Allograft Survival Research Articles

Pulmonary epithelial markers in phenotypes of chronic lung allograft dysfunction

Airway epithelial injury is thought to be a key event in the pathogenesis of chronic lung allograft dysfunction (CLAD). We investigated whether markers of epithelial activity and injury in bronchoalveolar lavage fluid (BAL) correlate with CLAD diagnosis and major CLAD phenotypes: bronchiolitis obliterans syndrome (BOS) vs. restrictive allograft syndrome (RAS)-related phenotypes (including RAS, mixed phenotype, and all other patients with RAS-like opacities). CLAD status and phenotypes were retrospectively determined in a cohort of all consecutive adult, first, bilateral lung transplants performed 2010-2015, with available BAL samples. All patients with RAS-related phenotypes were included and 1:1 matched with BOS patients based on the time from transplant to CLAD-onset. Subjects who were CLAD-free for a minimum of 3 years post-transplant were 1:1 matched to CLAD patients and included as controls. Proteins that maintain the barrier function of the airway epithelial mucosa (club cell secretory protein (CCSP), surfactant protein-D (SP-D) and epithelial mucins: MUC1, MUC5AC, MUC5B, MUC16), as well as epithelial cell death markers (M30&M65 representing epithelial cell apoptosis and overall death, respectively), were measured in BAL obtained within 6-months post CLAD onset using a double-sandwich ELISA or a multiplex bead assay. Protein levels were compared using Mann-Whitney-U-test. Association between protein levels and graft survival was assessed using Cox proportional hazards models, adjusted for CMV serology mismatch status and CLAD phenotype. Fifty-four CLAD (27 BOS, 11 RAS, 7 mixed, 9 others with RAS-like opacities) patients and 23 CLAD-free controls were included. Median BAL levels were significantly higher in patients with CLAD compared to CLAD-free controls for M30 (124.5 vs. 88.7 U/L), MUC1 (6.8 vs. 3.2 pg/mL), and MUC16 (121.0 vs. 30.1 pg/mL). When comparing CLAD phenotypes, M30 was significantly higher in patients with RAS-related phenotypes than BOS (160.9 vs. 114.6 U/L). In multivariable models, higher M30 and MUC5B levels were associated with decreased allograft survival after CLAD onset independent of phenotype (P<0.05 for all). Airway epithelial mucins and cell death markers are enhanced in the BAL of patients with CLAD and can assist in differentiating between CLAD phenotypes and post-CLAD outcomes. Abnormal airway mucin expression and epithelial cell death may be involved in the pathogenesis of CLAD, and therefore their detection may aid in future selection of targeted therapies.

Non-Traditional Non-Immunological Risk Factors for Kidney Allograft Loss-Opinion.

Rates of late allograft loss have improved slowly in the last decades. Well described traditional risk factors that influence allograft survival include cardiovascular events, rejection, infections and post-transplant neoplasia. Here, we critically evaluate the influence of several non-immunological, non-traditional risk factors and describe their impact on allograft survival and cardiovascular health of kidney transplant recipients. We assessed the following risk factors: arterial stiffness, persistent arteriovenous access, mineral bone disease, immunosuppressive drugs residual levels variability, hypomagnesemia, glomerular pathological alterations not included in Banff criteria, persistent inflammation and metabolic acidosis.

Donor noradrenaline use is associated with better allograft survival in recipients of pancreas transplantation.

Outcomes following pancreas transplantation are suboptimal and better donor selection is required to improve this. Vasoactive drugs (VaD) are commonly used to correct the abnormal haemodynamics of organ donors in intensive care units. VaDs can differentially affect insulin secretion positively (dobutamine) or negatively (noradrenaline). The hypothesis was that some VaDs might induce beta-cell stress or rest and therefore impact pancreas transplant outcomes. The aim of the study was to assess relationships between VaD use and pancreas transplant graft survival. Data from the UK Transplant Registry on all pancreas transplants performed between 2004 and 2016 with complete follow-up data were included. Univariable- and multivariable-adjusted Cox regression analyses determined risks of graft failure associated with VaD use. In 2,183 pancreas transplants, VaDs were used in the following numbers of donors: dobutamine 76 (3.5%), dopamine 84 (3.8%), adrenaline 161 (7.4%), noradrenaline 1,589 (72.8%) and vasopressin 1,219 (55.8%). In multivariable models, adjusted for covariates and the co-administration of other VaDs, noradrenaline use (vs non-use) was a strong predictor of better graft survival (hazard ratio [95% confidence interval] 0.77 [0.64-0.94], p = 0.01). Noradrenaline use was associated with better graft survival in models adjusted for donor and recipient variables - this may be related to inhibition of pancreatic insulin secretion initiating pancreatic beta-cell 'rest'. Further research is required to replicate these findings and establish whether relationships are causal. Identification of alternative methods of inducing beta-cell rest could be valuable in improving graft outcomes.

IL-10-producing memory B regulatory cells as a novel target for HLA-G to prolong human kidney allograft survival

Despite the growing interest in the role of regulatory B cells (Bregs) in autoimmunity, their distinct role and function in kidney transplant outcomes remain elusive. Here, we retrospectively analyzed the proportion of Bregs, transitional Bregs (tBregs) and memory Bregs (mBregs) and their capacity to produce IL-10 in non-rejected (NR) versus rejected (RJ) kidney transplant recipients. In the NR group, we observed a significant increase in the proportion of mBregs (CD19+CD24hiCD27+) but no difference in tBregs (CD19+CD24hiCD38+), as compared to the RJ group. We also observed a significant increase in IL-10-producing mBregs (CD19+CD24hiCD27+IL-10+) in the NR group. As our group and others have previously reported a potential role of the human leukocyte antigen G (HLA-G) in human renal allograft survival, notably through IL-10, we then investigated possible crosstalk between HLA-G and IL-10+ mBregs. Our ex vivo data suggest a role of HLA-G in enhancing IL-10+ mBreg expansion upon stimulation, which further decreased CD3+ T cell proliferation capability. Using RNA-sequencing (RNA-seq), we identified potential key signaling pathways involved in HLA-G-driven IL-10+ mBreg expansion, such as the MAPK, TNF and chemokine signaling pathways. Together, our study highlights a novel HLA-G-mediated IL-10-producing mBreg pathway that may serve as a therapeutic target to improve kidney allograft survival.

Remarkable 107-year-old kidney with a 49-year of long-term allograph survival through continuous azathioprine monotherapy

BackgroundThe main goal of kidney allograft transplantation is to improve survival in patients with end-stage kidney failure. Herein, we report a 49-year long-term allograft survival with non-identical human leukocyte antigens (HLA). The purpose of this study was to report the successful clinical outcome of 49 years of transplant survival in a 79-year-old patient with a 107-year-old kidney undergoing continued immunosuppressive monotherapy. Material and methodsThe patient was evaluated clinically and immunologically with HLA typing and anti-HLA antibodies before transplantation. Post-transplant, the patient's clinical and immunological survival were monitored for 49 years. The state of the chimerism was assessed using the polymerase chain reaction to amplify 24 short tandem repeats using a DNA thermocycler and DNA analyzer. ResultsThe patient and donor were haploidentical and the patient was treated with azathioprine monotherapy. Donor-specific antibodies were detected only for the HLA-DPB1* 03:01 mismatch. This patient developed multiple skin tumors 26 years after transplant, which were successfully treated with topical therapy or surgical removal. The patient developed an intestinal adenocarcinoma 43 years after kidney transplantation, which was surgically removal; six years later, adenocarcinoma was diagnosed in a finger, followed by axillar and hepatic metastases. After 49 years of graft survival of a kidney of 107 years old in a patient with 79 years of age, the patient's health worsened with severe dehydration, anemia, and bacterial infection. The patient was hospitalized with a serum creatinine level of 3.45 mg/dL, urea level of 188 mg/dL, and estimated glomerular filtration rate of 22 mL/1.72 m2; septicemia developed and was treated with antibiotics. The patient had poor clinical progress, was intubated, and later died due to septic shock. ConclusionsTo the best of our knowledge, this is the first case of a 107-year-old kidney, transplanted into a recipient who was treated with azathioprine monotherapy for 49 years.

Combination of Lactobacillus plantarum improves the effects of tacrolimus on colitis in a mouse model.

The gut microbiome has been considered to play an important role in inflammatory bowel disease (IBD). Our previous study reported that tacrolimus-altered gut microbiota elicited immunoregulatory effects in both colonic mucosa and circulation, contributing to an increased allograft survival rate in mice. Here, we aimed to observe the changes in the tacrolimus-induced microbiome in a dextran sulfate sodium (DSS)-induced colitis mouse model and explore the possibility and efficacy of combination therapy with tacrolimus and the microbiome on colitis. Mice were divided into the control, DSS, tacrolimus monotherapy and tacrolimus plus Lactobacillus plantarum 550 (Lacto)-treated groups. The body weight, stool consistency, hematochezia and survival of mice were observed daily. Total RNA from colonic mucosa was extracted and subjected to transcriptome sequencing. Cecal contents were collected and the 16S rRNA sequencing was performed to characterize the gut microbiome and the ultrahigh- performance liquid chromatography-MS/MS (UHPLC-MS/MS) was used for targeted quantification of bile acids. The results confirmed that tacrolimus significantly ameliorated DSS-induced colitis in mice. Beneficial alterations of the gut microbiome characterized by a remarkable expansion of the genus Lactobacillus were induced by tacrolimus treatment. Oral supplementation with Lacto further improved the tacrolimus-mediated suppression of body weight loss in colitis, while the survival time of mice was further prolonged and the inflammation of colonic mucosa was obviously relieved. The immune and inflammation-related signaling pathways, including IFN-γ and IFN-α response, allograft rejection, IL2 STAT5 signaling and the inflammatory response pathways, were further downregulated in the tacrolimus plus Lacto cotreatment group. Cotreatment also improved the diversity of the gut microbiome and rescued the concentration of taurochenodeoxycholic acid (TCDCA) in colitis. The latter was positively correlated with the abundance of Lactobacillus but negatively related to the disease activity index score. Overall, our results indicated that Lactobacillus plantarum promoted the therapeutic effect of tacrolimus in experimental colitis, offering a promising strategy to combine tacrolimus and Lactobacillus in the treatment of colitis patients.

Donor specific antibody surveillance among pediatric kidney transplant programs: A report from the improving renal outcome collaborative.

Kidney transplantation (KT) is the preferred treatment for children with end-stage kidney disease. Recent advances in immunosuppression and advances in donor specific antibody (DSA) testing have resulted in prolonged allograft survival; however, standardized approaches for surveillance DSA monitoring and management of de novo (dn) DSA are widely variable among pediatric KT programs. Pediatric transplant nephrologists in the multi-center Improving Renal Outcomes Collaborative (IROC) participated in a voluntary, web-based survey between 2019 and 2020. Centers provided information pertaining to frequency and timing of routine DSA surveillance and theoretical management of dnDSA development in the setting of stable graft function. 29/30 IROC centers responded to the survey. Among the participating centers, screening for DSA occurs, on average, every 3 months for the first 12months post-transplant. Antibody mean fluorescent intensity and trend most frequently directed changes in patient management. Increased creatinine above baseline was reported by all centers as an indication for DSA assessment outside of routine surveillance testing. 24/29 centers would continue to monitor DSA and/or intensify immunosuppression after detection of antibodies in the setting of stable graft function. In addition to enhanced monitoring, 10/29 centers reported performing an allograft biopsy upon detection of dnDSA, even in the setting of stable graft function. This descriptive report is the largest reported survey of pediatric transplant nephrologist practice patterns on this topic and provides a reference for monitoring dnDSA in the pediatric kidney transplant population.

Postoperative Outcomes in 415 Patients Following Liver Transplantation Using Extended Donor Criteria: A Study from a Single Center in Germany.

BACKGROUND Because of the massive organ shortage worldwide, marginal organs are increasingly being considered. The aim of this study was to present a comprehensive analysis of donor-related factors clinically supposed to influence the outcome after liver transplantation. This study from a single center in Germany aimed to evaluate postoperative outcomes in 415 patients following liver transplantation using extended donor criteria. MATERIAL AND METHODS Extended donor criteria (EDC) were considered according to the official guidelines issued through the German Medical Association. Other factors and the Eurotransplant Donor Risk Index (ET-DRI) were also considered. Correlation studies, logistic regression, and Kaplan-Meier-estimator were used to evaluate the outcome. RESULTS The postoperative outcomes with or without EDC were comparable. Other factors had an impact on early allograft failure (EAD), including male donors (χ²=14.135, P=0.0001). Other donor-unrelated factors, like cold ischemia time, also had an impact on EAD (r=0.135, P=0.010), especially in patients with model for end-stage liver disease (MELD) <25 (ß=0.001, P=0.008). ET-DRI was a crucial factor in estimating overall and allograft survival after liver transplantation. CONCLUSIONS The findings from this study support the possibility of liver transplantation using organs obtained by EDC. Other factors, like donor sex and cold ischemic time, are not part of the EDC, although they have an impact on EAD. Organs obtained by EDC continue to be an option to address the organ shortage.

Management of pre-renal transplant secondary hyperparathyroidism: parathyroidectomy versus cinacalcet.

Secondary hyperparathyroidism is a common consequence of end-stage renal disease. Despite the efficacy of kidney transplantation in treating renal failure, many transplant recipients still suffer from persistent or tertiary hyperparathyroidism. Furthermore, the impact of secondary hyperparathyroidism therapy choices on other renal transplant outcomes is poorly understood. We retrieved the clinical data of 334 patients who received a kidney allograft between January 2007 and December 2014 at the Sheffield Teaching Hospitals, NHS Foundation Trust, United Kingdom. We identified three groups: parathyroidectomy group (34 patients), including patients who had parathyroidectomy before transplantation; cinacalcet group (31 patients), including patients who received cinacalcet before transplantation; and control group (269 patients), including patients who receive a transplant in the same period but did not have any evidence of hyperparathyroidism. We reviewed the demographic data, biochemical parameters and graft survival of all groups. Patients who underwent parathyroidectomy before transplantation had significantly better post-transplant calcium and parathyroid hormone levels than patients in the cinacalcet group (p=0.003). In addition, a significantly lower number of patients had tertiary hyperparathyroidism in the parathyroidectomy group than in the cinacalcet group at 1 year of follow-up (p=0.001). However, short-term and long-term graft survival was comparable in all groups. Renal allograft survival was comparable in all groups. However, tertiary hyperparathyroidism was less likely to occur in patients who underwent parathyroidectomy than in those who were administered cinacalcet.

The First 5 Years of Uterus Transplant in the US—A Report From the United States Uterus Transplant Consortium

ABSTRACT Women affected by absolute uterine-factor infertility (AUFI) were previously considered to have an untreatable condition, although uterus transplant has now changed this calculation. Although AUFI is a cause of female infertility (affecting 1 in 500 women), the counseling describing potential family-building options (gestational carrier or adoption) now includes a third choice of uterus transplant. This procedure is meant to restore reproductive ability and to allow gestation and childbirth. Further data regarding uterus transplant are essential to counsel appropriate individuals regarding this potential option. The US Uterus Transplant Consortium was formed in 2019 by centers performing uterus transplant in the United States: Baylor University Medical Center, Dallas, Tex; Cleveland Clinic, Cleveland, Ohio; and the University of Pennsylvania, PA. Accounting for approximately half of worldwide cases and of live births after uterus transplant, these centers have been instrumental in the evolution of the procedure, including the invention of novel surgical techniques for deceased donors, early embryo transfer, using the superior uterine veins for live birth and graft survival, and fully robotic living donor hysterectomies. This study examined data from all uterine transplants performed in the United States between 2016 and 2021, including donor, recipient, and offspring outcomes. Follow-up included the time from uterine transplant until the most recent visit. Evaluation of patients took place via a multidisciplinary transplant team and an independent living advocate. Primary outcomes of the study included patient survival (primary living donor outcome), allograft survival (30 days, 1 year, and 3 years), and live birth. Offspring primary outcomes included weight percentile and gestational age at delivery. During the study years (2016–2021), a total of 33 uterus transplants were performed, with 21 living and 12 deceased donors. No mortality of living donors or recipients was recorded. Overall, 25 of 33 uterus transplants had a viable graft at 30 days, and 19 of the 33 participants (58%) were able to achieve at least 1 live birth. A total of 8 recipients experienced graft loss (26%), and infection occurred in 10 participants (30%). Acute cellular rejection occurred for 10 participants within the 1-year graft survival group, but these patients were successfully treated. Time to the first menstrual cycle after transplant was a mean of 30 days (range, 10–59 days). Pregnancy following the transplant requires in vitro fertilization, as fallopian tubes are not transplanted with the uterus. For those participants who were able to conceive, the most common complications were gestational diabetes (12%), gestational hypertension (24%), and preeclampsia (12%). The mean gestational age at delivery was 36 weeks 6 days (range, 30 weeks 1 day to 38 weeks), with more than half (52%) being born after 36 weeks' gestation. After live birth, patients underwent a graft hysterectomy, the timing of which was determined by the patient (either during delivery or later in the recovery process). Medical indications for hysterectomy were conditions such as preeclampsia, acute kidney injury, abnormal placentation, and gestational diabetes. Overall, the first 5 years of US clinical experience of uterus transplant demonstrate technical feasibility and the ability of patients to have a live birth. High rates of technical success (76%) within US centers performing uterus transplants are promising. Despite the fact that the 1-year survival rate of the uterus transplant (76%) is lower than other organ transplant graft survival rates, the required longevity of the uterus differs from others. Nevertheless, a learning curve is expected to allow for improvements to this success rate over time. Based on the outcomes of uterine transplant described in this report, the authors conclude that the procedure is safe for both mother and child, as success is not limited to single centers, and is reproducible. They note that the success of the procedure is achieved both with living and deceased donors, and the rate of success is comparable to other infertility treatments. They conclude that the procedure ought to be recognized as an option for AUFI-diagnosed individuals desiring parenthood.

Impact of Sex and Age at Lung Transplantation on Long-Term Survival of Patients with Cystic Fibrosis

Careful selection of lung transplant (LT) recipients with cystic fibrosis (CF) may improve outcomes; therefore, we studied the impact of sex and age at the time of LT on long-term survival of patients with CF. LT recipients with CF who received post-LT care at our center between July 1, 2007 and April 30, 2021 were included. The primary outcome was death or retransplantation. Cox proportional hazard analysis and the Kaplan-Meier method were used. Of 59 included LT recipients, the median age at first LT was 28 (22, 36) years, 36 (61%) patients were ≥25 years old, and 30 (51%) were male. At the end of the study, 21 (36%) had died and 17 (29%) had required retransplantation, with a median lung allograft survival of 33.4 (16.1, 66.4) months. The remaining 21 patients (36%) were alive at a median of 68 (28, 112) months after primary LT. The probability of survival of male patients trended higher than that of female patients (66.7% vs 44.8%, p = 0.069). Compared to age &lt; 25 years at LT, age ≥ 25 years was associated with a significantly higher probability of survival (63.9% vs 43.5%, p = 0.047). LT recipients with CF aged ≥ 25 years at LT had significantly higher survival than younger patients, and survival trended higher for male recipients compared to female recipients. These results identify an at-risk population of LT recipients who may warrant closer attention after LT. Large multicenter trials with adequate power are needed.

Sterile Pancreas Inflammation during Preservation and after Transplantation

The pancreas is very susceptible to ischemia-reperfusion injury. Early graft losses due to pancreatitis and thrombosis represent a major issue after pancreas transplantation. Sterile inflammation during organ procurement (during brain death and ischemia-reperfusion) and after transplantation affects organ outcomes. Sterile inflammation of the pancreas linked to ischemia-reperfusion injury involves the activation of innate immune cell subsets such as macrophages and neutrophils, following tissue damage and release of damage-associated molecular patterns and pro-inflammatory cytokines. Macrophages and neutrophils favor tissue invasion by other immune cells, have deleterious effects or functions, and promote tissue fibrosis. However, some innate cell subsets may promote tissue repair. This outburst of sterile inflammation promotes adaptive immunity activation via antigen exposure and activation of antigen-presenting cells. Better controlling sterile inflammation during pancreas preservation and after transplantation is of utmost interest in order to decrease early allograft loss (in particular thrombosis) and increase long-term allograft survival. In this regard, perfusion techniques that are currently being implemented represent a promising tool to decrease global inflammation and modulate the immune response.

Impact of early blood transfusion after kidney transplantation on the clinical outcomes and allograft survival

IntroductionAnemia in chronic kidney disease is of great concern regarding blood transfusions and the possibility of allosensitization for future kidney transplants and the occurrence of rejection and allograft loss in the post-transplant period. The aim of this study was to evaluate the effect of early blood transfusion on the occurrence of rejections, allograft function and survival in the first year after transplantation. Material and methodsThis retrospective study was carried out with 445 patients submitted to kidney transplant allocated to two groups. The first group received early blood transfusions after transplant (n = 125, 28.09%), and the second group did not receive blood transfusions (n = 320, 71.91%). The patient outcomes were evaluated during a 1-year follow-up. Results14 patients given blood transfusion (11.2%) lost their allograft in the first year in comparison with 8 (2.5%) without transfusion (p < 0.001). There were 9 deaths in each group, which corresponded to 7.2% of the patients who received blood transfusions and 2.81% of those who did not (p < 0.035). Patient hospitalization lasted 15 days in transfusion group and 8.5 days in non-transfusion group (p < 0.001). Creatinine levels were higher in the patients who received blood transfusion than in those without transfusion in the first and third months after transplantation (p = 0.012 and 0.038, respectively). During the first year, the patients who received blood products experienced more antibody-mediated rejection (ABMR) (13.60%) than patients who did not (4.38%) (p < 0.001). Those who received blood transfusions also developed de novo DSA in higher proportion than those without transfusion against both class I and class II HLA (p < 0.001). ConclusionThis study showed that blood transfusions in the first month after transplantation had a negative impact on kidney function, graft survival, and contributed to the development of de novo DSA, an increased risk of ABMR and infections.

Impact of Low-Level Donor-Specific Anti-HLA Antibody on Posttransplant Clinical Outcomes in Kidney Transplant Recipients.

The clinical significance of low-level donor-specific anti-HLA antibody (low-DSA) remains controversial. We investigated the impact of low-DSA on posttransplant clinical outcomes in kidney transplant (KT) recipients. We retrospectively reviewed 1,027 KT recipients, namely, 629 living donor KT (LDKT) recipients and 398 deceased donor KT (DDKT) recipients, in Seoul St. Mary's Hospital (Seoul, Korea) between 2010 and 2018. Low-DSA was defined as a positive anti-HLA-DSA result in the Luminex single antigen assay (LABScreen single antigen HLA class I - combi and class II - group 1 kits; One Lambda, Canoga Park, CA, USA) but a negative result in a crossmatch test. We compared the incidence of biopsy-proven allograft rejection (BPAR), changes in allograft function, allograft survival, patient survival, and posttransplant infections between subgroups according to pretransplant low-DSA. The incidence of overall BPAR and T cell-mediated rejection did not differ between the subgroups. However, antibody-mediated rejection (ABMR) developed more frequently in patients with low-DSA than in those without low-DSA in the total cohort and the LDKT and DDKT subgroups. In multivariate analysis, low-DSA was identified as a risk factor for ABMR development. Its impact was more pronounced in DDKT (odds ratio [OR]: 9.60, 95% confidence interval [CI]: 1.79-51.56) than in LDKT (OR: 3.76, 95% CI: 0.99-14.26) recipients. There were no significant differences in other outcomes according to pretransplant low-DSA. Pretransplant low-DSA has a significant impact on the development of ABMR, and more so in DDKT recipients than in LDKT recipients, but not on long-term outcomes.

Prevalence and risk factors of antibodies towards HLA Class I and Class II in Malaysian renal transplant candidates

Antibody-mediated rejection (AMR) still persists as the major hurdle towards successful renal allograft survival. This paper aims to report on the HLA antibody landscape of renal transplant candidates in Malaysia. A total of 2,219 adult samples from 2016 to 2019 were analysed for anti-HLA antibodies using solid-phase assay. Our findings highlight the prevalence and risk factors for antibodies against HLA antigens in renal transplant settings, which could be beneficial for selecting compatible recipients from deceased organ donors. To the best of our knowledge, this study is the first to demonstrate that ethnic Malay and Chinese showed significantly higher prevalence of anti-HLA antibodies. Based on our multivariate analysis: (i) female gender was associated with higher risk for panel reactive antibodies (PRAs) against Class I, Class II, and Class I and II (p < 0.001); (ii) older patients (≥ 38 years old) were associated with higher risk of positivity against Class I, Class II and Class I and II (p < 0.001); (iii) Malays showed significant association with Class II antibodies (p = 0.035); Chinese patients presented with higher risk of PRA positivity against Class II (p < 0.001) and Class I and II (p = 0.01); Indians were significantly associated with higher risk of HLA antibody sensitization against Class I (p = 0.022), Class II (p = 0.026) and Class I and II (p = 0.05). Thus, our findings suggested that female gender, older age (≥ 38 years old) and ethnicity may serve as independent risk factors for HLA antibody sensitization in adult renal transplant candidates.

De novo prostate cancer in renal transplant recipients: A single-center study.

326 Background: Renal transplant recipients (RTRs) are at an increased risk of developing solid organ malignancies. Given improved allograft survival and life expectancy, the incidence of prostate cancer (PC) in RTRs appears to be increasing. Previous studies have reported the incidence of PC among RTRs to be between 0.3% and 3.24%. Limited data is available on the clinical characteristics, treatment, predictive markers, and outcomes of PC in RTRs. Methods: We performed a single-center retrospective study of male RTRs who developed PC. We collected the following data on RTRs who underwent transplantation between January 1, 1999, and December 31, 2019: baseline demographics, cause of end-stage renal disease (ESRD), duration of dialysis prior to RT, type of RT (cadaveric vs. living donor), immunosuppressive regimen, interval from RT to diagnosis of PC, stage of PC, type of treatment received, allograft survival, and overall survival (OS) were collected. Results: Among 1093 male RTRs, 15 (1.37%) developed PC. The median age at diagnosis of PC was 60 (range, 49-75) years. Subject races were African American (n=7), Hispanic (n=3), White (n=3), and other (n=2). The median duration from transplant to diagnosis of PC was 72 (range, 12-156) months. PC was diagnosed at stage I in 13 patients, stage II in 1 patient, and stage IV in 1 patient. The management of these patients consisted of local radiation (LR) alone in 6 patients, LR with leuprolide therapy in 6 patients, and radical prostatectomy alone in 1 patient. The patient with stage IV PC was treated with leuprolide and abiraterone acetate and remains progression free at follow-up of 41 months. The 5-year OS for this cohort of patients was 73.3%. Allograft function was preserved in 13 patients 12 months after diagnosis of PC. No PC-related mortality was noted. Conclusions: The incidence of PC in our analysis appears to be consistent with prior published studies. Most of our RTRs with PC had early-stage disease with excellent 5-year survival. The current standard-of-care treatment modalities for PC appear to be effective in the management of these patients. Allograft function was preserved in the majority of RTRs with PC in this study. Further research is required to evaluate the predictive factors for developing PC in RTR.

Human Leucocyte Antigen–Matching Can Improve Long Term Outcome of Renal Allografts from Donors Older Than 75 Years

BackgroundRenal transplantation is the therapy of choice for kidney failure. The Eurotransplant Senior Program (ESP) has been established to allocate kidneys ≥65 years to recipients of the same age group considered a regional allocation with short cold ischemia (CIT) but not human-leukocyte-antigen (HLA)-matching. The acceptance of organs aged ≥75 years is also still controversial within the ESP. MethodsIn a multicenter approach, 179 kidney grafts ≥75 years (mean donor age 78 years) that were transplanted in 174 patients in 5 German transplant centers were analyzed. The primary focus of the analysis was long-term outcome of the grafts and the impact of CIT, HLA matching, and recipient related risk factors. ResultsThe mean graft survival was 59 months (median 67 months) with a mean donor age of 78.3 ± 2.9 years. Grafts with 0 to 3 HLA-mismatches had a significantly better overall graft survival compared to grafts with ≥4 mismatches (69 months vs 54 months; P = .008). The mean CIT was short (11.9 ± 5.3 hours) and had no impact on graft survival. ConclusionRecipients receiving a kidney graft from donors aged ≥75 years can benefit from nearly 5 years of survival with a functioning graft. Even minimal HLA matching may improve long term allograft survival.

IL-10 modified mRNA monotherapy prolongs survival after composite facial allografting through the induction of mixed chimerism

Vascularized composite allotransplantation has great potential in face transplantation by supporting functional restoration following tissue grafting. However, the need for lifelong administration of immunosuppressive drugs still limits its wide use. Modified mRNA (modRNA) technology provides an efficient and safe method to directly produce protein invivo. Nevertheless, the use of IL-10 modRNA-based protein replacement, which exhibits anti-inflammatory properties, has not been shown to prolong composite facial allograft survival. In this study, IL-10 modRNA was demonstrated to produce functional IL-10 protein invitro, which inhibited pro-inflammatory cytokines and invivo formation of an anti-inflammatory environments. We found that without any immunosuppression, C57BL/6J mice with fully major histocompatibility complex (MHC)-mismatched facial allografts and local injection of IL-10 modRNA had a significantly prolonged survival rate. Decreased lymphocyte infiltration and pro-inflammatory T helper 1 subsets and increased anti-inflammatory regulatory Tcells (Tregs) were seen in IL-10 modRNA-treated mice. Moreover, IL-10 modRNA induced multilineage chimerism, especially the development of donor Treg chimerism, which protected allografts from destruction because of recipient alloimmunity. These results support the use of monotherapy based on immunomodulatory IL-10 cytokines encoded by modRNA, which inhibit acute rejection and prolong allograft survival through the induction of donor Treg chimerism.

Bioengineered liver crosslinked with nano-graphene oxide enables efficient liver regeneration via MMP suppression and immunomodulation

Decellularized extracellular matrix scaffold, widely utilized for organ engineering, often undergoes matrix decomposition after transplantation and produces byproducts that cause inflammation, leading to clinical failure. Here we propose a strategy using nano-graphene oxide to modify the biophysical properties of decellularized liver scaffolds. Notably, we demonstrate that scaffolds crosslinked with nano-graphene oxide show high resistance to enzymatic degradation via direct inhibition of matrix metalloproteinase activity and increased mechanical rigidity. We find that M2-like macrophage polarization is promoted within the crosslinked scaffolds, which reduces graft-elicited inflammation. Moreover, we show that low activities of matrix metalloproteinases, attributed to both nano-graphene oxide and tissue inhibitors of metalloproteinases expressed by M2c, can protect the crosslinked scaffolds against in vivo degradation. Lastly, we demonstrate that bioengineered livers fabricated with the crosslinked scaffolds remain functional, thereby effectively regenerating damaged livers after transplantation into liver failure mouse models. Overall, nano-graphene oxide crosslinking prolongs allograft survival and ultimately improves therapeutic effects of bioengineered livers, which offer an alternative for donor organs.

Antibody-removal therapies for de novo DSA in pediatric intestinal recipients: Why, when, and how? Asingle-center experience.

Donor-specific anti-HLA antibodies (DSA) impact negatively on the outcome of intestinal grafts. Although the use of antibody-removal therapies (ART) is becoming more frequent in the last few years, issues regarding their timing and effectiveness remain under discussion. In the present study, we report our experience with eight ART procedures (based on plasmapheresis, intravenous immunoglobulin, and rituximab) in eight pediatric intestinal and multivisceral transplants with de novo DSA (dnDSA). ART were performed when dnDSA appeared in two contexts: (1) concomitant with rejection (acute or chronic) or (2) without rejection or any other clinical symptom. Complete DSA removal was observed in seven out of eight patients, showing an effectiveness of 88%. In the group treated for dnDSA without clinical symptoms, the success rate was 100%, with complete DSA removal and without rejection afterward. A shorter time between DSA detection and ART performance appeared as a significant factor for the success of the therapy (p = 0.0002). DSA against HLA-A and DQ alleles were the most resistant to ART, whereas anti-DR DSA were the most sensitive. In addition, the 8-year allograft survival rate in recipients undergoing ART was similar to that in those without DSA, being significantly lower in non-treated DSA-positive recipients (p = 0.013). The results confirm the effectiveness of ART in terms of DSA removal and allograft survival and encourage its early use even in the absence of clinical symptoms.