Methylation of FOXP3 TSDR Underlies the Impaired Suppressive Function of Tregs from Long-term Belatacept-Treated Kidney Transplant Patients.

Regulatory T cells (Tregs) are considered key players in the prevention of allograft rejection in transplanted patients. Belatacept (BLT) is an effective alternative to calcineurin inhibitors that appears to preserve graft survival and function; however, the impact of this drug in the homeostasis of Tregs in transplanted patients remains controversial. Here, we analyzed the phenotype, function, and the epigenetic status of the Treg-specific demethylated region (TSDR) in FOXP3 of circulating Tregs from long-term kidney transplant patients under BLT or Cyclosporine A treatment. We found a significant reduction in the proportion of CD4+CD25hiCD127lo/-FOXP3+ T cells in all patients compared to healthy individual (controls). Interestingly, only BLT-treated patients displayed an enrichment of the CD45RA+ "naïve" Tregs, while the expression of Helios, a marker used to identify stable FOXP3+ thymic Tregs remained unaffected. Functional analysis demonstrated that Tregs from transplanted patients displayed a significant reduction in their suppressive capacity compared to Tregs from controls, which is associated with decreased levels of FOXP3 and CD25. Analysis of the methylation status of the FOXP3 gene showed that BLT treatment results in methylation of CpG islands within the TSDR, which could be associated with the impaired Treg suppression function. Our data indicate that analysis of circulating Tregs cannot be used as a marker for assessing tolerance toward the allograft in long-term kidney transplant patients. Trial registration number IM103008.

Belatacept and Long-Term Outcomes in Kidney Transplantation.

BACKGROUND: In previous analyses of BENEFIT, a phase 3 study, belatacept-based immunosuppression, as compared with cyclosporine-based immunosuppression, was associated with similar patient and graft survival and significantly improved renal function in kidney-transplant recipients. Here we present the final results from this study. METHODS: We randomly assigned kidney-transplant recipients to a more-intensive belatacept regimen, a less-intensive belatacept regimen, or a cyclosporine regimen. Efficacy and safety outcomes for all patients who underwent randomization and transplantation were analyzed at year 7 (month 84). RESULTS: A total of 666 participants were randomly assigned to a study group and underwent transplantation. Of the 660 patients who were treated, 153 of the 219 patients treated with the more-intensive belatacept regimen, 163 of the 226 treated with the less-intensive belatacept regimen, and 131 of the 215 treated with the cyclosporine regimen were followed for the full 84-month period; all available data were used in the analysis. A 43% reduction in the risk of death or graft loss was observed for both the more-intensive and the less-intensive belatacept regimens as compared with the cyclosporine regimen (hazard ratio with the more-intensive regimen, 0.57; 95% confidence interval [CI], 0.35 to 0.95; P=0.02; hazard ratio with the less-intensive regimen, 0.57; 95% CI, 0.35 to 0.94; P=0.02), with equal contributions from the lower rates of death and graft loss. The mean estimated glomerular filtration rate (eGFR) increased over the 7-year period with both belatacept regimens but declined with the cyclosporine regimen. The cumulative frequencies of serious adverse events at month 84 were similar across treatment groups. CONCLUSIONS: Seven years after transplantation, patient and graft survival and the mean eGFR were significantly higher with belatacept (both the more-intensive regimen and the less-intensive regimen) than with cyclosporine. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00256750.).

[Kidney transplant program: Mexican Institute of Transplants. Model of synergy between private hospital and private assistance foundations]. / Programa de trasplante renal: Instituto Mexicano de Trasplantes. Modelo de sinergia entre hospital privado y fundaciones de asistencia privada.

INTRODUCTION: The Mexican Institute of Transplantation (IMT) was created in 1999 in response to the need to meet the demand for transplants in the south of the country for patients with limited resources. Thanks to the synergy with private assistance foundations this task has been accomplished. OBJECTIVE: To describe the IMT experience in kidney transplants. RESULTS: From November 1999 to May 23,2011, 754 kidney transplants were performed in the IMT, of which 733 were from living donors and only 21 from deceased donors. In our experience, the 10-year patient and graft survival were 84.4 and 72.4%, respectively. The average follow-up of patients was 44 months, it was during the first year after transplantation when most of patients were lost. More than 50% of patients have been supported by private assistance foundations. The IMT has participated in research protocols for phase II and phase III, for the development of new immunosuppressants. CONCLUSION: The synergy between our private medical institution and private assistance foundations has permitted to transplant low income patients, a similar association can be carried out in governmental health institutions that have overcharge in their transplant services.

[Determination of creatinine in drained liquid. Urinary leak or lymphocele?]. / Diagnóstico de colecciones líquidas postrasplante renal. ¿Fuga urinaria o linfocele?

BACKGROUND: Liquid collections around the renal graft that are displayed in 51% of cases implicate a diagnostic challenge and a risk for graft function. We undertook this study to determine the usefulness of creatinine concentration measurement in drainage in patients with renal transplantation. METHODS: We selected patients with surgically corrected urinary leak and patients with lymphocele from November 1, 1999, to November 30, 2008, in whom we determined the creatinine concentration in liquid drainage, plasma and urine. RESULTS: We included five patients with urinary leak and six patients with lymphocele. Two patients had urinary leak before the lymphocele. The t value of the plasma creatinine (Pcreat), drainage (Dcreat) and urine (Ucreat) was 0.89, 0.045 and 0.63, respectively. The diagnostic criteria of urinary leak represented a value between the creatinine of the drainage and plasma (D/Pcreat) >6, between urine and drainage (U/Dcreat) <3 and between urine and plasma (U/ Pcreat) <7. When we compared both groups the χ(2) values were 0.018, 0.007 and 0.094, respectively. CONCLUSIONS: There is a statistically significant difference among the creatinine drainage liquid values. Our study shows that D/Pcreat ratio >6 after the first week or U/Dcreat ratio <3 at any time during the postoperative period represents a six-times higher possibility of urinary leak.

Desensitization and renal transplant: plasmapheresis/IVIG standard dose in patients with high immunological risk.

BACKGROUND: Patients with high immunological risk have been relegated to the growing waiting list for an immunologically compatible donor. Our objective was to report the experience of a transplant center in desensitization of patients with high immunological risk. METHODS: We carried out a descriptive and retrospective study. Included were all the renal transplant patients from November 1999 to January 2008 in which we used plasmapheresis and standard dose of intravenous immunoglobulin (IVIG) as desensitization. RESULTS: Eight patients had history of alloimmunity (positive crossmatch or high panel-reactive antibodies (PRA >30%). Desensitization was accomplished with plasmapheresis and exchange of 1.5 plasma volume. Subsequent to each session we administered a standard dose of IVIG (5 g/dose). Immunosuppression began equal to the first plasmapheresis with calcineurin inhibitor (tacrolimus) plus six patients with mycophenolate mofetil and two patients with sirolimus. In seven cases, negative crossmatches were obtained before the transplantation, except in the eighth case in whom it was not done. Two patients received human antibodies against CD25 (basiliximab, 20 mg/dose). During their evolution, all patients maintained stable graft function. CONCLUSIONS: According to our experience, renal graft outcome in patients with high immunological risk after an adequate desensitization protocol is similar to that observed in nonsensitized patients, at least during the first year of transplantation.

Desensibilización y trasplante renal: plasmaféresis-IVIG a dosis estándar en pacientes con alto riesgo inmunológico / Desensitization and renal transplant: plasmapheresis/IVIG standard dose in patients with high immunological risk

Introducción: Los pacientes con alto riesgo inmunológico siguen siendo relegados a la cada vez más larga lista de espera de un donador inmunológicamente compatible. El objetivo de esta comunicación es informar la experiencia de un centro de trasplantes en la desensibilización de pacientes con alto riesgo inmunológico. Material y métodos: Estudio descriptivo y retrospectivo de todos los pacientes sometidos a trasplante renal de noviembre de 1999 a enero de 2008, en quienes se llevó a cabo desensibilización pretrasplante renal. Resultados: Ocho pacientes presentaron aloinmunización (pruebas cruzadas positivas o panel reactivo de anticuerpos alto, PRA > 30 %). La desensibilización se realizó mediante sesiones de plasmaféresis con recambio de 1.5 volúmenes plasmáticos, y posterior a cada una se administró una dosis estándar de inmunoglubulina intravenosa (IVIG 5 g/dosis). La inmunosupresión se inició en la primera sesión de plasmaféresis con base en un inhibidor de calcineurinas (tacrolimus); en seis pacientes se añadió mofetil micofenolato y en dos, sirolimus. En siete se obtuvieron pruebas cruzadas negativas con el donador previo al trasplante; en el octavo no se efectuaron. En dos se administró anticuerpos humanizados contra CD25 (20 mg/dosis de basiliximab). Todos los pacientes han mantenido función estable del injerto. Conclusiones: De acuerdo con nuestra experiencia, la sobrevida del injerto renal en pacientes con alto riesgo inmunológico posterior a un adecuado protocolo de desensibilización y estrecha vigilancia postrasplante es similar a la observada en pacientes no sensibilizados, al menos durante el primer año del trasplante.

BACKGROUND: Patients with high immunological risk have been relegated to the growing waiting list for an immunologically compatible donor. Our objective was to report the experience of a transplant center in desensitization of patients with high immunological risk. METHODS: We carried out a descriptive and retrospective study. Included were all the renal transplant patients from November 1999 to January 2008 in which we used plasmapheresis and standard dose of intravenous immunoglobulin (IVIG) as desensitization. RESULTS: Eight patients had history of alloimmunity (positive crossmatch or high panel-reactive antibodies (PRA >30%). Desensitization was accomplished with plasmapheresis and exchange of 1.5 plasma volume. Subsequent to each session we administered a standard dose of IVIG (5 g/dose). Immunosuppression began equal to the first plasmapheresis with calcineurin inhibitor (tacrolimus) plus six patients with mycophenolate mofetil and two patients with sirolimus. In seven cases, negative crossmatches were obtained before the transplantation, except in the eighth case in whom it was not done. Two patients received human antibodies against CD25 (basiliximab, 20 mg/dose). During their evolution, all patients maintained stable graft function. CONCLUSIONS: According to our experience, renal graft outcome in patients with high immunological risk after an adequate desensitization protocol is similar to that observed in nonsensitized patients, at least during the first year of transplantation.

Hipersecreción gástrica en la pancreatoduodeneeectomía / Gastric hypersecretion in pancreatoduodenectomy

La pancreatoduodenectomía, conocida como operación de Whipple se realiza principalmente para el tratamiento de tumores malignos de la encrucijada biliopanjcreatoduodenal. Existe, en la actualidad, controversia en cuanto a las causas que condicionan sugieren un factor vagal importante en la génesis de las lesiones pépticas que acompañan a este procedimiento quirúrgico. En el presente trabajo se analizan los resultados obtenidos en dos grupos de perros tratados con operación de Whipple; uno sin y otro con vagotomía troncular añadida. Encontramos úlcera péptica marginal en el 78 y 14% de los casos y perforación en 44 y 0% de los mismos, respectivamente. Estos resultados y el análisis de otros hallazgos, sugieren la importancia de practicar vagotomía troncular añadida a la pancreatoduodenectomía, como medida preventiva en la producción de úlcera péptica marginal y sus complicaciones