Post-transplant Rejection Research Articles

Pretransplant erythroferrone levels are predictive of 1-year all-cause mortality or acute rejection after heart transplantation

Abstract Background/Introduction Heart transplantation (HTx) remains the treatment of choice for selected advanced heart failure (HF) patients. Iron deficiency is a significant factor in the prognosis of HF, and iron metabolism may play a role after HTx since pretransplant hemoglobin levels predict posttransplant 1-year all-cause mortality. In addition, iron deficiency (ID) is known to impact antigen-specific immune response. Purpose The aim of this study was to quantify the impact of pretransplant iron metabolism components on the primary composite outcome 1-year all-cause mortality (ACM) or 1-year acute cellular rejection. Methods This prospective Swiss national cohort study included consecutive patients with HTx between 2008 to 2017. Iron metabolism was assessed measuring plasma iron, ferritin, erythroferrone (ERFE), hepcidin and interleukin-6 immediately before transplant surgery. Endomyocardial biopsies were procured in accordance with the common national posttransplant surveillance protocol. Acute cellular rejection was defined as histological 2R or 3R rejection according to the ISHLT nomenclature 2004 in the diagnosis of heart rejection. Results A total of 276 HTx recipients were included, median age was 52 [IQR 41;59] years, 24.6% (n=68) were females. HTx recipients with incident combined endpoint (n=118, 42.8%) were not significantly different from controls for demographic or transplant operation parameters, donor/recipient gender or HLA mismatch, ferritin, hepcidin (0.5 [IQR 0.5-1.5] vs. 0.5 [IQR 0.5-1.2]; p=0.382) µg/L), interleukin-6, and most biological parameters associated with posttransplant risk. However, participants with incident combined endpoint had lower haemoglobin levels (125 [IQR 102-134] vs. 128 [IQR 114-141 ] g/L; p=0.004), lower Na+ levels (137.5 [IQR 135-139 ] vs. 138 [IQR 136-140] mmol/L; p=0.017), and higher ERFE levels (1.40 [IQR 0.84-1.84 ] vs. 1.19 ng/mL [IQR 0.91-2.92]; p=0.013) compared to those without the endpoint (n=158, 57.2%). The incidence of the combined endpoint was higher in patients presenting with ERFE levels above the third quartile (>2.25 ng/mL; p=0.003). Multivariable analysis using stepwise backward elimination (table) showed that ERFE levels >2.25 ng/mL predicted the incidence of the combined endpoint with an OR of 2.17 (95% CI: 1.19-3.94) (p=0.011). Conclusion The study demonstrates that increased pretransplant ERFE levels are independently associated with 1-year posttransplant all-cause mortality and 1-year acute cellular rejection. This association is in line with results from chronic kidney disease indicating association of ERFE levels with cardiovascular outcome and studies showing iron-induced immune cell activation. In fact, ERFE reduces hepcidin expression as shown in the present and other studies. Thereby, intestinal iron uptake increases resulting in immune cell activation which may explain the higher incidence of heart rejection observed in the present study.FigureTable

Abstract 15799: Frequency and Etiology of Post-Operative Leukocytosis After Heart Transplantation

Introduction: Many factors contribute to post-operative leukocytosis after heart transplantation; it may be challenging to determine whether post-operative leukocytosis is caused by infection. Objective: To describe the frequency and causes of leukocytosis after heart transplantation. Methods: A representative sample of 207 of 308 patients who underwent heart transplant at our institution between 1/1/17 and 12/31/22 was examined. Leukocytosis was defined as a white blood cell (WBC) count peak >11 th/μL or a 30% increase in WBC if pre-transplant baseline was >11 th/μL. Leukocytosis was classified as early (post operative day [POD] 0-3), delayed (POD 4-7), or late (POD 8-60). Culture, biopsy, and other clinical data were used to adjudicate etiology. Groups were compared using χ 2 , Fisher’s, or t-test as indicated. Results: The sample was 27% female with a mean age of 51.2 (±12.6) years. A total of 404 leukocytosis episodes were identified affecting 204 patients. Common etiologies included: post-transplant surgery (47.0%), true infection (27.2%), corticosteroid bolus (4.0%), subsequent surgery (3.5%), rejection (3.0%), and thrombus (3.0%). Delayed (24/47) and late (59/146) leukocytosis were more likely to be associated with infection than early leukocytosis (27/211, p<0.0001 for both comparisons). Common causes of infection were: pneumonia (33%), bloodstream infection (20%), skin and soft tissue (12%), unknown (9%), urinary (5%), and colitis (3%). Post-operative infection was associated with increased hospital length of stay after transplantation (17 vs 46 days, p<0.0001), and increased in-hospital mortality (9.6% vs 2.7%, p=0.040). ECMO (p=0.08), non-ECMO temporary mechanical circulatory support (p=0.70), prior cardiac surgery (p=0.08), and donor bloodstream infection (p=0.40) were not associated with post-operative infection. There was no significant difference in cross clamp time (p=0.42), ischemic time (p=0.27), or age (p=0.07) in patients with vs without infection. Conclusion: Leukocytosis after transplant is nearly universal. Patients developing leukocytosis on POD ≥4 have a high rate of concurrent infection compared to those with early leukocytosis, which is in turn associated with increased LOS and in-hospital mortality.

Asarinin inhibits immunological rejection via the Toll-like receptor-myeloid differentiation factor 88 signaling pathway in vitro

Asarinin has been found to prolong allograft survival and inhibit post-transplant immune rejection via the Toll-like receptor (TLR) signaling pathway. However, the underlying mechanism is not completely understood. Therefore, elucidating the possible pathophysiological role of asarinin in the TLR signaling pathway is essential. Here, dendritic cells were isolated from Sprague–Dawley® rats and cultured with splenocytes from Wistar rats treated with asarinin, lipopolysaccharide (LPS), and/or dimethyl sulfoxide. mRNA expression of TLR-2, TLR-4, myeloid differentiation factor 88 (MyD88), and nuclear factor kB (NF-kB) was determined using real-time polymerase chain reaction. Interleukin (IL)-6 and IL-12 levels were examined using an enzyme-linked immunosorbent assay. LPS resulted in an increase in the expression of TLR-2 rather than TLR-4 and MyD88. Furthermore, it inhibited the secretion of IL-6 and IL-12. MyD88 can be silenced after lentiviral transduction, and LPS can activate MyD88, whereas asarinin can inhibit this kind of activation. The effect of LPS and asarinin on TLR-4 could only be achieved when MyD88 was not silenced by lentivirus transduction. Therefore, asarinin might suppress TLR-4-mediated activation via the MyD88-dependent pathway. Overall, asarinin has a pre-application effect in inhibiting graft rejection.

Uncovering the immune microenvironment and molecular subtypes of hepatitis B-related liver cirrhosis and developing stable a diagnostic differential model by machine learning and artificial neural networks.

Background: Hepatitis B-related liver cirrhosis (HBV-LC) is a common clinical disease that evolves from chronic hepatitis B (CHB). The development of cirrhosis can be suppressed by pharmacological treatment. When CHB progresses to HBV-LC, the patient's quality of life decreases dramatically and drug therapy is ineffective. Liver transplantation is the most effective treatment, but the lack of donor required for transplantation, the high cost of the procedure and post-transplant rejection make this method unsuitable for most patients. Methods: The aim of this study was to find potential diagnostic biomarkers associated with HBV-LC by bioinformatics analysis and to classify HBV-LC into specific subtypes by consensus clustering. This will provide a new perspective for early diagnosis, clinical treatment and prevention of HCC in HBV-LC patients. Two study-relevant datasets, GSE114783 and GSE84044, were retrieved from the GEO database. We screened HBV-LC for feature genes using differential analysis, weighted gene co-expression network analysis (WGCNA), and three machine learning algorithms including least absolute shrinkage and selection operator (LASSO), support vector machine recursive feature elimination (SVM-RFE), and random forest (RF) for a total of five methods. After that, we constructed an artificial neural network (ANN) model. A cohort consisting of GSE123932, GSE121248 and GSE119322 was used for external validation. To better predict the risk of HBV-LC development, we also built a nomogram model. And multiple enrichment analyses of genes and samples were performed to understand the biological processes in which they were significantly enriched. And the different subtypes of HBV-LC were analyzed using the Immune infiltration approach. Results: Using the data downloaded from GEO, we developed an ANN model and nomogram based on six feature genes. And consensus clustering of HBV-LC classified them into two subtypes, C1 and C2, and it was hypothesized that patients with subtype C2 might have milder clinical symptoms by immune infiltration analysis. Conclusion: The ANN model and column line graphs constructed with six feature genes showed excellent predictive power, providing a new perspective for early diagnosis and possible treatment of HBV-LC. The delineation of HBV-LC subtypes will facilitate the development of future clinical treatment of HBV-LC.

HLA-Ehigh /HLA-Ghigh /HLA-IIlow Human iPSC-Derived Cardiomyocytes Exhibit Low Immunogenicity for Heart Regeneration.

Although human pluripotent stem cells (hPSCs)-derived cardiomyocytes (hPSC-CMs) can remuscularize infarcted hearts and restore post-infarct cardiac function, post-transplant rejection resulting from human leukocyte antigen (HLA) mismatching is an enormous obstacle. It is crucial to identify hypoimmunogenic hPSCs for allogeneic cell therapy. This study is conducted to demonstrate the immune privilege of HLA-Ehigh /HLA-Ghigh /HLA-IIlow human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hiPSC-CMs). Ischemia-reperfusion surgery is done to create transmural myocardial infarction in rats. At post-infarct 4 days, hPSC-CMs (1.0×107 cells per kg), including human embryonic stem cell-derived cardiomyocytes (hESC-CMs), HLA-Elow/HLA-Glow/HLA-IIhigh hiPSC-CMs, and HLA-Ehigh /HLA-Ghigh /HLA-IIlow hiPSC-CMs, are injected into the infarcted myocardium. Under the treatment of very low dose cyclosporine A (CsA), only HLA-Ehigh /HLA-Ghigh /HLA-IIlow hiPSC-CMs survive in vivo and improved post-infarct cardiac function with infarct size reduction. HLA-Ehigh /HLA-Ghigh /HLA-IIlow hiPSC-CMs activate the SHP-1 signaling pathway of natural killer (NK) cells and cytotoxic T cells to evade attack by NK cells and cytotoxic T cells. Herein, it is demonstrated that using a clinically relevant CsA dose, HLA-Ehigh /HLA-Ghigh /HLA-IIlow hiPSC-CMs repair the infarcted myocardium and restore the post-infarct heart function. HLA-Ehigh /HLA-Ghigh /HLA-IIlow hiPSCs are less immunogenic and may serve as platforms for regeneration medicine.

Immunosuppression-Free Life after Pediatric Liver Transplant: A Case-Control Study from the Society of Pediatric Liver Transplant (SPLIT) Registry

To compare long-term outcomes of pediatric liver transplant (LT) recipients off immunosuppression (IS) with matched controls on IS using data from the Society of Pediatric Liver Transplant (SPLIT) registry. This was a retrospective case-control study. SPLIT participants <18years of age, ≥4years after isolated LT, and off IS for ≥1year (cases) were age- and sex-matched 1:2 to patients with the same primary diagnosis and post-LT follow-up duration (controls). Primary outcomes included retransplantation, allograft rejection, IS comorbidities, and prevalence of SPLIT-derived composite ideal outcome (c-IO) achieved at the end of the follow-up period. Differences were compared using multiple linear regression for continuous outcomes and logistic regression for dichotomous data. The study cohort was composed of 33 cases (42.4% male, 60.6% biliary atresia, median age at LT of 0.7 [P25, P75, 0.5, 1.6] years, median IS withdrawal time of 9 [P25, P75, 6, 12] years after LT) and 66 age- and sex-matched controls. No cases required retransplantation. Cases and controls had similar growth parameters, laboratory values, calculated glomerular filtration rates, rates of post-transplant lymphoproliferative disease, graft rejection, and attainment of c-IO. No differences in allograft rejection rates, IS complications, or c-IO prevalence were seen between SPLIT patients off IS and age- and sex-matched controls remaining on IS. Discontinuation of IS most commonly occurred in the context of rigorously designed IS withdrawal trials. The available sample size was small, affecting generalizability to the broader pediatric LT population.

A Case of Antiphospholipid Syndrome Nephropathy with Acute Thrombotic Microangiopathy After Renal Transplantation.

We experienced a 36-year-old man with lupus nephritis and antiphospholipid syndrome (APS) who received a donor kidney from his father. Twenty-two months after transplantation, at a time of poor adherence to immunosuppressants and warfarin, the patient developed sudden graft loss due to hemolytic uremic syndrome with rapid deterioration of renal function, thrombocytopenia, and hemolytic anemia. A kidney biopsy showed thrombotic microangiopathy (TMA) related to platelet thrombus formation; however, there was no recurrence of lupus and no findings suggestive of post-transplant rejection, so acute TMA associated with APS was thought to be the cause of the graft loss. This case highlights the importance of instructing patients with lupus nephritis to adhere to treatment with warfarin, a therapeutic drug for APS.

Abstract P100: Paradoxical Increase In Post-Captopril Aldosterone

Hypertension remains one of the strongest risk factors for cardiovascular disease. Primary aldosteronism, the most common form of secondary hypertension, can be confirmed using the captopril challenge test. This study aims to investigate a subset of patients who exhibit a paradoxical increase in aldosterone levels after the administration of captopril, despite the expected decrease in aldosterone production. A retrospective design was employed to evaluate patients who exhibited atypical captopril suppression test results. The cohort consisted of 120 patients who underwent the captopril suppression test as part of their diagnostic evaluation for resistant hypertension. Demographic data and clinical parameters were collected for each patient.Among the patients who tested positive on the captopril suppression test based on a post-aldosterone level criterion of &gt;12 mg/dL, one-third exhibited an increase equal to or greater than 50% in aldosterone levels (9 out of 27).We proposed different theories to explain this phenomenon. Intraindividual variability, which has been previously reported with a laboratory coefficient of variation between 2.7% and 4.4%, was ruled out using a cut-off ≥ 50%. Another possibility is the presence of extraadrenal aldosterone production independent of the regulation provided by captopril or ATII. This could be attributed to unrecognized compensation of aldosterone production by extra-adrenal tissues in response to a decrease in adrenal aldosterone levels. Additionally, conditions such as preeclampsia, post-transplant acute rejection, autoimmune diseases, lupus, and primary hyperaldosteronism have been associated with increased aldosterone production by zona glomerulosa cells due to the presence of activating antibodies.There are certain limitations to this study. Other biochemical tests were not performed, and the sample size was relatively small, making it challenging to draw definitive conclusions. In conclusion, this study aims to contribute to our understanding of the pathogenesis of primary aldosteronism. The findings highlight the utility of the captopril suppression test as a biochemical confirmation test for the diagnosis of primary aldosteronism and resistant hypertension.

Contemporary outcomes of pediatric cardiac transplantation with a positive retrospective crossmatch.

A positive crossmatch (+ XM) has traditionally been associated with adverse outcomes following pediatric heart transplantation. However, more recent studies suggest that favorable intermediate-term outcomes may be achieved despite a + XM. This study's hypothesis is that children with a + XM have similar long-term survival, but higher rate of complications such as rejection, coronary allograft vasculopathy (CAV), and infection, compared to patients with a negative (-) XM. The Pediatric Heart Transplant Society Registry (PHTS) database was queried from 2010-2021 for all patients <18 years of age with a known XM. Baseline demographics were compared between + XM and - XM groups using appropriate parametric and non-parametric group comparisons. Cox Proportional Hazards Modeling was used to identify risk factors for post-transplant graft loss, rejection, and CAV. Of 4599 pediatric heart transplants during the study period, XM results were available for 3914 (85%), of which 373 (9.5%) had a + XM. Univariate analysis showed lower 10-year survival for patients with + XM (HR = 1.3, p = .04). Multivariate analyses revealed no significant difference in 10-year survival in the 2 groups; however, time to first rejection (p = .0001) remained significantly shorter in the + XM group. Pediatric patients transplanted across a + XM experience earlier rejection; however, after multivariate adjustment, + XM is not independently associated with intermediate-term graft loss. The risk of heart transplantation against a + XM must be balanced with the ongoing risk of waitlist mortality.

Preemptive immune globulin therapy in sensitized lung transplant recipients

BackgroundSensitized lung transplant recipients are at increased risk of developing donor-specific antibodies, which have been associated with acute and chronic rejection. Perioperative intravenous immune globulin has been used in sensitized individuals to down-regulate antibody production. MethodsWe compared patients with a pre-transplant calculated panel reactive antibody ≥25% who did not receive preemptive immune globulin therapy to a historical control that received preemptive immune globulin therapy. Our cohort included 59 patients, 17 patients did not receive immune globulin therapy and 42 patients received therapy. ResultsDonor specific antibody development was numerically higher in the non-immune globulin group compared to the immune globulin group (58.8% vs 33.3%, respectively, odds ratio 2.80, 95% confidence interval [0.77, 10.79], p = 0.13). Median time to antibody development was 9 days (Q1, Q3: 7, 19) and 28 days (Q1, Q3: 7, 58) in the non-immune globulin and immune globulin groups, respectively. There was no significant difference between groups in the incidence of primary graft dysfunction at 72 h post-transplant or acute cellular rejection, antibody-mediated rejection, and chronic lung allograft dysfunction at 12 months. ConclusionThese findings are hypothesis generating and emphasize the need for larger, randomized studies to determine association of immune globulin therapy with clinical outcomes.

Polymeric Based Hydrogel Membranes for Biomedical Applications.

The development of biomedical applications is a transdisciplinary field that in recent years has involved researchers from chemistry, pharmacy, medicine, biology, biophysics, and biomechanical engineering. The fabrication of biomedical devices requires the use of biocompatible materials that do not damage living tissues and have some biomechanical characteristics. The use of polymeric membranes, as materials meeting the above-mentioned requirements, has become increasingly popular in recent years, with outstanding results in tissue engineering, for regeneration and replenishment of tissues constituting internal organs, in wound healing dressings, and in the realization of systems for diagnosis and therapy, through the controlled release of active substances. The biomedical application of hydrogel membranes has had little uptake in the past due to the toxicity of cross-linking agents and to the existing limitations regarding gelation under physiological conditions, but now it is proving to be a very promising field This review presents the important technological innovations that the use of membrane hydrogels has promoted, enabling the resolution of recurrent clinical problems, such as post-transplant rejection crises, haemorrhagic crises due to the adhesion of proteins, bacteria, and platelets on biomedical devices in contact with blood, and poor compliance of patients undergoing long-term drug therapies.

Computational approaches for evaluating morphological changes in the corneal stroma associated with decellularization.

Decellularized corneas offer a promising and sustainable source of replacement grafts, mimicking native tissue and reducing the risk of immune rejection post-transplantation. Despite great success in achieving acellular scaffolds, little consensus exists regarding the quality of the decellularized extracellular matrix. Metrics used to evaluate extracellular matrix performance are study-specific, subjective, and semi-quantitative. Thus, this work focused on developing a computational method to examine the effectiveness of corneal decellularization. We combined conventional semi-quantitative histological assessments and automated scaffold evaluations based on textual image analyses to assess decellularization efficiency. Our study highlights that it is possible to develop contemporary machine learning (ML) models based on random forests and support vector machine algorithms, which can identify regions of interest in acellularized corneal stromal tissue with relatively high accuracy. These results provide a platform for developing machine learning biosensing systems for evaluating subtle morphological changes in decellularized scaffolds, which are crucial for assessing their functionality.

Effect of the UNOS policy change on rates of rejection, infection, and hospital readmission following heart transplantation

The 2018 adult heart allocation policy soughtto improve waitlist risk stratification, reduce waitlist mortality, and increase organ access. This system prioritized patients at greatest risk for waitlist mortality, especially individuals requiring temporary mechanical circulatory support (tMCS). Posttransplant complications are significantly higher in patients on tMCS before transplantation, and early posttransplant complications impact long-term mortality. We sought to determine if policy change affected early posttransplant complication rates of rejection, infection, and hospitalization. We included all adult, heart-only, single-organ heart transplant recipients from the UNOS registry with pre-policy (PRE) individuals transplanted between November1, 2016, and October 31, 2017, and post-policy (POST) between November1, 2018, and October 31, 2019. We used a multivariable logistic regression analysis to assess the effect of policy change on posttransplant rejection, infection, and hospitalization. Two COVID-19 eras (2019-2020, 2020-2021) were included in our analysis. The majority of baseline characteristics were comparable between PRE and POST era recipients. The odds of treated rejection (p=0.8), hospitalization (p=0.69), and hospitalization due to rejection (p=0.76) and infection (p=0.66) were similar between PRE and POST eras; there was a trend towards reduced odds of rejection (p=0.08). In both COVID eras, there was a clear reduction in rejection and treated rejection with no effect on hospitalization for rejection or infection. Odds of all-cause hospitalization was increased in both COVID eras. The UNOS policy change improves access to heart transplantation for higher acuity patients without increasing early posttransplant rates of treated rejection or hospitalization for rejection or infection, factors which portend risk for long-term posttransplant mortality.

Bacteremia During the First Year After Solid Organ Transplantation: An Epidemiological Update.

There are limited contemporary data on the epidemiology and outcomes of bacteremia in solid organ transplant recipients (SOTr). Using the Swiss Transplant Cohort Study registry from 2008 to 2019, we performed a retrospective nested multicenter cohort study to describe the epidemiology of bacteremia in SOTr during the first year post-transplant. Of 4383 patients, 415 (9.5%) with 557 cases of bacteremia due to 627 pathogens were identified. One-year incidence was 9.5%, 12.8%, 11.4%, 9.8%, 8.3%, and 5.9% for all, heart, liver, lung, kidney, and kidney-pancreas SOTr, respectively (P = .003). Incidence decreased during the study period (hazard ratio, 0.66; P < .001). One-year incidence due to gram-negative bacilli (GNB), gram-positive cocci (GPC), and gram-positive bacilli (GPB) was 5.62%, 2.81%, and 0.23%, respectively. Seven (of 28, 25%) Staphylococcus aureus isolates were methicillin-resistant, 2/67 (3%) enterococci were vancomycin-resistant, and 32/250 (12.8%) GNB produced extended-spectrum beta-lactamases. Risk factors for bacteremia within 1 year post-transplant included age, diabetes, cardiopulmonary diseases, surgical/medical post-transplant complications, rejection, and fungal infections. Predictors for bacteremia during the first 30 days post-transplant included surgical post-transplant complications, rejection, deceased donor, and liver and lung transplantation. Transplantation in 2014-2019, CMV donor-negative/recipient-negative serology, and cotrimoxazole Pneumocystis prophylaxis were protective against bacteremia. Thirty-day mortality in SOTr with bacteremia was 3% and did not differ by SOT type. Almost 1/10 SOTr may develop bacteremia during the first year post-transplant associated with low mortality. Lower bacteremia rates have been observed since 2014 and in patients receiving cotrimoxazole prophylaxis. Variabilities in incidence, timing, and pathogen of bacteremia across different SOT types may be used to tailor prophylactic and clinical approaches.

Optimizing the Safe Washout Period for Liver Transplantation Following Immune Checkpoint Inhibitors with Atezolizumab, Nivolumab, or Pembrolizumab

Using immune checkpoint inhibitors (ICIs) as a downstaging therapy for liver transplantation (LT) has improved outcomes for patients with advanced hepatocellular carcinoma (HCC). However, this therapy carries a risk of post-transplant graft rejection. The washout (WO) period between the last ICI dose and LT seems critical in preventing postoperative rejection. This study aimed to optimize the WO period by balancing tumor burden suppression and rejection prevention using ICIs before LT. We reviewed published case reports or series from March 2020 to December 2022 regarding LT for HCC after downstaging or bridge therapy with ICIs and included 4 of our cases. Most patients received atezolizumab, nivolumab, or pembrolizumab; these ICIs shared a half-life of around 28 days. Therefore, we excluded cases without definite WO period data and those using non-atezolizumab/nivolumab/pembrolizumab ICIs and ultimately enrolled 22 patients for analysis. We compared their clinical outcomes and estimated the rejection-free survival for every 0.5 half-life interval. Most study subjects received nivolumab (n=25). Six patients had severe rejections (nivolumab group, n=5) and needed rescue management. Of the 6 cases, 1 patient died after rejection, and 2 underwent re-transplantation. The median WO period in these 6 patients was 22 days (IQR: 9-35 days). In addition, we found that a 1.5 half-life (42 days) was the shortest safe WO period associated with significant rejection-free survival (P=.005). Our results showed that 42 days was the safest WO period before LT for HCC after ICI with atezolizumab, nivolumab, or pembrolizumab.

Pretransplant C-peptide Levels and Pancreas Transplant Outcomes: Risk and Reward.

We read with interest the report by Parajuli et al1, chronicling the University of Wisconsin experience in simultaneous pancreas-kidney transplantation (SPKT) according to the pretransplant fasting serum C-peptide levels. The authors demonstrated that higher pretransplant C-peptide levels predicted the risk of a composite outcome (combination of pancreas graft failure according to the United Network for Organ Sharing definition and pancreas graft dysfunction defined as initiation of any antidiabetic agent) posttransplant in patients with a type 2 diabetes phenotype.1,2 Recipients were categorized into 3 groups based on pretransplant fasting serum C-peptide levels: low (≤2 ng/mL, n = 14), medium (>2–8 ng/mL, n = 47), and high (>8 ng/mL, n = 15). The uncensored composite outcome of pancreas graft failure or dysfunction occurred in 0% in the low, 23% in the medium, and 33% of patients in the high C-peptide groups, respectively, suggesting that higher levels of pretransplant C-peptide are associated with inferior posttransplant outcomes. These findings confirm our recent report based on a case-controlled, single-center, retrospective study of 46 SPKT patients with pretransplant fasting serum C-peptide levels ≥2.0 ng/mL compared with 46 control patients (C-peptide level <0.5 ng/mL) matched for recipient age, gender, race, and transplant date.3 In our study, we likewise reported inferior mid-term outcomes in the group with higher pretransplant C-peptide levels. In our overall SPKT experience, we have 205 patients with a minimum of 5-y follow-up. Using the above C-peptide categories as per the Wisconsin study, we identified 166 patients in the low, 32 patients in the medium, and 7 patients in the high C-peptide groups. Five-y actual (uncensored) patient and graft survival rates were as follows: patient (91% low versus 93.8% medium versus 85.7% high) and kidney (80.7% versus 71.9% versus 71.4%), respectively. Using the composite end point of pancreas graft failure or dysfunction, pancreas outcomes were 25.3% low versus 34.4% medium versus 71.4% high C-peptide (P = 0.10). Similar to the Wisconsin study, we are limited by the small sample size in the high pretransplant C-peptide group but the findings indicate a trend toward a greater need for supplemental antidiabetic therapy in patients with higher pretransplant C-peptide levels. Unfortunately, what is missing from these studies is a better characterization of patients with partial pancreas allograft function (dysfunction) who continue to be free from wide glycemic excursions and do not experience hypoglycemia (despite the need for antidiabetic therapy) because of preserved counterregulatory function of the pancreas allograft.4 In our experience, we identified posttransplant weight gain, insulin resistance, and rejection as potential mitigating factors to explain these inferior outcomes. Consequently, we recommend greater emphasis on weight management strategies, behavioral modification, nutritional counseling, structured physical training programs, timely adjustments in (and use of less diabetogenic) immunosuppression, more intense long-term monitoring by the transplant center, and increased use of novel antidiabetic agents such as Glucagon-like peptide 1 receptor agonists and Sodium-glucose cotransporter-2 inhibitors when indicated in this unique population. We congratulate the authors on this excellent study and agree that these findings should not be an impetus to limit access to pancreas transplantation but rather help guide clinical decision-making and optimize posttransplant management.

Cytopenias in pediatric kidney transplant recipients: preceding factors and clinical consequences.

Kidney trans plantation is associated with secondary complications, including the risk of developing posttransplant cytopenias. This study aimed to evaluate the characteristics, identify predictors, and assess the management and consequences of cytopenias in the pediatric kidney transplant population. This is a single-center retrospective analysis of 89 pediatric kidney transplant recipients. Possible factors preceding cytopenias were compared with the goal of recognizing predictors for posttransplant cytopenias. Posttransplant neutropenias were analyzed for the total study period and separately for the period beyond 6months posttransplant (late neutropenias), to rule out confounding influences of induction and initial intensive therapy. Sixty patients (67%) developed at least one episode of posttransplant cytopenia. All episodes of posttransplant thrombocytopenias were mild or moderate. Posttransplant infections and graft rejection were found to be significant predictors for thrombocytopenia (HR 6.06, 95% CI 1.6-22.9, and HR 5.82, 95% CI 1.27-26.6, respectively). A total of 30% of posttransplant neutropenias were severe (ANC ≤ 500). Pretransplant dialysis and posttransplant infections were significant predictors for late neutropenias (HR 11.2, 95% CI 1.45-86.4, and HR 3.32, 95% CI 1.46-7.57, respectively). Graft rejection occurred in 10% of patients with cytopenia, all following neutropenia, within 3months from cytopenia appearance. In all such cases, mycophenolate mofetil dosing had been held or reduced prior to rejection. Posttransplant infections are substantial contributors to developing posttransplant cytopenias. Preemptive transplantation appears to reduce risk of late neutropenia, the accompanying reduction in immunosuppressive therapy, and the ensuing risk of graft rejection. An alternative response to neutropenia, possibly using granulocyte colony stimulating factor, may diminish graft rejection. A higher resolution version of the Graphical abstract is available as Supplementary information.

Factors impacting the medication "Adherence Landscape" for transplant patients.

Medication non-adherence contributes to post-transplant graft rejection and failure; however, limited knowledge about the reasons for non-adherence hinders the development of interventions to improve adherence. We conducted focus groups with solid organ transplant recipients regarding overlooked challenges in the process of transplant medication self-management and examined their adherence strategies and perceptions towards the post-transplant medication regimen. We conducted four focus groups with n=31 total adult transplant recipients. Participants had received kidney, liver, or combined liver/kidney transplant at Johns Hopkins Hospital between 2014 and 2019. Focus groups were audio-recorded and transcribed. Transcripts were analyzed inductively, using the constant comparative method. Responses generally fell into two major categories: (1) barriers to adherence and (2) "adherence landscape". We define the former as factors directly labeled as barriers to adherence by participants and the latter as factors that heavily influence the post-transplant medication self-management process. We propose a shift in the way healthcare providers and researchers, address the question of medication non-adherence. Rather than asking why patients are non-adherent, we suggest that constructing and understanding patients' "adherence landscape" will provide an optimal way to align the goals of patients and providers and boost health outcomes.

Do vasoactive medications impact donor hearts clinical outcomes in pediatric heart transplantation?

There is limited data examining donor vasopressor and/or inotrope medications (vasoactives) on pediatric orthotopic heart transplant (OHT) outcomes. We aim to evaluate the effects of vasoactives on pediatric OHT outcomes. The United Network for Organ Sharing database was retrospectively reviewed from January 2000 to March 2018 for donor hearts. Exclusion criteria included multiorgan transplants and recipient age >18. Donors receiving vasoactives at the time of procurement were compared to donors not on vasoactives, including the number of vasoactives and the type. End-points of interest were survival at 30 days and 1year as well as post-transplant rejection at 1year. Logistic and Cox models were used to quantify survival end-points. Of 6462 donors, 3187 (49.3%) were receiving at least one vasoactive. Comparing any vasoactive medication versus none, there was no difference in 30-day survival (p= .27), 1 year survival (p= .89), overall survival (p= .68), or post-transplant rejection (p= .98). There was no difference in 30-day survival for donors receiving 2 or more vasoactive infusions (p= .89), 1 year survival (p= .53), overall survival (p= .75), or post-transplant rejection at 1year (p= .87). Vasopressin was associated with decreased 30-day mortality (OR=0.22; p= .028), dobutamine with decreased 1-year mortality (OR=0.37; p= .036), overall survival (HR=0.51; p= .003), and decreased post-transplant rejection (HR=0.63; p= .012). There is no difference in pediatric OHT outcomes when the cardiac donor is treated with vasoactive infusions at procurement. Vasopressin and dobutamine were associated with improved outcomes. This information can be used to guide medical management and donor selection.

Solid Phase Microextraction—A Promising Tool for Graft Quality Monitoring in Solid Organ Transplantation

Solid organ transplantation is a life-saving intervention for patients suffering from end-stage organ failure. Although improvements in surgical techniques, standards of care, and immunosuppression have been observed over the last few decades, transplant centers have to face the problem of an insufficient number of organs for transplantation concerning the growing demand. An opportunity to increase the pool of organs intended for transplantation is the more frequent use of organs from extended criteria and the development of analytical methods allowing for a better assessment of the quality of organs to minimize the risk of post-transplant organ injury and rejection. Therefore, solid-phase microextraction (SPME) has been proposed in various studies as an effective tool for determining compounds of significance during graft function assessment or for the chemical profiling of grafts undergoing various preservation protocols. This review summarizes how SPME addresses the analytical challenges associated with different matrices utilized in the peri-transplant period and discusses its potential as a diagnostic tool in future work.