Adult Renal Transplant Research Articles

The Genetic Polymorphism of CYP3A4 rs2242480 is Associated with Sirolimus Trough Concentrations Among Adult Renal Transplant Recipients.

The large interindividual variability in the genetic polymorphisms of sirolimus (SIR)- metabolizing enzymes, transporters, and receptors can lead to qualitatively and quantitatively distinct therapeutic responses. We examined the impact of numerous candidate single-nucleotide polymorphisms (SNPs) involved in the trough concentration of SIR-based immunosuppressant regimen. This is a retrospective, long-term cohort study involving 69 renal allograft recipients. Total DNA was isolated from recipient blood samples and trough SIR concentrations were measured by microparticle enzyme immunoassay. Genome sequence reading was targeted based on next-generation sequencing. The association of tagger SNPs to SIR trough concentrations with non-genetic covariate adjusting was analyzed using logistic regression. A total of 300 SNPs were genotyped in the recipient DNA samples using target sequencing analysis. Only the SNP of CYP3A4 (Ch7: 99361466 C>T, rs2242480) had a significantly higher association with SIR trough concentration as compared to the other 36 tagger SNPs. The mean trough SIR concentration of patients in the CYP3A4 rs2242480-CC group was more significant compared to that of the CYP3A4 rs2242480-TC and TT group, respectively 533.3; 157.4 and 142.5 (ng/ml)/mg/kg, P<0.0001. After adjusting the SNPs, there was no significant association between clinical factors such as age, follow-up period, the incidence of delayed graft function, immunosuppression protocol, and sex with SIR trough concentration. These findings indicated a significant association of polymorphism in the CYP3A4 (Ch7: 99361466 C>T, rs2242480) with SIR trough concentration after 1-year administration in patients who have undergone kidney transplantation.

Population Pharmacokinetics of Vancomycin in Kidney Transplant Recipients: Model Building and Parameter Optimization.

BackgroundDepending on the renal function of patients and many other influencing factors, studies on vancomycin pharmacokinetics show significant inter- and intra-individual variability. The present study was conducted using a population pharmacokinetics method to investigate the pharmacokinetic parameters and identified their influencing covariates for intravenous vancomycin in adult kidney transplant recipients.MethodsThe drug monitoring data included 56 adult renal transplant recipients who received intravenous vancomycin as prophylactic medication. The analysis was performed by a population approach with NONMEM. Data were collected mainly during the first week after transplantation. Monitoring of vancomycin trough concentration in blood was initiated mainly 3–5 days after the initial administration.ResultsThe one-compartment open model was optimal and adequately described the data. Body weight (WT) and estimated glomerular filtration rate (GFR) were identified as significant covariates of the pharmacokinetic parameters CL and V of intravenous vancomycin in the kidney transplant patients. The typical values of vancomycin CL and V were 2.08 L h-1 and 63.2 L, respectively. A dosage strategy scheme according to model results was also designed.ConclusionBoth WT and GFR of the kidney transplant patients positively influence the pharmacokinetic parameters CL and V for intravenous vancomycin. Our population pharmacokinetic model provides a reference for vancomycin dosage adjustment in kidney transplant recipients.

Association of graft survival with tacrolimus exposure and late intra-patient tacrolimus variability in pediatric and young adult renal transplant recipients-an international CTS registry analysis.

Adolescent and young adult age is a high-risk window with an alarmingly increased likelihood of premature kidney graft loss due to immunological rejection. Using the large database of the Collaborative Transplant Study, we analyzed whether a more intense and less variable exposure to tacrolimus could counteract this young age-related enhanced immunoreactivity. Kidney graft recipients aged 12-23years (n=964) with a 1-year tacrolimus trough level between 4.0 and 10.9ng/ml had a 5-year graft survival rate of 85.1%, significantly better than the poor 66.1% rate in patients with a trough level below 4.0ng/ml who showed a 2.38-fold increased risk of graft loss in the multivariable analysis (P<0.001). This association was not apparent in young children aged 0-11years (n=455) and less pronounced in adults aged 24-34years (n=1466). However, an intra-patient variability of tacrolimus (IPV) trough level ≥1.5 at post-transplant years 1 and 2 was associated with an increased graft loss risk in both 12- to 23-year-old and 0- to 11-year-old recipients (P<0.001 and P=0.045). Patients with high IPV made up as many as 30% of kidney graft recipients, indicating that a more intense and less variable exposure to tacrolimus could improve graft survival strongly in this high-risk group.

Loss to Follow-up in Adolescent and Young Adult Renal Transplant Recipients.

Patients' loss to follow-up (LFU) has significant impacts on outcomes and is a barrier to improving care, especially in adolescent and young adult (AYA) renal transplant recipients. There is limited information regarding the relationship between transfer of care from pediatric to adult transplant centers, age, and LFU among AYA renal transplant recipients. We studied 16 386 individuals aged 10-29 years who received kidney transplants between January 1, 2005 and December 31, 2015 using the Scientific Registry of Transplant Recipients. The primary outcome was LFU, which was defined as >1 year without follow-up in a transplant clinic/program. Death or graft failure within a year of the last follow-up was not classified as LFU. We performed a retrospective cohort study describing LFU using Pearson's chi-square tests. Multivariable logistic regression was used to estimate the change in likelihood of LFU associated with recipient characteristics and institution transfer. In total, 22.26% (n = 3647) of our study population met criteria for LFU. About 11.17% (n = 1830) transferred institutions during the study period. LFU occurred in 50.18% of recipients who transferred institutions. LFU peaked at the age of 20 years, with 7.4% of 20-year-olds having LFU. The odds of LFU among renal transplant recipients who transferred institutions were 3.36 times greater (95% confidence interval, 3.1-3.6) than the odds of LFU among those who did not transfer institutions. LFU is a critical problem faced by AYA renal transplant recipients, and institution transfer is a significant risk factor for LFU. Additional studies investigating the interplay between age, institution transfer, and LFU in the AYA population are still needed.

Effect of ABCB1 3435C>T Genetic Polymorphism on Pharmacokinetic Variables of Tacrolimus in Adult Renal Transplant Recipients: A Systematic Review and Meta-analysis

PurposeTacrolimus is the substrate of multidrug-resistance 1 (ABCB1). However, the effect of ABCB1 C3435T polymorphism on pharmacokinetic variables of tacrolimus is controversial in different studies. This meta-analysis was conducted to explore the relationship between ABCB1 3435C>T genetic polymorphism and pharmacokinetic variables of tacrolimus. MethodsA database search was conducted of PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov, as well as Chinese databases (SinoMed, Wan Fang, and China National Knowledge Infrastructure). We also scanned reference lists and corresponded with authors. The study explored the relationship between ABCB1 3435C>T genetic polymorphism and pharmacokinetic variables of tacrolimus stratified according to time of posttransplantation, ethnicity, methods of concentration measurement, and the initial doses of tacrolimus. FindingsSixteen studies were included in this meta-analysis. In the subgroup analysis, ABCB1 3435TT had a significantly lower weight-adjusted dose than ABCB1 3435CC, which was not observed in the ABCB1 3435CT group. The subgroup analysis then revealed that the tacrolimus concentration/weight-adjusted daily dose ratio of ABCB1 3435T carriers was significantly higher than that of the ABCB1 3435CC group at 1 and 6 months. Meanwhile, ABCB1 3435CT and TT both had a higher tacrolimus concentration/weight-adjusted daily dose ratio compared with ABCB1 3435CC. ImplicationsOur meta-analysis identified that the ABCB1 3435C>T genetic polymorphism affected the pharmacokinetic variables of tacrolimus in adult renal transplant recipients. However, individualized treatments based on genetic polymorphisms require further investigation.

IS GASTRIC SLEEVE SURGERY AN OPTIMAL THERAPY FOR WEIGHT REDUCTION POST RENAL TRANSPLANTATION?

Introduction: obesity post renal transplantation has negative impact on graft survival and related complications. Short term efficacy and weight reduction has been reported with various types of bariatric procedures and limited number of renal transplant patients underwent laparoscopic sleeve gastrectomy (LSG). We report the outcomes of sleeve gastrectomy among obese renal transplant patients. Method: A retrospective chart review study was conducted for adult (>18 years) renal transplant patients in Tawam hospital over 7 years (January 2013 to January 2020). Obese renal transplant patients who underwent laparoscopic sleeve gastrectomy were included. Clinical, laboratory, and outcomes related to surgery were studied and analyzed. Results: Five morbidly obese renal transplant patients had underwent LSG during study period. The mean age was 36.2 years (3 females and 2 males). The comorbid conditions in our cohort were hypertension (5[100%]), diabetes mellitus (4[80%]), dyslipidemia (4[80%]), chronic kidney disease stage 2 (100%) and obstructive sleep apnea (2[40%]). Three patients had baseline body mass index (BMI) between 35-39 kg/m2 and two patients had BMI more than 45 kg/m2. The mean baseline weight was 113.4 kg. The mean duration of transplantation was 9.8 years and all patients had transplant from living donors. The maintenance immunosuppression medications consist of triple therapy regime (prednisolone 5mg (100%), tacrolimus (100%), mycophenolate (60%), and mycophenolic acid (40%)) Trial of diet control and exercise failed to achieve the desire weight reduction in all patients prior to LSG. There was no major intraoperative surgical complications and mean duration of post-operative hospital stay was 2 to 3 days. One patient underwent LGS and hiatal hernia repair complicated by small hematoma managed with drain. Early post-operative complications were tacrolimus toxicity (at 2 and 4 weeks) observed in two patients associated with acute kidney injury managed with dose reduction and hydration. Three other patients had elevated tacrolimus trough levels 9 to 10 ng/mL (at 2, 3 and 8 weeks) without major symptoms and required dose reduction. Other complications were iron deficiency anemia (2), low vitamin B12 level (1) and one patient had bile reflux gastritis 5 years post-operative. The median follow up period post LSG was ranging from 3 months to 6 years. Weight reduction in our cohort were steady overtime with mean weight of 93.4 Kg at 3 months and 83.25kg at 9 months. There was positive effects on diabetes and blood pressure control with reduction of medications. Conclusion: Laparoscopic sleeve gastrectomy has good short-term outcomes for weight reduction and control of diabetes and hypertension in morbidly obese renal transplant recipients. Risks of tacrolimus toxicity and acute kidney injury need to be monitored in early post-operative period. Pharmacokinetic studies and large randomize control trials with long follow up are required.

Hypoperfusion warm ischaemia time in renal transplants from donors after circulatory death.

The donor hypoperfusion phase before asystole in renal transplants from donors after circulatory death (DCD) has been considered responsible for worse outcomes than those from donors after brain death (DBD). We included 10 309 adult renal transplants (7128 DBD and 3181 DCD; 1 January 2010-31 December 2016) from the UK Transplant Registry. We divided DCD renal transplants into groups according to hypoperfusion warm ischaemia time (HWIT). We compared delayed graft function (DGF) rates, primary non-function (PNF) rates and graft survival among them using DBD renal transplants as a reference. The DGF rate was 21.7% for DBD cases, but ∼40% for DCD cases with HWIT ≤30 min (0-10 min: 42.1%, 11-20 min: 43%, 21-30 min: 38.4%) and 60% for DCD cases with HWIT >30 min (P < 0.001). All DCD groups showed higher DGF risk than DBD renal transplants in multivariable analysis {0-10 min: odds ratio [OR] 2.686 [95% confidence interval (CI) 2.352-3.068]; 11-20 min: OR 2.531 [95% CI 2.003-3.198]; 21-30 min: OR 1.764 [95% CI 1.017-3.059]; >30 min: OR 5.814 [95% CI 2.798-12.081]}. The highest risk for DGF in DCD renal transplants with HWIT >30 min was confirmed by multivariable analysis [versus DBD: OR 5.814 (95% CI 2.798-12.081) versus DCD: 0-10 min: OR 2.165 (95% CI 1.038-4.505); 11-20 min: OR 2.299 (95% CI 1.075-4.902); 21-30 min: OR 3.3 (95% CI 1.33-8.197)]. No significant differences were detected regarding PNF rates (P = 0.713) or graft survival (P = 0.757), which was confirmed by multivariable analysis. HWIT >30 min increases the risk for DGF greatly, but without affecting PNF or graft survival.

ELIMINATING PATIENT CONTROLLED ANALGESIA REDUCES OPIOID USE IN RENAL TRANSPLANT RECIPIENTS

Introduction: Six percent of opioid-naïve patients develop opioid dependence post-operatively. Renal transplant recipients who fill opioid prescriptions for more than 90 days post-operatively are at increased risk for graft failure and death. We implemented a protocol in our renal transplant recipients that eliminated opioid patient-controlled analgesia (PCA) and included a multi-modal non-opioid regimen. The purpose of this study was to examine the impact of PCA elimination on opioid requirements at discharge in renal transplant recipients. Materials and Methods: We reviewed adult renal transplant recipients for the three months prior to, and following, implementation of the protocol. Patients with an intra-abdominal transplant, a simultaneous pancreas-renal transplant, or a history of chronic pain were excluded. The number of opioid pills prescribed on the day prior to discharge were categorized as A) 0, B) 1-3, and C) 4. Discharge opioid prescriptions were then evaluated based on a recent recommendation that group A receive 0 pills, group B 15 pills, and group C 30 pills, to satisfy the outpatient pain needs of 85% of patients. Pre- and post- metrics were compared using independent t-tests and Chi squared tests. Results and Discussion: 150 recipients were included (79 pre-intervention, 71 post; 51% male).PCA use decreased significantly (95.8% vs. 19%, p<0.001). PCAs were associated with increased OMEs prescribed at discharge (84.3 vs. 68.5, p=0.14). Post-intervention, gabapentin, topical lidocaine, and acetaminophen increased significantly (7% to 73%, 6% to 68%, 72% to 94%, respectively).Of patients requiring no opioids on the day prior to discharge, 51.5% of pre- and 35.5% of post- were prescribed excess opioids at discharge.Of patients prescribed 1-3 pills on the day prior to discharge, 24.2% of pre- and 25.8% of post patients were prescribed excessive opioids at discharge.Conclusion: A multidisciplinary approach to developing an opioid-reducing protocol significantly decreased the use of PCAs and increased the use of non-opioid adjunct medications in renal transplant recipients. Eliminating PCAs trended towards a decreased amount of opioids prescribed at discharge. Excess opioids at discharge remains a problem. While we implemented a systems-based intervention to eliminate inpatient PCA prescription, we failed to adequately communicate the ultimate goal of decreasing opioids prescribed at discharge. Changing prescriber behavior requires specific interventions targeting all the metrics of interest. Following this study, we sought to protocolize both inpatient and discharge opioid prescribing wherein all patients, regardless of how many opioids received while inpatient, receive 10 opioid pills at discharge. After a three-month pilot, we plan to analyze the number of refills needed to evaluate whether this opioid-sparing approach at discharge leads to sufficient pain control in the short post-operative term. Transplant surgery nursing staff, pharmacists, and clinical providers.

Cardiovascular Risk Factors are Inversely Associated With Omega-3 Polyunsaturated Fatty Acid Plasma Levels in Pediatric Kidney Transplant Recipients

High plasma levels of the omega-3 fatty acids eicosapentaenoic acid (EPA), docosahexaenoic acid, and docosapentaenoic acid associates with positive outcomes in adult renal transplant recipients. However, data from pediatric populations are scarce. The aim of the study was to assess the fatty acid profile in a pediatric renal transplantation cohort and to examine the associations between plasma omega-3 fatty acids and cardiovascular disease (CVD) risk factors. In this cross-sectional study comprising 53 children (median age, 12.2years; 32 boys) with a renal transplant, we assessed the prevalence of CVD risk factors as well as markers of end organ damage: carotid intima-media thickness (cIMT) and left ventricular mass index. The associations between plasma omega-3 fatty acids and CVD risk factors were assessed. Twenty-five (47%) patients were preemptively transplanted. Seventy-six percent had dyslipidemia and 51% had hypertension. The mean left ventricular mass index was 40.4±14.3g/m2.7, and 14% had left ventricular hypertrophy. The mean cIMT was 0.41±0.04mm. In a multivariate linear regression, EPA levels were inversely associated to blood pressure (β coeff.=-0.37, P=.007), triglycerides (β coeff.=-0.44, P=.01), and high-density lipoprotein cholesterol (β coeff.=-0.41, P=.01). EPA levels are inversely associated with components of the metabolic syndrome, which may provide support for specific dietary advice or supplementation in this patient population. cIMT is less pronounced in our cohort than in comparable cohorts with lower rate of preemptive transplantations. Our results need replication in prospective cohorts.

Clinical and Analytical Validation of a Novel Urine-Based Test for the Detection of Allograft Rejection in Renal Transplant Patients.

In this clinical validation study, we developed and validated a urinary Q-Score generated from the quantitative test QSant, formerly known as QiSant, for the detection of biopsy-confirmed acute rejection in kidney transplants. Using a cohort of 223 distinct urine samples collected from three independent sites and from both adult and pediatric renal transplant patients, we examined the diagnostic utility of the urinary Q-Score for detection of acute rejection in renal allografts. Statistical models based upon the measurements of the six QSant biomarkers (cell-free DNA, methylated-cell-free DNA, clusterin, CXCL10, creatinine, and total protein) generated a renal transplant Q-Score that reliably differentiated stable allografts from acute rejections in both adult and pediatric renal transplant patients. The composite Q-Score was able to detect both T cell-mediated rejection and antibody-mediated rejection patients and differentiate them from stable non-rejecting patients with a receiver–operator characteristic curve area under the curve of 99.8% and an accuracy of 98.2%. Q-Scores < 32 indicated the absence of active rejection and Q-Scores ≥ 32 indicated an increased risk of active rejection. At the Q-Score cutoff of 32, the overall sensitivity was 95.8% and specificity was 99.3%. At a prevalence of 25%, positive and negative predictive values for active rejection were 98.0% and 98.6%, respectively. The Q-Score also detected subclinical rejection in patients without an elevated serum creatinine level but identified by a protocol biopsy. This study confirms that QSant is an accurate and quantitative measurement suitable for routine monitoring of renal allograft status.

Dilated Cardiomyopathy in an Adult Renal Transplant Recipient: Recovery Upon Tacrolimus to Sirolimus Switch: A Case Report

The objective of immunosuppressive drugs used in solid organ transplantation is to achieve acceptable rejection rates, minimize infections, and prolong graft and patient survival. Cardiovascular disease is a major cause of death in kidney transplant recipients. The drugs commonly used to prevent rejection (calcineurin inhibitors [CNIs] and steroids) contribute to cardiac disease seen in transplant patients by increasing the risk of hypertension and diabetes. Direct cardiac toxicity of chemotherapeutic drugs such as doxorubicin is well-known but potential direct effect of CNIs on myocardium is less explored and understood. Cardiac toxicity a rare but serious adverse effect of tacrolimus, has been observed in patients receiving solid organ transplants such as liver, bowel and kidney. In this report, we describe a case of new onset severe dilated cardiomyopathy after kidney transplantation. Reversal of heart failure occurred after tacrolimus discontinuation and the switch to a mammalian target of rapamycin (mTOR) inhibitor: sirolimus.

Incorporating nonlinear kinetics to improve predictive performance of population pharmacokinetic models for ciclosporin in adult renal transplant recipients: A comparison of modelling strategies

BackgroundCiclosporin has been shown to follow nonlinear pharmacokinetics (PK) in renal transplant recipients who received ciclosporin (NeoralⓇ, Novartis)-based triple immunosuppressive therapy. Some of these nonlinear properties have not been fully considered in population PK (popPK) analysis. Therefore, the aim of this study was to determine the potential influence of nonlinearity and the functional forms of covariates on model predictability as well as to analyse multiple nonlinear factors in the in vivo process. MethodsA total of 2969 ciclosporin whole-blood measurements, including 1328 pre-dose and 1641 2-h post-dose concentrations, were collected from 173 patients who underwent their first renal transplantation. Four popPK models based on different modelling strategies were developed to investigate the discrepancy between empirical and theory-based, linear and nonlinear compartmental kinetic models and empirical formulae on model predictability. Prediction and simulation-based diagnostics (prediction-corrected visual predictive checks) were performed to determine the stability and predictive performance of these four models. ResultsModel predictability improved when nonlinearity was considered. The theory-based nonlinear model which incorporated nonlinear property based on known theoretical relationships performed better than the other two compartmental models. The nonlinear Michaelis-Menten model showed a remarkable improvement in predictive performance compared to the other three compartmental models. The saturated binding of ciclosporin to erythrocytes, auto-inhibition induced by the inhibitory effects of ciclosporin on cytochrome P450 3A4/P-glycoprotein may have contributed to the nonlinearity. Ciclosporin-prednisolone drug interaction should be given serious consideration in clinical settings. ConclusionsIncorporation of nonlinear properties is likely to be a promising approach for improving ciclosporin model predictability. Theory-based modelling is helpful to improve model predictability. However, ciclosporin nonlinear kinetics resources need further investigation.

Implementing an opioid reduction protocol in renal transplant recipients

BackgroundSix percent of opioid-naïve patients develop opioid dependence post-operatively. We implemented a protocol in our renal transplant recipients that eliminated opioid patient-controlled analgesia (PCA) and included a multi-modal non-opioid regimen. The purpose of this study was to examine the impact of PCA elimination on opioid requirements at discharge in renal transplant recipients. MethodsWe reviewed adult renal transplant recipients for the three months prior to, and following, the protocol’s implementation. Patients with an intra-abdominal transplant, pancreas-renal transplant, or chronic pain were excluded. The number of opioid pills prescribed on the day prior to discharge were categorized as A) 0, B) 1–3, and C) ≥4. Discharge opioid prescriptions were then evaluated based on a recent recommendation that group A receive 0 pills, group B 15 pills, and group C 30 pills, to satisfy the outpatient pain needs of 85% of patients. Pre- and post-intervention metrics were compared using independent t-tests and Chi squared tests. Results150 recipients were included (79 pre-intervention, 71 post; 51% male). PCA use decreased significantly (81% vs. 4.2%, p < 0.001). Post-intervention, gabapentin, topical lidocaine, and acetaminophen increased significantly (6.3%–69%, p < 0.001, 5.1%–66.2%, p < 0.001, 73.4%–93% respectively, p = 0.003.) PCA use did not impact the amount of opioids prescribed at discharge (median 75 OMEs in both groups). Of patients requiring no opioids on the day prior to discharge regardless of PCA use, 51.5% of pre- and 35.5% of post- were prescribed excess opioids at discharge. Of patients prescribed 1–3 pills on the day prior to discharge regardless of PCA use, 24.2% of pre- and 25.8% of post patients were prescribed excessive opioids at discharge. ConclusionsA multidisciplinary approach to developing an opioid-reducing protocol significantly decreased the use of PCAs and increased the use of non-opioid adjunct medications in renal transplant recipients. Patients continued to be prescribed excess opioids at discharge compared to inpatient opioid use the day prior to discharge. Ongoing communication with all providers caring for renal transplant recipients and protocolization of the different stages of a patient’s post-operative hospitalization are crucial.

P1685POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER (PTLD): SINGLE INSTITUTIONAL EXPERIENCE OF TWO DECADES

Abstract Background and Aims Post-transplant lymphoproliferative disorders (PTLD) are a group of heterogeneous lymphoid proliferations in chronic immunosuppressed recipients of solid organ and hematopoietic stem cell transplantation. Due to rarity of this disease, retrospective studies from transplant centers have been the main source to provide knowledge and treatment guidelines, which are still in evolution. This study examined the clinical outcomes and identified the predictors of mortality in adult renal transplant recipients who developed PTLD. Method We have studied the incidence of PTLD in adult renal transplant recipients who were transplanted in our hospital from 1996 to 2019. Data was collected for demographics, transplant and immunosuppression history, EBV and CMV serostatus, diagnosis, treatment and outcomes of PTLD. We performed univariate and multivariate analysis to identify prognostic factors. PTLD was classified according to 2018 WHO lymphoma classification. Results Twenty-four patients (12 males and 12 females) were eligible for the analysis. Mean age at time of the transplant was 43.1 ± 16.9 years, with a time between grafting and PTLD of 66 months (IQR 36-98 months). Mean follow-up time was 87 months (IQR 61-117 months). 25% of patients received a living donor renal transplant. 12,5% of patients received induction therapy with thymoglobulin. Mean age at time of PTLD diagnosis was 48,8 ± 17,9 years. Five cases were from Epstein-Barr virus (EBV) mismatched (D+/R-) transplants and there was seroconversion at time of PTLD diagnosis. 25% of patients had central nervous system involvement. 19 patients have monomorphic PTLD and the most common histological diagnosis was diffuse large B cell lymphoma. We identified that age &amp;gt;30 years at time of the transplant was predictor of mortality (HR 33.01; 95% CI: 3.24-336.14; p=0.003). Surprisingly, presence of B symptoms at time of PTLD diagnosis confer a better prognosis (HR 0,143; 95% CI: 0,035-0,579; p=0.006). All cases were managed with reduction in immunosuppression and converted to everolimus. 8 patients were treated with rituximab and there was no significant difference in the survival of these patients. By the end of follow-up, 7 patients went into remission, 1 returned to chronic dialysis, and 16 patients died (15 of them due to the disease). Mean time between PTLD and death was 3 months (IQR 1-6 months). Conclusion PTLD is an infrequent disease with a poor prognosis in renal transplant patients. Some cases have a close relationship with EBV, but it can also develop in the absence of the classical risk factors. The factor affecting mortality in our population was age &amp;gt;30 years at time of the transplant. Presence of B symptoms at time of PTLD diagnosis seems to confer a better prognosis probably due to early investigation and diagnosis of the disease.

Association between Posttransplant Opioid Use and Immunosuppressant Therapy Adherence among Renal Transplant Recipients

Introduction: Little is known about the effect of posttransplant opioid use on adherence to immunosuppressant therapy (IST) among adult renal transplant recipients (RTRs). Objective: The aim of this study was to examine the relationship between opioid use and IST adherence among adult RTRs during the first year posttransplant. Methods: Longitudinal data were analyzed from a retrospective cohort study examining US veterans undergoing renal transplant from October 1, 2007, through March 31, 2015. Data were collected from the US Renal Data System, Centers for Medicare and Medicaid Services Data (Medicare Part D), and Veterans Affairs pharmacy records. Dose of opioid prescriptions was collected and divided based on annual morphine milligram equivalent within a year of transplant. Proportion of days covered of greater than or equal to 80% indicated adherence to tacrolimus. Unadjusted and multivariable-adjusted logistic regression analyses were performed. Results: A study population of 1,229 RTRs included 258 with no opioid use, while 971 opioid users were identified within the first year after transplantation. Compared to RTRs without opioid usage, RTRs with opioid usage had a lower probability of being adherent to tacrolimus in unadjusted logistic regression (odds ratio [OR] (95% confidence interval [CI]): 0.22 [0.07–0.72]) and adjusted logistic regression (OR [95% CI]: 0.11 [0.03–0.44]). These patterns generally remained consistent in unadjusted and adjusted main and sensitivity analyses. Conclusions: Findings indicate RTRs who use prescription opioids during the first year posttransplant, regardless of the dosage/amount, are less likely to be adherent to tacrolimus. Future studies are needed to better understand underlying causes of the association between opioid use and tacrolimus nonadherence.

Characterization of Immune Phenotypes in Peripheral Blood of Adult Renal Transplant Recipients using Mass Cytometry (CyTOF)

Abstract Background Chronic immunosuppressive therapy in transplant patients can be associated with opportunistic infections and risks of cancer development. There is an important need to better measure the immune status of patients in a transplant setting to improve patient monitoring and guide development of appropriate immunosuppressive agents and regimen. Results In this study, CyTOF was performed to comprehensively characterize the immune differences between 10 renal transplant recipients and 11 age-matched healthy donors, longitudinally over 6 months. Overall, the immune cells of transplant patients showed signs of increased CD8+ T cell activation/differentiation. Higher levels of CD57 on CD8+ T cells were observed. CD8+ T cells and their memory subsets also showed increased production of MIP-1β and IFNγ. Further, CD107a and Granzyme B expression were also increased in CD8+ T cells and CD56hi NK cells, while Tregs had decreased IL-10 production. These changes are consistent with a more stimulated immune system, despite the administration of immune suppressants to the patients. However, there were also some signs of immune suppression in the transplant patients consistent with the treatment regimen. γδT cells showed decreased TNFα and IFNγ expression, while MIP-1β expression was reduced in NKT, CD56hi NK and γδT cells. CD8+ T memory cell subsets also showed decreased expression of IL-2, IL-17 and GM-CSF. Conclusions This mosaic pattern of functional changes highlights the importance of comprehensive immune monitoring of these patients. Such information will aid in optimizing individual treatment strategies and development of improved immunosuppressants that specifically target overly activated populations.

The necessity of voiding cystourethrogram for the evaluation of recipient candidates in adult renal transplantation

Objective . While international guidelines necessitate Voiding Cystourethrogram (VCUG) for pediatric patients, it is unnecessary for the evaluation of adult patients without urological disorders as renal transplant candidates. The objective of this study was to evaluate the results of adult candidates who underwent VCUG before transplantation and to demonstrate the necessity for this imaging. Methods . A retrospective study of the data of 1265 adult candidates who underwent VCUG before transplantation at our center, was undertaken. VUR, the presence of Postvoiding residual urine (PVR) (>100 ml), Low bladder capacity (LBC) (<100 ml), and urethral pathologies were evaluated with VCUG. Results . The mean age was 42.3 ± 1.3. The mean dialysis period was 27.8 ± 4.2 months. According to the VCUG results, 19.2% of the patients had pathological findings. On the other hand, the rate of urological disorders was only 5.1%, according to end-stage renal disease (ESRD) etiologies. VCUG outcomes indicated bilateral high-grade reflux in native kidneys in 4.4% (n = 56) of the candidates, unilateral high-grade reflux in 4.1% (n = 52), bilateral low grade reflux in 2.1% (n = 26), unilateral low-grade reflux in 2.4% (n = 30), and reflux in rejected transplanted kidney in 2.3% (n = 29). In addition, significant LBC was noted in 4.8% (n = 61), significant PVR in 1.1% (n = 14), and urethral stricture in 0.5% (n = 6) of the candidates. Conclusion . VCUG should be considered as a part of routine evaluation in adult renal transplant recipient candidates as well as in pediatric candidates, even if their ESRD etiologies are not due to urological disorders.

Adverse Events and Discontinuation Rates Associated with Sirolimus Treatment in Adult Renal Transplant Patients in Latin America vs Non–Latin American Countries

BackgroundSirolimus is approved for prophylaxis of organ rejection following renal transplantation. Rates of treatment-emergent adverse events (TEAEs) leading to sirolimus discontinuation differ geographically. MethodsRates of TEAEs, serious AEs (SAEs), and discontinuations were evaluated in 3 clinical trials of conversion from calcineurin inhibitors to sirolimus. Posttransplantation, patients were treated over 4 years (study 1), over 1 year (study 2), and over 2 years (study 3). TEAEs, SAEs, and discontinuation rates were compared between Latin America (LATAM) vs North America (NA) and Europe/rest of world (EU/ROW). Data from studies 2 and 3, with similar times to conversion, were pooled. ResultsStudy 1 comprised 551 patients (LATAM, n=189); studies 2/3 comprised 395 (LATAM, n=111). LATAM patients were significantly younger than NA or EU/ROW patients in study 1 and studies 2/3 (P < .0001), with a lower proportion of white patients and higher proportion of patients of other races in LATAM vs NA (P < .0001) and EU/ROW (P = .02) groups. Almost all patients reported TEAEs. Discontinuation because of medical events was significantly lower (P < .05) in LATAM vs NA or EU/ROW. Hypercholesterolemia and hypertriglyceridemia were more common, and anemia and peripheral edema less common in LATAM; diarrhea and proteinuria did not differ by region. Types of AEs leading to discontinuation did not differ by region. ConclusionLATAM renal transplant recipients converted to sirolimus were more likely to remain on therapy than patients in other regions.

SUN-294 IMPACT OF POST-TRANSPLANT INFECTIONS ON LONG TERM OUTCOMES OF RENAL ALLOGRAFT RECIPIENTS

Post Transplant Infections (PTI) are a major cause of morbidity in the form of graft loss and mortality in renal transplant recipients. Infections account for the major cause of death of the patients with functioning graft in developing Asian countries. A number of factors in the pre and peri transplant period increase the susceptibility to post-transplant infections affecting the overall graft and patient survival. The aim of this study is to analyze the epidemiology of infectious episodes; their risk factors in adult renal transplant recipients and to evaluate their long term graft and patient outcomes. An observational study of 644 adult renal transplant recipients(=>18years) between Jan 2010 and Dec 2015 followed till Jun 2019. The number, site, and treatment of infections were noted in each case. The risk factors for post-transplant infections were also analyzed. The outcomes in terms of graft survival and patient survival on subsequent follow-up were also analysed. Kaplan Meier survival analysis was used to compare the outcomes in patients with and without infection. PTI were seen in 83.1%; a majority (64%) occurred in the first year. Of all infections; 55.5% were bacterial; 18.5% viral; 10.8% parasitic; 8% fungal; and remaining 7.1% mycobacterial. UTI (37.4%) was most common with E. Coli (18.9%) being the commonest. Relative risk with PTI for graft dysfunction was 4 times higher (95%CI 3.5-6.6; p<0.01); graft loss was 3 times higher (95%CI 1.4-6.1; p<0.01) and death was 3 times higher (95%CI 1.3-8.1; p=0.01) as compared to non PTI. Recurrence of PTI had 2 times higher risk of graft dysfunction (95%CI 1.2-3.1; p<0.01) and 3 times higher risk of graft loss (95% CI 1.9-5.0; p=0.00). On multivariate analysis; the predictors of PTI were ATG induction (p<0.01), pre-transplant tuberculosis (p=0.02) and dialysis vintage (p=0.02). On KM survival analysis; graft and patient survival with inferior with PTI as compared to non-PTI. The 1-, 5-and 9-years graft survival with PTI was 94.6%;81.7%;70.3% and non PTI 98%; 92.2%; 90%; p=0.004 respectively; and patient survival with PTI 97.9%;88.2%;81.9% and non PTI 98.3%; 95.2%; 92.9%;p=0.012 respectively. Post-transplant infections fungal infections, in particular, had a significant impact on long term graft loss and mortality in renal transplant recipients. The predictors of PTI were ATG induction, pre-transplant Tuberculosis, and dialysis vintage.

Bleeding Complications and Adverse Events After Desmopressin Acetate for Percutaneous Renal Transplant Biopsy

Percutaneous renal biopsy remains critical for the workup of renal allograft dysfunction but is associated with the risk of bleeding. Prophylactic intravenous desmopressin has been proposed to reduce bleeding risk in native renal biopsies, but its efficacy in the renal transplant population is unclear and adverse events such as severe hyponatraemia have been reported. We conducted a single-centre retrospective cohort study involving adult (≥21 years old) renal transplant recipients with impaired renal function (serum creatinine ≥150 µmol/L) who underwent ultrasound-guided renal allograft biopsies from 2011‒2015 to investigate the effect of prebiopsy desmopressin on the risk of bleeding and adverse events. Desmopressin was administered to 98 of 195 cases who had lower renal function, lower haemoglobin and more diuretic use. Postbiopsy bleeding was not significantly different between the 2 groups (adjusted odds ratio [OR] 0.79, 95% confidence interval [CI] 0.26‒2.43, P = 0.68) but desmopressin increased the risk of postbiopsy hyponatraemia (sodium [Na] <135 mmol/L) (adjusted OR 2.24, 95% CI 1.10‒4.59, P = 0.03). Seven cases of severe hyponatraemia (Na <125 mmol/L) developed in the desmopressin group, while none did in the non-desmopressin group. Amongst those who received desmopressin, risk of hyponatraemia was lower (OR 0.26, 95% CI 0.09‒0.72, P = 0.01) if fluid intake was <1 L on the day of biopsy. Prophylactic desmopressin for renal allograft biopsy may be associated with significant hyponatraemia but its effect on bleeding risk is unclear. Fluid restriction (where feasible) should be recommended when desmopressin is used during renal allograft biopsy. A randomised controlled trial is needed to clarify these outcomes.