The 50 most-cited articles in Transplantation, 2021

BACKGROUND: In kidney patients COVID-19 is associated with severely increased morbidity and mortality. A comprehensive comparison of the immunogenicity, tolerability, and safety of COVID-19 vaccination in different cohorts of kidney patients and a control cohort is lacking. METHODS: This investigator driven, prospective, controlled multicenter study included 162 participants with chronic kidney disease (CKD) stages G4/5 (eGFR < 30 mL/min/1.73m2), 159 participants on dialysis, 288 kidney transplant recipients, and 191 controls. Participants received 2 doses of the mRNA-1273 COVID-19 vaccine (Moderna). The primary endpoint was seroconversion. RESULTS: Transplant recipients had a significantly lower seroconversion rate when compared with controls (56.9% versus 100%, P < 0.001), with especially mycophenolic acid, but also, higher age, lower lymphocyte concentration, lower eGFR, and shorter time after transplantation being associated with nonresponder state. Transplant recipients also showed significantly lower titers of neutralizing antibodies and T-cell responses when compared with…

BACKGROUND: Enhanced Recovery After Surgery (ERAS) is a multimodal, evidence-based, program of care developed to minimize the response to surgical stress, associated with reduced perioperative morbidity and hospital stay. This study presents the specific ERAS Society recommendations for liver transplantation (LT) based on the best available evidence and on expert consensus. METHODS: PubMed and ClinicalTrials.gov were searched in April 2019 for published and ongoing randomized clinical trials on LT in the last 15 y. Studies were selected by 5 independent reviewers and were eligible if focusing on each validated ERAS item in the area of adult LT. An e-Delphi method was used with an extended interdisciplinary panel of experts to validate the final recommendations. RESULTS: Forty-three articles were included in the systematic review. A consensus was reached among experts after the second round. Patients should be screened for malnutrition and treated whenever possible. Prophylactic nasogastric intubation and prophylactic abdominal drainage may be omitted, and early extubation should be…

BACKGROUND: Organ transplant recipients comprise an immunocompromised and vulnerable cohort. Outcomes of coronavirus disease 2019 (COVID-19) in solid organ transplant (SOT) recipients remain understudied. METHODS: We used a multicenter federated research network to compare clinical outcomes of COVID-19 in patients with SOT to a propensity--matched cohort of patients without SOT. RESULTS: We identified 2307 SOT recipients and 231 047 nontransplant patients with COVID-19. Transplant patients were more likely to be male individuals, older, have a body mass index >30 kg/m2, and have comorbid hypertension, diabetes, nicotine dependence, heart failure, and ischemic heart disease compared with the nontransplant group (P < 0.05). One-to-one matching was performed for diabetes, hypertension, chronic lung diseases, race, nicotine dependence, heart failure, ischemic heart disease, and gender. There was no difference in the composite outcome of intubation or mechanical ventilation at 30 days (risk ratio [RR], 1.04; 95% confidence interval [CI], 0.86-1.26) or 60 days (RR, 1.03; 95% CI,…

Data about coronavirus disease 2019 (COVID-19) vaccine in the general population provided an excellent profile of immunogenicity strong antibody response following the second dose of mRNA-1273 or BNT162b2 vaccines,1 associated with a potent T-cell immune response.2 Kidney transplant recipients (KTRs) exhibit lower immunogenicity to vaccines. A recent study reported a poor immune response after the first dose of mRNA anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in KTRs treated with calcineurin inhibitors.3 In abatacept (CTLA4-Ig)-treated patients, vaccination against influenza/H1N1 was associated with poor antibody response.4 This could be related to the inhibition of the crosstalk between B and T cells by the cytotoxique-T-lymphocyte-antigen 4 protein, leading to impaired germinal center formation and improper antibody response. We aimed to assess the humoral and T-cell postvaccinal responses in 101 belatacept-treated KTRs including 54 (53.5%) at Necker Hospital (Paris, France) and 47 (46.5%) at Rangueil Hospital (Toulouse, France). We included 101…

BACKGROUND: Kidney transplantation (KT) is the optimal treatment for kidney failure and is associated with better quality of life and survival relative to dialysis. However, knowledge of the current capacity of countries to deliver KT is limited. This study reports on findings from the 2018 International Society of Nephrology Global Kidney Health Atlas survey, specifically addressing the availability, accessibility, and quality of KT across countries and regions. METHODS: Data were collected from published online sources, and a survey was administered online to key stakeholders. All country-level data were analyzed by International Society of Nephrology region and World Bank income classification. RESULTS: Data were collected via a survey in 182 countries, of which 155 answered questions pertaining to KT. Of these, 74% stated that KT was available, with a median incidence of 14 per million population (range: 0.04-70) and median prevalence of 255 per million population (range: 3-693). Accessibility of KT varied widely; even within high-income countries, it was disproportionately…

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BACKGROUND: Donation after circulatory death (DCD) in Italy, given its 20-min stand-off period, provides a unique bench test for normothermic regional perfusion (NRP) and dual hypothermic oxygenated machine perfusion (D-HOPE). METHODS: We coordinated a multicenter retrospective Italian cohort study with 44 controlled DCD donors, who underwent NRP, to present transplant characteristics and results. To rank our results according to the high donor risk, we matched and compared a subgroup of 37 controlled DCD livers, preserved with NRP and D-HOPE, with static-preserved controlled DCD transplants from an established European program. RESULTS: In the Italian cohort, D-HOPE was used in 84% of cases, and the primary nonfunction rate was 5%. Compared with the matched comparator group, the NRP + D-HOPE group showed a lower incidence of moderate and severe acute kidney injury (stage 2: 8% versus 27% and stage 3: 3% versus 27%; P = 0.001). Ischemic cholangiopathy remained low (2-y proportion free: 97% versus 92%; P = 0.317), despite the high-risk profile resulting from the longer donor warm…

Donation after circulatory death (DCD) grafts are commonly used in liver transplantation. Attributable to the additional ischemic event during the donor warm ischemia time (DWIT), DCD grafts carry an increased risk for severe ischemia/reperfusion injury and postoperative complications, such as ischemic cholangiopathy. The actual ischemia during DWIT depends on the course of vital parameters after withdrawal of life support and varies widely between donors. The ischemic period (functional DWIT) starts when either Spo2 or blood pressure drop below a certain point and lasts until the start of cold perfusion during organ retrieval. Over the years, multiple definitions and thresholds of functional DWIT duration have been used. The International Liver Transplantation Society organized a Consensus Conference on DCD, Liver Preservation, and Machine Perfusion on January 31, 2020 in Venice, Italy. The aim of this conference was to reach consensus about various aspects of DCD liver transplantation in context of currently available evidence. Here we present the recommendations with regards to…

BACKGROUND: As the number of donation after circulatory death (DCD) liver transplants (LTs) performed in the United States continues to increase annually, there has been interest by policy makers to develop a more robust exception point safety net for patients who develop ischemic cholangiopathy (IC) following DCD LT. As such, there is a need for better understanding of the clinical course and long-term outcomes in patients who develop IC, as well as determining if IC can be classified into distinct categories with distinctly different clinical outcomes. METHODS: All DCD LT performed at Mayo Clinic Florida, Mayo Clinic Arizona, and Mayo Clinic Rochester from January 1999 to March 2020 were included (N = 770). Outcomes were compared between 4 distinct radiologic patterns of IC: diffuse necrosis, multifocal progressive, confluence dominant, and minor form. RESULTS: In total, 88 (11.4%) patients developed IC, of which 42 (5.5%) were listed for retransplantation of liver (ReLT). Patients with diffuse necrosis and multifocal progressive patterns suffered from frequent hospital admissions…

De novo malignancies (DNMs) following liver transplantation (LT) have been reported as 1 of the major causes of late mortality, being the most common cause of death in the second decade after LT. The overall incidence of DNMs is reported to be in the range of 3.1% to 14.4%, and the incidence is 2- to 3-fold higher in transplant recipients than in age- and sex-matched healthy controls. Long-term immunosuppressive therapy, which is the key in maintaining host tolerance and achieving good long-term outcomes, is known to contribute to a higher risk of DNMs. However, the incidence and type of DNM also depends on different risk factors, including patient demographics, cause of the underlying chronic liver disease, behavior (smoking and alcohol abuse), and pre-existing premalignant conditions. The estimated standardized incidence ratio for different DNMs is also variable. The International Liver Transplantation Society-Spanish Society of Liver Transplantation Consensus Conference working group on DNM has summarized and discussed the current available literature on epidemiology, risk…

BACKGROUND: We studied the safety and reactogenicity SARS-CoV-2 mRNA vaccines in transplant recipients because immunosuppressed patients were excluded from vaccine trials. METHODS: US transplant recipients were recruited into this prospective cohort study through social media; those who completed the full vaccine series between December 9, 2020 and March 1, 2021 were included. We collected demographics, medical history, and safety information within 7 d after doses 1 and 2 (D1, D2). Associations between characteristics and reactions were evaluated using modified Poisson regression. RESULTS: We studied 741 transplant recipients who underwent BNT162b2 (54%) or mRNA-1273 (46%) vaccination. Median (interquartile range) age was 60 (44-69) y, 57% were female, and 10% were non-White. Although local site reactions decreased after D2 (85% D1 versus 78% D2, P < 0.001), systemic reactions increased (49% D1 versus 69% D2, P < 0.001). Younger participants were more likely to develop systemic symptoms after D1 (adjusted incidence rate ratio [aIRR] per 10 y = 0.850.900.94, P < 0.001) and D2 (aIRR…

Mitochondria are essential organelles for cellular energy and metabolism. Like with any organ, the liver highly depends on the function of these cellular powerhouses. Hepatotoxic insults often lead to an impairment of mitochondrial activity and an increase in oxidative stress, thereby compromising the metabolic and synthetic functions. Mitochondria play a critical role in ATP synthesis and the production or scavenging of free radicals. Mitochondria orchestrate many cellular signaling pathways involved in the regulation of cell death, metabolism, cell division, and progenitor cell differentiation. Mitochondrial dysfunction and oxidative stress are closely associated with ischemia-reperfusion injury during organ transplantation and with different liver diseases, including cholestasis, steatosis, viral hepatitis, and drug-induced liver injury. To develop novel mitochondria-targeting therapies or interventions, a better understanding of mitochondrial dysfunction and oxidative stress in hepatic pathogenesis is very much needed. Therapies targeting mitochondria impairment and oxidative…

The increased utilization of high-risk renal grafts for transplantation requires optimization of pretransplant organ assessment strategies. Current decision-making methods to accept an organ for transplantation lack overall predictive power and always contain an element of subjectivity. Normothermic machine perfusion (NMP) creates near-physiological conditions, which might facilitate a more objective assessment of organ quality before transplantation. NMP is rapidly gaining popularity, with various transplant centers developing their own NMP protocols and renal viability criteria. However, to date, no validated sets of on-pump viability markers exist nor are there unified NMP protocols. This review provides a critical overview of the fundamentals of current renal NMP protocols and proposes a framework to approach further development of ex vivo organ evaluation. We also comment on the potential logistical implications of routine clinical use of NMP, which is a more complex procedure compared with static cold storage or even hypothermic machine perfusion.

Adenoviruses result in a wide array of clinical presentations, including primarily respiratory, gastrointestinal, genitourinary, or systemic infections. Although adenovirus causes mild disease limited to a single organ system in immunocompetent individuals, severe and life-threatening infections do rarely occur. Disseminated disease and severe localized disease resulting in significant morbidity and mortality have been well described in the immunocompromised populations. Although asymptomatic viremia, respiratory tract, and gastrointestinal infections are the most common disease in most transplant patients, renal transplant patients more commonly experience urinary tract infections, including hemorrhagic cystitis or nephritis. Diagnosis requires astute clinical awareness of the patient's clinical presentation that would be compatible with adenovirus combined with cultures, molecular testing, polymerase chain reaction, and tissue sampling. There is no Food and Drug Administration-approved treatment for adenovirus; however, several studies have evaluated therapeutic options including…

Kidney transplant recipients (KTRs) are at increased risk of developing renal cell carcinoma (RCC). The cancer can be encountered at different steps in the transplant process. RCC found during work-up of a transplant candidate needs treatment and to limit the risk of recurrence usually a mandatory observation period before transplantation is recommended. An observation period may be omitted for candidates with incidentally discovered and excised small RCCs (<3 cm). Likewise, RCC in the donor organ may not always preclude usage if tumor is small (<2 to 4 cm) and removed with clear margins before transplantation. After transplantation, 90% of RCCs are detected in the native kidneys, particularly if acquired cystic kidney disease has developed during prolonged dialysis. Screening for RCC after transplantation has not been found cost-effective. Treatment of RCC in KTRs poses challenges with adjustments of immunosuppression and oncologic treatments. For localized RCC, excision or nephrectomy is often curative. For metastatic RCC, recent landmark trials in the nontransplanted population…

The last few years have seen an explosion in clinical research focusing on the use of donor-derived cell-free DNA (dd-cfDNA) in solid-organ transplants (SOT). Although most of the literature published so far focuses on kidney transplants, there are several recent as well as ongoing research studies on heart, lung, pancreas, and liver transplants. Though initially studied as a noninvasive means of identifying subclinical or acute rejection in SOT, it is rapidly becoming clear that instead of being a specific marker for allograft rejection, dd-cfDNA is more appropriately described as a marker of severe injury, although the most common cause of this injury is allograft rejection. Multiple studies in kidney transplants have shown that although sensitivity for the diagnosis of antibody-mediated rejection is excellent, it is less so for T-cell-mediated rejection. It is possible that combining dd-cfDNA with other novel urine- or blood-based biomarkers may increase the sensitivity for the diagnosis of rejection. Irrespective of the cause, though, elevated dd-cfDNA seems to portend adverse…

BACKGROUND: Recent trials in liver machine perfusion (MP) have revealed unique challenges beyond those seen in most clinical studies. Correct trial design and interpretation of data are essential to avoid drawing conclusions that may compromise patient safety and increase costs. METHODS: The International Liver Transplantation Society, through the Special Interest Group "DCD, Preservation and Machine Perfusion," established a working group to write consensus statements and guidelines on how future clinical trials in liver perfusion should be designed, with particular focus on relevant clinical endpoints and how different techniques of liver perfusion should be compared. Protocols, abstracts, and full published papers of clinical trials using liver MP were reviewed. The use of a simplified Grading of Recommendations Assessment, Development, and Evaluation working group (GRADE) system was attempted to assess the level of evidence. The working group presented its conclusions at the International Liver Transplantation Society consensus conference "DCD, Liver Preservation, and Machine…

The safety of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines in solid organ transplant recipients (SOTRs) is unknown because immunosuppressed individuals were generally excluded from phase 1 to 3 studies. To better understand perivaccination reactogenicity in immunosuppressed individuals, we studied SOTRs who underwent early vaccination. SOTRs in the United States were recruited to participate in this study by invitation through their transplant centers or social media. Participants completed a detailed online questionnaire 1 week following their first dose. This study was approved by the Institutional Review Board at the Johns Hopkins School of Medicine. We studied 187 SOTRs who received their first SARS-CoV-2 vaccination dose between December 16, 2020 and January 16, 2021, of whom 64% were identified as front-line healthcare workers. Median (interquartile range) age was 48 (37–59) years; 69% were female individuals, and 87% were White and 6% Hispanic/Latino. Median (interquartile range) years since transplantation was 6 (3–13); 52% were kidney, 19%…

BACKGROUND: Circulating donor-derived cell-free DNA (cfDNA), a minimally invasive diagnostic tool for kidney transplant rejection, was validated using traditional histology. The molecular microscope diagnostic system (MMDx) tissue gene expression platform may provide increased precision to traditional histology. METHODS: In this single-center prospective study of 208 biopsies (median = 5.8 mo) posttransplant, we report on the calibration of cfDNA with simultaneous biopsy assessments using MMDx and histology by area under the curve (AUC) analyses for optimal criterion, as well as for, previously published cfDNA cutoffs ≤ 0.21% to "rule-out" rejection and ≥1% to "rule-in" rejection. RESULTS: There were significant discrepancies between histology and MMDx, with MMDx identifying more antibody-mediated rejection (65; 31%) than histology (43; 21%); the opposite was true for T cell-mediated rejection [TCMR; histology: 27 (13%) versus MMDx: 13 (6%)]. Most of the TCMR discrepancies were seen for histologic borderline/1A TCMR. AUC for cfDNA and prediction of rejection were slightly better…

Macrophages have emerged at the forefront of research in immunology and transplantation because of recent advances in basic science. New findings have illuminated macrophage populations not identified previously, expanded upon traditional macrophage phenotypes, and overhauled macrophage ontogeny. These advances have major implications for the field of transplant immunology. Macrophages are known to prime adaptive immune responses, perpetuate T-cell-mediated rejection and antibody-mediated rejection, and promote allograft fibrosis. In this review, macrophage phenotypes and their role in allograft injury of solid organ transplants will be discussed with an emphasis on kidney transplantation. Additionally, consideration will be given to the prospect of manipulating macrophage phenotypes as cell-based therapy. Innate immunity and macrophages represent important players in allograft injury and a promising target to improve transplant outcomes.

BACKGROUND: Belatacept may impair humoral immunity, impacting the effectiveness of SARS-CoV-2 mRNA vaccines in transplant recipients. We investigated immunogenicity after SARS-CoV-2 mRNA vaccines in kidney transplant recipients who are and are not taking belatacept. METHODS: Participants were recruited between December 9, 2020, and April 1, 2021. Blood samples were collected after dose 1 and dose 2 (D1, D2) and analyzed using either an anti-SARS-CoV-2 enzyme immunoassay against the S1 domain of the SARS-CoV-2 spike protein or immunoassay against the receptor-binding domain of the SARS-CoV-2 spike protein. Stabilized inverse probability of treatment weights was used to compare immunogenicity, and a weighted logistics regression was used to calculate fold change of positive response. RESULTS: Among the 609 participants studied, 24 (4%) were taking belatacept. After dose 1, 0/24 (0%) belatacept patients had detectable antibodies, compared with 77 of 568 (14%) among the equivalent nonbelatacept population (P = 0.06). After dose 2, 1/19 (5%) belatacept patients had detectable antibodies,…

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The use of cold preservation solutions to rapidly flush and cool the kidney followed by static cold storage in ice has been the standard kidney preservation technique for the last 50 y. Nonetheless, changing donor demographics that include organs from extended criteria donors and donation after circulatory death donors have led to the adoption of more diverse techniques of preservation. Comparison of hypothermic machine perfusion and static cold storage techniques for deceased donor kidneys has long been debated and is still contested by some. The recent modification of hypothermic machine perfusion techniques with the addition of oxygen or perfusion at subnormothermic or near-normothermic temperatures are promising strategies that are emerging in clinical practice. In addition, the use of normothermic regional perfusion to resuscitate abdominal organs of donation after circulatory death donors in situ before cold flushing is also increasingly being utilized. This review provides a synopsis of the different types of preservation techniques including their mechanistic effects and the…

In contrast to the mRNA vaccines, Ad26.COV2.S (Janssen COVID-19 vaccine) is single-shot replication-incompetent adenovirus-type-26 vectored vaccine encoding a stabilized variant of the SARS-CoV-2 S protein.1 Adenovirus vaccines have been widely used,2 efficiently infect host cells, and may be expected to elicit stronger Th1-biased cellular immunity than mRNA vaccines, which contributes to B-cell differentiation and antibody production.3 For transplant recipients, given limited immunogenicity of mRNA vaccines,4 the Janssen vaccine platform might be a better choice. We sought to quantify the antispike antibody response to Janssen COVID-19 vaccination in transplant recipients and compare it to recipients of the mRNA series. We leveraged our prospective cohort of transplant recipients without prior COVID-19 who underwent SARS-CoV-2 vaccination between December 16, 2020, and March 27, 2021.5 Serologic testing was undertaken on the Roche Elecsys anti-SARS-CoV-2 S enzyme immunoassay (range <0.4 to >250 U/mL [positive ≥0.8 U/mL]), which tests for antibodies against the receptor-binding…

BACKGROUND: Nonpathogenic torque teno viruses (TTVs) are highly prevalent in transplant recipients and associated with immunosuppression. Studies in kidney transplant patients have proposed assessment of TTV load for risk stratification of clinically overt graft rejection. The value of TTV quantification in the context of subclinical rejection has not been evaluated. METHODS: In this prospective trial, 307 consecutive kidney transplant recipients were subjected to per-protocol monitoring of plasma TTV. TTV was analyzed in the context of protocol biopsies (n = 82), scheduled 1 year posttransplantation. RESULTS: TTV load at the time of biopsy was lower in recipients with rejection (n = 19; according to Banff, including borderline changes suspicious for acute T cell-mediated rejection) than those without rejection (n = 63) whereby each log increase in TTV copies/mL decreased the risk for rejection by 9% (risk ratio 0.91, 95% confidence interval, 0.85-0.97; P = 0.004). Development of chronic lesions (cg, cv, ci, ct, ah, ptcml) was associated with the number of days with a TTV load <1 ×…

The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus responsible for the coronavirus disease 2019 (COVID-19) pandemic has raised concerns for programs overseeing donation and transplantation of cells, tissues, and organs (CTO) that this virus might be transmissible by transfusion or transplantation. Transplant recipients are considered particularly vulnerable to pathogens because of immunosuppression, and SARS-CoV-2 is likely to generate complications if contracted. Several signs and symptoms observed in COVID-19 positive patients reflect damage to multiple organs and tissues, raising the possibility of extrapulmonary SARS-CoV-2 infections and risk of transmission. At the beginning of the pandemic, a consensus has emerged not to consider COVID-19 positive patients as potential living or deceased donors, resulting in a global decrease in transplantation procedures. Medical decision-making at the time of organ allocation must consider safely alongside the survival advantages offered by transplantation. To address the risk of transmission by…

Severe allograft dysfunction, as opposed to the expected immediate function, following liver transplantation is a major complication, and the clinical manifestations of such that lead to either immediate retransplant or death are the catastrophic end of the spectrum. Primary nonfunction (PNF) has declined in incidence over the years, yet the impact on patient and healthcare teams, and the burden on the organ pool in case of the need for retransplant should not be underestimated. There is no universal test to define the diagnosis of PNF, and current criteria are based on various biochemical parameters surrogate of liver function; moreover, a disparity remains within different healthcare systems on selecting candidates eligible for urgent retransplantation. The impact on PNF from traditionally accepted risk factors has changed somewhat, mainly driven by the rising demand for organs, combined with the concerted approach by clinicians on the in-depth understanding of PNF, optimal graft recipient selection, mitigation of the clinical environment in which a marginal graft is reperfused,…

Although the utilization of donation after circulatory death donors (DCDs) for liver transplantation (LT) has increased steadily, much controversy remains, and no common acceptance criteria exist with regard to donor and recipient risk factors and prediction models. A consensus conference was organized by International Liver Transplantation Society on January 31, 2020, in Venice, Italy, to review the current clinical practice worldwide regarding DCD-LT and to develop internationally accepted guidelines. The format of the conference was based on the grade system. International experts in this field were allocated to 6 working groups and prepared evidence-based recommendations to answer-specific questions considering the currently available literature. Working group members and conference attendees served as jury to edit and confirm the final recommendations presented at the end of the conference by each working group separately. This report presents the final statements and recommendations provided by working group 2, covering the entire spectrum of donor and recipient risk factors…

BACKGROUND: Recently, continuous nonoxygenated hypothermic machine perfusion (HMP) has been implemented as standard preservation method for deceased donor kidneys in the Netherlands. This study was designed to assess the effect of the implementation of HMP on early outcomes after transplantation. METHODS: Kidneys donated in the Netherlands in 2016 and 2017 were intended to be preserved by HMP. A historical cohort (2010-2014) preserved by static cold storage was chosen as the control group. Primary outcome was delayed graft function (DGF). Additional analyses were performed on safety, graft function, and survival up until 2 y after transplantation. RESULTS: Data were collected on 2493 kidneys. Analyses showed significantly more donation after circulatory death, preemptive transplantation, and retransplants in the project cohort. Of the 681 kidneys that were transplanted during the project, 81% were preserved by HMP. No kidneys were discarded due to HMP-related complications. DGF occurred in 38.2% of the project cohort versus 43.7% of the historical cohort (P < 0.001), with a…

BACKGROUND: Initial reports in adult kidney transplant recipients (KTR) indicate low immunogenicity after 2 doses of the BNT162b2 COVID-19 mRNA vaccine. We describe the immunogenicity of this vaccine compared to the serologic response in naturally infected COVID-19 positive adolescent and young adult KTR. METHODS: For this prospective observational study, the study group included 38 KTR who received 2 doses of the tested vaccine, and the control group included 14 KTR who had a previous polymerase chain reaction-confirmed COVID-19 infection. RESULTS: The mean age was 18 ± 3 y. Positive serologic responses were observed in 63% and 100% of the study and control groups, respectively (P = 0.01). Antibody titers were almost 30-fold higher in the control than the study group (median [interquartile range (IQR)]: 2782 [1908-11 000] versus 100.3 [4.7-1744] AU/mL, P < 0.001), despite the longer time from the COVID-19 infection to serologic testing compared to time from vaccination (median [IQR]: 157.5 [60-216] versus 37 [20.5-53] d, P = 0.011). Among vaccinated patients, higher proportions of…

We discuss what therapeutic regimen might be acceptable/successful in the first clinical trial of genetically engineered pig kidney or heart transplantation. As regimens based on a calcineurin inhibitor or CTLA4-Ig have proved unsuccessful, the regimen we administer to baboons is based on induction therapy with antithymocyte globulin, an anti-CD20 mAb (Rituximab), and cobra venom factor, with maintenance therapy based on blockade of the CD40/CD154 costimulation pathway (with an anti-CD40 mAb), with rapamycin, and a corticosteroid. An anti-inflammatory agent (etanercept) is administered for the first 2 wk, and adjuvant therapy includes prophylaxis against thrombotic complications, anemia, cytomegalovirus, and pneumocystis. Using this regimen, although antibody-mediated rejection certainly can occur, we have documented no definite evidence of an adaptive immune response to the pig xenograft. This regimen could also form the basis for the first clinical trial, except that cobra venom factor will be replaced by a clinically approved agent, for example, a C1-esterase inhibitor. However,…

BACKGROUND: Normothermic machine perfusion (NMP) has become a clinically established tool to preserve livers in a near-physiological environment. However, little is known about the predictive value of perfusate parameters toward the outcomes after transplantation. METHODS: Fifty-five consecutive NMP livers between 2018 and 2019 were included. All of the livers were perfused on the OrganOx metra device according to an institutional protocol. Transplant and perfusion data were collected prospectively. RESULTS: Forty-five livers were transplanted after NMP. Five livers stem from donors after circulatory death and 31 (68.9%) from extended criteria donors. Mean (SD) cold ischemia time was 6.4 (2.3) h; mean (SD) total preservation time was 21.4 (7.1) h. Early allograft dysfunction (EAD) occurred in 13 of 45 (28.9%) patients. Perfusate aspartate aminotransferase (P = 0.008), alanine aminotransferase (P = 0.006), lactate dehydrogenase (P = 0.007) and their development over time, alkaline phosphatase (P = 0.013), and sodium (P = 0.016) correlated with EAD. Number of perfusate platelets…

Immunocompromised patients were excluded from the trials of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines. Boyarsky et al1,2 recently reported that only 17% of transplant recipients who received a single dose of SARS-CoV-2 vaccine developed detectable antispike antibody (compared with 100% of the nonimmunocompromised subjects in the pivotal trials) and after 2 doses, response increased to 54% in transplant recipients. However, the clinical impact of this low antibody response remains unclear, especially in light of second doses. We performed a retrospective chart review of 14 solid organ transplant (SOT) recipients (10 kidney, 2 liver, 1 lung, and 1 heart) with a median age of 62 (27–78) y who were diagnosed with COVID-19, a median of 23.5 (3–57) d after completion of SARS-CoV-2 vaccination. Demographics of these patients are summarized in Table 1. Eight patients completed the BNT162b2 (Pfizer-BioNTech) series, 5 completed the mRNA-1273 (Moderna) series, and 1 patient received the JNJ-78436735 (Janssen/Johnson & Johnson) SARS-CoV-2 vaccine. Six (42.8%)…

Casirivimab-imdevimab is a formulation of 2 recombinant human immunoglobulin G1 monoclonal antibodies (MABs) that targets the receptor-binding domain of the spike protein of severe acute respiratory syndrome coronavirus-2, blocking the viral attachment and entry into human cells. Casirivimab-imdevimab and bamlanivimab are the 2 coronavirus disease 2019 (COVID-19) MABs to receive Emergency Use Authorization by the US Food and Drug Administration for the treatment of patients with mild-to-moderate COVID-19 who are at high risk for progression to severe disease.1 Solid organ transplant (SOT) recipients may be at a higher risk of hospitalization, intensive care unit stays, and death when compared with the general population.2 Among predefined high-risk patients with COVID-19, 3% of those treated with casirivimab-imdevimab compared with 9% who received placebo required hospitalization or emergency room visit.1,3 Data regarding safety and efficacy of MABs in SOT recipients are limited. During our experience from March to August 2020, in 59 adult SOT patients diagnosed with COVID-19 at…

BACKGROUND: Immunization of varicella-zoster virus (VZV)-seronegative solid organ transplant (SOT) patients using the live-attenuated varicella vaccine is generally contraindicated, leaving no widely applicable immunization option. The recombinant subunit herpes zoster vaccine (RZV) is indicated for VZV-seropositive persons to prevent shingles but could potentially also protect VZV-seronegative persons against varicella. We performed a safety and immunogenicity evaluation of RZV in VZV-seronegative SOT recipients as an option for protection. METHODS: VZV-seronegative adult SOT patients with no history of varicella/shingles vaccine or disease were given 2 doses of RZV vaccine 2-6 mo apart. Blood was drawn prevaccination (V1), before the second dose (V2), and 4 wk after the second dose (V3). Humoral immunity (anti-glycoprotein E) and cell-mediated immunity were evaluated, with polyfunctional cells defined as cells producing ≥2 cytokines. RESULTS: Among 31 eligible VZV-seronegative SOT patients screened, 23 were enrolled. Median age was 38 y and median time since transplant procedure…

INTRODUCTION Liver transplantation (LT) is indicated in unresectable hepatocellular carcinoma (HCC) with limited tumor load. Evidence also supports LT as a rescue treatment when more advanced patients achieve stable downstaging after locoregional therapies. Immunotherapy with immune checkpoint inhibitors(ICIs) targeting programmed death 1 and its ligand (PDL1) are now used alone or in combination as first- or second-line systemic treatment. We present a case showing the feasibility and efficacy of rescue LT following response to the PDL1 inhibitor durvalumab. This study was exempt from approval from an ethics board. A 61-y-old male with chronic hepatitis B virus infection under tenofovir therapy had a moderately differentiated binodular (12 and 9 mm) HCC resected in April 2015, which showed no microvascular invasion. Four mo later, CT scan disclosed intrahepatic progression with multiple lesions involving both lobes (13 lesions, the largest one 47 mm in size). Chemoembolization was contraindicated based on the impossibility to perform superselective embolization (13 lesions). He…

BACKGROUND: Data about SARS-CoV-2 vaccines efficacy in renal transplant recipients (RTR) are lacking. METHODS: To reveal predictors for humoral response to BNT162b2 vaccine among RTR, patients were divided into positive (N = 42) and negative (N = 78) response groups based on receptor-binding domain (RBD) immunoglobulin G (IgG) ≥1.1 and neutralizing antibodies (NA) ≥16 dilution versus RBD IgG <1.1 or NA <16, respectively. NA were detected using a SARS-CoV-2 pseudo-virus. RESULTS: NA were detected in only 42 of 120 (35%) of RTR versus 197 of 202 (97.5%) immunocompetent controls (P < 0.001). NA geometric mean titers in RTR were significantly lower versus the control group {83.7 (95% confidence interval [CI], 50.5-138.8) versus 482 (95% CI, 411-566), P < 0.001}. In a multivariable analysis, mycophenolic acid (MPA) dose and hemoglobin level were found to be independent predictors for antibody response in RTR. A positive response rate of 27% versus 63% was observed in patients on and off MPA, respectively. An increase in MPA dose by 1 mg/kg weight reduced the odds for a positive response…

BACKGROUND: Renal ischemia-reperfusion injury (IRI) predictably causes acute kidney injury after shock and major cardiovascular procedures in all kidneys procured for transplantation. The earliest events of IRI are triggered by molecules released from injured cells, damage-associated molecular patterns (DAMPs), that bind pattern recognition receptors (PRRs) constitutively expressed on many cells within the kidney. Activation of PRR signaling leads to production of proinflammatory molecules, which incite a cascade of inflammatory events leading to acute kidney injury. Renal tubular epithelial cells (RTECs) are particularly susceptible to ischemic injury, and proximal RTEC injury is pathognomonic of renal IRI. To better understand how injured RTECs contribute to the cycle of deleterious inflammation in the setting of renal IRI, this study asked whether DAMPs released from injured RTECs induced PRR signals in healthy RTECs. METHODS: Human RTECs were necrosed ex vivo to release intracellular DAMPs and resulting necrotic supernatant used to stimulate healthy RTECs, T lymphocytes, and…

BACKGROUND: The Japanese Liver Transplantation Society (JLTS), a cooperative research consortium, was established in 1980 to characterize and follow trends in patient characteristics and graft survival among all liver transplant patients in Japan. This study analyzed factors that may affect the current outcomes of pediatric patients who undergo liver transplantation (LT) by evaluating one of the largest pediatric LT cohorts in the world. METHODS: Between November 1989 and December 2018, 3347 pediatric patients underwent LT in Japan. The survival outcomes of each donor and recipient variant were evaluated. RESULTS: The procedures performed during the study period included living donor LT (LDLT; n = 3271), deceased donor LT (DDLT; n = 69), and domino LT (n = 7). There were 1510 male (45.1%) and 1837 female (54.9%) recipients with a median age of 1.7 y (range: 9 d to 17.9 y). The graft survival rates at 1, 10, 20, and 30 y were 88.9%, 82.2%, 77.1%, and 75.4%, respectively. Donor age, donor BMI, blood type incompatibility, recipient age, etiology of liver disease, transplant type,…

BACKGROUND: Sex differences in kidney graft loss rates were reported in the United States. Whether these differences are present in other countries is unknown. METHODS: We estimated the association between recipient sex and death-censored graft loss in patients of all ages recorded in the Scientific Registry of Transplant Recipients, Australia and New Zealand Dialysis and Transplant Registry, and Collaborative Transplant Study registries who received a first deceased donor kidney transplant (1988-2019). We used multivariable Cox regression models, accounting for the modifying effects of donor sex and recipient age, in each registry separately; results were combined using individual patient data meta-analysis. RESULTS: We analyzed 438 585 patients. Young female patients 13-24 y old had the highest crude graft loss rates (female donor: 5.66; male donor: 5.50 per 100 person-years). Among young recipients of male donors, females showed higher graft loss risks than males (0-12 y: adjusted hazard ratio [aHR] 1.42, (95% confidence interval [CI], 1.17-1.73); 13-24 y: 1.24 (1.17-1.32); 25-44…

Transplant candidates should undergo an assessment of their mental health, social support, lifestyle, and behaviors. The primary aims of this "psychosocial evaluation" are to ensure that transplantation is of benefit to life expectancy and quality of life, and to allow optimization of the candidate and transplant outcomes. The content of psychosocial evaluations is informed by evidence regarding pretransplant psychosocial predictors of transplant outcomes. This review summarizes the current literature on pretransplant psychosocial predictors of transplant outcomes across differing solid organ transplants and discusses the limitations of existing research. Pretransplant depression, substance misuse, and nonadherence are associated with poorer posttransplant outcomes. Depression, smoking, and high levels of prescription opioid use are associated with reduced posttransplant survival. Pretransplant nonadherence is associated with posttransplant rejection, and nonadherence may mediate the effects of other psychosocial variables such as substance misuse. There is evidence to suggest that…

INTRODUCTION More than 80 000 patients with end-stage renal disease (ESRD) are on the waitlist for kidney transplantation in the United States,1 most of whom are receiving chronic hemodialysis. The 5-year mortality of waitlisted patients is approximately 40%,2-5 whereas the median waiting time to receive a deceased human donor kidney is 4 years.6 Many patients will not live long enough to undergo kidney allotransplantation. Chronic dialysis is associated with relatively high mortality and increased comorbidities that may render the patient unsuitable for renal transplantation. Furthermore, the quality of life is inferior to that of a patient with a functioning kidney allograft.7-9 Prolonged dialysis may have adverse economic implications for the patient and his/her family.10,11 Xenotransplantation using genetically engineered pigs as sources of kidneys has several advantages over allotransplantation (Table 1) and is a potential option for patients on chronic dialysis, either as a bridge to allotransplantation or as destination therapy. Life-supporting genetically modified pig kidney…

Hemodynamic instability (HDI) during liver transplantation (LT) can be difficult to manage and increases postoperative morbidity and mortality. In addition to surgical causes of HDI, patient- and graft-related factors are also important. Nitric oxide-mediated vasodilatation is a common denominator associated with end-stage liver disease related to HDI. Despite intense investigation, optimal management strategies remain elusive. In this consensus article, experts from the International Liver Transplantation Society, the Liver Intensive Care Group of Europe, and the Society for the Advancement of Transplant Anesthesia performed a rigorous review of the most current literature regarding the epidemiology, causes, and management of HDI during LT. Special attention has been paid to unique LT-associated conditions including the causes and management of vasoplegic syndrome, cardiomyopathies, LT-related arrhythmias, right and left ventricular dysfunction, and the specifics of medical and fluid management in end-stage liver disease as well as problems specifically related to portal…

Daratumumab is a human IgG1κ monoclonal antibody directed against CD38, which is expressed on some subsets of lymphocytes and plasma cells. Mechanisms of action include complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and apoptotic signaling.1 Daratumumab is mainly used to treat multiple myeloma. Targeting CD38-positive plasma cells might decrease antibody production in antibody-mediated nonneoplastic diseases. Successful use of daratumumab to treat post-stem cell transplantation refractory autoimmune hemolytic anemia has been reported too. Its use has also been suggested in antibody-mediated rejection (AMR) in solid organ transplantation.2,3 We present the case of a 29-year-old male with a refractory AMR after a heart transplant (HTx) successfully treated with daratumumab. Our patient received a HTx at the age of 16. Follow-up was complicated by 2 episodes of acute cellular rejection 1 and 3 years after HTx. A previous AMR 7 years after HTx was successfully treated with intravenous immunoglobulin, plasmapheresis,…

Decline in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antispike antibodies over time following natural infection and vaccination have been reported,1–3 though kinetics and durability of antispike antibodies in vaccinated transplant recipients are unknown. We sought to quantify antispike antibody titers over a 3 mo period in transplant recipients who completed the mRNA vaccine series. As previously reported,4,5 serologic testing was undertaken on the Roche Elecsys anti-SARS-CoV-2 S enzyme immunoassay (range <0.4–>250 U/mL [positive ≥0.8 U/mL]) which tests for antibodies against the receptor-binding domain of the spike protein or EUROIMMUN enzyme immunoassay (positive ≥1.1 arbitrary units) which tests for IgG to the S1 domain of the spike protein at 3 time points: before dose 2, 1 mo and 3 mo after dose 2. Participants underwent vaccination between 16 December 2020 and 13 March 2021, and this study was approved by the Johns Hopkins Institutional Review Board. Overall, 40/305 (13%) had detectable antibody at median (interquartile range [IQR]) 21 (18–25) d after dose…

Donation after circulatory death (DCD) donors are an increasingly more common source of livers for transplantation in many parts of the world. Events that occur during DCD liver recovery have a significant impact on the success of subsequent transplantation. This working group of the International Liver Transplantation Society evaluated current evidence as well as combined experience and created this guidance on DCD liver procurement. Best practices for the recovery and transplantation of livers arising through DCD after euthanasia and organ procurement with super-rapid cold preservation and recovery as well as postmortem normothermic regional perfusion are described, as are the use of adjuncts during DCD liver procurement.

Background. Circulating graft-derived cell-free DNA (dd-cfDNA) is a new marker of cardiac allograft damage that is used for noninvasive rejection diagnostics. We performed dd-cfDNA (%) in heart transplant recipients during the first posttransplant year. Methods. In 87 patients, serial dd-cfDNA determination at predefined time-points was performed in 770 single samples. dd-cfDNA fraction (%) was measured using an established universal droplet digital polymerase chain reaction method, providing same-day turn-around. Rejection was diagnosed according to clinical parameters and biopsies. Results. Median dd-cfDNA (%) was high (5.36%) immediately after reperfusion and decreased to a median (interquartile range) of 0.10% (0.05%–0.24%) in clinically stable patients by postoperative day 10. Compared to dd-cfDNA (%) samples in clinically stable patients, values were higher (P < 0.001) in biopsy-proven rejection ISHLT 1R (0.42% [0.15%–0.53%]) and 2R rejection (0.84% [0.39%–0.97%]). Moreover, dd-cfDNA (%) was already significantly increased 9–30 days before biopsy-proven rejection (0.36%…