The 50 most-cited articles in Transplantation, 2018

Despite recent advances, cytomegalovirus (CMV) infections remain one of the most common complications affecting solid organ transplant recipients, conveying higher risks of complications, graft loss, morbidity, and mortality. Research in the field and development of prior consensus guidelines supported by The Transplantation Society has allowed a more standardized approach to CMV management. An international multidisciplinary panel of experts was convened to expand and revise evidence and expert opinion-based consensus guidelines on CMV management including prevention, treatment, diagnostics, immunology, drug resistance, and pediatric issues. Highlights include advances in molecular and immunologic diagnostics, improved understanding of diagnostic thresholds, optimized methods of prevention, advances in the use of novel antiviral therapies and certain immunosuppressive agents, and more savvy approaches to treatment resistant/refractory disease. The following report summarizes the updated recommendations.

The Banff Classification of Allograft Pathology is an international consensus classification for the reporting of biopsies from solid organ transplants. Since its initial conception in 1991 for renal transplants, it has undergone review every 2 years, with attendant updated publications. The rapid expansion of knowledge in the field has led to numerous revisions of the classification. The resultant dispersal of relevant content makes it difficult for novices and experienced pathologists to faithfully apply the classification in routine diagnostic work and in clinical trials. This review shall provide a complete and simple illustrated reference guide of the Banff Classification of Kidney Allograft Pathology based on all publications including the 2017 update. It is intended as a concise desktop reference for pathologists and clinicians, providing definitions, Banff Lesion Scores and Banff Diagnostic Categories. An online website reference guide hosted by the Banff Foundation for Allograft Pathology (www.banfffoundation.org) is being developed, which will be updated with future…

Nonalcoholic fatty liver disease (NAFLD) represents a growing cause of chronic liver injury, especially in western countries, where it is becoming the most frequent indication for liver transplantation. Nonalcoholic fatty liver disease encompasses a spectrum of diseases that from simple steatosis (pure NAFLD) can progress to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD and the mechanisms behind its progression to NASH have been extensively studied. However, although the processes that determine fat accumulation are mostly clear, the mechanisms associated with the progression of the disease are not fully characterized. In predisposed patients, lipid accumulation can promote lipotoxicity and mitochondrial dysfunction, thus triggering hepatocyte death, inflammation and fibrosis. The specific role of different lipids has been identified and free fatty acids as well as free cholesterol have been identified as toxic species. To make the picture more complex, the pathogenesis of NAFLD involves pathological connections between…

Nonalcoholic fatty liver disease (NAFLD) affects 25% of the global adult population with a range of 13.5% in Africa and 31.8% in the Middle East. Nonalcoholic fatty liver disease is closely associated with a constellation of metabolic comorbidities which include: obesity, type 2 diabetes mellitus, hypertension, and hypercholesteremia. In fact, the increasing number of metabolic comorbidities not only increases the prevalence of NAFLD but also places patients at higher risk for progressive liver disease. As such, NAFLD is presently among the top etiologies for hepatocellular carcinoma and an indication for liver transplantation (LT) in the United States. Therefore, the following recommendations are made based on our current knowledge of NAFLD and its consequences: (1) the evaluation of the risk of liver disease progression can be affected by patient's ethnic origin and sex; (2) fibrosis in NAFLD is the most important predictor of mortality; (3) we recommend that individuals who present with features of metabolic syndrome in the presence of elevated liver enzymes should be screened…

In Brief Effective immunosupression management is central to achieving optimal outcomes in liver transplant recipients. Current immunosuppression regimens and agents are highly effective in minimizing graft loss due to acute and chronic rejection but can also produce a substantial array of toxicities. The utilization of immunosuppression varies widely, contributing to the wide disparities in posttransplant outcomes reported between transplant centers. The International Liver Transplantation Society (ILTS) convened a consensus conference, comprised of a global panel of expert hepatologists, transplant surgeons, nephrologists, and pharmacologists to review the literature and experience pertaining to immunosuppression management to develop guidelines on key aspects of immunosuppression. The consensus findings and recommendations of the ILTS Consensus guidelines on immunosuppression in liver transplant recipients are presented in this article. The ILTS consensus document on immunosuppression in liver transplant recipients covers both the scope of therapeutic agents for induction and…

BACKGROUND: There is increasing interest in the use of noninvasive biomarkers to reduce the risks posed by invasive biopsy for monitoring of solid organ transplants (SOTs). One such promising marker is the presence of donor-derived cell-free DNA (dd-cfDNA) in the urine or blood of transplant recipients. METHODS: We systematically reviewed the published literature investigating the use of cfDNA in monitoring of graft health after SOT. Electronic databases were searched for studies relating cfDNA fraction or levels to clinical outcomes, and data including measures of diagnostic test accuracy were extracted. Narrative analysis was performed. RESULTS: Ninety-five articles from 47 studies met the inclusion criteria (18 kidneys, 7 livers, 11 hearts, 1 kidney-pancreas, 5 lungs, and 5 multiorgans). The majority were retrospective and prospective cohort studies, with 19 reporting diagnostic test accuracy data. Multiple techniques for measuring dd-cfDNA were reported, including many not requiring a donor sample. dd-cfDNA falls rapidly within 2 weeks, with baseline levels varying by organ…

BACKGROUND: Ex situ normothermic machine perfusion (NMP) can be used to assess viability of suboptimal donor livers before implantation. Our aim was to assess the diagnostic accuracy of bile biochemistry for the assessment of bile duct injury (BDI). METHODS: In a preclinical study, 23 human donor livers underwent 6 hours of end-ischemic NMP to determine biomarkers of BDI. Livers were divided into groups with low or high BDI, based on a clinically relevant histological grading system. During NMP, bile was analyzed biochemically and potential biomarkers were correlated with the degree of BDI. Receiver operating characteristics curves were generated to determine optimal cutoff values. For clinical validation, identified biomarkers were subsequently included as viability criteria in a clinical trial (n = 6) to identify transplantable liver grafts with low BDI. RESULTS: Biliary bicarbonate and pH were significantly higher and biliary glucose was significantly lower in livers with low BDI, compared with high BDI. The following cutoff values were associated with low BDI: biliary…

BACKGROUND: Sex-based disparities in liver transplantation (LT) are incompletely understood. We assessed the role of height, Model for End-Stage Liver Disease (MELD), MELD-Na, and exception points in the disparate access to LT. METHODS: Adults waitlisted for LT at Organ Procurement and Transplantation Network between 2002 and 2013 were included. Covariates associated with likelihood of LT were analyzed by Cox proportional model. In a separate cohort of waitlisted adults with glomerular filtration rate measurement by iothalamate clearance (n = 611), we determined the number of creatinine-derived MELD points in men versus women, across all ranges of glomerular filtration rate. The impact of correcting the MELD score deficit in women on LT was modeled. RESULTS: Among 90 720 Organ Procurement and Transplantation Network registrants, women had higher mortality than men (4 years after listing: 22% vs 18%, P < 0.0001), and lower likelihood of LT (49% vs 58%, P < 0.0001); women were 20% less likely to be transplanted (hazard ratio, 0.80; 95% confidence interval, 0.78-0.81). Differences in…

BACKGROUND: Current treatments for antibody-mediated rejection (AMR) in kidney transplantation are based on low-quality data from a small number of controlled trials. Novel agents targeting B cells, plasma cells, and the complement system have featured in recent studies of AMR. METHODS: We conducted a systematic review and meta-analysis of controlled trials in kidney transplant recipients using Medline, EMBASE, and CENTRAL from inception to February 2017. RESULTS: Of 14 380 citations, we identified 21 studies, including 10 randomized controlled trials, involving 751 participants. Since the last systematic review conducted in 2011, we found nine additional studies evaluating plasmapheresis + intravenous immunoglobulin (IVIG) (two), rituximab (two), bortezomib (two), C1 inhibitor (two), and eculizumab (one). Risk of bias was serious or unclear overall and evidence quality was low for the majority of treatment strategies. Sufficient RCTs for pooled analysis were available only for antibody removal, and here there was no significant difference between groups for graft survival (HR 0.76;…

Since the implementation of the Model of End-stage Liver Disease score-based allocation system, the number of transplant candidates with impaired renal function has increased. The aims of this review are to present new insights in the definitions and predisposing factors that result in acute kidney injury (AKI), and to propose guidelines for the prevention and treatment of postliver transplantation (LT) AKI. This review is based on both systematic review of relevant literature and expert opinion. Pretransplant AKI is associated with posttransplant morbidity, including prolonged post-LT AKI which then predisposes to posttransplant chronic kidney disease. Prevention of posttransplant AKI is essential in the improvement of long-term outcomes. Accurate assessment of baseline kidney function at evaluation is necessary, taking into account that serum creatinine overestimates glomerular filtration rate. New diagnostic criteria for AKI have been integrated with traditional approaches in patients with cirrhosis to potentially identify AKI earlier and improve outcomes. Delayed introduction or…

BACKGROUND: Considerable differences exist among the living donor Kidney Exchange Programmes (KEPs) that are in use and being built in Europe, contributing to a variation in the number of living donor transplants (Newsletter Transplant; International figures on donation and transplantation 2016). Efforts of European KEPs to exchange (best) practices and share approaches to address challenges have, however, been limited. METHODS: Experts from 23 European countries, collaborating on the European Network for Collaboration on Kidney Exchange Programmes Cooperation on Science and Technology Action, developed a questionnaire to collect detailed information on the functioning of all existing KEPs in Europe, as well as their opportunities and challenges. Following a comparative analysis, results were synthesized and interpreted by the same experts. RESULTS: The practices, opportunities and challenges reported by 17 European countries reveal that some of the 10 operating programs are mature, whereas others are in earlier stages of development. Over 1300 transplants were performed through…

BACKGROUND: Among community-dwelling older adults, frailty is associated with heightened markers of inflammation and subsequent mortality. Although frailty is common among end-stage renal disease (ESRD) patients, the role of frailty and markers of inflammation in this population remains unclear. We quantified these associations in patients on the kidney transplant waitlist and tested whether frailty and/or markers of inflammation improve waitlist mortality risk prediction. METHODS: We studied 1975 ESRD patients on the kidney transplant waitlist (November 1, 2009, to February 28, 2017) in a multi-center cohort study of frailty. Serum inflammatory markers (interleukin-6 [IL-6], soluble tumor necrosis factor-α receptor-1 [sTNFR1], and C-reactive protein [CRP]) were analyzed in 605 of these participants; we calculated the inflammatory index score using IL-6 and sTNFR1. We compared the C-statistic of an established registry-based prediction model for waitlist mortality adding frailty and/or inflammatory markers (1 SD change in log IL-6, sTNFR1, CRP, or inflammatory index). RESULTS: The…

BACKGROUND: Heart transplantation (HTx) remains the most effective long-term treatment for advanced heart failure. Primary graft dysfunction (PGD) continues to be a potentially life-threatening early complication. In 2014, a consensus statement released by International Society for Heart and Lung Transplantation (ISHLT) established diagnostic criteria for PGD. We studied the incidence of PGD across the United Kingdom. METHODS: We analyzed the medical records of all adult patients who underwent HTx between October 2012 and October 2015 in the 6 UK heart transplant centers Preoperative donor and recipient characteristics, intraoperative details, and posttransplant complications were compared between the PGD and non-PGD groups using the ISHLT definition. Multivariable analysis was performed using logistic regression. RESULTS: The incidence of ISHLT PGD was 36%. Thirty-day all-cause mortality in those with and without PGD was 31 (19%) versus 13 (4.5%) (P = 0.0001). Donor, recipient, and operative factors associated with PGD were recipient diabetes mellitus (P = 0.031), recipient…

BACKGROUND: In the United States, 1 in 10 infants and 1 in 20 older children die on the liver transplant waiting list. Increasing split liver transplantation could increase organ availability for these children, without decreasing transplants in adults. METHODS: Using United Network for Organ Sharing Standard Transplant Analysis and Research data, we identified livers transplanted 2010 to 2015 that could potentially have been used for split transplant, based on strict criteria. Livers not suitable for pediatric patients or allocated to high-risk recipients were excluded. Number and distribution of potentially "split-able" livers were compared to pediatric waitlist deaths in each region. RESULTS: Of 37 333 deceased donor livers transplanted, 6.3% met our strict criteria for utilization in split liver transplant. Only 3.8% of these were actually utilized for split liver transplantation. 96% were used for a single adult recipient. Of the 2253 transplanted as whole livers, 82% of their recipients were listed as willing to accept a segmental liver, and only 3% were listed as requiring a…

BACKGROUND: Antibody-mediated rejection is a major cause of premature graft loss in kidney transplantation. Multiple scoring systems are available to assess the HLA mismatch between donors and recipients at the molecular level; however, their correlation with the development of de novo donor-specific antibody (dnDSA) has not been compared in recipients on active immunosuppression. METHODS: HLA-DRβ1/3/4/5/DQα1β1 molecular mismatch was determined using eplet analysis, amino acid mismatch, and electrostatic mismatch for 596 renal transplant recipients and correlated with HLA-DR/DQ dnDSA development. The molecular mismatch scores were evaluated in multivariate models of posttransplant dnDSA-free survival. RESULTS: Eplet mismatch correlated with amino acid mismatch and electrostatic mismatch (R = 0.85-0.96). HLA-DR dnDSA-free survival correlated with HLA-DR eplet mismatch (hazards ratio [HR], 2.50 per 10 eplets mismatched; P < 0.0001), amino acid mismatch (HR, 1.49 per 10 amino acids mismatched; P < 0.0001), and electrostatic mismatch (HR, 1.23 per 10 units mismatched; P < 0.0001).…

Nonalcoholic steatohepatitis (NASH)-related cirrhosis has become one of the most common indications for liver transplantation (LT), particularly in candidates older than 65 years. Typically, NASH candidates have concurrent obesity, metabolic, and cardiovascular risks, which directly impact patient evaluation and selection, waitlist morbidity and mortality, and eventually posttransplant outcomes. The purpose of these guidelines is to highlight specific features commonly observed in NASH candidates and strategies to optimize pretransplant evaluation and waitlist survival. More specifically, the working group addressed the following clinically relevant questions providing recommendations based on the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system supported by rigorous systematic reviews and consensus: (1) Is the outcome after LT similar to that of other etiologies of liver disease? (2) Is the natural history of NASH-related cirrhosis different from other etiologies of end-stage liver disease? (3) How should cardiovascular risk be assessed in the…

In parallel with the pandemic of obesity and diabetes, the prevalence of nonalcoholic fatty liver disease has progressively increased. Nonalcoholic steatohepatitis (NASH), a subtype of nonalcoholic fatty liver disease has also augmented considerably being currently cirrhosis due to NASH the second indication for liver transplantation in the United States. Innovative treatments for NASH have shown promising results in phase 2 studies and are being presently evaluated in phase 3 trials. On the other hand, the high mortality on the liver transplant waitlist and the organ shortage has obligated the transplant centers to consider suboptimal grafts, such as steatotic livers for transplantation. Fatty livers are vulnerable to preservation injury resulting in a higher rate of primary nonfunction, early allograft dysfunction and posttransplant vascular and biliary complications. Macrosteatosis of more than 30% in fact is an independent risk factor for graft loss. Therefore, it needs to be considered into the risk assessment scores. Growing evidence supports that moderate and severe…

We review contemporary coagulation management for patients undergoing liver transplantation. A better understanding of the complex physiologic changes that occur in patients with end-stage liver disease has resulted in significant advances in anesthetic and coagulation management. A group of internationally recognized experts have critically evaluated current approaches for coagulopathy detection and management. Strategies for blood component and factor replacement have been evaluated and recommended therapies proposed. Pharmacologic treatment and prevention of coagulopathy, management of patients receiving antiplatelet medications, and the role of transesophageal echocardiography for early detection and management of thromboses are presented.

BACKGROUND: Somatic stem cell (SC) therapy can improve cardiac performance following ischemic injury. In this study, we investigated whether induced pluripotent SC-derived cardiomyocytes (iPS-CMs) are more effective than somatic SCs, such as skeletal myoblasts (SM) and mesenchymal (M)SCs, in promoting functional recovery upon transplantation in a porcine model of myocardial infarction. METHODS: Myocardial injury was induced by ameroid ring placement in immunosuppressed female mini pigs; after 1 month, epicardial cell transplantation was performed with iPS-CMs (n = 7), SMs (n = 7), and MSCs (n = 7). Control pigs underwent sham operation (n = 8). RESULTS: Cell therapy improved functional recovery 2 months after myocardial infarction, as evidenced by increased ejection fraction (iPS-CM, +7.3% ± 2.2% and SM, +5.8% ± 5.4% vs control, -4.4% ± 3.8%; P < 0.05). The analysis of regional contractile function in the infarcted zone revealed an increase in transverse peak strain (iPS-CM, +4.6% ± 2.2% vs control, -3.8% ± 4.7%; P < 0.05). The C-11 acetate kinetic analysis by positron emission…

BACKGROUND: The feasibility of liver transplantation (LT) in elderly recipients remains a topic of debate. METHODS: This cohort study evaluated the impact of recipient's age on LT outcome between January 2007 and May 2016 covered by the Korean National Health Insurance system (n = 9415). Multilevel regression models were used to determine the impact of recipient's age on in-hospital and long-term mortality after LT. RESULTS: All patients had a first LT, with 2473 transplanted with liver from deceased donors (DD) and 6942 from living donors. The mean age was 52.2 ± 9.0 years. Most LT were performed on patients in their 50s (n = 4290, 45.6%) and 0.9% (n = 84) of the LT was performed on patients older 70 years. The overall in-hospital mortality was 6.3%, and the 3-year mortality was 11.3%. The in-hospital mortality included, 13.5% associated with DDLT and 3.7% involved living donor LT. When compared with that for patients aged 51 to 55 years, the risk of death among recipients older than 70 years was about fourfold higher after adjusting for baseline liver disease (odds ratio, 4.1; 95%…

BACKGROUND: Antibody-mediated rejection (AMR) is a leading cause of morbidity and mortality after kidney transplantation. Early diagnosis and treatment of subclinical AMR based on the donor-specific antibody (DSA) testing may result in better outcomes. METHODS: We tested this hypothesis in 220 kidney transplant recipients who underwent an indication or DSA-based surveillance protocol biopsies between March 1, 2013 and December 31, 2016. Patients were divided into 3 groups: clinical AMR (n = 118), subclinical AMR (n = 25), or no rejection on protocol biopsy (controls; n = 77). RESULTS: Both clinical and subclinical AMR groups underwent similar treatment including plasmapheresis, pulse steroids, IVIG, and rituximab (P = ns). Mean follow-up after AMR was 29.5 ± 16.8 months. There were 2 (3%), 2 (8%), and 54 (46%) death-censored graft failures in the control, subclinical, and clinical AMR groups, respectively (P < 0.001). Graft outcomes were similar in the subclinical rejection and control groups. In adjusted Cox regression analysis, only clinical rejection (hazards ratio [HR], 4.31;…

BACKGROUND: Hepatic steatosis is strongly associated with cardiovascular disease in the general population. Whether recurrent or de novo, it can occur in the allograft, but the impact on survival and long-term clinical outcomes remains unclear. In this study, we aim to determine both the frequency and impact of allograft steatosis on long-term posttransplant outcomes. METHODS: A retrospective review of 588 adult liver transplant (LT) recipients (1999-2006) was performed. Cox regression analysis (time-dependent) was used to evaluate differences in time to steatosis post-LT, patient survival, and cardiovascular outcomes. RESULTS: Mean age 51.9 ± 10.6 years, 64.6% males, underlying nonalcoholic steatohepatitis (NASH) (9.4%), previous tobacco (52%), pre-LT diabetes mellitus (30.3%), pre-LT hypertension (23.2%), and known cardiovascular disease (9.7%). Overall, 254 recipients developed allograft steatosis (at 10 years: 77.6% NASH recipients, 44.7% Non-NASH recipients). Risk factors for allograft steatosis were female sex (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.09-2.00;…

TRANSPLANT DEMOGRAPHICS Stable living donation rate representing approximately one third of total kidney transplantation. Near universal use of laparoscopic donor nephrectomy. 17% reduction in transplant waiting list largely driven by increased deceased circulatory death donation, the use of extended criteria donors, and developments within the UK Living Kidney Sharing Schemes to maximize the effectiveness of paired/pooled donation and nondirected altruistic donors. RISK FACTOR ASSESSMENT Updated thresholds for donation take account of the higher baseline glomerular filtration rate of men than women and are slightly less restrictive than previous recommendations. Updated pathway and recommended timeframes for donor assessment. Template screening questionnaire for the assessment of donor health. No upper limit for donation; however, careful risk factor assessment in donors older than 60. No formal upper limit of body mass index for donation, but increased risk when body mass index 30 to 35 kg/m2 and limited safety data greater than 35 kg/m2. Criteria for donor hypertension unchanged,…

β-cell replacement therapy, available currently as pancreas or islet transplantation, has developed without a clear definition of graft functional and clinical outcomes. The International Pancreas and Islet Transplant Association and European Pancreas and Islet Transplantation Association held a workshop to develop consensus for an International Pancreas and Islet Transplant Association and European Pancreas and Islet Transplant Association Statement on the definition of function and failure of current and future forms of β-cell replacement therapy. There was consensus that β-cell replacement therapy could be considered as a treatment for β-cell failure, regardless of etiology and without requiring undetectable C-peptide, accompanied by glycemic instability with either problematic hypoglycemia or hyperglycemia. Glycemic control should be assessed at a minimum by glycated hemoglobin (HbA1c) and the occurrence of severe hypoglycemia. Optimal β-cell graft function is defined by near-normal glycemic control (HbA1c ≤6.5% [48 mmol/mol]) without severe hypoglycemia or requirement for…

Nonalcoholic steatohepatitis (NASH) is a growing indication for liver transplant whether the primary or secondary cause of liver disease, and it is expected to be the leading indication in the years to come. Nonalcoholic steatohepatitis recurs after transplant but the impact of the recurrence on allograft and patient outcomes is unclear. A group of multidisciplinary transplant practice providers convened at the International Liver Transplantation Society NASH consensus conference with the purpose of determining the current knowledge and future directions for understanding the recurrence rates, risk and management of NASH in the transplant allograft. Specific questions relating to posttransplant NASH were proposed and reviewed in detail with recommendations on future actions to fill the knowledge gaps.

BACKGROUND: The gold standard for organ preservation before transplantation is static cold storage, which is unable to fully protect suboptimal livers from ischemia/reperfusion injury. An emerging alternative is normothermic machine perfusion (NMP), which permits organ reconditioning. Here, we aimed to explore the feasibility of a pharmacological intervention on isolated rat livers by using a combination of NMP and human liver stem cells-derived extracellular vesicles (HLSC-EV). METHODS: We established an ex vivo murine model of NMP capable to maintain liver function despite an ongoing hypoxic injury induced by hemodilution. Livers were perfused for 4 hours without (control group, n = 10) or with HLSC-EV (treated group, n = 9). Bile production was quantified; perfusate samples were collected hourly to measure metabolic (pH, pO2, pCO2) and cytolysis parameters (AST, alanine aminotransferase, lactate dehydrogenase). At the end of perfusion, we assessed HLSC-EV engraftment by immunofluorescence, tissue injury by histology, apoptosis by terminal deoxynucleotidyl transferase dUTP…

BACKGROUND: We provide the results of the first interventional study of cytomegalovirus (CMV)-specific immune monitoring to direct the length of antiviral prophylaxis in lung transplantation (LTx). METHODS: Patients (n = 118) at risk of CMV infection were randomized 1:2 to either 5 months or variable length valganciclovir prophylaxis (5-11 mo post-LTx), as determined by the QuantiFERON (QFN)-CMV assay. Patients with a negative QFN-CMV assay (< 0.2 IU/mL) received prolonged valganciclovir prophylaxis. RESULTS: The primary endpoint that was the incidence of CMV infection in the lung allograft within 18 months of LTx was significantly reduced in the QFN-CMV directed arm (37% versus 58%, P = 0.03). Secondary endpoints that included blood viremia, acute rejection, and chronic lung allograft dysfunction did not differ between the 2 arms. Of the 80/118 patients who ceased antiviral prophylaxis at 5 months, the incidence of viremia (> 600 copies/mL) within the blood was significantly reduced in patients with a positive QFN-CMV assay compared with those without protective immunity (13%…

BACKGROUND: Prolonged duration of delayed graft function (DGF) may be associated with adverse allograft outcomes, but the association between threshold duration of DGF, acute rejection and long-term allograft loss remains undefined. We aimed to determine the impact of DGF duration on allograft outcomes and to assess whether this association was mediated by acute rejection. METHODS: Using data from the Australian and New Zealand Dialysis and Transplant Registry, Cox proportional modeling was used to determine the association between quartiles of DGF duration, acute rejection at 6 months and death-censored graft loss (DCGL). Mediation analysis was conducted to determine whether acute rejection was a causal intermediate between DGF and DCGL. RESULTS: Of 7668 deceased donor kidney transplants between 1997 and 2014, 1497 (19.5%) recipients experienced DGF requiring dialysis. The median (interquartile range) duration of DGF was 7 (9) days, with 25% requiring dialysis for 14 days or longer. Among recipients who had experienced a DGF duration of 1 to 4 days, the adjusted hazard ratio for…

BACKGROUND: Hypothermic machine perfusion (HMP) of deceased donor kidneys is associated with better outcome when compared to static cold storage (CS). Nevertheless, there is little evidence whether kidneys with short cold ischemia time (CIT) also benefit from HMP and whether HMP can safely extend CIT. METHODS: We analyzed prospectively collected data from the Machine Preservation Trial, an international randomized controlled trial. Seven hundred fifty-two consecutive renal transplants were included: 1 kidney of each of the 376 donors was preserved by HMP, the contralateral organ was preserved by CS. RESULTS: The mean CIT was 3:05 PM (SD, 4:58 AM). A subgroup analysis was performed, groups were based on CIT duration: 0 to 10 hours, 10 to 15 hours, 15 to 20 hours, or 20 hours or longer. Delayed graft function (DGF) incidence in the subgroup with up to 10 hours CIT was 6.0% (N = 3/50) in the HMP arm and 28.1% (N = 18/64) in the CS arm (univariable P = 0.002; multivariable odds ratio [OR], 0.02; P = 0.007). Cold ischemia time remained an independent risk factor for DGF for machine…

BACKGROUND: Posttransplant lymphoproliferative disorders (PTLD) are a complication of solid organ transplantation (SOT) associated with Epstein-Barr virus (EBV). METHODS: We analyzed the incidence of and risk factors for PTLD among adult SOT recipients at our center over 30 years (1984-2013). We also compared PTLD incidence before and after a prevention strategy of EBV viral load monitoring in EBV serology mismatched patients was adapted in 2001 (ie, transplant era 1 [1983-2001] vs era 2 [2002-2013]). RESULTS: Among 4171 SOT patients, 109 developed PTLD. Cumulative incidence at 1, 10, and 20 years posttransplant was 0.95, 2.3, and 3.5 per 100 person-years, respectively. Beyond the first year peak of almost exclusively EBV-positive PTLD, a lower incidence of PTLD, predominantly EBV negative, persisted for 20 years. Thoracic transplant (hazard ratio [HR], 2.1; P = 0.007) and negative EBV serology (HR, 7.7; P < 0.001) were independent risk factors for PTLD on multivariate Cox regression analysis. EBV seronegativity significantly increased risk of early (HR, 18.5) and EBV-positive PTLD…

BACKGROUND: BK polyomavirus-associated nephropathy (BKPyVAN) constitutes a serious cause of kidney allograft failure, but large-scale data in pediatric renal transplant recipients and a comprehensive analysis of specific risk factors are lacking. METHODS: We analyzed the data of 313 patients in the Cooperative European Pediatric Renal Transplant Initiative Registry, with an observation period of 3.3 years (range, 1-5). The net state of immunosuppressive therapy was assessed by the modified Vasudev score. RESULTS: Presumptive BKPyVAN (defined as sustained [>3 wk] high-level BK viremia >10 copies/mL) within 5 years posttransplant occurred in 49 (15.8%) of 311 patients, and biopsy-proven BKPyVAN in 14 (4.5%) of 313. BKPyV viremia was observed in 115 (36.7%) of 311 patients, of whom 11 (9.6%) of 115 developed viremia late, that is, after the second year posttransplant. In 6 (12.5%) of 48 patients with high-level viremia and in 3 (21.4%) of 14 with BKPyVAN, this respective event occurred late. According to multivariable analysis, BKPyV viremia and/or BKPyVAN were associated not only with…

BACKGROUND: Among kidney transplant recipients, gender differences in medication adherence may contribute to higher graft failure risks observed in girls and young women compared with boys and young men. Our aim was to determine whether adherence differs by gender, and whether gender differences vary by age in adolescent and young adult kidney transplant recipients. METHODS: We examined data from the 3-month run-in period (no intervention) of the randomized Teen Adherence in Kidney transplant Effectiveness of Intervention trial. Adherence was monitored using electronic pillboxes in 136 patients (11-24 y) followed in 8 transplant centers in Canada and the United States. We used ordinal logistic regression with generalized estimating equations to estimate the association between gender and each of daily taking (proportion of prescribed doses taken) and timing (proportion of prescribed doses taken on time) adherence, considering effect modification by age (11-16 y vs 17-24 y). RESULTS: No difference in taking adherence was observed by gender among participants aged 11 to 16 years (odds…

BACKGROUND: The potential of a mesenchymal stem cell (MSC) therapy to accelerate the repair of ischemically damaged human kidneys during 24 hours of warm perfusion was evaluated. The hypothesis was that by administering MSC directly to the renal tissue, there would be an improved opportunity for cellular repair mediated by intrarenal paracrine effects. METHODS: Studies were performed using the exsanguinous metabolic support (EMS) tissue-engineering platform. Five pairs of human kidney allografts from donation after circulatory death donors were studied. One human kidney was EMS perfused for 24 hours (control), whereas its paired kidney was EMS perfused with MSC (1 × 10). The kidneys were evaluated for DNA synthesis, cytokine/chemokine synthesis, cytoskeletal regeneration, and mitosis. RESULTS: Treatment with MSC resulted in reduced inflammatory cytokines synthesized by the kidneys. Mesenchymal stem cell treatment led to a significant increase in the synthesis of adenosine triphosphate and growth factors resulting in normalization of metabolism and the cytoskeleton. Toluidine Blue…

BACKGROUND: Tacrolimus (TAC) is the cornerstone of immunosuppressive regimen in liver transplantation (LT). Its pharmacokinetics is characterized by a high interpatient and intrapatient variability (IPV) leading to an unpredictable dose-response relationship. The aim of our study was to evaluate the impact of TAC IPV (IPV) on graft and patient outcomes after LT. METHODS: We retrospectively analyzed 812 LT recipients treated with TAC. The IPV of TAC concentrations was estimated by calculating the coefficient of variation (CV) of whole blood trough concentrations. Patients were categorized in 2 groups: low IPV (CV < 40%) and high IPV (CV ≥ 40%). RESULTS: There were significantly more neurologic complications (31.2% vs 16.6%, P < 0.001), cardiovascular complications (19.7% vs 9.7%, P < 0.001), and acute renal failure requiring dialysis (8.5% vs 2.2%, P < 0.001) in the high CV group than in the low CV group. Moreover, graft survival was significantly poorer in the high CV group (hazard ratio, 1.42; 95% confidence interval, 1.04-1.95; P = 0.03). A pretransplantation elevated Model for…

Beta cell replacement has the potential to restore euglycemia in patients with insulin-dependent diabetes. Although great progress has been made in establishing allogeneic islet transplantation from deceased donors as the standard of care for those with the most labile diabetes, it is also clear that the deceased donor organ supply cannot possibly treat all those who could benefit from restoration of a normal beta cell mass, especially if immunosuppression were not required. Against this background, the International Pancreas and Islet Transplant Association in collaboration with the Harvard Stem Cell Institute, the Juvenile Diabetes Research Foundation (JDRF), and the Helmsley Foundation held a 2-day Key Opinion Leaders Meeting in Boston in 2016 to bring together experts in generating and transplanting beta cells derived from stem cells. The following summary highlights current technology, recent significant breakthroughs, unmet needs and roadblocks to stem cell-derived beta cell therapies, with the aim of spurring future preclinical collaborative investigations and progress toward…

BACKGROUND: The pure laparoscopic approach to donor hepatectomy is being taken more often. However, few centers perform pure laparoscopic donor right hepatectomy (PLDRH) because it requires a high level of surgical skill. Studies reporting initial outcomes of PLDRH may prompt further implementation of the technique and help reduce initial learning curves at other transplant centers. This study reports performance of PLDRH at a single center with extensive experience of adult living donor liver transplantation. METHODS: Data from 115 donors (and recipients) who underwent PLDRH between November 2015 and June 2017 were analyzed retrospectively. Subgroup analysis was performed to compare outcomes between the initial (November 2015 to October 2016) and more recent (November 2016 to June 2017) periods. RESULTS: During the initial period, 3 (2.6%) donors experienced complications greater than grade III on the Clavien-Dindo scale. By contrast, no donors developed complications during the recent period. The operative time (293.6 minutes vs 344.4 minutes; P < 0.001) and hospital stay (7.3…

BACKGROUND: As the population in the United States continues to age, an increase in the number of potential donation after circulatory death (DCD) donors with advanced chronological age can be expected. The aim of this study was to analyze a multi-institutional experience in liver transplantation using DCD donors 50 years or older. METHODS: All DCD liver transplant (LT) performed at Mayo Clinic Florida, Mayo Clinic Rochester, and Mayo Clinic Arizona from 2002 to 2016 were included. Recipients of DCD LT were divided into 2 groups: those with donors 50 years or older (N = 155) and those with donors younger than 50 years(N = 316). RESULTS: Graft survival was similar between the DCD donors 50 years or older group and DCD donors younger than 50 group(P = 0.99). Graft survival at 1, 3, and 5 years was 87.0%, 75.6%, and 71.8% in the DCD donors 50 years or older group and 85.8%, 76.0%, and 70.4% in the DCD donors younger than 50 group.The rate of total biliary complications (32.3% vs 23.7%; P = 0.049) and of anastomotic strictures (16.1% vs 8.2%; P = 0.01) were higher in the DCD donors 50…

Chagas disease (ChD) is a zoonotic protozoan infection caused by Trypanosoma cruzi and naturally transmitted by domestic and sylvatic blood-sucking triatomine bugs, known as “kissing bugs.” In the human host, trypomastigotes circulate in the blood stream, whereas intracellular amastigotes appear in tissues, especially muscle (heart) and ganglion cells. T. cruzi may be alternatively transmitted to humans congenitally, orally, or via transfusion and organ transplantation.1,2 Acute infection from vectorial transmission in endemic areas is mostly asymptomatic with high parasitemia, which generally becomes controlled in immunocompetent hosts after a few months. Without treatment, the infection proceeds to the chronic phase, characterized by low-level parasitemia and poor response to treatment. Although most chronically infected patients do not develop clinical symptoms (a period of clinical latency called indeterminate form), approximately 30% progress to irreversible cardiac, gastrointestinal, and/or more rarely, peripheral nervous system disease characterized by the involvement of the…

Viruses are the leading cause of infections after solid organ transplant. The antiviral properties of mammalian target of rapamycin inhibitors (mTORis) have been ascribed to a variety of mechanisms and historical data have supported their use over other immunosuppressants for a myriad of viruses. Herein, we summarize the most current data to highlight the role of mTORis in the management of viral infections after solid organ transplant. The mTORis play a clear role in the management of cytomegalovirus, and have data supporting their potential use for BK virus and human herpesvirus 8-related Kaposi sarcoma. No data definitively supports mTORis for use in Epstein-Barr virus-mediated posttransplant lymphoproliferative disorder or hepatitis C virus viral replication. Although theoretically an advantageous therapy for hepatitis C virus-related liver allograft fibrosis and human immunodeficiency virus, mTORi use specifically for these indications is less attractive with modern treatments currently available. Data surrounding mTORi efficacy in preventing rejection, and their toxicity…

BACKGROUND: Frail kidney transplant (KT) recipients have higher risk of adverse post-KT outcomes. Yet, there is interest in measuring frailty at KT evaluation and then using this information for post-KT risk stratification. Given long wait times for KT, frailty may improve or worsen between evaluation and KT. Patterns, predictors, and post-KT adverse outcomes associated with these changes are unclear. METHODS: Five hundred sixty-nine adult KT candidates were enrolled in a cohort study of frailty (November 2009-September 2017) at evaluation and followed up at KT. Patterns of frailty transitions were categorized as follows: (1) binary state change (frail/nonfrail), (2) 3-category state change (frail/intermediate/nonfrail), and (3) raw score change (-5 to 5). Adjusted Cox proportional hazard and logistic regression models were used to test whether patterns of frailty transitions were associated with adverse post-KT outcomes. RESULTS: Between evaluation and KT, 22.0% became more frail, while 24.4% became less frail. Black race (relative risk ratio, 1.98; 95% confidence interval [CI],…

BACKGROUND: Controlled donation after circulatory death (cDCD) has been associated with a high incidence of ischemic cholangiopathy and other perioperative complications. In an attempt to avoid these complications, we implemented an active protocol of cDCD liver transplant (LT) with normothermic regional perfusion (NRP) preservation. METHODS: This is a descriptive analysis of data collected from a prospective date base of cDCD LT preserved with NRP from January 2015 to June 2017 with a minimum follow up of 9 months. RESULTS: Fifty-seven potential cDCD donors were connected to the NRP system. Of these, 46 livers were transplanted over a 30-month period (80% liver recovery rate). The median posttransplant peak in alanine transaminase was 1136 U/L (220-6683 U/L). Seven (15%) patients presented postreperfusion syndrome and 11 (23%) showed early allograft dysfunction. No cases of ischemic cholangiopathy were diagnosed, and no graft loss was observed over a medium follow-up period of 19 months. Of note, 13 donors were older than 65 years, achieving comparable perioperative and midterm…

BACKGROUND: Patients with nonalcoholic fatty liver disease (NAFLD) are at risk of developing hepatocellular carcinoma (HCC), but the magnitude of the association still needs to be determined to define the need for a specific surveillance strategy. METHODS: We based our assessment on a previously published review by White et al (1992-2011) and on a systematic review(2012-2017). RESULTS: The new search identified 328 abstracts. Combining both eras (1992-2011 and 2012-2017), 25 studies were included in the analysis. Four were prospective, 2 described a retrospective analysis of a prospective database, and the others were retrospective. All studies were published after 2004, but the inclusion period of half of them ended before the year 2000. Studies showed variation in the definition of NAFLD, in the incidence of fibrosis/cirrhosis, in the presence of comorbidities (potentially affecting HCC incidence), and in the type and duration of screening. Considering only studies strictly including patients with or without cirrhosis, the reported incidence of HCC in NAFLD patients with cirrhosis…

The Recommendations for Management of Endemic Diseases and Travel Medicine in Solid-Organ Transplant Recipients and Donors: Latin America clinical practice guideline is intended to guide clinicians caring for solid-organ transplant (SOT) donors, candidates and recipients regarding infectious diseases (ID) issues related to this geographical region, mostly located in the tropics. These recommendations are based on both systematic reviews of relevant literature and expert opinion from both transplant ID and travel medicine specialists. The guidelines provide recommendations for risk evaluation and laboratory investigation, as well as management and prevention of infection of the most relevant endemic diseases of Latin America. This summary includes a brief description of the guideline recommendations but does not include the complete rationale and references for each recommendation, which is available in the online version of the article, published in this journal as a supplement. The supplement contains 10 reviews referring to endemic or travel diseases (eg, tuberculosis, Chagas…

Kidney donors face a small but definite risk of end-stage renal disease 15 to 30 years postdonation. The development of proteinuria, hypertension with gradual decrease in kidney function in the donor after surgical resection of 1 kidney, has been attributed to hyperfiltration. Genetic variations, physiological adaptations, and comorbidities exacerbate the hyperfiltration-induced loss of kidney function in the years after donation. A focus on glomerular hemodynamics and capillary pressure has led to the development of drugs that target the renin-angiotensin-aldosterone system (RAAS), but these agents yield mixed results in transplant recipients and donors. Recent work on glomerular biomechanical forces highlights the differential effects of tensile stress and fluid flow shear stress (FFSS) from hyperfiltration. Capillary wall stretch due to glomerular capillary pressure increases tensile stress on podocyte foot processes that cover the capillary. In parallel, increased flow of the ultrafiltrate due to single-nephron glomerular filtration rate elevates FFSS on the podocyte cell body.…

Despite major advances in understanding the pathophysiology of antibody-mediated rejection (AMR); prevention, diagnosis and treatment remain unmet medical needs. It appears that early T cell-mediated rejection, de novo donor-specific antibody (dnDSA) formation and AMR result from patient or physician initiated suboptimal immunosuppression, and represent landmarks in an ongoing process rather than separate events. On April 12 and 13, 2017, the Food and Drug Administration sponsored a public workshop on AMR in kidney transplantation to discuss new advances, importance of immunosuppressive medication nonadherence in dnDSA formation, associations between AMR, cellular rejection, changes in glomerular filtration rate, and challenges of clinical trial design for the prevention and treatment of AMR. Key messages from the workshop are included in this summary. Distinction between type 1 (due to preexisting DSA) and type 2 (due to dnDSA) phenotypes of AMR needs to be considered in patient management and clinical trial design. Standardization and more widespread adoption of routine…

Mammalian or mechanistic target of rapamycin (mTOR) is a serine-threonine kinase that plays essential roles in cell growth, proliferation, metabolism, and survival. Increased activation of the mTOR pathway is observed in patients and animal models of renal transplant rejection, autosomal dominant polycystic kidney disease, renal cell carcinoma, diabetic nephropathy, lupus nephritis, and angiomyolipoma. Agents that inhibit mTOR, such as sirolimus and everolimus, are incorporated in immunosuppressive regimens to prevent renal allograft rejection and are often used to facilitate calcineurin inhibitor minimization or to reduce the incidence of tumor recurrence. There are data from basic or animal studies to suggest that sirolimus and its analogs may also benefit patients with autosomal dominant polycystic kidney disease and metabolic- or immune-mediated renal diseases through its ability to reduce glomerular hypertrophy, renal parenchymal inflammation and fibrosis, but translation into clinical use has proved challenging. This review summarizes the current understanding of mTOR…

RNA interference is a naturally occurring specific method to silence genes with wide potential for treating human disease. Engineered RNA oligonucleotides targeting proprotein convertase subtilisin-kexin type 9 were recently shown to reliably lower LDL cholesterol, with a single injectable dose lasting 6 to 12 months.1 Applying short interfering RNA (siRNA) therapy to livers via ex vivo machine perfusion before transplantation may open the door to using organs from extended criteria donors that would otherwise be discarded. Treating isolated livers would also reduce costs compared with systemic therapy. We show for the first time that siRNA against the Fas receptor added directly to perfusion solution is uptaken into rat livers during hypothermic (4°C) and normothermic (37°C) perfusion. The Fas receptor expressed in liver signals hepatocytes to apoptose after binding its respective ligand. In mice, reduced FAS expression via siRNA confers protection against chemically induced acute liver failure.2 We aim to silence FAS during the ischemic period before transplantation and thus…

BACKGROUND: Although surgical technique in living donor liver transplantation (LDLT) has evolved with a focus on donor safety and recipient challenges, the donor selection criteria remain considerably disparate. METHODS: A questionnaire on donor selection was sent to 41 centers worldwide. 24 centers with a combined experience of 19 009 LDLTs responded. RESULTS: Centers were categorized into predominantly LDLT (18) or deceased donor liver transplantation (6), and high- (10) or low-volume (14) centers. At most centers, the minimum acceptable graft-to-recipient weight ratio was 0.7 or less (67%), and remnant was 30% (75%). The median upper limit of donor age was 60 years and body mass index of 33 kg/m. At 63% centers, age influenced the upper limit of body mass index inversely. Majority preferred aspartate transaminase and alanine transaminase less than 50 IU/mL. Most accepted donors with nondebilitating mild mental or physical disability and rejected donors with treated coronary artery disease, cerebrovascular accident and nonbrain, nonskin primary malignancies. Opinions were divided…

BACKGROUND: Recent studies have demonstrated that IL-34 is implicated in the regulation of macrophage functions. However, the effect of IL-34 on Kupffer cells (KCs) in acute rejection (AR) of liver transplantation remains unclear. METHODS: IL-34 expression was detected in graft and serum from allotransplantation and syngeneic transplantation groups. The adeno-associated virus-expressing IL-34 was used to assess the effect of IL-34 on AR of rat liver transplantation. The effect of IL-34 on KC polarization was evaluated by in vitro and in vivo assays. Kupffer cells in donors were depleted by clodronate treatment before transplantation, and the nontreated KCs or lipopolysaccharide-treated KCs were transferred into recipients during liver transplantation. RESULTS: IL-34 expression levels in grafts and serum were decreased in the allotransplantation group compared with the syngeneic transplantation group. Adeno-associated virus-expressing IL-34 treatment induced KC M2 polarization in vivo and inhibited the AR of rat liver transplantation. Moreover, we found that IL-34 switched the…

BACKGROUND: Supplemental oxygenation of the standard hypothermic machine perfusion (HMP) circuit has the potential to invoke favorable changes in metabolism, optimizing cadaveric organs before transplantation. METHODS: Eight pairs of porcine kidneys underwent 18 hours of either oxygenated (HMP/O2) or aerated (HMP/Air) HMP in a paired donation after circulatory death model of transplantation. Circulating perfusion fluid was supplemented with the metabolic tracer universally labeled glucose.Perfusate, end-point renal cortex, and medulla samples underwent metabolomic analysis using 1-dimension and 2-dimension nuclear magnetic resonance experiments in addition to gas chromatography-mass spectrometry. Analysis of C-labeled metabolic products was combined with adenosine nucleotide levels and differences in tissue architecture. RESULTS: Metabolomic analysis revealed significantly higher concentrations of universally labeled lactate in the cortex of HMP/Air versus HMP/O2 kidneys (0.056 mM vs 0.026 mM, P < 0.05). Conversely, newly synthesized [4,5-C] glutamate concentrations were higher in…