Highly purified and functionally stable in vitro expanded allospecific Tr1 cells expressing immunosuppressive graft-homing receptors as new candidates for cell therapy in solid organ transplantation.

The development of new strategies based on the use of Tr1 cells has taken relevance to induce long-term tolerance, especially in the context of allogeneic stem cell transplantation. Although Tr1 cells are currently identified by the co-expression of CD49b and LAG-3 and high production of interleukin 10 (IL-10), recent studies have shown the need for a more exhaustive characterization, including co-inhibitory and chemokines receptors expression, to ensure bona fide Tr1 cells to be used as cell therapy in solid organ transplantation. Moreover, the proinflammatory environment induced by the allograft could affect the suppressive function of Treg cells, therefore stability of Tr1 cells needs to be further investigated. Here, we establish a new protocol that allows long-term in vitro expansion of highly purified expanded allospecific Tr1 (Exp-allo Tr1). Our expanded Tr1 cell population becomes highly enriched in IL-10 producers (> 90%) and maintains high expression of CD49b and LAG-3, as well as the co-inhibitory receptors PD-1, CTLA-4, TIM-3, TIGIT and CD39. Most importantly, high dimensional analysis of Exp-allo Tr1 demonstrated a specific expression profile that distinguishes them from activated conventional T cells (T conv), showing overexpression of IL-10, CD39, CTLA-4 and LAG-3. On the other hand, Exp-allo Tr1 expressed a chemokine receptor profile relevant for allograft homing and tolerance induction including CCR2, CCR4, CCR5 and CXCR3, but lower levels of CCR7. Interestingly, Exp-allo Tr1 efficiently suppressed allospecific but not third-party T cell responses even after being expanded in the presence of proinflammatory cytokines for two extra weeks, supporting their functional stability. In summary, we demonstrate for the first time that highly purified allospecific Tr1 (Allo Tr1) cells can be efficiently expanded maintaining a stable phenotype and suppressive function with homing potential to the allograft, so they may be considered as promising therapeutic tools for solid organ transplantation.

Assessment of the Relationship Between Inflammation and Glomerular Filtration Rate.

Background: Chronic kidney disease (CKD) is a global health problem. As it progresses to end stages, renal replacement therapy is required but ultimately, the best treatment is transplantation. Decreased renal function has been associated with an inflammatory state associated to primary CKD and in kidney transplant recipients (KTRs). Objective: To establish how the serum concentrations of some cytokines, such as interleukin (IL)-2, IL-8, IL-22, IL-17α, interferon-gamma, IL-4, and transforming growth factor-ß, correlate with various CKD stages. Methods: One hundred and forty-one KTRs between the ages of 18 and 75 years were included in the study. We also included 112 live kidney donors, 37 CKD PGCKD+3, and 76 GPhealthy. Participants were grouped according to their glomerular filtration rate (GFR) and their circulating cytokine levels, previously quantified by ELISA. Results: By linear regression analysis, we established the relation of each cytokine with the GFR. Transforming growth factor-ß correlated positively with the GFR in the study population, except in healthy individuals. A negative correlation of IL-8 and IL-17α and GFR was found in all cases. Conclusions: Whether these cytokines (IL-8 and IL-17α) could be used as inflammatory biomarkers indicating CKD progression, regardless of the type of population, remains to be prospectively determined.

Contexte: L'insuffisance rénale chronique (IRC) est un problème de santé mondial. Une thérapie de remplacement rénal est nécessaire au fur et à mesure que la maladie évolue vers les stades terminaux. Mais, en définitive, le meilleur traitement reste la transplantation. La réduction de la fonction rénale a été associée à un état inflammatoire associé à l'IRC primaire; une association observée aussi chez les receveurs d'une greffe de rein. Objectif: Déterminer la façon dont les concentrations sériques de certaines cytokines, notamment IL-2, IL-8, IL-22, IL-17a, IFN-γ, IL-4 et TGF-ß, corrèlent avec divers stades de l'IRC. Méthodologie: Ont été inclus dans l'étude 141 receveurs d'une greffe rénale âgés de 18 à 75 ans, 112 donneurs vivants de rein, 37 personnes atteintes d'IRC (PGIRC+3) et 76 personnes en bonne santé (PGen santé). Les sujets ont été regroupés en fonction de leur débit de filtration glomérulaire (DFGe) et de leur taux de cytokines en circulation, quantifiés préalablement par ELISA. Résultats: Une analyse de régression linéaire a servi à établir la relation entre chaque cytokine et le DFGe. Dans la population étudiée, une corrélation positive a été observée entre TGF-ß et le DFGe, sauf chez les individus sains. Dans tous les cas, la corrélation s'est avérée négative entre le DFGe et les taux d'IL-8 et d'IL-17a. Conclusion: Il reste à déterminer prospectivement si ces cytokines (IL-8 et IL-17a) pourraient être utilisées comme biomarqueurs inflammatoires pour indiquer la progression de l'IRC, quelle que soit la population.

Chronic Kidney Disease Risk Profile in Renal Donors in Aguascalientes, Mexico: A Retrospective Cohort Study.

BACKGROUND: In the last decade, kidney donation has been recognized as a risk factor for end-stage renal disease (ESRD). ESRD risk calculators have been recently perfected in North American populations. In Mexico, the rates of overweight, obesity, and diabetes mellitus (DM) are among the highest worldwide; nevertheless, most kidney transplants are obtained from living donors. This study aims to describe the risk profile for chronic kidney disease (CKD) development in kidney donors in a highly active transplant center in Central Mexico. METHODS: We conducted a retrospective, observational, descriptive cohort study of kidney donors followed at the Hospital Centenario Miguel Hidalgo (CHMH). We used the pretransplant CKD risk calculator at 15 years and over a lifetime (www.transplantmodels.com/esrdrisk). Aside from the calculator of kidney failure risk, we also used the calculator for postdonation CKD risk (www.transplantmodels.com/donesrd/). Factors associated with a glomerular filtration rate (GFR) <60 mL/min were evaluated by univariate and multivariate analysis. RESULTS: The study included 543 donors. The average follow-up period was 1.7 years (±2.7) with a median of 0.7 years (interquartile range, 0.2-2.1). The average predicted risk for ESRD development at 15 years was 0.08% (±0.1); 25.6% had a risk >0.1%, and only 1 patient had a risk >1%. The lifetime ESRD risk was 0.62% (±0.5); 15% had a risk >1%, and the greatest risk was 3.5%. The median of patients at risk of developing postdonation ESRD was 1 in 10,000 donors (0.6-1.5) at 5 years, 5.7 in 10,000 donors (3.5-8.8) at 10 years, 15 in 10,000 donors (9.1-23.2) at 15 years, and 31 in 10,000 donors (18.9-47.7) at 20 years. During the follow-up period, 52 patients developed a GFR of <60 mL/min. Both risk estimation formulas were significantly associated with a GFR of <60 mL/min. Among the individual factors, the GFR (hazard ratio 0.96, 95% confidence interval 0.94-0.97, P < .001) and the urinary albumin to creatinine ratio (hazard ratio 1.009, 95% confidence interval 1.005-1.01, P < .001) remained statistically significant. CONCLUSION: The risk of ESRD in kidney donors in Aguascalientes, Mexico, is similar to that described in the United States. Risk calculators are an indispensable decision-making tool to better understand kidney donors in our milieu.

Highly Purified Alloantigen-Specific Tregs From Healthy and Chronic Kidney Disease Patients Can Be Long-Term Expanded, Maintaining a Suppressive Phenotype and Function in the Presence of Inflammatory Cytokines.

The adoptive transfer of alloantigen-specific regulatory T cells (alloTregs) has been proposed as a therapeutic alternative in kidney transplant recipients to the use of lifelong immunosuppressive drugs that cause serious side effects. However, the clinical application of alloTregs has been limited due to their low frequency in peripheral blood and the scarce development of efficient protocols to ensure their purity, expansion, and stability. Here, we describe a new experimental protocol that allows the long-term expansion of highly purified allospecific natural Tregs (nTregs) from both healthy controls and chronic kidney disease (CKD) patients, which maintain their phenotype and suppressive function under inflammatory conditions. Firstly, we co-cultured CellTrace Violet (CTV)-labeled Tregs from CKD patients or healthy individuals with allogeneic monocyte-derived dendritic cells in the presence of interleukin 2 (IL-2) and retinoic acid. Then, proliferating CD4+CD25hiCTV- Tregs (allospecific) were sorted by fluorescence-activated cell sorting (FACS) and polyclonally expanded with anti-CD3/CD28-coated beads in the presence of transforming growth factor beta (TGF-ß), IL-2, and rapamycin. After 4 weeks, alloTregs were expanded up to 2,300 times the initial numbers with a purity of >95% (CD4+CD25hiFOXP3+). The resulting allospecific Tregs showed high expressions of CTLA-4, LAG-3, and CD39, indicative of a highly suppressive phenotype. Accordingly, expanded alloTregs efficiently suppressed T-cell proliferation in an antigen-specific manner, even in the presence of inflammatory cytokines (IFN-γ, IL-4, IL-6, or TNF-α). Unexpectedly, the long-term expansion resulted in an increased methylation of the specific demethylated region of Foxp3. Interestingly, alloTregs from both normal individuals and CKD patients maintained their immunosuppressive phenotype and function after being expanded for two additional weeks under an inflammatory microenvironment. Finally, phenotypic and functional evaluation of cryopreserved alloTregs demonstrated the feasibility of long-term storage and supports the potential use of this cellular product for personalized Treg therapy in transplanted patients.

Fibroblast growth factor 21 is associated with increased serum total antioxidant capacity and oxidized lipoproteins in humans with different stages of chronic kidney disease.

Background and aims: Oxidative stress (OS) induces the production of fibroblast growth factor 21 (FGF21). Previous data have revealed that FGF21 protects cells from OS injury and death, making it a potential therapeutic option for many diseases with increased OS. However, the association of this growth factor with OS markers in humans with chronic kidney disease (CKD) remains unknown. This study aims to evaluate the association of serum FGF21 with serum total antioxidant capacity (TAC) and oxidized low-density lipoproteins (OxLDL) in subjects in different stages of kidney disease. Methods: This is a cross-sectional study that included 382 subjects with different stages of CKD, irrespective of type 2 diabetes (T2D) diagnosis. Associations of serum FGF21 with OxLDL, TAC, sex, age, body mass index (BMI), fasting plasma glucose, estimated glomerular filtration rate (eGFR), T2D, and smoking, were evaluated through bivariate and partial correlation analyses. Independent associations of these variables with serum FGF21 were evaluated using multiple linear regression analysis. Results: Serum FGF21 was significantly and positively correlated with age (r = 0.236), TAC (lnTAC) (r = 0.217), and negatively correlated with eGFR (r = -0.429) and male sex (r = -0.102). After controlling by age, sex, BMI, T2D, smoking, and eGFR; both TAC and OxLDL were positively correlated with FGF21 (r = 0.117 and 0.158 respectively, p < 0.05). Using multiple linear regression analysis, eGFR, male sex, T2D, OxLDL, and TAC were independently associated with serum FGF21 (STDß = -0.475, 0.162, -0.153, 0.142 and 0.136 respectively; p < 0.05 for all) adjusted for age, BMI, smoking, and fasting plasma glucose. Conclusion: A positive association between serum FGF21 and OS has been found independently of renal function in humans. Results from the present study provide novel information for deeper understanding of the role of FGF21 in OS in humans with CKD and T2D; mechanistic studies to explain the association of serum FGF21 with oxidative stress in CKD are needed.

Large-Scale Generation of Human Allospecific Induced Tregs With Functional Stability for Use in Immunotherapy in Transplantation.

Regulatory T cells play an important role in the control of autoimmune diseases and maintenance of tolerance. In the context of transplantation, regulatory T cells (Tregs) have been proposed as new therapeutic tools that may induce allospecific tolerance toward the graft, avoiding the side effects induced by generalized immunosuppressors. Although most clinical trials are based on the use of thymic Tregs in adoptive therapy, some reports suggest the potential use of in vitro induced Tregs (iTregs), based on their functional stability under inflammatory conditions, indicating an advantage in a setting of allograft rejection. The aim of this work was to generate and expand large numbers of allospecific Tregs that maintain stable suppressive function in the presence of pro-inflammatory cytokines. Dendritic cells were derived from monocytes isolated from healthy donors and were co-cultured with CTV-labeled naïve T cells from unrelated individuals, in the presence of TGF-ß1, IL-2, and retinoic acid. After 7 days of co-culture, proliferating CD4+CD25++CTV- cells (allospecific iTregs) were sorted and polyclonally expanded for 6 weeks in the presence of TGF-ß1, IL-2, and rapamycin. After 6 weeks of polyclonal activation, iTregs were expanded 230,000 times, giving rise to 4,600 million allospecific iTregs. Allospecific iTregs were able to specifically suppress the proliferation of autologous CD4+ and CD8+ T cells in response to the allo-MoDCs used for iTreg generation, but not to third-party allo-MoDCs. Importantly, 88.5% of the expanded cells were CD4+CD25+FOXP3+, expressed high levels of CCR4 and CXCR3, and maintained their phenotype and suppressive function in the presence of TNF-α and IL-6. Finally, analysis of the methylation status of the FOXP3 TSDR locus demonstrated a 40% demethylation in the purified allospecific iTreg, prior to the polyclonal expansion. Interestingly, the phenotype and suppressive activity of expanded allospecific iTregs were maintained after 6 weeks of expansion, despite an increase in the methylation status of the FOXP3 TSDR. In conclusion, this is the first report that demonstrates a large-scale generation of allospecific iTregs that preserve a stable phenotype and suppressor function in the presence of pro-inflammatory cytokines and pave the way for adoptive cell therapy with iTregs in transplanted patients.

Bilateral Proximal Forearm Transplantation: Case Report at 7 Years.

BACKGROUND: Although return of function has been reported in patients undergoing proximal forearm transplantations (PFTs), reports of long-term function are limited. In this study, we evaluated the clinical progress and function 7 years postoperatively in a patient who underwent bilateral PFT. CASE PRESENTATION: A 58-year-old man underwent bilateral PFT in May 2012. Transplantation involved all of the flexor and extensor muscles of the forearm. Neurorrhaphies of the median, ulnar, and radial nerves were epineural and 7 cm proximal to the elbow. Immunosuppressive maintenance medications during the first 3 years postoperatively were tacrolimus, mycophenolate, and steroids, and later, tacrolimus, sirolimus, and steroids. Forearm function was evaluated annually using the Disabilities of the Arm, Shoulder, and Hand; Carroll; Hand Transplantation Score System; Short Form-36; and Kapandji scales. We also evaluated his grip and pinch force. RESULTS: Postoperatively, the patient developed hypertriglyceridemia and systemic hypertension. He experienced 6 acute rejections, and none were resistant to steroids. Motor function findings in his right/left hand were: grip strength: 10/13 kg; key pinch: 3/3 kg; Kapandji score: 6/9 of 10; Carroll score: 66/80; Hand Transplantation Score System score: 90/94. His preoperative Disabilities of the Arm, Shoulder, and Hand score was 50 versus 18, postoperatively; his Short Form-36 score was 90. This function improved in relation with the function reported in the second year. CONCLUSIONS: Seven years following PFT, the patient gained limb strength with a functional elbow and wrist, although with diminished digital dexterity and sensation. Based on data presented by other programs and our own experience, PFT is indicated for select patients.

II. THE RESEARCH ETHICS INVOLVING VULNERABLE GROUPS.

Vulnerability in research occurs when the participant is incapable of protecting his or her interests and therefore, has an increased probability of being intentionally or unintentionally harmed. This manuscript aims to discuss the conditions that make a group vulnerable and the tools and requirements that can be used to reduce the ethical breaches when including them in research protocols. The vulnerability can be due either to an inability to understand and give informed consent or to unequal power relationships that hinder basic rights. Excluding subjects from research for the only reason of belonging to a vulnerable group is unethical and will bias the results of the investigation. To consider a subject or group as vulnerable depends on the context, and the investigator should evaluate each case individually.

II. The research ethics involving vulnerable groups

Abstract Vulnerability in research occurs when the participant is incapable of protecting his or her interests and therefore, has an increased probability of being intentionally or unintentionally harmed. This manuscript aims to discuss the conditions that make a group vulnerable and the tools and requirements that can be used to reduce the ethical breaches when including them in research protocols. The vulnerability can be due either to an inability to understand and give informed consent or to unequal power relationships that hinder basic rights. Excluding subjects from research for the only reason of belonging to a vulnerable group is unethical and will bias the results of the investigation. To consider a subject or group as vulnerable depends on the context, and the investigator should evaluate each case individually.

I. THE ROLE OF RESEARCH ETHICS COMMITTEES IN OBSERVATIONAL STUDIES: EPIDEMIOLOGICAL REGISTRIES, CASE REPORTS, INTERVIEWS, AND RETROSPECTIVE STUDIES.

It is often unclear to the clinical investigator whether observational studies should be submitted to a research ethics committee (REC), mostly because, in general, no active or additional interventions are performed. Moreover, obtaining an informed consent under these circumstances may be challenging, either because these are very large epidemiological registries, or the subject may no longer be alive, is too ill to consent, or is impossible to contact after being discharged. Although observational studies do not involve interventions, they entail ethical concerns, including threats such as breaches in confidentiality and autonomy, and respect for basic rights of the research subjects according to the good clinical practices. In this context, in addition to their main function as evaluators from an ethical, methodological, and regulatory point of view, the RECs serve as mediators between the research subjects, looking after their basic rights, and the investigator or institution, safeguarding them from both legal and unethical perils that the investigation could engage, by ensuring that all procedures are performed following the international standards of care for research. The aim of this manuscript is to provide information on each type of study and its risks, along with actions to prevent such risks, and the function of RECs in each type of study.

I. The role of research ethics committees in observational studies: epidemiological registries, case reports, interviews, and retrospective studies

Abstract It is often unclear to the clinical investigator whether observational studies should be submitted to a research ethics committee (REC), mostly because, in general, no active or additional interventions are performed. Moreover, obtaining an informed consent under these circumstances may be challenging, either because these are very large epidemiological registries, or the subject may no longer be alive, is too ill to consent, or is impossible to contact after being discharged. Although observational studies do not involve interventions, they entail ethical concerns, including threats such as breaches in confidentiality and autonomy, and respect for basic rights of the research subjects according to the good clinical practices. In this context, in addition to their main function as evaluators from an ethical, methodological, and regulatory point of view, the RECs serve as mediators between the research subjects, looking after their basic rights, and the investigator or institution, safeguarding them from both legal and unethical perils that the investigation could engage, by ensuring that all procedures are performed following the international standards of care for research. The aim of this manuscript is to provide information on each type of study and its risks, along with actions to prevent such risks, and the function of RECs in each type of study.

Is delayed graft function associated with ureteral stenosis in the kidney transplant recipient? A case-control study.

INTRODUCTION: Ureteral stricture (US) in the kidney transplant recipient is a rare complication that can lead to morbidity and graft loss. Risk factor recognition is crucial in the prevention and management of this entity. Delayed graft function (DGF), as defined by the need for dialysis in the first week after transplantation, has been proposed as a risk factor in previous studies. Our objective is to determine the impact of DGF in US development in kidney transplant patients. METHODS: We designed a matched case-control study. US cases in kidney transplant recipients were identified in the 2008-2017 period. We defined US as the rise in serum creatinine associated with findings suggesting obstruction in ultrasound, scintigraphy, or retrograde pyelogram; any other cause of graft dysfunction was excluded. Controls were defined as kidney transplant recipients from the same population and period without US, matched in a 1:2 fashion by age, sex, and donor type. RESULTS: From 532 kidney transplant patients, 31 cases and 62 controls were included. Cumulative US incidence was 58 per 1000 cases. When calculating for odds ratio (OR), post-operative urinoma (OR 3.2; 95% confidence interval [CI] 2.36-4.37) and ureteral duplication (OR 3.29; 95% CI 2.40-4.51) were associated with an increased risk for US, while DGF was not found to be statistically significant as a risk factor (OR 3.3; 95% CI 0.96-11.52). No statistically significant differences were found between groups in other pre- and post-transplant-related factors CONCLUSIONS:: DGF was not associated with US in our cohort; however, ureteral duplication and postoperative urinoma were associated with an increased risk of graft ureteral stenosis development.

Acute Appendicitis After Kidney Transplantation: Experience at a Tertiary Care Hospital in Mexico City.

OBJECTIVES: Here, we describe the presentation, treatment, and outcomes of acute appendicitis in kidney transplant recipients at a tertiary care hospital in Mexico City. MATERIALS AND METHODS: We conducted a retrospective case series study at a tertiary care hospital in Mexico City from January 2000 to January 2015. RESULTS: During our study period, 1186 patients received a kidney transplant; among these patients, we identified 10 cases of acute appendicitis (0.008%). Four patients (40%) were diagnosed on day 5 of symptom onset. Nine patients (90%) showed abdominal pain, 2 patients (20%) presented with a typical migratory pattern, and 2 patients (20%) showed symptoms of small bowel intestinal obstruction. Thirty percent of patients (3/10) presented a rule-out Alvarado score (≤ 3 points). A computed tomography scan was performed in all but one patient; among these 9 patients, 1 (11.1%) had a false-negative result. Among all patients with acute appendicitis, 50% (5/10) presented with a periappendiceal abscess and 40% (4/10) showed localized peritonitis. An open and laparoscopic appendectomy was performed in 7 of 10 patients (70%) and 3 of 10 patients (30%), respectively. All patients received ceftriaxone plus metronidazole or ertapenem for 5 to 7 days. There were no reported treatment failures or recurrence of symptoms. CONCLUSIONS: The diagnosis of acute appendicitis in kidney transplant recipients requires a high index of suspicion. Kidney transplant recipients with acute appendicitis had good outcomes with a therapeutic approach similar to that used in the general population.

[Donor/recipient age index (DoRAIn) as an independent predictor of long-term living-donor renal graft function]. / Índice de edad donador/receptor (DoRAIn) como un predictor independiente de la función del injerto de donante vivo renal a largo plazo.

PROBLEM: The effect of donor/recipient age disparity on living-donor renal graft function is controversial. The objective of this study is to find new clinical predictors of renal graft function and evaluate the effect of donor/recipient age disparity in our series. METHODS: A retrospective review of our institutional renal transplantation database was performed. We calculated the glomerular filtration rate of our patients with the Chronic Kidney Disease Epidemiology Collaboration formula. Our receptors were categorized using a cut-off of 60 ml/min calculated glomerular filtration rate. An index called "Donor/Recipient Age Index" was created based on the interaction between donor/recipient ages. Univariable and multivariable regression analysis were performed. The Mantel-Cox model was used for statistical analysis. RESULTS: A total of 220 donor/recipient pairs were selected from January 2005 to August 2013. Only 186 pairs completed the one-year follow-up. The mean age of the donors was 35.3 ± 10.4 years and 31.6 ± 11.7 years for the recipients. The Donor/Recipient Age Index significantly predicted a glomerular filtration rate < 60 ml/min at one-year follow-up in univariable (p = 0.02) and multivariable (p = 0.033) regression models. CONCLUSION: We propose the Donor/Recipient Age Index as a significant predictor of long-term graft function.

[The impact of donor-to-recipient gender match and mismatch on the renal function of living donor renal graft recipients]. / Compatibilidad de género entre donador y receptor puede ser un factor pronóstico en la funcióndel injerto de trasplante renal de donador vivo.

INTRODUCTION: Donor-to-recipient gender match and mismatch may be a potential prognostic factor for living donor renal graft function. METHODS: A retrospective review of donor-to-recipient pairs undergoing living donor kidney transplantation was done. They were classified according to gender match as: male-to-male, female-to-female, male-to-female, and female-to-male. Serum creatinine was recorded during one year for donors and for up to four years for recipients. Renal function was evaluated by estimating the glomerular filtration rate with the Chronic Kidney Disease-Epidemiology Collaboration formula. A comparative statistical analysis was performed. RESULTS: The analysis included 217 donor-to-recipient pairs. No significant differences across the four groups in estimated glomerular filtration rate and serum creatinine at any cut-off time point except at day one serum creatinine were found. Recipients had a significant difference in serum creatinine up to the first year of follow-up, with higher values for male recipients; no significant differences were found during the second through fourth year of follow-up. A significant difference was observed in estimated glomerular filtration rate throughout all follow-ups among the four groups, favoring female recipients of male kidneys. CONCLUSIONS: Donor-recipient mismatch may have a deleterious effect over long-term graft function. Female recipients of male kidneys have the best prognosis.

Bilateral Forearm Transplantation in Mexico: 2-Year Outcomes.

BACKGROUND: Patients with proximal forearm and arm transplantation have obtained and/or maintained function of the elbow joint and full active range of motion of the extrinsic muscles of the hand, but with diminished protective sensibility and a lack of good function of the intrinsic muscles. These patients have improved function, as measured by the Disabilities of the Arm, Shoulder and Hand questionnaire. METHODS: We report the case of a 52-year-old man who suffered a high-voltage electrical burn requiring amputation of his upper limbs. He underwent bilateral proximal forearm transplantation in Mexico City in May 2012. RESULTS: At 2-year follow-up, immunosuppressive treatment has not led to metabolic, oncologic, or infectious complications. Keloid scars developed at the graft-recipient interface. There have been 4 acute rejections: the fourth was treated with methylprednisolone, rituximab, and immunoglobulin. Chronic rejection has not been detected. The extrinsic muscles of the wrist and digits have good function. Although the intrinsic muscles demonstrated electrical activity 15 months postoperatively, clinically, they are nonuseful. After 2 years, hand function is sufficient to allow the patient to grasp lightweight and medium-sized objects. The patient's Disabilities of the Arm, Shoulder and Hand questionnaire score improved from 50.00 points to 30.83 points, and his Hand Transplantation Score System rating is good, at 69/73 (right/left) of 100. The patient and his family are very satisfied with the functional and aesthetic outcomes. CONCLUSIONS: Upper arm or proximal forearm transplantation is a reconstructive option for patients who have experienced amputation because of trauma.

[Patients with solid organ transplantation and skin cancer: determination of risk factors with emphasis in photoexposure and immunosuppressive regimen. Experience in a third level hospital]. / Pacientes con trasplante de órgano sólido y cáncer de piel: determinación de factores de riesgo con énfasis en la fotoexposición y el esquema inmunosupresor. Experiencia de un hospital de tercer nivel.

BACKGROUND: Non-melanoma skin cancer (NMSC) is the most common malignancy in transplant patients. The incidence of basal cell carcinoma (BCC) is 10 times greater than in the general population, while squamous cell carcinoma (SCC) is 100 times greater. The relationship between the BCC and SCC reverses and increases according to the degree of immunosuppression and sun exposure. One way to predict the risk of NMSC should be based on factors such as: total sun burden factor (TSB). OBJECTIVE: To determine the influence of various risk factors in the development of NMSC and its relation to the type and duration of immunosuppressive treatment, type of transplant, and TSB. METHODS: We worked with a fledgling historical cohort in which patients with kidney or liver transplant were identified and recorded if they developed some form of skin cancer. To study the factors associated with NMSC, we resorted to the strategy of a case-control study. Dermatological examination was performed and a questionnaire of risk factors made in both groups. RESULTS: Of the 140 patients enrolled, 51 were women and 89 men, 120 were renal transplant recipients and 20 liver transplants. Of patients who developed NMSC, 100% were renal transplant recipients. The median age was 48.5 years. Most cancer patients worked outdoors. A total of 78 lesions were found in 40 NMSC patients, 59 (76%) of them were SCC, and 19 (24%) BCC; 45% of all skin cancer patients had more than one injury. The worst affected areas were those photoexposed: 60% head and neck, trunk and upper extremities 18% 50%. In 30% of patients (12/40) 22 new tumors were identified (SCC 18 and BCC 4). No lesions were identified for melanoma. In multivariate logistic regression analysis, statistically significant features were: type-based immunosuppressive regimen of cyclosporine A, azathioprine and prednisone (OR: 59.7; 95% CI: 10.2-348), TSB > 10 (OR: 19; 95% CI: 3-120) and duration of use of immunosuppressive therapy (OR: 1.06; 95% CI: 0.9-1.1). The mean time from transplantation to first dermatological assessment was six years (+5.4). Of the patients, 93% had not regularly used sunscreen before and after transplantation. CONCLUSIONS: The dermatological assessment is convenient and easy to perform. Primary prevention, close monitoring, diagnosis, and treatment of skin lesions are essential components of a comprehensive program for the evaluation of transplant recipients, the purpose of which is to reduce the incidence and morbidity associated with cancer.

Trasplantes en mmérica latina y el caribe: difusión del documento de aguascalientes / Transplants n laatin america and the caribbean: release of the aguascalientes document / Transpantes na aamérica latina e no caribe: difusão do documento de aguascaiientes

Durante el primer Foro de Bioética de la Sociedad de Trasplantes de Latinoamérica y el Caribe 2010 se redactó el Documento de Aguascalientes que busca salvaguardar la integridad del donante vivo. El artículo tiene por objeto indagar sobre el Documento de Aguascalientes entre los participantes del Congreso de la SLANH 2012. Se aplicó un cuestionario con 21 preguntas sobre temas abordados por el dicho documento. Los resultados muestran que el 36,3% acepta al donante vivo no relacionado; 36,3% considera que hay margen de crecimiento en la tasa de donantes fallecidos; 57,9% garantiza la salud con medicamentos inmunosupresores de calidad; 61,5% no conoce el documento. Se concluye que el Documento de Aguascalientes tiene recomendaciones útiles para vigilar aspectos bioéticos de trasplantes.

The Aguascalientes Document was drafted during the first 2010 Bioethics Forum of the Transplantation Society in Latin America and the Caribbean. The object of the document is to safeguard the integrity of the living donor. This article aims to investigate the Aguascalientes Document among the participants to the 2012 SLANH Congress. A questionnaire was applied, with 21 questions on topics covered by said document. The results show that 36.3% of the respondents accepts the unrelated living donor; 36.3% believes there is a margin of growth in the rate of deceased donors; 57.9% guarantees health with quality immunosuppressive drugs; 61.5% does not know the document. In view of the above, it is concluded that the Aguascalientes Document contains useful recommendations for monitoring the bioethical aspects of transplants.

Durante o primeiro Fórum de Bioética da Sociedade de Transplantes da América Latina e do Caribe 2010, redigiu-se o Documento de Aguascalientes, que pretende assegurar a integridade do doador vivo. O artigo tem por objetivo indagar sobre o Documento de Aguascalientes entre os participantes do Congresso da SLANH 2012. Aplicou-se um questionário com 21 perguntas sobre temas abordados por tal documento. Os resultados mostram que 36,3% aceitam o doador vivo não relacionado; 36,3% consideram que há margem de crescimento na taxa de doadores falecidos; 57,9% garantem a saúde com medicamentos imunossupressores de qualidade; 61,5% não conhecem o documento. Conclui-se que o Documento de Aguascalientes tem recomendações úteis para vigiar aspectos bioéticos de transplantes.

[Incidence of acute rejection in patients with renal graft dysfunction]. / [Incidencia de rechazo agudo en pacientes con disfunción del injerto renal].

INTRODUCTION: Acute rejection has been identified as the main cause of renal graft dysfunction during the first year after transplantation; it is associated with chronic structural and functional damage, which causes loss of graft and decrease in patient survival. MATERIAL AND METHODS: We performed a retrospective and descriptive research consisting in a review of the final reports of biopsies performed due to renal graft dysfunction during the postransplant period. Patients included were transplanted at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ) from January 2007 to December 2011. RESULTS: A total number of 223 patients underwent renal transplantation during the period considered for this study purpose, 222 biopsies were performed due to renal graft dysfunction in 118 patients (52.9%). 74.5% of patients developed graft dysfunction in the first year after transplantation. The main histopathological findings reported were immunologic events in both living donor (LDRTR) and deceased donor renal transplant recipients (DDRTR), borderline changes were the most common diagnosis. The median time to detect immune events as cause of dysfunction was shorter for DDRTR and they tend to occur in the first 4 months after transplantation. CONCLUSION: We observed an incidence of 11.8% for acute rejection in the first year after transplantation for LDRTR and 17.4% for DDRTR. Further studies are needed to determine the causes of immunological events and their implications in the evolution of renal graft and patient's survival.