Rejection Episodes Research Articles

Assessment of CTLA-4 Gene Expression Levels on CD8+ T Cells in Renal Transplant Patients and Relation with Serum sCTLA-4 Levels.

CTLA-4 (Cytotoxic T Lymphocyte Antigen-4) is an immune regulator molecule that is expressed on a variety of immune cells, including CD4+ and CD8+ T cells. After realizing the significance of this regulator molecule, researchers began to concentrate on its activation or inhibition in cancer. Even though there have been some studies on organ transplantation and autoimmunity, the role of the CTLA-4 molecule in renal transplantation has not been demonstrated. The goal of this study was to see how CTLA-4 gene expression and serum sCTLA-4 levels affected renal transplant patients. Peripheral blood samples were collected before and 1-3 months after renal transplantation from 29 recipients.CD8+ T lymphocytes were separated using magnetic beads and purity of the cells controlled by Flow cytometry. CTLA-4 mRNA levels were determined by Real-Time PCR while serum sCTLA-4 levels were assessed by ELISA. 55% of the patient had decreased level of CTLA-4 mRNA after transplantation when compared to pre-transplantation levels. Moreover 61% of the patient had lower serum sCTLA-4 levels after transplantation. sCTLA-4 levels were decreased 11% of the patients with rejection episode after transplantation when compared to stabile patients (5%). Kidney rejection is a complicated process influenced by numerous unknown factors. Several parameters should be evaluated together to precise rejection episodes or graft dysfunctions. Further research focused on the other immune checkpoint regulator molecules could give an opportunity to have an idea about the effect of these molecules on renal transplantation.

Immunosuppressive strategies in face and hand transplantation: a comprehensive systematic review of current therapy regimens and outcomes.

Recipients of Vascularized Composite Allotransplants require effective immunosuppressive therapy to prevent graft rejection. This systematic review summarizes the current body of literature on immunosuppressive regimens used in face and hand transplants while summarizing their outcome in terms of rejection, renal failure, and infections. A systematic search of electronic databases was conducted to identify relevant studies from 1998 until July 1st, 2023. We included all studies that discussed immunosuppressive strategies in face and hand transplant recipients according to PRISMA. The standard triple maintenance therapy was mostly adjusted due to nephrotoxicity or high incidence of rejection. The most common alternative treatments utilized were sirolimus (25/91; 27.5%) or everolimus (9/91; 9.9%) following hand- and photophoresis (7/45; 15.6%), sirolimus (5/45; 11.1%) or belatacept (1/45; 2.2%) following face transplantation. Episodes of rejection were reported in 60 (65.9%) of hand- and 33 (73%) of face transplant patients respectively. Graft loss of 12 (13.2%) hand and 4 (8.9%) face transplants was reported. Clinical CMV infection was observed in 6 (6.6%) hand and 7 (15.5%) face transplant recipients. Based on the herein presented data, facial grafts exhibited a heightened incidence of rejection episodes and CMV infections. Facial mucosa adds complexity to the immunological graft composition highlighting the need of individualized immunosuppressive regimens and further research.

UV light-mediated corneal crosslinking as (lymph)angioregressive pretreatment to promote graft survival after subsequent high-risk corneal transplantation (CrossCornealVision): protocol for a multicenter, randomized controlled trial

BackgroundGood vision highly depends on the transparency of the cornea, which is the “windscreen” of the eye. In fact, corneal blindness due to transparency loss is the second most common cause of blindness worldwide, and corneal transplantation is the main cure. Importantly, the cornea is normally avascular but can secondarily be invaded by pathological (blood and lymphatic) vessels due to severe inflammation, and the survival prognosis of a corneal graft mainly depends on the preoperative vascular condition of the recipient’s cornea. Whereas transplants placed into avascular recipient beds enjoy long-term survival rates of > 90%, survival rates significantly decrease in pathologically pre-vascularized, so-called high-risk recipients, which account for around 10% of all performed transplants in Germany and > 75% in lower and middle-income countries worldwide.MethodsThis parallel-grouped, open-randomized, multicenter, prospective controlled exploratory investigator-initiated trial (IIT) intends to improve graft survival by preconditioning pathologically vascularized recipient corneas by (lymph)angioregressive treatment before high-risk corneal transplantation. For this purpose, corneal crosslinking (CXL) will be used, which has been shown to potently regress corneal blood and lymphatic vessels. Prior to transplantation, patients will be randomized into 2 groups: (1) CXL (intervention) or (2) no pretreatment (control). CXL will be repeated once if insufficient reduction of corneal neovascularization should be observed. All patients (both groups) will then undergo corneal transplantation. In the intervention group, remaining blood vessels will be additionally regressed using fine needle diathermy (on the day of transplantation). Afterwards, the incidence of graft rejection episodes will be evaluated for 24 months (primary endpoint). Overall graft survival, as well as regression of corneal vessels and/or recurrence, among other factors, will be analyzed (secondary endpoints).DiscussionBased on preclinical and early pilot clinical evidence, we want to test the novel concept of temporary (lymph)angioregressive pretreatment of high-risk eyes by CXL to promote subsequent corneal graft survival. So far, there is no evidence-based approach to reliably improve graft survival in the high-risk corneal transplantation setting available in clinical routine. If successful, this approach will be the first to promote graft survival in high-risk transplants. It will significantly improve vision and quality of life in patients suffering from corneal blindness.Trial registrationClinicalTrials.gov NCT05870566. Registered on 22 May 2023.

A modern heart transplant rejection surveillance protocol utilizing cell-free DNA: A single-center experience

INTRODUCTIONEndomyocardial biopsy (EMBx) is considered the gold standard for rejection monitoring after heart transplantation; however, it is invasive and histologic interpretation has limitations. Sensitive blood biomarkers including donor-derived cell-free DNA (dd-cfDNA) have emerged to decrease EMBx frequency. METHODSWe retrospectively reviewed data on 237 patients who underwent heart transplantation at our institution. Of these, 125 patients underwent monitoring using dd-cfDNA, combined with a fewer number of EMBx, and 112 patients underwent monitoring using EMBx only. We compared rates of rejection, graft dysfunction, and survival at 1 year. RESULTSMedian age at time of transplant was 59.8 years, and 77.6% were men. In the dd-cfDNA group, there were significantly fewer episodes of EMBx defined ACR (2.5% vs. 18.8%, P<0.001) and treated ACR (4.2% vs. 19.6%, P=0.001). Comparatively, there were more EMBx defined AMR (5% vs. 0.9%) and treated AMR (5% vs. 2.7%) in the dd-cfDNA group. No significant differences were observed in graft dysfunction, presence of donor-specific antibodies, or survival at 1 year. CONCLUSIONSIn conclusion, a modern rejection surveillance protocol utilizing non-invasive testing is safe, led to significantly fewer EMBx, fewer treated rejection episodes, and no difference in survival at 1 year. More AMR episodes identified via dd-cfDNA could lead the way for more accurate diagnostic and treatment decisions.

Post-Transplant Glomerulonephritis: Challenges and Solutions.

Glomeruli can be damaged in several conditions after kidney transplantation, with a potential impact on the graft function and survival. Primary glomerulonephritis, a group of glomerular immunological damage that results in variable histological patterns and clinical phenotypes, can occur in kidney transplant recipients as a recurrent or de novo condition. Specific immunologic conditions associated with kidney transplantation, such as acute rejection episodes, can act as an additional trigger after transplantation, impacting the incidence of these glomerulopathies. The post-transplant GN recurrence ranges from 3% to 15%, varying according to the GN subtype and post-transplant time, mainly occurring after 3-5 years of kidney transplantation. Advances in the knowledge of glomerulonephritis pathophysiology have provided new approaches to pre-transplant risk evaluation and post-transplant monitoring. Glomeruli can be affected by several systemic viral infections, such as human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis B virus (HBV), severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), cytomegalovirus (CMV), and BK virus. The diagnosis of these infections, as well as the identification of possible complications associated with them, are important to minimize the negative impacts of these conditions on kidney transplant recipients' outcomes.

Clinicopathologic Spectrum and Outcomes of Infections Diagnosed on Graft Biopsies and Nephrectomy in Live Renal Allograft Recipients: An Institutional Experience.

Modern immunosuppressive regimens have reduced rejection episodes in renal allograft recipients but have increased the risk of opportunistic infections. Infections are considered to be the second leading cause of death after cardiovascular complications in renal allograft recipients. Data on opportunistic infections affecting the allograft itself are scarce. The present study describes the spectrum of renal opportunistic infections and their outcomes diagnosed on renal allograft biopsies and nephrectomy specimens. Our retrospective observational study was conducted from December 2011 to December 2021. We analyzed infectious episodes diagnosed on renal allograft biopsies or graft nephrectomy specimens. We obtained clinical, epidemiological, and laboratory details for analyses from hospital records. BK virus nephropathy was the most common opportunistic infection affecting the allograft, accounting for 47% of cases, followed by bacterial graft pyelonephritis (25%). Mucormycosis was the most common fungal infection. The diagnosis of infection from day of transplant ranged from 14 days to 39 months. Follow-up periods ranged from 1 to 10 years. Mortality was highest among patients with opportunistic fungal infection (62%), followed by viral infections, and graft failure rate was highest in patients with graft pyelonephritis (50%). Among patients with BK polyomavirus nephropathy, 45% had stable graft function compared with just 33% of patients with bacterial graft pyelonephritis. BK polyoma virus infection was the most common infection affecting the renal allograft in our study. Although fungal infections caused the highest mortality among our patients, bacterial graft pyelonephritis was responsible for maximum graft failure. Correctly identifying infections on histology is important so that graft and patient life can be prolonged.

Rejection in the setting of combined Heart and Liver Transplantation

IntroductionEach year the number of combined heart-liver transplants (HLT) increases, with two distinct patient populations proceeding down this pathway. The first are patients with congenital heart disease (CHD), most commonly single ventricle patients palliated with Fontan. The second group are those with long standing congestive hepatopathy, amyloidosis, hemochromatosis, or alcohol induced myopathies and liver disease.One argument for HLT has been the low rate of rejection even among sensitized patients, with reported rejection rates ranging from 0% to 31%. Historically, those with CHD have been highly sensitized which in some cases may prevent or at least delay transplantation. As such, a recent consensus statement by Emamaulee et al. suggest that “there may be an immunological benefit to proceed with HLT with significantly fewer acute cellular and humoral rejection episodes”. The aim of this study is to demonstrate that HLT patients remain at risk for rejection and have required treatment for it. ResultsThere were 15 patients who underwent HLT from January 2017 to February 2022. Of the four patients who did not have CHD, none were considered sensitized, and all underwent induction with basiliximab per our institutional protocol. One of these had rejection. Rejection episodes were identified in four of the 11 CHD patients (36%) patients. ConclusionsIn our study of 15 HLT, including 11 CHD patients (73% denied transplant at ≥ 1 center) demonstrated a higher rate of rejection than previously reported. While theoretically, HLT may mitigate the likelihood of rejection, the risk still exists, and patients benefit from close monitoring commensurate with single organ transplant.

Solid organ transplantation and gut microbiota: a review of the potential immunomodulatory properties of short-chain fatty acids in graft maintenance.

Transplantation is the treatment of choice for several end-stage organ defects: it considerably improves patient survival and quality of life. However, post-transplant recipients may experience episodes of rejection that can favor or ultimately lead to graft loss. Graft maintenance requires a complex and life-long immunosuppressive treatment. Different immunosuppressive drugs (i.e., calcineurin inhibitors, glucocorticoids, biological immunosuppressive agents, mammalian target of rapamycin inhibitors, and antiproliferative or antimetabolic agents) are used in combination to mitigate the immune response against the allograft. Unfortunately, the use of these antirejection agents may lead to opportunistic infections, metabolic (e.g., post-transplant diabetes mellitus) or cardiovascular (e.g., arterial hypertension) disorders, cancer (e.g., non-Hodgkin lymphoma) and other adverse effects. Lately, immunosuppressive drugs have also been associated with gut microbiome alterations, known as dysbiosis, and were shown to affect gut microbiota-derived short-chain fatty acids (SCFA) production. SCFA play a key immunomodulatory role in physiological conditions, and their impairment in transplant patients could partly counterbalance the effect of immunosuppressive drugs leading to the activation of deleterious pathways and graft rejection. In this review, we will first present an overview of the mechanisms of graft rejection that are prevented by the immunosuppressive protocol. Next, we will explain the dynamic changes of the gut microbiota during transplantation, focusing on SCFA. Finally, we will describe the known functions of SCFA in regulating immune-inflammatory reactions and discuss the impact of SCFA impairment in immunosuppressive drug treated patients.

Conversion from twice-daily everolimus to once-daily sirolimus in long-term stable liver transplant recipients

BackgroundAfter organ transplantation, strategies for simplifying the therapeutic regimen may improve adherence and prevent acute organ rejection and/or late graft loss. The present study aimed to evaluate the safety and efficacy of conversion from everolimus (EVR) twice daily to sirolimus (SIR) once daily in a large cohort of liver transplantation (LT) patients. MethodsWe included 108 LT patients with at least 12 months of post-transplant follow-up and no rejection episodes in the last year. Conversion was based on a 1:1 ratio (but eventually adapted to available formulations of SIR). ResultsThe median age at the time of conversion was 68.9 years (range: 26.1–83.6); 75.0% were men. The main indications for mTOR inhibitor use were renal failure (38.9%) and/or a history of malignancy (37.0%). Median conversion time after LT was 14.8 years (range: 2.3–31.5). The median dose of EVR and SIR (initially) was 1.50 mg/day (range: 0.5–4.5). The mean follow-up after conversion was 15.8±4.4 months. Median serum EVR/SIR trough levels before/after conversion were 3.85 ng/mL vs. 6.32 ng/mL (p < 0.05), i.e. a 1:1.64 ratio. At the end of follow-up after conversion, the median dose of SIR was 1.25 mg/day (range: 0.5–3.5), and the mean serum SIR trough level was 5.23 ng/mL; 9 patients (8.3%) had returned to EVR, because of side effects (mainly digestive), that resolved thereafter. No biopsy-proven acute rejection episode was observed. Finally, 87.1% of patients considered the conversion beneficial and the cost was reduced by 50.3%. ConclusionThe results of our study indicate that conversion from once-daily EVR to once-daily SIR in stable LT patients is safe, but needs dose adaptations and careful monitoring.

Lithium-Associated Kidney Failure: Predictors and Outcomes

Despite the widespread use of lithium for bipolar disorders and depression, little is known about the characteristics of patients with lithium-associated kidney failure receiving kidney replacement therapy (KRT). We conducted a retrospective study using the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA) to investigate the predictors and outcomes of patients with lithium-associated kidney failure receiving KRT. A total of 437 patients with lithium-associated kidney failure were compared to 1280 ANZDATA allocated controls of patients with kidney failure not associated with lithium. Patients with lithium-associated kidney failure commenced KRT at significantly older age (62 ± 10 vs. 58 ± 15 years; P< 0.001) and were more likely to be European (93% vs. 68%, P< 0.001), to be female (63% vs. 40%, P< 0.001), and to live in a postcode with a higher socioeconomic status (SES) (P< 0.001). In patients with lithium-associated kidney failure, there were lower rates of coronary artery disease (17% vs. 37%, P< 0.001), peripheral vascular disease (7% vs. 25%, P< 0.001), cerebrovascular disease (8% vs. 14%, P= 0.004) and diabetes mellitus (16% vs. 47%, P< 0.001). There were no differences between first KRT modality, although kidney transplantation and retransplantation rates were lower (21% vs. 27%, P= 0.008; 0.2% vs 3%, P= 0.001) with shorter wait-times to first transplantation (20 months vs. 29 months, P= 0.02) in the patients with lithium-associated kidney failure. Rates of at least 1 rejection episode was comparable (21% vs. 22%, P= 0.85) between the 2 groups. In addition, there were no survival differences regardless of KRT modality between the 2 groups. Lithium-associated kidney failure represents a unique cohort which is predominantly older, female, European, with a higher SES and less comorbidities. Despite this, there are no differences in survival. Given the lower rate of transplantation, barriers to transplantation need further exploration.

Peri-operative and long-term outcomes of kidney transplantation in patients with cystic fibrosis.

There is a lack of data regarding the peri-operative and long-term outcomes of kidney transplantation in cystic fibrosis (CF) patients. Herein, we report the peri-operative and long-term outcomes of kidney transplantation in CF patients. All CF patients who received a kidney transplant at the national kidney transplant center between 1993 and 2022 were identified. Recipients of the contralateral donor kidney were selected as a control group. Primary outcomes included 1-, 5-, and 10- year death-censored graft survival and overall survival. Secondary outcomes included peri-operative morbidity, acute graft rejection, delayed graft function (DGF), and length of stay (LOS). Fourteen patients received a kidney transplant over the study period. Median age at transplantation was 35 (IQR 31, 40) years. The 1-, 5-, and 10-year death-censored graft survival was 92, 74, and 74% in the CF group compared to 100, 92, and 92% in the control group (p=.44). The 1-, 5-, and 10-year overall survival in the CF group was 85, 66, and 57% compared to 100, 92, and 82% in the control group (p=.036). There was no significant difference in peri-operative outcomes including LOS (10vs. 11 days, p=.84), ICU admission (1vs. 0 patients, p>.99), acute rejection episodes (2vs. 1 patients, p>.99), and DGF (1vs. 2 patients, p=.60). CF patients have good long-term graft survival, however, overall survival was worse compared to a matched cohort. These data provide important information for transplant surgeons when considering suitable donor allografts in this unique patient population.

CLINICAL OUTCOMES OF INFLAMMATORY BOWEL DISEASE AFTER ORTHOTOPIC HEART TRANSPLANT

Abstract BACKGROUND Limited data are available on outcomes of patients with pre-existing inflammatory bowel disease (IBD) who undergo orthotopic heart transplantation (OHT) or develop de novo IBD post-OHT. We aimed to assess the incidence and disease outcomes of pre-existing and de novo IBD in OHT patients while evaluating the effect of IBD on OHT outcomes. METHODS A retrospective review of records was performed from a tri-site tertiary care system between July 2000 and July 2022. A total of 83 OHT receipients were concomitantly diagnosed with colitis of infectious or inflammatory etiology. Only patients with a diagnosis of IBD were included. Sub-analyses of the outcomes and immunosuppressive regimens of OHT recepients were done relative to those with pre-existing or de novo IBD. RESULTS A total of 8 OHT patients with concomitant IBD were identified. The median patient age (IQR) was 54 (23) with OHT and IBD onset at 50 (21.2) and 32.5 (15.7), respectively. Six patients were diagnosed with ulcerative colitis (UC) and 2 were diagnosed with Crohn’s disease. Five of the patients were female. All patients developed IBD within 11.5 (8) years within OHT. Only 1 patient developed de novo IBD 15 years after the first OHT and 7 years prior to a second OHT. OHT immunosuppressive regimens included a combination of tacrolimus (TAC) and prednisone (n=2), TAC and mycophenolate mofetil (MMF) (n=2), TAC, MMF, and sirolimus (n=2), TAC and sirolimus (n=1), and MMF with sirolimus (n=1). Therapy for pre-existing IBD included maintenance of 5-aminosalicylic (5-ASA) (n=3), escalation to vedolizumab (VD) (n=2), and discontinuation of IBD therapy (5-ASA and azathioprine) (n=3). De novo IBD consistent with UC (15 years post-OHT) was managed with 5-ASA (n=1). Six patients (including de novo IBD case) maintained clinical and endoscopic remission of IBD with no flares post-OHT while 2 patients (1 UC and 1 CD) with active disease flares responded clinically and endoscopically to VD escalation from 5-ASA and azathioprine. Among two UC patients with ileal J-pouch pre-OHT, 1 developed refractory pouchitis requiring diverting ileostomy (while on TAC and prednisone) with no pouchitis in the other (maintained on TAC and MMF). Good graft tolerance limited to mild acute cellular rejection episodes was noted in 6 patients, while multiple or no rejection episodes were noted in the remaining two. None of the patients developed CMV or MMF-induced colitis. One patient died due to progressive functional decline unrelated to graft failure or IBD. DISCUSSION The clinical course and treatment of IBD preceding OHT or de novo (though rare) is not significantly worsened or altered post-OHT. The majority of patients achieve clinical and endoscopic remission while on heart transplant-related immunosuppression. Biologic therapy escalation to VD resulted in clinical remission with no effect on graft tolerance. Table 1 Clinical outcomes of OHT patients with concomitant IBD

P358 Impact of end-ileostomy versus ileal pouch-anal anastomosis on graft-survival following liver transplantation for primary sclerosing cholangitis

Abstract Background IBD-PSC patients may require both liver transplantation and ileoanal pouch (IPAA) construction. Recently, concerns have been raised regarding an increased rates of hepatic artery thrombosis, biliary strictures, and graft loss in individuals who underwent IPAA after liver transplantation compared to those who underwent end-ileostomy (EI). We hypothesized that graft survival was not negatively affected by IPAA compared with EI. Methods A prospectively maintained database from a large tertiary center was searched for patients meeting the inclusion criteria for liver transplantation, primary sclerosing cholangitis, ulcerative colitis, and total colectomy with IPAA or EI. Univariate analysis and Kaplan-Meier survival curves were calculated. Results Between January 1990 and December 2023, 55 patients met inclusion criteria. Of these, 46 (83.6%) underwent IPAA, and 9 (16.4%) underwent EI. The average age at colectomy (41.7 vs. 45.7 years; p=0.44), sex distribution (female: 26.1% vs. 22.2%, p=1), and MELD score before transplantation (20.3 vs. 14; p=0.06) were comparable between patients with IPAA and EI patients. The rates of re-transplantation (21.7% vs. 22.2%; p=1), hepatic artery thrombosis (8.7% vs. 0; p=1), episodes of acute rejection (32.6% vs. 44.4%; p=0.7), chronic rejection (4.3% vs. 11.1%; p=0.42), recurrence of primary sclerosing cholangitis (23.9% vs. 22.2%; p=1), and biliary complications (21.7% vs. 33.3%; p=0.43) were similar between the IPAA and EI groups, respectively. None of the EI patients developed parastomal varices. Survival analyses for time to re-transplantation (p=0.97), overall survival (p=0.3), and time to graft loss or mortality (p=0.73) were similar. Conclusion In contrast to a previous study, we observed similar rates of liver transplant graft loss, biliary complications, and recurrent PSC after IPAA compared to those after end-ileostomy. IPAA may be associated with an increased rate of hepatic artery thrombosis.

Serum uric acid concentration is associated with lower glomerular filtration rate in children undergoing kidney transplantation.

The relationship between serum concentration of uric acid (UA) and chronic kidney disease is complex due to many confounding variables. There is currently debate over whether hyperuricemia acts as a marker of kidney disease or as an independent risk factor. To test the impact of serum UA concentration on the estimated glomerular filtration rate (GFR) of children undergoing kidney transplantation. Prospective longitudinal study of children and adolescents after kidney transplantation. We analyzed clinical, anthropometric, and laboratory data at pre-transplant and 1, 3, and 6 months after transplant. We developed models of repeated measures analysis, using the generalized estimating equations technique for the outcome evolution of the estimated GFR at 1, 3 and 6 months. High serum UA concentration at 1 and 3 months was modeled as the main exposure variable. We included 103 transplant patients. In a model adjusted for time, recipient sex and age, the occurrence of acute rejection episodes, and the estimated glomerular filtration at baseline, the trajectory of GFR exhibited an inverse relationship with UA (β = -7.1, 95% CI: -11.5 to -2.6, p < .01). Serum UA increase was associated with lower graft function over time.

Durable immunity to EBV after rituximab and third-party LMP-specific T cells: a Children’s Oncology Group study

AbstractPosttransplant lymphoproliferative disease (PTLD) in pediatric solid organ transplant (SOT) recipients is characterized by uncontrolled proliferation of Epstein-Barr virus–infected (EBV+) B cells due to decreased immune function. This study evaluated the feasibility, safety, clinical and immunobiological outcomes in pediatric SOT recipients with PTLD treated with rituximab and third-party latent membrane protein–specific T cells (LMP-TCs). Newly diagnosed (ND) patients without complete response to rituximab and all patients with relapsed/refractory (R/R) disease received LMP-TCs. Suitable LMP-TC products were available for all eligible subjects. Thirteen of 15 patients who received LMP-TCs were treated within the prescribed 14-day time frame. LMP-TC therapy was generally well tolerated. Notable adverse events included 3 episodes of rejection in cardiac transplant recipients during LMP-TC therapy attributed to subtherapeutic immunosuppression and 1 episode of grade 3 cytokine release syndrome. Clinical outcomes were associated with disease severity. Overall response rate (ORR) after LMP-TC cycle 1 was 70% (7/10) for the ND cohort and 20% (1/5) for the R/R cohort. For all cohorts combined, the best ORR for LMP-TC cycles 1 and 2 was 53% and the 2-year overall survival was 70.7%. vβT-cell receptor sequencing showed persistence of adoptively transferred third-party LMP-TCs for up to 8 months in the ND cohort. This study establishes the feasibility of administering novel T-cell therapies in a cooperative group clinical trial and demonstrates the potential for positive outcomes without chemotherapy for ND patients with PTLD. This trial was registered at www.clinicaltrials.gov as #NCT02900976 and at the Children's Oncology Group as ANHL1522.

HLA-B*51 Frequency in Transplant Patients and Donors.

HLA molecules play a crucial role in transplantation. The best treatment modality in patients with end-stage renal disease is renal transplant. HLA mismatches between patients and donors can prolong time for renal transplant therapy, reduce graft survival, and increase mortality. HLA region is the most polymorphic genetic region and is essential for antigen presentation. The main target of the recipient's immune system is HLA molecules on the surface of donor cells. HLA-B*51 is associated with Behcet disease, a rare multisystemic disease characterized by autoimmunity and inflammatory processes. In transplant recipients, inflammation and vasculitis are immunologic mechanisms that are responsible for damage of graft tissue. In this retrospective study, we aimed to investigate the frequency of HLA-B*51 in patients diagnosed with end-stage renal disease and in controls and to investigate correlations with rejection episodes. Patients who applied to Baskent University Adana Dr. Turgut Noyan Research and Medical Center (between 2010 and 2022) with end-stage renal disease (n = 1732) and a control group (n = 5277) received HLA typing for class I (HLA-A, HLA-B). Sequence-specific primers or sequencespecific oligonucleotides were used. Among patients diagnosed with end-stage renal disease, 321 had kidney transplant. Frequency of HLA-B*51 was 25.92% in patients and 25.22% in controls. No significant differences were found between patients and controls in the frequency of HLA-B*51. Among kidney transplant recipients with HLA-B*51 (n = 72), 38.89% had rejection episodes and 61.11% had no rejection. No significant association was found between HLA-B*51 allele positivity and rejection. No significant relationship was shown between patients diagnosed with end-stage renal disease and HLA-B*51 positivity. Previous studies support frequency of the HLA-B*51 allele in the control group. Although Behçet disease is known to cause renal vasculitis, HLA-B*51 positivity alone was not associated with vasculitis or inflammation.

Positive Long-Term Outcome of Kidney Allocation via Acceptable Mismatch Program in Highly Sensitized Patients

Introduction: Eurotransplant established the acceptable mismatch (AM) program to facilitate timely kidney transplantations of highly sensitized patients, but long-term granular clinical and immunological outcomes regarding overall graft survival and de novo DSA (dnDSA) formation are still intensively researched. The right choice of induction therapy in patients with differing immunological risk is not conclusively determined, as well as the impact of human leukocyte antigen (HLA) epitope matching on dnDSA formation. Methods: This monocentric, retrospective study analyzed 94 patients transplanted within the AM program between 2000 and 2019 compared to case-control matched cohorts of non- (PRA 0–5%; PRA-0) and intermediately sensitized (PRA 6–84%; PRA-6/84) patients transplanted through Eurotransplant Kidney Allocation System. Results: Estimated 10-year overall graft survival between the PRA-0 and AM cohorts was similar, whereas PRA-6/84 was significantly disadvantageous compared to PRA-0. Estimated 10-year incidence of antibody-mediated rejection rates was significantly lower in the PRA-0 group compared to AM and PRA-6/84 groups. Compared to the AM group, estimated incidence of de novo donor-specific antibody (dnDSA) was significantly lower in PRA-0 patients, with no differences between the AM and PRA-6/84 cohorts. The PRA-6/84 cohort was the only subgroup in which interleukin-2 receptor antagonist (IL2RA) induction was associated with longer overall graft survival, patient survival, and graft survival compared to depleting induction (ATG or OKT3). Broad HLA-A, -B, -DR mismatches (mmABDR) and HLA epitope mismatches determined by Eplets and PIRCHE-II were predictive for dnDSA formation in the total cohort, and the AM subgroup. Discussion: The high efforts expended on AM patients are justified to allow timely organ transplantation with acceptable risk profile and non-inferior outcomes. IL2RA induction in intermediately sensitized patients is associated with superior overall graft survival, patient survival, and graft survival compared to ATG/OKT3 induction, without negative effects on rejection episodes or dnDSA formation. In silico epitope matching might further help reduce dnDSA formation, particularly in high-risk AM patients.

Role of Octreotide and Instillation of Povidone-Iodine in the Treatment of Lymphorrhea in Renal Transplantation: A Comparative Study

Background: Lymphorrhea is a minor complication after kidney transplantation but may develop into a lymphocele and prolong hospital stay. Treatment is conservative based on percutaneous drainage until lymphatic leakage cessation. It has been reported that povidone iodine instillation and octreotide has beneficial effects to treat lymphorrhea after renal transplantation. Aims and Objectives: The aim of this study was to compare the povidone iodine instillation and octreotide treatment in lymphorrea after kidney transplantation. To evaluate the efficacy of povidone iodine and octreotide injection in comparison to control group for the treatment of lymphorrhea in renal transplant patient. Materials and Methods: It was comparative analytical study included 60 recipients of both cadaveric and live kidney allografts with posttransplant lymphorrhea including 20 treated with instillation of betadine solution, 20 with octreotide (0.1 mg three times a day subcutaneously), and 20 was control group (no betadine and octreotide was used). We reviewed the daily amount of fluid collection, duration of lymphorrhea, complications, lymphocele formation, rejection episodes, graft outcomes, and hospital stay. Results: The average duration of lymphorrhea was (8.85 ± 0.88) and (11.6 ± 0.94) and (16.15 ± 0.81) days for the betadine groups, the octreotide groups and control groups respectively. (P &lt; 0.05). No lymphoceles occurred among the betadine group, while three lymphoceles were found among patients treated with octreotide and five lymphocele were found among control groups. No differences were observed for wound infection, graft dysfunction episodes or renal function and death between the groups. No octreotide and povidone related adverse events were noted. Conclusion: The mean length of lymphorrhea was lower with povidone iodine instillation as compared to octreotide treatment. There was a shorter hospital stay and minor patient discomfort in betadine groups. In conclusion, lymphatic leakage after kidney transplantation may be successfully managed by betadine instillation as compared to octreotide and control groups.

Influence of Cyp3A4, Cyp3A5 and ABCB1 Polymorphisms on Tacrolimus Concentrations and Rejection Risk in Indian Kidney Transplant Recipients

Background: Tacrolimus metabolism is known to be determined by gene polymorphisms. Cyp3A5 genotype has most widely been seen to be associated with tacrolimus metabolism. Studies on other genes have produced mixed results. Objective: We studied the association of three polymorphisms CYP3A4*1B (-392 G&gt;A), CYP3A5 (6986 A&gt;G), and ABCB1 (3435 T&gt;C) on tacrolimus levels and their association with either rejection or nephrotoxicity (infection or tacrolimus toxicity) in renal transplant recipients from India. Materials and Methods: In this prospective cohort study, patients who underwent kidney transplantation between July 2018 and July 2023 were studied. Inclusion criteria: Patients who underwent Kidney Transplantation and were (i) on tacrolimus-based immunosuppression and (ii) not on medications known to interact with calcineurin inhibitors, such as ketoconazole, phenytoin, and diltiazem, were studied. Tacrolimus levels, tacrolimus concentration/dose (C/D) and tacrolimus C/D per kg body weight, at monthly time points posttransplant for 6 months and biopsy-proven rejection, infection, tacrolimus toxicity, and acute tubular necrosis data were collected. Results: Three hundred and twenty-seven patients were included in the study. Two hundred and fifty-seven were male and 70 were female. A total of 1402 tacrolimus samples were collected, with an average of 3.2 ± 2.1 samples per patient. Tacrolimus levels were significantly lower in the Cyp3A5 AG and AA GG genotypes versus GG (5.27 ± 2.95 and 6.22 ± 2.79 vs. 8.05 ± 4.83, P &lt; 0.001) as were C/D (3.45 ± 2.29 and 3.37 ± 1.91 vs. 6.47 ± 4.44, P &lt; 0.001) and C/D/W (52.45 ± 33.98 and 52.19 ± 32.61 vs. 98.09 ± 73.80, P &lt; 0.001). Cyp3A5 AA and AG had higher rejection rates than GG (20% vs. 13 vs. 8%, P = 0.03). The relative risk of rejection with A versus G polymorphism was 1.9 (confidence interval: 1.03–3.58), P = 0.03. Cyp3A4 and ABCB1 polymorphism studies did not show any association with the parameters studied. Conclusion: Our study showed that Cyp3A5 gene polymorphisms were significantly associated with tacrolimus metabolism, rejection episodes, and rejection risk. Cyp3A4 and ABCB1 were not significantly associated with the parameters studied.

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.