Post-transplant Rejection Research Articles

Distinct Microbial Communities in Dilated Cardiomyopathy Explanted Hearts Are Associated With Different Myocardial Rejection Outcomes.

BackgroundIdiopathic dilated cardiomyopathy (IDCM) myocardial inflammation may be associated with external triggering factors such as infectious agents. Here, we searched if moderate/severe heart transplantation rejection is related to the presence of myocardial inflammation in IDCM explanted hearts, associated with microbial communities.MethodReceptor myocardial samples from 18 explanted hearts were separated into groups according to post-transplant outcome: persistent moderate rejection (PMR; n = 6), moderate rejection (MR; n = 7) that regressed after pulse therapy, and no rejection (NR; n = 5)/light intensity rejection. Inflammation was quantified through immunohistochemistry (IHC), and infectious agents were evaluated by IHC, molecular biology, in situ hybridization technique, and transmission electron microscopy (TEM).ResultsNR presented lower numbers of macrophages, as well as B cells (p = 0.0001), and higher HLA class II expression (p ≤ 0.0001). PMR and MR showed higher levels of Mycoplasma pneumoniae (p = 0.003) and hepatitis B core (p = 0.0009) antigens. NR presented higher levels of parvovirus B19 (PVB19) and human herpes virus 6 (HHV6) and a positive correlation between Borrelia burgdorferi (Bb) and enterovirus genes. Molecular biology demonstrated the presence of M. pneumoniae, Bb, HHV6, and PVB19 genes in all studied groups. TEM revealed structures compatible with the cited microorganisms.ConclusionsThis initial study investigating on infectious agents and inflammation in the IDCM explanted hearts showed that the association between M. pneumoniae and hepatitis B core was associated with a worse outcome after HT, represented by MR and PMR, suggesting that different IDCM microbial communities may be contributing to post-transplant myocardial rejection.

Donor selection for multiorgan transplantation.

There is limited data and guidance on donor selection for multiorgan transplantation. In this article, we review the current Organ Procurement and Transplantation Network policy on multiorgan allocation and the ideal donor criteria for each specific organ, in order to provide a framework to guide donor selection for various scenarios of multiorgan transplantation, including heart-kidney, heart-lung, heart-liver and heart-kidney-liver transplant procedures. Combined heart-kidney transplantation is the most common multiorgan transplant procedure and requires the most stringent HLA matching to ensure optimal graft survival. Using the virtual crossmatch and desensitization therapies can shorten waitlist times without increasing posttransplant rejection or mortality rates. The ideal heart-lung donor tends to be younger than other multiorgan transplants, and more tolerant to HLA mismatch, but ideally requires donors with no prior history of smoking, a short period of time on mechanical ventilation, adequate oxygenation and absence of pulmonary infection. The ideal heart-liver donor is often driven by criteria specific to the donor heart. Finally, several observational studies suggest that livers are more tolerant to HLA mismatch than other organs, and offer some degree of immune protection in combined organ transplants. Multiorgan transplantation is a steadily growing field. The required short ischemic time for the donor heart is often the limiting factor, as well as the scarcity of appropriate donors available within geographical confines. In general, as with single organ transplantation, younger age, size matching, few medical comorbidities and HLA compatibility confer the best posttransplant outcomes.

Do pretransplant C-peptide levels predict outcomes following simultaneous pancreas-kidney transplantation? A matched case-control study.

Following simultaneous pancreas-kidney transplantation (SPKT), survival outcomes are reported as equivalent in patients with detectable pretransplant C-peptide levels (Cp+) and a "type 2″ diabetes mellitus (DM) phenotype compared to type 1 (Cp negative [Cp-]) DM. We retrospectively compared 46 Cp+ patients pretransplant (≥2.0ng/mL, mean 5.4ng/mL) to 46 Cp- (level<0.5ng/mL) case controls matched for recipient age, gender, race, and transplant date. Early outcomes were comparable. Actual 5-year patient survival (91% versus 94%), kidney graft survival (69% versus 86%, p=.15), and pancreas graft survival (60% versus 86%, p=.03) rates were lower in Cp+ versus Cp- patients, respectively. The Cp+ group had more pancreas graft failures due to insulin resistance (13% Cp+ versus 0% Cp-, p=.026) or rejection (17% Cp+ versus 6.5% Cp-, p=.2). Post-transplant weight gain>5kg occurred in 72% of Cp+ versus 26% of Cp- patients (p=.0001). In patients with functioning grafts, mean one-year post-transplant HbA1c levels (5.0 Cp+ versus 5.2% Cp-) were comparable, whereas Cp levels were higher in Cp+ patients (5.0 Cp+ versus 2.6ng/mL Cp-). In this matched case-control study, outcomes were inferior in Cp+ compared to Cp- patients following SPKT, with post-transplant weight gain, insulin resistance, and rejection as potential mitigating factors.

Combination of matrine and tacrolimus alleviates acute rejection in murine heart transplantation by inhibiting DCs maturation through ROS/ERK/NF-κB pathway

Matrine, an alkaloid derived from traditional Chinese herbs, has been confirmed to regulate immunity and exert anti-inflammatory effects. Matrine injection has been widely used in clinic therapy for anti-tumor and anti-inflammatory diseases. Heart transplantation(HT) is the only solution for the end-stage heart failure, but it is restricted by the cardiac allograft rejection. One of the important pathophysiological processes of post-transplantation rejection is inflammatory cell infiltration. Matrine has been shown to exert a positive protective effect against oxidative stress injury and inflammation, which likely benefits allograft survival. However, it remains unclear whether matrine inhibits alloimmunity or allograft rejection. In this study, we established the heart transplantation model in mouse and extracted bone marrow-derived dendritic cells (BMDCs) to explore the function and mechanism of matrine in heart transplantation. Moreover, combination treatment with matrine and tacrolimus(FK506) had a synergistic effect in preventing acute rejection of heart transplants. Here we found that matrine can prolong the survival of post-transplant and inhibit inflammatory cell infiltration in transplanted hearts of mice. At the same time, matrine increased Treg ratio and decreased CD4+/CD8 + ratio in mice. More importantly, matrine inhibited DCs maturation in mice and reduced oxidative damage and apoptosis in allograft hearts. Furthermore, matrine also downregulated NF-κB pathway and upregulated ERK1/2 signaling pathway. Overall, our study reveals a novel immunosuppressive agent that has the potential to reduce the side effects of existing immunosuppressive agents when used in combination with them.

S1078 Heart Failure Associated With Worse Outcome in Liver Transplant Recipients: A Nationwide Analysis

Introduction: Liver disease and heart failure frequently occur concomitantly. Heart failure can lead to liver diseases and liver diseases can affect cardiac function. In our nationwide study, we have tried to measure the effect of pre-existing heart failure on hospital-based outcomes of patients who are admitted for liver transplant. Methods: We examined the national inpatient sample (NIS) from 2016-2018. Patients with history of heart failure who underwent liver transplantation were identified. We only included those who were admitted for new liver transplants. We used International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10) codes to identify these patients. The primary outcomes we studied are effect of heart failure on mortality, transplant failure and post-transplant infection. Secondary outcomes of measurement were length of stay and total hospital charges. Utilizing STATA MP 16.1 we performed multivariate logistic regression analysis. Various comorbidities including previous history of cirrhosis, alcohol abuse,stroke and chronic kidney disease were included in the study.Data was considered statistically significant if p-value was < 0.05. Results: A total 4546 patients were included in the study, of which 870 (3.8%) had a history of heart failure.In multivariable regression analysis, patients who had heart failure and underwent liver transplantation had more odds of death (aOR 2.3, p= 0.02, 95% CI, 1.14 - 4.69) and increased length of stay by 8 days (OR 7.8, p= < 0.01 , 95% CI 3.86 – 11.92). These patients also incurred more hospital charges (co-efficient 35273, p= 0.02, 95% CI,13141 - 57405). Older study population had higher odds of death (OR 1.02, p= 0.001, 95% CI 1.01 – 1.03).We studied the post-transplant complications and rejection in patients with heart failure, and found that there were less odds of post-transplant complications like infection in heart failure patients but more odds of rejection/failure, but these results were not statistically significant. Conclusion: In our study we found that pre-existing heart failure is associated with worse clinical outcomes in liver transplant recipients. These patients had prolonged hospital stay and mortality. They also showed a tendency towards higher odds of transplant rejection. This study shows the significance of monitoring heart-failure liver transplant recipients more closely than the average liver post-liver transplant patients. This includes considering admission to cardiac intensive care units if critical.Table 1.: Adjusted odds of post liver transplant complications in Heart failure patients.

Graft rejection after pediatric living related liver transplantation

Background: Rejection is an important adverse event after pediatric liver transplantation (LT). Aim: We aimed to study the incidence and risk factors for post-transplant rejection in pediatrics. Methods: The study included 40 pediatric patients underwent LT. All patients' records were reviewed. A wide range of potential risk factors for rejection, were recorded. Results: Rejection occurred in 13/40 (32.5%) of recipients. For the 13 rejecters, a total of 24 rejection attacks have occurred. 25% of which occurred during the 1st month post-LT. Acute rejection accounted for 54% of total rejection attacks, while chronic rejection occurred in 46%. LT for biliary atrasia (BA) was a significant risk factor for rejection. The means of transaminases levels were 268 ± 141 (IU/L) AST and 221 ± 119 (IU/L) ALT, biliary enzymes were 962 ± 687 (IU/L) for the ALKP and 485 ± 347 (IU/L) for the GGT, total BIL was 6.5 ± 7.1 (mg/dl), and FKL levels were 10.4 ± 5.6 (ng/ml) during the rejection attacks. Chronic rejection contributed to death of only one of the cases. Conclusion: BA was a significant risk for rejection. Elevated transaminases and biliary enzymes but not FK trough level is alarming signs for presence of rejection. Keywords: liver transplantation; pediatrics; rejection.

Donor-Derived Cell-Free DNA to Diagnose Graft Rejection Post-Transplant: Past, Present and Future

Donor-derived cell-free DNA (dd-cfDNA) is a non-invasive biomarker that is more sensitive and specific towards diagnosing any graft injury or rejection. Due to its applicability over all transplanted organs irrespective of age, sex, race, ethnicity, and the non-requirement of a donor sample, it emerges as a new gold standard for graft health and rejection monitoring. Published research articles describing the role and efficiency of dd-cfDNA were identified and scrutinized to acquire a brief understanding of the history, evolution, emergence, role, efficiency, and applicability of dd-cfDNA in the field of transplantation. The dd-cfDNA can be quantified using quantitative PCR, next-generation sequencing, and droplet digital PCR, and there is a commendatory outcome in terms of diagnosing graft injury and monitoring graft health. The increased levels of dd-cfDNA can diagnose the rejection prior to any other presently used biochemistry or immunological assay methods. Biopsies are performed when these tests show any signs of injury and/or rejection. Therefore, by the time these tests predict and show any unusual or improper activity of the graft, the graft is already damaged by almost 50%. This review elucidates the evolution, physiology, techniques, limitations, and prospects of dd-cfDNA as a biomarker for post-transplant graft damage and rejection.

Pretransplant ascites and encephalopathy and their influence on survival and liver graft rejection in alcoholic cirrhosis disease.

IntroductionThe Child-Pugh and model for end-stage liver disease (MELD) scores are widely used to predict the outcomes of liver transplant (LT). Both have similar prognostic values in most cases, although their benefits might differ in some specific conditions. The aim of our study was to analyze the influence of pre-transplant ascites and encephalopathy in post-transplant liver rejection development and survival in alcohol cirrhosis (AC) patients undergoing LT to determine the usefulness of the Child-Pugh score for the assessment of prognosis in such patients.Material and methodsTwo hundred and eighty-one AC patients, classified according to viral infections and pre-transplant complications, were analyzed. Acute (AR) and chronic (CR) liver rejections and Child-Pugh, MELD and albumin-bilirubin (ALBI) scores were studied in all cases.ResultsSimilar AC rejection percentages were observed in ascites or encephalopathy groups (18.5% and 16.5%, p = 0.735), although a higher but not statistically significant AC rate was observed in patients with grade III ascites (p = 0.777) and with grade II encephalopathy (p = 0.089). Chronic rejection was only developed by 9.1% of AC patients, regardless of the presence of ascites (6.2%) or encephalopathy (5.5%). The presence of ascites and encephalopathy complications did not seem to influence post-transplant survival. Neither the Child-Pugh nor the ALBI score can be considered the best for predicting patient survival in the short or long term.ConclusionsAscites and encephalopathy do not seem to influence AC or CR in patient survival, regardless of the presence of viral infections, so in our study neither the Child-Pugh nor ALBI score seems to be the best score to predict the outcomes of these patients.

Functional Status of Heart Transplant Recipients Predicts Survival

PurposeRecipient functional status prior to transplantation, can significantly impact post-transplant survival.MethodsThe 2020 release UNOS data was analyzed. From November 15, 1987 to March 16, 2020 there were 38,643 adult donor hearts meeting inclusion criteria (ejection fraction >10% & <85 & not missing recovery date or recipient functional status). Survival outcomes were compared for recipient's pretransplant level of functional status versus those with near death status. Categories of function were total, some, no assistance needed, and near death. These were compared using adjusted logistic regression (odds of death at 30 days and 1 year) and Cox models (overall survival and time until post-transplant rejection). All models were adjusted for donor age, sex, ethnicity, ischemic time, as well as recipient age, sex, ethnicity, length of stay, region, ventricular assist devices, creatinine, and days on the waiting list.ResultsThere were 11,619 recipients defined as being near death or severely disabled. 7,715 were defined as requiring total assistance in daily living, with 11,780 needing some assistance, and 7,529 needing no assistance. In adjusted models, the probabilities of death for the lowest functioning groups within 30 days and 1 year were 4.7% and 9.7%, respectively. Those requiring total assistance had analogous probabilities of 3.1% (OR=0.61; p<0.001) and 8.9% (OR=0.89; p=0.028). Those requiring some assistance had probabilities of 3.0% (OR=0.58; p<0.001) and 8.5% (OR=0.85; p=0.002). And finally, those requiring no assistance had probabilities of 2.1% (OR=0.39; p<0.001) and 7.2% (OR=0.70; p<0.001). Overall survival outcomes are displayed in the Kaplan-Meier graph of Figure 1.ConclusionRecipient functional status as listed in the UNOS recipient pretransplant evaluation is a strong predictor of survival outcomes. Recipient functional status prior to transplantation, can significantly impact post-transplant survival. The 2020 release UNOS data was analyzed. From November 15, 1987 to March 16, 2020 there were 38,643 adult donor hearts meeting inclusion criteria (ejection fraction >10% & <85 & not missing recovery date or recipient functional status). Survival outcomes were compared for recipient's pretransplant level of functional status versus those with near death status. Categories of function were total, some, no assistance needed, and near death. These were compared using adjusted logistic regression (odds of death at 30 days and 1 year) and Cox models (overall survival and time until post-transplant rejection). All models were adjusted for donor age, sex, ethnicity, ischemic time, as well as recipient age, sex, ethnicity, length of stay, region, ventricular assist devices, creatinine, and days on the waiting list. There were 11,619 recipients defined as being near death or severely disabled. 7,715 were defined as requiring total assistance in daily living, with 11,780 needing some assistance, and 7,529 needing no assistance. In adjusted models, the probabilities of death for the lowest functioning groups within 30 days and 1 year were 4.7% and 9.7%, respectively. Those requiring total assistance had analogous probabilities of 3.1% (OR=0.61; p<0.001) and 8.9% (OR=0.89; p=0.028). Those requiring some assistance had probabilities of 3.0% (OR=0.58; p<0.001) and 8.5% (OR=0.85; p=0.002). And finally, those requiring no assistance had probabilities of 2.1% (OR=0.39; p<0.001) and 7.2% (OR=0.70; p<0.001). Overall survival outcomes are displayed in the Kaplan-Meier graph of Figure 1. Recipient functional status as listed in the UNOS recipient pretransplant evaluation is a strong predictor of survival outcomes.

Panel Reactive Antibodies (PRA) and Donor-Specific Antibodies (DSA) in Lung Transplantation: An Indian Experience

Purpose Lung Transplantation data on Panel Reactive Antibodies (PRA) and Donor -Specific Antibodies (DSA) in Indian Settings is limited. Panel-reactive antibody (PRA) testing estimates the percentage of potential donors to whom a recipient has HLA antibodies and approximates the risk of positive crossmatch which estimates the risk of rejection post transplant. Single antigen bead (SAB) assay is the most sensitive tool available for detecting HLA antibodies and assessing the immunological risk for organ transplant. We examined the prevalence of transplant anti-HLA antibodies at varying thresholds and evaluated the common Anti HLA antibodies correlating with AMR. Methods We performed a retrospective cohort study including all patients listed for lung transplantation between March 2017 and August 2020. Per protocol patients, transplant candidates were assessed by Luminex bead-based assays Quantitative as well as Qualitative for PRA Class I and II and Luminex bead based Single Antigen Bead assays with MFI (mean fluorescence intensity) values. Outcomes in terms of Rejection (Antibody Mediated) were taken into consideration. Results Among 135 patients, 12 (8.88%) patients showed PRA activity (Class I/II) less than 10 %, 8(5.9%) patients showed PRA activity between 11-50% and 1 patient (0.7%) had PRA activity more than 50 % pre-operatively. 1 patients (0.7%) had anti-HLA antibodies at MFI lesser than or equal to 1,000 pretransplant (group I). 24 patients (17.7%) had a history of circulating anti-HLA antibodies at MFI between 1,000 and 3,000 (group II), and 26 (19.2%) had anti-HLA antibodies at MFI greater than or equal to 3,000 (group III) and 35 (25.9%) patients had no anti-HLA antibodies detected. 3 LTx recipients developed biopsy proven AMR. Out of 3 recipients, 2 recipients had Class I anti-HLA antibodies between 1000-3000 and Class II antibodies more than 3000. HLA DQB1 was the most common Class II locus which showed MFI more than 3000 and correlated with Biopsy proven AMR in above 2 recipients. Conclusion HLA DQB1 seems to be common allele correlating with Biopsy proven AMR in our study. PRA screening (Quantitative) pre-operatively and if positive, doing Donor-Specific Antibodies assay is an important step in deciding transplant candidacy. Post operatively, doing Donor Specific Antibodies helps diagnosis of AMR in suspected cases of Rejection.

Psychosocial Evaluation of Candidates for Solid Organ Transplantation.

Transplant candidates should undergo an assessment of their mental health, social support, lifestyle, and behaviors. The primary aims of this "psychosocial evaluation" are to ensure that transplantation is of benefit to life expectancy and quality of life, and to allow optimization of the candidate and transplant outcomes. The content of psychosocial evaluations is informed by evidence regarding pretransplant psychosocial predictors of transplant outcomes. This review summarizes the current literature on pretransplant psychosocial predictors of transplant outcomes across differing solid organ transplants and discusses the limitations of existing research. Pretransplant depression, substance misuse, and nonadherence are associated with poorer posttransplant outcomes. Depression, smoking, and high levels of prescription opioid use are associated with reduced posttransplant survival. Pretransplant nonadherence is associated with posttransplant rejection, and nonadherence may mediate the effects of other psychosocial variables such as substance misuse. There is evidence to suggest that social support is associated with likelihood of substance misuse relapse after transplantation, but there is a lack of consistent evidence for an association between social support and posttransplant adherence, rejection, or survival across all organ transplant types. Psychosocial evaluations should be undertaken by a trained individual and should comprise multiple consultations with the transplant candidate, family members, and healthcare professionals. Tools exist that can be useful for guiding and standardizing assessment, but research is needed to determine how well scores predict posttransplant outcomes. Few studies have evaluated interventions designed to improve psychosocial functioning specifically pretransplant. We highlight the challenges of carrying out such research and make recommendations regarding future work.

The effects of increased donor support time from organ donation referral to donor procurement on heart transplant recipient survival.

Given the known deleterious cardiac effects of brain death (BD) physiology, we hypothesized that time from cardiac donation referral to procurement (donor support time [DST]), would negatively impact cardiac transplant recipient survival. The United Network for Organ Sharing database was queried from 2007 to 2018, identifying 22,593 donor hearts for analysis. Multivariate logistic models for 30-day and 1-year survival, as well as Cox models for overall survival and posttransplant rejection, were used to assess adjusted outcomes. median DST was 3 days (interquartile range: 2-5 days). Ischemic time; distance between donor and recipient hospitals; and recipient age, creatinine, waitlist time, and length of stay were adjusted predictors of survival and rejection. DST was not associated with either outcome in aggregate; however, differential association by donor race was identified, with DST in any race recipient associated with 4% higher odds of 1-year mortality (p = .001; p value for interaction.005) but only a trend towards worse overall mortality (p = .064; p value for interaction.046). Thus, duration of exposure to BD physiology may have a differential impact on recipient outcomes based on donor race, suggesting that additional research is needed on donor immunologic, socioeconomic, and healthcare access factors that may impact cardiac transplant recipient outcomes.

Delayed Gastric Emptying in Prelung Transplant Patients Is Associated With Posttransplant Acute Cellular Rejection Independent of Reflux.

The goal of this study was to evaluate the relationship between pretransplant delayed gastric emptying (DGE) and posttransplant acute cellular rejection (ACR) in lung transplant recipients. DGE is very prevalent (23% to 91%) after lung transplantation but pretransplant prevalence has not been well studied. DGE may lead to poor posttransplant outcomes by predisposing to microaspiration. Pretransplant testing for DGE may help identify patients at risk for negative posttransplant outcomes including ACR. A retrospective review of a prospectively collected database of consecutive patients undergoing prelung transplant evaluation at a tertiary referral center from 2010 to 2015 was performed. Patients with pretransplant gastric emptying scintigraphy were included in the study. ACR diagnosis was made using International Society for Heart and Lung Transplantation (ISHLT) histologic criteria. Typical gastroparesis symptoms at the time of gastric emptying scintigraphy and pretransplant 24-hour pH impedance monitoring (MII-pH) data was collected. Logistic regression was used for multivariate analysis. Subgroup analyses were performed to account for gastroesophageal reflux (GER). A total of 83 subjects (18 with DGE, 51.8% male, mean age: 53.6 y) met the criteria for inclusion. Patients with DGE were more likely to have typical symptoms of gastroparesis, though 61.1% of DGE patients were asymptomatic. ACR was more prevalent in patients with DGE (33.3% vs. 12.3%, P=0.04). This correlation was independent of GER as measured by MII-pH on subgroup analysis (75% vs. 14.3%, n=0.02). Lung transplant recipients with pretransplant DGE have a higher incidence of ACR, independent of GER. Routine pretransplant testing for DGE may help identify patients at greater risk for adverse posttransplant outcomes as the majority of patients with DGE are asymptomatic.

Local and Systemic Effects of Cyclosporine A on the Severity of Gingival Overgrowth in Post-Transplant Renal Patients.

Background:Cyclosporine A (CsA) is a potent immunosuppressant widely used to prevent renal post transplantation rejection. Gingival overgrowth (GO) is among various side effects of the long-term administration of CsA. Up to 90% of the patients under CsA therapy has been reported to develop CsA-induced GO.Objectives:The aim of the present prospective pilot study is to determine the local and systemic effects of Cyclosporine A (CsA) on the severity of gingival overgrowth and its relationship with periodontal parameters in post-transplant renal patientsMethods:Twenty post-transplant renal patients, 12 females and 8 males, presenting gingival overgrowth were selected from Rizk Hospital’s clinic in Beirut. Patient’s CsA plaque levels were evaluated when CsA is administered by syrup and capsules mode. Periodontal parameters including gingival overgrowth, papillary bleeding, plaque and gingival indices were assessed for all patients.Results:Plaque concentration CsA levels, when administered in syrup mode, affected significantly the severity of gingival overgrowth as opposed to the administration by capsule mode. Significant correlations between severity of gingival overgrowth on one hand and plaque index, gingival index, and papillary bleeding index on the other hand were only observed in the Capsule group but not in the syrup group. A significant relationship was established between the severity of gingival overgrowth and all periodontal parameters (gingival, papillary and plaque).Conclusion:The present study underlines CsA dental plaque local effect, as a co-factor, in the development of gingival overgrowth. Cyclosporine plaque accumulation acts as a reservoir in the gingival inflammation and the periodontal indices seem to be the most accurate parameters associated with gingival overgrowth severity. Plaque CsA concentrations could be considered as a risk factor for inflammation and gingival overgrowth depending on CsA delivery mode in renal transplant patients.

The Post-Transplant Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio in Relation to Graft Function among Renal Transplant Recipients

Aim: The aim of this study was to evaluate the association of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) with acute rejection after kidney transplantation. Material and Methods: A total of 36 adult renal transplant recipients (33 males, 3 females) with a median age of 41 (range, 19-64) years were included in this retrospective study conducted between January 2016 and January 2019. Data on patient demographics and laboratory findings (neutrophil, lymphocyte, platelet, creatinine, eGFR, serum uric acid and C-reactive protein) were recorded. Acute rejection was defined via renal biopsy in accordance with Banff criteria. Results: Acute rejection occurred in 16 (44.4%) patients. NLR (median 3.75 vs. 1.99, p=0.001) and PLR (median 125.59 vs. 99.23, p=0.008) values were significantly higher in the acute rejection group than in the control group. Area under the curve was calculated to be 0.822 for NLR and to be 0.759 for PLR. Cut-off values were determined to be &amp;gt;2.5 (75% sensitivity and 75% specificity) for NLR and to be &amp;gt;108 (81% sensitivity and 65% specificity) for PLR. Univariate analysis revealed a strong correlation of acute rejection both with NLR &amp;gt;2.5 (Odds Ratio (OR)=0.267, 95% Confidence Interval (CI)=0.089-0.803, p=0.019) and PLR &amp;gt;108 (OR=0.231, 95% CI=0.066-0.810, p=0.022). Conclusion: In kidney transplant patients, there is a strong relationship between high NLR and PLR values and the development of acute rejection. As simple, easy-to-access, inexpensive and non-invasive methods, PLR, and particularly NLR, may be potential tests to diagnose post-transplant acute rejection.

Treatment of Anti-HLA Donor-Specific Antibodies Results in Increased Infectious Complications and Impairs Survival after Liver Transplantation.

Donor-specific anti-human leukocyte antigen antibodies (DSA) are controversially discussed in the context of liver transplantation (LT). We investigated the relationship between the presence of DSA and the outcome after LT. All the LTs performed at our center between 1 January 2008 and 31 December 2015 were examined. Recipients < 18 years, living donor-, combined, high-urgency-, and re-transplantations were excluded. Out of 510 LTs, 113 DSA-positive cases were propensity score-matched with DSA-negative cases based on the components of the Balance of Risk score. One-, three-, and five-year survival after LT were 74.3% in DSA-positive vs. 84.8% (p = 0.053) in DSA-negative recipients, 71.8% vs. 71.5% (p = 0.821), and 69.3% vs. 64.9% (p = 0.818), respectively. Rejection therapy was more often applied to DSA-positive recipients (n = 77 (68.1%) vs. 37 (32.7%) in the control group, p < 0.001). At one year after LT, 9.7% of DSA-positive patients died due to sepsis compared to 1.8% in the DSA-negative group (p = 0.046). The remaining causes of death were comparable in both groups (cardiovascular 6.2% vs. 8.0%; p = 0.692; hepatic 3.5% vs. 2.7%, p = 0.788; malignancy 3.5% vs. 2.7%, p = 0.788). DSA seem to have an indirect effect on the outcome of adult LTs, impacting decision-making in post-transplant immunosuppression and rejection therapies and ultimately increasing mortality due to infectious complications.

Abstract 15953: Impact of Citizenship on Heart Transplantation Outcomes in the United States

Background: Non-citizens of the United States face complex social and economic issues, which may impact their post-transplant outcomes compared to US citizens. To this end, we utilized the United Network for Organ Sharing (UNOS) database to examine post-heart transplant (OHT) outcomes, stratified by citizenship status. Methods: UNOS was queried to identify OHT recipients from 03/01/12 (start of new schema for citizenship categorization) through 10/18/18 (start of new heart allocation algorithm). Groups for analysis, were as follows: US Citizen, Non-US Citizen/Resident (NC-R) and Non-US Citizen/Non-US Resident (NC-NR). Post-transplant survival and rate of post-transplant rejection were assessed via Kaplan-Meier analysis and tests of proportions. Results: Of the 16,211 OHT recipients identified, 15,677 (96.7%) were US citizens and 534 (3.3%) were Non-Citizens. Among Non-Citizens, 430 were NC-R and 104 were NC-NR, representing 2.7% and 0.6% of the total transplants. Notably, NC-NR were younger than either Citizens or NC-R, and had the shortest median time from listing to transplant (NC-R 80 days vs. Citizens 107 days vs. NC-NR 76 days, p=0.001). The proportion of transplants received by non-citizens varied widely by region, ranging from 0.59% in region 8 (6/1018) to 8.31% (84/1011) in region 9. There was no significant difference in post-transplant survival estimates in citizens vs. non-citizens (logrank p = 0.542), nor in the proportion of patients treated for rejection by one year (15.0% vs. 16.1%, p= 0.504) Conclusion: Non-US Citizens receive three percent of heart transplants performed in the US each year. Post-heart transplant survival and rate of rejection are similar in US citizens and non-citizens. These data may be relevant in the context of evolving UNOS policies. Additional studies are needed are to further inform organ allocation policy.

Hypoxia-induced downregulation of cyclooxygenase 2 leads to the loss of immunoprivilege of allogeneic mesenchymal stem cells.

Allogeneic mesenchymal stem cells (MSCs) from young and healthy donors are reported to hold the potential to treat several immunological and degenerative disorders. However, recent data from animal studies and clinical trials demonstrate that immunogenicity and poor survival of transplanted MSCs impaired the efficacy of cells for regenerative applications. It is reported that initially immunoprivileged under in vitro conditions, MSCs are targeted by the host immune system after transplantation in the ischemic tissues in vivo. We performed in vitro (in MSCs) and in vivo (in the rat model of myocardial infarction [MI]) studies to elucidate the mechanisms responsible for the change in the immunophenotype of MSCs from immunoprivileged to immunogenic under ischemic conditions. We have recently reported that a soluble factor prostaglandin E2 (PGE2) preserves the immunoprivilege of allogeneic MSCs. In the current study, we found that PGE2 levels, which were elevated during normoxia, decreased in MSCs following exposure to hypoxia. Further, we found that proteasome-mediated degradation of cyclooxygenase-2 (COX2, rate-limiting enzyme in PGE2 biosynthesis) in hypoxic MSCs is responsible for PGE2 decrease and loss of immunoprivilege of MSCs. While investigating the mechanisms of COX2 degradation in hypoxic MSCs, we found that in normoxic MSCs, COP9 signalosome subunit 5 (CSN5) binds to COX2 and prevents its degradation by the proteasome. However, exposure to hypoxia leads to a decrease in CSN5 levels and its binding to COX2, rendering COX2 protein susceptible to proteasome-mediated degradation. This subsequently causes PGE2 downregulation and loss of immunoprivilege of MSCs. Maintaining COX2 levels in MSCs preserves immunoprivilege in vitro and improves the survival of transplanted MSCs in a rat model of MI. These data provide novel mechanistic evidence that PGE2 is downregulated in hypoxic MSCs which is responsible for the post-transplantation rejection of allogeneic MSCs. Therefore, our data suggest that the new strategies that target CSN5-COX2 signaling may improve survival and utility of transplanted allogeneic MSCs in the ischemic heart.

STUDY OF DONORS WEIGHT AND SEX CORRELATION WITH RECIPIENTS GRAFT FUNCTION IN LIVING RELATED RENAL TRANSPLANT

Background and Objectives: Renal allograft function, is not only dependent on immunological factors but also on age, gender and the weight of the donor which has not been studied much. The objective of this study was to see the outcome with mismatch of the sex and especially the weight of the donor and recipient graft function. Materials and Method: A retrospective analysis of 50 patients with stable graft function was noted at the end of 15 days,3 months, 6 months and 1 year after renal transplant. Patients who had infection and rejection post transplant were excluded from study. Donor-recipient sex pairings (male donor–male recipient; female donor–female recipient; male donor–female recipient; female donor–male recipient) was done. Weight was used a surrogate marker for kidney size and mismatch was categorized into match (donor weight/recipient weight x 100): less than 75%(small donor kidney),75-125%(weight matched kidney) and greater than 125%(large donor kidney). Age was divided in 5 groups into 30-40 yr,41-45 yr,46-55yr, 56-65yr and 66-70 yr). Similarly donor weight(kg) was also divided into five groups(51-60,61-70,71-80,81-90and>90kg). Paired ‘T’ test and correlation and regression analysis were applied. Results: Out of the total 50 donor studied, 20 were male and 30 were female. Female recipient had better outcomes as compared to male recipient(1.07 vs 1.18mg/dl). Female to female had the best outcome(1.01mg/dl) while female to male had worst outcome(1.19mg/dl). According to weight match, the outcome for large donor was better especially in initial 6 months(1.13 vs 1.19mg/dl). Weight of the donor had a moderate negative correlation(r=-0.31) with s.creatinine level while the weight of recipient had a weak positive correlation(r=+0.07). The recipient with higher donor weight had better graft function(1.06 vs 1.27mg/dl) but without recipient weight adjustment. The paired ’T’’ test was statistically not significant(p value>0.05).Discussion: As found in this study, females had better graft function as recipients compared with males, whereas males served as better donors. It is hypothesized that larger donor kidney mass as compared with recipient provides more number of glomeruli with less demand of hyperfiltration on the transplanted kidney and less injury over the long term.The actual volume of the transplanted organ and BSA has been measured in studies and have found variable data. Female kidneys are smaller and have lesser nephrons as compared to male and can cause mismatch in equal weighted female donor and male recipient. Conclusion: Male recipients should receive weight-matched donors, preferably a male or higher weight if donor is female. Whereas a female recipient can receive equally matched female or male donor. The long-term graft function is dependent on these factors and should be taken into consideration before rushing for early transplantation. Further similar larger studies would provide a better insight.

Prevalence, Characteristics, and Outcomes of Incidental IgA Glomerular Deposits in Donor Kidneys

IntroductionIncidental IgA deposits in donor kidneys have unknown sequelae and may predate clinical kidney disease if primed by adverse immunologic or hemodynamic stimuli or may remain dormant.MethodsThe presence of incidental IgA in post-implantation (T0) biopsies from living (LDK) and deceased donor (DDK) kidneys, and its relationship to post-transplant patient and graft outcomes was investigated in an ethnically diverse US population at a large transplant center.ResultsMesangial IgA was present in 20.4% of 802 T0 biopsies; 13.2% and 24.5% of LDK and DDK, respectively. Donors with incidental IgA deposits were more likely to have hypertension and be of Hispanic or Asian origin. Intensity of IgA staining was 1+ (57.3%), 2+ (26.8%), or 3+ (15.8%) of the T0 IgA+ biopsies. Mesangial pathology correlated with higher-intensity IgA staining with less clearance on follow-up (53.8%) versus 79.2% without mesangial pathology. IgA cleared in 91%, 63%, and 40% of follow-up biopsies with 1+, 2+, and 3+ IgA staining, respectively. Early post-transplant rejection and rejection-related graft loss occurred more frequently in IgA+ kidney recipients; however, 5-year kidney function and graft survival were comparable to kidneys without IgA.ConclusionThis first and largest report of incidental IgA in T0 biopsies of LDK and DDK in a US ethnically diverse population demonstrated no adverse association between the presence of IgA in donor kidneys and graft or patient survival. Whether IgA in donor kidneys represents latent IgA nephropathy (IgAN) is uncertain; nevertheless, living donors who demonstrate IgA on T0 biopsy deserve careful follow-up.