Journal: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
Prolonged hypothermic storage causes ischemia-reperfusion injury (IRI) in the renal graft, which is considered to contribute to the occurrence of the delayed graft function (DGF) and chronic graft failure. Strategies are required to protect the graft and to prolong renal graft survival. We demonstrated that xenon exposure to human proximal tubular cells (HK-2) led to activation of range of protective proteins. Xenon treatment prior to or after hypothermia-hypoxia challenge stabilized the HK-2 cellular structure, diminished cytoplasmic translocation of high-mobility group box (HMGB) 1 and suppressed NF-κB activation. In the syngeneic Lewis-to-Lewis rat model of kidney transplantation, xenon exposure to donors before graft retrieval or to recipients after engraftment decreased caspase-3 expression, localized HMGB-1 within nuclei and prevented TLR-4/NF-κB activation in tubular cells; serum pro-inflammatory cytokines IL-1β, IL-6 and TNF-α were reduced and renal function was preserved. Xenon treatment of graft donors or of recipients prolonged renal graft survival following IRI in both Lewis-to-Lewis isografts and Fischer-to-Lewis allografts. Xenon induced cell survival or graft functional recovery was abolished by HIF-1α siRNA. Our data suggest that xenon treatment attenuates DGF and enhances graft survival. This approach could be translated into clinical practice leading to a considerable improvement in long-term graft survival.
In heart transplant (HTx) recipients, there has been reluctance to recommend high-intensity interval training (HIIT) due to denervation and chronotropic impairment of the heart. We compared the effects of 12 weeks' HIIT versus continued moderate exercise (CON) on exercise capacity and chronotropic response in stable HTx recipients >12 months after transplantation in a randomized crossover trial. The study was completed by 16 HTx recipients (mean age 52 years, 75% males). Baseline peak oxygen uptake (VO2peak ) was 22.9 mL/kg/min. HIIT increased VO2peak by 4.9 ± 2.7 mL/min/kg (17%) and CON by 2.6 ± 2.2 mL/kg/min (10%) (significantly higher in HIIT; p < 0.001). During HIIT, systolic blood pressure decreased significantly (p = 0.037) with no significant change in CON (p = 0.241; between group difference p = 0.027). Peak heart rate (HRpeak ) increased significantly by 4.3 beats per minute (p = 0.014) after HIIT with no significant change in CON (p = 0.34; between group difference p = 0.027). Heart rate recovery (HRrecovery ) improved in both groups with a trend toward greater improvement after HIIT. The 5-month washout showed a significant loss of improvement. HIIT was well tolerated, had a superior effect on oxygen uptake, and led to an unexpected increase in HRpeak accompanied by a faster HRrecovery . This indicates that the benefits of HIIT are partly a result of improved chronotropic response.
In a cross-sectional study, we assessed effects of calcineurin inhibitor (CNI) or rapamycin on T-regulatory (Treg) cells from children with stable liver (n = 53) or kidney (n = 9) allografts several years posttransplant. We analyzed Treg number, phenotype, suppressive function, and methylation at the Treg-specific demethylation region (TSDR) using Tregs and peripheral blood mononuclear cells. Forty-eight patients received CNI (39 as monotherapy) and 12 patients received rapamycin (9 as monotherapy). Treg numbers diminished over time on either regimen, but reached significance only with CNI (r =-0.424, p = 0.017). CNI levels inversely correlated with Treg number (r =-0.371, p = 0.026), and positively correlated with CD127+ expression by Tregs (r = 0.437, p = 0.023). Patients with CNI levels >3.6 ng/mL had weaker Treg function than those with levels <3.6 ng/mL, whereas rapamycin therapy positively correlated with Treg numbers (r = 0.628, p = 0.029) and their expression of CTLA4 (r = 0.726, p = 0.041). Overall, CTLA4 expression, TSDR demethylation and an absence of CD127 were important for Treg suppressive function. We conclude that rapamycin has beneficial effects on Treg biology, whereas long-term and high dose CNI use may impair Treg number, function and phenotype, potentially acting as a barrier to attaining host hyporesponsiveness to an allograft.
Bronchiolitis obliterans syndrome (BOS), a condition of irreversible small airway fibrosis, is the principal factor limiting long-term survival after lung transplantation. Bronchoscopy and bronchoalveolar lavage (BAL), techniques central to lung transplant clinical practice, provide a unique opportunity to interrogate the lung allograft during BOS development and identify potential disease mechanisms or biomarkers. Over the past 20 years, numerous studies have evaluated the BAL cellular composition, cytokine profiles and protein constituents in lung transplant recipients with BOS. To date, however, no summative evaluation of this literature has been reported. We developed and applied objective criteria to qualitatively rank the strength of associations between BAL parameters and BOS in order to provide a comprehensive and systematic assessment of the literature. Our analysis indicates that several BAL parameters, including neutrophil count, interleukin-8, alpha defensins and MMP-9, demonstrate highly replicable associations with BOS. Additionally, we suggest that considerable opportunity exists to increase the knowledge gained from BAL analyses in BOS through increased sample sizes, covariant adjustment and standardization of the BAL technique. Further efforts to leverage analysis of BAL constituents in BOS may offer great potential to provide additional in-depth and mechanistic insights into the pathogenesis of this complex disease.
In 2016 over 5 million reconstructive procedures were performed in the USA. The recent successes of clinical vascularized composite allotransplantations (VCA), hand and face transplantations included, established the tremendous potential of these life-enhancing reconstructions. Nevertheless, Due to limited availability and lifelong immunosuppression, application is limited. Long term banking of composite transplants may increase the availability of esthetically compatible parts with partial or complete HLA matching, reducing the risk of rejection and the immunosuppressive burden. The study purpose was to develop efficient protocols for the cryopreservation and transplantation of a complete rodent limb. Directional freezing is a method in which a sample is cooled at a constant velocity linear temperature gradient enabling precise control of the process and ice crystal formation. Vitrification is an alternative cryopreservation method in which the sample solidifies without the formation of ice crystals. Testing both methods on a rat hindlimb composite tissue transplantation model, we found reliable, reproducible and stable ways to preserve composite tissue. We believe that with further research and development cryopreservation may lead to composite tissue “banks”. This may lead to a paradigm shift from few and far apart emergent surgeries to wide scale, well planned, and better controlled elective surgeries. This article is protected by copyright. All rights reserved.
In 2015, 2409 active candidates aged 12 years or older were added to the lung transplant waiting list; 2072 transplants were performed, the most of any year. The median waiting time for candidates listed in 2015 was 3.4 months; the shortest waiting time was for diagnosis group D. Despite the highest recorded transplant rate of 157 per 100 waitlist years, waitlist mortality continued a steady decade-long rise to a high of 16.5 deaths per 100 waitlist years. Measures of short- and long-term survival showed no trend toward improved overall survival in the past 5 years, except that 6-month death rates decreased from 9.4% in 2005 to 7.9% in 2014. At 5 years posttransplant, 55.5% of recipients remained alive. In 2015, 23 new child (ages 0-11 years) candidates were added to the list; 17 transplants were performed. Incidence of death was 6.1% at 6 months and 8.2% at 1 year for transplants in 2013-2014. Important policy changes will affect access to transplant. In February 2015, OPTN implemented a comprehensive revision of the lung allocation score to better reflect mortality risk. Broader geographic sharing of donor lungs for pediatric candidates and allowance for selected transplants across blood types for candidates aged younger than 2 years have been approved and are expected to improve pediatric access to transplant. The impact of these changes on lung transplant trends will be observed in the coming years.
Previous publications have described unethical organ procurement procedures in the People’s Republic of China. International awareness and condemnation contributed to the announcement abolishing the procurement of organs from executed prisoners starting from January 2015. Eighteen months after the announcement, and aligned with the upcoming International Congress of the Transplantation Society in Hong Kong, this paper revisits the topic and discusses whether the declared reform has indeed been implemented. It is noticeable that China has neither addressed nor included in the reform a pledge to end the procurement of organs from prisoners of conscience, nor have they initiated any legislative amendments. Recent reports have discussed an implausible discrepancy of officially reported steady annual transplant numbers and a steep expansion of the transplant infrastructure in China. This paper expresses the viewpoint that, in the current context, it is not possible to verify the veracity of the announced changes and it thus remains premature to include China as an ethical partner in the international transplant community. Until we have independent and objective evidence of a complete cessation of unethical organ procurement from prisoners, the medical community has a professional responsibility to maintain the academic embargo on Chinese transplant professionals. This article is protected by copyright. All rights reserved.
We previously developed a mobile- and web-based decision aid (iChoose Kidney) that displays individualized risk estimates of survival and mortality, for the treatment modalities of dialysis versus kidney transplantation. We examined the effect of iChoose Kidney on change in transplant knowledge and access to transplant in a randomized controlled trial among patients presenting for evaluation in three transplant centers. A total of 470 patients were randomized to standard transplantation education (control) or standard education plus iChoose Kidney (intervention). Change in transplant knowledge (primary outcome) among intervention vs. control patients was assessed using 9-items in pre- and post-evaluation surveys. Access to transplant (secondary outcome) was defined as a composite of waitlisting, living donor inquiries, or transplantation. Among 443 patients (n=226 intervention; n=216 control), the mean knowledge scores were 5.1 ± 2.1 pre- and 5.8 ± 1.9 post-evaluation. Change in knowledge was greater among intervention (1.1 ± 2.0) vs. control (0.4 ± 1.8) patients (p<0.0001). Access to transplantation was similar among intervention (n=168; 74.3%) versus control patients (n=153; 70.5%; p=0.37). The iChoose Kidney decision aid improved patient knowledge at evaluation, but did not impact transplant access. Future studies should examine whether combining iChoose Kidney with other interventions can increase transplantation. (Clinicaltrials. gov NCT02235571) This article is protected by copyright. All rights reserved.
Despite countless media campaigns, organ donation rates in the United States have remained static while need has risen dramatically. New efforts to increase organ donation through public education are necessary to address the waiting list of over 100,000 patients. On May 1, 2012, the online social network, Facebook, altered its platform to allow members to specify “Organ Donor” as part of their profile. Upon such choice, members were offered a link to their state registry to complete an official designation, and their “friends” in the network were made aware of the new status as a donor. Educational links regarding donation were offered to those considering the new organ donor status. On the first day of the Facebook organ donor initiative, there were 13,054 new online registrations, representing a 21.1-fold increase over the baseline average of 616 registrations. This first-day effect ranged from 6.9× (Michigan) to 108.9× (Georgia). Registration rates remained elevated in the following 12 days. During the same time period, no increase was seen in registrations from the DMV. Novel applications of social media may prove effective in increasing organ donation rates and likewise might be utilized in other refractory public health problems in which communication and education are essential.
Currently, the ability to predict or monitor efficacy of HLA antibody removal therapies is deficient. We previously reported that titration studies are a consistent and accurate means of assessing antibody strength. To test whether titration studies can also predict which patients are better candidates for desensitization, we studied 38 patients from 3 centers (29 receiving plasmapheresis/low-dose IVIg; 9 patients receiving high-dose IVIg). For patients undergoing plasmapheresis/low-dose IVIg, antibody titer reduction correlated with number of treatment cycles for both Class I and II antibodies, but only up to approximately 4 cycles. Reduction in titer slowed with additional cycles, suggesting a limit to the efficacy of this approach. Furthermore, initial titer (pre-desensitization) can guide selection of candidates for successful antibody-removal treatment. In our experience, patients with antibodies at an initial titer >1:512 could not be reduced to the goal of a negative lymphocyte crossmatch, corresponding to a 1:16 titer, despite a significant increase in the number of treatment cycles. Change in MFI value did not correlate with success of treatment if initial MFI values were >10,000, likely due to single antigen bead saturation. Overall, we present a potential prognostic tool to predict candidacy and monitoring tool to assess efficacy of desensitization treatment. This article is protected by copyright. All rights reserved.