Showing papers in "Transplantation in 2016"

Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma: A Randomized, Multicenter, Open-Label Phase 3 Trial

Abstract: Background We investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC). Methods In a prospective-randomized open-label international trial, 525 LTx recipients with HCC initially receiving mammalian target of rapamycin inhibitor-free immunosuppression were randomized 4 to 6 weeks after transplantation into a group on mammalian target of rapamycin inhibitor-free immunosuppression (group A: 264 patients) or a group incorporating sirolimus (group B: 261). The primary endpoint was recurrence-free survival (RFS); intention-to-treat (ITT) analysis was conducted after 8 years. Overall survival (OS) was a secondary endpoint. Results Recurrence-free survival was 64.5% in group A and 70.2% in group B at study end, this difference was not significant (P = 0.28; hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62; 1.15). In a planned analysis of RFS rates at yearly intervals, group B showed better outcomes 3 years after transplantation (HR, 0.7; 95% CI, 0.48-1.00). Similarly, OS (P = 0.21; HR, 0.81; 95% CI, 0.58-1.13) was not statistically better in group B at study end, but yearly analyses showed improvement out to 5 years (HR, 0.7; 95% CI, 0.49-1.00). Interestingly, subgroup (Milan Criteria-based) analyses revealed that low-risk, rather than high-risk, patients benefited most from sirolimus; furthermore, younger recipients (age 60) also benefited, as well sirolimus monotherapy patients. Serious adverse event numbers were alike in groups A (860) and B (874). Conclusions Sirolimus in LTx recipients with HCC does not improve long-term RFS beyond 5 years. However, a RFS and OS benefit is evident in the first 3 to 5 years, especially in low-risk patients. This trial provides the first high-level evidence base for selecting immunosuppression in LTx recipients with HCC.

International liver transplant society practice guidelines: Diagnosis and management of hepatopulmonary syndrome and portopulmonary hypertension

Abstract: 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 transplantation; and V. Suggestions for future clinical research.

Cell-free DNA comprises an in vivo nucleosome footprint that informs its tissues-of-origin

Abstract: Nucleosome positioning varies between cell types. By deep sequencing cell-free DNA (cfDNA), isolated from circulating blood plasma, we generated maps of genome-wide in vivo nucleosome occupancy and found that short cfDNA fragments harbor footprints of transcription factors. The cfDNA nucleosome occupancies correlate well with the nuclear architecture, gene structure, and expression observed in cells, suggesting that they could inform the cell type of origin. Nucleosome spacing inferred from cfDNA in healthy individuals correlates most strongly with epigenetic features of lymphoid and myeloid cells, consistent with hematopoietic cell death as the normal source of cfDNA. We build on this observation to show how nucleosome footprints can be used to infer cell types contributing to cfDNA in pathological states such as cancer. Since this strategy does not rely on genetic differences to distinguish between contributing tissues, it may enable the noninvasive monitoring of a much broader set of clinical conditions than currently possible.

Within-Patient Variability in Tacrolimus Blood Levels Predicts Kidney Graft Loss and Donor-Specific Antibody Development.

Abstract: Background Lack of adherence to immunosuppressive drugs is a risk factor for development of de novo donor-specific antibodies (dnDSA) and can contribute to antibody-mediated rejection and graft loss. Moreover, nonadherence is the main determinant of immunosuppressive drug level variability. High intrapatient variability of tacrolimus relates to a worse outcome in transplant recipients through unknown mechanisms. We hypothesized that a high within-patient variability of tacrolimus could increase the rate of dnDSA development and contribute to further death-censored graft loss (DCGL). Methods We included 310 adult renal transplants receiving twice-daily tacrolimus throughout their first posttransplant year, with (1) at least 3 blood trough levels available to calculate coefficient of variation (CV) from month 4 to 12, (2) graft survival longer than 1 year, and (3) absence of pretransplant DSA. The dnDSA were analyzed in sera at 1, 3, and 5 years and around 6 month before the last follow-up visit or graft loss by single-antigen beads. Results During the follow-up, 53 patients lost their graft excluding death. A total of 116 patients (37.4%) had a CV greater than 30% and 39 (12.6%) developed dnDSA. Coefficient of variation greater than 30% (hazards ratio, 2.613; 95% confidence interval, 1.361-5.016; P = 0.004) independently related to DCGL. Acute rejection, re-transplant and CV greater than 30% (hazards ratio, 2.925; 95% confidence interval, 1.473-5.807; P = 0.002) were the only variables related to dnDSA development by Cox regression analysis. Conclusions Tacrolimus level variability is a strong risk factor for dnDSA development and DCGL. Variability must be added to the current monitoring of kidney transplant recipients due to its relationship with adherence and to graft outcome.

One-year Results of the Effects of Rituximab on Acute Antibody-Mediated Rejection in Renal Transplantation: RITUX ERAH, a Multicenter Double-blind Randomized Placebo-controlled Trial.

Abstract: BackgroundTreatment of acute antibody-mediated rejection (AMR) is based on a combination of plasma exchange (PE), IVIg, corticosteroids (CS), and rituximab, but the place of rituximab is not clearly specified in the absence of randomized trials.MethodsIn this phase III, multicenter, double-blind, pl

Calcineurin Inhibitor Nephrotoxicity Through the Lens of Longitudinal Histology: Comparison of Cyclosporine and Tacrolimus Eras.

Abstract: 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 10-year prevalence moderate arteriolar hyalinosis was similar: CSA was 5.4%, 38.4%, and 79.1%; and TAC was 4.3%, 33.6% and 77.2%, respectively (P = NS). Morphometric measurement demonstrated lumenal narrowing from inwards collapse of hyalinized arteriolar walls unable to maintain its structural integrity. Severe hyalinosis was calculated to reduce arteriolar blood flow to 20 ± 34% of normal. Severity of arteriolar hyalinosis correlated with contemporaneous glomerulosclerosis (r = 0.44, P < 0.001), and subsequent progression in 1356 sequential biopsy pairs, consistent with glomerular ischemia. CONCLUSIONS Tacrolimus-based therapy appeared superior to the CSA era, with less early CNI nephrotoxicity and fewer rejection episodes, but comparable chronic arteriolar toxicity. Calcineurin inhibitors are imperfect long-term maintenance immunosuppressive agents because of frequent and irreversible chronic toxicity.

APOL1 Genotype and Kidney Transplantation Outcomes From Deceased African American Donors.

Abstract: BackgroundTwo apolipoprotein L1 gene (APOL1) renal-risk variants in donors and African American (AA) recipient race are associated with worse allograft survival in deceased-donor kidney transplantation (DDKT) from AA donors. To detect other factors impacting allograft survival from deceased AA kidne

The Prevalence and Prognostic Significance of Frailty in Patients With Advanced Heart Failure Referred for Heart Transplantation.

Abstract: BACKGROUND Frailty is a clinically recognized syndrome of decreased physiological reserve. The heightened state of vulnerability in these patients confers a greater risk of adverse outcomes after even minor stressors. Our aim was to assess the prevalence and prognostic significance of the frailty phenotype in patients referred for heart transplantation. METHODS Consecutive patients referred or on the waiting list for heart transplantation from March 2013 underwent frailty assessment. Frailty was defined as a positive response to 3 or more of the following 5 components: weak grip strength, slowed walking speed, poor appetite, physical inactivity, and exhaustion. In addition, markers of disease severity were obtained, and all patients underwent cognitive (Montreal Cognitive Assessment) and depression (Depression in Medical Illness-10) screening. RESULTS One hundred twenty patients (83 men:37 women; age, 53 ± 12 years, range, 16-73 years; left ventricular ejection fraction, 27 ± 14%) underwent frailty assessment. Thirty-nine of 120 patients (33%) were assessed as frail. Frailty was associated with New York Heart Association class IV heart failure, lower body mass index, elevated intracardiac filling pressures, lower cardiac index, anemia, hypoalbuminemia, hyperbilirubinemia, cognitive impairment, and depression (all ρ < 0.05). Frailty was independent of age, sex, heart failure duration, left ventricular ejection fraction, or renal function. Frailty was an independent predictor of increased all-cause mortality: 1 year actuarial survival was 79 ± 5% in the nonfrail group compared with only 54 ± 9% for the frail group (P < 0.005). CONCLUSIONS Frailty is prevalent among patients with advanced symptomatic heart failure referred for heart transplantation and is associated with increased mortality.

Innate Immune Regulations and Liver Ischemia-Reperfusion Injury.

Abstract: 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 effective therapeutic strategy to ameliorate liver ischemia-reperfusion injury in patients.

Portal Vein Thrombosis Is a Risk Factor for Poor Early Outcomes After Liver Transplantation: Analysis of Risk Factors and Outcomes for Portal Vein Thrombosis in Waitlisted Patients.

Abstract: BackgroundPortal vein thrombosis (PVT) is common in patients with cirrhosis, but the risk factors associated with PVT and its impact on outcomes following liver transplantation (LT) are not well defined. The objectives of this study were to determine the impact of PVT on post-LT patient and graft su

The Risk of Transplant Failure With HLA Mismatch in First Adult Kidney Allografts From Deceased Donors.

Abstract: BackgroundSince 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 c

A Comparison of Muscle Function, Mass, and Quality in Liver Transplant Candidates: Results From the Functional Assessment in Liver Transplantation Study.

Abstract: BackgroundSarcopenia 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.MethodsAdults

Controlled Oxygenated Rewarming of Cold Stored Livers Prior to Transplantation: First Clinical Application of a New Concept.

Abstract: BackgroundAbrupt temperature shift from hypothermia to normothermia incurred on reperfusion of organ grafts has been delineated as a genuine factor contributing to reperfusion injury and graft dysfunction after transplantation.MethodsIn a first clinical series of 6 patients, cold-stored livers, all

A Prospective Cohort Study of Mineral Metabolism After Kidney Transplantation.

Abstract: Kidney transplantation is the preferred treatment for end-stage renal disease (ESRD) because it reverses many complications of chronic kidney disease (CKD), improves recipients' quality of life, and prolongs survival.1 Advances in immune suppression, which vastly enhanced short-term allograft outcomes, have enabled the transplant community to focus more attention on managing the nonimmune aspects of the posttransplant period to optimize recipients' long-term health. Disordered mineral metabolism is a common complication of CKD that begins early in the course of disease and progressively worsens as patients approach ESRD.2 In its most severe form, disordered mineral metabolism in ESRD is characterized by hyperphosphatemia, hypocalcemia, deficiencies of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and markedly elevated levels of parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23).3-8 Individually and in aggregate, these alterations are associated with increased risks of cardiovascular disease, fracture, and death.8-12 Although restoring normal kidney function by transplanting a healthy kidney might be expected to fully reverse disordered mineral metabolism due to ESRD, most existing data suggest that transplantation only partially corrects certain alterations.13-18 Furthermore, presence of a healthy allograft that can respond to the hormonal effects of lingering elevations in PTH and FGF23 levels can precipitate de novo alterations in mineral metabolism, including hypercalcemia and hypophosphatemia.19,20 Posttransplant hypercalcemia and hypophosphatemia present clinicians with management challenges because they may jeopardize graft function and bone health and exacerbate fracture and cardiovascular risk.20-22 The postkidney transplant period should be considered a unique phase in the natural history of disordered mineral metabolism associated with CKD that requires dedicated investigation.14 Few studies have systematically studied mineral metabolism in the posttransplant period. Among those that did, most previous studies were small, single-center, brief, and failed to measure a comprehensive panel of mineral metabolites.23-28 As a result, the frequency of hypercalcemia, hypophosphatemia, and persistent hyperparathyroidism during the first year after kidney transplantation remain incompletely characterized. We conducted the current prospective, observational study to examine the evolution of persistent hyperparathyroidism and associated alterations in mineral metabolism during the first year after kidney transplantation.

Outcomes in Transplant Recipients Treated With Foscarnet for Ganciclovir-Resistant or Refractory Cytomegalovirus Infection.

Abstract: Background Antiviral-resistant or refractory 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.

Chronic Lung Allograft Dysfunction: A Systematic Review of Mechanisms.

Abstract: 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 mechanisms.

Improving National Results in Liver Transplantation Using Grafts From Donation After Cardiac Death Donors.

Abstract: BackgroundPublished 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 nationa

The influence of immunosuppressive agents on the risk of de novo donor-specific HLA antibody production in solid organ transplant recipients.

Abstract: Production of de novo donor-specific antibodies (dnDSA) is a major risk factor for acute and chronic antibody-mediated rejection and graft loss after all solid organ transplantation. In this article, we review the data available on the risk of individual immunosuppressive agents and their ability to prevent dnDSA production. Induction therapy with rabbit antithymocyte globulin may achieve a short-term decrease in dnDSA production in moderately sensitized patients. Rituximab induction may be beneficial in sensitized patients, and in abrogating rebound antibody response in patients undergoing desensitization or treatment for antibody-mediated rejection. Use of bortezomib for induction therapy in at-risk patients is of interest, but the benefits are unproven. In maintenance regimens, nonadherent and previously sensitized patients are not suitable for aggressive weaning protocols, particularly early calcineurin inhibitor withdrawal without lymphocyte-depleting induction. Early conversion to mammalian target of rapamycin inhibitor monotherapy has been reported to increase the risk of dnDSA formation, but a combination of mammalian target of rapamycin inhibitor and reduced-exposure calcineurin inhibitor does not appear to alter the risk. Early steroid therapy withdrawal in standard-risk patients after induction has no known dnDSA penalty. The available data do not demonstrate a consistent effect of mycophenolic acid on dnDSA production. Risk minimization for dnDSA requires monitoring of adherence, appropriate risk stratification, risk-based immunosuppression intensity, and prospective DSA surveillance.

Oxygenated Hypothermic Machine Perfusion After Static Cold Storage Improves Hepatobiliary Function of Extended Criteria Donor Livers

Abstract: 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 alone. In contrast, there were no differences in levels of hepatobiliary injury markers AST, ALT, LDH, and gamma-GT after 6 hours of NMP. Hepatic histology at baseline and after 6 hours of NMP revealed no differences in the amount of ischemic necrosis between both groups. CONCLUSIONS: Two hours of oxygenated HMP after traditional SCS restores hepatic ATP levels and improves hepatobiliary function but does not reduce (preexisting) hepatobiliary injury in ECD livers.

Impact of Immune-Modulatory Drugs on Regulatory T Cell.

Abstract: Immunosuppression strategies that selectively inhibit effector T cells while preserving and even enhancing CD4FOXP3 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.

Nonalcoholic Steatohepatitis is the Most Rapidly Growing Indication for Simultaneous Liver Kidney Transplantation in the United States.

Abstract: Background Frequency of liver transplantation (LT) is increasing in nonalcoholic steatohepatitis (NASH) with good post-transplant outcomes. Similar data on simultaneous liver kidney (SLK) transplants are limited. Methods United Network for Organ Sharing database (2002-2011) queried for deceased donor first LT for primary biliary cirrhosis, primary sclerosing cholangitis, or alcoholic cirrhosis (group I), NASH, and cryptogenic cirrhosis with body mass index greater than 30 (group II), and hepatitis C virus with and without alcohol, hepatitis B virus, and hepatocellular carcinoma (group III). Results Of 38 533 LT (9495, 3665, and 25 383 in groups I-III, respectively), about 5.6% (N = 2162) received SLK with 584 (6.2%), 320 (8.7%), and 1258 (5%) in groups I-III, respectively. The SLK performed for group II increased from 6.3% in 2002 to 2003 to 19.2% in 2010 to 2011. Similar trends remained unchanged in group I (26.1 to 26.6%) and decreased in group III (67.6 to 54.5%). Five-year outcomes were similar comparing group II versus group I for liver graft (78 vs 74%, P = 0.14) and patient survival (81 vs 76%, P = 0.07). In contrast, kidney graft outcome was worse for group II (70 vs 79%, P = 0.002). Risk of kidney graft loss was over 1.5-fold higher among group II SLK recipients compared to group I after controlling for recipient characteristics. Estimated glomerular filtration rate remained lower in group II compared with group I at various time points after SLK transplantation. Conclusions The NASH is the most rapidly growing indication for SLK transplantation with poor renal outcomes. Studies are needed to examine mechanisms of these findings and develop strategies to improve renal outcomes in SLK recipients for NASH.

Spontaneously Breathing Extracorporeal Membrane Oxygenation Support Provides the Optimal Bridge to Lung Transplantation.

Abstract: BackgroundExtracorporeal 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 s

Progress in Clinical Encapsulated Islet Xenotransplantation.

Abstract: 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 capsule and/or the minimization of a foreign body reaction; (3) pig genetic modification to induce a greater secretion of insulin by the islets, and/or to reduce the immune response to islets released from damaged capsules; and (4) reduction of the inflammatory response to the capsules/islets by improvements in the structure of the capsules and/or in genetic engineering of the pigs and/or in some form of drug therapy. Ethical and regulatory frameworks for islet xenotransplantation are already available in several countries, and there is now a wider international perception of the importance of developing an internationally harmonized ethical and regulatory framework.

Chronic Rejection in Human Vascularized Composite Allotransplantation (Hand and Face Recipients): An Update

Abstract: 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 important questions remain to be answered: a more accurate definition of CR in VCA is needed to establish criteria allowing an accurate and early diagnosis. The pathogenetic mechanisms of CR need to be better understood to allow more efficacious treatment. Favoring/triggering factors of CR need to be better known so that they can be avoided. As in SOT, there is a need for efficient tolerance-inducing protocols that will favor graft acceptance and (ideally) circumvent the necessity of lifelong immunosuppression.

Report from IPITA-TTS Opinion Leaders Meeting on the Future of β-Cell Replacement

Abstract: At the time the first pancreas transplant was performed by Kelly and Lillehei in 1966, insulin therapy for diabetes was generally available but administered in a form that is known today as “conventional therapy.”1 In this era, as many as half of all juvenile onset diabetics did not reach the age of 55 years. Early mortality from accelerated cardiovascular disease, renal failure, and hypoglycemia-related events were commonplace. The early low success rate and mortality of pancreas transplantation by comparison were also suboptimal. As will be characterized in the succeeding 8 chapters, the outcome of “best medical therapy” with newer forms of insulin and insulin delivery systems along with dramatically improved outcomes of islet and pancreas transplantation and novel β-cell sources hold great promise for those afflicted.

Perioperative Events and Complications in Minimally Invasive Live Donor Nephrectomy: A Systematic Review and Meta-Analysis

Abstract: BackgroundMinimally 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.MethodsA l

Establishing Biomarkers in Transplant Medicine: A Critical Review of Current Approaches.

Abstract: 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 improves patient or transplant outcomes.

Criteria for and Appropriateness of Renal Transplantation in Elderly Patients With End-Stage Renal Disease: A Literature Review and Position Statement on Behalf of the European Renal Association-European Dialysis and Transplant Association Descartes Working Group and European Renal Best Practice.

Abstract: 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 scores and frailty assessment scales might help the decision making on eligibility. Psychosocial issues should also be evaluated. To overcome the scarcity of organ donors, elderly RT candidates should be encouraged to consider expanded criteria donors and living donors, as alternatives to deceased standard criteria donors. It has been demonstrated that expanded criteria donor RT in patients 60 years or older is associated with higher survival rates than remaining on dialysis, whereas living donor RT is superior to all other options.

Graft Versus Host Disease after Liver Transplantation in Adults: A Case series, Review of Literature, and an Approach to Management

Abstract: BackgroundGraft-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.MethodsData were systematically extracted from reports of GVHD a

BK Polyomavirus and the Transplanted Kidney: Immunopathology and Therapeutic Approaches

Abstract: 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.