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Ex vivo normothermic perfusion (EVNP) is increasingly recognised as a viability tool to increase organ utilisation in deceased donor transplantation. We report the use of EVNP to assess graft perfusion quality following indication nephrectomy and back-bench arterial reconstruction in a case of renal artery stenosis, unamenable to endovascular treatment. Once explanted, it was not possible to effectively cold perfuse the graft through the main renal artery or collaterals. An arterial reconstruction was performed with patch angioplasty using the largest collateral creating a single common stem. EVNP was used to assess organ perfusion and, therefore, viability. Excellent global perfusion was evident alongside urine production, demonstrating that the arterial reconstruction was satisfactory. A patient with end-stage renal disease was consented with particular attention to the uncertainty of the underlying donor disease process and long-term outcome of the reconstruction. Primary function was achieved and recipient estimated glomerular filtration rate (eGFR) remains stable at 58 mL/min/1.73 m² at 6 months.

This is the unformatted version of the accepted review paper manuscript "Extended criteria grafts and emerging therapeutics strategy in liver transplantation. The unstable balance between damage and repair" published on Transplant Rev (Orlando)2021 Dec;35(4):100639. doi: 10.1016/j.trre.2021.100639., by Ghinolfi D, Melandro F, Torri F, Martinelli C, Cappello V, Babboni S, Silvestrini B, De Simone P, Basta G,Del Turco S. Due to increasing demand for donor organs, "extended criteria" donors are increasingly considered for liver transplantation, including elderly donors and donors after cardiac death. The grafts of this subgroup of donors share a major risk to develop significant features of ischemia reperfusion injury, that may eventually lead to graft failure. Ex-situ machine perfusion technology has gained much interest in liver transplantation, because represents both a useful tool for improving graft quality before transplantation and a platform for the delivery of therapeutics directly to the organ. In this review, we survey ongoing clinical evidences supporting the use of elderly and DCD donors in liver transplantation, and the underlying mechanistic aspects of liver aging and ischemia reperfusion injury that influence graft quality and transplant outcome. Finally, we highlight evidences in the field of new therapeutics to test in MP in the context of recent findings of basic and translational research.

Background Mortality for infants on the heart transplant wait list remains unacceptably high, and available mechanical circulatory support is suboptimal. Our goal is to demonstrate the feasibility of utilizing genetically engineered pig (GEP) heart as a bridge to allotransplantation by transplantation of a GEP heart in a baboon. Methods Four baboons underwent orthotopic cardiac transplantation from GEP donors. All donor pigs had galactosyl-1,3-galactose knocked out. Two donor pigs had human complement regulatory CD55 transgene and the other 2 had human complement regulatory CD46 and thrombomodulin. Induction immunosuppression included thymoglobulin, and Anti-CD20. Maintenance immunosuppression was Rapamycin, AntiCD-40 and methylprednisolone. One donor heart was preserved with University of Wisconsin (UW) solution and the other three with del Nido solution. Results All baboons weaned from cardiopulmonary bypass. B217 received a donor heart preserved with UW. Ventricular arrhythmias and depressed cardiac function resulted in early death. All recipients of del Nido preserved hearts easily weaned from cardiopulmonary bypass with minimal inotropic support. B15416 and B1917 survived for 90 days and 241 days respectively. Histopathology in B15416 revealed no significant myocardial rejection but cellular infiltrate around Purkinje fibers. Histopathology in B1917 was consistent with severe rejection. B37367 had uneventful transplant but developed significant respiratory distress with a cardiac arrest. Conclusions Survival of B15416 and B1917 demonstrates the feasibility of pursuing additional research to document the ability to bridge an infant to cardiac allotransplant with a GEP heart.

Domino liver transplantation (DLT) utilizes a phenotypically normal explant from select recipients as a donor graft in another patient. The procedure is not widely employed and remains restricted to a small number of centers. The purpose of this study was to assess the national profile of DLT in the United States (US) and evaluate current survival outcomes.The United Network for Organ Sharing (UNOS) database was queried for all liver transplants (LT) between 1996 and 2020. Outcomes of interest were long-term graft and patient survival.Of 181,976 LTs performed nationally during the study period, 185 (0.1%) were DLTs. Amyloidosis and maple syrup urine disease (MSUD) accounted for 83% of dominoed allografts. Out of 210 explants with amyloidosis, 103 (49%) were dominoed into secondary recipients. Only 50 (22%) of all MSUD explants (n = 227) were dominoed. Graft survival was 79%, 73% and 53% at 3-, 5- and 10-years, respectively, for DLT recipients. Overall patient survival was 83%, 76% and 57% at 3-, 5- and 10-years.Despite excellent long-term survival outcomes, DLT allografts comprise a very small percentage of the liver donor pool. A large proportion of potential DLTs may be unconscionably excluded despite shortages in deceased donor organs.

Background In the recent years, an increased use of marginal donors and grafts and a growing prevalence of peripheral arterial disease in the recipients have been observed. Meanwhile, the open surgical technique for kidney transplantation has not changed. The aim of this study is to analyze all surgical complications occurring in the first year after kidney transplant and to determine potential predictive risk factors. Method Data of the 399 patients who underwent kidney transplant in our University Hospital between January 2006 and December 2015 were retrospectively reviewed. The primary endpoint was the overall rate of vascular, parietal and urological complications at 1 year following kidney transplantation. The secondary outcomes were graft and patient’ survival rates, and the identification of predictive factors of the surgical complications. Results Twenty-four percent of patients developed 134 complications. Vascular complication represented 39% of all complications and resulted in 9 graft losses. Parietal and urological complications represented 46% and 15% of all complications, respectively, No parietal or urological complications were associated with graft loss. Five patients died during the first year, none of these cases was associated with graft loss. The graft survival rate reached 96% at 1 year, including patients still alive. The occurrence of surgical complication was associated with reduced graft survival at 1 year. Using a multivariate analysis, 4 predictive factors were identified: age, deceased donor, operative time and dyslipidemia. Conclusion Surgical complications after kidney transplantation remained frequent and age, deceased kidney donors, and operative time were identified as risk factors. As vascular complications were a major cause of early graft loss, efforts should aim to reduce their occurrence to increase graft survival.

Increased recipient and donor age are associated with worse solid organ pancreas transplant outcomes. However, donor and recipient age criteria vary between jurisdictions. We systematically reviewed studies reporting the association between transplanting older recipients and donors beyond current Transplantation Society of Australia and New Zealand (TSANZ) limits with solid pancreas transplant outcomes.To review current outcomes of solid pancreas transplantation in recipients and donors over the TSANZ reference ages.Studies comparing transplant outcomes between a reference-age and an older-age donor (45 years) or recipient (≥50 years) cohort for solid pancreas transplantation were included. Primary outcomes were pancreas/kidney graft and patient survival at 1 and 5 years. Secondary outcomes were post-transplant complications (graft thrombosis, acute rejection and relaparotomy rates).Eleven studies were included (two studies assessing solid pancreas outcomes between older vs reference-aged donors and nine studies assessing outcomes between older vs reference-aged recipients). Seven of 11 studies were judged to be at high risk of bias. Primary and secondary outcomes were not significantly different between recipient age groups in nine studies. A sensitivity analysis of older versus reference-aged studies excluding studies at high risk of bias also showed non-inferior primary and secondary outcomes at 1 year. Two studies comparing outcomes by donor age showed worse graft survival but non-inferior patient survival with older donors.Increased donor or recipient age alone should not absolutely contraindicate solid pancreas transplantation, especially if other risk predictors are minimised.

As the number of donation after circulatory death (DCD) liver transplants (LTs) performed in the United States continues to increase annually, there has been interest by policy makers to develop a more robust exception point safety net for patients who develop ischemic cholangiopathy (IC) following DCD LT. As such, there is a need for better understanding of the clinical course and long-term outcomes in patients who develop IC, as well as determining if IC can be classified into distinct categories with distinctly different clinical outcomes.All DCD LT performed at Mayo Clinic Florida, Mayo Clinic Arizona, and Mayo Clinic Rochester from January 1999 to March 2020 were included (N = 770). Outcomes were compared between 4 distinct radiologic patterns of IC: diffuse necrosis, multifocal progressive, confluence dominant, and minor form.In total, 88 (11.4%) patients developed IC, of which 42 (5.5%) were listed for retransplantation of liver (ReLT). Patients with diffuse necrosis and multifocal progressive patterns suffered from frequent hospital admissions for cholangitis in the first year following DCD LT (median 3 and 2), were largely stent dependent (100% and 85.7%), and almost universally required ReLT. Patients with confluence dominant disease were managed with multiple stents and frequently recovered, ultimately becoming stent free without need for ReLT. Patients with the minor form IC did well with limited need for stent placement or repeat procedures and did not require ReLT. Graft survival was different between the 4 distinct IC patterns (P 0.001).The present analysis provides a detailed analysis on the natural history and clinical course of IC. Patients developing IC can be classified into 4 distinct patterns with distinct clinical courses.

The futility of liver transplantation in elderly recipients remains under debate in the HCV eradication era.The aim was to assess the effect of older age on outcome after liver transplantation. We used the ELTR to study the relationship between recipient age and post-transplant outcome. Young and elderly recipients were compared using a PSM method.A total of 10,172 cases were analysed. Recipient age65 years was identified as an independent risk factor associated with reduced patient survival (HR:1.42 95%CI:1.23-1.65,p 0.001). After PSM, 2124 patients were matched, and the same association was found between elderly recipients and patient survival and graft survival (p 0.001). As hepatocellular carcinoma and alcoholic cirrhosis were independent prognostic factors for patient and graft survival a propensity score-matching was performed for each. Patient and graft survival were significantly worse (p 0.05) in the alcoholic cirrhosis elderly group. However, patient and graft survival in the hepatocellular carcinoma cohort were similar (p 0.05) between groups.Liver transplantation is an acceptable and safe curative option for elderly transplant candidates, with worse long-term outcomes compare to young candidates. The underlying liver disease for liver transplantation has a significant impact on the selection of elderly patients.

BACKGROUND Third time liver transplantation is a technically demanding exercise with variable outcomes in single center series. There has been no national level description of survival following third time liver transplant in the US in the MELD era. METHODS Third time liver transplants between March 1, 2002 and January 1, 2018 in the UNOS dataset were analyzed. RESULTS Patient survival among the 240 third time liver transplant recipients in the study at 1, 3, 5, and 10 years (71.8%, 62.4%, 59.1%, 49.5%) was significantly worse compared to primary liver transplant (90.6%, 83.9%, 78.8%, 67.6%; p

Background. The effect of pregnancy on the course of estimated glomerular filtration rate (eGFR) is unknown in kidney transplant recipients (KTRs). Methods. We conducted a nationwide multicenter cohort study in KTRs with pregnancy (>20 wk) after kidney transplantation (KT). Annual eGFRs after KT until death or graft loss and additional eGFRs before each pregnancy were collected according to protocol. Changes in eGFR slope before and after each pregnancy were analyzed by generalized estimating equations multilevel analysis adjusted for transplant vintage. Results. We included 3194 eGFR measurements before and after pregnancy in 109 (55%) KTRs with 1, 78 (40%) with 2, and 10 (5%) with 3 pregnancies after KT. Median follow-up after first delivery post-KT was 14 y (interquartile range, 18 y). Adjusted mean eGFR prepregnancy was 59 mL/min/1.73 m2(SEM [standard error of the mean] 1.72; 95% confidence interval [CI], 56-63), after the first pregnancy 56 mL/min/1.73 m2(SEM 1.70; 95% CI, 53-60), after the second pregnancy 56 mL/min/1.73 m2(SEM 2.19; 95% CI, 51-60), and after the third pregnancy 55 mL/min/1.73 m2(SEM 8.63; 95% CI, 38-72). Overall eGFR slope after the first, second, and third pregnancies was not significantly worse than prepregnancy (P = 0.28). However, adjusted mean eGFR after the first pregnancy was 2.8 mL/min/1.73 m2(P = 0.08) lower than prepregnancy. Conclusions. The first pregnancy has a small, but insignificant, effect on eGFR slope in KTRs. Midterm hyperfiltration, a marker for renal reserve capacity, was associated with better eGFR and death-censored graft survival. In this KTR cohort with long-term follow-up, no significant effect of pregnancy on kidney function was detected.

BACKGROUND: At Eurotransplant (ET), kidneys are transferred to "rescue allocation" (RA), whenever the standard allocation (SA) algorithms Eurotransplant Kidney Allocation System (ETKAS) and Eurotransplant Senior Program (ESP) fail. We analyzed the outcome of RA. METHODS: Retrospective patient clinical and demographic characteristics association analyses were performed with graft outcomes for 2422 recipients of a deceased donor renal transplantation (DDRT) after RA versus 25 481 after SA from 71 centers across all ET countries from 2006 to 2018. RESULTS: Numbers of DDRTs after RA increased over the time, especially in Germany. RA played a minor role in ESP versus ETKAS (2.7% versus 10.4%). RA recipients and donors were older compared with SA recipients and donors, cold ischemia times were longer, waiting times were shorter, and the incidence of primary nonfunction was comparable. Among ETKAS recipients, HLA matching was more favorable in SA (mean 3.7 versus 2.5). In multivariate modeling, the incidence of graft loss in ETKAS recipients was reduced in RA compared with SA (subdistribution hazard ratio, 0.80; 95% confidence interval [0.70-0.91], P

Objective To characterize the association between prolonged supine postoperative positioning of patients undergoing Descemet-stripping automated endothelial keratoplasty (DSAEK) and graft dislocation rate. Methods In this retrospective cohort study, medical records of patients who underwent uncomplicated DSAEK surgery at Yitzhak Shamir Medical Center between 2010 and 2019 were reviewed. Nursing documentation of patients’ adherence to supine positioning during the postoperative hospitalization period was collected. A patient was considered compliant if he or she was documented as cooperative with supine positioning throughout the first 24 hours. Results A total of 170 eyes of 138 patients were found eligible. Main indications for surgery were pseudophakic bullous keratopathy (50.6%), previous graft failure (25.9%), and Fuch's endothelial dystrophy (FED; 20.6%). Twelve surgeries were combined with cataract extraction. Postoperative graft detachment occurred in 26 eyes (15.3%) after an average period of 1 day (range, 0–20 days). Compliance with supine positioning was documented in 84.1% (n = 143 patients). Noncompliance rates during the first 24 hours in the detached and nondetached groups were 26.9% (n = 7) and 14.4% (n = 20), respectively; after adjustment for possible confounders, the odds ratio (OR) was 1.44 (p = 0.249). Graft dislocation was observed in 13.3% (19 of 143) and 25.9% (7 of 27) of cooperative and noncooperative patients, respectively (p = 0.17). Subanalysis of 120 eyes with either BPK or FED for which it was the first transplantation demonstrated a protective effect of supine positioning (OR 3.42, confidence interval 1.095–10.700; p = 0.034). Findings for both groups remained unchanged in multivariate analysis. Conclusions We found a statistically significant protective effect of 24 hours of postoperative supine positioning against graft detachment after DSAEK in eyes with no prior transplantations.

BACKGROUND Outcomes of left lateral segment (LLS) grafts in pediatric recipients were compared between living (LD-LLS) and deceased donor (DD-LLS) grafts. METHODS 195 LLS grafts (99DD-LLS-96LD-LLS) were analyzed with a median follow-up of 9.1years. The primary endpoints were overall patient/graft survival. RESULTS LD-LLS grafts were younger (0.9vs.1.4years, p = 0.039), more likely to have a fulminant liver failure (17.9%vs.5.3%,p = 0.002), less likely to have a metabolic disorder (6.3%vs.25.5%,p = 0.002), and less likely to be undergoing retransplantation (5.3% vs.16.2%,p = 0.015). There was a trend toward decreased hepatic artery thrombosis in LD-LLS grafts (6.6% vs. 15.5%,p = 0.054). No differences in the overall biliary complications occurred. The LD-LLS group had prolonged survival compared to the DD-LLS group with 10-year survival rates of 81%, and 74% (p = 0.005), respectively. LD-LLS grafts had longer graft survival compared to DD-LLS grafts (10-year graft survival 85%vs.67%,p = 0.005). Recipient age >1year (HR 2.39,p = 0.026), aortic reconstruction (HR 2.12,p = 0.046) and vascular complication (HR 3.12,p

Antibody-mediated rejection (AMR) is a major barrier to long-term graft survival following solid organ transplantation (SOT). Major histocompatibility antigens mismatched between donor and recipient are well-recognized targets of humoral alloimmunity in SOT and thought to drive most cases of AMR. In contrast, the implication of minor histocompatibility antigens (mHAs) in AMR has not been fully investigated, and their clinical relevance remains controversial. Recent technological advances, allowing for genome-wide comparisons between donors and recipients, have uncovered novel, polymorphic mHA targets with potential influence on the graft outcome following SOT. Here, we review these latest studies relating to mHAs and discuss their clinical significance.

The gold standard treatment of end-stage liver disease continues to be liver transplantation (LT). The challenges of LT require skilled anesthesiologists to anticipate physiologic changes associated with end-stage liver disease and surgical considerations that affect multiple organ systems. While on the waiting list, patients may be placed on new anticoagulation medications that can confound already complex coagulopathy in LT patients. Pain management often is an afterthought for such a complex procedure, but appropriate medications can help control pain while limiting opioid medications. Surgical stress and medications for immunosuppression can affect perioperative glucose management in ways that have implications for patient and graft survival. The coronavirus disease 2019 pandemic in 2020 provided a new challenge for anesthesiologists. The uncertainty of the novel respiratory virus challenged providers beyond just LT patients.

Background Exact dose-response relationship between body mass index at transplantation and clinical outcomes after kidney transplantation remained unclear, and no specific body mass index threshold and pretransplant weight loss aim were recommended for kidney transplantation candidates among transplant centers. Methods PubMed, Embase, Web of Science, and Cochrane Library were searched for literature published up to December 31, 2019. The two-stage, random effect meta-analysis was performed to estimate the dose-response relationship between body mass index and clinical outcomes after kidney transplantation. Results Ninety-four studies were included for qualitative assessment and 50 for dose-response meta-analyses. There was a U-shaped relationship between graft loss, patient death, and body mass index. Body mass index with the lowest risk of graft loss was 25.2 kg/m2, and preferred body mass index range was 22–28 kg/m2. Referring to a body mass index of 22 kg/m2, the risk of graft loss was 1.088, 0.981, 1.003, and 1.685 for a body mass index of 18, 24, 28, and 40 kg/m2, respectively. Body mass index with the lowest risk of patient death was 24.7 kg/m2, and preferred body mass index range was 22–27 kg/m2. Referring to a body mass index of 22 kg/m2, the patient death risk was 1.115, 0.981, 1.032, and 2.634 for a body mass index of 18, 24, 28, and 40 kg/m2, respectively. J-shaped relationships were observed between body mass index and acute rejection, delayed graft function, primary graft nonfunction, and de novo diabetes. Pair-wise comparisons showed that higher body mass index was also a risk factor for cardiovascular diseases, hypertension, infection, longer length of hospital stay, and lower estimated glomerular filtration rate level. Conclusion Underweight and severe obesity at transplantation are associated with a significantly increased risk of graft loss and patient death. A target body mass index at kidney transplantation is 22–27 kg/m2.

Describe graft and overall survival outcomes in multiple myeloma (MM) patients who underwent kidney transplant (KT) compared to the general KT population.The Organ Procurement and Transplantation Network/National United Network for Organ Sharing (OPTON/UNOS) database was analyzed from 1988 to 2019 with R 4.00 and the 2013-2017 United States Renal Data System (USRDS) was surveyed for incidence and mortality of MM ESRD.USRDS analysis revealed 961 patients diagnosed with ESRD due to MM on average annually, accounting for 0.8% of the ESRD population. Without KT, 44.4% of MM patients died in the first year of renal replacement initiation. OPTON/UNOS analysis identified 218 MM KT patients, compared to 490,089 patients without MM. There was no difference in graft survival between MM KT and the general population (P-value = .13, HR = 1.19 [0.95, 1.49], 95% CI). Median graft survival in MM KT was 2683 days (7.4 years). KT patients with MM had a higher risk for death (P-value = .0001, HR = 1.83 [1.41, 2.37], 95% CI), and median overall survival was 3076 days (8.4 years). Survival difference was lost when comparing patients ≥50 years (P-value = .42, HR = 1.14 [0.83, 1.56], 95% CI).Patients with MM renal failure who underwent KT had equivalent graft and age-matched overall survival compared to the general KT population. Therefore select patients with MM renal failure have potential for excellent KT outcomes, should be considered for transplantation when feasible, and should not be excluded from KT based on a history of MM.

En bloc kidney transplant is a surgical treatment option that increases available donor organs and has excellent graft survival for patients with end-stage renal disease. Herein, we report a case of dissection of the external iliac artery that occurred during en bloc kidney transplant in an adult recipient. The en bloc kidneys were removed, flushed, and then reimplanted after restoring the blood flow to the lower limb. To our knowledge, this is the first case of dissection of the external iliac artery managed successfully during en bloc kidney transplant.

Donor/recipient incompatibility in kidney transplantation classically refers to ABO/HLA-incompatibility. Kidney paired donation (KPD) was historically established to circumvent ABO/HLA-incompatibility, with the goal of identifying ABO/HLA-compatible matches. However, there is a broad range of donor factors known to impact recipient outcomes beyond ABO/HLA-incompatibility, such as age and weight, and quantitative tools are now available to empirically compare potential living donors across many of these factors, such as the living donor kidney donor profile index (LKDPI). Moreover, the detrimental impact of mismatch at other HLA antigens (such as DQ) and epitope mismatching on post-transplant outcomes has become increasingly recognized. Thus, it is time for a new paradigm of incompatibility that considers all of these risks factors together in assessing donor/recipient compatibility and the potential utility for KPD. Under this new paradigm of incompatibility, we show how the LKDPI and other tools can be used to identify donor/recipient incompatibilities that could be improved through KPD, even for those with a traditionally 'compatible' living donor.

Postmortem normothermic regional perfusion (NRP) is a rising preservation strategy in controlled donation after circulatory determination of death (cDCD). Herein, we present results for cDCD liver transplants performed in Spain 2012-2019, with outcomes evaluated through December 31, 2020. Results were analyzed retrospectively and according to recovery technique (abdominal NRP [A-NRP] or standard rapid recovery [SRR]). During the study period, 545 cDCD liver transplants were performed with A-NRP and 258 with SRR. Median donor age was 59 years (interquartile range 49-67 years). Adjusted risk estimates were improved with A-NRP for overall biliary complications (OR 0.300, 95% CI 0.197-0.459, p

Objectives Recent national organ distribution rule changes could have implications on distance between donor and recipient hospitals and cold ischemia time. With cold ischemia time being an unavoidable detriment to organ quality, any strategies that minimize it should maximize organ quality. This study evaluated the significance of the kidney allocation system and the Share 35 rule changes on kidney and liver transplant outcomes. Materials and methods This retrospective study included deceased liver and kidney donor and their recipient data from the Organ Procurement and Transplantation Network. Variables were analyzed using propensity score matching and Cox hazards model distance (from donor hospital to organ recovery center), and effects on survival outcomes of trans-planted livers and kidneys in the context of the recent rule changes were analyzed. Results Transplanted organs have significantly better outcomes when the distance is 0 miles versus median distances for locally transported organs of 18 and 22 miles for kidney and liver, respectively. Cold ischemia time, when corrected, accounts for this finding, thus suggesting that cold ischemia time is the factor most responsible for viability of a transplanted organ. This significance remains evident for liver transplants even after the Share 35 rule change but not for kidney transplants following the December 2014 kidney allocation system change. Conclusions Liver transplants showed a higher risk of lower viability with travel, and the Share 35 rule did not appear to change this result. Kidney transplant outcomes appear to have improved after the kidney allocation system change. Potential strategies for minimizing cold ischemia time and improving outcomes include more free-standing organ recovery centers in centralized locations.

Sensitization, defined as the presence of circulating antibodies, presents challenges, particularly in patients undergoing heart transplantation (HTx) bridged with durable mechanical circulatory support (MCS). We aimed to investigate the post-transplantation outcomes of sensitized MCS patients.Among 889 consecutively enrolled heart transplant (HTx) recipients between 2010 and 2018, 86 (9.7%) sensitized MCS patients (Group A) were compared with sensitized non-MCS patients (Group B, n = 189), non-sensitized MCS patients (Group C, n = 162), and non-sensitized non-MCS patients (Group D, n = 452) regarding post-HTx outcomes, including the incidence of primary graft dysfunction (PGD), 1-year survival, and 1-year freedom from antibody-mediated rejection (AMR).Sensitized MCS patients (Group A) showed comparable rates of PGD, 1-year survival, and 1-year freedom from AMR with Groups C and D. However, Group A showed significantly higher rates of 1-year freedom from AMR (95.3% vs 85.7%, p = 0.02) and an earlier decline in panel-reactive antibody (PRA) levels (p0.01) than sensitized non-MCS patients (Group B). Desensitization therapy effectively reduced the levels of PRA in both Groups A and B. When Group A was further divided according to the presence of preformed donor-specific antibodies (DSA), patients with preformed DSA showed significantly lower rates of 1-year freedom from AMR than those without (84.2% vs 98.5%, p = 0.01).Sensitized MCS patients showed significantly lower rates of AMR and an earlier decline in PRA levels following HTx than sensitized non-MCS patients. Removal of MCS at the time of transplantation might underlie these observations.

Liver transplantation (LT) from donors-with-HIV to recipients-with-HIV (HIV D+/R+) is permitted under the HOPE Act. There are only three international single-case reports of HIV D+/R+ LT, each with limited follow-up. We performed a prospective multicenter pilot study comparing HIV D+/R+ to donors-without-HIV to recipients-with-HIV (HIV D-/R+) LT. We quantified patient survival, graft survival, rejection, serious adverse events (SAEs), human immunodeficiency virus (HIV) breakthrough, infections, and malignancies, using Cox and negative binomial regression with inverse probability of treatment weighting. Between March 2016-July 2019, there were 45 LTs (8 simultaneous liver-kidney) at 9 centers: 24 HIV D+/R+, 21 HIV D-/R+ (10 D- were false-positive). The median follow-up time was 23 months. Median recipient CD4 was 287 cells/µL with 100% on antiretroviral therapy; 56% were hepatitis C virus (HCV)-seropositive, 13% HCV-viremic. Weighted 1-year survival was 83.3% versus 100.0% in D+ versus D- groups (p = .04). There were no differences in one-year graft survival (96.0% vs. 100.0%), rejection (10.8% vs. 18.2%), HIV breakthrough (8% vs. 10%), or SAEs (all p .05). HIV D+/R+ had more opportunistic infections, infectious hospitalizations, and cancer. In this multicenter pilot study of HIV D+/R+ LT, patient and graft survival were better than historical cohorts, however, a potential increase in infections and cancer merits further investigation.

Islet transplantation is a promising therapy for insulin-dependent diabetes, but large-scale application is hampered by the lack of a consistent source of insulin-producing cells and need for lifelong administration of immunosuppressive drugs, which are associated with severe side effects. To avoid chronic immunosuppression, islet grafts can be enveloped in immunoisolating polymeric membranes. These immunoisolating polymeric membranes protect islet grafts from cell-mediated rejection while allowing diffusion of oxygen, nutrients, and insulin. Although clinical trials have shown the safety and feasibility of encapsulated islets to control glucose homeostasis, the strategy does up till now not support long-term graft survival. This partly can be explained by a significant loss of insulin-producing cells in the immediate period after implantation. The loss can be prevented by combining immunoisolation with immunomodulation, such as combined administration of immunomodulating cytokines or coencapsulation of immunomodulating cell types such as regulatory T cells, mesenchymal stem cells, or Sertoli cells. Also, administration of specific antibodies or apoptotic donor leucocytes is considered to create a tolerant microenvironment around immunoisolated grafts. In this review, we describe the outcomes and limitations of these approaches, as well as the recent progress in immunoisolating devices.Impact statementImmunoisolation by enveloping islets in semipermeable membranes allows for successful transplantation of islet grafts in the absence of chronic immunosuppression, but the duration of graft survival is still not permanent. The reasons for long-term final graft failure is not fully understood, but combining immunoisolation with immunomodulation of tissues or host immune system has been proposed to enhance the longevity of grafts. This article reviews the recent progress and challenges of immunoisolation, as well as the benefits and feasibility of combining encapsulation approaches with immunomodulation to promote longevity of encapsulated grafts.

Obesity initiates a chronic inflammatory network linked to perioperative complications and increased acute rejection rates in organ transplantation. Bariatric surgery is the most effective treatment of obesity recommended for morbidly obese transplant recipients. Here, we delineated the effects of obesity and bariatric surgery on alloimmunity and transplant outcomes in diet-induced obese (DIO) mice. Allograft survival was significantly shorter in DIO-mice. When performing sleeve gastrectomies (SGx) prior to transplantation, we found attenuated T cell-derived alloimmune responses resulting in prolonged allograft survival. Administering taurodeoxycholic acid (TDCA) and valine, metabolites depleted in DIO-mice and restored through SGx, prolonged graft survival in DIO-mice comparable with SGx an dampened Th1 and Th17 alloimmune responses while Treg frequencies and CD4+ T cell-derived IL-10 production were augmented. Moreover, in recipient animals treated with TDCA/valine, levels of donor-specific antibodies had been reduced. Mechanistically, TDCA/valine restrained inflammatory M1-macrophage polarization through TGR5 that compromised cAMP signaling and inhibited macrophage-derived T cell activation. Consistently, administering a TGR5 agonist to DIO-mice prolonged allograft survival. Overall, we provide novel insights into obesity-induced inflammation and its impact on alloimmunity. Furthermore, we introduce TDCA/valine as a noninvasive alternative treatment for obese transplant patients.

Purpose To describe 10-year outcomes for graft and endothelial cell survival after Descemet stripping endothelial keratoplasty (DSEK), including risk factors for graft failure. Design Retrospective clinical cohort study. Methods 356 consecutive DSEK grafts performed by 10 surgeons using a standardized protocol were analyzed. Primary outcomes were cumulative graft survival and percentage endothelial cell loss (ECL) from 6 months to 10 years; secondary outcomes included risk factors for graft failure, postoperative complications, visual outcomes, and central corneal thickness. Results Indications include Fuchs’ endothelial dystrophy (n=209), bullous keratopathy (n=88), and previous graft failure (n=39). 104 eyes (29%) had preoperative glaucoma. Cumulative graft survival of all eyes at 1, 3, 5, and 10 years were 97%, 90%, 85%, and 79%. 10-year graft survival for Fuchs’ endothelial dystrophy was 92%. Percentage ECL of all grafts were 46.6 ± 17.3 at year 1, 54.9 ± 18.7 at year 3, 59.6 ± 17.4 at year 5, and 73.1 ± 9.7 at year 10. Cox regression identified preoperative glaucoma (HR 8.41, 95% CI, 1.30-54.5, P= 0.026), including previous glaucoma surgery (HR 3.63, 95% CI, 1.03-12.74, P=0.04), and regrafts (HR 5.29, 95% CI, 2.02-13.89, P=0.001) as significant risk factors for graft failure. Conclusion At 10 years, DSEK survival rate was 79% for all eyes, including complex grafts, and ECL was 73%. For FED, 10-year graft survival was 92%. Despite a mean 10-year endothelial cell count of only 692 cells/mm2, graft survival remained high with good vision. DSEK continues to be a viable treatment option, especially in complex eyes with comorbidity.

Belatacept was developed to replace calcineurin inhibitors in kidney transplantation. Its use is associated with better kidney transplant function, a lower incidence of anti-donor antibodies and higher graft survival. However, it is also associated with a higher risk of cellular rejection. We studied the activation and proliferation mechanisms of belatacept-resistant T lymphocytes (TLs), to identify new pathways for control. We performed a transcriptomic analysis on CD4+ CD57+ PD1- memory TLs, which are responsible for a higher incidence of graft rejection, after allogeneic stimulation with activated dendritic cells (aDCs) in the presence or absence of belatacept. After six hours of contact with aDCs, the (CD4+ CD57+ PD1- ) (CD4+ CD57+ PD1+ ) and (CD4+ CD57- ) lymphocytes had different transcriptional profiles with or without belatacept. In the CD4+ CD57+ PD1- population, the IFNα-dependent activation pathway was positively overrepresented, and IRF7 transcript levels were high. IRF7 was associated with IFNα/β and IL-6 regulation. The inhibition of both these cytokines in a context of belatacept treatment inhibited the proliferation of CD4+ CD57+ PD1- T cells. Our results show that IRF7 is rapidly upregulated in belatacept-resistant CD4+ CD57+ PD1- TLs. The inhibition of type I IFN or IL-6 in association with belatacept treatment reduces the proliferation of belatacept-resistant TLs, paving the way for new treatments for use in organ transplantation.

Background Improvement of long-term outcomes in kidney transplantation remains one of the most pressing challenges, yet drug development is stagnating. Human genetics offers an opportunity for much-needed target validation in transplantation. Conflicting data exist about the effect of transforming growth factor-beta 1 (TGF-β1) on kidney transplant survival, since TGF-β1 has pro-fibrotic and protective effects. We investigated the impact of a recently discovered functional TGFB1 polymorphism on kidney graft survival. Methods We performed an observational cohort study analysing recipient and donor DNA in 1271 kidney transplant pairs from the University Medical Centre Groningen in The Netherlands, and associated a low-producing TGFB1 polymorphism (rs1800472-C > T) with 5-, 10- and 15-year death-censored kidney graft survival. Results Donor genotype frequencies of rs1800472 in TGFB1 differed significantly between patients with and without graft loss (P = 0.014). Additionally, the low-producing TGFB1 polymorphism in the donor was associated with an increased risk of graft loss following kidney transplantation (hazard ratio = 2.12 for the T-allele; 95% confidence interval 1.18–3.79; P = 0.012). The incidence of graft loss within 15 years of follow-up was 16.4% in the CC-genotype group and 31.6% in the CT-genotype group. After adjustment for transplant-related covariates, the association between the TGFB1 polymorphism in the donor and graft loss remained significant. In contrast, there was no association between the TGFB1 polymorphism in the recipient and graft loss. Conclusions Kidney allografts possessing a low-producing TGFB1 polymorphism have a higher risk of late graft loss. Our study adds to a growing body of evidence that TGF-β1 is beneficial, rather than harmful, for kidney transplant survival.

Despite the common detection of non-donor specific anti-HLA antibodies (non-DSAs) after lung transplantation, their clinical significance remains unclear. In this retrospective single-center cohort study of 325 lung transplant recipients, we evaluated the association between donor specific HLA antibodies (DSAs) and non-DSAs with subsequent CLAD development. DSAs were detected in 30% of recipients and were associated with increased CLAD risk, with higher HRs for both de novo and high MFI (>5000) DSAs. Non-DSAs were detected in 56% of recipients, and 85% of DSA positive tests had concurrent non-DSAs. In general, non-DSAs did not increase CLAD risk in multivariable models accounting for DSAs. However, non-DSAs in conjunction with high BAL CXCL9 levels were associated with increased CLAD risk. Multivariable proportional hazards models demonstrate the importance of the HLA antibody-CXCL9 interaction: CLAD risk increases when HLA antibodies (both DSAs and non-DSAs) are detected in conjunction with high CXCL9. Conversely, CLAD risk is not increased when HLA antibodies are detected with low CXCL9. This study supports the potential utility of BAL CXCL9 measurement as a biomarker to risk stratify HLA antibodies for future CLAD. The ability to discriminate between high versus low-risk HLA antibodies may improve management by allowing for guided treatment decisions.

OBJECTIVE Paediatric lung transplantation poses unique management challenges. Experience regarding indications and outcome is scarce, especially in younger children. The primary aim of this study was to investigate outcome after first lung transplantation in children