Acute Graft Rejection Research Articles

Renal xenotransplantation : state of the art

Xenotransplantation could be an inexhaustible source of organs and change the life of end-stage kidney disease patients with reduction of morbidity and mortality. Through genetic engineering it is now possible to reduce the risk of hyperacute and acute graft rejection and improve the overall immune compatibility between two different species. Some experiments have already brought promising perspectives. Nevertheless, there are still difficulties to overcome. The risk of animal-related infectious diseases, ethnic limitations, safety, and applicability of large-scale xenotransplantation should be assessed. We still need to improve the technical aspects and define the purpose of these procedures: definitive replacement or temporary solution?

Tacrolimus's Time Below Therapeutic Range Is Associated With Acute Pancreatic Graft Rejection and the Development of De Novo Donor-specific Antibodies.

Tacrolimus is pivotal in pancreas transplants but poses challenges in maintaining optimal levels due to recipient differences. This study aimed to explore the utility of time spent below the therapeutic range and intrapatient variability in predicting rejection and de novo donor-specific antibody (dnDSA) development in pancreas graft recipients. This retrospective unicentric study included adult pancreas transplant recipients between January 2006 and July 2020. Recorded variables included demographics, immunosuppression details, HLA matching, biopsy results, dnDSA development, and clinical parameters. Statistical analysis included ROC curves, sensitivity, specificity, and predictive values. A total of 131 patients were included. Those with biopsy-proven acute rejection (BPAR, 12.2%) had more time (39.9% ± 24% vs. 25.72% ± 21.57%, p = 0.016) and tests (41.95% ± 13.57% vs. 29.96% ± 17.33%, p = 0.009) below therapeutic range. Specific cutoffs of 31.5% for time and 34% for tests below the therapeutic range showed a high negative predictive value for BPAR (93.98% and 93.1%, respectively). Similarly, patients with more than 34% of tests below the therapeutic range were associated with dnDSA appearance (38.9% vs. 9.4%, p = 0.012; OR 6.135, 1.346-27.78). In pancreas transplantation, maintaining optimal tacrolimus levels is crucial. Suboptimal test percentages below the therapeutic range prove valuable in identifying acute graft rejection risk.

Khodadoust Line Indicating Graft Rejection in Descemet’s Stripping Automated Endothelial Keratoplasty: A Unique Case Report

Abstract Purpose: To highlight the rarity of the endothelial rejection line, also known as the Khodadoust line, as a manifestation following Descemet’s stripping automated endothelial keratoplasty (DSAEK). The objective is to present a meticulously detailed case, including imaging and anterior optical coherence tomography (OCT), to enhance understanding and recognition of this phenomenon. Methods: A detailed case presentation involving a 50-year-old male, 3 years post-DSAEK transplantation for endothelial damage resulting from intraocular surgeries. The patient urgently sought consultation due to vision loss while under daily fluorometholone use. Clinical examination revealed acute graft rejection characterized by corneal edema, anterior chamber reaction, and the presence of keratic precipitates forming a Khodadoust line. The management approach included the initiation of a tapered dexamethasone regimen. Results: The identified acute graft rejection, marked by the presence of a Khodadoust line, demonstrated favorable responsiveness to the initiated tapered dexamethasone regimen. Corneal OCT and imaging played crucial roles in providing detailed insights into the manifestation. Conclusions: While the endothelial rejection line (Khodadoust line) is a rare occurrence following DSAEK, this case underscores its potential association with graft rejection. The successful management outlined in this report suggests the importance of prompt recognition and appropriate anti-inflammatory intervention in such cases to achieve positive outcomes.

Could the Cytomegalovirus Viral Load Be Correlated with Cellular Rejection in Asymptomatic Heart Transplant Recipients? A Brief Report

Abstract Introduction: Cytomegalovirus (CMV) infection is mainly associated with acute or chronic graft rejection in various solid organs. This study was conducted with the aim of evaluating the plasma viral load of CMV infection in postheart transplant patients and its correlation with the grading of cellular graft rejection in endomyocardial biopsies. Materials and Methods: In a cross-sectional study, 90 samples from 65 asymptomatic heart transplant recipients scheduled for routine endomyocardial biopsy were obtained. All the recipients had a history of positive serology for CMV infection before transplantation. Evaluation of their DNA was tracked using the polymerase chain reaction technique and the use of specific virus DNA primers, and based on this, the peak virus load (the number of virus copies per milliliter) was determined. A peak viral load >10,000 copies/mL was considered positive. Graft rejection grading was determined based on the ISHLT grading system. Results: The mean (standard deviation) age of the patients (37 men) was 67 (37.3) years. The graft rejection grading was as follows: 22.2% grade 0, 38.9% Quilty effect (QE), 35.6% grade 1, and 3.3% grade 2. The mean plasma viral load level of CMV infection was 2197.4 (1256.2) μg/μL, 1970.4 (1150.3) μg/μL, and 4567.2 (1669.1) μg/μL in grades 0, QE, and 1 and/or 2, respectively (P < 0.001). The virus load was significantly higher in those with higher grades of cellular rejection. Conclusion: The relationship between the plasma level of CMV viral load and the grading of cellular graft rejection in heart transplant patients could emphasize the role of CMV virus in the pathophysiology of graft rejection. A closer surveillance for CMV infection using the viral load is also recommended in particular in those who have higher grades of graft rejection.

Management of Kidney Transplant Outpatients With COVID-19: A Single Center Experience.

Patients undergoing kidney transplant are at risk of severe COVID-19. Our single-center retrospective analysis evaluated the outcomes of kidney transplant outpatients with COVID-19 who were managed with reduced immunosuppression and treatment with molnupiravir. Between January 2022 and May 2023, we included 93 patients (62 men, average age 56years), serum creatinine 127 (101-153) µmol/L. Molnupiravir was administered, and immunosuppressive therapy was reduced immediately following the confirmation of SARS-CoV-2 infection by PCR, which was 2 (1-3) days after the onset of symptoms. Only three (3.2%) patients required hospitalization, and one patient died. Acute kidney injury was observed in two patients. During the follow-up period of 19 (15-22) months, there was no significant increase in proteinuria, no acute or new chronic graft rejection, and kidney graft function remained stable; serum creatinine was 124 (106-159) µmol/L post-COVID-19 infection and 128 (101-161) µmol/L at the end of the follow-up period. Our results demonstrate that early initiation of molnupiravir treatment combined with a temporary reduction in immunosuppressive therapy results in favorable clinical outcomes in patients with COVID-19, with preservation of good graft function and no episodes of graft rejection.

Diabetes mellitus in Kabuki syndrome 1 on a background of post-transplant diabetes mellitus.

Kabuki syndrome is a genetic disorder characterised by distinctive facial features, developmental delays, and multisystem congenital anomalies. Endocrine complications such as premature thelarche and short stature are common, whereas disorders of glycaemic control are less frequent. We describe a 23-year-old white female referred to the diabetes clinic for hyperglycaemia during haemodialysis. She was subsequently diagnosed with Kabuki syndrome based on characteristic clinical features, confirmed by detecting a heterozygous pathogenic variant in KMT2D. She was known to have had multiple congenital anomalies at birth, including complex congenital heart disease and a single dysplastic ectopic kidney, and received a cadaveric transplanted kidney at the age of 13. She had hyperglycaemia consistent with post-transplant diabetes mellitus (DM) and was started on insulin. Examination at the time revealed truncal obesity. She developed acute graft rejection and graft failure 14 months post-transplant and she was started on haemodialysis. Her blood glucose levels normalised post-graft explant, but she was hyperglycaemic again during haemodialysis at the age of 23. Given her clinical phenotype, negative diabetes antibodies and normal pancreas on ultrasound, she was assumed to have type 2 DM and achieved good glycaemic control with gliclazide. Involve clinical genetics early in the investigative pathway of sick neonates born with multiple congenital anomalies to establish a diagnosis to direct medical care. Consider the possibility of Kabuki syndrome (KS) in the differential diagnoses in any neonate with normal karyotyping or microarray analysis and with multiple congenital anomalies (especially cardiac, renal, or skeletal), dysmorphic facial features, transient neonatal hypoglycaemia and failure to thrive. Consider the possibility of diabetes as an endocrine complication in KS patients who are obese or who have autoimmune disorders.

Anti-thymocyte globulin for treatment of T-cell-mediated allograft rejection.

Anti-thymocyte globulin (ATG) is a pivotal immunosuppressive therapy utilized in the management of T-cell-mediated rejection and steroid-resistant rejection among renal transplant recipients. Commercially available as Thymoglobulin (rabbit-derived, Sanofi, United States), ATG-Fresenius S (rabbit-derived), and ATGAM (equine-derived, Pfizer, United States), these formulations share a common mechanism of action centered on their interaction with cell surface markers of immune cells, imparting immunosuppressive effects. Although the prevailing mechanism predominantly involves T-cell depletion via the com plement-mediated pathway, alternate mechanisms have been elucidated. Optimal dosing and treatment duration of ATG have exhibited variance across ran domised trials and clinical reports, rendering the establishment of standardized guidelines a challenge. The spectrum of risks associated with ATG administration spans from transient adverse effects such as fever, chills, and skin rash in the acute phase to long-term concerns related to immunosuppression, including susceptibility to infections and malignancies. This comprehensive review aims to provide a thorough exploration of the current understanding of ATG, encom passing its mechanism of action, clinical utility in the treatment of acute renal graft rejections, specifically steroid-resistant cases, efficacy in rejection episode reversal, and a synthesis of findings from different eras of maintenance immunosuppression. Additionally, it delves into the adverse effects associated with ATG therapy and its impact on long-term graft function. Furthermore, the review underscores the existing gaps in evidence, particularly in the context of the Banff classification of rejections, and highlights the challenges faced by clinicians when navigating the available literature to strike the optimal balance between the risks and benefits of ATG utilization in renal transplantation.

Abstract 15486: In-Hospital Outcomes After Cardiac Transplantation in Patients With Autism Spectrum Disorders: Insights From the National Inpatient Sample 2011-2019

Introduction: Many governing bodies and major international societies recommend against heart transplantation (HTx) in patients with severe cognitive-behavioral disabilities, however no clear criteria are offered to define severity. Patients with Autism Spectrum Disorders (ASD) may face systematic discrimination when being evaluated for HTx. There is a lack of data regarding outcomes after HTx in patients with ASD. Methods: The NIS was queried from 2011-2019 for relevant ICD-9 and ICD-10 codes to identify patients with and without ASD who underwent HTx. Baseline characteristics and in-hospital outcomes between patients were compared. Binary logistic regression was used to adjust outcomes for significantly different baseline characteristics (p<0.05). Results: We identified a weighted sample of 25,456 patients who underwent HTx, of which 80 had a concurrent diagnosis of ASD. Because less than .05% of the adult HTx population had ASD, the outcome analysis was restricted to the pediatric population. After restriction there were 3,769 pediatric patients who underwent HTx, of which 70 had a diagnosis of ASD. There were no significant differences in mortality, transplant related complications (acute graft rejection, acute graft failure, acute cardiac allograft vasculopathy and unspecified complications), cardiac arrest, periprocedural sepsis, mechanical circulatory support, stroke and bleeding/vascular complications between groups. While unadjusted values signaled a difference in the rate of complete heart block (CHB), there was no significant difference after application to a binary logistic regression model (CHB aOR: 1.83, 95% CI .70 to 4.77, p=0.22) Total cost of stay was significantly higher in the ASD group ($2,017,389±$2,136,742 versus $1,675,459±$1,604,926, p<0.05) while total length of stay was higher in the non ASD group (79.6±72 days versus 64.8±53.7 days, p<0.05). Conclusion: There are no significant differences in outcomes after HTx between pediatric patients with and without ASD. The exclusion of patients with ASD from some transplant programs represents a major disparity in healthcare and transplant teams should consider a multidisciplinary approach to evaluating ASD patients for Htx.

Compassionate Use of Emapalumab in Children with Life-Threatening Disorders: Real-World Data

Introduction: Life threatening hyperinflammation occurs in hemophagocytic lymphohistiocytosis (HLH) and during acute rejection of hematopoietic stem cell (HSC) grafts. Both conditions reflect acute activation of the immune system, in part due to overproduction of proinflammatory cytokines, particularly interferon gamma (IFNγ). Emapalumab, a fully human monoclonal antibody that binds to IFNγ, is approved by the FDA for refractory or recurrent primary HLH (pHLH) or in patients intolerant to conventional therapy. Off-label use of emapalumab has been reported for treatment of secondary HLH (sHLH) and for HSC graft rejection. The European Medicines Agency did not approve emapalumab for the treatment of HLH and many other regulatory authorities, including the Israeli Ministry of Health, have yet to approve emapalumab for clinical use. Pending such regulatory approval, emapalumab is available in Israel exclusively though the Managed Access Request Program (MAP) on a compassionate basis sponsored by Sobi (Swedish Orphan Biovitrum AB,Reg. no. 556038-9321). Experience that accumulates through on- and off-label use of emapalumab obtained via MAP enriches the knowledge base regarding the uses of this drug in the real-world clinical setting. Methods: We summarized the data of patients receiving emapalumab at our tertiary pediatric center. The medication was received after application to the MAP sponsored by Sobi International with import approval of the Israel Ministry of Health on a named-patient basis. Results: Seven patients (Pt) aged 2.5 months-17.5 years were treated with emapalumab between 3/2020-6/2023. Patients 1-5 fulfilled HLH-2004 diagnostic criteria. Indications for the use of emapalumab included treatment of HLH in a newborn with severe hepatotoxicity after treatment with the standard HLH-94 protocol (Pt. 3), treatment of acute graft rejection with recurrence of HLH in a patient with pHLH (Pt.1), secondary HSC graft failure and disease relapse in a child with pHLH (Pt. 4), sHLH with multi-organ failure (MOF) requiring extracorporeal membrane oxygenation (ECMO) (Pts 2&5) and HSC primary graft rejection with suspected 2 nd rejection (Pts.6&7). Table 1 summarizes the clinical characteristics of all cases. The patient outcomes were closely related to their clinical status at treatment initiation. Pt.3 was able to reach remission and successfully bridge to SCT without complications after only 4 doses of VP-16 with continuation therapy using only dexamethasone and emapalumab. Pt.4, who experienced relapsed pHLH with concomitant HSC graft loss, attained complete remission with emapalumab, dexamethasone and IVIG, facilitating a successful second HSC graft. Pt. 1 expired after initial graft failure, severe sepsis and relapse of pHLH. Pts. 2&5, despite showing improvement of their HLH criteria after treatment with emapalumab, succumbed to MOF that was already present when they were referred to our center for ECMO support. Following unsuccessful emapalumab treatment for primary graft rejection, Pts. 6&7 underwent successful 2 nd HSC transplants with early emapalumab treatment for suspected re-rejection. Conclusions: Emapalumab is a safe, effective, and well tolerated treatment for various HLH scenarios, and for similar hyper-inflammatory medical conditions. Administration of emapalumab early in the disease course is likely to be more effective as compared to administration of the drug when MOF has occurred or when the HSC graft has already been rejected. Since these diseases are life-threatening, eliminating delays in procurement of emapalumab is essential to expedite treatment before irreversible organ failure ensues.

Short-Term and Long-Term Effects of Ischemic Conditioning on Liver Transplantation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Although liver transplantation (LT) is one of the definitive treatments for patients with end-stage liver failure, it inevitably results in ischemic reperfusion injury. It is known that prognosis is improved when temporary ischemic conditioning (IC) is applied to patients with ischemic reperfusion injury. The objective of this meta-analysis was to determine the short-term and long-term effects of IC on the clinical outcomes of LT recipients. Randomized controlled studies on IC in patients with LTs were included. Patients were compared between an IC group and a sham group. Studies were retrieved from PubMed, Embase, and Cochrane Library. The risk of bias was evaluated using RoB 2.0. Mortality, graft function, and major complications were synthesized using RevMan 5.4.1. Among 316 papers, 17 articles (1196 patients) were included. There was an insignificant increase in short-term mortality (risk ratio [RR]: 3.00, 95% CI: 0.32-28.14, P=.34). However, long-term mortality was lower in the IC group than in the sham group, but not significantly (RR: 0.75; 95% CI: 0.47-1.20, P=.23). Short-term graft function (acute graft rejection and primary graft non-function) was not improved by IC. One-year graft loss tended to show better results in the IC group (RR: 0.53, 95% CI: 0.26-1.07, P=.08). Ischemic conditioning did not have a beneficial effect on LT. Although long-term outcomes appear to be better in the IC group than in the sham group, further randomized controlled trials are needed.

A Comprehensive Investigation Into the Outcomes of Descemet's Stripping Endothelial Keratoplasty (DSEK) as a Treatment for Corneal Endothelial Disorders.

Descemet's stripping endothelial keratoplasty (DSEK) has emerged as the preferred method for posterior lamellar keratoplasty, as it enables the replacement of the compromised host endothelium with a viable donor lamella. The objective of this study was to assess the impact of DSEK on surgical outcomes and visual acuity. The research was carried out from November 2019 to October 2021, encompassing a sample of 18 patients (18 eyes) who satisfied the inclusion criteria for DSEK. The pre-operative evaluation was performed once before the surgery, while post-operative evaluations were conducted at one, three, and six months after the surgical intervention. The main variables assessed in this study encompassed demographic characteristics, visual acuity, surgical techniques, and surgical complications employed during the surgical procedure. The collected data were statistically analyzed using IBM SPSS software version 21 (IBM Corp., Armonk, NY, USA). Patients in the study ranged in age from 25 to 70, with a mean age of 53.16 ± 14.19 years. The participants were 61% male and 39% female. The main reasons for DSEK use were pseudophakic bullous keratopathy (61%) and post-penetrating keratoplasty (PK) graft failure (17%). The other indications were aphakic bullous keratopathy (11%), bullous keratopathy with cataracts (5%), and Fuchs's endothelial dystrophy (5%). The study included 18 eyes: 14 eyes underwent DSEK, two underwent DSEK with small-incision cataract surgery (SICS) and posterior chamber intraocular lens (PCIOL) implantation, and two underwent DSEK with scleral-fixated FIL. A significant improvement in best-corrected visual acuity (BCVA) was observed at six-month follow-up (0.73 ± 0.37 vs. 1.73 ± 0.59 logMAR pre-operatively). During donor cornea dissection, buttonholing was the main concern, occurring 11% of the time. Descemet's perforation and donor preparation thickness variations were also observed. Reverse donor unfolding, incomplete DM stripping, and donor button displacement were quickly addressed and managed. Post-operative graft failure occurred in 22% of cases, while acute graft rejection occurred in 11%. Graft dislocation, pupillary block, and secondary glaucoma each had a 5% prevalence. Descemet's stripping endothelial keratoplasty is a safe and effective treatment for corneal endothelial disorders, particularly in cases where scarring is not present. Surgical skills are essential to achieving the desired results. Descemet's stripping endothelial keratoplasty is favored over conventional keratoplasty for endothelial dysfunction due to its technical advantages and manageable risks. Our research demonstrates a significant improvement in visual acuity through DSEK. Despite manageable post-operative complications, it is vital to educate patients and medical professionals on surgical complexities. Descemet's stripping endothelial keratoplasty appears promising for the treatment of endothelial disorders, but its long-term implications must be studied.

An analysis of the relationship between donor and recipient biomarkers and kidney graft function, dysfunction, and rejection

BackgroundThe study aimed to find predictive biomarkers to evaluate donor kidney function to predict graft dysfunction as well as to assess an early signs of acute graft rejection. MethodTwenty-seven deceased donors and 54 recipients who underwent a successful kidney transplantation were enrolled in the study. An assessment was made in serum and urine from donors and recipients to measure the following biomarkers: neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), tissue inhibitor of metalloproteinase 2 (TIMP-2) and urinary N-acetyl-b-D-glucosaminidase (uNAG). These biomarkers were used to establish a model for predicting a reduced graft function (RGF) classified as either a delayed or slow graft function. ResultOur analysis suggest that out of four tested biomarkers, the serum TIMP-2 and uNAG levels of the donors had a predictive value for RGF; the area under the receiver operating characteristic curves (AUROC) of serum TIMP-2 and uNAG were 0.714 and 0.779, respectively. The combined best fitting prediction model of serum TIMP-2, uNAG, and creatinine levels was better in predicting RGF than the serum creatinine level alone. In addition, the recipient serum TIMP-2 level on the third day post-transplantation (D3) was associated with the estimated glomerular filtration rate (eGFR) on the seventh day post-transplantation (D7; OR 1.119, 95% CI 1.016–1.233, p = 0.022). Furthermore, the ROC curve value revealed that the AUROC of TIMP-2 on D3 was 0.99 (95% CI 0.97–1, p < 0.001), and this was the best predictive value of the renal function on D7. ConclusionsDonor serum TIMP-2 and uNAG levels are useful predictive biomarkers because they can provide the donor-based prediction for RGF.

Single-cell analysis of graft-infiltrating host cells identifies caspase-1 as a potential therapeutic target for heart transplant rejection.

Understanding the cellular mechanisms underlying early allograft rejection is crucial for the development of effective immunosuppressant strategies. This study aims to investigate the cellular composition of graft-infiltrating cells during the early rejection stage at a single-cell level and identify potential therapeutic targets. A heterotopic heart transplant model was established using enhanced green fluorescent protein (eGFP)-expressing mice as recipients of allogeneic or syngeneic grafts. At 3 days post-transplant, eGFP-positive cells infiltrating the grafts were sorted and subjected to single-cell RNA-seq analysis. Potential molecular targets were evaluated by assessing graft survival and functions following administration of various pharmacological inhibitors. A total of 27,053 cells recovered from syngrafts and allografts were classified into 20 clusters based on expression profiles and annotated with a reference dataset. Innate immune cells, including monocytes, macrophages, neutrophils, and dendritic cells, constituted the major infiltrating cell types (>90%) in the grafts. Lymphocytes, fibroblasts, and endothelial cells represented a smaller population. Allografts exhibited significantly increased proportions of monocyte-derived cells involved in antigen processing and presentation, as well as activated lymphocytes, as compared to syngrafts. Differential expression analysis revealed upregulation of interferon activation-related genes in the innate immune cells infiltrating allografts. Pro-inflammatory polarization gene signatures were also enriched in these infiltrating cells of allografts. Gene profiling and intercellular communication analysis identified natural killer cells as the primary source of interferon-γ signaling, activating inflammatory monocytes that displayed strong signals of major histocompatibility complexes and co-stimulatory molecules. The inflammatory response was also associated with promoted T cell proliferation and activation in allografts during the early transplant stages. Notably, caspase-1 exhibited specific upregulation in inflammatory monocytes in response to interferon signaling. The regulon analysis also revealed a significant enrichment of interferon-related motifs within the transcriptional regulatory network of downstream inflammatory genes including caspase-1. Remarkably, pharmacological inhibition of caspase-1 was shown to reduce immune infiltration, prevent acute graft rejection, and improve cardiac contractile function. The single-cell transcriptional profile highlighted the crucial role of caspase-1 in interferon-mediated inflammatory monocytes infiltrating heart transplants, suggesting its potential as a therapeutic target for attenuating rejection.

Baricitinib with cyclosporine eliminates acute graft rejection in fully mismatched skin and heart transplant models.

Solid organ transplant represents a potentially lifesaving procedure for patients suffering from end-stage heart, lung, liver, and kidney failure. However, rejection remains a significant source of morbidity and immunosuppressive medications have significant toxicities. Janus kinase (JAK) inhibitors are effective immunosuppressants in autoimmune diseases and graft versus host disease after allogeneic hematopoietic cell transplantation. Here we examine the role of JAK inhibition in preclinical fully major histocompatibility mismatched skin and heart allograft models. Baricitinib combined with cyclosporine A (CsA) preserved fully major histocompatibility mismatched skin grafts for the entirety of a 111-day experimental period. In baricitinib plus CsA treated mice, circulating CD4+T-bet+ T cells, CD8+T-bet+ T cells, and CD4+FOXP3+ regulatory T cells were reduced. Single cell RNA sequencing revealed a unique expression profile in immune cells in the skin of baricitinib plus CsA treated mice, including decreased inflammatory neutrophils and increased CCR2- macrophages. In a fully major histocompatibility mismatched mismatched heart allograft model, baricitinib plus CsA prevented graft rejection for the entire 28-day treatment period compared with 9 days in controls. Our findings establish that the combination of baricitinib and CsA prevents rejection in allogeneic skin and heart graft models and supports the study of JAK inhibitors in human solid organ transplantation.

Heterotopic intestine and abdominal wall transplantation in a miniature swine: A model for graft immunology.

In order to accurately monitor graft immunology, we have developed a method for performing intestine and abdominal wall transplantation heterotopically in miniature swine. The procedure consisted of simultaneous segmental terminal ileum and full-thickness abdominal wall transplantation in Lanyu miniature swine, with the intestinal and the abdominal wall grafts being placed on the recipient's bilateral rear flank. Five transplantations were technically successful. One animal died on the first post-transplant day due to anesthesia-related issues, three abdominal wall and four intestinal grafts survived, while one abdominal wall graft failed due to vascular thrombosis. Acute cellular rejection (ACR) of the intestinal graft could occur preceding, simultaneously with or following ACR of the abdominal wall graft. Our experimental model demonstrates the technical feasibility of heterotopic intestine and abdominal wall transplantation in miniature swine without grafting in gastrointestinal continuity. This model could be suitable for further studies of graft immunology.

Peripheral Blood Absolute Lymphocyte Count as a Predictor of Cytomegalovirus Infection in Kidney Transplant Recipients

Cytomegalovirus viremia and infection have been reported to increase the risks for acute graft rejection and mortality in kidney transplant recipients. Previous studies demonstrated that a lower absolute lymphocyte count in peripheral blood is associated with cytomegalovirus infection. The aim of this study was to investigate whether absolute lymphocyte count could predict cytomegalovirus infection in kidney transplant recipients. From January 2010 to October 2021, 48 living kidney transplant recipients in whom both donor and recipient were positive for immunoglobulin G of cytomegalovirus were included in this retrospective study. The primary outcome was defined as cytomegalovirus infection occurring ≥28 days after kidney transplantation. All recipients were followed for 1 year after kidney transplantation. The diagnostic accuracy of absolute lymphocyte count on day 28 post-transplantation for cytomegalovirus infection was analyzed using receiver operating characteristic curves. A Cox proportional hazards model was used to calculate hazard ratios for the incidence of cytomegalovirus infection. There were 13 patients (27%) with cytomegalovirus infection. The sensitivity and specificity for cytomegalovirus infection were 62% and 71%, respectively; the negative predictive value was 83% when an absolute lymphocyte count of 1100 cells/μL on day 28 post-transplantation was used as the cutoff. The incidence of cytomegalovirus infection was significantly higher when the absolute lymphocyte count was <1100 cells/μL on day 28 post-transplantation (hazard ratio, 3.32; 95% CI, 1.08-10.2). Absolute lymphocyte count is an inexpensive and easy test that can effectively predict cytomegalovirus infection. Further validation is needed to confirm its utility.

Gut Microbiota and Liver Transplantation: Immune Mechanisms behind the Rejection.

Liver transplantation (LT) is the treatment of choice for patients with cirrhosis, decompensated disease, acute liver failure, and hepatocellular carcinoma (HCC). In 3-25% of cases, an alarming problem is acute and chronic cellular rejection after LT, and this event can lead to the need for new transplantation or the death of the patient. On the other hand, gut microbiota is involved in several mechanisms sustaining the model of the "gut-liver axis". These include modulation of the immune response, which is altered in case of gut dysbiosis, possibly resulting in acute graft rejection. Some studies have evaluated the composition of the gut microbiota in cirrhotic patients before and after LT, but few of them have assessed its impact on liver rejection. This review underlines the changes in gut microbiota composition before and after liver transplantation, hypothesizing possible immune mechanisms linking dysbiosis to transplantation rejection. Evaluation of changes in the gut microbiota composition in these patients is therefore essential in order to monitor the success of LT and eventually adopt appropriate preventive measures.

The results of orthotopic heart transplantation using the bicaval technique

Circulatory failure, which develops in the final stages of the course of the most heart diseases, is a link in the progressive process. This process is accompanied by a significant decrease in the quality of life, as well as high disability and mortality.&#x0D; Heart transplantation increases the survival of patients with chronic heart failure, increases tolerance to physical exertion, improves the quality of life of patients and allows most of them to return to vigorous activity.&#x0D; Aim. The work is devoted to the analysis of the results of orthotopic heart transplantation in patients with a progressive course of chronic heart failure that cannot be treated conservatively.&#x0D; Materials and methods. We analyzed the clinical course of heart transplants in 55 patients. There were 46 (83.6 %) men and 9 (16.4 %) women among the recipients. The average age was 46.0 ± 10.0 years.&#x0D; Results. The result of the conducted retrospective study revealed that in-hospital (early) and one-year (longterm) survival among patients in our study was 92.7 % and 81.8 %, respectively.&#x0D; Conclusions. Heart transplantation is the most effective method of treatment for terminal heart failure. The quality of life of heart transplant patients improves significantly after surgery and is the main factor in the development of heart transplantation nowadays.&#x0D; The main causes of death were acute graft dysfunction, rejection reactions, and coronary heart disease of the transplanted heart. Problems related to cardiac graft dysfunction and rejection in the early and long-term period still need to be definitively resolved.

#6915 IMMUNOLOGIC EFFECTS OF THE DECREASE OF IMMUNOSUPPRESSION AFTER SARS-COV-2 INFECTION IN KIDNEY TRASPLANT RECIPIENTS

Abstract Background and Aims The decrease of immunosuppression (IS) in kidney transplant (KT) recipients with SARS-CoV-2 infection was proposed during the first years of the pandemic due to the lack of knowledge of the course of the infection and the absence of vaccines and specific treatment. The effects of this decrease are being assessed in a medium-long term. Method Unicentric retrospective study that included 19 patients with a kidney biopsy after a SARS-CoV-2 infection (120 days). We measured acute kidney injury (AKI) after de infection, decrease in the IS during the infection, rejection episodes and renal function evolution during 24 months after the infection. Results The studied group was constituted by 19 patients from which 57.9% (11/19) men, age 56 (51, 70), being the first KT in 78.9% (15/19) of them. The IS induction was in a 57.9% (11/19) Basilximab and in a 42.1% (8/19) thymoglobulin, and the usual IS of all of them was done with prednisone, tacrolimus and mycophenolic acid. There was a graft loss in 26.3% (5/19), being all of immunologic cause, and 10.5% (2/19) of patients died. The severity of the SARS-CoV-2 infection was different between patients (21.1% (4/11) asymptomatic, 47.1% (9/19) mild respiratory symptoms, 5.3% (1/19) severe pneumonia not requiring critical care unit and 26.3% (5/19) severe pneumonia requiring critical care unit, with a decrease in IS in a 42% (8/19) of patients (steroids in monotherapy in a 31.6% (6/19) and bitherapy with steroids and tacrolimus in a 10,5% (2/19), to achieve 5-7ng/mL blood levels). AKI was found after the first month after the infection in a 57.9% (11/19) of patients, being in a 42% (8/19) AKI KDIGO1 and in a 16% (3/19) AKI KDIGO3. Renal function kept worsening until the sixth month after the infection [CKDEPI before SARS-CoV-2 37mL/min (32, 45) vs CKDEPI 6months after 34mL/min (22, 48.3); p = 0.3]. There was an improvement in renal function in 12 months after the infection (38mL/min (25, 48)). Acute graft rejection was detected in renal biopsies after the infection in 31.6% (6/19) being cellular in 15.8% (3/19), humoral in 10.5% (2/19) and mixed in 5.3% (1/19), de novo DSA were found in 15.8% (3/19). Conclusion The decrease in IS after SARS-CoV-2 in KT recipient has an elevated immunologic price. Glomerular filtrate rate decreases after 6 months from infection with a recovery at 1 year.

#2649 INFECTIOUS COMPLICATIONS AFTER KIDNEY TRANSPLANTATION IN RELATION TO INDUCTION IMMUNOSUPPRESSIVE THERAPY

Abstract Background and Aims Infections are the most common non-cardiac cause of death after kidney transplantation (KT). The main goal of immunosuppressive therapy is to find a balance between the low incidence of acute rejection and infectious complications. Method We conducted a retrospective, monocentric analysis of transplant patients at the Transplant Center University Hospital Martin from 2011 to 2020 with various induction immunosuppressive therapies. We monitored the incidence of infections in terms of etiology, localization and severity at different intervals after KT. Results Our study included 39 patients on induction therapy with basiliximab to whom we paired 39 patients with induction therapy with thymoglobulin based on gender and age, in total our population consisted of 78 patients (56 men, 22 women), the mean age was 45 years. In the group of patients with induction therapy with thymoglobulin, we noted a higher proportion of fungal (P=0.0409), urogenital infections (P=0.0384), sepsis (P=0.0497) and leukopenia (0.0384) from 1st to 6th month after KTx, higher incidence of skin infections (P= 0.0218) and serious infections requiring hospitalization (P = 0.0269) from 6th-12th months to TO. On the other hand, in the basiliximab patient group, we identified a higher incidence of acute humoral and cellular rejection (P=0.0218) after 6 months of TO. From the perspective of recurrent infections, in the Thymoglobulin induction group, we noted a higher incidence of infections by localization, etiology and severity. Risk factors for recurrent bacterial infections from 1st to 6th month after KT are: history of respiratory diseases (P = 0.0108), thrombocytopenia (P = 0.0104) and infections caused by multi-resistant bacteria (P = 0.0003). Conclusion Patients on inductive immunosuppressive therapy with thymoglobulin are at a higher risk of recurrent, multidrug-resistant and severe infections after KT compared to induction with basiliximab with identical maintenance immunosuppressive therapy. On the other hand, patients on induction therapy with basiliximab have a higher risk of developing acute rejection. Therefore, it is essential to identify risk groups of patients benefiting from milder or more intensive inductive immunosuppressive therapy without a concomitant increased risk of infectious complications or acute graft rejection