABCB1 3435C>T and IL-10 -1082G>A were significantly associated with log C/D (P=0.0016 and 0.0394, respectively). Mean SRL C/D was 48% higher in patients with ABCB1 3435CT/TT genotype than those with 3435CC genotype, and was 24% higher in IL-10 -1082GG compared with -1082AG/AA. CONCLUSIONS: ABCB1 3435C>T and IL-10 -1082G>A were significantly associated with long-term SRL dose requirements. Genetics can play a significant role in SRL dosing and may be useful in therapeutic monitoring of SRL in renal transplantation. Future replication studies are needed to confirm these associations.

Asunto(s)

Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Inmunosupresores/administración & dosificación , Trasplante de Riñón , Polimorfismo de Nucleótido Simple , Sirolimus/administración & dosificación , Subfamilia B de Transportador de Casetes de Unión a ATP , Adulto , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Terapia de Inmunosupresión , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Tiempo

RESUMEN

BACKGROUND: Chemokines and their receptors play a critical role in leukocyte trafficking, and inhibition of select chemokines has been shown to attenuate kidney disease and allograft rejection in animal models. Therefore, we evaluated chemokine and chemokine receptor transcripts in human renal allograft biopsies, correlating transcript levels with clinical course and immunohistochemical analysis to relate chemokine expression to relevant clinical human disease phenotypes. METHODS: Renal biopsies were grouped as postreperfusion (n=10), stable function (n=10), subclinical (n=10) or acute rejection (n=17), or calcineurin inhibitor nephrotoxicity (n=9) based on clinical presentation and histopathologic assessment. Using quantitative real-time polymerase chain reaction analysis, chemokine transcripts were assessed relative to transcript levels in preprocurement biopsies from live donor kidneys (n=15). RESULTS: Transcripts from several inflammatory chemokines (CCL3, CCL5, CXCL9, CXCL10, and CXCL11) and chemokine receptors (CCR5, CCR7, and CXCR3) were significantly increased in allografts with subclinical and clinical acute rejection, indicating a strong polarization toward a T-helper 1 effector phenotype during rejection. These transcripts also distinguished acutely rejecting allografts from allografts with nonrejection causes of renal dysfunction. Biopsies from patients with stable function without histologic evidence of rejection had increased chemokine transcript levels that were qualitatively similar but quantitatively reduced compared with rejecting allografts. CONCLUSIONS: This comprehensive evaluation of chemokines and their receptors in human renal transplantation defines associations between chemokine expression and clinical phenotypes, may have diagnostic utility, and highlights relevant pathways for therapeutic intervention.

Asunto(s)

Quimiocinas CXC/inmunología , Trasplante de Riñón/inmunología , Receptores CXCR/inmunología , Enfermedad Aguda , Adulto , Biopsia , Femenino , Rechazo de Injerto/inmunología , Humanos , Inflamación/inmunología , Trasplante de Riñón/patología , Masculino , Persona de Mediana Edad , Resultado del Tratamiento

RESUMEN

In a cohort of 32 renal transplant patients who are potentially at risk for adverse events, we compared tacrolimus (TAC) abbreviated AUC values calculated by a method developed in Asians (AUCw) with those derived for Caucasians (AUCa). The relationships between TAC trough (C0), abbreviated AUC, and biopsy results were also assessed. Forty-eight AUCs and 15 associated biopsies were evaluated. For AUCs obtained only from Caucasian patients, median AUCw value was lower than that of AUCa (104 vs. 115 ng×h/mL, n=29, p<0.0001). AUCs obtained from the two methods for all patients correlated with C0 (rs>0.72, n=48, p<0.0001). Median AUCw (72.9 vs. 174 ng×h/mL, p=0.043) and AUCa (81.0 vs. 203 ng×h/mL, p=0.043) were lower in patients experiencing biopsy-proven acute rejection (AR) than those with normal histology. C0 tended to be lower in biopsies showing AR>6 months post-transplant (5.80 vs. 11.0 ng/mL, p=0.110). Thus, lower abbreviated AUCs were obtained for Caucasians using a method developed in Asians. C0 correlated well with abbreviated AUCs. Lower C0 and AUC appeared to be associated with biopsy-proven AR>6 months post-transplant. Further prospective evaluation of TAC AUC and C0 monitoring in a larger cohort of patients is warranted.

Asunto(s)

Monitoreo de Drogas , Rechazo de Injerto/prevención & control , Inmunosupresores/uso terapéutico , Trasplante de Riñón , Tacrolimus/uso terapéutico , Adolescente , Adulto , Anciano , Área Bajo la Curva , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tasa de Supervivencia , Factores de Tiempo , Resultado del Tratamiento , Adulto Joven

RESUMEN

Assessment of pulsatile perfusion (PP) is limited to measurements of flow (V) and resistance (R). We investigated infrared (IR) imaging during PP as a means for precise organ assessment. IR was used to monitor 10 porcine kidneys during 18 hr of PP in an uncontrolled Donation after Cardiac Death model. An IR camera (Lockheed Martin) was focused on the anterior surfaces of the kidneys. The degree of temperature homogeneity was compared with standard measurements of V and R. IR thermal images correlated with V and R (R=0.92, P<0.001). IR detected an increase in homogeneity during PP by comparing standard deviation differences before and after PP (P=0.002), which was not evident by standard measurements of V and R. Finally, IR assessment allowed for measurement of dynamic changes in perfusion.

Asunto(s)

Cadáver , Supervivencia Celular/fisiología , Riñón/fisiología , Flujo Pulsátil/fisiología , Donantes de Tejidos , Animales , Velocidad del Flujo Sanguíneo , Temperatura Corporal , Supervivencia Celular/efectos de la radiación , Humanos , Rayos Infrarrojos , Trasplante de Riñón/fisiología , Selección de Paciente , Circulación Renal , Porcinos , Trasplante Homólogo/fisiología , Resistencia Vascular

RESUMEN

BACKGROUND: Standard methods for assessment of organ viability during surgery are typically limited to visual cues and tactile feedback in open surgery. However, during laparoscopic surgery, these processes are impaired. This is of particular relevance during laparoscopic renal donation, where the condition of the kidney must be optimized despite considerable manipulation. However, there is no in vivo methodology to monitor renal parenchymal oxygenation during laparoscopic surgery. METHODS: We have developed a method for the real time, in vivo, whole organ assessment of tissue oxygenation during laparoscopic nephrectomy to convey meaningful biological data to the surgeon during laparoscopic surgery. We apply the 3-CCD (charge coupled device) camera to monitor qualitatively renal parenchymal oxygenation with potential real-time video capability. RESULTS: We have validated this methodology in a porcine model across a range of hypoxic conditions, and have then applied the method during clinical laparoscopic donor nephrectomies during clinically relevant pneumoperitoneum. 3-CCD image enhancement produces mean region of interest (ROI) intensity values that can be directly correlated with blood oxygen saturation measurements (R2 > 0.96). The calculated mean ROI intensity values obtained at the beginning of the laparoscopic nephrectomy do not differ significantly from mean ROI intensity values calculated immediately before kidney removal (p > 0.05). CONCLUSION: Here, using the 3-CCD camera, we qualitatively monitor tissue oxygenation. This means of assessing intraoperative tissue oxygenation may be a useful method to avoid unintended ischemic injury during laparoscopic surgery. Preliminary results indicate that no significant changes in renal oxygenation occur as a result of pneumoperitoneum.

Asunto(s)

Procesamiento de Imagen Asistido por Computador , Laparoscopía , Monitoreo Intraoperatorio/métodos , Nefrectomía , Consumo de Oxígeno/fisiología , Recolección de Tejidos y Órganos , Adulto , Algoritmos , Animales , Femenino , Humanos , Trasplante de Riñón , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Análisis Espectral , Porcinos , Supervivencia Tisular/fisiología

RESUMEN

Obesity is an important co-morbidity within end-stage renal disease (ESRD) and renal transplant populations. Previous studies have suggested that chronic corticosteroids result in increased body weight post-transplant. With the recent adoption of steroid-sparing immunosuppressive strategies, we evaluated the effect of these strategies on body mass index (BMI) after renal transplantation. We examined 95 renal transplant recipients enrolled in National Institutes of Health clinical transplant trials over the past three yr who received either lymphocyte depletion-based steroid sparing or traditional immunosuppressive therapy that included steroids for maintenance immunosuppression. Recipients were overweight prior to transplant and no significant differences existed in pre-transplant BMI among treatment groups. Regardless of therapy, BMI increased post-transplant in all recipients. The BMI increase consisted of an average weight gain of 5.01 +/- 7.12 kg (mean, SD) post-transplant. Additionally, in a number of recipients placed on maintenance steroids, subsequent withdrawal at a mean of 100 d post-transplant had no impact on weight gain. Thus, body weight and BMI increase following kidney transplantation, even in the absence of steroids. Thus, patients gain weight after renal transplantation regardless of the treatment strategy. Steroid avoidance alone does not reduce risk factors associated with obesity in our patient population.

Asunto(s)

Terapia de Inmunosupresión/métodos , Trasplante de Riñón , Obesidad/etiología , Adolescente , Adulto , Anciano , Alemtuzumab , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Anticuerpos Antineoplásicos/administración & dosificación , Suero Antilinfocítico , Índice de Masa Corporal , Femenino , Estudios de Seguimiento , Humanos , Inmunosupresores/administración & dosificación , Masculino , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Ácido Micofenólico/análogos & derivados , Obesidad/prevención & control , Factores de Riesgo , Sirolimus/administración & dosificación , Esteroides/administración & dosificación , Tacrolimus/administración & dosificación

RESUMEN

Humans are protected from a daily onslaught of pathogenic organisms by an immune system that provides multiple layers of protection. Until solid organ transplantation became technically feasible in the early twentieth century, this constant state of surveillance for foreign cells that are associated with the immune response mostly was viewed as advantageous. Unfortunately for patients who have end-stage failure of heart, lungs, kidney, liver, and pancreas, the immune system is incapable of distinguishing between the presence of beneficial foreign tissue and harmful foreign pathogens; it mounts an effective attack against both. Improving our understanding of the factors that initiate and perpetuate the alloimmune response will result in the development of more refined and better tolerated immunosuppressive strategies.

Asunto(s)

Inmunología del Trasplante , Animales , Humanos , Inmunidad Activa , Inmunidad Innata , Terapia de Inmunosupresión , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Tolerancia al Trasplante

RESUMEN

T cell depletion, sirolimus and "mega" dose donor specific bone marrow (DSBM) infusion promotes stable multilineage chimerism and indefinite survival of skin allografts in completely mismatched mice. The purpose of this study is to determine whether the addition of low dose busulfan can reduce the amount of DSBM required while preserving efficacy. C57BL/6 recipients of BALB/c skin allografts were treated with alphaCD4 and alphaCD8 monoclonal antibodies, DSBM, sirolimus and various doses of busulfan. The kinetics and phenotype of chimerism and the presence of clonal deletion of alloreactive T-cells were defined using flow cytometry. In vitro reactivity was determined using mixed lymphocyte culture. Second skin grafts confirmed the presence of tolerance. All doses of busulfan resulted in engraftment when combined with this regimen using a reduced dose of donor marrow. The level, kinetics and character of chimerism observed were dose related. Chimerism was associated with indefinite allograft acceptance (>200 days). Tolerance was documented both in vitro/in vivo and was associated with clonal deletion. Addition of a single low dose of busulfan to an established tolerance protocol reduced the required DSBM dose by over 80% while still promoting comparable levels of donor chimerism and donor-specific tolerance.

Asunto(s)

Busulfano/farmacología , Supervivencia de Injerto/efectos de los fármacos , Tolerancia Inmunológica/efectos de los fármacos , Agonistas Mieloablativos/farmacología , Trasplante de Piel/inmunología , Quimera por Trasplante/inmunología , Animales , Trasplante de Médula Ósea/inmunología , Supresión Clonal/efectos de los fármacos , Supresión Clonal/inmunología , Supervivencia de Injerto/inmunología , Tolerancia Inmunológica/inmunología , Depleción Linfocítica/métodos , Ratones , Ratones Endogámicos BALB C , Trasplante Homólogo

RESUMEN

BACKGROUND: Perioperative lymphocyte depletion induces allograft tolerance in some animal models, but in humans has only been shown to reduce immunosuppressive requirements. Without maintenance immunosuppression, depleted human renal allograft recipients experience rejection characterized by infiltration of the allograft with monocytes and macrophages. T-cell depletion combined with a brief course of deoxyspergualin (DSG), a drug with inhibitory effects on monocytes and macrophages, induces tolerance in nonhuman primates. We therefore performed a trial to determine if lymphocyte depletion with alemtuzumab combined with DSG would induce tolerance in humans. METHODS: Five recipients of live donor kidneys were treated perioperatively with alemtuzumab and DSG and followed postoperatively without maintenance immunosuppression. Patients were evaluated clinically, by flow cytometry, and by protocol biopsies analyzed immunohistochemically and with real-time polymerase chain reaction. Results were compared to previously studied patients receiving alemtuzumab alone or standard immunosuppression. RESULTS: Despite profound T-cell depletion and therapeutic DSG dosing, all alemtuzumab/DSG patients developed reversible rejection that was similar in timing, histology, and transcriptional profile to that seen in patients treated with alemtuzumab alone. Chemokine expression was marked prior to and during rejections. CONCLUSIONS: We conclude that treatment with alemtuzumab and DSG does not induce tolerance in humans. Chemokine production may not be adequately suppressed using this approach.

Asunto(s)

Anticuerpos Monoclonales/farmacología , Anticuerpos Antineoplásicos/farmacología , Guanidinas/farmacología , Inmunosupresores/farmacología , Trasplante de Riñón/inmunología , Depleción Linfocítica , Tolerancia al Trasplante/efectos de los fármacos , Adulto , Alemtuzumab , Anticuerpos Monoclonales Humanizados , Quimiocinas/genética , Quimiocinas/metabolismo , Creatina/sangre , Femenino , Rechazo de Injerto/metabolismo , Humanos , Riñón/citología , Riñón/inmunología , Riñón/fisiología , Ganglios Linfáticos/citología , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Linfocitos T/efectos de los fármacos , Transcripción Genética

RESUMEN

Short-term outcomes following organ transplantation have improved considerably since the availability of cyclosporine ushered in the modern era of immunosuppression. In spite of this, many of the current limitations to progress in the field are directly related to the existing practice of relatively non-specific immunosuppression. These include increased risks of opportunistic infection and cancer, and toxicity associated with long-term immunosuppressive drug exposure. In addition, long-term graft loss continues to result in part from a failure to adequately control the anti-donor immune response. The development of a safe and reliable means of inducing tolerance would ameliorate these issues and improve the lives of transplant recipients, yet given the improving clinical standard of care, the translation of new therapies has become appropriately more cautious and dependent on increasingly predictive preclinical models. While convenient and easy to use, rodent tolerance models have not to date been reliably capable of predicting a therapy's potential efficacy in humans. Non-human primates possess an immune system that more closely approximates that found in humans, and have served as a more rigorous preclinical testing ground for novel therapies. Prior to clinical adaptation therefore, tolerance regimens should be vetted in non-human primates to ensure that there is sufficient potential for efficacy to justify the risk of its application.

Asunto(s)

Terapia de Inmunosupresión/métodos , Modelos Animales , Modelos Inmunológicos , Transducción de Señal/inmunología , Tolerancia al Trasplante/inmunología , Animales , Anticuerpos Monoclonales/uso terapéutico , Suero Antilinfocítico/uso terapéutico , Primates , Quimera por Trasplante/inmunología

RESUMEN

CD154-specific antibody therapy prevents allograft rejection in many experimental transplant models. However, initial clinical transplant trials with anti-CD154 have been disappointing suggesting the need for as of yet undetermined adjuvant therapy. In rodents, donor antigen (e.g., a donor blood transfusion), or mTOR inhibition (e.g., sirolimus), enhances anti-CD154's efficacy. We performed renal transplants in major histocompatibility complex-(MHC) mismatched rhesus monkeys and treated recipients with combinations of the CD154-specific antibody IDEC-131, and/or sirolimus, and/or a pre-transplant donor-specific transfusion (DST). Therapy was withdrawn after 3 months. Triple therapy prevented rejection during therapy in all animals and led to operational tolerance in three of five animals including donor-specific skin graft acceptance in the two animals tested. IDEC-131, sirolimus and DST are highly effective in preventing renal allograft rejection in primates. This apparently clinically applicable regimen is promising for human renal transplant trials.

Asunto(s)

Anticuerpos Monoclonales/farmacología , Ligando de CD40/inmunología , Inmunosupresores/farmacología , Sirolimus/farmacología , Animales , Anticuerpos Monoclonales Humanizados , Transfusión Sanguínea , Complejo CD3/biosíntesis , Rechazo de Injerto , Supervivencia de Injerto/efectos de los fármacos , Isoanticuerpos/química , Trasplante de Riñón/métodos , Leucocitos Mononucleares/metabolismo , Prueba de Cultivo Mixto de Linfocitos , Linfocitos/metabolismo , Macaca mulatta , Complejo Mayor de Histocompatibilidad , Primates , Proteínas Quinasas/metabolismo , Trasplante de Piel , Serina-Treonina Quinasas TOR , Factores de Tiempo

RESUMEN

BACKGROUND: Chronic allograft nephropathy (CAN) remains the leading cause of late renal allograft loss that is minimally responsive to therapy once graft dysfunction is clinically evident. A screening test capable of identifying individuals at high risk for CAN would be a valuable adjunct to patient care, but to be cost effective, should be administered during routine evaluations by transplantation clinicians. STUDY DESIGN: We have compared the resistive index (RI) as measured by Doppler ultrasonography with subsequent biopsy findings on 91 renal allograft recipients who had a subsequent protocol-directed biopsy at least 3 months after renal transplant. All ultrasonography was performed by the transplantation surgical staff without involving the radiology department or a separate appointment time. RESULTS: Twenty-one patients had RI >/= 80 (average 621 days posttransplantation). Among these individuals, the subsequent incidence of CAN was 38%. Length of time between initial assessment of increased RI and biopsy-proved CAN averaged 233 days. The remaining 70 patients with RI < 80 had an incidence of CAN of 11.4% (p = 0.018). There were minimal complications from these biopsies. Sensitivity and specificity of an elevated RI in predicting CAN were 50% and 83%, respectively. The negative predicted value of an elevated RI in determination of CAN was 89%. CONCLUSIONS: These results suggest that elevated RI is an early predictor of histologically relevant CAN, possibly a result of burgeoning vasculopathy. The technical expertise required to make this appraisal is well within the capabilities of transplantation surgeons and trainees. Early evidence of CAN may allow for a targeted change in therapy before clinically significant injury. Ultrasonography should become a routine part of a transplantation clinic evaluation.

Asunto(s)

Enfermedades Renales/diagnóstico por imagen , Trasplante de Riñón , Complicaciones Posoperatorias/diagnóstico por imagen , Ultrasonografía Doppler , Adolescente , Adulto , Anciano , Biopsia , Femenino , Rechazo de Injerto/diagnóstico por imagen , Rechazo de Injerto/patología , Humanos , Incidencia , Riñón/diagnóstico por imagen , Riñón/patología , Enfermedades Renales/patología , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Examen Físico , Complicaciones Posoperatorias/patología , Sensibilidad y Especificidad , Trasplante Homólogo

RESUMEN

T-cell depletion facilitates reduced immunosuppression following organ transplantation and has been suggested to be pro-tolerant. However, the characteristics of post-depletional T cells have not been evaluated as they relate to tolerance induction. We therefore studied patients undergoing profound T-cell depletion with alemtuzumab or rabbit anti-thymocyte globulin following renal transplantation, evaluating the phenotype and functional characteristics of their residual cells. Naive T cells and T cells with potential regulatory function (CD4+CD25+) were not prevalent following aggressive depletion. Rather, post-depletion T cells were of a single phenotype (CD3+CD4+CD45RA-CD62L-CCR7-) consistent with depletion-resistant effector memory T cells that expanded in the first month and were uniquely prevalent at the time of rejection. These cells were resistant to steroids, deoxyspergualin or sirolimus in vitro, but were calcineurin-inhibitor sensitive. These data demonstrate that therapeutic depletion begets a limited population of functional memory-like T cells that are easily suppressed with certain immunosuppressants, but cannot be considered uniquely pro-tolerant.

Asunto(s)

Memoria Inmunológica/efectos de los fármacos , Inmunosupresores/farmacología , Subgrupos de Linfocitos T/efectos de los fármacos , Alemtuzumab , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Anticuerpos Antineoplásicos/inmunología , Anticuerpos Antineoplásicos/farmacología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Inhibidores de la Calcineurina , Humanos , Memoria Inmunológica/inmunología , Trasplante de Riñón/inmunología , Subgrupos de Linfocitos T/inmunología

RESUMEN

Renal allograft acute cellular rejection (ACR) is a T-cell mediated disease that is diagnosed histologically. However, many normally functioning allografts have T-cell infiltrates and histological ACR, and many nonimmune processes cause allograft dysfunction. Thus, neither histological nor functional criteria are sufficient to establish a significant rejection, and the fundamental features of clinical rejection remain undefined. To differentiate allograft lymphocyte infiltration from clinically significant ACR, we compared renal biopsies from patients with ACR to patients with: sub-clinical rejection (SCR, stable function with histological rejection); no rejection; and nontransplanted kidneys. Biopsies were compared histologically and transcriptionally by RT-PCR for 72 relevant immune function genes. Neither the degree nor the composition of the infiltrate defined ACR. However, transcripts up-regulated during effector T(H)1 T-cell activation, most significantly the transcription factor T-bet, the effector receptor Fas ligand and the costimulation molecule CD152 clearly (p = 0.001) distinguished the patient categories. Transcripts from other genes were equivalently elevated in SCR and ACR, indicating their association with infiltration, not dysfunction. Clinically significant ACR is not defined solely by the magnitude nor composition of the infiltrate, but rather by the transcriptional activity of the infiltrating cells. Quantitative analysis of selected gene transcripts may enhance the clinical assessment of allografts.

Asunto(s)

Rechazo de Injerto/diagnóstico , Trasplante de Riñón , ARN Mensajero , Transcripción Genética , Adulto , Biopsia , Femenino , Perfilación de la Expresión Génica , Rechazo de Injerto/fisiopatología , Humanos , Riñón/metabolismo , Riñón/patología , Masculino

RESUMEN

Preclinical testing of a mixed chimerism mediated organ transplant tolerance strategy, in a cynomolgus macaque model, would be facilitated by the establishment of a reliable technique for quantitative assessment of chimerism. Among various techniques used for measurement of chimerism in humans, microsatellite DNA profiling has been considered the most versatile one that can discriminate between two individuals. We adopted a commercially available short tandem repeat profiling methodology to cynomolgus monkeys using two human specific alleles, TPOX and CSF1PO. Polymerase chain reaction (PCR) was used to amplify these alleles, and the analysis of the PCR products was performed by capillary electrophoresis. Of 54 cynomolgus macaques investigated, only one pair with the same ABO blood type demonstrated identity at both alleles. This implies that this technique should interfere minimally with the assignment of donor-recipient pairs based upon molecular tissue typing or mixed lymphocyte cultures.

Asunto(s)

Quimera por Trasplante , Animales , Humanos , Macaca fascicularis , Repeticiones de Microsatélite/genética , Reacción en Cadena de la Polimerasa/métodos , Trasplante Heterólogo/inmunología

RESUMEN

Immunosuppression remains the cause of most morbidity following organ transplantation. However, its use is also responsible for the outstanding graft and patient survival rates commonplace in modern transplantation. Thus, the predominant challenge for transplant clinicians is to provide a level of immunosuppression that prevents graft rejection while preserving immunocompetence against environmental pathogens. This review will outline several strategies for minimizing or tailoring the use of immunosuppressive drugs. The arguments for various strategies will be based on clinical trial data rather than animal studies. A distinction will be made between conventional immunosuppressive drug reduction based on over-immunosuppression, and newer induction methods specifically designed to lessen the need for chronic immunosuppression. Based on the available data we suggest that most patients can be transplanted with less immunosuppression than is currently standard.

Asunto(s)

Terapia de Inmunosupresión/métodos , Trasplante de Riñón/inmunología , Relación Dosis-Respuesta a Droga , Rechazo de Injerto/prevención & control , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Complicaciones Posoperatorias/inducido químicamente , Complicaciones Posoperatorias/epidemiología , Sirolimus/uso terapéutico