The 50 most-cited articles in Transplantation, 2016

In Brief Two distinct pulmonary vascular disorders, hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH) may occur as a consequence of hepatic parenchymal or vascular abnormalities. HPS and POPH have major clinical implications for liver transplantation. A European Respiratory Society Task Force on Pulmonary-Hepatic Disorders convened in 2002 to standardize the diagnosis and guide management of these disorders. These International Liver Transplant Society diagnostic and management guidelines are based on that task force consensus and should continue to evolve as clinical experience dictates. Based on a review of over 1000 published HPS and POPH articles identified via a MEDLINE search (1985-2015), clinical guidelines were based on, selected single care reports, small series, registries, databases, and expert opinion. The paucity of randomized, controlled trials in either of these disorders was noted. Guidelines are presented in 5 parts; I. Definitions/Diagnostic criteria; II. Hepatopulmonary syndrome; III. Portopulmonary hypertension; IV. Implications for liver…

The success of kidney transplants is limited by the lack of robust improvements in long-term survival. It is now recognized that alloimmune responses are responsible for the majority of allograft failures. Development of novel therapies to decrease allosensitization is critical. The lack of new drug development in kidney transplantation necessitated repurposing drugs initially developed in oncology and autoimmunity. Among these is tocilizumab (anti-IL-6 receptor [IL-6R]) which holds promise for modulating multiple immune pathways responsible for allograft injury and loss. Interleukin-6 is a cytokine critical to proinflammatory and immune regulatory cascades. Emerging data have identified important roles for IL-6 in innate immune responses and adaptive immunity. Excessive IL-6 production is associated with activation of T-helper 17 cell and inhibition of regulatory T cell with attendant inflammation. Plasmablast production of IL-6 is critical for initiation of T follicular helper cells and production of high-affinity IgG. Tocilizumab is the first-in-class drug developed to treat…

BACKGROUND: Degenerative disc disease often causes severe low-back pain, a public health problem with huge economic and life quality impact. Chronic cases often require surgery, which may lead to biomechanical problems and accelerated degeneration of the adjacent segments. Autologous mesenchymal stromal cells (MSC) treatments have shown feasibility, safety and strong indications of clinical efficacy. We present here a randomized, controlled trial using allogeneic MSC, which are logistically more convenient than autologous cells. METHODS: We randomized 24 patients with chronic back pain diagnosed with lumbar disk degeneration and unresponsive to conservative treatments into 2 groups. The test group received allogeneic bone marrow MSCs by intradiscal injection of 25 × 10 cells per segment under local anesthesia. The control group received a sham infiltration of paravertebral musculature with the anesthetic. Clinical outcomes were followed up for 1 year and included evaluation of pain, disability, and quality of life. Disc quality was followed up by magnetic resonance imaging. RESULTS:…

BACKGROUND: Since the beginning of the technology, there has been active debate about the role of human leucocyte antigen (HLA) matching in kidney allograft survival. Recent studies have reported diminishing importance of HLA matching, which have, in turn, been challenged by reports that suggest the continuing importance of these loci. Given the controversies, we examined the effect of HLA compatibility on kidney allograft survival by studying all first adult kidney transplants in the United States from a deceased donor. METHODS: Using the United Network for Organ Sharing data, we identified first deceased donor kidney transplants between October 1, 1987, and December 31, 2013. Recipients were classified by their number of HLA mismatches. Cox multivariate regression analyses adjusting for recipient and donor transplant characteristics were performed to determine the impact of HLA compatibility on kidney allograft survival. RESULTS: Study cohort included 189 141 first adult kidney alone transplants, with a total of 994 558 years of kidney allograft follow-up time. Analyses adjusted…

BACKGROUND: The contribution of calcineurin inhibitors (CNI) nephrotoxicity to progressive kidney transplant injury remains debated, with little long-term data from the modern tacrolimus (TAC) era using lower doses. METHODS: This longitudinal cohort study evaluated histological evidence of CNI nephrotoxicity from normal donor kidneys of successful kidney-pancreas transplant recipients during cyclosporine (CSA) and TAC eras, analyzed by intention-to-treat. RESULTS: From 200 patients, 1622 adequate prospective protocol (84.3%) and indication (15.7%) kidney biopsies yielded 8.1 ± 4.1 samples per patient, over 7.4 ± 4.4 years posttransplant. The TAC era demonstrated less rejection and reduced early immune-mediated tubular damage, compared with CSA (P < 0.001). The incidences of acute mild arteriolopathy, striped interstitial fibrosis, glomerular congestion, and tubular microcalcification were all greater with CSA (hazard ratios of 1.70, 9.35, and 3.78, respectively) and maximal within the first posttransplant year, compared with TAC-treated patients (P < 0.001). However, the 1-, 5-, and…

Liver ischemia reperfusion activates innate immune system to drive the full development of inflammatory hepatocellular injury. Damage-associated molecular patterns (DAMPs) stimulate myeloid and dendritic cells via pattern recognition receptors (PRRs) to initiate the immune response. Complex intracellular signaling network transduces inflammatory signaling to regulate both innate immune cell activation and parenchymal cell death. Recent studies have revealed that DAMPs may trigger not only proinflammatory but also immune regulatory responses by activating different PRRs or distinctive intracellular signaling pathways or in special cell populations. Additionally, tissue injury milieu activates PRR-independent receptors which also regulate inflammatory disease processes. Thus, the innate immune mechanism of liver ischemia-reperfusion injury involves diverse molecular and cellular interactions, subjected to both endogenous and exogenous regulation in different cells. A better understanding of these complicated regulatory pathways/network is imperative for us in designing safe and…

BACKGROUND: Antiviral-resistant or refractory cytomegalovirus (CMV) infection is challenging, and salvage therapies, foscarnet, and cidofovir, have significant toxicities. Several investigational anti-CMV agents are under development, but more information is needed on outcomes of current treatments to facilitate clinical trial design for new drugs. METHODS: Records of solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients at a single center over a 10-year period were reviewed retrospectively to characterize those who had received foscarnet treatment for ganciclovir-resistant or refractory CMV infection. Data were collected on virologic responses, mortality, and nephrotoxicity. RESULTS: Of 39 patients (22 SOT, 17 HCT), 15 had documented ganciclovir resistance mutations and 11 (28%) of 39 had tissue-invasive CMV. Median duration of foscarnet was 32 days. Virologic failure occurred in 13 (33%) of 39 and relapses of viremia occurred in 31%. Mortality was 12 (31%) of 39 and was higher in HCT than SOT (P = 0.001), although ganciclovir resistance was more common in…

BACKGROUND: The ability to predict graft failure or primary nonfunction at liver transplant decision time assists utilization of scarce resource of donor livers, while ensuring that patients who are urgently requiring a liver transplant are prioritized. An index that is derived to predict graft failure using donor and recipient factors, based on local data sets, will be more beneficial in the Australian context. METHODS: Liver transplant data from the Austin Hospital, Melbourne, Australia, from 2010 to 2013 has been included in the study. The top 15 donor, recipient, and transplant factors influencing the outcome of graft failure within 30 days were selected using a machine learning methodology. An algorithm predicting the outcome of interest was developed using those factors. RESULTS: Donor Risk Index predicts the outcome with an area under the receiver operating characteristic curve (AUC-ROC) value of 0.680 (95% confidence interval [CI], 0.669-0.690). The combination of the factors used in Donor Risk Index with the model for end-stage liver disease score yields an AUC-ROC of 0.764…

BACKGROUND: Skeletal muscle depletion has been shown to be an independent risk factor for poor survival in various diseases. However, in surgery, the significance of other body components including visceral and subcutaneous adipose tissue remains unclear. METHODS: This retrospective study included 250 adult patients undergoing living donor liver transplantation (LDLT) between January 2008 and April 2015. Using preoperative plain computed tomography imaging at the third lumbar vertebra level, skeletal muscle mass, muscle quality, and visceral adiposity were evaluated by the skeletal muscle mass index (SMI), intramuscular adipose tissue content (IMAC), and visceral to subcutaneous adipose tissue area ratio (VSR), respectively. The cutoff values of these parameters were determined for men and women separately using the data of 657 healthy donors for LDLT between 2005 and 2016. Impact of these parameters on outcomes after LDLT was analyzed. RESULTS: VSR was significantly correlated with patient age (P = 0.041), neutrophil-lymphocyte ratio (P < 0.001), body mass index (P < 0.001), and…

BACKGROUND: Frailty increases early hospital readmission and mortality risk among kidney transplantation (KT) recipients. Although frailty represents a high-risk state for this population, the correlates of frailty, the patterns of the 5 frailty components, and the risk associated with these patterns are unclear. METHODS: Six hundred sixty-three KT recipients were enrolled in a cohort study of frailty in transplantation (12/2008-8/2015). Frailty, activities of daily living (ADL)/instrumental ADL (IADL) disability, Centers for Epidemiologic Studies Depression Scale depression, education, and health-related quality of life (HRQOL) were measured. We used multinomial regression to identify frailty correlates. We identified which patterns of the 5 components were associated with mortality using adjusted Cox proportional hazards models. RESULTS: Frailty prevalence was 19.5%. Older recipients (adjusted prevalence ratio [PR], 2.22; 95% confidence interval [CI], 1.21-4.07) were more likely to be frail. The only other factors that were independently associated with frailty were IADL…

BACKGROUND: The proportion of deceased donor kidneys recovered for transplant but discarded increased steadily in the United States over 2 decades, from 5.1% in 1988 to 19.2% by 2009. Over 100 000 patients are waiting for a kidney transplant, yet 3159 kidneys were discarded in 2015. METHODS: We evaluated trends in donor characteristics, discard reasons, and Organ Procurement Organization-specific discard rates. Multivariable regression and propensity analysis were used to estimate the proportion of the discard rate rise in the 2000s attributable to changes in donor factors and decisions to biopsy and pump kidneys. RESULTS: This study found that at least 80% of the discard rate rise can be explained by the recovery of kidneys from an expanding donor pool and changes in biopsy and pumping practices. However, a residual discard rate increase could not be explained by changes in these factors. From 1987 to 2009, median donor age rose from 26 to 43 years; median Kidney Donor Risk Index increased from 1.1 in 1994 to 1.3 in 2009. Our findings suggest that the increase from 10% to 30% in…

In Brief Background Sarcopenia and functional impairment are common and lethal extrahepatic manifestations of cirrhosis. We aimed to determine the association between computed tomography (CT)-based measures of muscle mass and quality (sarcopenia) and performance-based measures of muscle function. Methods Adults listed for liver transplant underwent testing of muscle function (grip strength, Short Physical Performance Battery [SPPB]) within 3 months of abdominal CT. Muscle mass (cm2/m2) = total cross-sectional area of psoas, paraspinal, and abdominal wall muscles at L3 on CT, normalized for height. Muscle quality = mean Hounsfield units for total skeletal muscle area at L3. Results Among 292 candidates, median grip strength was 31 kg, SPPB score was 11, muscle mass was 49 cm2/m2, and muscle quality was 35 Hounsfield units. Grip strength weakly correlated with muscle mass (ρ = 0.26, P < 0.001) and quality (ρ = 0.27, P < 0.001) in men, and muscle quality (ρ = 0.23, P = 0.02), but not muscle mass, in women. Short Physical Performance Battery correlated weakly with muscle quality in men…

BACKGROUND: Penetrating keratoplasty (PK) ranks among the oldest and most common kinds of human tissue transplantation. Based on the hypothesis that reported indications for PK significantly vary between global regions and over time, the present systematic review aimed to provide a thorough overview of global PK indications as reported in peer-reviewed manuscripts. METHODS: A literature search of PubMed and MEDLINE was conducted to retrieve articles published from January 1980 to May 2014. Indications for PK within 7 global regions were compared using a modified classification system for PK indications and analyzed via multivariate regression. RESULTS: A total of 141 publications from 37 countries were included, recording 180 865 PK cases. Postcataract surgery edema was the predominant indication in North America (28.0%) and ranked second in Europe (20.6%), Australia (21.1%), the Middle East (13.6%), Asia (15.5%), and South America (18.6%). Keratoconus was the leading indication in Europe (24.2%), Australia (33.2%), the Middle East (32.8%), Africa (32.4%), and South America (22.8%).…

Malignancy is the second most common single cause of death observed in organ transplant recipients. The excess cancer risk is related to intensity and duration of immunosuppressive therapy and inversely to recipient age. Immunodeficiency and (chronic/oncogenic) viral infections together constitute a major risk. Nonmelanoma skin cancer, Kaposi sarcoma, and posttransplant lymphoproliferative disease have standardized incidence ratios exceeding 10- or 50-fold. The mammalian target of rapamycin (mTOR) inhibitors, sirolimus and everolimus, are increasingly used after organ transplantation with potential advantages in virus-associated posttransplant malignancies as well as anti-cancer properties. Despite a seemingly clear mechanism of action and solid rationale for their use in cancer therapy, mTORis have met only modest success rates in clinical trials with advanced malignancies except for specific tumors, such as Kaposi sarcoma and mantle cell lymphoma. Because mTORis are primarily cytostatic, not cytotoxic, the observed clinical efficacy is a reflection of disease stabilization rather…

In Brief Living donor liver transplantation (LDLT) has been increasingly embraced around the world as an important strategy to address the shortage of deceased donor livers. The aim of this guideline, approved by the International Liver Transplantation Society (ILTS), is to provide a collection of expert opinions, consensus, and best practices surrounding LDLT. Recommendations were developed from an analysis of the National Library of Medicine living donor transplantation indexed literature using the Grading of Recommendations Assessment, Development and Evaluation methodology. Writing was guided by the ILTS Policy on the Development and Use of Practice Guidelines (www.ilts.org). Intended for use by physicians, these recommendations support specific approaches to the diagnostic, therapeutic, and preventive aspects of care of living donor liver transplant recipients. Compared to cadaveric liver transplantation, live donor LT (LDLT) is challenged by ethical, medical and surgical considerations, many of which are still unresolved. The aim of this guideline is to provide a collection of…

In Brief Chronic lung allograft dysfunction (CLAD) is the major limitation of long-term survival after lung transplantation. Chronic lung allograft dysfunction manifests as bronchiolitis obliterans syndrome or the recently described restrictive allograft syndrome. Although numerous risk factors have been identified so far, the physiopathological mechanisms of CLAD remain poorly understood. We investigate here the immune mechanisms involved in the development of CLAD after lung transplantation. We explore the innate or adaptive immune reactions induced by the allograft itself or by the environment and how they lead to allograft dysfunction. Because current literature suggests bronchiolitis obliterans syndrome and restrictive allograft syndrome as 2 distinct entities, we focus on the specific factors behind one or the other syndromes. Chronic lung allograft dysfunction is a multifactorial disease that remains irreversible and unpredictable so far. We thus finally discuss the potential of systems-biology approach to predict its occurrence and to better understand its underlying…

BACKGROUND: Transplant recipients are treated with immunosuppressive (IS) therapies, which impact host-microbial interactions. We examined the impact of IS drugs on gut microbiota and on the expression of ileal antimicrobial peptides. METHODS: Mice were treated for 14 days with prednisolone, mycophenolate mofetil, tacrolimus, a combination of these 3 drugs, everolimus, or water. Feces were collected before and after treatment initiation. Ileal samples were collected after sacrifice. Fecal and ileal microbiota were analyzed by pyrosequencing of 16S rRNA genes and enumeration of selected bacteria by culture, and C-type lectins were assessed in ileal tissues by reverse transcriptase-quantitative polymerase chain reaction. RESULTS: Prednisolone disrupted fecal microbiota community structure, decreased Bacteroidetes, and increased Firmicutes in the feces. Prednisolone, tacrolimus, and mycophenolate mofetil modified fecal microbiota at the family level in each experimental replicate, but changes were not consistent between the replicates. In ileal samples, the genus Clostridium sensu…

BACKGROUND: Given high dialysis mortality rates for patients older than 60 years, accepting a kidney with a high Kidney Donor Profile Index (KDPI) score could enable earlier and potentially preemptive transplantation (preKT). However, evidence regarding the risks of high KDPI allografts in older patients is limited. Our objective was to determine the relative benefit for older patients of KDPI greater than 85% transplant either preemptively or not compared with remaining on the waitlist. METHODS: United Network of Organ Sharing data from 2003 to 2012 for adult deceased donor kidney transplant candidates was analyzed to evaluate patient survival in patients older than 60 years for preKT and non-preKT KDPI greater than 85% transplants compared with candidates remaining on the waitlist including patients who received KDPI 0% to 85% transplants according to multivariate Cox regression models. RESULTS: In the first year posttransplant for KDPI greater than 85% of transplants in recipients older than 60 years, preKT had a reduced mortality hazard (hazards ratio [HR], 0.61; 95% confidence…

BACKGROUND: Published reports describing the national experience with liver grafts from donation after cardiac death (DCD) donors have resulted in reservations with their widespread utilization. The present study aimed to investigate if temporal improvements in outcomes have been observed on a national level and to determine if donor and recipient selection have been modified in a fashion consistent with published data on DCD use in liver transplantation (LT). METHODS: Patients undergoing DCD LT between 2003 and 2014 were obtained from the United Network of Organ Sharing Standard Transplant Analysis and Research file and divided into 3 equal eras based on the date of DCD LT: era 1 (2003-2006), era 2 (2007-2010), and era 3 (2011-2014). RESULTS: Improvement in graft survival was seen between era 1 and era 2 (P = 0.001) and between era 2 and era 3 (P < 0.001). Concurrently, an increase in the proportion of patients with hepatocellular carcinoma and a decrease in critically ill patients, retransplant recipients, donor age, warm ischemia time greater than 30 minutes and cold ischemic…

In Brief Immunosuppression strategies that selectively inhibit effector T cells while preserving and even enhancing CD4+FOXP3+ regulatory T cells (Treg) permit immune self-regulation and may allow minimization of immunosuppression and associated toxicities. Many immunosuppressive drugs were developed before the identity and function of Treg were appreciated. A good understanding of the interactions between Treg and immunosuppressive agents will be valuable to the effective design of more tolerable immunosuppression regimens. This review will discuss preclinical and clinical evidence regarding the influence of current and emerging immunosuppressive drugs on Treg homeostasis, stability, and function as a guideline for the selection and development of Treg-friendly immunosuppressive regimens. Immunosuppressive medications inhibit not only Teff but also Treg. Nevertheless, Treg have different critical intracellular pathways that may allow targeting Teff and not Treg. Several of these differences are not absolute but quantitative. Future Treg friendly treatments will consider which drugs…

BACKGROUND: Antibody-mediated rejection (AMR) represents one of the cardinal causes of late allograft loss after kidney transplantation, and there is great need for noninvasive tools improving early diagnosis of this rejection type. One promising strategy might be the quantification of peripheral blood DNA levels of the highly prevalent and apathogenic Torque Teno virus (TTV), which might mirror the overall level of immunosuppression and thus help determine the risk of alloimmune response. METHODS: To assess the association between TTV load in the peripheral blood and AMR, 715 kidney transplant recipients (median, 6.3 years posttransplantation) were subjected to a systematical cross-sectional AMR screening and, in parallel, TTV quantification. RESULTS: Eighty-six of these recipients had donor-specific antibodies and underwent protocol biopsy, AMR-positive patients (n = 46) showed only 25% of the TTV levels measured in patients without AMR (P = 0.003). In a generalized linear model, higher TTV levels were associated with a decreased risk for AMR after adjustment for potential…

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is being increasingly used as a bridge to lung transplantation. Small, single-institution series have described increased success using ECMO in spontaneously breathing patients compared with patients on ECMO with mechanical ventilation, but this strategy has not been evaluated on a large scale. METHODS: Using the United Network for Organ Sharing database, all adult patients undergoing isolated lung transplantation from May 2005 through September 2013 were identified. Patients were categorized by their type of pretransplant support: no support, ECMO only, invasive mechanical ventilation (iMV) only, and ECMO + iMV. Kaplan-Meier survival analysis with log-rank testing was performed to compare survival based on type of preoperative support. A Cox regression model was used to determine whether type of preoperative support was independently associated with survival, using previously established predictors of survival as covariates. RESULTS: Approximately 12,403 primary adult pulmonary transplantations were included in this analysis.…

BACKGROUND: Hepatic epithelioid hemangioendothelioma (HEHE) is a rare vascular tumor which has an intermediate aggressive behavior. Although the value of liver transplantation (LT) is well established, its place in the management of HEHE is still unclear. The aim of this study is to confirm, based on a very large patient cohort, the value of LT in the management of HEHE and to identify risk factors for post-LT recurrence. METHODS: The outcome of 149 transplant recipients with HEHE recorded in the European Liver Transplant Registry during the period November 1984 to May 2014 was analyzed. Median post-LT follow-up was 7.6 years (interquartile range, 2.8-14.4). RESULTS: Cox regression analysis showed that macrovascular invasion (hazard ratio [HR], 4.8; P < 0.001), pre-LT waiting time of 120 days or less (HR, 2.6; P = 0.01) and hilar lymph node invasion (HR = 2.2; P = 0.03), but not pre-LT extrahepatic disease, were significant risk factors for recurrence. These findings, which were also confirmed in a propensity score analysis, allowed the development of a HEHE-LT score enabling…

In Brief Background The mechanism through which oxygenated hypothermic machine perfusion (HMP) improves viability of human extended criteria donor (ECD) livers is not well known. Aim of this study was to examine the benefits of oxygenated HMP after static cold storage (SCS). Methods Eighteen ECD livers that were declined for transplantation underwent ex situ viability testing using normothermic (37°C) machine perfusion (NMP) after traditional SCS (0°C-4°C) for 7 to 9 hours. In the intervention group (n = 6), livers underwent 2 hours of oxygenated HMP (at 12°C) after SCS and before NMP. Twelve control livers underwent NMP without oxygenated HMP after SCS. Results During HMP, hepatic ATP content increased greater than 15-fold, and levels remained significantly higher during the first 4 hours of NMP in the HMP group, compared with controls. Cumulative bile production and biliary secretion of bilirubin and bicarbonate were significantly higher after HMP, compared with controls. In addition, the levels of lactate and glucose were less elevated after HMP compared with SCS preservation…

In Brief Background Early allograft dysfunction (EAD) after living donor liver transplantation (LDLT) has often been attributed to inadequate graft size, and termed small-for-size syndrome. Early allograft dysfunction definitions include a variable constellation of findings, including hyperbilirubinemia, coagulopathy, encephalopathy, and ascites formation. Among putative causes of EAD after LDLT are excessive portal pressure and/or flow. Our objective was to evaluate patterns of EAD after LDLT. Methods In this study, 631 LDLT recipients were monitored for complications, EAD (defined by postoperative day 7 bilirubin >10 mg/dL or international normalized ratio >1.6), and graft failure. Approximately 200 had portal venous and arterial pressure and flow measurements before and after LDLT. Portal inflow modification (splenic artery ligation, hemiportocaval shunt, or splenectomy) was performed at the discretion of the operating surgeon. Associations between EAD and recipient, donor, and transplant factors were examined using multivariable logistic regression. Results Risk of EAD was…

BACKGROUND: Natural killer (NK) cells localize in the microcirculation in antibody-mediated rejection (AMR) and have been postulated to be activated by donor-specific anti-HLA antibodies triggering their CD16a Fc receptors. However, direct evidence for NK cell CD16a triggering in AMR is lacking. We hypothesized that CD16a-inducible NK cell-selective transcripts would be expressed in human AMR biopsies and would offer evidence for CD16a triggering. METHODS: We stimulated human NK cells through CD16a in vitro, characterized CD16a-inducible transcripts, and studied their expression in human kidney transplant biopsies with AMR and in an extended human cell panel to determine their selectivity. RESULTS: In NK cells, CD16a stimulation induced increased expression of 276 transcripts (FC > 2x, false discovery rate < 0.05), including IFNG, TNF, CSF2, chemokines, such as CCL3, CCL4, and XCL1, and modulators of NK cell effector functions (TNFRSF9, CRTAM, CD160). Examination in an extended human cell panel revealed that CD160 and XCL1 were likely to be selective for NK cells in AMR. In…

BACKGROUND: High intrapatient tacrolimus variability has been associated with worse clinical outcomes postrenal transplantation. Theoretically, tacrolimus levels consistently outside the target therapeutic window may result in allograft dysfunction as subtherapeutic tacrolimus levels predispose to episodes of acute rejection, whereas supratherapeutic levels may cause nephrotoxicity. METHODS: We investigated the effect of tacrolimus variability in a "Symphony" style low-dose tacrolimus based regime, by collecting data from 432 patients over a 4-year period.Three hundred seventy-six patients were included, with a mean follow-up of 1495 days. Tacrolimus variability 6 to 12 months after renal transplantation was calculated, and outcomes were compared in low (n = 186) and high variability (n = 190) groups. RESULTS: High variability patients were found to be at increased risk of rejection during the first posttransplant year (P = 0.0054) and to have reduced rejection-free survival (hazard ratio, 1.953; 95% confidence interval, 1.234-3.093; P = 0.0054). High variability patients had…

In Brief Although the management of kidney transplant recipients has greatly improved over recent decades, the assessment of individual risks remains highly imperfect. Individualized strategies are necessary to recognize and prevent immune complications early and to fine-tune immunosuppression, with the overall goal to improve patient and graft outcomes. This review discusses current biomarkers and their limitations, and recent advancements in the field of noninvasive biomarker discovery. A wealth of noninvasive monitoring tools has been suggested that use easily accessible biological fluids such as urine and blood, allowing frequent and sequential assessments of recipient's immune status. This includes functional cell-based assays and the evaluation of molecular expression on a wide spectrum of platforms. Nevertheless, the translation and validation of exploratory findings and their implementation into standard clinical practice remain challenging. This requires dedicated prospective interventional trials demonstrating that the use of these biomarkers avoids invasive procedures and…

BACKGROUND: Graft-versus-host-disease (GVHD) after liver transplantation (LT) is a deadly complication with very limited data on risk factors, diagnosis and management. We report a case series and a comprehensive review of the literature. METHODS: Data were systematically extracted from reports of GVHD after LT, and from the United Network for Organ Sharing database. Group comparisons were performed. RESULTS: One hundred fifty-six adult patients with GVHD after LT have been reported. Median time to GVHD onset was 28 days. Clinical features were skin rash (92%), pancytopenia (78%), and diarrhea (65%). Six-month mortality with GVHD after LT was 73%. Sepsis was the most common cause of death (60%). Enterobacter bacteremia, invasive aspergillosis, and disseminated Candida infections were frequently reported. Recipient age over 50 years is a risk factor for GVHD after LT. Hepatocellular carcinoma was overrepresented, whereas chronic hepatitis C was underrepresented, in reported United States GVHD cases relative to all United Network for Organ Sharing database LT cases. Mortality rate…

Vascularized composite tissue allografts (VCA) have become a viable option to restore severely damaged parts of the body that cannot be repaired with conventional surgical techniques. Acute rejection develops frequently in the early postgraft period both in human and experimental VCA, but the possibility of human VCA to undergo chronic rejection (CR) remained initially unknown. The experience gained over the years shows that, similar to solid organ transplants (SOT), human VCA can also develop CR. Chronic rejection is clinically mostly apparent on the skin and targets preferentially skin and deep vessels, leading, as in SOT, to graft vasculopathy and often to graft loss. Dermal sclerosis and adnexal atrophy are additional features of CR. The pathogenetic immune mechanisms involved (cell-mediated versus humoral) remain incompletely known. The changes of CR can be detected with skin and deep tissue biopsies. Modern in vivo imaging tools can detect vascular narrowing and have the advantage of being noninvasive. However, the diagnosis and treatment of CR remain challenging, as several…

BACKGROUND: Minimally invasive live donor nephrectomy has become a fully implemented and accepted procedure. Donors have to be well educated about all risks and details during the informed consent process. For this to be successful, more information regarding short-term outcome is necessary. METHODS: A literature search was performed; all studies discussing short-term complications after minimally invasive live donor nephrectomy were included. Outcomes evaluated were intraoperative and postoperative complications, conversions, operative and warm ischemia times, blood loss, length of hospital stay, pain score, convalescence, quality of life, and costs. RESULTS: One hundred ninety articles were included in the systematic review, 41 in the meta-analysis. Conversion rate was 1.1%. Intraoperative complication rate was 2.3%, mainly bleeding (1.5%). Postoperative complications occurred in 7.3% of donors, including infectious complications (2.6%), of which mainly wound infection (1.6%) and bleeding (1.0%). Reported mortality rate was 0.01%. All minimally invasive techniques were comparable…

At the 2015 combined congress of the Cell Transplant Society, International Pancreas and Islet Transplant Association, and International Xenotransplantation Association, a symposium was held to discuss recent progress in pig islet xenotransplantation. The presentations focused on 5 major topics - (1) the results of 2 recent clinical trials of encapsulated pig islet transplantation, (2) the inflammatory response to encapsulated pig islets, (3) methods to improve the secretion of insulin by pig islets, (4) genetic modifications to the islet-source pigs aimed to protect the islets from the primate immune and/or inflammatory responses, and (5) regulatory aspects of clinical pig islet xenotransplantation. Trials of microencapsulated porcine islet transplantation to treat unstable type 1 diabetic patients have been associated with encouraging preliminary results. Further advances to improve efficacy may include (1) transplantation into a site other than the peritoneal cavity, which might result in better access to blood, oxygen, and nutrients; (2) the development of a more biocompatible…

BACKGROUND: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly used as a short-term circulatory support in patients with refractory cardiogenic shock providing a bridge to long-term mechanical circulatory support or transplantation. In France, a higher priority status is granted to transplant candidates on VA-ECMO than to those on long-term mechanical circulatory support. This study aimed to evaluate the impact of transplantation as primary therapy on survival in patients on VA-ECMO at listing. METHODS: This was a retrospective analysis of data from the French national registry CRISTAL including all patients (n = 866) newly registered on the waiting list for heart transplantation between January 2010 and December 2011. We compared outcomes of 80 patients on VA-ECMO at listing to outcomes of the comparison group. In the VA-ECMO group, a Cox proportional hazard model with transplantation as a time dependent variable was used to evaluate the effect of transplantation on survival. RESULTS: Patients on VA-ECMO were more often on ventilator and dialysis and had a…

BACKGROUND: Successful xenotransplantation will likely depend, in part, on the induction of immunological tolerance, because the high levels of immunosuppression otherwise required would likely have unacceptable side effects. Rapid clearance of administered porcine hematopoietic stem cells by primate macrophages has hampered previous attempts to induce tolerance through mixed hematopoietic chimerism across a pig-to-primate barrier. Phagocytosis is normally inhibited by binding of cell surface protein CD47 to macrophage signal regulatory protein α receptors. However, pig CD47 has previously been shown to be ineffective in transducing signals through primate signal regulatory protein α. METHODS: Mobilized peripheral blood hematopoietic cells from transgenic swine expressing high or low levels of human CD47 were infused into conditioned baboons at 3 time points over a 9-week period. Xenogeneic peripheral blood chimerism was assessed after each infusion. Split thickness skin grafts from the hematopoietic cell donor swine were placed on recipients 5 weeks after the last cell infusion and…

In Brief BK polyomavirus is ubiquitous, with a seropositivity rate of over 75% in the adult population. Primary infection is thought to occur in the respiratory tract, but asymptomatic BK virus latency is established in the urothelium. In immunocompromised host, the virus can reactivate but rarely compromises kidney function except in renal grafts, where it causes a tubulointerstitial inflammatory response similar to acute rejection. Restoring host immunity against the virus is the cornerstone of treatment. This review covers the virus-intrinsic features, the posttransplant microenvironment as well as the host immune factors that underlie the pathophysiology of polyomavirus-associated nephropathy. Current and promising therapeutic approaches to treat or prevent this complication are discussed in relation to the complex immunopathology of this condition. Lamarche et al review the virus-intrinsic features, the posttransplant micro-environmentand the host immunological factors that underlie the pathophysiology of BK virus nephropathy.

All causes of renal allograft injury, when severe and/or sustained, can result in chronic histological damage of which interstitial fibrosis and tubular atrophy are dominant features. Unless a specific disease process can be identified, what drives interstitial fibrosis and tubular atrophy progression in individual patients is often unclear. In general, clinicopathological factors known to predict and drive allograft fibrosis include graft quality, inflammation (whether "nonspecific" or related to a specific diagnosis), infections, such as polyomavirus-associated nephropathy, calcineurin inhibitors (CNI), and genetic factors. The incidence and severity of chronic histological damage have decreased substantially over the last 3 decades, but it is difficult to disentangle what effects individual innovations (eg, better matching and preservation techniques, lower CNI dosing, BK viremia screening) may have had. There is little evidence that CNI-sparing/minimization strategies, steroid minimization or renin-angiotensin-aldosterone system blockade result in better preservation of…

BACKGROUND: A measure of donor liver quality, the donor liver index, was developed and validated for the UK population of transplant recipients. Unlike previously proposed measures, this index is only based on variables that are available at the point of retrieval, and so does not include cold ischemic time. METHODS: Indices of liver quality were based on data from the UK Transplant Registry on all 7929 liver transplants between January 2000 and December 2014. RESULTS: The donor liver index (DLI) was based on factors shown to affect graft survival, which included donor age, sex, height, type (donor after brain death or circulatory death), bilirubin, smoking history, and whether the liver was split. A separate index (DLI1) looking at 1-year survival showed donor cardiac disease, black ethnicity, and steatosis to be additional risk factors. A strong association was found between DLI and whether or not a surgeon accepts an offered liver for transplant, with a marked fall in acceptance rates for livers with an index greater than 1.31. Since 2000, there has been a notable reduction in…

BACKGROUND: Perioperative antimicrobial prophylaxis is administered to liver transplant (LTx) recipients to prevent surgical site infections (SSIs), but regimens are not standardized, and there are limited effectiveness data. Prevention and treatment of SSIs have been complicated by the emergence of multidrug-resistant (MDR) pathogens. METHODS: We retrospectively reviewed SSIs among 331 LTx recipients at our center in 2010 to 2014. RESULTS: Culture-proven superficial and deep SSIs occurred in 3% and 15% of patients, respectively, at median 12.5 and 13.5 days post-LTx. Recipients with superficial SSIs and those without SSIs were similar in demographics, clinical characteristics, length of hospital stay, and mortality. Deep SSIs included abscesses (58%), peritonitis (28%), deep incisional infections (8%), and cholangitis (6%). Rates of deep SSIs were comparable among patients receiving prophylaxis with ampicillin-sulbactam, aztreonam and vancomycin, or tigecycline (P = 0.61). Independent risk factors for deep SSIs were bile leak (P < 0.001) and operative time (P < 0.001).…

BACKGROUND: Solid organ transplant recipients (SOTR) with a pretransplant malignancy (PTM) are at increased risk for cancer recurrence. However, it is unclear whether differences in survival and incidence of posttransplant de novo malignancies exist between recipients with PTM and those without PTM. We designed a systematic review to synthesize all available evidence assessing these outcomes. METHODS: A systematic search was performed in MEDLINE, EMBASE, and Cochrane Library to identify studies comparing the following outcomes in SOTR by PTM status: (1) all-cause mortality, (2) cancer-specific mortality, and (3) incidence of posttransplant de novo malignancy. Risk of bias was assessed using the Newcastle-Ottawa Scale. RESULTS: Thirty-two cohort studies were included. Recipients with PTM were at increased risk of all-cause mortality compared to recipients without PTM (pooled hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.27-1.81). Similarly, recipients with PTM were 3 times more likely to die of cancer (pooled HR, 3.13; 95% CI, 2.29-4.27). The pooled HR for developing…

BACKGROUND: We report the ability to extend lung preservation up to 24 hours (24H) by using autologous whole donor blood circulating within an ex vivo lung perfusion (EVLP) system. This approach facilitates donor lung reconditioning in a model of extended normothermic EVLP. We analyzed comparative responses to cellular and acellular perfusates to identify these benefits. METHODS: Twelve pairs of swine lungs were retrieved after cardiac arrest and studied for 24H on the Organ Care System (OCS) Lung EVLP platform. Three groups (n = 4 each) were differentiated by perfusate: (1) isolated red blood cells (RBCs) (current clinical standard for OCS); (2) whole blood (WB); and (3) acellular buffered dextran-albumin solution (analogous to STEEN solution). RESULTS: Only the RBC and WB groups met clinical standards for transplantation at 8 hours; our primary analysis at 24H focused on perfusion with WB versus RBC. The WB perfusate was superior (vs RBC) for maintaining stability of all monitored parameters, including the following mean 24H measures: pulmonary artery pressure (6.8 vs 9.0 mm Hg),…

BACKGROUND: Vascularized composite allografts, particularly hand and forearm, have limited ischemic tolerance after procurement. In bilateral hand transplantations, this demands a 2 team approach and expedited transfer of the allograft, limiting the recovery to a small geographic area. Ex situ perfusion may be an alternative allograft preservation method to extend allograft survival time. This is a short report of 5 human limbs maintained for 24 hours with ex situ perfusion. METHODS: Upper limbs were procured from brain-dead organ donors. Following recovery, the brachial artery was cannulated and flushed with 10 000 U of heparin. The limb was then attached to a custom-made, near-normothermic (30-33°C) ex situ perfusion system composed of a pump, reservoir, and oxygenator. Perfusate was plasma-based with a hemoglobin concentration of 4 to 6 g/dL. RESULTS: Average warm ischemia time was 76 minutes. Perfusion was maintained at an average systolic pressure of 93 ± 2 mm Hg, flow 310 ± 20 mL/min, and vascular resistance 153 ± 16 mm Hg/L per minute. Average oxygen consumption was 1.1 ± 0.2…

In Brief During the last 20 years, waiting lists for renal transplantation (RT) have grown significantly older. However, elderly patients (ie ≥65 years of age) are still more rarely referred or accepted to waiting lists and, if enlisted, have less chances of actually receiving a kidney allograft, than younger counterparts. In this review, we looked at evidence for the benefits and risks of RT in the elderly trying to answer the following questions: Should RT be advocated for elderly patients? What should be the criteria to accept elderly patients on the waiting list for RT? What strategies might be used to increase the rate of RT in waitlisted elderly candidates? For selected elderly patients, RT was shown to be superior to dialysis in terms of patient survival. Virtually all guidelines recommend that patients should not be deemed ineligible for RT based on age alone, although a short life expectancy generally might preclude RT. Concerning the assessment of comorbidities in the elderly, special attention should be paid to cardiac evaluation and screening for malignancy. Comorbidity…

In Brief Background We previously showed that bortezomib (BTZ) partially depletes plasma cells, yet has limited efficacy for desensitization in kidney transplant candidates when up to 16 doses is given. Methods This study aimed to determine the safety and efficacy of 32 doses of BTZ (1.3 mg/m2 of body surface area) in 10 highly sensitized kidney transplant candidates with alloantibodies against their intended living donor. Results Dose reduction was needed in 2 patients and 2 others completely discontinued therapy for adverse events. Anti-HLA antibodies mean fluorescence intensity (MFI) values were stable prior to BTZ (P = 0.96) but decreased after therapy (mean decrease of 1916 [SE, 425] MFI, P < 0.01). No patient developed a negative crossmatch against their original intended donor, and the calculated panel-reactive antibodies based on MFI of 2000, 4000, and 8000 was unchanged in all patients. Conclusions These data suggest that 32 doses of BTZ monotherapy was not well tolerated and resulted in only a modest reduction in anti-HLA antibodies. Extending bortezomib to 32 doses for…

In Brief Background Community-acquired respiratory virus (CARV) infections occur frequently after lung transplantation and may adversely impact outcomes. We hypothesized that while asymptomatic carriage would not increase the risk of chronic lung allograft dysfunction (CLAD) and graft loss, severe infection would. Methods All lung transplant cases between January 2000 and July 2013 performed at our center were reviewed for respiratory viral samples. Each isolation of virus was classified according to clinical level of severity: asymptomatic, symptomatic without pneumonia, and viral pneumonia. Multivariate Cox modeling was used to assess the impact of CARV isolation on progression to CLAD and graft loss. Results Four thousand four hundred eight specimens were collected from 563 total patients, with 139 patients producing 324 virus-positive specimens in 245 episodes of CARV infection. Overall, the risk of CLAD was elevated by viral infection (hazard ratio [HR], 1.64; P < 0.01). This risk, however, was due to viral pneumonia alone (HR, 3.94; P < 0.01), without significant impact from…

In Brief The following guideline represents the position of the International Liver Transplantation Society (ILTS) on key preoperative, operative, and postoperative aspects surrounding living liver donation. These recommendations were developed from experts in the field from around the world. The authors conducted an analysis of the National Library of Medicine indexed literature on “living donor liver transplantation” [Medline search] using Grading of Recommendations Assessment, Development and Evaluation methodology. Writing was guided by the ILTS Policy on the Development and Use of Practice Guidelines (www.ilts.org). ILTS members, and many more nonmembers, were invited to comment. Recommendations have been based on information available at the time of final submission (March 2016). The lack of randomized controlled trials in this field to date is acknowledged and is reflected in the grading of evidence. Intended for use by physicians, these recommendations support specific approaches to the diagnostic, therapeutic, and preventive aspects of care. The ILTS presents a practice…

In Brief Alcohol-related liver disease is the second most frequent indication for liver transplantation (LT), yet as many as 90% to 95% of patients with alcohol-related end-stage liver disease are never formally evaluated for LT. Furthermore, despite its significance as a cause of chronic liver disease and indication for LT, it has received little attention in recent years for several reasons, including the good posttransplant short-term results, and the lack of specific “drugs” used for this disease. A writing group, endorsed by the International Liver Transplant Society, was convened to write guidelines on Liver Transplantation for Alcoholic Liver Disease to summarize current knowledge and provide answers to controversial and delicate ethical as well as clinical problems. We report here a short version of the guidelines (long version available at www.ilts.org) with the final recommendations graded for level of evidence. The writing group membership is expected to remain active for 5 years, reviewing the guideline annually, and updating the online version when appropriate. The ILTS…

BACKGROUND: Prolonged ischemia is a known risk factor for delayed graft function (DGF) and its interaction with donor characteristics, the pathways of donor death, and graft outcomes may have important implications for allocation policies. METHODS: Using data from the Australian and New Zealand Dialysis and Transplant registry (1994-2013), we examined the relationship between total ischemic time with graft outcomes among recipients who received their first deceased donor kidney transplants. Total ischemic time (in hours) was defined as the time of the donor renal artery interruption or aortic clamp, until the time of release of the clamp on the renal artery in the recipient. RESULTS: A total of 7542 recipients were followed up over a median follow-up time of 5.3 years (interquartile range of 8.2 years). Of these, 1823 (24.6%) experienced DGF and 2553 (33.9%) experienced allograft loss. Recipients with total ischemic time of 14 hours or longer experienced an increased odd of DGF compared with those with total ischemic time less than 14 hours. This effect was most marked among those…

BACKGROUND: The first prospective observational study of uterus transplantation was initiated in 2013 with live donation to 9 women with absolute uterine factor infertility. We explored the medical complications and psychosocial wellbeing of the donors during the first postoperative year. METHODS: Complications were registered and graded according to the Clavien-Dindo (C-D) classification. Symptoms related to the surgery were registered. Data on length of hospital stay, sick leave, socioeconomic parameters, and life events were obtained. Psychological evaluations (Psychological General Well-Being, Dyadic Adjustment Scale, Hospital Anxiety and Depression Scale [HADS], SF-36) questionnaires focusing on quality of life, mood, and relationship, were conducted at inclusion and at 3, 6, and 12 months after uterus donation. RESULTS: One major surgical complication (C-D IIIb) occurred. A ureteric-vaginal fistula developed 2 weeks after uterus procurement. The fistula was surgically repaired. Two self-reported and transient complications (C-D I) were noted (nocturia, meralgia paresthetica).…

BACKGROUND: This is a cross-sectional study designed to evaluate the histologic characteristics of graft injury in the presence of anti-angiotensin II type 1 receptor antibody (AT1R-Ab) and anti-endothelial cell antibody (AECA). METHODS: Non-HLA antibody testing was included in the posttransplant evaluation for 70 kidney recipients. Biopsies were performed for cause for 47 patients and as protocol for the remaining 23 patients. Biopsy-proven rejection was defined according to the Banff 2009-2013 criteria. AT1R-Ab was measured on an ELISA platform. Patients were divided into 3 groups based on AT1R-Ab levels (>17, 10-17, and <10 U/ml). AECA was evaluated using an endothelial cell crossmatch (ECXM) in patients whose HLA antibody level was insufficient to cause a positive flow cytometric crossmatch. RESULTS: AT1R-Ab levels were higher in patients diagnosed with antibody mediated rejection compared to those with no rejection (P = 0.004). Glomerulitis (g) and peritubular capillaritis (ptc) scores were independently correlated with increased AT1R-Ab concentrations in the presence or…

BACKGROUND: Renal transplantation is a lifesaving intervention for end-stage renal disease. The demand for renal transplantation outweighs the availability of organs; however, up to 20% of recovered kidneys are discarded before transplantation. We aimed to better characterize the risk factors for deceased donor kidney discard. METHODS: We performed a secondary analysis of the Organ Procurement and Transplantation Network database from 2000 to 2012 of all solid organ donors. The cohort was split into training (80%) and validation (20%) subsets. We performed a stepwise logistic regression to develop a multivariate risk prediction model for kidney graft discard and validated the model. The performance of the models was evaluated with respect to calibration, and area under the curve (AUC) of receiver operating characteristic curves. RESULTS: There were no significant baseline differences between the training (n = 57 474) and validation (n = 14 368) cohorts. The multivariate model validation showed very good discriminant function in predicting kidney discard (AUC = 0.84). Predictors of…