Risk Of Graft Rejection Research Articles

Antithymocyte Globulin Inhibits CD8+ T Cell Effector Functions via the Paracrine Induction of PDL-1 on Monocytes.

Antithymocyte globulins (ATG) are T cell-depleting antibodies used in solid organ transplantation for induction therapy in sensitized patients with a high risk of graft rejection. Previously described effects besides the depletion of T cells have suggested additional modes of action and identified further cellular targets. We examined the transcriptional changes arising in immune cells from human blood after ex vivo stimulation with ATG at the single-cell level to uncover additional mechanisms by which ATG regulates T cell activity and effector functions. Analysis of the paracrine factors present in the plasma of ATG-treated whole blood revealed high levels of chemokines and cytokines, including interferon-γ (IFN-γ). Furthermore, we identified an increase in the surface expression of the programmed death ligand 1 (PDL-1) on monocytes mediated by the released paracrine factors. In addition, we showed that this induction is dependent on the activation of JAK/STAT signaling via the binding of IFN-γ to interferon-γ receptor 1 (IFN-γR1). Lastly, we demonstrated that the modulation of the immune regulatory axis of programmed cell death protein 1 (PD1) on activated CD8+ T cells with PDL-1 found on monocytes mediated by ATG potently inhibits effector functions including the proliferation and granzyme B release of activated T cells. Together, our findings represent a novel mode of action by which ATG exerts its immunosuppressive effects.

Pilot longitudinal kidney transplant transition program promotes peer connections and transition readiness.

Adolescents who have received a kidney transplant are at high risk of graft rejection and transplant-related comorbidities around the time of transition from pediatric to adult care. While there has been a progress in tracking transition readiness, further work is needed to prepare adolescents for healthcare transitions. We describe a longitudinal cohort-based transition curriculum designed to prepare kidney transplant recipients for adult transplant care. Adolescent kidney transplant recipients aged 17 and older participated in the pilot cohort of the 2-year transition curriculum. Session topics included communication with the healthcare team, insurance, job skills, reflective practice, reproductive health, medications, and adult clinic introduction. Surveys were given to obtain narrative feedback, assess participant self-management behavior, and track curriculum knowledge. Each participant attended an average of two sessions, with 18 out of 30 eligible adolescents participating in at least one session. After transitioning to a virtual platform, there was increased attendance of participants who live greater than 150 miles from the transplant center. Adolescents highlighted the value of the program's group structure to relate to and learn from other participants. The pilot transition program successfully provided adolescent kidney transplant recipients the opportunity to learn alongside their peers and gain interdisciplinary knowledge to prepare for healthcare transition. The program converted to a virtual platform during the COVID-19 pandemic, with increased accessibility for participants who live further from the transplant center. Group-based programming for adolescents should be enhanced to further prepare them for transitions to adult medicine.

Nephrology: what's new in 2022

Severe cases of IGA nephropathy might benefit from corticosteroid therapy. Inflimidase may be a promising treatment of Goodpasture disease. SGLT2 inhibitors and acetazolamide act synergistically with loop diuretics in the treatment of acute cardiac failure. In hemodialysis, use of lung ultrasound to determine the ultrafiltration seems to decrease hospitalizations due to acute heart failure but does not reduce patient-centered outcomes. Icodextrin may mitigate the loss of ultrafiltration in PD patients who are carriers of the Aquaporin I promotor TT genotype. MICA-antibodies have an impact on the risk of graft rejection. Xenotransplantation may become a reality.

When immunotherapy meets liver transplantation for hepatocellular carcinoma: A bumpy but promising road.

Liver transplantation (LT) is a highly curative therapy for patients with hepatocellular carcinoma (HCC). However, due to the shortage of donor livers and rapid progression of HCC, a majority of patients are dropped out from the waitlist. Recently, immunotherapy has shown great promise in the treatment of advanced HCC. However, the use of immunotherapy is limited in LT mainly due to the potentially increasing risk of graft rejection. One of the main challenges for researchers is the protection of donor graft from an immunotherapy-boosted immune response mounted by the host. Besides, the safety, availability, and costs of immunotherapy are other challenges that need to be addressed. Here, we reviewed the literature involving patients who received immunotherapy prior to transplant to avoid waitlist dropouts and following transplantation to prevent the progression of tumor recurrence and metastasis. Statistically, the incidence of rejection was 25.0% pre-transplant and 18.5% post-transplant. Based on the review of these clinical studies, we can conclude that conducting clinical trials on the safety and efficacy of currently available immunotherapy drugs and identifying novel immunotherapy targets through extensive research may be promising for patients who do not meet the selection criteria for LT and who experience post-transplant recurrence. To date, the clinical experience on the use of immunotherapy before or after LT comes from individual case studies. Although some of the reported results are promising, they are not sufficient to support the standardized use of immunotherapy in clinical practice.

Donor gender effect on graft function in adult Egyptian patients undergoing living donor liver transplantation: A single centre study

ABSTRACT Background The aim of this study was to evaluate the role of donor-to-recipient gender match in the setting of living donor liver transplant as a potential predictor of graft and recipient survivals. Methods In this retrospective, single-center study, the data of 342 adult primary liver transplants were analyzed. The donor and recipient’s characters, intraoperative data, and postoperative outcomes were recorded. Results The donor-recipient gender matched patients had significantly better graft survival outcomes than the gender mismatched ones. The 2-year graft survival probability was 95.7% in the matched group compared to 89.1% in the mismatched one (p = 0.026). A female donor-male recipient combination (87.3%) showed worse 2-years graft survival than a male-to-male transplant (94.8%), while it gave better graft survival than male to female (61.3%). The estimated relative risk of graft rejection was 5.91 times significantly higher in a male–female combination than in a male-to-male one (Hazard ratio = 5.91, 95% CI = 1.34–26.11). Conclusion This study suggests that donor-recipient gender mismatch is associated with poor liver graft survival outcomes, with higher risk of graft rejection in male-female transplants than in male-to-male ones. Though, further larger studies including multiple datasets are needed, with adjustments for various graft, donor, and recipient factors to reach solid evidence.

Update on Femtosecond Laser-Enabled Keratoplasty.

The application of femtosecond lasers to corneal transplantation is an intriguing proposition with many potential benefits to patients with various corneal diseases. The customized trephination pattern for donor and host matching offers many advantages regarding wound integrity and high precision of donor and recipient match at the interface, which should lead to faster healing and visual rehabilitation. Femtosecond laser-enabled keratoplasty (FLEK) is an advancement of conventional trephination penetrating keratoplasty, and in large clinical cohorts to date, there are meaningful improvements in visual outcomes and a lower risk of graft rejection. Femtosecond laser-enabled deep anterior lamellar keratoplasty (Femto-DALK) combines the advantage of a customized trephination pattern with the deep anterior lamellar keratoplasty procedure, which eliminates the risk of endothelial rejection. Furthermore, the precision of the femtosecond laser may offer additional novel approaches to lamellar keratoplasties. In time, advancements in femtosecond laser platforms will help cornea surgeons realize the added benefits and better optimize outcomes for patients, such that the cost-benefit calculus shifts toward wider accessibility for patients. Prospective randomized-controlled trials are needed to definitively determine the impact of femtosecond laser-enabled keratoplasties on long-term outcomes.

The obstetric implications of pulmonary hypertension and lung transplant.

Pulmonary hypertension (PH) is present when the mean pulmonary artery pressure is elevated to >20mmHg as determined by right heart catheterization. It is categorized into five groups according to the underlying causes. Its presence is considered a contraindication to pregnancy for which therapeutic termination is usually advised due to grave maternal prognosis and pregnancy outcome. Nevertheless, pregnancies in affected women are increasingly reported, about half of which were unplanned, and two-thirds resulted in live births without increased foetal anomalies, notwithstanding increased risks of preterm birth, low birth weight, pre-eclampsia, other obstetric complications, and medical comorbidities, when managed under a multidisciplinary team in specialized centres. Successful lung transplant, the ultimate treatment for PH and other progressive lung diseases, restores fertility, and pregnancy is increasingly encountered, but there is a higher risk of graft rejection and mortality, compared with recipients of other organs. Preconception assessment is vital in optimizing maternal and pregnancy outcomes.

Allogeneic Peripheral Blood Stem Cell Transplantation for Bone Marrow Failure Syndromes Using CD34+-Selected Progenitor Cells Co-Infused with a Reduced Number of Non-Mobilized T-Cells

Background Severe aplastic anemia (SAA) patients who fail immunosuppressive therapy (IST) may be candidates for curative allogeneic hematopoietic stem cell transplantation (HCT). Patients with SAA are often heavily transfused with underlying immune-mediated disease, which increases their risk for graft rejection when bone marrow (BM) is used as a graft source. Peripheral Blood Stem Cell (PBSC) grafts have been associated with better engraftment but at a cost of a higher incidence of graft-versus-host disease (GVHD). We developed a novel protocol combining high numbers of GCSF-mobilized CD34+ peripheral blood stem cells with a BM transplant-equivalent dose of T-cells (collected from donors before GCSF administration) to improve engraftment and decrease the risk of GVHD associated with a conventional, unmanipulated PBSC HCT. Methods In this phase II trial, eligible patients included those age 4-80 years with a diagnosis of SAA or other bone marrow failure (BMF) syndromes with ≥ 9/10 HLA-matched related (sibling/family) donors (MRD) or 10/10 matched unrelated donors (MUD). All patients received conditioning with cyclophosphamide (day -7 to -6), anti-thymocyte globulin (day -5 to -2), and fludarabine (day -5 to -1). For MUD patients, low dose total body irradiation (200 cGy) was added to the regimen on day -1. GVHD prophylaxis included cyclosporin (day -4 until at least day +30) and methotrexate (5 mg/m2 , day +1, +3 and +6). The primary outcome of the study was chronic GVHD at 1 year. Secondary outcomes included mortality, engraftment and chimerism, acute and chronic GVHD, immune reconstitution, and comparisons of MRD vs. MUD patients. Results Thirty-five patients (27 with MRD and 8 with MUD) were transplanted between February 2011 and December 2021. Patients had a median age of 30 (range 6-70) years, 46% were males and 54% were females, including 31 having SAA, 3 with SAA transformed to myelodysplastic syndrome (MDS), and one with MDS; 11 patients also had PNH clone pre-transplant. The median numbers of transplanted CD34+ and CD3+ T-cells were 8 ´ 106 cells/kg and 2 ´ 107 cells/kg, respectively. After HCT transplants, all patients had neutrophil recovery with a median 14 (10-32) days. Except for 2/35 (6%) patients having late graft failure, all other 33 (94%) patients achieved sustained engraftment. Platelet recovery was reached in 29 (83%) patients at a median 19 (13-321) days. A total of 97% of patients achieved >95% donor myeloid chimerism (median 14 days), and 94% of patients achieved >95% donor T-cell chimerism (median 30 days). Reactivation of CMV occurred in 21/29 (72%) patients at risk with none developing CMV disease. Full immune reconstitution occurred for most patients by 1-year post-transplant. With a median follow-up of 5 years, the estimated 200-day survival and overall survival were 89% and 85%, respectively. The cumulative incidence of acute grade II-IV GVHD was 23%, and 1-year chronic GVHD rate was 11%, which was significantly lower than our hypothesis that this regimen would lower the chronic GVHD rate to 50% (P < .001). The subgroups of patients with MRD and MUD were compared (Table 1): patients with MUD showed a slower time to achieve neutrophil recovery (P = .001) and platelet recovery (P = .03), and a slightly high graft failure incidence (2 cases), but most other outcomes were similar, compared to patients with MRD. Conclusion For patients with SAA and other BMF syndromes, transplanting high doses of mobilized CD34+ selected cells from MRD and MUD donors combined with a bone marrow transplant equivalent of non-mobilized donor T-cells (a partially T-cell depleted PBSC transplant) achieves rapid and durable donor engraftment and excellent survival. The cumulative incidence of both acute and chronic GVHD with this regimen was significantly lower than that historically reported with conventional PBSC transplants. Notably, low acute and chronic GVHD rates were also achieved in SAA patients with disease refractory to conventional IST who received a graft from a 10/10 HLA-matched MUD donor, although hematopoietic recovery was slightly delayed compared to recipients of a partially T-cell depleted graft from a MRD donor. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Cemiplimab for advanced cutaneous squamous cell carcinoma in kidney transplant recipients.

Kidney transplant recipients (KTR) are at increased risk of cancer due to chronic immunosuppression. Non-melanoma skin cancer has an excess risk of approximately 250 times higher than the general population. Moreover, in solid organ transplant recipients (SOTR) these cancers have a more aggressive behavior, with an increased risk of metastasis and death. Cemiplimab, a human monoclonal IgG4 antibody against programmed cell death (PD-1) has shown considerable clinical activity in metastatic and locally advanced cutaneous squamous cell carcinoma (cSCC) in patients for whom no widely accepted standard of care exists. Cemiplimab has therefore been approved since 2018 for the treatment of advanced cSCC. However, data regarding the use of cemiplimab in SOTR and particularly in KTR are scarce and based on published case reports and small case series. In this study, we report on the real-life outcome of cemiplimab use in a Belgian cohort of seven KTR suffering from advanced cSCC. To report on the overall response rate (ORR) and safety of cemiplimab in KTR in Belgium. Seven patients suffering from advanced cSCC, treated with cemiplimab, between 2018 and 2022, in Belgium were identified. Three patients were on corticosteroid monotherapy, one patient on tacrolimus monotherapy and three patients were on at least 2 immunosuppressants at start of cemiplimab. The ORR was 42.8%, stable disease was seen in 14.3% and progressive disease was found in 42.8% of the patients, respectively. The median administered number of cycles was 12, interquartile range (IQR) 25-75 [3.5 - 13.5]. All patients were treated with surgery before administration of cemiplimab, 71.4% received additional radiotherapy and only 1 patient was treated with chemotherapy prior to receiving cemiplimab. Biopsy-proven acute renal allograft rejection was observed in one patient, who eventually lost his graft function but showed a complete tumor response to treatment. Low grade skin toxicity was seen in one patient of the cohort. The present case series shows that the use of cemiplimab in KTR with advanced cSCC who failed to respond to previous surgery, chemo - and/or radiotherapy treatment is associated with an ORR of 42.8% with minimal risk of graft rejection (14.3%) and good tolerance.

T-cell depleted haploidentical hematopoietic cell transplantation for pediatric malignancy.

Access to allogenic hematopoietic cell transplantation (HCT), a potentially curative treatment for chemotherapy-resistant hematologic malignancies, can be limited if no human leukocyte antigen (HLA) identical related or unrelated donor is available. Alternative donors include Cord Blood as well as HLA-mismatched unrelated or related donors. If the goal is to minimize the number of HLA disparities, partially matched unrelated donors are more likely to share 8 or 9 of 10 HLA alleles with the recipient. However, over the last decade, there has been success with haploidentical HCT performed using the stem cells from HLA half-matched related donors. As the majority of patients have at least one eligible and motivated haploidentical donor, recruitment of haploidentical related donors is frequently more rapid than of unrelated donors. This advantage in the accessibility has historically been offset by the increased risks of graft rejection, graft-versus-host disease and delayed immune reconstitution. Various ex vivo T-cell depletion (TCD) methods have been investigated to overcome the immunological barrier and facilitate immune reconstitution after a haploidentical HCT. This review summarizes historical and contemporary clinical trials of haploidentical TCD-HCT, mainly in pediatric malignancy, and describes the evolution of these approaches with a focus on serial improvements in the kinetics of immune reconstitution. Methods of TCD discussed include in vivo as well as ex vivo positive and negative selection. In addition, haploidentical TCD as a platform for post-HCT cellular therapies is discussed. The present review highlights that, as a result of the remarkable progress over half a century, haploidentical TCD-HCT can now be considered as a preferred alternative donor option for children with hematological malignancy in need of allogeneic HCT.

Management and Treatment Outcomes of High-Risk Corneal Transplantations.

Corneal transplantation is the most effective treatment for corneal blindness. Standard planned keratoplasties have a high success rate. Conditions such as active inflammation at the time of surgery, the presence of ocular surface disease, previous graft disease, or neovascularization make them more susceptible to rejection. These are so-called high-risk corneal transplantations. In our study, we selected 52 patients with a higher risk of graft rejection. A total of 78 procedures were performed. The main indications for the first keratoplasty were infections (59.6%) and traumas (21.2%). Visual acuity (VA) significantly improved from 2.05 logMAR on the day of keratoplasty to 1.66 logMAR in the latest examination (p = 0.003). An analysis of the graft survival showed a 1-year survival of 54% and a 5-year survival of 19.8% of grafts. The mean observation time without complications after the first, second, and third surgery was 23, 13, and 14 months, respectively. The best results were noted among patients with infectious indications for keratoplasty (p = 0.001). Among them, those with bacterial infection had the best visual outcomes (p = 0.047).

P8.134: Advanced Cancers Treated With PD-L1 Inhibitors and CTLA-4 Antagonist in Transplanted Immunosuppressed Patients: Systematic Review of Graft Outcome

Background: Cancer is a major cause of morbidity and mortality in transplanted patients: its overall risk is increased two to three times compared to the general population, and it’s inversely related to age, with younger recipients experiencing a greater relative increase in risk compared to older recipients. Plus, the prognosis is worse for recipients diagnosed with cancer, compared to the general population, because of immunosuppressive drugs. The aim of this study is to demonstrate a correlation between use of CTLA-4 antagonist and PD-L1 inhibitors in transplanted patients with de novo malignancies and grafts outcome. Methods: A literature review concerning the use of anti PD-L1 and CTLA-4 antagonists in transplanted patients with advanced neoplasm was performed. The analyzed variables were: age, sex, transplanted solid organ, immunosuppressive induction and maintenance therapy performed, type of cancer developed, developmental latency time, anticancer drugs administered, possible rejection and related therapy administered, patient outcome. Results: A sample of 52 patients was sort from the literature review. The statistical analysis revealed that no variables had a significant correlation with graft rejection after the use of checkpoint inhibitors. The use of CTLA-4 antagonists seems to be associated with a less significant risk of development of graft rejection than PD-L1 inhibitors (OR = 4.00, p = 0.06). Conclusions: The available data suggest that CTLA-4 antagonists are safer in transplanted patients than PD-L1 inhibitors, which were associated with a higher risk of allograft rejection. This study didn’t identify an agent responsible for different outcomes between patients treated with PD-L1 inhibitors and CTLA-4 antagonists. Checkpoint inhibitors have proved to be valid for treatment of various malignancies, but transplanted cancer patients have never been included in clinical trials on their efficacy, because of the risk of graft rejection. Further studies and trials are needed to ensure these patients the best possible treatments.

Cemiplimab for advanced cutaneous squamous cell carcinoma in kidney transplant recipients

Kidney transplant recipients (KTR) are at increased risk of cancer due to chronic immunosuppression. The cumulative incidence ratio of non-melanoma skin cancer has been estimated to be > 60% compared to the general population. Cemiplimab, a human monoclonal IgG4 antibody against programmed cell death (PD-1) has shown considerable clinical activity in metastatic and locally advanced cutaneous squamous cell carcinoma (cSCC) in patients for whom no widely accepted standard of care exists. Data regarding the use of cemiplimab in SOTR and particularly in KTR are scarce. In this study, we report on the real-life outcome of cemiplimab use in a Belgian cohort of seven KTR suffering from advanced cSCC. To report on the overall response rate (ORR) and safety of cemiplimab in KTR in Belgium. Retrospective study of kidney transplant recipients, suffering from advanced cSCC treated with cemiplimab. Sept patients suffering from advanced cSCC, treated with cemiplimab, between 2018 and 2022, in Belgium were identified. 3 patients were on corticosteroid monotherapy, 1 patient on tacrolimus monotherapy and 3 patients were on at least 2 immunosuppressive treatments at start of cemiplimab. The ORR was 42.8%, SD was seen in 14.3% and PD was found in 42.8% of the patients, respectively. Biopsy-proven acute renal allograft rejection was observed in 1 patient, who eventually lost his graft function but showed a complete tumor response to treatment. Low grade skin toxicity was seen in 1 patient of the cohort ( Fig. 1 ). The present case series shows that the use of cemiplimab in KTR with advanced cSCC who failed to respond to conventional treatment is associated with an ORR of 42.8% with minimal risk of graft rejection (14.3%) and good tolerance. Cemiplimab may therefore be a feasible treatment for KTR with advanced cSCC and this treatment should therefore not be withheld in this difficult to treat patient population.

Allogeneic Hematopoietic Cell Transplantation for Patients With Deficiency of Adenosine Deaminase 2 (DADA2): Approaches, Obstacles and Special Considerations.

Deficiency of adenosine deaminase 2 (DADA2) is an inherited autosomal recessive disease characterized by autoinflammation (recurrent fever), vasculopathy (livedo racemosa, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages, end organ vasculitis), immunodeficiency, lymphoproliferation, immune cytopenias, and bone marrow failure. Allogeneic hematopoietic cell transplantation (HCT) is curative for DADA2 as it reverses the hematological, immune and vascular phenotype of DADA2. The primary goal of HCT in DADA2, like in other non-malignant diseases, is engraftment with the establishment of normal hematopoiesis and normal immune function. Strategies in selecting a preparative regimen should take into consideration the specific vulnerabilities to endothelial dysfunction and liver toxicity in DADA2 patients. Overcoming an increased risk of graft rejection while minimizing organ toxicity, graft-versus-host disease, and infections can be particularly challenging in DADA2 patients. This review will discuss approaches to HCT in DADA2 patients including disease-specific considerations, barriers to successful engraftment, post-HCT complications, and clinical outcomes of published patients with DADA2 who have undergone HCT to date.

Post-transplant Diabetes Mellitus: What Physicians Need to Know.

Post-transplant diabetes mellitus (PTDM) is a common problem among solid organ transplant recipients contributing to morbidity and affecting patient as well as graft survival adversely. It can occur at any period following transplantation, but maximum incidence is observed in the first few months, with a second peak after a few years after transplantation. The pathogenesis is complex and poorly understood, however, it is associated with both dysfunctional beta-cells and insulin resistance. Both nonpharmacologic and antidiabetic therapies are important for adequate glycemic control. This point of view article provides a short review on PTDM in solid organ transplantation (SOT) recipients from a general physician's perspective.

Impact of vaccination on keratoplasty.

Corneal graft rejection has been reported after coronavirus disease 2019 (COVID-19) vaccination. The purpose of this review is to evaluate the literature regarding corneal graft rejection after vaccination, including rejection rates and risk factors. We aim to create a framework to identify patients who are at higher risk for graft rejection and may warrant consideration of prophylactic interventions. Graft rejection has been reported following administration of mRNA, viral vector, and inactivated whole-virion COVID-19 vaccines. Most cases had additional risk factors associated with rejection. Vaccination increases circulation of proinflammatory cytokines, CD4+ and CD8+ T-cell responses, and antispike neutralizing antibody, all of which may contribute to graft rejection. Two prospective studies have found no relationship between recent vaccination and rejection but 20% of cornea specialists report to have seen a vaccine-associated rejection and 22% recommend delaying vaccination in certain circumstances. Many specialists recommend prophylactic topical corticosteroids before and after vaccination to mitigate rejection risk but there is no evidence to support this practice on a wider scale. Our framework identified 96.8% of penetrating keratoplasty patients with vaccine-associated rejection as higher risk. Further research is needed in order to develop evidence-based guidelines.

Liver Injuries Associated with Coronavirus Disease 2019: View on the Problem

Introduction. Major cardiovascular and pulmonary comorbidities, as well as diabetes mellitus and certain cancers, are associated with worse clinical outcomes of coronavirus disease-2019 (COVID-19). Meanwhile, the impact of concomitant liver diseases on the COVID-19 natural course together with the influence of the COVID-19 on the hepatic tissues have been rarely investigated. The aim of the study was to analyse the available data regarding impact of liver pathologies on COVID-19 natural course and outcome, and, reciprocally, hepatic injuries development induced by COVID-19. Materials and methods. Content analysis, systematic and comparative analysis, bibliosemantic method of investigation of current scientific research results on liver damage associated with COVID-19 were used. Results. The potential mechanism of liver injury in COVID-19 is complex and includes direct cytopathic viral injury, proinflammatory cytokine outbreak, hypoxia/reperfusion damage and potential drug induced liver injury. Among the medications used for the treatment of COVID-19 patients, there are certain that could potentially cause drug-induced liver injury. Treatment of liver transplant patients can be challenging taking into consideration the possible necessity of immunosuppressive therapy correction combined with the needs to find a balance between the risk of graft rejection and effective elimination of the virus. Conclusions. Current review of the available database revealed that liver diseases are among substantive comorbidities in COVID-19 patients alongside with liver injuries which are rather frequent complications of COVID-19 treatment. Potential drug-induced liver injuries in patients subjected tocertain antiviral agents in combination with supportive therapy drugs should be taken into consideration. Special precautions are required to prevent potential drug-to-drug interactions in case of COVID-19 treatment in liver transplant patients.

Paxlovid (Nirmatelvir/Ritonavir) and Tacrolimus Drug-Drug Interaction in a Kidney Transplant Patient with SARS-2-CoV infection: A Case Report

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has had a significant impact on communities and health systems. New antiviral medications against this disease have not been properly tested yet, and their efficiency, side effects, and drug–drug interactions are not entirely known. Organ transplant recipients receive immunosuppressive medications such as tacrolimus to prevent graft rejection. Tacrolimus is metabolized by the cytochrome P450 3A4 enzyme system. Many medications can either induce or inhibit this enzyme and affect the level. Awareness of possible drug–drug interactions is vital because tacrolimus levels should be kept within a specific narrow range determined by the recipient's immunologic risk. Underexposure increases the risk of graft rejection, whereas overexposure may lead to adverse effects. Paxlovid, a novel antiviral medication approved for emergency use to treat SARS-CoV-2, is a combination of nirmatrelvir and ritonavir, a cytochrome P450 34A inhibitor. In this case report, we present a case of a kidney transplant patient receiving tacrolimus treated with Paxlovid, leading to an abruptly high tacrolimus level, significant symptoms, treatment interruption, and acute kidney injury. We conclude that the drug–drug interaction between Paxlovid and tacrolimus is indeed robust and noteworthy and leads to high tacrolimus levels and its metabolites, adverse effects, and acute kidney injury. Physicians managing immunocompromised patients receiving tacrolimus should be aware of this significant drug–drug interaction and consider other options or reduction of daily tacrolimus dose during treatment in addition to timely monitoring of both tacrolimus levels and serum creatinine. Consulting with the transplant pharmacist is foremost in alerting for these interactions.

Posttransplant VEGFR1R2 Trap Eye Drops Inhibit Corneal (Lymph)angiogenesis and Improve Corneal Allograft Survival in Eyes at High Risk of Rejection.

PurposeTo assess whether topical application of VEGFR1R2 Trap after corneal transplantation can impair corneal (lymph)angiogenesis and promote murine corneal allograft survival in eyes at high risk of rejection.MethodsWe used the murine model of suture-induced neovascularization and subsequent keratoplasty in eyes at high risk of rejection, which is an established model for local drug application. After transplantation, the mice were treated with either VEGFR1R2 Trap (aflibercept) or human IgG Fc as eye drops for 2 weeks (three times/d). Deposition of VEGFR1R2 Trap in corneal tissue was detected by immunohistochemistry. Two and 8 weeks after transplantation, corneal (lymph)angiogenesis was assessed morphometrically. Dendritic cells (DCs) and regulatory T cells (Tregs) in the draining lymph nodes (dLNs) were examined by flow cytometry. Allograft survival was determined by corneal graft opacity scores.ResultsTopically applied VEGFR1R2 Trap penetrated into corneal host and graft stroma after keratoplasty in eyes at high risk of rejection. Additional postsurgical corneal hemangiogenesis (P < 0.0001) and lymphangiogenesis (P < 0.01) as well as infiltrating CD45+ leukocytes (P < 0.001) and macrophages (P < 0.01) were significantly reduced in the VEGFR1R2 Trap group compared to controls. VEGFR1R2 Trap eye drops significantly decreased the frequency of total CD11c+ DCs (P < 0.01), as well as activated CD11c+MHC II+ DCs (P < 0.01) and CD11c+CD40+ DCs (P < 0.05). In contrast, the frequency of CD200R+ regulatory DCs (P < 0.05) and Tregs in dLNs (P < 0.01) was enhanced. Moreover, long-term allograft survival was also improved (P < 0.05).ConclusionsTemporary, topical application of VEGFR1R2 Trap after corneal transplantation can achieve sufficient anti-VEGF activity, inhibit additional (lymph)angiogenesis, and significantly improve corneal allograft survival in eyes at high risk of rejection.Translational RelevanceVEGFR1R2 Trap eye drops after transplantation present a new therapeutic option for patients undergoing corneal transplantation and are at high risk of graft rejection.

Chronic Kidney Failure Provokes the Enrichment of Terminally Differentiated CD8+ T Cells, Impairing Cytotoxic Mechanisms After Kidney Transplantation.

Chronic kidney failure (KF) provokes the development of immune senescent CD8+ cytotoxic T cells, affecting the occurrence of graft rejection, viral infections, and malignancies after kidney transplantation. In this study, we analyzed the impact of KF, subsequent dialysis treatment, and kidney transplantation on the differentiation of CD8+CD31+CD45RA+CCR7+ recent thymic emigrant (CCR7+ RTE) Tregs/Tresps into CD8+CD31-CD45RA- memory (CD31- memory) Tregs/Tresps and its effect on the release of cytokines, Fas receptor, Fas ligand as well as cytotoxic mediators by naïve, central memory (CM), effector memory (EM), and terminally differentiated effector memory (TEMRA) Tresps. We found that normal age-dependent differentiation of CD8+ Tregs/Tresps generally differs in the way that TEMRA cells only arise in Tresps. Compared to healthy controls, KF patients revealed an age-independently decreased frequency of CCR7+ RTE Tregs/Tresps, but increased frequencies of CCR7+ MN Tregs/Tresps and CD31- memory Tregs/Tresps, suggesting an increased differentiation via CD31+CD45RA- memory (CD31+ memory) Tregs/Tresps into CD31- memory Tregs/Tresps. Intensified differentiation via CD31+ memory Tresps increased the emergence of apoptosis-resistant CM Tresps with strong Fas ligand-mediated cytotoxicity. CCR7+ RTE Tresp proliferation generated TEMRA Tresps, secreting high levels of cytotoxic mediators. In dialysis and transplant patients, CD31+ TEMRA Tregs/Tresps accumulated, proposing an impaired CCR7+ RTE Treg/Tresp differentiation via CD31+ memory Tregs/Tresps into CD31- memory Tregs/Tresps. Increased percentages of CD31- TEMRA Tresps, but not of CD31- TEMRA Tregs, were observed in all patient groups, indicating impaired proliferation of CCR7+ RTE Tresps, but not of CCR7+ RTE Tregs, into CD31- memory Tregs/Tresps. In transplant patients, CCR7+ RTE Tregs accumulated, while frequencies of CCR7+ RTE Tresps were decreased, suggesting that the immunosuppressive therapy only prevented excessive CCR7+ RTE Treg differentiation but not that of CCR7+ RTE Tresps. Presumably, this caused the accumulation of TEMRA Tresps with decreased release of cytotoxic mediators, such as perforin. In conclusion, we propose that chronic KF affects both the differentiation of CD8+ Tregs and CD8+ Tresps. However, the immunosuppressive therapy after transplantation may successfully prevent excessive Treg differentiation, but not as suffciently that of Tresps. Therefore, the risk for graft rejection may be reduced, while the susceptibility for infections and malignancies may be increased in these patients.