High Risk Of Rejection Research Articles

Socioeconomic Status and Major Adverse Transplant Events in Pediatric Heart Transplant Recipients

Low socioeconomic status (SES) has been associated with higher risk of rejection and graft loss in pediatric heart transplant (HT) recipients. The association of SES with other posttransplant morbidities is unknown. To assess whether low SES is associated with higher risk of a major adverse transplant event (MATE) among pediatric HT recipients. Retrospective single-center cohort study at a children's hospital in Boston with consecutive primary HT recipients from 2006 to 2019 and follow-up through 2022. Data were analyzed from June 2023 to March 2024. Very low or low, moderate, and high or very high Childhood Opportunity Index (COI) for neighborhood (census tract) of patient residence. Primary outcome was 3-year MATE-6 score assessed in 6-month survivors as cumulative burden of acute cellular rejection, antibody-mediated rejection, coronary vasculopathy, lymphoproliferative disease, kidney dysfunction, and infection, each as an ordinal score from 0 to 4 (24 for death or retransplant). Secondary outcomes were freedom from rejection during first 6 months, freedom from death or retransplant, MATE-3 score for events 1 to 3 (under immune suppression) and events 4 to 6 (chronic immune suppression effects), and each MATE component. Of 153 children analyzed, the median (IQR) age at HT was 7.2 (1.5-14.8) years, 99 (65%) were male, 16 (10%) were Black, 17 (11%) were Hispanic, and 106 (69%) were White. Fifty patients (33%) lived in very low or low, 17 (11%) in moderate, and 86 (56%) in high or very high COI neighborhoods. There was no significant group difference in mean (SD) 3-year MATE-6 score (very low or low COI, 3.4 [6.5]; moderate COI, 2.4 [6.3]; and high or very high COI, 4.0 [6.9]). Furthermore, there was no group difference in mean (SD) MATE-3 scores for underimmune suppression (very low or low COI, 1.9 [3.5]; moderate COI, 1.2 [3.2]; and high or very high COI, 2.2 [3.6]), chronic immune suppression effects (very low or low COI, 1.6 [3.3]; moderate COI, 1.1 [3.2]; and high or very high COI, 1.8 [3.6]), individual MATE components, rejection during the first 6 months, or death or retransplant. In this cohort study of pediatric HT recipients, there was no difference in posttransplant outcomes among recipients stratified by SES, a notable improvement from prior studies. These findings may be explained by state-level health reform, standardized posttransplant care, and early awareness of outcome disparities.

Role of mTOR Inhibitors in Pediatric Liver Transplant Recipients: A Systematic Review.

Immunosuppressive medications play a crucial role in determining both organ and patient survival following liver transplantation (LT). Typically, immunosuppressive protocols for pediatric LT patients rely on calcineurin inhibitors (CNIs). While inhibitors of mammalian target of rapamycin (mTOR) have demonstrated beneficial outcomes in adult recipients of liver allografts, such as improved renal function post-LT, their application in pediatric liver transplant recipients is a subject of debate due to uncertain efficacy and potential adverse effects. This review evaluates the potential roles of mTOR inhibitors in the context of pediatric LT patients. This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol for conduct and reporting. Databases until 31 August 2023 were searched using specific terms and keywords. All clinical studies focusing on mTOR inhibitors in pediatric LT were included. Out of 888 identified articles, 30 studies, involving 386 children who had undergone liver transplantation and received mTOR-inhibitor-based immunosuppressive regimens, met the inclusion criteria. The beneficial impacts of switching from a CNI to an mTOR inhibitor or adding an mTOR inhibitor to CNI-reduced immunosuppression in LT pediatric patients with impaired kidney function are controversial, and high-powered clinical studies are need. It appears that enhancing immunosuppression by adding an mTOR inhibitor to CNI is helpful for pediatric LT recipients who are experiencing refractory acute rejection or chronic rejection. mTOR-inhibitor-containing regimens failed to reduce the occurrence of post-transplant lymphoproliferative disorders (PTLD) among children with LT that may be due to concomitant high CNI concentration among studied patients. The effectiveness of mTOR inhibitors in treating PTLD remains uncertain; however, in patients with PTLD who are at high risk of rejection, mTOR inhibitors may be administered. Conversion to or the addition of mTOR inhibitors to maintenance immunosuppression seems to be suitable for pediatric patients who received a transplant due to hepatic malignancies such as hepatoblastoma or hepatocellular carcinoma or for those with post-transplant primary or recurrent malignancies. Switching to an mTOR inhibitor may improve some CNI-related adverse effects such as gingival hyperplasia, neurotoxicity, nephropathy, hypertrophic cardiomyopathy, or thrombotic microangiopathy. Although the exact role of mTOR inhibitors among pediatric patients who have received a liver transplant needs further study, two algorithms are presented in this review to guide conversion from CNIs to mTOR inhibitors or the addition of mTOR inhibitor to a CNI-minimization immunosuppressive regimen for pediatric patients who may benefit from this class of drugs. This review mainly consisted of retrospective studies with inadequate sample sizes and lacked a control group, which represents the main limitation of this study.

What makes the kidney so tolerant?

Various organ allografts differ in their propensity to be spontaneously accepted without any immunosuppressive treatment. Understanding the mechanisms behind these differences can aid in managing alloimmune responses in general. C57BL/6 mice naturally accept DBA/2J kidney allografts, forming tertiary lymphoid organs containing regulatory T cells (rTLOs), crucial for graft acceptance. In this issue of the JCI, Yokose and colleagues revealed that rTLOs promote conversion of cytotoxic alloreactive CD8+ T cells into exhausted/regulatory ones, through an IFN-γ-mediated mechanism. Their study provides insights into tolerance development that could help promote the acceptance of grafts at higher risk of rejection.

Comparative outcomes of DSA positive, crossmatch negative living donor kidney transplants versus remaining on the waitlist for an HLA compatible deceased donor

IntroductionThe clinical relevance of preformed donor specific antibodies in the setting of a negative crossmatch (DSA + XM-) remains controversial. In this study we investigate the outcomes of patients with a DSA + XM- living donor (LDi) who proceeded with an HLA-incompatible (HLAi) transplant compared with those who waited for an HLA-compatible deceased donor (DDc). Materials and methodsWe investigated 359 patients on the transplant waiting list who had at least one potential HLAi living donor, from which 203 DSA + XM- pairs were identified and outcomes analysed. ResultsOut of 203 patients, 96 (47.3%) received a LD transplant: 52/96 (54.2%) a LDi, and 44/96 (45.8%) an alternative compatible LD. In addition, 107 patients out of 203(52.7%) waited for a DDc, of which 47(43.9%) were subsequently transplanted. Our adjusted analysis showed that the LDi transplantation did not offer a superior patient survival over waiting for a DDc transplant. For those transplanted, there was no difference in patient (p = 0.065) or death censored allograft survival (p = 0.37) between DDc and LDi recipients. However, there was a higher incidence of acute allograft rejection (p = 0.043) and antibody-mediated rejection (p = 0.005) in the LDi group. Having a high pre-transplant calculated reaction frequency and preformed DSA to both class I and class II antigens were associated with inferior outcomes in the LDi transplants. ConclusionsGiven the lack of difference in allograft survival between LDi and DDc transplants, in the absence of an alternative compatible living donor, proceeding with a LDi should be supported despite a higher rejection risk, providing individual risk assessment and shared decision making is undertaken.

Impact of donor-specific antibody with low mean fluorescence intensity on allograft outcomes in kidney transplant

BackgroundImmune-mediated rejection is the most common cause of allograft failure in kidney transplant (KT) patients. Exposure to alloantigen, including human leukocyte antigen (HLA), results in the production of donor-specific antibodies (DSA). There are limited data about low levels of mean fluorescence intensity (MFI) DSA, especially post-transplantation. This study evaluated allograft outcomes in KT patients with low MFI DSA. MethodsFrom January 2007 to December 2021, KT patients who were tested for post-transplant DSA at Ramathibodi Hospital, Bangkok, Thailand, with the DSA MFI ≤ 1000 were evaluated. These KT patients were categorized into two groups: very low DSA (VLL; MFI = 1–500) and low DSA (LL; MFI = 501–1000). All KT patients were evaluated for the primary outcomes, such as the incidence of acute rejection, serum creatinine levels at one and five years after transplantation as well as allograft and patient survivals. ResultsAmong 36 KT patients 25 were included as those with VLL and 11 as those with LL. The LL group had significantly higher T-cell mediated allograft rejection (TCMR) than the VLL group (45% vs. 12%, P = 0.04). In addition, 10 patients, 5 in the VLL group and 5 in the LL group developed antibody-mediated allograft rejection (ABMR). Both TCMR and ABMR were confirmed by biopsy results. There was a trend toward higher MFI in KT patients with ABMR than without ABMR (P = 0.22). At 5 post-transplant years, serum creatinine, allograft and patient survivals were comparable between these two groups. Furthermore, the univariate and multivariate analyzes revealed that the LL group was a high risk for rejection. ConclusionLow MFI DSA values after transplantation may be associated with a higher incidence of rejection, but this finding did not show differences in allograft and patient survival in this study's analysis.

Use of Donor-derived Cell-free DNA to Inform Tapering of Immunosuppression Therapy in Kidney Transplant Recipients: An Observational Study.

Immunosuppression therapy (IST) is required for allograft survival but can cause significant adverse effects. Donor-derived cell-free DNA (dd-cfDNA) is a validated noninvasive biomarker for active rejection in kidney transplant (KTx). Evidence supporting dd-cfDNA testing use in IST management is limited. In this single-center observational study, dd-cfDNA testing was performed in 21 KTx patients considered good candidates for mycophenolic acid (MPA) reduction. Patients with dd-cfDNA <1% at the first visit (enrollment) had their MPA dosage reduced; those with dd-cfDNA ≥1% had their MPA dosage maintained. Patients were monitored with dd-cfDNA for 6 additional visits. Of 21 patients enrolled in the study, 17 were considered low risk for rejection by dd-cfDNA and underwent MPA reduction; 4 patients were considered high risk for rejection by dd-cfDNA and had their initial MPA dosage maintained. Of the 4 patients considered high risk for rejection by dd-cfDNA, 1 experienced chronic allograft nephropathy and graft loss, and another received an indication biopsy that showed no evidence of rejection. Of the 17 patients considered low risk for rejection by dd-cfDNA, none experienced allograft rejection. dd-cfDNA was used for surveillance in a 6-mo period following MPA reduction; no untoward results were noted. This proof-of-concept study reports the use of dd-cfDNA to directly inform IST management in a cohort of KTx who were candidates for IST reduction.

Better Rejection-Free Survival at Three Years in Kidney Transplant Recipients With Model-Informed Precision Dosing of Mycophenolate Mofetil.

The clinical impact of individual dose adjustment of mycophenolate mofetil is still debated, due to conflicting results from randomized clinical trials. This retrospective study aimed to compare 3-year rejection-free survival and adverse effects between adult kidney transplant recipients (KTRs) with or without mycophenolate mofetil model-informed precision dosing (MIPD). MIPD is defined here as mycophenolic acid area under the curve (AUC0-12h) estimation using a limited sampling strategy, pharmacokinetic models and Bayesian estimators; dose recommendation to reach AUC0-12h = 45 mg.h/L; using a widely used online expert system. The study, nested in two multicenter prospective cohort studies, focused on patients who received a mycophenolate drug and were followed up for 1-3 years. Mycophenolate mofetil MIPD was prescribed as per local practice, on a regular basis, when deemed necessary, or not at all. The MIPD group included 341 KTRs and the control group 392. At 3 years, rejection-free survival was respectively 91.2% and 80.6% (P < 0.001) and the cumulative incidence of rejection 5.08% vs. 12.7% per patient × year (hazard ratio = 0.49 (0.34, 0.71), P < 0.001), corresponding to a 2.5-fold reduction. Significant association with rejection-free survival was confirmed in patients at low or high risk of rejection (P = 0.017 and 0.013) and in patients on tacrolimus, but not on cyclosporine (P < 0.001 and 0.205). The mycophenolate mofetil MIPD group had significantly more adverse effects, but most occurred before the first AUC0-12h, suggesting some may be the reason why MIPD was ordered.

Impact of Infection-Related Immunosuppressant Reduction on Kidney Transplant Outcomes: A Retrospective Study Considering the Temporal Dynamics of Immunosuppressive Requirements.

Immunosuppressant reduction (ISR) is a common treatment for kidney transplant recipients experiencing infections, but its impacts on kidney transplant outcomes remains unclear. This retrospective single-center study included 300 patients who underwent kidney transplantation between January 2017 and April 2020. The post-transplant timeline was divided into four distinct phases: ≤1month, 2-6months, 7-12months, and >12months. Patients were categorized based on the presence of clinically relevant infections and whether they received ISR. Significant differences were observed in the spectrum of clinically relevant infections across the post-transplant phases. During the ≤1month phase, primary infections were associated surgical operation, such as urinary tract infections involving Enterococcus spp. and Candida spp. Cytomegalovirus and BK polyomavirus (BKPyV) infections increased during the 2-6months and 7-12months periods. Approximately one-third of patients experienced ISR due to infection, with BKPyV infections being the primary causes. Recipients who experienced their first ISR due to infection between 2-6months and 7-12months had worse graft survival comparing with patients without any infections. ISR due to infections between 2 and 6months was associated with a higher risk of rejection. Tailored ISR strategies should be developed according to temporal dynamics of immunosuppressive intensity to prevent rejection.

Outcomes of asymptomatic histologic pyelonephritis of kidney transplant.

Urinary Tract Infections are the most common post-transplant infection and can have varied presentations. This study aimed to describe the outcomes of kidney transplant recipients with asymptomatic histologic pyelonephritis on allograft biopsy. Histologic Pyelonephritis was defined as neutrophil cast or neutrophilic tubulitis, interstitial infiltrates with predominant neutrophils, and no evidence of rejection or glomerulonephritis on biopsy. The study included 123 kidney transplant recipients, of whom 95 underwent protocol biopsies, and 28 had biopsies for elevated creatinine within the first 2 years of a kidney transplant. The mean age of the cohort was 55.3 years, with 52% females and 78% deceased donor transplants. The risk factors for asymptomatic histologic pyelonephritis were recipient female sex (OR 1.89, 1.3-2.7, diabetes mellitus (OR 2.479, 1.687-3.645), and deceased donation (OR 1.69, 1.098-2.63). The incidence of asymptomatic pyelonephritis on protocol biopsy was 1.7%, with 52% having positive urine cultures and Escherichia coli being the most common bacteria. Subjects with asymptomatic pyelonephritis had inferior graft survival compared to the matched cohort HR 1.88 (1.06-3.35), p=.0281. In addition, of these 123 subjects, 68 (55%) subsequently developed pyelonephritis, and 34 subjects had pyelonephritis within 6 months after this episode. Subjects with recurrent infections exhibited lower survival HR 2.86 (1.36-6.02) and a trend toward higher rejection risk. Asymptomatic histologic pyelonephritis can occur in kidney transplant recipients and is associated with inferior graft survival.

198 Novel natural antibodies targeted against cardiolipin are associated with higher risk of rejection in kidney transplant recipients

198 Novel natural antibodies targeted against cardiolipin are associated with higher risk of rejection in kidney transplant recipients

Field Trial of a Shopworker Robot with Friendly Guidance and Appropriate Admonishments

We developed an admonishing service for a shopworker robot and conducted a field trial to investigate the impressions of a shop’s staff and customers. Applying the admonishing service in a real-world robot is difficult due to the high risk of rejection by society. We wanted to achieve an acceptable admonishing service while simultaneously avoiding the impression of a forceful request from a machine. We proposed a harmonized design that provided friendly and admonishing services. First, we interviewed a shop’s staff to learn their strategies for both friendly and admonishing services. From our evaluation of the interview results, we derived three design principles: friendly impressions, zero erroneous admonishments, and polite requests. Based on the design principles, we implemented our harmonized design on a social robot that guides customers to product locations and admonishes those who are not wearing face masks. We conducted a 13-day field trial in a retail shop and interviewed the customers and shopworkers to learn their impressions of our robot. The results of the field trial imply that our harmonized design approach is successful. Both the customers and the shop staff had overall positive impressions of the robot, its admonishing and friendly services, and expressed an intention to use it in the future. Furthermore, we studied the robot’s autonomous service-providing capability in the field and conducted an evaluation with hired participants to deepen our study of the robot’s mask recognition capability.

Involvement of circulating soluble HLA-G after liver transplantation in the low immunogenicity of hepatic allograft.

Graft rejection is a critical risk in solid-organ transplantation. To decrease such risk, an understanding of the factors involved in low immunogenicity of liver allografts could potentially make it possible to transfer this tolerogenic property to other transplanted organs. HLA-G, a natural physiological molecule belonging to the Human Leukocyte Antigen class (HLA) Ib family that induces tolerance, is associated with fewer rejections in solid-organ transplantation. In contrast to HLA-G, HLA antigen incompatibilities between donor and recipient can lead to rejection, except in liver transplantation. We compared HLA-G plasma levels and the presence of anti-HLA antibodies before and after LT to understand the low immunogenicity of the liver. We conducted a large prospective study that included 118 patients on HLA-G plasma levels during a 12-month follow-up and compared them to the status of anti-HLA antibodies. HLA-G plasma levels were evaluated by ELISA at seven defined pre- and post-LT time points. HLA-G plasma levels were stable over time pre-LT and were not associated with patient characteristics. The level increased until the third month post-LT, before decreasing to a level comparable to that of the pre-LT period at one year of follow-up. Such evolution was independent of biological markers and immunosuppressive treatment, except with glucocorticoids. An HLA-G plasma level ≤ 50 ng/ml on day 8 after LT was significantly associated with a higher rejection risk. We also observed a higher percentage of rejection in the presence of donor specific anti-HLA antibodies (DSA) and an association between the increase in HLA-G plasma levels at three months and the absence of DSA. The low immunogenicity of liver allografts could be related to early elevated levels of HLA-G, which lead, in turn, to a decrease in anti-HLA antibodies, opening potential new therapeutic strategies using synthetic HLA-G proteins.

Protocol Biopsy After Kidney Transplant: Clinical Application and Efficacy to Detect Allograft Rejection.

Background Kidney transplant rejection is a major cause of graft dysfunction and failure. In recent years, there has been increased interest in renal allograft protocol biopsies to allow earlier detection of acute or chronic graft dysfunction or rejection to improve long-term graft survival and reduce graft failure. This study aimed to determine if renal allograft protocol biopsies performed within the first 12 months after transplantation help detect subclinical graft dysfunction or rejection. Methods We performed a retrospective analysis utilizing SUNY Upstate University Hospital data from January 2016 to March 2022 to assess transplant outcomes and biopsies. The study population was divided into two subgroups: non-protocol biopsies and protocol biopsies within the 12 months post-transplant. Results A total of 332 patients met our inclusion criteria and were included in the study. Patients were divided into two subgroups: 135 patients (40.6%) in the protocol biopsy group and 197 patients (59.4%) with non-protocol indication biopsies during the first year after the transplant. The overall number of rejection episodes reported was eight episodes (4.6%) in the protocol biopsy group and 56 episodes (18.3%) in the non-protocol indication biopsy group, which was significantly higher in the non-protocol biopsy group (P=0.001). Antibody-mediated rejection (ABMR) and T-cell-mediated rejection (TCMR) diagnoses were significantly higher in the non-protocol biopsy group (P=0.03 and P=0.03, respectively). We also mentioned a trend in terms of mixed antibody-mediated rejection and T-cell-mediated rejection diagnosis (P=0.07). One year after the rejection, the mean glomerular filtration rate(GFR) was 56.78 mL/min/1.73m2 in the protocol biopsy group and 49.14 mL/min/1.73m2 in the non-protocol indication biopsy group, and there was no significant difference anymore (P=0.11). The patient survival rate was not significantly higher in the protocol biopsy group compared to the non-protocol indication biopsy group (P=0.42). Conclusion This study suggests that performing protocol biopsies does not significantly benefit rejection rates, graft survival, or renal function within the first 12 months post-transplant. Given these results and the small but non-zero risk of complications associated with protocol biopsies, they should be reserved for those patients at high risk of rejection. It may be more feasible and beneficial to utilize less invasive tests, such as DSA and dd-cfDNA testing, for early diagnosis of a rejection episode.

Associations of Perioperative Red Blood Cell Transfusion With Outcomes of Kidney Transplantation in Korea Over a 16-Year Period.

This study investigated the associations between transfusion of different types of red blood cell (RBC) preparations and kidney allograft outcomes after kidney transplantation (KT) over a 16-year period in Korea using a nationwide population-based cohort. We investigated the reported use of RBCs during hospitalization for KT surgery, rejection, and graft failure status using nationwide data from the National Health Information Database (2002-2017). The associations between the type of perioperative RBC product and transplant outcomes were evaluated among four predefined groups: no RBC transfusion, filtered RBCs, washed RBCs, and packed RBCs (pRBCs). A total of 17,754 KT patients was included, among which 8,530 (48.0%) received some type of RBC transfusion. Of the patients who received RBC transfusion, 74.9%, 19.7%, and 5.4% received filtered RBCs, pRBCs, or washed RBCs, respectively. Regardless of the type of RBC products, the proportions of acute rejection and graft failure was significantly greater in patients receiving transfusion (P < 0.001). Cox proportional hazards regression analyses showed that the filtered RBC and pRBC groups were significantly associated with both rejection and graft failure. The washed RBC group also had hazard ratios greater than 1.0 for rejection and graft failure, but the association was not significant. Rejection-free survival of the pRBC group was significantly lower than that of the other groups (P < 0.001, log-rank test), and graft survival for the no RBC transfusion group was significantly greater than in the other groups (P < 0.001, log-rank test). Perioperative RBC transfusion was associated with poor graft outcomes. Notably, transfusion of pRBCs significantly increased transplant rejection. Therefore, careful consideration of indications for RBC transfusion and selection of the appropriate type of RBCs is necessary, especially for patients at high risk of rejection or graft failure.

New approaches to improving corneal transplant survival in a pre‐clinical model

AbstractCornea transplantation has been a target for mesenchymal stromal cell (MSC) therapy for several years with a number of publications highlighting the therapeutic potential and mechanism of action of these cells. It is widely known that MSC possess potent anti‐inflammatory capabilities and are able to modulate the activity of a wide array of immune cells including T cells, B cells, dendritic cells and macrophages. This modulation occurs through both cell–cell contact and the paracrine release of soluble factors such as nitric oxide and prostaglandin E2.High risk cornea transplant recipients suffer from a much higher rate of rejection than the average patient. Factors which place patients at high risk of rejection include corneal ulcers, bullous keratopathy or a failed previous graft. These conditions frequently lead to increased blood and lymphatic vessel infiltration to the recipient graft bed and/or some pre‐existing high immunological risk. As outcomes for lower risk cornea transplant recipients, such as those who require a transplant as a result of keratoconus, improves the field is shifting its focus to improve outcomes for more complex cases.In this presentation, I will discuss the therapeutic potential of MSC to promote corneal transplant survival in both low‐ and high‐risk pre‐clinical models and its pathway to potential clinical translation.Funding received for this work.This work was supported by Science Foundation Ireland (12/IA/1624), by a grant from the European Commission [FP7 Collaborative Health Project VISICORT (grant number 602470), www.visicort.eu], by infrastructural funds from the European Regional Development Fund and by the European Union's Horizon 2020 research and innovation programme under grant agreement no. 814439.Keywords: corneal transplantation, high risk, mesenchymal stromal cells, immunomodulation, regulatory cells, tolerance.

Insights into the Pharmacogenetics of Tacrolimus Pharmacokinetics and Pharmacodynamics.

The influence of pharmacogenetics in tacrolimus pharmacokinetics and pharmacodynamics needs further investigation, considering its potential in assisting clinicians to predict the optimal starting dosage and the need for a personalized adjustment of the dose, as well as to identify patients at a high risk of rejection, drug-related adverse effects, or poor outcomes. In the past decade, new pharmacokinetic strategies have been developed to improve personalized tacrolimus treatment. Several studies have shown that patients with tacrolimus doses C0/D < 1 ng/mL/mg may demonstrate a greater incidence of drug-related adverse events and infections. In addition, C0 tacrolimus intrapatient variability (IPV) has been identified as a potential biomarker to predict poor outcomes related to drug over- and under-exposure. With regard to tacrolimus pharmacodynamics, inconsistent genotype-phenotype relationships have been identified. The aim of this review is to provide a concise summary of currently available data regarding the influence of pharmacogenetics on the clinical outcome of patients with high intrapatient variability and/or a fast metabolizer phenotype. Moreover, the role of membrane transporters in the interindividual variability of responses to tacrolimus is critically discussed from a transporter scientist’s perspective. Indeed, the relationship between transporter polymorphisms and intracellular tacrolimus concentrations will help to elucidate the interplay between the biological mechanisms underlying genetic variations impacting drug concentrations and clinical effects.

Selective laser trabeculoplasty for steroid-induced ocular hypertension following endothelial keratoplasty.

Purpose: To examine the safety and efficacy of selective laser trabeculoplasty (SLT) in patients responding to topical steroids with elevated intraocular pressure following endothelial keratoplasty. Methods: Patients that underwent Descemet Membrane Endothelial Keratoplasty (DMEK) or Descemet Stripping Automated Endothelial Keratoplasty (DSAEK) were offered SLT as first-line therapy if they presented with steroid response and met inclusion criteria. Patient demographics, best-corrected visual acuity (BCVA), steroid and glaucoma regimens were recorded before and after SLT. Results: Twelve eyes of 8 patients were recruited to the study. All patients demonstrated a reduction in IOP and only one patient remained on anti-glaucoma drops after SLT. The mean (±SD) reduction in IOP following SLT was 8.8 (±4.9) mmHg (p < 0.0001). BCVA remained stable and no adverse events following treatment were observed. Conclusions: SLT may be a safe and effective treatment option that reduces topical antihypertensive burden while allowing continuance of corticosteroids in steroid-responsive eyes at high risk of rejection following endothelial keratoplasty. Larger randomized studies are needed to compare SLT efficacy with topical medication in this patient group and to review any impact on graft survival and glaucoma progression.

Endogenesis

With the term “Endogenesis”, we aim to highlight design practices and expressions that come from within, bottom-up dynamics, and understand where design belongs as a native species. The focus is dedicated to empirical and vernacular knowledge, first-hand experimentations, and to chase a kind of design that is owned by people and not vice versa. A space in which to question aesthetics and revisit our semiotic biases in matters of form and beauty. Speaking in biological terms, issue 76 aims for a reflection around design as an endogenous act, that lives and grows in specific contexts, rather than being an exogenous element implanted in existing systems with a high risk of rejection. The text also includes reflections and comments on the articles submitted by the authors invited to write for diid’s Open Debate section.

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.

Meta-analysis of the associations of IMPDH and UGT1A9 polymorphisms with rejection in kidney transplant recipients taking mycophenolic acid.

To investigate the associations of IMPDH and UGT1A9 polymorphisms with rejection in kidney transplant recipients taking mycophenolic acid (MPA). PubMed, Web of Science, Embase, Cochrane Library, Wanfang Data, and the China Academic Journal Network Publishing Database were systematically searched for studies investigating the associations of IMPDH1, IMPDH2, and UGT1A9 polymorphisms with rejection in kidney transplant recipients taking MPA. Associations were evaluated by pooled odds ratios (ORs) and effect sizes (ESs) with 95% confidence intervals (CIs). Twelve studies were included in the analysis, including a total of 2342 kidney transplant recipients. The results showed that compared with the TC + CC variant genotypes, the TT genotype of IMPDH2 3757T > C was significantly associated with a higher risk of rejection (ES = 1.60, 95% CI = 1.07-2.40, P = 0.021), while there was no significant association of the IMPDH2 3757T > C polymorphism with acute rejection within 1year in kidney transplant recipients (OR = 1.49, 95% CI = 0.79-2.80, P = 0.217; ES = 1.44, 95% CI = 0.88-2.36, P = 0.142). The GG genotypes of IMPDH1 125G > A and IMPDH1 106G > A were significantly associated with a higher risk of rejection (ES = 1.91, 95% CI = 1.11-3.28, P = 0.019) and acute rejection within 1year (ES = 2.12, 95% CI = 1.45-3.10, P < 0.001) than the variant genotypes GA + AA. The TT genotype of UGT1A9 275T > A showed a decreased risk of rejection compared with the variant genotypes TA + AA (ES = 0.44, 95% CI = 0.23-0.84, P = 0.013). IMPDH1, IMPDH2, and UGT1A9 polymorphisms were associated with rejection in kidney transplant recipients, and the genetic backgrounds of patients should be considered when using MPA.