Severe Acute Rejection Research Articles

P1773BENEFITS OF CONTROL RENAL BIOPSIES IN THE ASSESSMENT OF ANTI-REJECTION THERAPY EFFICACY IN PATIENTS WITH HISTOLOGICAL LESIONS DIAGNOSED EITHER BY PROTOCOL OR BY “FOR CAUSE” BIOPSIES

Abstract Background and Aims Efficacy of acute rejection (AR) therapy has always been evaluated based upon improvement of renal function. On the contrary, the degree of histological lesion (HL) regression has rarely been considered for this purpose. The main goal of this study was to evaluate the percentage of failures in HLs regression after treatment aimed at both “subclinical” and “clinical” AR. Treatment efficacy was therefore evaluated with control renal biopsies (CBs) performed 30-60 days after anti-rejection therapy. In addition, the correlation between graft function and histological data was assessed. The results of treatment for “subclinical" and "clinical” AR were considered separately. Method Real-time ultrasound-guided CBs were performed in an outpatient setting using 16G tru-cut needles. The HLs considered were: interstitial inflammation (i), tubulitis (t), glomerulitis (g), arteritis (v), capillaritis (ptc). Each lesion was graded from 0 to 3 (sec Banff 2013-2017). For this study, only HLs with a score ≥2 were considered. Therapy failure was determined both by the percentage of patients (pts) with persistence of HLs and by the change of HLs score after treatment, in the control biopsies. Anti-rejection therapy varied according to AR type and severity. In patients failing AR therapy, serum creatinine was evaluated before and after the treatment. Results 111 BCs were performed after treatment either for subclinical (n = 47) or for clinical (n = 64) AR. Before therapy, HLs (with score ≥2) present in subclinical and clinical AR were: i: 23% and 52%; t: 30% and 30%; g: 34% and 41%; ptc: 11% and 28%; v: 15% and 19%. After therapy, in the setting of subclinical AR, HLs were still present with a range between 29% (v) and 81% (g) with stable or improved histological score. In this scenario, renal function resulted stable and satisfactory (Tab 1). In the case of clinical AR, the persistence of histological lesions ranged from 25% (v) to 92% (g), also with stable or improved histological scores. In this case, therapy was always followed by an improvement in renal function (Tab 2). Conclusion After AR therapy, only the morphological data obtained with histological analysis can disclose failures of anti-rejection therapy, both in presence of subclinical and clinical AR. The high rate of treatment failure may explain the correlation between AR and worse graft survival. Our results could lead us to consider the need for a more aggressive anti-rejection treatment. Control renal biopsies after AR therapy should always be considered on clinical grounds.

Validation of the usefulness of 2-dimensional strain parameters to exclude acute rejection after heart transplantation: a multicenter study

Introduction and objectivesTwo-dimensional speckle-tracking echocardiography has emerged as a promising alternative to endomyocardial biopsy to rule out acute cellular rejection after orthotopic heart transplantation (OHT) in single center studies. In an original cohort, 15.5% and 17% of cutoff points for left ventricular global longitudinal strain (LVGLS) and free-wall right ventricular longitudinal strain, respectively, achieved 100% negative predictive value to exclude moderate or severe acute cellular rejection (ACR ≥ 2R). Our objective was to demonstrate the usefulness of speckle-tracking and validate these cutoff points in an external cohort. MethodsA prospective, multicenter study that included patients who were monitored during their first year after OHT was conducted. Echocardiographic studies analyzed by local investigators were compared with simultaneous paired endomyocardial biopsies samples. ResultsA total of 501 endomyocardial biopsy-echocardiographic studies were included in 99 patients. ACR≥2R was present in 7.4% of samples. LVGLS and free-wall right ventricular longitudinal strain were significantly reduced during ACR≥2R on univariate analysis. On multivariate analysis, LVGLS was independently associated with the presence of ACR≥2R. The original cutoff points demonstrated a negative predictive value of 94.3% to exclude ACR≥2R. ConclusionsThis study maintained a strong negative predictive value to exclude ACR≥2R after OHT and LVGLS was independently associated with the presence of ACR≥2R. We propose the use of speckle-tracking, especially LVGLS, as part of the noninvasive diagnosis and management of ACR.

Anorectal Transplantation: The First Long-Term Success in a Canine Model

Background: Anorectal transplantation is a challenging procedure but a promising option for patients with weakened or completely absent anorectal function. We constructed a canine model of anorectal transplantation, evaluated the long-term outcomes, and controlled rejection and infection in allotransplantation. Methods: In the pudendal nerve function study, six dogs were randomly divided into two groups: transection and anastomosis, and were compared with a control using anorectal manometry, electromyography, and histological examination of the anorectal segment. In the anorectal transplantation model, four dogs were assigned to four groups: autotransplant, allotransplant with immunosuppression, allotransplant without immunosuppression, and normal control. Long-term function was evaluated by defecography, videography, and histological examination of the graft. Findings: In the pudendal nerve function study, anorectal manometry indicated that the anastomosis group recovered partial function 6 months postoperatively, but the resection group never regained function. Microscopically, the pudendal nerve and the sphincter muscle regenerated, and function was well-maintained in the anastomosis group at the end of the study. Anorectal transplantation was technically successful with a three-stage operation: colostomy preparation, anorectal transplantation, and stoma closure. The dog who underwent allotransplantation and immunosuppression had two episodes of mild rejection, which were reversed with methylprednisolone and tacrolimus. The dog who underwent allotransplantation without immunosuppression had a severe acute rejection that resulted in graft necrosis. Successful dogs had full defecation control at the end of the study. Interpretation: We described the first long-term success with anorectal transplantation in a canine model. This report is a proof-of-concept study for anorectal transplantation as a treatment for patients with an ostomy because of anorectal dysfunction. Funding Statement: This study was funded by a Japanese Society of Gastroenterology (JSPS) Fellows Grant (number: 201600159), and a JSPS KAKENHI Grant (number: JP 19K18075). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All animal experiments were approved by the Animal Experimental Committee of Kyoto University and the University of Tokyo Animal Care and use Committee.

Evaluation and Treatment of Acute Rejection in Kidney Allografts.

Advances in immunosuppressive therapy have drastically improved acute rejection rates in kidney transplant recipients over the past five decades. Nevertheless, it should remain high on any differential diagnosis of unexplained graft dysfunction because of the potential negative effect on graft longevity. Understanding the pre- and post-transplant risk factors for acute rejection can help estimate the probability of immunologic graft damage, and accurate identification of the type and severity of acute rejection will guide appropriate treatment. Tissue biopsy remains the gold standard for evaluating immunologic graft damage, and the histologic definition of acute rejection has evolved in recent years. Intravenous steroids and T cell depletion remain the standard therapy for T cell-mediated rejection and are effective in reversing most cases. Plasma exchange and intravenous Ig, with or without rituximab, are most commonly used for the treatment of antibody-mediated rejection and several newer agents have recently been investigated for severe cases. This review aims to provide the general nephrologist caring for transplant recipients with an approach to immunologic risk assessment and a summary of recent advances in the diagnosis and treatment of acute graft rejection.

Prognosis of heart transplant patients in Mashhad University of Medical Sciences.

IntroductionHeart transplant is the ultimate treatment for patients with end-stage heart failure.AimTo assess 50 heart transplant patients for underlying diseases, transplantation outcome and mortality rate during a 5-year follow-up program.Material and methodsFifty heart transplant patients who underwent heart transplantation from 2012 to 2017 were assessed for underlying diseases, organ rejection, duration of hospitalization, extubation time, cardiac output and survival. Biopsy samples were obtained after surgery for evaluation of rejection.ResultsDilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM) were the most common underlying diseases with prevalence of 56% and 12%, respectively. Significant improvement in ejection fraction was observed following heart transplant. Minimum and maximum extubation and hospitalization times were 3–408 hours and 1–51 days, respectively. Organ rejection evaluation 10 days after heart transplantation revealed that 50% of patients did not show any rejection while 10% had severe rejection. At 30 days post-operatively the number of patients with grade III rejection decreased to 2% while 56% of patients had no sign of rejection. The 5-year survival rate was 66% while infection and arrhythmia were the most common causes of death.ConclusionsDCM and ICM are considered the most prevalent underlying diseases in heart transplant candidates. Ejection fraction reached normal ranges following transplant, which provides good quality of life. Low incidence of severe acute rejection demonstrates the effectiveness of our immunosuppressive therapy. In the cases of increased rejection, the patient’s immunosuppressive regimen was re-assessed accordingly.

CD47 blockade alleviates acute rejection of allogeneic mouse liver transplantation by reducing ischemia/reperfusion injury

Despite advances in immunosuppressive therapies, acute rejection response is still a serious concern especially in the early phase after liver transplantation. This study aimed to evaluate whether blocking the TSP1-CD47 signaling pathway could attenuate the acute rejection after liver transplantation. An allogeneic mouse orthotopic liver transplantation model (Balb/c→C3H) with prolonged cold ischemic phase was used to induce severe IRI and lethal acute rejection. CD47mAb or isotype matched-control IgG2a was administered to donor liver during graft perfusion. Recipients were sacrificed at 1d, 3d, 5d and 7d after reperfusion. Blood samples were collected to evaluate serum alanine aminotransferase, total bilirubin, HMGB-1,TNF-α, IL-2 and INF-γ level. Flow cytometric analysis was used to detect the strength of innate and adaptive immune response. Liver tissue was obtained for HE, TUNEL staining and F4/80 immumohistochemical staining. Moreover, we conducted a mixed lymphocyte reaction treated with IgG2a or CD47mAb. Mice in CD47mAb-treated group demonstrated improved survival and significantly lower increase in Suzuki score, apoptosis index, acute rejection index, serum alanine aminotransferase, total bilirubin, HMGB-1, TNF-α, IL-2, INF-γ level and the degree of Kupffer cells' activation especially in the early phase of acute rejection. In addition, Pearson's correlation analysis confirmed significant correlation between Suzuki score/ALT and acute rejection index. The in vitro inhibition assay showed that CD47 blockade couldn’t directly inhibit recipient lymphocyte proliferation. Based on the evidence that TSP1-CD47 signaling blockade with CD47mAb could alleviate acute rejection by reducing the extent of IRI after liver transplantation indirectly, this study provided a basis for new interventions and management methods to support better transplant outcomes.

Severe Late-Onset Acute Cellular Rejection in a Pediatric Patient With Isolated Small Intestinal Transplant Rescued With Aggressive Immunosuppressive Approach: A Case Report

Small intestinal transplantation is performed for patients with intestinal failure who failed other surgical and medical treatment. It carries notable risks, including, but not limited to, acute and chronic cellular rejection and graft malfunction. Late severe acute intestinal allograft rejection is associated with increased risk of morbidity and mortality and, in the majority of cases, ends with total enterectomy. It usually results from subtherapeutic immunosuppression or nonadherence to medical treatment. We present the case of a 20-year-old patient who underwent isolated small bowel transplant for total intestinal Hirschsprung disease at age 7. Due to medication nonadherence, she developed severe late-onset acute cellular rejection manifested by high, bloody ostomy output and weight loss. Ileoscopy showed complete loss of normal intestinal anatomic landmarks and ulcerated mucosa. Graft biopsies showed ulceration and granulation tissue with severe architectural distortion consistent with severe intestinal graft rejection. She initially received intravenous corticosteroids and increased tacrolimus dose without significant improvement. Her immunosuppression was escalated to include infliximab and finally antithymocyte globulin. Graft enterectomy was considered repeatedly; however, clinical improvement was noted eventually with evidence of histologic improvement and salvage of the graft. The aggressive antirejection treatment was complicated by development of post-transplant lymphoproliferative disorder that resolved with reducing immunosuppression. Her graft function is currently maintained on tacrolimus, oral prednisone, and a periodic infliximab infusion. We conclude that a prompt and aggressive immunosuppressive approach significantly increases the chance of rescuing small bowel transplant rejection.

Association of medication non-adherence with short-term allograft loss after the treatment of severe acute kidney transplant rejection

BackgroundMedication non-adherence is a risk factor for acute kidney transplant rejection. The association of non-adherence with short-term allograft loss in patients who develop acute rejection and are subsequently treated with maximal therapy is unknown.MethodsWe conducted a retrospective single center cohort study of adult patients who developed acute rejection from January 2003 to December 2017 and were treated with lymphocyte depletion. Clinicopathologic characteristics including adherence status were collected and descriptive statistics utilized to compare groups. The primary outcome was all-cause graft loss at 6 months after acute rejection treatment. A multivariable logistic regression quantified the association of non-adherence with the outcome.ResultsA total of 182 patients were included in the cohort, of whom 71 (39%) were non-adherent. Compared to adherent patients, non-adherent patients were younger (mean age 37y vs 42y), more likely to be female (51% vs 35%) and developed acute rejection later (median 2.3y vs 0.5y from transplant). There were no differences in estimated glomerular filtration rate or need for dialysis on presentation, Banff grade, or presence of antibody mediated rejection between the 2 groups. Overall, 48 (26%) patients lost their grafts at 6 months after acute rejection treatment. In adjusted analysis, non-adherence was associated with all-cause graft loss at 6 months after acute rejection treatment [OR 2.64 (95% CI 1.23–5.65, p = 0.012].ConclusionsAfter adjusting for common confounders, non-adherent patients were at increased risk for short-term allograft loss after a severe acute rejection despite lymphocyte depletion. This finding may aid clinicians in risk stratifying patients for poor short-term outcomes and treatment futility.

2399 West Nile Encephalitis in a Post-Liver Transplant Patient

INTRODUCTION: West Nile Virus (WNV) is a neurotropic flavivirus that is transmitted from animals to humans by the bite of the Aedes, Anaphales, or Culex mosquito, with disease incidence peaking in the late summer and early fall. It is the leading cause of arboviral illness in the U.S. While many infected with WNV are asymptomatic, 25% of patients develop fever, and less than 1% of patients will develop neurologic symptoms. Age over 75-years old and immunosuppressed state are risk factors for developing neuroinvasive disease. CASE DESCRIPTION/METHODS: A 65-year old woman with a history of HCV cirrhosis complicated by HCC status post successful orthotopic liver transplantation (OLT) in 2016 compliant with tacrolimus and everolimus immunosuppression (ISP) presented with painless jaundice and acute transaminemia. Liver biopsy revealed severe acute cellular rejection (ACR), so steroids and thymoglobulin were started. Tacrolimus was increased and everolimus was changed to mycophenolate mofetil. Clinically, she appeared well and her LFTs responded to treatment. Suddenly, she developed fever to 103º associated with bilateral hand tremors. Infectious workup was obtained, and she was started on broad-spectrum antibiotics. Initially, symptoms were attributed to changes in ISP and treatment of ACR. However, she developed progressively worsening dyskinesia and encephalopathy eventually requiring intubation. Given initial negative infectious workup, lumbar puncture was obtained; see Table 1. HSV, VZV, and Lyme PCR as well as VDRL in the CSF were negative. Given clinical symptoms, positive WNV IgM in the CSF, and MRI Brain concerning for WNV neuroinvasive disease, patient was treated with IVIG for 5 days. WNV IgG became positive as well on repeat lumbar puncture 2 weeks later. Patient’s encephalopathy improved, and she was able to be extubated. DISCUSSION: There may be a delay in diagnosis and treatment of WNV encephalitis in post-liver transplant patients as neurologic symptoms may be attributed to ISP or as in this patient, to the treatment of acute cellular rejection. West Nile encephalitis must remain on the differential diagnosis when neurologic symptoms are present in a post-liver transplant patient, especially in endemic areas during the summer and fall months. A change in this patient’s ISP for the treatment of ACR may have caused the development of a more severe, neuroinvasive response to WNV infection and ISP management in such patients should be studied further.

Induction Therapy in Half-Haplotype Low Risk Kidney Transplant Patients: Impact on Acute Rejection, Graft Survival, Infection and Surgical Complications at 3 Years

Objective: This retrospective study discusses the need for induction therapy in half haplotype low immunological risk kidney transplant patients. Material and Methods: Records of 70 adult kidney transplant patients were reviewed with 3 years follow up. All patients were half haplotype matched with their living related donors and had PRA Results: We did not find any significant difference between the 2 groups regarding the length of hospital stay, the rate and severity of acute rejection, the rate of CMV infection, the occurrence of delayed graft function and the rate and type of surgical complications at 1 year. Furthermore, the patient and graft survival as well as the serum creatinine levels upon discharge and at 1, 3, 6, 12 and 36 months were also comparable. Nevertheless, the rate and type of out of Hospital infections and 1-year infection rate as well as the treatment cost were significantly higher in Group I. Conclusion: Induction therapy might not be desirable in low-immunological risk half-haplotype kidney transplant patients.

P1.57: Severe Late Onset Acute Cellular Rejection in a Pediatric Patient with isolated small intestinal transplant rescued with aggressive immunosuppressive approach

Introduction: Small intestinal transplantation has been the standard treatment modality for pediatric patient with intestinal failure who failed other surgical and medical treatment. At its current stage, it carries its own risks including but not limited to acute and chronic cellular rejection, graft malfunctions, development of PTLD, viral and bacterial infections. Acute cellular rejection of the intestinal graft is an important and major complication secondary to its rich lymphatic supply. It is usually results from sub therapeutic immunosuppression or non-adherence to medical management. The current management includes modifying the immunosuppression to achieve therapeutic level. Late severe acute intestinal allograft rejection is associated with increased risks of sepsis, bleeding and in the majority of cases with graft loss that ends up in graft enterectomy. We present a case of a 20 year old patient who underwent isolated small bowel transplant for complete intestinal Hirschsprung Disease at age 7 years old, but due to medication non-adherence developed severe late-onset acute cellular rejection manifested by large ostomy OP, fever, weight loss. Underwent ileoscopy on presentation that showed complete loss of normal anatomical intestinal landmarks, bleeding, and ulcerated mucosa. Graft biopsies showed ulceration and granulation tissue with severe architectural distortion, and rare residual consistent with severe intestinal graft rejection. She initially received pulse doses of Intravenous corticosteroids and increased dose of tacrolimus without significant improvement. Her immunosuppression plan was escalated to include infliximab and finally had Antithymocyte globulin (ATG). Graft enterectomy option was entertained frequently during the treatment course; however clinical improvement was noted with evidence of histological improvement and salvage of the graft. The aggressive anti-rejection treatment was complicated with the development of monomorphic, plasmacytoma (PTLD) that was managed with modifying her immunosuppression. Now her graft function is maintained on tacrolimus, oral prednisone, and routine Remicade infusion. Conclusion: 1-Small bowel graft rejection is associated with increased morbidity and mortality, increased risks of sepsis, bleeding and graft loss. 2-We believe that prompt and aggressive immunosuppressive approach significantly increases the chance of rescuing small bowel transplant rejection.

P3A.05: Young donors (age ≤ 6 months) for Intestinal transplantation (ITX): are they high risk?

Introduction: ITX is accepted treatment for children with irreversible intestinal failure. Shortage of size matched organs for children especially those with restricted abdominal domain due to various aetiologies resulted in development of various techniques including use of organs from young donors. There is no data on the utilization and outcome of young donors in ITX. Subject and Methods: Retrospective review of medical records between 1993–2018 of all ITX from donors less than 6 months of age. Donor and recipients demographics, intra and early post-transplant complications, short and long term graft and patient outcome were analysed. Results: 4 females median age 20 months & weight 9kg underwent ITX from young female DBD donors median age 3.5 months & weight 6kg with median donor to recipient weight ratio 0.5 (Table 1). All donors with brain death, blood group identical/compatible with median cold ischemia time 5.5 hours. No surgical complications noted intra or early post-transplant. Two died early within 3 months of ITx following severe acute rejection. One established early full enteral feeding and required laparotomy for stoma prolapse 3 months post ITX, but eventually died secondary to complications. The second child took longtime to establish feeding due to fluid and electrolyte imbalance, but eventually died following complications associated with stoma closure. One year patient and graft survival was 50%, whilst 3 year patient and graft survival was 0%. Conclusion: It is technically feasible to consider young donors for intestinal transplantation. In our experience it is associated with a high mortality. Further investigation to understand the complex interactions between the naive immune system of the young donors with the mature immune system of the older recipients may hold the key to understanding the development of the immunological complications.

C3 expression by lung transplants reduces alloimmune-mediated injury

Abstract Allograft injury is a major risk factor for death in lung transplant recipients. Complement protein C3 is primarily synthesized in the liver. However, a recent study by our group has demonstrated that C3 present in pulmonary epithelial cells can be augmented to facilitate their own ability to withstand acute environmental stress. Here, we hypothesized that pulmonary C3 expression reduces the severity of allograft rejection. To address this question, C3−/−left lungs [on a C57BL/6 (B6) background] were orthotopically transplanted into wildtype (WT) fully MHC mismatched (CBA/J) recipients. The right lung, native to the recipient, served as an internal control. CBA/J lungs transplanted into C3−/− recipients, C3−/− lungs transplanted into C3−/− recipients and CBA/J lungs transplanted into WT B6 recipients were also employed as controls. One week after transplantation, recipients were euthanized and evaluated for C3 levels and graft injury. C3 protein in C3−/− recipients of WT B6 and CBA/J lungs was not detected in the peripheral circulation but was expressed within graft tissues suggesting locally expressed C3 is sequestered within the lung. Signs of graft tissue injury were only observed in allogeneic recipients. However, acute rejection severity was significantly higher in C3−/− allografts when compared to WT allografts. Additionally, C3−/− allografts had a distinct pattern of acute alveolar damage and increased cellularity not evident in WT allografts. Taken collectively, our data indicate that expression of C3 by lung allografts attenuates alloimmunedependent responses that are associated with reduced survival in humans.

Hypothermic Oxygenated Perfusion: A Simple and Effective Method to Modulate the Immune Response in Kidney Transplantation.

Hypothermic oxygenated perfusion (HOPE) has been shown to protect liver recipients from acute rejection in an allogeneic model of liver transplantation in rats. Here we investigate the impact of HOPE on the T cell-mediated immune response following kidney transplantation. Kidneys from Lewis rats were transplanted into Brown Norway recipients to trigger acute rejection (allogeneic untreated group). Next, Brown Norway recipients were treated either with tacrolimus,= or donor kidneys underwent 1h-HOPE-treatment before implantation without additional immunosuppression in recipients. Syngeneic kidney transplants (Brown Norway to Brown Norway) served as controls. In a second set of experiments, the immune response was assessed in a donation after circulatory death model of kidney transplantation comparing standard cold storage with subsequent HOPE treatment and hypothermic nitrogenated perfusion, where oxygen was replaced during cold perfusion. Allogeneic kidney transplantation led to death in all untreated recipients within 10 days due to severe acute rejection. In contrast, immune activation was prevented by tacrolimus with significantly improved recipient survival. Similarly, HOPE treatment, without any immunosuppression, protected recipients from acute immune response, as measured by less cytokine release, T-cell, and macrophage activation. Additionally, HOPE-treated kidneys showed better function and less early fibrosis leading to a significantly improved recipient survival, compared with untreated allogeneic controls. Similarly, HOPE treatment protected recipients of extended donation after circulatory death kidneys from immune activation. This effect was lost when deoxygenated perfusate was used. In summary, this is the first study demonstrating the beneficial effects of HOPE on the immune response following kidney transplantation in an allogeneic rodent model.

Effects of Panax notoginseng saponins on liver graft rejection in rats and the mechanisms

To investigate the effects of Panax notoginseng saponins (PNS) on the functional status of Kupffer cells (KCs) and immune environment after liver transplantation and explore the possible mechanisms. KCs were isolated from rats and assessed for phagocytic activity and viability using ink and Trypan blue staining. The cells were exposed to lipopolysaccharide (LPS) alone or in combination with PNS treatment at 0, 10 or 20 μmol/L. The expressions of the inflammatory factors and the oxidative stress products in the cells and the supernatant were assayed with Western blotting and ELISA; the expression of CD206 was detected using immunofluorescence assay, and the expressions of NF-κB and Keap1-Nrf2-ARE pathway proteins were detected using Western blotting. We established an orthotopic liver transplantation (LT) model in rats and assessed the effect of 200 mg/kg PNS on the graft function, inflammatory factors, pathology of the liver tissue, hepatocyte apoptosis and survival time of the rats in comparison with those in rats receiving a sham operation or PBS treatment following LT. Treatment with PNS significantly lowered the levels of inflammatory factors and oxidative stress products and increased the levels of interleukin-10 (IL-10) and SOD in a concentration-dependent manner in the KCs (P < 0.05). Immunofluorescence assay showed that PNS treatment obviously increased the expression of CD206 in the KCs. PNS treatment also significantly reduced the expressions of IRAK4, p-IKKα, p-IκBα, p-p65 and Keap1 proteins and increased the expression levels of Nrf2 and ARE proteins in the KCs (P < 0.05). In the rat models of LT, PNS treatment significantly improved the liver graft function, lowered the expression of the pro-inflammatory factors, and reduced hepatocyte apoptosis as compared with PBS treatment. PNS treatment obviously alleviated pathological changes in the liver graft and significantly prolonged the survival time of the rats following LT (P < 0.05). In addition, injection of GdCl3 to block KC function resulted in severe acute graft rejection in the rats regardless of PNS treatment (P > 0.05). PNS can reduce inflammatory response and oxidative stress in activated KCs by inhibiting NF-κB and Keap1-Nrf2-ARE pathways and promote the polarization of KCs into M2 phenotype to prolong the survival time of rats after LT.

Clinical Outcomes of Perioperative Desensitization in Orthotopic Heart Transplant Recipients

Purpose Transplantation of sensitized recipients is associated with suboptimal post-transplant outcomes. This study assessed the effects of a perioperative desensitization strategy in virtual crossmatch (VXM)-positive orthotopic heart transplant (OHT) recipients compared to a historical cohort of VXM-negative OHT recipients. Methods This single-center, retrospective study included OHT recipients from 2010-2018. VXM-positive patients received perioperative plasmapheresis, intravenous immunoglobulin (IVIg), and antithymocyte globulin (rATG). VXM-negative historical controls received either high-dose steroids or alemtuzumab induction. Maintenance immunosuppression consisted of tacrolimus, mycophenolate, and a steroid taper. The primary endpoint was graft survival at 12 months. Secondary endpoints included freedom from acute rejection and freedom from severe (i.e., grade ≥ 2) acute cellular rejection or antibody-mediated rejection at 12 months. Results Of 91 patients included, 7 received desensitization. Baseline demographics, disease etiology, and comorbid conditions were similar between groups. VXM-positive recipients received a median of 5.1 (4.8-5.3) mg/kg of rATG, 0.9 (0-1.2) g/kg of IVIg, and 6 (3-7) plasmapheresis sessions. Maintenance immunosuppression was similar at all time points. There was one graft loss, which occurred in the VXM-negative cohort at 70 days post-OHT. The median time to rejection was 44.5 (16.5-93.5) days in the VXM-negative group versus 46.5 (10-83) days in the VXM-positive group (p=0.76). There were no differences in any other rejection outcomes. Six VXM-positive recipients cleared donor-specific antibodies (DSA) by day 21 and all cleared DSA by day 60 (Figure 1). Conclusion These data suggest that transplantation of VXM-positive OHT recipients receiving perioperative desensitization is feasible without excess graft loss or acute rejection at 12 months. The rapid clearance and lack of DSA recurrence is promising for long-term outcomes.

DON'T GO BREAKING MY HEART: ACUTE CELLULAR GRAFT REJECTION AFTER HEART TRANSPLANTATION COMPLICATED BY CARDIOGENIC SHOCK AND RESCUED WITH EXTRACORPOREAL MEMBRANE OXYGENATION

Early recognition of acute severe rejection in orthotopic heart transplant (OHT) patients and judicious management with mechanical circulatory support is key to averting a fatal outcome. A 64-year-old male status post OHT 4 months ago presents with 3 days of fevers, chills and lethargy. He was

3281 Management of Acute Rejection in Penile Allotransplantation

3281 Management of Acute Rejection in Penile Allotransplantation

High Calcineurin Inhibitor Intrapatient Variability Is Associated With Renal Allograft Inflammation, Chronicity, and Graft Loss.

High calcineurin inhibitor (CNI) intrapatient variability (IPV) has been associated with poor kidney allograft outcomes. However, the relationship between early allograft histological changes, their progression, and CNI-IPV is less well studied. Hence, we evaluated effect of CNI-IPV defined by the degree of fluctuation of CNI levels in all kidney transplant patients over 2 to 12 months posttransplant on early allograft inflammation, subsequent chronicity, and later clinical outcomes. Two hundred eighty-six patients transplanted from January 2013 to November 2014 were enrolled with protocol and indication biopsies. The mean CNI-IPV was 28.5% and a quarter of our cohort had IPV of 35% or greater (high CNI IPV). Baseline demographic differences were similar between high and low CNI IPV groups. High CNI-IPV was associated with a higher incidence of acute rejection (AR) within 1 year (52% vs 31% P < 0.001), more persistent/recurrent AR by 1 year (18.2% vs 6.2%, P = 0.002), higher-grade AR (≥Banff 1B, 27.5% vs 7.3%, P < 0.001), and worse interstitial fibrosis/tubular atrophy (P = 0.005). High CNI-IPV was associated with increased graft loss (GL) and impending graft loss (iGL, defined as eGFR<30 ml/min and >30% decline in eGFR from baseline), regardless of donor-specific antibody, delayed graft function, rejection, or race. In a multivariate Cox Proportional Hazards Model, high CNI-IPV was independently associated with GL + iGL (hazard ratio, 3.1; 95% confidence interval, 1.6-5.9, P < 0.001). High CNI-IPV within 1 year posttransplant is associated with higher incidence of AR, severe AR, allograft chronicity, GL, and iGL. This represents a subset of patients who are at risk for poor kidney transplant outcomes and potentially a modifiable risk factor for late allograft loss.

Use of speckle-tracking echocardiography\u2013derived strain and systolic strain rate measurements to predict rejection in transplant hearts with preserved ejection fraction

BackgroundNoninvasive diagnosis of allograft rejection in heart transplant recipients is challenging. The utility of 2-dimensional speckle-tracking echocardiography (2D-STE) to predict severe rejection in heart transplant recipients with preserved left ventricular ejection fraction (LVEF) was evaluated.MethodsAdult heart transplant patients with preserved LVEF (> 55%) and severe rejection by biopsy (Rejection Grade ≥ 2R) or no rejection between 1997 and 2011 at the Mayo Clinic in Rochester, Minnesota were evaluated. Transthoracic echocardiography was performed within 1 month of the biopsy. LV global longitudinal and circumferential strain and strain rates (GLS, GLSR, GCS, and GCSR) were analyzed retrospectively.ResultsOf 65 patients included, 25 had severe rejection and 40 were normal transplant controls without rejection. Both groups had more men than women (64 and 75%, respectively). Baseline clinical variables were similar between the groups. Both groups had normal LVEF (64.3% vs 64.5%; P = .87). All non-strain echocardiographic variables were similar between the 2 groups. Strain analysis showed significantly increased early diastolic longitudinal strain rate (P = .02) and decreased GCS (P < .001) and GCSR (P = .02) for the rejection group compared with the control group. The area under the receiver operating characteristic curve for GCS was 0.77. With a GCS cutoff of − 17.60%, the sensitivity and specificity of GCS to detect severe acute rejection were 81.8 and 68.4%, respectively.Conclusions2D-STE may be useful in detecting severe transplant rejection in heart transplant patients with normal LVEF.