The 50 most-cited articles in Transplantation, 2019

With the development of modern solid-phase assays to detect anti-HLA antibodies and a more precise histological classification, the diagnosis of antibody-mediated rejection (AMR) has become more common and is a major cause of kidney graft loss. Currently, there are no approved therapies and treatment guidelines are based on low-level evidence. The number of prospective randomized trials for the treatment of AMR is small, and the lack of an accepted common standard for care has been an impediment to the development of new therapies. To help alleviate this, The Transplantation Society convened a meeting of international experts to develop a consensus as to what is appropriate treatment for active and chronic active AMR. The aim was to reach a consensus for standard of care treatment against which new therapies could be evaluated. At the meeting, the underlying biology of AMR, the criteria for diagnosis, the clinical phenotypes, and outcomes were discussed. The evidence for different treatments was reviewed, and a consensus for what is acceptable standard of care for the treatment of…

Organ transplantation as an option to overcome end-stage diseases is common in countries with advanced healthcare systems and is increasingly provided in emerging and developing countries. A review of the literature points to sex- and gender-based inequity in the field with differences reported at each step of the transplant process, including access to a transplantation waiting list, access to transplantation once waitlisted, as well as outcome after transplantation. In this review, we summarize the data regarding sex- and gender-based disparity in adult and pediatric kidney, liver, lung, heart, and hematopoietic stem cell transplantation and argue that there are not only biological but also psychological and socioeconomic issues that contribute to disparity in the outcome, as well as an inequitable access to transplantation for women and girls. Because the demand for organs has always exceeded the supply, the transplant community has long recognized the need to ensure equity and efficiency of the organ allocation system. In the spirit of equity and equality, the authors call for…

Human corneal transplantation (keratoplasty) is typically considered to have superior short- and long-term outcomes and lower requirement for immunosuppression compared to solid organ transplants because of the inherent immune privilege and tolerogenic mechanisms associated with the anterior segment of the eye. However, in a substantial proportion of corneal transplants, the rates of acute rejection and/or graft failure are comparable to or greater than those of the commonly transplanted solid organs. Critically, while registry data and observational studies have helped to identify factors that are associated with increased risk of corneal transplant failure, the extent to which these risk factors operate through enhancing immune-mediated rejection is less clear. In this overview, we summarize a range of important recent clinical and basic insights related to high-risk corneal transplantation, the factors associated with graft failure, and the immunological basis of corneal allograft rejection. We highlight critical research areas from which continued progress is likely to drive…

In 2001, a Statement was published that described indications for intestinal transplantation in patients with intestinal failure expected to require parenteral nutrition indefinitely. Since 2001, advances in the management of intestinal failure including transplantation and patient survival, both on extended parenteral nutrition and after transplantation, have improved, leading to a reduction in the number of intestinal transplants worldwide from a peak of 270 per year in 2008 to 149 per year in 2017. These changes suggest that the original 2001 Statement requires reassessment. All patients with permanent intestinal failure should be managed by dedicated multidisciplinary intestinal rehabilitation teams. Under care of these teams, patients should be considered for intestinal transplantation in the event of progressive intestinal failure-associated liver disease, progressive loss of central vein access, and repeated life-threatening central venous catheter-associated infections requiring critical care. Additional indications for transplantation include large desmoid tumors and other…

BACKGROUND: The true incidence and unique risk factors for recurrent and de novo nonalcoholic fatty liver (NAFLD) and nonalcoholic steatohepatitis (NASH) post-liver transplant (LT) remain poorly characterized. We aimed to identify the incidence and risk factors for recurrent and de novo NAFLD/NASH post-LT. METHODS: MEDLINE via PubMed, Embase, Scopus, and CINAHL were searched for studies from 2000 to 2018. Risk of bias was adjudicated using the Newcastle-Ottawa Scale. RESULTS: Seventeen studies representing 2378 patients were included. All were retrospective analyses of patients with post-LT liver biopsies, with the exception of 2 studies that used imaging for outcome assessment. Seven studies evaluated occurrence of recurrent NAFLD/NASH, 3 evaluated de novo occurrence, and 7 evaluated both recurrent and de novo. In studies at generally high or moderate risk of bias, mean 1-, 3-, and ≥5-year incidence rates may be 59%, 57%, and 82% for recurrent NAFLD; 67%, 40%, and 78% for de novo NAFLD; 53%, 57.4%, and 38% for recurrent NASH; and 13%, 16%, and 17% for de novo NASH. Multivariate…

BACKGROUND: The aims of this study were to evaluate the efficacy of US Food and Drug Administration-approved drugs in genetically engineered pig-to-baboon kidney xenotransplantation and compare the results with those using an anti-CD40 monoclonal antibody (mAb)-based regimen. METHODS: Ten life-supporting kidney transplants were carried out in baboons using α1,3-galactosyltransferase gene-knockout/CD46 pigs with various other genetic manipulations aimed at controlling coagulation dysregulation. Eight transplants resulted in informative data. Immunosuppressive therapy consisted of induction with antithymocyte globulin and anti-CD20mAb, and maintenance based on either (1) CTLA4-Ig and/or tacrolimus (+rapamycin or mycophenolate mofetil) (GroupA [US Food and Drug Administration-approved regimens], n = 4) or (2) anti-CD40mAb + rapamycin (GroupB, n = 4). All baboons received corticosteroids, interleukin-6R blockade, and tumor necrosis factor-α blockade. Baboons were followed by clinical and laboratory monitoring of kidney function, coagulation, and immune parameters. At euthanasia,…

BACKGROUND: African Americans (AA) have lower rates of kidney transplantation (KT) compared with Whites (WH), even after adjusting for demographic and medical factors. In this study, we examined whether the racial disparity in KT waitlisting persists after adjusting for social determinants of health (eg, cultural, psychosocial, and knowledge). METHODS: We prospectively followed a cohort of 1055 patients who were evaluated for KT between 3 of 10 to 10 of 12 and followed through 8 of 18. Participants completed a semistructured telephone interview shortly after their first KT evaluation appointment. We used the Wilcoxon rank-sum and Pearson chi-square tests to examine race differences in the baseline characteristics. We then assessed racial differences in the probability of waitlisting while accounting for all predictors using cumulative incidence curves and Fine and Gray proportional subdistribution hazards models. RESULTS: There were significant differences in the baseline characteristics between non-Hispanic AA and non-Hispanic WH. AA were 25% less likely (95% confidence interval,…

BACKGROUND: The safety profiles of standard therapy versus everolimus with reduced-exposure calcineurin inhibitor (CNI) therapy using contemporary protocols in de novo kidney transplant recipients have not been compared in detail. METHODS: TRANSFORM was a randomized, international trial in which de novo kidney transplant patients were randomized to everolimus with reduced-exposure CNI (N = 1014) or mycophenolic acid (MPA) with standard-exposure CNI (N = 1012), both with induction and corticosteroids. RESULTS: Within the safety population (everolimus 1014, MPA 1012), adverse events with a suspected relation to study drug occurred in 62.9% versus 59.2% of patients given everolimus or MPA, respectively (P = 0.085). Hyperlipidemia, interstitial lung disease, peripheral edema, proteinuria, stomatitis/mouth ulceration, thrombocytopenia, and wound healing complications were more frequent with everolimus, whereas diarrhea, nausea, vomiting, leukopenia, tremor, and insomnia were more frequent in the MPA group. The incidence of viral infections (17.2% versus 29.2%; P < 0.001), cytomegalovirus…

BACKGROUND: Given the potential utility of frailty, a clinical phenotype of decreased physiologic reserve and resistance to stressors, to predict postkidney transplant (KT) outcomes, we sought to understand the perceptions and practices regarding frailty measurement in US KT programs. METHODS: Surveys were emailed to American Society of Transplantation Kidney/Pancreas Community of Practice members and 202 US transplant programs (November 2017 to April 2018). Program characteristics were gleaned from Scientific Registry of Transplant Recipients. RESULTS: The 133 responding programs (response rate = 66%) represented 77% of adult KTs and 79% of adult KT candidates in the United States. Respondents considered frailty to be a useful concept in evaluating candidacy (99%) and endorsed a need to develop a frailty measurement specific to KT (92%). Frailty measurement was more common during candidacy evaluation (69%) than during KT admission (28%). Of the 202 programs, 38% performed frailty assessments in all candidates while 23% performed assessments only for older candidates. There was…

BACKGROUND: The objectives of this position statement were to provide evidence-based and expert-informed recommendations for exercise training in adult and children solid organ transplant (SOT) candidates and recipients and on the outcomes relevant to exercise training and physical function that should be evaluated in SOT. METHODS: We identified randomized controlled trials (RCTs) and systematic reviews of exercise interventions in adult and pediatric SOT candidates and recipients. When RCTs were not available, studies of any design were reviewed. The key recommendations were based on scientific evidence and expert-informed opinion. RESULTS: We recommended that exercise training should be offered in the pre- and posttransplant phase for both adults and children. In adults, exercise training pretransplant was safe, but there was insufficient evidence to provide specific guidelines on the training characteristics. RCTs in adult SOT recipients demonstrated that exercise training improved exercise capacity, lower extremity muscle strength, and health-related quality of life. To obtain…

BACKGROUND: Hypothermic machine perfusion (HMP) has become standard care in many center's to preserve kidneys donated after circulatory death (DCD). Despite a significant reduction in metabolism at low temperatures, the remaining cellular activity requires oxygen. Because of the role and safety of oxygen during HMP has not been fully clarified, its supply during HMP is not standard yet. This study investigates the effect of administering oxygen during HMP on renal function in a porcine DCD model. METHODS: After 30 minutes of warm ischemia, porcine slaughterhouse kidneys were preserved for 24 hours by means of cold storage (CS), or HMP with Belzer Machine Perfusion Solution supplemented with no oxygen, 21% or 100% oxygen. Next, kidneys were reperfused for 4 hours in a normothermic machine perfusion setup. RESULTS: HMP resulted in significantly better kidney function during normothermic machine perfusion. Thiobarbituric acid-reactive substances, markers of oxidative stress, were significantly lower in HMP preserved kidneys. HMP preserved kidneys showed significantly lower aspartate…

BACKGROUND: Active antibody-mediated rejection (AMR) that occurs during the amnestic response within the first month posttransplant is a rare but devastating cause of early allograft loss after kidney transplant. Prior reports of eculizumab treatment for AMR have been in heterogeneous patient groups needing salvage therapy or presenting at varied time points. We investigated the role of eculizumab as primary therapy for active AMR early posttransplant. METHODS: We performed a retrospective observational study of a consecutive cohort of solitary kidney transplant recipients who were transplanted between January 1, 2014, and January 31, 2018, and had AMR within the first 30 days posttransplant and treated with eculizumab ± plasmapheresis. RESULTS: Fifteen patients had early active AMR at a median (interquartile range [IQR]) of 10 (7-11) days posttransplant and were treated with eculizumab ± plasmapheresis. Thirteen cases were biopsy proven, and 2 cases were presumed on the basis of donor-specific antibody trends and allograft function. Within 1 week of treatment, the median estimated…

Cardiac allograft vasculopathy remains a major limiting factor in the long-term survival of the heart transplant recipient. Our understanding of its pathogenesis is continuously evolving as advances in imaging modalities have allowed a direct window into the natural history of the disease. Innovation in diagnostic modalities has spurred the proliferation of prognostic tools and biomarkers. And in parallel, pharmacological advances have emerged that have helped ameliorate the disease's progressive course.

BACKGROUND: Better preservation strategies for the storage of donation after circulatory death grafts are essential to improve graft function and to increase the kidney donor pool. We compared continuous normothermic ex vivo kidney perfusion (NEVKP) with hypothermic anoxic machine perfusion (HAMP) and static cold storage (SCS) in a porcine kidney autotransplantation model. METHODS: Porcine kidneys were exposed to 30 minutes of warm ischemia and then reimplanted following either 16 hours of either SCS, HAMP (LifePort 1.0), or NEVKP before autotransplantation (n = 5 per group). The contralateral kidney was removed. Animals were followed for 8 days. RESULTS: Grafts preserved by NEVKP demonstrated improved function with more rapid recovery compared with HAMP and SCS (mean peak serum creatinine: 3.66 ± 1.33 mg/dL [postoperative d 1 [(POD1)], 8.82 ± 3.17 mg/dL [POD2], and 12.90 ± 2.19 mg/dL [POD3], respectively). The NEVKP group demonstrated significantly increased creatinine clearance calculated on POD3 (63.6 ± 19.0 mL/min) compared with HAMP (13.5 ± 10.3 mL/min, P = 0.001) and SCS (4.0…

BACKGROUND: The incidence of pregnancy in kidney transplantation (KT) recipients is increasing. Studies report that the incidence of graft loss (GL) during pregnancy is low, but less data are available on long-term effects of pregnancy on the graft. METHODS: Therefore, we performed a meta-analysis and systematic review on GL and graft function, measured by serum creatinine (SCr), after pregnancy in KT recipients, stratified in years postpartum. Furthermore, we included studies of nulliparous KT recipients. RESULTS: Our search yielded 38 studies on GL and 18 studies on SCr. The pooled incidence of GL was 9.4% within 2 years after pregnancy, 9.2% within 2-5 years, 22.3% within 5-10 years, and 38.5% >10 years postpartum. In addition, our data show that, in case of graft survival, SCr remains stable over the years. Only within 2 years postpartum, Δ SCr was marginally higher (0.18 mg/dL, 95%CI [0.05-0.32], P = 0.01). Furthermore, no differences in GL were observed in 10 studies comparing GL after pregnancy with nulliparous controls. Systematic review of the literature showed that mainly…

BACKGROUND: Tacrolimus (TAC) is the most important agent for maintenance immunosuppression and prevention of immunologic injury to the renal allograft, yet there remains no consensus on how best to monitor drug therapy. Both high TAC intrapatient variability and low TAC time in therapeutic range (TTR) have been associated with risk of de novo donor-specific antibodies (dnDSA). In this study, we hypothesized that the risk associated with high TAC coefficient of variation (CV) is a result of low TAC TTR rather than the variability itself. METHODS: We analyzed the risk of dnDSA, acute rejection, or death-censored graft loss by non-dosed-corrected TAC CV and TAC TTR during the first posttransplant year in a cohort of 538 patients with a median follow-up period of 4.1 years. RESULTS: Patients with CV >44.2% and TTR <40% (high intrapatient variability and low TTR) had a high risk of dnDSA (adjusted OR = 4.93, 95% confidence interval = 2.02-12.06, P < 0.001) and death-censored graft loss by 5 years (adjusted HR = 4.00, 95% confidence interval = 1.31-12.24, P = 0.015) when compared with…

The immunosuppressive agent mycophenolate is used extensively in kidney transplantation, yet dosing strategy applied varies markedly from fixed dosing ("one-dose-fits-all"), to mycophenolic acid (MPA) trough concentration monitoring, to dose optimization to an MPA exposure target (as area under the concentration-time curve [MPA AUC0-12]). This relates in part to inconsistent results in prospective trials of concentration-controlled dosing (CCD). In this review, the totality of evidence supporting mycophenolate CCD is examined: pharmacological characteristics, observational data linking exposure to efficacy and toxicities, and randomized controlled trials of CCD, with attention to dose optimization method and exposure achieved. Fixed dosing of mycophenolate consistently leads to underexposure associated with rejection, as well as overexposure associated with toxicities. When CCD is driven by pharmacokinetic calculation to a target concentration (target concentration intervention), MPA exposure is successfully controlled and clinical benefits are seen. There remains a need for…

BACKGROUND: Tacrolimus trough concentrations (mean/variability), as well as concentration-to-dose ratio (C/D ratio), affect kidney allograft outcomes. We investigated the link between the C/D ratio and death-censored kidney graft survival (DCGS). METHODS: We performed a retrospective study on 1029 kidney transplant patients (2004-2016) with the following criteria: tacrolimus-based immunosuppression, >1-year graft survival, no initial use of everolimus, and available anti-human leukocyte antigen antibody data. We analyzed the impact of the time-varying C/D ratio on DCGS. Fast metabolizers were defined by a C/D ratio < 1.05. We also investigated the effect of an early (mo 3 to mo 6 post transplantation) C/D ratio below 1.05. Cox survival analyses were performed, adjusting for potential confounders (tacrolimus trough, variability of tacrolimus trough, de novo donor-specific antibody development, cytochrome P450 3A5 genotype, pregraft sensitization, mo 3 glomerular filtration rate). RESULTS: Time-varying C/D ratio was significantly associated with DCGS (hazard ratio [HR], 2.35; P <…

Kidney allograft failure is a serious condition, as it implies the need for reinitiation of dialysis with associated morbidity and mortality, reduced quality of life, and higher economic cost. Despite improvements in short-term survival of kidney allografts, this progress was not matched in long-term graft survival. In this viewpoint article, we summarize the available literature on the causes of kidney allograft failure, both early and late, both nonimmune and alloimmune, to gain better insight into the causes of graft failure. Such insight is necessary to better target therapies or take preventative measures that improve long-term outcome after kidney transplantation.

BACKGROUND: Chronic antibody-mediated rejection (cAMR) results in the majority of renal allograft losses. Currently, there are no approved therapies. We recently reported on clinical use of tocilizumab (TCZ) for treatment of cAMR in HLA-sensitized kidney transplant patients. IgG1 and IgG3 subclasses of IgG are potent effectors of complement- and antibody-dependent cellular cytotoxicity, which are critical mediators of AMR. Here, we examined the impact of TCZ treatment for cAMR on total IgG, IgG1-4 subclasses, and anti-HLA-IgG (total and subclasses). METHODS: Archived plasma obtained pre- and post-TCZ treatment (8 mg/kg, 6×, monthly) from 12 cAMR patients who failed standard of care treatment with intravenous immune globulin + rituximab with or without plasma exchange were tested for total IgG and IgG1-4 by ELISA, anti-HLA-total IgG, IgG3 and IgG4, and donor-specific antibody by Luminex assay. Archived plasma from 14 cAMR patients treated with the standard of care were included as controls. RESULTS: Total IgG and IgG1-3 were significantly reduced post-TCZ, whereas no reduction was…

BACKGROUND: Non-Hispanic black (NHB) and Hispanic patients have lower access to kidney transplantation compared to non-Hispanic whites (NHWs). We examined whether differences in the prevalence of comorbidities that affect eligibility for transplant contribute to disparities in receipt of transplantation. METHODS: We performed a retrospective study of 986 019 adults who started dialysis between 2005 and 2014, according to the United States Renal Data System. We compared prevalence of comorbidities that could influence transplant eligibility by race/ethnicity. We examined time to first transplant by race/ethnicity in this overall cohort and in a very healthy sub-cohort without conditions that could be contraindications to transplantation. RESULTS: During 2.3 years of mean follow-up, 64 892 transplants occurred. NHBs and Hispanics had a lower prevalence of medical barriers to transplantation at the time of dialysis initiation than NHWs, including age >70 years (26% in NHB versus 47% in NHW) and malignancy (4% in Hispanics versus 10% in NHWs). Access to transplant was 65% lower (95% CI,…

BACKGROUND: Time spent on the waiting list before liver transplantation (LT) provides an opportunity to optimize recipient fitness through prehabilitation, potentially reducing the physiological impact of major surgery. We assessed the feasibility and effectiveness of a 6-week exercise program in patients with cirrhotic liver disease awaiting LT. METHODS: This single-center, prospective cohort, feasibility study, enrolled patients awaiting LT to a 6-week period of thrice weekly, supervised exercise on a static bike. Cardiopulmonary exercise testing (CPET) was used to objectively assess cardiopulmonary fitness at baseline and after 6 weeks of exercise. A follow-up CPET was performed at 12 weeks. CPET-derived measures were used to guide prescription of the training program. A nonrandomized control cohort of LT patients were selected to match the exercise group based on specific demographic data. Allocation to study arms was primarily based on the distance participants lived from the hospital where training occurred. Both groups received structured nutritional advice. RESULTS: The…

Families play an essential role in deceased organ procurement. As the person cannot directly communicate his or her wishes regarding donation, the family is often the only source of information regarding consent or refusal. We provide a systematic description and analysis of the different roles the family can play, and actions the family can take, in the organ procurement process across different jurisdictions and consent systems. First, families can inform or update healthcare professionals about a person's donation wishes. Second, families can authorize organ procurement in the absence of deceased's preferences and the default is not to remove organs, and oppose donation where there is no evidence of preference but the default is to presume consent; in both cases, the decision could be based on their own wishes or what they think the deceased would have wanted. Finally, families can overrule the known wishes of the deceased, which can mean preventing donation, or permitting donation when the deceased refused it. We propose a schema of 4 levels on which to map these possible family…

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) artificially supports respiratory and cardiac function when conventional techniques fail. ECMO has been described as a treatment modality for acute pulmonary and cardiac failure following orthotopic liver transplantation (OLT). Here, we present a series of adult OLT recipients placed on ECMO after transplantation for both respiratory and cardiac indications and review the literature on the role of ECMO in the setting of OLT. METHODS: For the patient series, we cross-referenced all patients who underwent OLT at our institution between 2007 and 2018 with the ECMO database of our institution and described these cases. For the literature review, we identified cases and series that described the use of ECMO after liver transplantation in adult recipients. RESULTS: A total of 1792 patients underwent OLT. Eight patients were placed on ECMO (0.4%), 5 men and 3 women aged 28 to 68 years (4 venovenous and 4 venoarterial). Three of (38%) 8 patients survived to discharge and are alive today. In the literature, we identified 3 series and 12…

BACKGROUND: Regenerative medicine using stem cell technology is an emerging field that is currently tested for inborn and acquired liver diseases. OBJECTIVE: This phase I/II prospective, open label, multicenter, randomized trial aimed primarily at evaluating the safety of Heterologous Human Adult Liver-derived Progenitor Cells (HepaStem) in pediatric patients with urea cycle disorders (UCDs) or Crigler-Najjar (CN) syndrome 6 months posttransplantation. The secondary objective included the assessment of safety up to 12 months postinfusion and of preliminary efficacy. METHODS: Fourteen patients with UCDs and 6 with CN syndrome were divided into 3 cohorts by body weight and intraportally infused with 3 doses of HepaStem. Clinical status, portal vein hemodynamics, morphology of the liver, de novo detection of circulating anti-human leukocyte antigen antibodies, and clinically significant adverse events (AEs) and serious adverse events to infusion were evaluated by using an intent-to-treat analysis. RESULTS: The overall safety of HepaStem was confirmed. For the entire study period,…

BACKGROUND: Early detection of rejection in kidney transplant recipients holds the promise to improve clinical outcomes. Development and implementation of more accurate, noninvasive methods to detect allograft rejection remain an ongoing challenge. The limitations of existing allograft surveillance methods present an opportunity for donor-derived cell-free DNA (dd-cfDNA), which can accurately and rapidly differentiate patients with allograft rejection from patients with stable organ function. METHODS: This study evaluated the analytical performance of a massively multiplexed polymerase chain reaction assay that targets 13 962 single-nucleotide polymorphisms, characterized and validated using 66 unique samples with 1064 replicates, including cell line-derived reference samples, plasma-derived mixtures, and transplant patient samples. The dd-cfDNA fraction was quantified in both related and unrelated donor-recipient pairs. RESULTS: The dd-cfDNA assay showed a limit of blank of 0.11%, a limit of detection and limit of quantitation of 0.15% for unrelated donors, and limit of blank of…

BACKGROUND: The optimal method of oxygen delivery to donor kidneys during ex vivo machine perfusion has not been established. We have recently reported the beneficial effects of subnormothermic (22°C) blood perfusion in the preservation of porcine donation after circulatory death kidneys. Since using blood as a clinical perfusate has limitations, including matching availability and potential presence of pathogen, we sought to assess hemoglobin-based oxygen carrier (HBOC-201) in oxygen delivery to the kidney for renal protection. METHODS: Pig kidneys (n = 5) were procured after 30 minutes of warm in situ ischemia by cross-clamping the renal arteries. Organs were flushed with histidine tryptophan ketoglutarate solution and subjected to static cold storage or pulsatile perfusion with an RM3 pump at 22°C for 4 hours with HBOC-201 and blood. Thereafter, kidneys were reperfused with normothermic (37°C) oxygenated blood for 4 hours. Blood and urine were subjected to biochemical analysis. Total urine output, urinary protein, albumin/creatinine ratio, flow rate, resistance were measured.…

Preamble Organ transplantation, one of the greatest medical success stories of the twentieth century, has prolonged and improved the lives of hundreds of thousands of patients worldwide. Countless acts of generosity by organ donors and their families, as well as the many important scientific and clinical advances achieved by dedicated health professionals, have made transplantation not only a life-saving therapy but a symbol of human solidarity. Yet these accomplishments have been tarnished by numerous instances of organ trafficking, of trafficking in persons for the purpose of organ removal, and of patients who travel abroad to purchase organs from poor and vulnerable people. In 2007 it was estimated that up to 10% of transplants worldwide involved such practices.1 To address the urgent and growing problems posed by these unethical activities, the Transplantation Society (TTS) and the International Society of Nephrology (ISN) convened a Summit Meeting in Istanbul in April 2008. 151 participants—representatives of scientific and medical bodies, government officials, social…

BACKGROUND: Comorbidity is increasingly common in kidney transplant recipients, yet the implications for transplant outcomes are not fully understood. We analyzed the relationship between recipient comorbidity and survival outcomes in a UK-wide prospective cohort study-Access to Transplantation and Transplant Outcome Measures (ATTOM). METHODS: A total of 2100 adult kidney transplant recipients were recruited from all 23 UK transplant centers between 2011 and 2013. Data on 15 comorbidities were collected at the time of transplantation. Multivariable Cox regression models were used to analyze the relationship between comorbidity and 2-year graft survival, patient survival, and transplant survival (earliest of graft failure or patient death) for deceased-donor kidney transplant (DDKT) recipients (n = 1288) and living-donor kidney transplant (LDKT) recipients (n = 812). RESULTS: For DDKT recipients, peripheral vascular disease (hazard ratio [HR] 3.04, 95% confidence interval [CI]: 1.37-6.74; P = 0.006) and obesity (HR 2.27, 95% CI: 1.27-4.06; P = 0.006) were independent risk factors for…

BACKGROUND: Kidneys from deceased donors with acute kidney injury (AKI) are more likely to be discarded because of concerns for poor outcomes after transplantation. The aim of this study was to determine the long-term outcomes of a large cohort of patients transplanted utilizing kidneys from deceased donors with AKI. METHODS: All patients receiving a deceased donor kidney transplant during a recent 10-year period were included. Acute Kidney Injury Network (AKIN) criteria were used to classify the donors. Donor kidneys with >10% cortical necrosis or more than mild chronic changes were discarded. The primary outcome is the combined endpoint of death or graft loss. RESULTS: The cohort included 1313 kidneys from 974 donors, AKIN stage 0 (no AKI) in 319 (24.3%), stage 1 in 370 (28.2%), stage 2 in 177 (13.5), and stage 3 in 447 (34.0%). Estimated 5-year graft survival (95% confidence interval) was 78.5% (72.5-84.5), 77.8% (72.8-82.1), 83.8% (76.8-88.9), and 84.6% (79.5-88.7) for AKIN donor stage 0 to 3, respectively (log-rank P = 0.10). After adjusting for baseline differences, the hazard…

BACKGROUND: The French uncontrolled donors after circulatory death (DCD) protocol restricts donor age to <55 years, no-flow time to <30 minutes, and functional warm ischemia time to <150 minutes. In situ kidney perfusion can be performed at either 4°C (in situ cooling [ISC]) or 33-36°C (normothermic regional perfusion [NRP]). Hypothermic machine perfusion is systematically used. Only nonimmunized first transplant recipients were eligible. To improve the management of uncontrolled DCD, we tried to identify factors predictive of outcome. METHODS: We identified all kidney transplants from uncontrolled DCD between 2007 and 2014 from the French Transplant Registry. Risk factors for primary nonfunction (PNF; n = 37) and poor renal function (estimated glomerular filtration rate < 30 mL/min or graft loss at 1 y, n = 66) were analyzed by using a multivariate logistic model. RESULTS: This study analyzed 499 kidney transplantations, 50% of which were performed with NRP. Mean functional warm ischemia time was 135 minutes. Mean cold ischemia time was 14 hours. The principal PNF risk factor was…

BACKGROUND: Patient survival with end-stage renal disease is longer after kidney transplantation (KT) compared with those remaining on dialysis. Nevertheless, this remains uncertain when receiving a kidney from a donor ≥80 years old. METHODS: In a longitudinal mortality study in the Catalan Renal Registry including 2585 patients ≥60 years old on dialysis and placed on the KT waiting list, 1084 received a first KT from a deceased donor aged 60 to 79 years and 128 from a deceased donor ≥80 years. We calculated adjusted risk of graft loss by means of competing-risks regression, considering patient death with functioning graft as a competing event. To assess patient survival benefit from KT, we calculated the adjusted risk of death by nonproportional hazard analysis, taking the fact of being transplanted as a time-dependent effect. Considering all KT ≥60 (n = 1212), we assessed whether the benefit of KT varied per different recipient characteristics by calculating the interaction effect between all potential mortality risk factors and the treatment group. RESULTS: Compared with kidneys…

BACKGROUND: We examined the association between sarcopenia and post-transplant mortality in acutely ill inpatients with cirrhosis who underwent urgent liver transplantation. METHODS: Included were inpatients at 4 centers who were urgently listed as nonstatus 1 and transplanted from 2005 to 2017 with an abdominal computed tomography scan <90 days before transplantation. Skeletal muscle index (SMI) = total skeletal muscle cross-sectional area at the L3 vertebral level, normalized to height. Cox regression associated SMI with post-transplant mortality. Optimal search identified SMI cutoffs to detect survival. RESULTS: Of 126 inpatients, 63% were male patients, model for end-stage liver disease (MELDNa) was 32, and follow up was 5.1 years. Among men, 23% died. Median SMI was lower in men who died versus survived (45 versus 51 cm/m). SMI was associated with post-transplant mortality (hazard ratio [HR] = 0.96 per cm/m, 95% CI 0.92-0.99). Patients with SMI ≤ 48 cm/m versus >48 cm/m experienced higher rates of death at 1 year (86% versus 95%) and 3 years (73% versus 95%) (Log-rank P =…

Complement plays important roles in both ischemia-reperfusion injury (IRI) and antibody-mediated rejection (AMR) of solid organ allografts. One approach to possibly improve outcomes after transplantation is the use of C1 inhibitor (C1-INH), which blocks the first step in both the classical and lectin pathways of complement activation and also inhibits the contact, coagulation, and kinin systems. C1-INH can also directly block leukocyte-endothelial cell adhesion. C1-INH contrasts with eculizumab and other distal inhibitors, which do not affect C4b or C3b deposition or noncomplement pathways. Authors of reports on trials in kidney transplant recipients have suggested that C1-INH treatment may reduce IRI and delayed graft function, based on decreased requirements for dialysis in the first month after transplantation. This effect was particularly marked with grafts with Kidney Disease Profile Index ≥ 85. Other clinical studies and models suggest that C1-INH may decrease sensitization and donor-specific antibody production and might improve outcomes in AMR, including in patients who are…

BACKGROUND: The morbidity and mortality from alcohol-related liver disease (ALD) is increasing in the United States. However, little is known about gender differences in evaluation and listing for liver transplantation (LT) in patients with ALD. METHODS: This is a retrospective review of adult patients with ALD evaluated for LT at a single transplant center from January 1, 2010, to March 1, 2017. Univariate, multivariate, and time-series analyses were performed. RESULTS: Among the 949 patients with ALD evaluated, mean age was 53 years, 84% were Caucasian, and 33% were women. The median model for end-stage liver disease score was similar between the genders. Women were less likely to be listed for LT (10% versus 19%; P < 0.05). The proportion of women not listed due to active substance use was significantly higher versus men (42% versus 35%; P < 0.05), while the frequency of medical contraindications was comparable between the genders. During a median follow-up of 416 days (range: 0-2784), listed women with ALD were less likely to undergo transplantation (42% versus 47%; P < 0.05).…

BACKGROUND: Sorafenib (SOR) is currently used for hepatocellular carcinoma (HCC) recurring after liver transplantation (LT) when HCC is unsuitable for surgical/locoregional treatments. We evaluated safety and effectiveness of early introduction of SOR after HCC-recurrence. METHODS: All patients with HCC-recurrence after LT treated with SOR in 2 centers were included (January 2008 to June 2018). Baseline and on-treatment data were collected. RESULTS: Fifty patients early treated with SOR for HCC-recurrence after LT (74% mammalian target of rapamycin inhibitor [mTORi], 54% HCC-treated at baseline) were enrolled. During 7.3 (0.3-88) months of SOR, all patients had at least one adverse event (AE), 56% graded 3-4. SOR was reduced in 68%, being AEs the main cause of reduction, and discontinued in 84% (60% symptomatic progression, 33% AE). Objective response was obtained in 16% and stable disease in 50%. Median time to radiological progression was 6 months (95% confidence Interval [CI], 4-8). Thirty-three patients (69%) died, 94% for HCC progression. Median overall survival (OS) was 18…

BACKGROUND: Islet transplantation is a promising option for the treatment of type 1 diabetes. However, the current lack of practical techniques for the isolated islets preservation still hampers the advancement of life-saving islet transplantation. Islet suffers from internal or external stimuli-induced oxidative stress and subsequent inflammation during preservation, which leads to disappointing outcomes regarding islet yield, survival, and function. Reactive oxygen species (ROS) overproduction is the primary cause of oxidative stress that induces islet loss and dysfunction. Thus, in this article, we hypothesized that an endogenous antioxidant, bilirubin, that could efficiently scavenge ROS and inhibit inflammatory reactions could be beneficial for islet preservation. METHODS: Herein, we studied the effect of bilirubin on the hypothermic preserved (4°C) islets and evaluate the islets viability, insulin secretory function, oxidative stress levels, and in vivo transplantation performance. RESULTS: Bilirubin could prevent cellular damages during short-term preservation and maintain…

BACKGROUND: There are no instruments that can identify patients at an increased risk of poor outcomes after liver transplantation (LT) based only on their preoperative characteristics. The primary aim of this study was to develop such a scoring system. Secondary outcomes were to assess the discriminative performance of the predictive model for 90-day mortality, 1-year mortality, and 5-year patient survival. METHODS: The study population was represented by 30 458 adults who underwent LT in the United States between January 2002 and June 2013. Machine learning techniques identified recipient age, Model for End-Stage Liver Disease score, body mass index, diabetes, and dialysis before LT as the strongest predictors for 90-day postoperative mortality. A weighted scoring system (minimum of 0 to a maximum of 6 points) was subsequently developed. RESULTS: Recipients with 0, 1, 2, 3, 4, 5, and 6 points had an observed 90-day mortality of 6.0%, 8.7%, 10.4%, 11.9%, 15.7%, 16.0%, and 19.7%, respectively (P ≤ 0.001). One-year mortality was 9.8%, 13.4%, 15.8%, 17.2%, 23.0%, 25.2%, and 35.8% (P ≤…

BACKGROUND: The innovative pure laparoscopic living donor right hepatectomy (LLDRH) procedure for liver transplantation has never been fully compared to open living donor right hepatectomy (OLDRH). We aimed to compare the donor safety and graft results of pure LLDRH to those of OLDRH. METHODS: From May 2013 to July 2017, 288 consecutive donors underwent either OLDRH (n = 197) or pure LLDRH (n = 91). After propensity score matching, 72 donors were included in each group. The primary outcome was postoperative complications during a 90-day follow-up period. Comprehensive complication index, duration of hospital stay, need for additional pain control, readmission, and donor outcomes were also compared. RESULTS: The incidence of major complication during the 90-day follow-up was higher in the LLDRH group than the OLDRH group (6.6% vs 15.4%, P = 0.017) but was not statistically significant in propensity-matched analysis (11.1% vs 13.9%, odds ratio [OR], 1.29; 95% confidence interval [CI], 0.47-3.51; P = 0.62). A right hepatic duct <1 cm was independently associated with complication in…

BACKGROUND: Frailty is a clinically recognized syndrome of decreased physiological reserve and a key contributor to suboptimal clinical outcomes in various lung disease groups. Interstitial lung disease (ILD) is fast approaching chronic obstructive pulmonary disease as the number one indication for lung transplantation worldwide. Our aim was to assess whether frailty is a predictor of mortality in patients with ILD referred for lung transplantation in an Australian cohort. METHODS: Consecutive patients with ILD referred or on the waiting list for lung transplantation from May 2013 to December 2017 underwent frailty assessment using the modified Fried's frailty phenotype. Frailty was defined as a positive response to ≥3 of the following 5 components: weak grip strength, slowed walking speed, poor appetite, physical inactivity, and exhaustion. RESULTS: One hundred patients (82 male:18 female; age, 59 ± 7 y; range, 30-70) underwent frailty assessment. Twenty-four of 100 (24%) were assessed as frail. Frailty was associated with anemia, hypoalbuminemia, low creatinine, and the use of…

BACKGROUND: Although allogeneic-induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) exhibit potential in cardiomyogenesis for heart failure, whether major histocompatibility complex (MHC)-matched allogenic iPSC implantation (MMAI) minimizes immune rejection for cell survival or functional recovery remains unknown. We herein explored whether MMAI with an iPSC-CM sheet is stable for a longer period and therapeutically more effective than MHC-mismatched AI in a primate ischemic cardiomyopathy model. METHODS: Green fluorescent protein-transfected iPSC-CM sheets, derived from cynomolgus macaques with homozygous MHC haplotypes ''HT1,'' were transplanted on the left ventricle, generated by ligating the left anterior descending artery for 2 weeks in an ischemic model with or without heterozygous HT1 as MMAI and MHC-mismatched AI. Sham models were made by opening the chest at 14 days after left anterior descending ligation without any treatment. RESULTS: Stereomicroscopy revealed that at 4 months after transplantation, green fluorescent protein intensity was higher in the MMAI…

BACKGROUND: A calcineurin inhibitor (CNI)-free immunosuppressive regimen has been demonstrated to improve renal function early after heart transplantation, but long-term outcome of such a strategy has not been well described. METHODS: In the randomized SCHEDULE trial, de novo heart transplant recipients received (1) everolimus with reduced-exposure CNI (cyclosporine) followed by CNI withdrawal at week 7-11 posttransplant or (2) standard-exposure cyclosporine, both with mycophenolate mofetil and corticosteroids; 95/115 randomized patients were followed up at 5-7 years posttransplant. RESULTS: Mean measured glomerular filtration rate was 74.7 mL/min and 62.4 mL/min with everolimus and CNI, respectively. The mean difference was in favor of everolimus by 11.8 mL/min in the intent-to-treat population (P = 0.004) and 17.2 mL/min in the per protocol population (n = 75; P < 0.001). From transplantation to last follow-up, the incidence of biopsy-proven acute rejection (BPAR) was 77% (37/48) and 66% (31/47) (P = 0.23) with treated BPAR in 50% and 23% (P < 0.01) in the everolimus and CNI…

Following successful kidney transplantation, recipients usually regain fertility. Post-engraftment pregnancies should be planned and the teratogenic mycophenolic acid should be replaced with azathioprine before conception. To avoid unintentional pregnancies, pre-conception counseling is mandatory in women of reproductive age who are scheduled for a kidney transplant. Counseling should be repeated after transplantation. Female recipients should receive advice to use long-acting reversible contraception and avoid pregnancy for a minimum of 1 year following transplantation. Conception should be deferred even longer in female recipients with moderate to severe proteinuria, uncontrolled hypertension or reduced graft function and be very carefully discussed in highly HLA-sensitized patients. The recipient wishes, values and acceptance of pregnancy-related risk should receive attention. Assisted fertilization increases the risk of pre-eclampsia, but still result in live births. Pregnancy management in kidney transplant recipients should be provided by a multidisciplinary team consisting of…

BACKGROUND: In a randomized controlled trial, lung transplant recipients (LTRs) using a mobile health intervention, Pocket Personal Assistant for Tracking Health (Pocket PATH), showed better adherence to the medical regimen than LTRs receiving usual care during the first year posttransplant. We examined whether these effects were maintained beyond the end of the trial and evaluated other potential risk factors for long-term nonadherence. METHODS: Adherence in 8 areas was evaluated at follow-up in separate LTR and family caregiver (collateral) assessments. Pocket PATH and usual care groups' nonadherence rates were compared; multivariable regression analyses then examined and controlled for other patient characteristics' associations with nonadherence. RESULTS: One hundred five LTRs (75% of survivors) were assessed (M = 3.9 years posttransplant, SD = 0.8). Nonadherence rates in the past month were 23%-81% for self-care and lifestyle requirements (diet, exercise, blood pressure monitoring, spirometry), 13%-23% for immunosuppressants and other medications, and 4% for tobacco use, with…

BACKGROUND: Letermovir, a new viral terminase complex inhibitor, has been approved for the prevention of cytomegalovirus (CMV) infection in hematopoietic stem cell transplant patients. However, data on the efficacy and safety of letermovir for the treatment of CMV infection in transplant recipients remain scarce. METHODS: We performed a single-center retrospective study of stem cell and organ transplant recipients who received letermovir for the treatment of CMV infection from November 2017 to October 2018. RESULTS: Six patients were included, and 5 were evaluable. All received letermovir in the context of a refractory or resistant CMV infection including asymptomatic CMV viremia (n = 3), CMV syndrome (n = 1), and CMV pneumonitis and colitis (n = 1). The 3 asymptomatic patients experienced a decrease of the viral load (VL) to <200 IU/mL after letermovir therapy. One patient displayed a partial VL response (2-log of VL reduction) but a good clinical response, and one who received a suboptimal dose of letermovir experienced an increase of viremia. There were no treatment-related…

The human liver is an organ with a diverse array of immunologic functions. Its unique anatomic position that leads to it receiving all the mesenteric venous blood, combined with its unique micro anatomy, allows it to serve as a sentinel for the body's immune system. Hepatocytes, biliary epithelial cells, Kupffer cells, stellate cells, and liver sinusoidal endothelial cells express key molecules that recruit and activate innate and adaptive immunity. Additionally, a diverse array of lymphoid and myeloid immune cells resides within and traffics to the liver in specific circumstances. Derangement of these trafficking mechanisms underlies the pathophysiology of autoimmune liver diseases, nonalcoholic steatohepatitis, and liver transplantation. Here, we review these pathways and interactions along with potential targets that have been identified to be exploited for therapeutic purposes.

A recent technological advance that shows promise for applications in health care, including transplantation medicine, is the implementation of nanoparticles. Nanoparticles can be composed of a variety of organic or inorganic materials and confer many advantages over conventional treatments available, such as low toxicity, low-effective dosage required, and a high degree of manipulability. Although also used for imaging and diagnostics, nanoparticles' utility as a drug or genetic delivery system is of particular interest in transplantation medicine. Currently, researchers are exploring options to integrate nanoparticles into both diagnostics and therapy for both grafts ex-situ before transplantation and for patients following transplantation. These studies have demonstrated that nanoparticles can mitigate damage to organs and patients through a large variety of mechanisms-ranging from the induction of cellular genetic changes to the enhancement of immunosuppressive drug delivery. Specifically, with the advent of machine perfusion preservation ex vivo, treatment of the graft became a…

Membranous nephropathy (MN) is a common cause of nephrotic syndrome after transplantation and is associated with an increased risk of allograft loss. MN may occur either as a recurrent or as a de novo disease. As in native kidneys, the pathophysiology of the MN recurrence is in most cases associated with antiphospholipid A2 receptor antibodies. However, the posttransplant course has some distinct features when compared with primary MN, including a lower chance of spontaneous remission and a greater requirement for adjuvant immunosuppressive therapy to induce complete remission. Although the efficacy of rituximab in primary MN is now well established, no randomized studies have assessed its effectiveness in MN after transplant, and there are no specific recommendations for the management of these patients. This review aims to synthesize and update the pathophysiology of posttransplant MN, as well as to address unsolved issues specific to transplantation, including the prognostic value of antiphospholipid A2 receptor, the risk of living-related donation, the link between de novo MN…

BACKGROUND: Highly sensitized patients are difficult to match with suitable renal allograft donors and may benefit from xenotransplant trials. We evaluate antibody binding from sensitized patients to pig cells and engineered single allele cells to identify anti-human leukocyte antigen (HLA) antibody cross-species reactivity with swine leukocyte antigen (SLA). These novel testing strategies assess HLA/SLA epitopes and antibody-binding patterns and introduce genetic engineering of SLA epitopes. METHODS: Sensitized patient sera were grouped by calculated panel reactive antibody and luminex single antigen reactivity profile and were tested with cloned GGTA1/CMAH/B4GalNT2 glycan knockout porcine cells. Pig reactivity was assessed by direct flow cytometric crossmatch and studied following elution from pig cells. To study the antigenicity of individual class I HLA and SLA alleles in cells, irrelevant sera binding to lymphoblastoid cells were minimized by CRISPR/Cas9 elimination of endogenous class I and class II HLA, B-cell receptor, and Fc receptor genes. Native HLA, SLA, and mutants of…

BACKGROUND: New-onset diabetes is common after kidney transplantation, but the benefit of lifestyle intervention to improve glucose metabolism posttransplantation is unproven. METHODS: We conducted a single-center, randomized controlled trial involving 130 nondiabetic kidney transplant recipients with stable function between 3 and 24 months post-transplantation. Participants were randomly assigned in a 1:1 ratio to receive active intervention (lifestyle advice delivered by renal dietitians using behavior change techniques) versus passive intervention (leaflet advice alone). Primary outcome was 6-month change in insulin secretion, insulin sensitivity, and disposition index. Secondary outcomes included patient-reported outcomes, cardiometabolic parameters, clinical outcomes, and safety endpoints. RESULTS: Between August 17, 2015 and December 18, 2017, 130 individuals were recruited, of whom 103 completed the study (drop-out rate 20.8%). Active versus passive intervention was not associated with any change in glucose metabolism: insulin secretion (mean difference, -446; 95% confidence…