Frequency Of Acute Rejection Research Articles

Factors Associated With Recurrence of Underlying Diseases Among Liver Transplant Recipients: A Single-Center Study.

The recurrence of underlying diseases remains a major cause of graft failure after liver transplant. This study aimed to identify factors associated with the recurrence of underlying diseases and investigate the incidence of these factors and recurrence at the main liver transplant center in Iran. We included adult liver transplant recipients followed at Shiraz Transplant Center between 2011 and 2018 with a confirmed diagnosis of recurrence of underlying disease in our study. We reviewed medical records and extracted data on demographic characteristics, clinical and paraclinical features, medication use, and current status. We used a systematic random sampling method to select a control group of 95 transplant recipients who did not have recurrence. Of 3022 total transplant recipients, 76 recipients experienced a recurrence of their underlying disease. Model for End-Stage Liver Disease score, underlying disease, recipient blood group, donor sex, donor blood group, and rejection frequency were significantly different between study groups with and without recurrence of underlying diseases. Liver transplant recipients with recurrence had lower mean Model for End-Stage Liver Disease score. Recipients with recurrence also had higher rate of drug consumption (eg, prednisolone, tacrolimus, mycophenolate mofetil, sirolimus). Regression analysis showed that donor sex and rejection frequency had an effect on disease recurrence. Death occurred more frequently in liver transplant recipients with recurrence than in the control group (39.5% vs 26.3%), butthe difference was not significant. Donor sex and acute rejection frequency are independent factors predictive of the recurrence of underlying disease. Modifying risk factors can help minimize the recurrence of underlying diseases after liver transplant.

Factors Associated with Chronic Rejection in Liver Transplant Recipients: A Retrospective Cohort Study From Shiraz Organ Transplant Center.

Identification of chronic rejection risk factors in liver transplant recipients is critical for early detection and prevention of further graft loss. We investigated characteristics of liver transplant recipients who had experienced chronic rejection and the associated risk factors versus patients without chronic rejection. Data from 3022 adult liver transplant recipients between 2011 and 2018 were analyzed; of these, 80 patients had experienced chronic rejection. The control group included 98 randomly selected liver transplant recipients who did not have chronic rejection. The age of the recipients and the donors was significantly lower in the group with chronic rejection versus the group without chronic rejection.The results indicated that chronic rejection was significantly associated with the sex of the recipients (hazard ratio 3.2, 95% CI 1.77-6.08; P < .001) and with the sex concordance between the recipients and donors (hazard ratio 2.93, 95% CI 1.67-5.13; P < .001, respectively). Also, in the group without chronic rejection, there were no male donors; however, the group with chronic rejection had mostly male donors (P <.001). Cold ischemia time was longer in patients with chronic rejection versus that shown in the control group (P = .031), and there was a significant difference between the 2 groups in acute rejection frequency (P < .001). Recipient sex and sex concordance were independent risk factors for chronic rejection. Most transplantrecipients with chronic rejection responded to medicaltreatment, and the rate of graftloss was low among our recipients.

Clinical Outcomes of Transplanted Kidneys from Deceased Donors Using Different Generic Preservation Solutions.

Background and Objectives: StoreProtect Plus® is a preserving solution for cold organ storage, with a composition identical to Institute Georges Lopez (IGL-1) solution. The aim of this single center study was to compare the clinical performance of StoreProtect Plus with the generic counterpart of University of Wisconsin preservation fluid, named SPS-1®. Materials and Methods: The clinical outcomes of 168 consecutive organs preserved with StoreProtect Plus solution and 167 organs preserved with SPS-1 solution were compared. During an 18-month post-transplant follow-up period, kidney graft function, the frequency of acute rejection, post-transplant diabetes, and infectious complications, as well as patient and graft survival were analyzed. Results: There was significantly more immediate graft function (IGF) (39.3 vs. 24.0%; p &lt; 0.01) and less slow graft function (SGF) (38.7 vs. 51.5%; p &lt; 0.05) in the StoreProtect Plus group in comparison with the SPS-1 group, whereas the occurrence of DGF was similar in both groups. Long-term kidney graft function was comparable. Multivariate regression analysis showed that the use of StoreProtect Plus vs. SPS-1 solution (rpartial = 0.217; p &lt; 0.001) and the amount of residual diuresis (rpartial = 0.147; p &lt; 0.001) independently increased the occurrence of IGF, whereas Scr &gt; 1.5 mg/dL prior to organ procurement (rpartial = -0.198; p &lt; 0.001), longer CIT (rpartial = -0.170; p &lt; 0.01), and CVD donor death (rpartial = -0.214; p &lt; 0.001) were associated with SGF. Conclusions: The higher occurrence of IGF was found in kidney transplant recipients whose organs were preserved using StoreProtect Plus solution as compared with SPS-1 solution. The two groups did not differ in kidney graft function, the frequency of post-transplant complications, as well as patient and graft survival.

Encouraging outcomes of using a small-donor single graft in pediatric kidney transplantation.

The use of small pediatric kidneys as single graftsfor transplantation is controversial, due to the potential risk for graft thrombosis and insufficient nephron mass. Aiming to test the benefits of transplanting these kidneys, 375 children who underwent kidney transplantation in a single center were evaluated: 49 (13.1%) received a single graft from a small pediatric donor (≤ 15kg, SPD group), 244 (65.1%) from a bigger pediatric donor (> 15kg, BPD group), and 82 (21.9%) from adult living donors (group ALD). Groups had similar baseline main characteristics. After 5years of follow-up, children from the SPD group were comparable to children from BPD and ALD in patient survival (94%, 96%, and 98%, respectively, p = 0.423); graft survival (89%, 88%, and 93%, respectively, p = 0.426); the frequency of acute rejection (p = 0.998); the incidence of post-transplant lymphoproliferative disease (p = 0.671); the odds ratio for severely increased proteinuria (p = 0.357); the rates of vascular thrombosis (p = 0.846); and the necessity for post-transplant surgical intervention prior to discharge (p = 0.905). The longitudinal evolution of eGFR was not uniform among groups. The three groups presented a decrease in eGFR, but the slope of the curve was steeper in ALD children. At 5years, the eGFR of the ALD group was 10ml/min/1.73m2 inferior to the others. At that time, the eGFR from the SPD group was statistically similar to the BPD group (p = 0.952). In a specialized transplant center, the use of a single small pediatric donor kidney for transplantation is as successful as bigger pediatric or adult living donors, after 5years of follow-up. A higher resolution version of the Graphical abstract is available as Supplementary information.

New markers for predictions of acute and chronic rejection and graft outcomes in kidney transplant recipients; HLA-G gene 3'UTR 14bp polymorphism and sHLA-G.

The aim of this study was to evaluate the relation of Human Leukocyte Antigen-G (HLA-G) 14bp ins/del (insertion/deletion) polymorphism and soluble HLA-G (sHLA-G) level with rejection in kidney transplant recipients. The study was planned as a case-control study involving two hundred fifty kidney transplant recipients. The case group consisted of 125 (female/male: 56/69) kidney transplant recipients diagnosed with acute (n=52) and chronic rejection (n=73). The control group consisted of one hundred twenty-five kidney transplant patients with no acute or chronic rejection matched by gender and age in the case group. The sHLA-G level in the recipient's plasma (at the time of rejection for the case, the same time as the case after the transplant for control) was analyzed by Enzyme-Linked Immunosorbent Assay (ELISA). HLA-G 3' untranslated region (3'UTR) polymorphism of recipient and donor was determined using agarose gel electrophoresis and DNA sequencing method. In our study, it was shown that acute rejection rate increased 1.06 times and chronic rejection rate increased 1.14 times in kidney transplant recipients with low serum sHLA-G levels. The rejection patients with the HLA-G 14bp del/del genotype had higher sHLA-G levels post-transplantation. The frequency of acute rejection was lower in patients with HLA-G 14bp del/del polymorphism than those with ins/ins and ins/del polymorphisms. This study proposes that HLA-G 3'UTR polymorphism and sHLA-G level might be useful in prediction of rejection in kidney transplant recipients.

The Effect of Different Induction Therapies on Graft Functions in Renal Transplantation

Introduction: Rejection and delayed graft function (DGF) are frequent problems after renal transplant. The use of induction therapies increases graft survival and reduces acute rejection frequency. Here, we wanted to see one-year outcomes of patients who did not receive induction therapy and those who received basiliximab or anti-thymocyte globulin (rabbit) (rATG). Patients and Methods: 741 renal transplant recipients were divided into 3 groups: 223 patients who received rATG, 213 who received basiliximab, and 305 patients who did not receive any induction therapy. Patients’ demographic characteristics, ischemia times, creatinine levels, presence of DGF and acute rejection were studied. Results: 35.6% (n=264) of the patients were female and 64.4% (n=477) were male; their ages were 4 to 72 years. During follow-up, 27 (3.6%) patients had DGF and 152 (20.5%) had acute rejection. There was no difference in DGF and rejection between the 3 groups. Conclusion: Although there wasn’t statistically difference in DGF, acute rejection, or 1- year creatinine levels between groups, the rATG group had higher hemodialysis rate, longer dialysis time, lower rate of preemptive transplantation, and lower mean age.

Protective Role of ECMO on Reperfusion Injury and Acute Rejection in Lung Transplantation: A Pathological Analysis

Purpose The routine utilization of intraoperative extracorporeal membrane oxygenation (ECMO) in lung transplantation is recently extensively investigated for its protective role, especially on reperfusion injury. The purpose of this study is to compare pathological features on pre and post-reperfusion biopsies and on 30 and 90-days surveillance trans-bronchial biopsies in lung transplantations performed with or without ECMO support to assess its protective role on the graft Methods 51 patients (13 with ECMO support, 38 without ECMO support) underwent bilateral lung transplantation at our Institution between 2012 and 2019. Only patients on ECMO at time of anesthetic induction or before the first clamping of the pulmonary artery were included. Patients submitted to graft volume reduction before lung reperfusion were excluded from the analysis.Intra-operative pre and post-reperfusion biopsies were collected to analyze edema, leucocyte margination and congestion/extravasation (score 0-3). The presence of acute rejection (grade A0-3, grade B0-2) diffuse alveolar damage (DAD), organizing pneumonia (OP) on 30 and 90-days trans-bronchial surveillance biopsies was also compared in the two groups. Results No significant differences were found between the two groups in terms of edema, leucocyte margination and congestion in pre reperfusion biopsies. On post reperfusion biopsies, leucocyte margination was significantly less frequent in ECMO group (46% vs 76%; p=0.043). A lower frequency of acute rejection (grade A0-3) was also found in the ECMO group on 30-days biopsies (25% vs 58%, p=0.047). Conclusion In conclusion, this analysis does not show significant differences between the two groups except for a lower frequency of leucocyte margination at post-reperfusion biopsies and acute rejection at 30-days biopsies in the ECMO group. Other studies, with a larger population, are needed in order to evaluate whether the positive clinical impact of using ECMO as a prevention of reperfusion edema after lung transplantation can also be explained by a defined pathological picture

Acute rejection and growth outcomes in paediatric kidney allograft recipients treated with a corticosteroid minimisation immunosuppressive protocol.

Corticosteroid minimisation immunosuppressive protocols (CMP) for children are an approach to safely reduce unwanted medication side effects associated with long-term exposure following kidney transplantation. Here, we provide data regarding the incidence of acute rejection and growth over an extended follow-up in children receiving the CMP used in our centre. We retrospectively analysed all children treated with a CMP who received a kidney transplant and had follow-up care in our centre between 2009 and 2019. Data were compared to 5 control groups from recent studies. Ninety-nine kidney allograft recipients were included in the study (mean follow-up 4.4 years). There was no difference in the cumulative frequency of acute rejection in CMP-treated graft recipients compared to controls. Graft function at latest follow-up was significantly lower in graft recipients experiencing acute rejection compared to those without acute rejection (53.7 mL/min/1.73 m2 vs. 66.8 mL/min/1.73 m2, p = 0.021). Children experiencing >1 acute rejection episode had a greatly elevated risk of graft failure (p = 0.0009, OR 68.25). At latest follow-up, 64/90 (71.1%) graft recipients had a normal height, and younger graft recipients demonstrated greater catch up growth than older children. CMP-treated graft recipients showed a reduced rate of height deficit (28.9% vs. 55.1%, p = 0.0025), less obesity (12.2% vs. 23.9%, p = 0.031), and reduced rates of hypertension (35.4% vs. 68.2%, p< 0.0001). Children treated with a CMP show greater height attainment, lower frequency of obesity, and reduced rates of hypertension, without an increased risk of acute rejection. Graphical abstract.

Diagnosis of Acute Rejection of Liver Grafts in Young Children Using Acoustic Radiation Force Impulse Imaging.

OBJECTIVE. Frequency of acute rejection (AR) after pediatric liver transplant remains high despite progress in immunosuppression. Liver biopsy (LB) is the reference standard for the diagnosis of AR despite its potential for morbidity. The purpose of our study was to evaluate the ability of acoustic radiation force impulse (ARFI) imaging to distinguish AR from other causes of short- and medium-term liver dysfunction and to identify liver transplant cases with normal liver function. MATERIALS AND METHODS. ARFI imaging was used to evaluate shear wave velocity (SWV) after liver transplant in young children. All pediatric liver grafts that had LB and ARFI examination between January 2014 and December 2017 were included in this retrospective study. Results of LB were compared with those of SWV. Collected data included age at biopsy and transplant, sex, weight, height, body mass index, interval between liver transplant and shear wave elastography and LB, kind of graft, type of donor, and diagnosis at transplant. ROC curve analysis was performed to assess the diagnostic performance of SWV. Optimal cutoff of SWV using ARFI imaging in predicting AR was identified using the Youden index. RESULTS. Statistical analysis was performed on 54 children; six of the original 60 were excluded because of confounding alterations or changes in outcome. Median SWV was higher in patients with AR (2.03 m/s; interquartile range [IQR], 1.80-2.45 m/s) compared with those with idiopathic hepatitis (1.33 m/s; IQR, 1.12-1.53 m/s), portal hypertension (1.42 m/s; IQR, 1.32-1.72 m/s), cholangitis (1.56 m/s; IQR, 1.07-1.62 m/s) or normal liver function (1.23 m/s; IQR 1.12-1.29 m/s) at protocol biopsies (all comparisons, p < 0.01). SWV higher than 1.73 m/s was predictive for AR (AUC, 0.966). SWV also showed good diagnostic accuracy in normal liver function (AUC, 0.791). ARFI imaging was not predictive for hepatitis (AUC, 0.402), portal hypertension (AUC, 0.556), or cholangitis (AUC, 0.420). CONCLUSION. ARFI imaging could be routinely used in place of LB in pediatric patients with liver dysfunction after liver transplant, restricting indication and risks of biopsy to selected cases.

P0408KIDNEY TRANSPLANTATION OUTCOMES IN PATIENTS WITH IGA NEPHROPATHY IN THE MODERN ERA OF IMMUNOSUPPRESSION: A CASE CONTROL STUDY

Abstract Background and Aims Advances in immunosuppressants, used for kidney transplantation (KTx) have significantly improved outcomes in this field. We aimed to compare the long-term results of KTx in recipients with IgAN, as cause of end stage kidney disease (ESKD), with those of patients, with non-glomerular causes of renal failure, during the modern era of immunosuppression for KTx. Method This is a retrospective, case control study, in which were included patients who received a KTx after 2000. Patients were eligible to be included, if they had IgAN in a native kidney biopsy specimen and follow up longer than 1 year after KTx. IgAN patients were compared to a control-group of patients with non-glomerular primary causes of ESKD matched for age, gender, date of KTx and donor source. Graft biopsies were performed by clinical indication. Patients with ABO incompatible KTx, preemptive KTx, re-KTx, PRA&amp;gt;50%, major surgical complications during the 1st post-KTx month or non-compliance were excluded from the analysis of outcome. Primary outcomes of interest included graft function, patient and graft survival at end of follow up. The rate of IgAN recurrence in the graft and its impact in renal function and survival were also recorded. Computed GFR was calculated using the Modification of Diet in Renal Disease formula. Results A total of 102 KTx recipients with biopsy-proven IgAN, were compared to 204 controls with non-glomerular causes of ESKD. The mean age of patients with IgAN was 43.2(±10.15) years and 68(66.7%) were men. The mean time in dialysis was 50.2(±48.7) months and 59(57.8%) of them received a graft from a living donor. The mean cold ischemia time was 17.5(±6.7) hours, while 22(21.6%) of patients experienced delayed graft function. 97.05% of patients received induction therapy with an anti-CD25 inhibitor and 99.3% were maintained with a triple immunosuppressive regimen consisted of a mycophenolate mofetil formulation, a calcineurin inhibitor and glucocorticoids. The mean serum creatinine and eGFR at end of follow up were significantly lower for the IgAN group (p=0.001 and p=0.02 respectfully) with no difference in the frequency of acute rejection. However, graft and patient survival were not different even after controlling for follow up longer than one decade. During a mean follow up time of 120.8(±49.1) months, IgAN recurrence in the graft was documented in 23(22.5%) patients. The mean time to recurrence was 47.8(41.8) months, with a mean serum creatinine 1.83(±0.52) mg/dl and eGFR of 43.45(±18.4) ml/min/1.73m2 at the end of follow up. Within the IgAN group, although graft function was significantly lower in patients with disease recurrence, compared with that of patients without recurrence (p=0.003), graft loss remained not different between these two subgroups (p=0.49). Conclusion In the newer era of immunosuppression, long-term outcomes of KTx in patients with IgAN, as primary disease, appear significantly improved, and although graft function was significantly lower in patients with IgAN at the end of follow up, graft and patient survival was not different, compared to patients with non-glomerular causes of ESKD. Recurrence of IgAN in the graft was documented in 22.5% of patients and was associated with significantly lower eGFR at end of follow up compared to patients without recurrence but it did not impact graft survival in this time period.

P5414Factors influencing mortality in a long-term follow-up after heart transplantation; role of immunomonitoring

Abstract Background Despite relevant improvements in the last years, increased mortality limits the success of heart transplantation therapy. Although many factors influencing mortality have been identified, the most studies analyzed relatively short follow-up time following heart transplantation. Purpose Therefore, the aim of our present study was to evaluate risk factors for enhanced mortality with emphasis on quantitative changes in immunological blood cells late after heart transplantation. Methods 174 patients with a mean time after heart transplantation of 13.1±6.5 years were retrospectively analyzed using data collected during follow-up visits in our center. Clinical examinations, results of laboratory tests, including immunomonitoring of CD4+, CD8+, CD19+ cells and natural killer cells, ultrasound vessel visualization and coronary angiography were evaluated with respect to the all-cause mortality. Results In patients who were still alive at the time of data analysis (group 1, n=134), glomerular filtration rate, erythrocyte count, hemoglobin and mean corpuscular hemoglobin concentration were significantly increased compared to the group encompassing patients who died before this time point (group 2, n=40) (p&lt;0.05 for all). In contrast, c- reactive protein (CRP), leukocyte count, triglycerides and N-terminal pro-brain natriuretic peptide were significantly decreased in group 1 versus group 2 (p&lt;0.05 for all). In the first group the patients were relevantly less frequently on dialysis, presented lower NYHA classes, later onset of cardiac allograft vasculopathy and received hearts from donors with lower body mass (p&lt;0.05 for all). Additionally, patients from the first group were characterized by significantly higher CD4 and lower CD8 percentages as well as a tendency towards higher CD19 cell count. In a multivariate cox regression analysis CD4 percentage (hazard ratio (HR): 0.454, confidence interval (CI): 0.236–0.871; p=0.018), onset of cardiac allograft vasculopathy (HR: 0.422, CI: 0.190–0.941; p=0.035) and CRP (HR: 0.325, CI: 0.170–0.621; p=0.018) were independent risk factors for increased mortality. Conclusions Increased inflammation, anemia, renal and heart insufficiency, early onset of cardiac allograft vasculopathy, worse functional status and donor associated factors such as higher body mass correlated significantly with enhanced mortality among patients after heart transplantation. In contrast to the early phase following heart transplantation, where the suppression of CD4+ cell number contributes to the decrease in the frequency of acute rejections, aggressive reduction of CD4+ cells by high doses of immunosuppressive agents late after cardiac transplantation may augment risk of mortality. It may be explained due to the creation of a subclinical chronic immunosuppressive condition and potentiation of side effects of immunosuppressive drugs.

Pre-transplant CD200 and CD200R1 concentrations are associated with post-transplant events in kidney transplant recipients.

CD200 is an immunoglobulin superfamily membrane protein that binds to a myeloid cell-specific receptor and induces inhibitory signaling. The aim of this study was to investigate the role of CD200 and its receptor (CD200R1) on kidney transplant (KTx) outcome. In a collective of 125 kidney recipients (University hospital, Heidelberg, Germany), CD200 and CD200R1 concentrations were evaluated immediately before transplantation. Recipient baseline and clinical characteristics and KTx outcome, including acute rejection (AR), acute tubular necrosis, delayed graft function, cytomegalovirus (CMV) and human polyomaviridae (BK) virus infections, and graft loss were evaluated during the first post-transplant year. The association of CD200 and CD200R1 concentrations and CD200R1/CD200 ratios with the outcome of KTx was investigated for the first time in a clinical setting in a prospective cohort. There was a positive association between pre-transplant CD200R1 concentrations and CMV (re)activation (P = .041). Also, increased CD200R1 concentration was associated with a longer duration of CMV infection (P = .049). Both the frequency of AR and levels of creatinine (3 and 6 months after KTx) were significantly higher in patients with an increased CD200R1/CD200 ratio (median: 126 vs 78, P = .008). Increased pre-transplant CD200R1/CD200 ratios predict immunocompetence and risk of AR, whereas high CD200R1 concentrations predict immunosuppression and high risk of severe CMV (re)activation after KTx.

Some Aspects of Aging Are Advantageous: Elderly Organ Recipients May Get Away With Less Immunosuppression

Aging impacts health care broadly. In organ transplantation, most patients currently waiting for an organ transplant are older than 55 years, with >20% of transplant recipients being over the age of 65.1 Demographic changes are also relevant for the deceased donor population with approximately 20% of donors being older than 50 years and approximately 5% >65 years old.2 Markedly are geographic differences with close to 50% of donors being older than 60 years in Spain.3 Although relevance and necessity of age-specific aspects of immunosuppression in the elderly have been recognized, clinical immunosuppressive trials in organ transplantation have mostly excluded older patients. The aging immune system is characterized by reduced amounts of naïve T cells because of limited thymic outputs, an accumulation of less effective memory T cells, and a constricted T-cell receptor repertoire. Additional age specifics of T-cell metabolisms have started to be appreciated. The effects of immunosenescence on B-cell responses are less well understood. The efficacy of B cells may be influenced through compromised T cell function, with additional limitations in class switch recombinations playing a role.4 Clearly, understanding immunosuppression in the elderly is of clinical relevance. It is important to understand that an optimization of immunosuppression in aging may not be as simple as applying less of the same immunosuppression. Immunosuppressants that work effectively in young recipients may operate differently in the elderly. Tacrolimus, for example, has been more efficient at lower doses with age-specific effects based on lower calcineurin levels in older human CD-4 T cells. Moreover, mammalian target of rapamycin inhibition has been more effective in experimental models with reduced proinflammatory interferon-γ production and augmented amounts of interleukin (IL)-10 by old CD4+ T cells.5 Studying age-specific aspects of clinical immunosuppression appears, therefore, timely and relevant. While previous studies have compared the application of the polyclonal antibody Thymoglobulin (ATG) and Basiliximab (BSX) targeting the IL-2 receptor on activated T cells as induction treatments, those regimens have not been compared in the elderly. Masset et al6 from France showed that both ATG and BSX were effective in immunological low risk older (≥65 y) recipients. Three-year graft survival was different (74% for ATG- and 68% for BSX-treated recipients), however, not reaching statistical significant difference. BSX-treated patients also had higher rates of acute T-cell–mediated rejections. As the most prominent finding of this study, the occurrence of posttransplant diabetes (PTD) had been significantly higher in BSX compared to ATG-treated recipients (23% versus 15%, P = 0.04), potentially related to higher tacrolimus trough levels in the BSX group (BSX 9.48 versus ATG 7.30 ng/mL, P = 0.023). As T-cell–mediated rejections had been significantly higher in BSX-treated recipients, those patients may have also had an additional corticosteroid burden. A few additional aspects, including center-specific approaches of protocol versus for-cause biopsies and an overall small cohort, need to be contemplated. Moreover, conclusions of this study are based on a retrospective analysis with a broad center-specific variance of immunosuppressive treatments and only a small albeit significant difference for the incidence of PTD. Do those results confirm that less is more when it comes to immunosuppression in the elderly, or are there additional aspects to consider? We have come to understand that alloimmunity is determined by the sum of recipient’s alloimmune responses. The immunogenicity of the graft itself is playing an additional role. In aging, this constellation appears of particular relevance: older organs elicit more frequent acute rejections linked to activated intragraft dendritic cells.7-9 Remarkably, the frequency of acute rejections when transplanting older organs is blunted when older organs are transplanted into older recipients. Of additional clinical relevance, older recipients are more likely to receive an older organ that is, in turn, more likely to develop a delayed graft function,10 emphasizing the importance to postpone the initiation of calcineurin inhibitors. Immunosuppressive protocols for the elderly will thus need to have those complexities in mind. Although more frequent rates of PTD may very well be linked to increased tacrolimus trough levels, this finding may not necessarily make an argument for a BSX induction in elderly transplant recipients. A reduced Thymoglobulin dosage in parallel to a reduced tacrolimus dosage, initiated days after transplantation, may be a preferable alternative. Masset et al6 have helped us to focus on the elderly in transplantation with the goal to work toward an optimized immunosuppression in this growing transplant population. Future prospective immunosuppressive studies in the aging population with an additional detailed evaluation of alloimmune responses may provide further clarification for a clinically pressing problem in organ transplantation (Figure 1).FIGURE 1.: Future immunosuppressive trials in the elderly may address dosing of established immunosuppressants in addition to age-specific effects and alloimmune responses. ATG, antibody thymoglobulin.

The carnitine-butyrobetaine-TMAO pathway after cardiac transplant: Impact on cardiac allograft vasculopathy and acute rejection

Alterations in the partly microbiota-dependent carnitine-γ-butyrobetaine (γBB)-trimethylamine N-oxide (TMAO) pathway have been linked to the progression of heart failure and atherosclerotic disease. We evaluated if circulating γBB, TMAO, and their common precursors carnitine and trimethyllysine (TML) were dysregulated after heart transplantation and associated with development of cardiac allograft vasculopathy (CAV) and acute rejection. We measured these metabolites in plasma from heart transplant recipients with everolimus-based (n = 32) and standard cyclosporine-based immunosuppression (n = 30) at different time-points and accompanied by assessment of CAV by intravascular ultrasound. Baseline levels of carnitine, TMAO, and TML were elevated in heart transplant recipients compared with controls, and TML remained elevated throughout the observation period. The microbiota-dependent metabolite γBB increased steadily during 3 years of follow-up, with a similar decrease in its endogenous precursor TML. The increase in γBB and the change in TML were associated with a change in total atheroma volume from baseline to 3 years. Increases in γBB and carnitine levels from baseline to 1 year were associated with an increased frequency of acute rejection within the first year after heart transplant. Our study reveals alterations of the carnitine-γBB-TMAO pathway after heart transplant, with increasing levels of γBB being associated with acute rejection and increase in total atheroma volume during 3 years of follow-up. Future studies should clarify whether interactions between dietary factors, immunosuppressive drugs, and the gut microbiota could influence acute rejection and CAV development to delineate mechanisms and potential novel treatment targets.

Endomyocardial Biopsy after Heart Transplantation. When is Too Late?

Purpose Endomyocardial biopsy (EMB) remains the gold standard for the diagnosis of graft rejection after heart transplantation (HT). The exact time point at which the first EMB could be safely performed varies between centers and the majority performs the first EMB within 7 days after HT. Our purpose was to evaluate the frequency of acute rejection after HT at the first EMB performed later than usual protocols. Methods Retrospective study that evaluated first EMB results in patients after HT from January 2013 to December 2017 at Heart Institute. Acute rejection was defined as the grade ≥2R according to the International Society for Heart and Lung Transplantation. Demographic data and immunosuppressive drugs at the time of EMB were collected. Continuous variables were expressed as media ± standard deviation. Results We analyzed 168 patients who performed the first EMB. The majority was male (61.9%) and the mean age was 48.1±12.8 years. No patients received induction immunosuppressive therapy. The mean time for the first EMB was 13.9 + 6.7 days. Forty-six (27.4%) episodes of cell-mediated acute rejection (> 2R) and 7 (4.2%) episodes of antibody-mediated acute rejection were identified. The time for the first EMB in the group that had rejection was 11.59±3.7 days and in the group without rejection was 14.7±7.4 days (p= 0.01). 30-day mortality was 3 (2.5%) in no rejection group and in 0 in rejection group whitout statistical difference (p: 0.283). Conclusion Our analysis reveals that despite late (after 10 days) first EMB, the frequency of acute rejection is similar to previous reported even without an induction immunosuppressive therapy. In addition, the presence of acute rejection in the first biopsy did not increase mortality in the first 30 days. The study suggests that this approach is safe and should be further evaluated in order to adopt a less invasive protocol.

Investigation of the Factors Affecting Allograft Kidney Functions: Results of 10 Years

IntroductionSignificant improvements in patient and graft survival and reductions in the frequency of acute rejection were obtained in the early period after renal transplantation, but this success was not sufficiently reflected in the long term. Allograft kidney losses in the long term remain a significant problem. In this study, we investigated the specific causes of graft losses in patients who had a good clinical course in the first year but developed graft loss in the long term. MethodsA total of 118 patients who underwent kidney transplantation in 2005 and 2006 in the Organ Transplantation Center of Ege University Medical Faculty Hospital were evaluated. The inclusion criteria were to be older than 18 years and have a serum creatinine value of <2 mg/dL at the 12th month after transplantation. ResultsSixty-one percent of the recipients were male, and the mean age at the time of transplantation was 34 ± 11 years (18 to 61). We observed 29 graft losses during the mean follow-up period of 129 ± 35 months (27 to 162). Three of the graft losses were death by functional graft. Of the 26 patients with graft loss, 16 had chronic rejection, and 8 had recurrent glomerulonephritis. The relationship between nonimmune causes and graft loss was not detected. ConclusionsIn conclusion, nonimmune factors may not be as important as we think in relatively young and healthier recipients. Chronic rejection and recurrent glomerulonephritis are the main causes of long-term graft loss of patients with good graft function at the end of the first year. Improvement of long-term survival will be possible with the prevention and effective treatment of these 2 problems.

High-Dimensional Renal Profiling: Towards a Better Understanding of Renal Transplant Immune Suppression

The goal of this review is to discuss new approaches to avoid CNI/CCS toxicities with a focus on new biologics and new methods to understand transplant rejection at the single-cell level. Recently developed biologics hold significant promise as the next wave of therapeutics designed to promote CNI/CCS-free long-term allograft acceptance. Indeed, belatacept, soluble CTLA4-Ig, is largely devoid of CNI-like toxicities, although it is accompanied by an increased frequency of acute rejection. Besides belatacept, other biologics hold promise as CNI-free immune suppressive approaches. Finally, powerful new single cell approaches can enable characterization of cellular populations that drive rejection within the rejecting allograft. We propose that the incorporated single cell profiling into studies investigating new biologics in transplantation, could be tailored to each patient, correlated with potential biomarkers in the blood and urine, and provide a platform where therapeutic targets can be rationally defined, mechanistically-based, and exploited.

Patient and Graft Outcome Among High Immunologic Risk Renal Transplant Recipients

Introduction Kidney transplantation (KT) is the preferred treatment for ESRD. However, some patients had prior HLA sensitization making them immunologically high risk for graft rejection and poorer graft survival. Hence, desensitization protocols were developed to clear the circulating alloantibody and therefore prevent rejection. However, desensitization therapy is expensive and associated with higher risk of infection. Our study looked at the patient and graft survival of high immunologic risk KT recipients at National Kidney and Transplant Institute. Methods This is a retrospective cohort study that included patients who underwent KT from January 2012 to June 2016. Out of 1,804 patients, 52 were highly sensitized and we divided them into DSA positive and DSA negative group, and further divided into subgroups based on PRA; ≤20%, >20% ≤80%, and >80%. Results There were 42.3% DSA(+) and 57.7% DSA(-) patients. Male to female ratio was 1:2. There were 56.8% multigravid, 63.5% had prior blood transfusions.There were 21.2% who underwent desensitization: 9 (81.8%) had Rituximab+Plasmapheresis(TPE)+Intravenous immunoglobulin(IVIg), 1 (9.1%) had TPE+IVIg, and 1 (9.1%) had TPE+Rituximab.Rabbit ATG was given to 92.3% and 7.7% were given Basiliximab. Three patients (2 DSA(+), 1 DSA(-)) were given Rituximab as induction therapy in addition to rATG. Most common immunosuppresive was Tacrolimus+Mycophenolic acid, 90.4%. All patients were on Prednisone. The mean Creatinine level (mg/dL) were 1.0, 1.0, 1.3, and 1.0 mg/dL at 6, 12, 24, and 60 months post KT, respectively. The 5-year biopsy-proven acute rejection rate was 9.6% and higher among DSA(+). In contrast, chronic rejection rate was 7.7% and higher among DSA(-). The most common complication was infection (26.9%). The patient survival was 95, 81, and 80% at 1,2, and 5 years post KT. The graft survival was 95, 75, and 70% at 1,2, and 5 years post KT. Discussion Desensitization therapy did not confer additional risk of infection as this occurred to 26.9% of cases across all subgroups. This supports the findings of Kahwaji J et. al. that the rate of infection was similar in patients who received Rituximab+IVIG for desensitization compared with patients who did not receive Rituximab. Patients who received rATG had lower graft rejection rate compared to Basiliximab (16.7% vs 25%). This finding approximates the results of several studies like that of Brennan et. al. (15.6% vs. 25.5%, P=0.02), and Kesiraju et. al. (14.2% and 18.1%). The frequency of acute rejection is higher among DSA(+) patients and inversely, chronic rejection is more frequent among DSA(-) patients.Conclusions Patient and graft survival decreased over time, 95% after 1 year, 81 and 75% after 2 years, and 80 and 70% after 5 years, respectively. Infection was the most common complication regardless of desensitization history. The 5-year biopsy proven rejection was 17.3%.

Influence of Sudden Cardiac Arrest in Deceased Kidney Donors on Organ Function After Transplantation

IntroductionDue to the increasing number of organ recipients, expanded criteria donors (ECD) are qualified for transplantation, including donors after sudden cardiac arrest (SCA). The aim of this study was to evaluate the influence of SCA on kidney function immediately after transplantation. Patients and MethodsThe analysis includes 186 kidney recipients, mean age 49 years (19–74), who were transplanted between January 2014 to July 2015. In 44 cases, kidneys were retrieved from donors after SCA (23.6%). Delayed graft function (DGF) was recognized if the patient needed at least one hemodialysis after the kidney transplant. Acute rejection (AR) was confirmed by biopsy. ResultsSixty-five (34.9%) patients presented with DGF, 14 of them received kidneys from donors after SCA (31.8% of the SCA group), and 51 of them are from donors without SCA (35.9% of the non-SCA group). Eleven AR episodes were observed in the first month, including 4 cases in the SCA group. The study revealed no influence of donors' SCA on the frequency of DGF and AR or high creatine level after transplantation. The differences between both groups were not significant (P > .05). ConclusionsSCA episodes in donors during ICU treatment before organ retrieval had no influence on immediate kidney function after kidney transplant. There is no correlation between SCA and episodes of DGF or AR. SCA donors should be considered as standard criteria donors.

O-19 Incidence and risk factors of adverse events during immunosuppressive therapy after renal transplantation in children

Background Transplantation has become an important treatment option in children with end-stage renal dis-ease. In the last decades progress in immunosuppressive treatment options and surgical techniques have reduced the frequency of acute rejection, graft loss and mortality. However, adverse events occur in patients treated with immunosuppressive therapy. These adverse events are well described for adults but few data are available for children. Our objective was to describe the frequency of adverse events (AEs) under different immunosuppres-sive regimen including either ciclosporin or tacrolimus in children after renal transplantation. Secondary objectives include comparison of AEs with known adverse drug re-actions (ADRs) as described in the Summary of Product Characteristics. Furthermore, risk factors for AEs will be examined. Methods Children receiving a renal transplant at our institution between 2002 to 2015 were included in the study. Initial immunosuppression was obtained by thy-moglobulin or monoclonal antibody, calcineurin inhib-itors (tacrolimus or ciclosporin), mycophenolate mofetil, and corticoids. AEs reported after transplantation were collected from medical reports and coded using Med-DRA (version 19.1). Descriptive statistical analyses were performed using SAS 9.4. Data were stratified by tacrolim-us or ciclosporin treatment schedule at the time of the AE. Results A total of 164 children fulfilled the inclusion cri-teria. Finally, complete medical records were available for 125 children (53 girls and 72 boys). The median age was 12 (2 – 19) years old. The indication for renal transplan-tation included congenital, familial and genetic disorders for 61% of the patients and renal and urinary disorders for 39% (including 30% of nephritis). The median time of observation until last follow up was 2.7 (0.6–4.3) years. Initially, 91 patients were treated with tacrolimus and 34 with ciclosporin. During the observation period 6 patients switched from tacrolimus to ciclosporin and 14 switched from ciclosporin to tacrolimus. A total of 1520 AEs were reported. For patients receiving tacrolimus 1122 AEs (233.6 person-years of exposure) were reported and 372 AEs (71.4 person-years of expo-sure) for those treated with ciclosporin. Twenty-six AEs were reported in patients not receiving any calcineurin inhibitor. The most frequent medical AEs reported for pa-tients treated with tacrolimus and ciclosporin by system organ class were renal and urinary disorders (0.3 vs 0.3 AEs per person-year of exposure), infections (0.3 vs 0.4 AEs per person-year of exposure), vascular disorders (0.2 vs 0.3 AEs per person-year of exposure) and gastrointestinal disor-ders (0.2 vs 0.2 AEs per person-year of exposure). For 46 patients at least one episode of transplant rejection was reported. Conclusion This study describes AEs up to 4 years after renal transplantation in children treated with immuno-suppressive therapy. Our findings will contribute to the understanding of the benefit-risk balance of immuno-suppressive therapy following renal transplantation in children.