In View
Organ Procurement and Transplantation in Italy
Transplantation. 103(6):1065-1069, June 2019.
Cross-examination of Oxidative Stress–induced DNA Glycosylase OGG1, a Mediator of Innate Inflammation
Transplantation. 103(6):1071-1073, June 2019.
Stephen P. Cobbold, MA, PhD, Professor of Cellular Immunology "A personal approach to translational research"
Transplantation. 103(6):1073-1075, June 2019.
Commentaries
Patient Navigators in Transplantation—Where Do We Go From Here?
Transplantation. 103(6):1076-1077, June 2019.
Everyday People Sing a Simple Song: Establishing a Core Outcome for Life Participation
Transplantation. 103(6):1078-1079, June 2019.
Societal and Professional Obligation in the Care of the Living Organ Donor
Transplantation. 103(6):1080-1081, June 2019.
Biomarkers for Chronic Rejection: In Angiotensin Proteins We Trust?
Transplantation. 103(6):1082-1083, June 2019.
Cyclosporin A: Teaching an Old Drug New Tricks?
Transplantation. 103(6):1084-1085, June 2019.
In Brief
Trafficking of Grafted Pancreatic Islets Into the Brain Lateral Ventricles: Implications for Cognition
Transplantation. 103(6):e137-e138, June 2019.
Reviews
Subclinical Inflammation in Renal Transplantation
Transplantation. 103(6):e139-e145, June 2019.
Abstract:
The standardization of renal allograft pathology began in 1991 at the first Banff Conference held in Banff, Alberta, Canada. The first task of transplant pathologists, clinicians, and surgeons was to establish diagnostic criteria for T-cell–mediated rejection (TCMR). The histological threshold for this diagnosis was arbitrarily set at "i2t2": a mononuclear interstitial cell infiltrate present in at least 25% of normal parenchyma and >4 mononuclear cells within the tubular basement membrane of nonatrophic tubules. TCMR was usually found in dysfunctional grafts with an elevation in the serum creatinine; however, our group and others found this extent of inflammation in "routine" or "protocol" biopsies of normally functioning grafts: "subclinical" TCMR. The prevalence of TCMR is higher in the early months posttransplant and has decreased with the increased potency of current immunosuppressive agents. However, the pathogenicity of lesser degrees of inflammation under modern immunosuppression and the relation between ongoing inflammation and development of donor-specific antibody has renewed our interest in subclinical alloreactivity. Finally, the advances in our understanding of pretransplant risk assessment, and our increasing ability to monitor patients less invasively posttransplant, promises to usher in the era of precision medicine.
GFR Assessment of Living Kidney Donors Candidates
Transplantation. 103(6):1086-1093, June 2019.
Abstract:
Living kidney donation provides the best outcomes (survival, cost, and quality of life) of all renal replacement modalities. Living kidney donors, on the other hand, are at the increased risk of end-stage kidney disease (ESKD) after donation compared with healthy nondonors for multiple possible reasons. Extensive predonation screening is required to assess eligibility for donation to avoid the rejection of suitable candidates and minimize acceptance of donors with increased risk of ESKD. The association between the lower predonation glomerular filtration rate (GFR) and increased ESKD risk in donors highlights the relevance of GFR assessment for living kidney donor candidates. However, the method to evaluate GFR is still debated, and the thresholds of acceptable predonation GFR vary across guidelines. All guidelines favor GFR measurement with an exogenous tracer over estimated GFR, but only the British Transplant Society guidelines mandates it. While the Kidney Disease Improving Global Outcomes Group guidelines advocates for age-independent GFR thresholds, most other guidelines propose various age-dependent GFR thresholds with resulting profound differences in assessment of donor suitability between guidelines. Many important questions are not addressed by any guidelines, including the approach to discordant GFR measurement and estimated GFR results, the use of method-specific GFR thresholds and thresholds dependent on comorbidities or race. Further data are required exploring the associations between these variables and the course of postdonation GFR. Last, GFR evaluation studies conducted in approved donors and not in those initially presenting as potential candidates are questionable regarding their suitability for potential donor evaluation.
Equally Interchangeable? How Sex and Gender Affect Transplantation
Transplantation. 103(6):1094-1110, June 2019.
Abstract:
Organ transplantation as an option to overcome end-stage diseases is common in countries with advanced healthcare systems and is increasingly provided in emerging and developing countries. A review of the literature points to sex- and gender-based inequity in the field with differences reported at each step of the transplant process, including access to a transplantation waiting list, access to transplantation once waitlisted, as well as outcome after transplantation. In this review, we summarize the data regarding sex- and gender-based disparity in adult and pediatric kidney, liver, lung, heart, and hematopoietic stem cell transplantation and argue that there are not only biological but also psychological and socioeconomic issues that contribute to disparity in the outcome, as well as an inequitable access to transplantation for women and girls. Because the demand for organs has always exceeded the supply, the transplant community has long recognized the need to ensure equity and efficiency of the organ allocation system. In the spirit of equity and equality, the authors call for recognition of these inequities and the development of policies that have the potential to ensure that girls and women have equitable access to transplantation.
Original Basic Science—General
Urine Angiotensin II Signature Proteins as Markers of Fibrosis in Kidney Transplant Recipients
Transplantation. 103(6):e146-e158, June 2019.
Abstract:
Interstitial fibrosis/tubular atrophy (IFTA) is an important cause of kidney allograft loss; however, noninvasive markers to identify IFTA or guide antifibrotic therapy are lacking. Using angiotensin II (AngII) as the prototypical inducer of IFTA, we previously identified 83 AngII-regulated proteins in vitro. We developed mass spectrometry–based assays for quantification of 6 AngII signature proteins (bone marrow stromal cell antigen 1, glutamine synthetase [GLNA], laminin subunit beta-2, lysophospholipase I, ras homolog family member B, and thrombospondin-I [TSP1]) and hypothesized that their urine excretion will correlate with IFTA in kidney transplant patients.
Methods.Urine excretion of 6 AngII-regulated proteins was quantified using selected reaction monitoring and normalized by urine creatinine. Immunohistochemistry was used to assess protein expression of TSP1 and GLNA in kidney biopsies.
Results.The urine excretion rates of AngII-regulated proteins were found to be increased in 15 kidney transplant recipients with IFTA compared with 20 matched controls with no IFTA (mean log 2 [fmol/µmol of creatinine], bone marrow stromal cell antigen 1: 3.8 versus 3.0, P = 0.03; GLNA: 1.2 versus −0.4, P = 0.03; laminin subunit beta-2: 6.1 versus 5.4, P = 0.06; lysophospholipase I: 2.1 versus 0.6, P = 0.002; ras homolog family member B: 1.2 versus −0.1, P = 0.006; TSP1_GGV: 2.5 versus 1.9; P = 0.15; and TSP1_TIV: 2.0 versus 0.6, P = 0.0006). Receiver operating characteristic curve analysis demonstrated an area under the curve = 0.86 for the ability of urine AngII signature proteins to discriminate IFTA from controls. Urine excretion of AngII signature proteins correlated strongly with chronic IFTA and total inflammation. In a separate cohort of 19 kidney transplant recipients, the urine excretion of these 6 proteins was significantly lower following therapy with AngII inhibitors ( P < 0.05).
Conclusions.AngII-regulated proteins may represent markers of IFTA and guide antifibrotic therapies.
Mesenchymal Stem Cell Therapy in Submandibular Salivary Gland Allotransplantation: Experimental Study
Transplantation. 103(6):1111-1120, June 2019.
Abstract:
Allotransplantation of submandibular salivary glands (SMGs) could be an alternative treatment option for severe keratoconjunctivitis sicca in noncandidates for autologous SMG transplantation. This study was conducted to evaluate the effect of allogeneic mesenchymal stem cell (MSC) therapy on the survival of allotransplanted SMGs.
Methods.Thirty-six SMG allotransplantations (n = 6 per group) were performed in New Zealand white rabbits and randomly divided into the following groups: allograft control (Allo-Ctrl), low-dose FK506 (FK506-L), high-dose FK506 (FK506-H), allogeneic MSCs, MSCs+FK506-L, and MSCs+FK506-H. Rabbits were closely observed for 2 weeks. Gland viability and rejection were assessed by monitoring interleukin-2 levels by ELISA, sialoscintigraphy, M3-muscarinic acetylcholine receptor expression, histological evaluation, and apoptosis assay.
Results.Intraoperatively, all glands showed patency and saliva flow except 1 gland. Sialoscintigraphy revealed significantly higher saliva production within the MSC-treated glands. Histologically, MSC-treated glands showed higher glandular tissue preservation and less acini atrophy. The MSCs+FK506-H group revealed significantly lower apoptosis percentage. The highest survival was observed in the MSCs+FK506-H group, followed by the FK506-H and MSCs+FK506-L groups, and lastly less in the FK506-L and MSCs groups.
Conclusions.Concurrent administration of MSCs with FK506-H (0.16 mg/kg) resulted in higher survival rate with greater glandular tissue preservation and salivary secretion. MSCs with FK506-L (0.08 mg/kg) could be an alternative to FK506-H (0.16 mg/kg) in salivary gland allotransplantation.
- SDC
Effect of Timing and Complement Receptor Antagonism on Intragraft Recruitment and Protolerogenic Effects of Mesenchymal Stromal Cells in Murine Kidney Transplantation
Transplantation. 103(6):1121-1130, June 2019.
Abstract:
Mesenchymal stromal cells (MSCs) have protolerogenic effects in renal transplantation, but they induce long-term regulatory T cells (Treg)-dependent graft acceptance only when infused before transplantation. When given posttransplant, MSCs home to the graft where they promote engraftment syndrome and do not induce Treg. Unfortunately, pretransplant MSC administration is unfeasible in deceased-donor kidney transplantation.
Methods.To make MSCs a therapeutic option also for deceased organ recipients, we tested whether MSC infusion at the time of transplant (day 0) or posttransplant (day 2) together with inhibition of complement receptors prevents engraftment syndrome and allows their homing to secondary lymphoid organs for promoting tolerance. We analyzed intragraft and splenic MSC localization, graft survival, and alloimmune response in mice recipients of kidney allografts and syngeneic MSCs given on day 0 or on posttransplant day 2. C3a receptor (C3aR) or C5a receptor (C5aR) antagonists were administered to mice in combination with the cells or were used together to treat MSCs before infusion.
Results.Syngeneic MSCs given at day 0 homed to the spleen increased Treg numbers and induced long-term graft acceptance. Posttransplant MSC infusion, combined with a short course of C3aR or C5aR antagonist or administration of MSCs pretreated with C3aR and C5aR antagonists, prevented intragraft recruitment of MSCs and graft inflammation, inhibited antidonor T-cell reactivity, but failed to induce Treg, resulting in mild prolongation of graft survival.
Conclusions.These data support testing the safety/efficacy profile of administering MSCs on the day of transplant in deceased-donor transplant recipients and indicate that complement is crucial for MSC recruitment into the kidney allograft.
- SDC
Genetic Variants Associated With Immunosuppressant Pharmacokinetics and Adverse Effects in the DeKAF Genomics Genome-wide Association Studies
Transplantation. 103(6):1131-1139, June 2019.
Abstract:
The immunosuppressants tacrolimus and mycophenolate are important components to the success of organ transplantation, but are also associated with adverse effects, such as nephrotoxicity, anemia, leukopenia, and new-onset diabetes after transplantation. In this report, we attempted to identify genetic variants which are associated with these adverse outcomes.
Methods.We performed a genome-wide association study, using a genotyping array tailored specifically for transplantation outcomes containing 722 147 single nucleotide polymorphisms, and 2 cohorts of kidney allograft recipients—a discovery cohort and a confirmation cohort—to identify and then confirm genetic variants associated with immunosuppressant pharmacokinetics and adverse outcomes.
Results.Several genetic variants were found to be associated with tacrolimus trough concentrations. We did not confirm variants associated with the other phenotypes tested although several suggestive variants were identified.
Conclusions.These results show that adverse effects associated with tacrolimus and mycophenolate are complex, and recipient risk is not determined by a few genetic variants with large effects with but most likely are due to many variants, each with small effect sizes, and clinical factors.
- SDC
Cyclosporine A as a Cardioprotective Agent During Donor Heart Retrieval, Storage, or Transportation: Benefits and Limitations
Transplantation. 103(6):1140-1151, June 2019.
Abstract:
Storage of donor hearts in cardioplegic solutions supplemented with conditioning agents activating endogenous mitochondrial protective signaling enhanced their postreperfusion recovery. The present study investigates the role of timing and duration of cardiac exposure to cyclosporine A (CsA), another putative mitochondrial protectant, on cardiac functional recovery and potential mechanisms of CsA action in an isolated working rat heart model of donor heart retrieval and storage.
Methods.After measurement of baseline function, hearts were arrested and stored for 6 hours at 4°C in either Celsior alone or Celsior + CsA (0.2 µM), then reperfused for 45 minutes in Krebs solution, when functional recovery was assessed. Two additional groups of Celsior-alone stored hearts were exposed to 0.2 µM CsA for the initial 15 minutes (nonworking period) or the full 45-minute period of reperfusion. Coronary effluent was collected pre- and poststorage for assessment of lactate dehydrogenase release. Tissue samples were collected at the end of each study for immunoblotting and histological studies.
Results.CsA supplementation during cold storage or the first 15-minute reperfusion significantly improved functional recovery and significantly increased phospho-AMPKα Thr172 and phospho-ULK-1 Ser757 . Hearts exposed to CsA for 45 minutes at reperfusion recovered poorly with no phospho–AMP-activated protein kinase α activation, decreased phospho-eNOS Ser633 , and decreased mitochondrial cytochrome c content with increased lactate dehydrogenase release.
Conclusions.Inclusion of CsA during cold storage is cardioprotective. Effects of CsA addition to the perfusate during reperfusion were time dependent, with benefits at 15 minutes but not 45 minutes of reperfusion. The toxic effect with the presence of CsA for the full 45-minute reperfusion is associated with impaired mitochondrial integrity and decreased eNOS phosphorylation.
- SDC
Original Clinical Science—Liver
Renal Safety of Intravenous Gadolinium-enhanced MRI in Patients Following Liver Transplantation
Transplantation. 103(6):e159-e163, June 2019.
Abstract:
Intravenous contrast-enhanced imaging is invaluable in diagnosing pathology following liver transplantation. Given the potential risk of contrast nephropathy associated with iodinated computed tomography contrast, alternate contrast modalities need to be examined, especially in the setting of renal insufficiency. The purpose of this study was to examine the renal safety of MRI with gadolinium following liver transplantation.
Methods.The study involved a retrospective analysis of 549 cases of abdominal MRI with low-dose gadobenate dimeglumine in liver transplant recipients at a single center. For each case, serum creatinine values before and after the MRI were compared. In addition, cases were analyzed for the development of nephrogenic systemic fibrosis.
Results.Pre-MRI creatinine values ranged from 0.32 to 6.57 mg/dL (median, 1.28 g/dL), with 191 cases having values ≥1.5 mg/dL (median, 1.86 g/dL). A comparison of the pre- and post-MRI creatinine values showed no significant difference, including those patients with pre-MRI values ≥1.5 mg/dL (mean change of −0.04 [95% confidence interval, −0.07 to −0.01; P = 0.004]). No cases of nephrogenic systemic fibrosis were noted.
Conclusions.Our findings suggest that, irrespective of baseline renal function, MRI with gadobenate dimeglumine is a nonnephrotoxic imaging modality in liver transplant recipients. Importantly, this intravenous contrast-enhanced imaging modality can be considered in those posttransplant patients who have a contraindication to computed tomography contrast due to renal insufficiency.
The Transplant Index: A Novel Method to Predict Adult Liver Transplant Waitlist Outcomes
Transplantation. 103(6):1152-1158, June 2019.
Abstract:
The field of transplantation is shifting outcome priorities from 1-year survival to more comprehensive metrics including transplant rate and waitlist mortality. Identifying disenfranchised candidates (high waitlist death risk, low transplantation chance) can be a focus to improve outcomes.
Methods.Given the waitlist outcomes (continued waiting, death, and transplantation), we aimed to identify factors predicting the likelihood candidates would undergo transplant or death by performing multivariate competing risk analyses of 121 198 candidates in the United Network for Organ Sharing database. We incorporated these probabilities (likelihood of transplantation and waitlist death) into the Transplant Index (TI) to identify disenfranchised candidates (high likelihood of death, low likelihood of transplantation).
Results.Half of the patients had low incidences of death and transplantation within 90 days (TI-inactive). The remaining were stratified into 10 groups within a predictive index, the TI. Low TI groups (TI 10, 20, 30) had 90-day transplant rates of 50.8%, 41.6%, and 39.8% respectively, and their respective 90-day death rates were 22.8%, 15.1%, and 10.9%. High TI groups (TI 80, 90, >90) had 90-day transplantation rates of 53.7%, 64.3%, and 73.9%, respectively, and 90-day death rates of 5.9%, 6.5%, and 6.7% respectively. As TI increased, the likelihood of transplantation increased and that of death decreased. Low-TI groups represent the disenfranchised candidates.
Conclusions.The TI identifies disenfranchised candidates on the adult liver transplant waitlist. This is the subgroup that would benefit the most from efforts to increase access to transplantation.
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