Smoking exposure-induced bronchus-associated lymphoid tissue in donor lungs does not prevent tolerance induction after transplantation.

The presence of bronchus-associated lymphoid tissue (BALT) in donor lungs has been suggested to accelerate graft rejection after lung transplantation. Although chronic smoke exposure can induce BALT formation, the impact of donor cigarette use on alloimmune responses after lung transplantation is not well understood. Here, we show that smoking-induced BALT in mouse donor lungs contains Foxp3+ T cells and undergoes dynamic restructuring after transplantation, including recruitment of recipient-derived leukocytes to areas of pre-existing lymphoid follicles and replacement of graft-resident donor cells. Our findings from mouse and human lung transplant data support the notion that a donor's smoking history does not predispose to acute cellular rejection or prevent the establishment of allograft acceptance with comparable outcomes to nonsmoking donors. Thus, our work indicates that BALT in donor lungs is plastic in nature and may have important implications for modulating proinflammatory or tolerogenic immune responses following transplantation.

Association between cytomegalovirus viremia and long-term outcomes in lung transplant recipients.

Although cytomegalovirus (CMV) viremia/DNAemia has been associated with reduced survival after lung transplantation, its association with chronic lung allograft dysfunction (CLAD) and its phenotypes is unclear. We hypothesized that, in a modern era of CMV prophylaxis, CMV DNAemia would still remain associated with death, but also represent a risk factor for CLAD and specifically restrictive allograft syndrome (RAS)/mixed phenotype. This was a single-center retrospective cohort study of all consecutive adult, first, bilateral-/single-lung transplants done between 2010-2016, consisting of 668 patients. Risks for death/retransplantation, CLAD, or RAS/mixed, were assessed by adjusted cause-specific Cox proportional-hazards models. CMV viral load (VL) was primarily modeled as a categorical variable: undetectable, detectable to 999, 1000 to 9999, and ≥10 000 IU/mL. In multivariable models, CMV VL was significantly associated with death/retransplantation (≥10 000 IU/mL: HR = 2.65 [1.78-3.94]; P < .01), but was not associated with CLAD, whereas CMV serostatus mismatch was (D+R-: HR = 2.04 [1.30-3.21]; P < .01). CMV VL was not associated with RAS/mixed in univariable analysis. Secondary analyses with a 7-level categorical or 4-level ordinal CMV VL confirmed similar results. In conclusion, CMV DNAemia is a significant risk factor for death/retransplantation, but not for CLAD or RAS/mixed. CMV serostatus mismatch may have an impact on CLAD through a pathway independent of DNAemia.

Allostimulation leads to emergence of a human B cell population with increased expression of HLA class I antigen presentation associated molecules and the immunoglobulin receptor FcRL5.

In the extensive literature characterizing lymphocyte contributions to transplant-related pathologies including allograft rejection and graft-versus-host disease, T cell-focused investigation has outpaced investigation of B cells. Most B cell-related reports describe regulatory and antibody-producing functions, with less focus on the potential role of antigen-presenting capacity. Using in vitro human mixed lymphocyte reactions (MLRs) to model allostimulation, we analyzed responder B cells using transcriptional analysis, flow cytometry and microscopy. We observed emergence of an activated responder B cell subpopulation phenotypically similar to that described in individuals with graft-versus-host disease or allograft rejection. This population had markedly increased expression of FcRL5 (Fc receptor like 5) and molecules associated with HLA class I antigen presentation. Consistent with this phenotype, these cells demonstrated increased internalization of irradiated cell debris and dextran macromolecules. The proportion of this subpopulation within MLR responders also correlated with emergence of activated, cytotoxic CD8+ T cells. B cells of similar profile were quite infrequent in unstimulated blood from healthy individuals but readily identifiable in disaggregated human splenocytes and increased in both cases upon allostimulation. Further characterization of the emergence and function of this subpopulation could potentially contribute to identification of novel biomarkers and targeted therapeutics relevant to curbing transplant-related pathology.

Impact of pre-transplant immune checkpoint inhibitor use on post-transplant outcomes in HCC: A systematic review and individual patient data meta-analysis.

BACKGROUND AND AIM: Treatment with immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC) prior to liver transplantation (LT) has been reported; however, ICIs may elevate the risk of allograft rejection and impact other clinical outcomes. This study aims to summarize the impact of ICI use on post-LT outcomes. MATERIALS AND METHODS: In this individual patient data meta-analysis, we searched databases to identify HCC cases treated with ICIs before LT, detailing allograft rejection, HCC recurrence, and overall survival. We performed Cox regression analysis to identify risk factors for allograft rejection. RESULTS: Among 91 eligible patients, with a median (interquartile range [IQR]) follow-up of 690.0 (654.5) days, there were 24 (26.4%) allograft rejections, 9 (9.9%) HCC recurrences, and 9 (9.9%) deaths. Age (adjusted hazard ratio [aHR] per 10 years=0.72, 95% confidence interval [CI]=0.53, 0.99, P=0.044) and ICI washout time (aHR per 1 week=0.92, 95% CI=0.86, 0.99, P=0.022) were associated with allograft rejection. The median (IQR) washout period for patients with ≤20% probability of allograft rejection was 94 (196) days. Overall survival did not differ between cases with and without allograft rejection (log-rank test, p=0.2). Individuals with HCC recurrence had fewer median (IQR) ICI cycles than those without recurrence (4.0 [1.8]) vs. 8.0 [9.0]); p=0.025). The proportion of patients within Milan post-ICI was lower for those with recurrence vs. without (16.7% vs. 65.3%, p=0.032) CONCLUSION: Patients have acceptable post-LT outcomes after ICI therapy. Age and ICI washout length relate to the allograft rejection risk, and a 3-month washout may reduce it to that of patients without ICI exposure. Number of ICI cycles and tumor burden may affect recurrence risk. Large prospective studies are necessary to confirm these associations. IMPACT AND IMPLICATIONS: This systematic review and individual patient data meta-analysis of 91 patients with hepatocellular carcinoma and immune checkpoint inhibitors use prior to liver transplantation suggests acceptable overall post-transplant outcomes. Older age and longer immune checkpoint inhibitor washout period have a significant inverse association with the risk of allograft rejection. A 3-month washout may reduce it to that of patients without ICI exposure. Additionally, a higher number of immune checkpoint inhibitor cycles and tumor burden within Milan criteria at the completion of immunotherapy may predict a decreased risk of hepatocellular carcinoma recurrence, but this observation requires further validation in larger prospective studies. CODE FOR INTERNATIONAL PROSPECTIVE REGISTER OF SYSTEMATIC REVIEWS (PROSPERO): CRD42023494951.

BATF and BATF3 deficiency alters CD8+ effector/exhausted T cells balance in skin transplantation.

BACKGROUND: It is well-established that CD8+ T-cells play a critical role in graft rejection. The basic leucine zipper ATF-like transcription factor (BATF) and BATF3 are transcriptional factors expressed in T lymphocytes. Herein, we investigated the functions of BATF and BATF3 in the differentiation and exhaustion of CD8+ T cells following alloantigen activation. METHODS: Wild-type CD8+ T cells, BATF-deficient (Batf-/-) CD8+ T cells, and CD8+ T cells deficient in both BATF and BATF3 (Batf-/-Batf3-/-) were transferred to B6.Rag1-/- mice, which received skin allografts from BALB/c mice. Flow cytometry was conducted to investigate the number of CD8+ T cells and the percentage of effector subsets. RESULTS: BATF expression positively correlated with effector CD8+ T cell differentiation. BATF and BATF3 deficiency promoted skin allograft long-term survival and attenuated the CD8+ T cell allo-response and cytokine secretion. Finally, BATF and BATF3 deficiency prompted the generation of exhausted CD8+ T cells. CONCLUSIONS: Overall, our findings provide preliminary evidence that both BATF and BATF3 deficiency influences the differentiation of effector CD8+ T cells and mediates the exhaustion of CD8+ T cells, prolonging transplant survival. Targeting BATF and BATF3 to inhibit CD8+ T cell function has huge prospects for application as a therapeutic approach to prevent transplant rejection.

Two novel assays demonstrate persistent daratumumab exposure in a pediatric patient with delayed engraftment following allogeneic hematopoietic stem cell transplantation.

BACKGROUND AIMS: Daratumumab, a human IgG monoclonal antibody targeting CD38, is a promising treatment for pediatric patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL). We describe a case of delayed engraftment following a mismatched, unrelated donor hematopoietic stem cell transplant (HSCT) in a 14-year-old female with relapsed T-ALL, treated with daratumumab and chemotherapy. By Day 28 post-HSCT, the patient had no neutrophil engraftment but full donor myeloid chimerism. METHODS: We developed two novel, semi-quantitative, antibody-based assays to measure the patient's bound and plasma daratumumab levels to determine if prolonged drug exposure may have contributed to her slow engraftment. RESULTS: Daratumumab levels were significantly elevated more than 30 days after the patient's final infusion, and levels inversely correlated with her white blood cell counts. To clear daratumumab, the patient underwent several rounds of plasmapheresis and subsequently engrafted. CONCLUSIONS: This is the first report of both delayed daratumumab clearance and delayed stem cell engraftment following daratumumab treatment in a pediatric patient. Further investigation is needed to elucidate the optimal dosing of daratumumab for treatment of acute leukemias in pediatric populations as well as daratumumab's potential effects on hematopoietic stem cells and stem cell engraftment following allogenic HSCT.

Pregnancy after deceased donor vs living donor kidney transplant: associated obstetric and graft outcomes.

BACKGROUND: Outside of pregnancy, recipients of a deceased donor kidney transplant experience worse graft and overall survival compared with recipients of a living donor kidney transplant. In pregnancy, it is unknown whether the type of donor graft modifies either graft health in the peripartum period or pregnancy outcomes. OBJECTIVE: This study aimed to define characteristics and outcomes in pregnancy based on donor type in kidney transplant recipients. STUDY DESIGN: This was a retrospective cohort study of adult kidney transplant recipients who received their graft between 2000 and 2019 with a subsequent pregnancy enrolled in the Transplant Pregnancy Registry International. The primary outcome was graft loss within 2 years of delivery. The secondary outcomes included severe maternal morbidity and neonatal composite morbidity. Univariate, multivariable logistic regression, and Cox proportional-hazards models were constructed for statistical analysis, with recipients of a living unrelated donor as the referent. RESULTS: Overall, 638 pregnant patients after kidney transplant had pregnancy outcomes that met our inclusion criteria. Of these patients, 168 (26.3%) received a graft from a deceased donor, 310 (48.6%) received a graft from a living related donor, and 160 (25.1%) received a graft from a living unrelated donor. Recipients of a deceased donor were more likely to be nulliparous, have an unplanned pregnancy, and self-identify as non-White. Moreover, recipients of a deceased donor were more likely to experience urinary tract infections (deceased donor: 21.8%; living related donor: 10.1%; living unrelated donor: 20.6%; P=.018). Severe maternal morbidity (deceased donor: 3.4%; living related donor: 2.8%; living unrelated donor: 7.2%) and neonatal composite morbidity (deceased donor: 8.4%; living related donor: 17.1%; living unrelated donor: 14.4%) did not differ by donor type. Deceased donor transplant was associated with graft loss within 2 years of delivery (deceased donor: 6.7%; living related donor: 3.7%; living unrelated donor: 1.3%; adjusted odds ratio, 7.52; 95% confidence interval, 1.53-60.8) and long-term graft loss from transplant (adjusted hazard ratio, 2.08; 95% confidence interval, 1.10-3.95). CONCLUSION: Although our study demonstrated an association between deceased donor transplant and graft loss after pregnancy, it did not provide evidence that pregnancy itself causes graft loss. Recipients of a deceased donor kidney transplant should not be discouraged from pursuing pregnancy based on their donor type, but these patients should undergo preconception counseling with a discussion of their individualized obstetrical and graft risks, close intrapartum monitoring for infection and hypertensive disease, and continued surveillance for at least 2 years after delivery with a multidisciplinary obstetrics and transplant team.

Utility of a fusion protein T-cell co-stimulation blocker Belatacept in heart transplant recipients: Real world experience from a high volume center.

BACKGROUND: Belatacept (BTC), a fusion protein, selectively inhibits T-cell co-stimulation by binding to the CD80 and CD86 receptors on antigen-presenting cells (APCs) and has been used as immunosuppression in adult renal transplant recipients. However, data regarding its use in heart transplant (HT) recipients are limited. This retrospective cohort study aimed to delineate BTC's application in HT, focusing on efficacy, safety, and associated complications at a high-volume HT center. METHODS: A retrospective cohort study was conducted of patients who underwent HT between January 2017 and December 2021 and subsequently received BTC as part of their immunosuppressive regimen. Twenty-one HT recipients were identified. Baseline characteristics, history of rejection, and indication for BTC use were collected. Outcomes included renal function, graft function, allograft rejection and mortality. Follow-up data were collected through December 2023. RESULTS: Among 776 patients monitored from January 2017 to December 2021 21 (2.7%) received BTC treatment. Average age at transplantation was 53 years (± 12 years), and 38% were women. BTC administration began, on average, 689 [483, 1830] days post-HT. The primary indications for BTC were elevated pre-formed donor-specific antibodies in highly sensitized patients (66.6%) and renal sparing (23.8%), in conjunction with reduced calcineurin inhibitor dosage. Only one (4.8%) patient encountered rejection within a year of starting BTC. Graft function by echocardiography remained stable at 6 and 12 months posttreatment. An improvement was observed in serum creatinine levels (76.2% of patients), decreasing from a median of 1.58 to 1.45 (IQR [1.0-2.1] to [1.1-1.9]) over 12 months (p = .054). eGFR improved at 3 and 6 months compared with 3 months pre- BTC levels; however, this was not statistically significant (p = .24). Treatment discontinuation occurred in seven patients (33.3%) of whom four (19%) were switched back to full dose CNI. Infections occurred in 11 patients (52.4%), leading to BTC discontinuation in 4 patients (19%). CONCLUSION: In this cohort, BTC therapy was used as alternative immunosuppression for management of highly sensitized patients or for renal sparing. BTC therapy when combined with CNI dose reduction resulted in stabilization in renal function as measured through renal surrogate markers, which did not, however, reach statistical significance. Patients on BTC maintained a low rejection rate and preserved graft function. Infections were common during BTC therapy and were associated with medication pause/discontinuation in 19% of patients. Further randomized studies are needed to assess the efficacy and safety of BTC in HT recipients.

The influence of neighborhood income on healthcare utilization in pediatric liver transplant.

OBJECTIVES: Neighborhood contextual factors are associated with liver transplant outcomes. We analyzed associations between neighborhood-level socioeconomic status and healthcare utilization for pediatric liver transplant recipients. METHODS: We merged the Pediatric Health Information System and Scientific Registry of Transplant Recipients databases and included liver transplant recipients ≤21 years hospitalized between January 2004 and May 2022. Outcomes were annual inpatient bed-days, risk of hospitalizations, and risk of liver biopsies. The primary exposure was zip code-based neighborhood income at transplant. We applied causal inference for variable selection in multivariable analysis. We modeled annual inpatient bed-days with mixed-effect zero-inflated Poisson regression, and rates of hospitalization and liver biopsy with a Cox-type proportional rate model. RESULTS: We included 1006 participants from 29 institutions. Children from low-income neighborhoods were more likely to be publicly insured (67% vs. 46%), Black (20% vs. 12%), Hispanic (30% vs. 17%), and have higher model for end-stage liver disease/pediatric end-stage liver disease model scores at transplant (17 vs. 13) than the remaining cohort. We found no differences in inpatient bed-days or rates of hospitalization across neighborhood groups. In univariable analysis, low-income neighborhoods were associated with increased rates of liver biopsy (rate ratio [RR]: 1.57, 95% confidence interval [CI]: 1.04-2.34, p = 0.03). These findings persisted after adjusting for insurance, race, and ethnicity (RR: 1.86, 95% CI: 1.23-2.83, p < 0.01). CONCLUSIONS: Children from low-income neighborhoods undergo more liver biopsies than other children. These procedures are invasive and potentially preventable. In addition to improving outcomes, interventions to mitigate health inequities among liver transplant recipients may reduce resource utilization.

Optimizing the approach to monitoring allograft inflammation using serial urinary CXCL10/creatinine testing in pediatric kidney transplant recipients.

BACKGROUND: Urinary CXCL10/creatinine (uCXCL10/Cr) is proposed as an effective biomarker of subclinical rejection in pediatric kidney transplant recipients. This study objective was to model implementation in the clinical setting. METHODS: Banked urine samples at a single center were tested for uCXCL10/Cr to validate published thresholds for rejection diagnosis (>80% specificity). The positive predictive value (PPV) for rejection diagnosis for uCXCL10/Cr-indicated biopsy was modeled with first-positive versus two-test-positive approaches, with accounting for changes associated with urinary tract infection (UTI), BK and CMV viremia, and subsequent recovery. RESULTS: Seventy patients aged 10.5 ± 5.6 years at transplant (60% male) had n = 726 urine samples with n = 236 associated biopsies (no rejection = 167, borderline = 51, and Banff 1A = 18). A threshold of 12 ng/mmol was validated for Banff 1A versus no-rejection diagnosis (AUC = 0.74, 95% CI = 0.57-0.92). The first-positive test approach (n = 69) did not resolve a clinical diagnosis in 38 cases (55%), whereas the two-test approach resolved a clinical diagnosis in the majority as BK (n = 17/60, 28%), CMV (n = 4/60, 7%), UTI (n = 8/60, 13%), clinical rejection (n = 5/60, 8%), and transient elevation (n = 18, 30%). In those without a resolved clinical diagnosis, PPV from biopsy for subclinical rejection is 24% and 71% (p = .017), for first-test versus two-test models, respectively. After rejection treatment, uCXCL10/Cr level changes were all concordant with change in it-score. Sustained uCXCL10/Cr after CMV and BK viremia resolution was associated with later acute rejection. CONCLUSIONS: Urinary CXCL10/Cr reliably identifies kidney allograft inflammation. These data support a two-test approach to reliably exclude other clinically identifiable sources of inflammation, for kidney biopsy indication to rule out subclinical rejection.

Non-invasive molecular biomarkers for monitoring solid organ transplantation: A comprehensive overview.

Solid organ transplantation is a life-saving intervention for individuals with end-stage organ failure. Despite the effectiveness of immunosuppressive therapy, the risk of graft rejection persists in all viable transplants between individuals. The risk of rejection may vary depending on the degree of compatibility between the donor and recipient for both human leucocyte antigen (HLA) and non-HLA gene-encoded products. Monitoring the status of the allograft is a critical aspect of post-transplant management, with invasive biopsies being the standard of care for detecting rejection. Non-invasive biomarkers are increasingly being recognized as valuable tools for aiding in the detection of graft rejection, monitoring graft status and evaluating the efficacy of immunosuppressive therapy. Here, we focus on the importance of molecular biomarkers in solid organ transplantation and their potential role in clinical practice. Conventional molecular biomarkers used in transplantation include HLA typing, detection of anti-HLA antibodies, killer cell immunoglobulin-like receptor genotypes, and anti-MHC class 1-related chain A antibodies, which are important for assessing the compatibility of the donor and recipient. Emerging molecular biomarkers include the detection of donor-derived cell-free DNA, microRNAs (regulation of gene expression), exosomes (small vesicles secreted by cells), and kidney solid organ response test, in the recipient's blood for early signs of rejection. This review highlights the strengths and limitations of these molecular biomarkers and their potential role in improving transplant outcomes.

Efficacy of Integrated Risk Score Using Omics-Based Biomarkers for the Prediction of Acute Rejection in Kidney Transplantation: A Randomized Prospective Pilot Study.

Acute rejection (AR) is critical for long-term graft survival in kidney transplant recipients (KTRs). This study aimed to evaluate the efficacy of the integrated risk score of omics-based biomarkers in predicting AR in KTRs. This prospective, randomized, controlled, multicenter, pilot study enrolled 40 patients who recently underwent high-immunologic-risk kidney transplantation (KT). Five omics biomarkers were measured, namely, blood mRNA (three-gene signature), urinary exosomal miRNA (three-gene signature), urinary mRNA (six-gene signature), and two urinary exosomal proteins (hemopexin and tetraspanin-1) at 2 weeks and every 4 weeks after KT for 1 year. An integrated risk score was generated by summing each biomarker up. The biomarker group was informed about the integrated risk scores and used to adjust immunosuppression, but not the control group. The outcomes were graft function and frequency of graft biopsy. Sixteen patients in the biomarker group and nineteen in the control group completed the study. The mean estimated glomerular filtration rate after KT did not differ between the groups. Graft biopsy was performed in two patients (12.5%) and nine (47.4%) in the biomarker and control groups, respectively, with the proportion being significantly lower in the biomarker group (p = 0.027). One patient (6.3%) in the biomarker group and two (10.5%) in the control group were diagnosed with AR, and the AR incidence did not differ between the groups. The tacrolimus trough level was significantly lower in the biomarker group than in the control group at 1 year after KT (p = 0.006). Integrated omics biomarker monitoring may help prevent unnecessary or high-complication-risk biopsy and enables tailored immunosuppression by predicting the risk of AR in KTRs.

Risk factors for corneal graft rejection after penetrating keratoplasty for keratoconus.

PURPOSE: To evaluate the association between donor-related factors and the risk of rejection in patients undergoing penetrating keratoplasty (PKP) for keratoconus. METHODS: A retrospective review was performed of keratoconus patients with no corneal neovascularization who underwent PKP from November 2014 to December 2016 and completed at least two years of follow-up. Preoperative, donor, operative, and postoperative data were collected and analyzed to identify factors leading to corneal graft rejection. RESULTS: A total of 201 eyes (of 201 patients) that underwent PKP for keratoconus were included. Of these, 22.9% (95% CI 17.6-29.2%) had an episode of graft rejection. The overall graft survival rate was 98.5%. Receipts with a history of corneal transplant in the fellow eye (IRR 1.69, 95% CI 1.01, 2.80; p = 0.044) and those with postoperative stromal neovascularization (IRR 2.51, 95% CI 1.49, 4.21; p = 0.001) had a significantly higher incidence of rejection than those without these features. In univariate analysis, death-to-surgery time and death-to-excision time (DET) showed a weak association with graft rejection (p 0.05 and 0.08 respectively); However, in the multivariable analysis, this significance was lost. Grafts with a death-to-excision time (DET) greater than 8 h had a 0.53X lower risk of rejection compared with grafts with DET within 8 h or less (p = 0.05). Rejection was higher in patients receiving grafts with a preservation time within 7 days or less compared with preservation time greater than 7 days (30.6% vs. 21.2%, respectively, p = 0.291). CONCLUSION: In the multivariable analysis, none of the donor-related factors were significantly associated with graft rejection; however, short death-to-surgery time may be associated with rejection after PKP. Recipients with a history of PKP in the fellow eye and those who developed corneal neovascularization were also at increased risk of developing rejection after keratoplasty.

[Modern techniques and features of selective keratoplasty]. / Sovremennye tekhnologii i vozmozhnosti selektivnoi keratoplastiki.

Selective keratoplasty involves replacing the affected layers of the cornea with similar donor tissue. In case of pathological changes in the middle and posterior stroma, deep anterior lamellar keratoplasty (DALK) is performed. Chronic corneal edema caused by endothelial dysfunction is an indication for endothelial keratoplasty - Descemet membrane endothelial keratoplasty (DMEK) or Descemet Stripping Endothelial Keratoplasty (DSAEK). Compared to penetrating keratoplasty (PK), these operations are characterized by a low risk of damage to intraocular structures and a relatively short rehabilitation period. Complications of selective keratoplasty include the formation of a false chamber between the lamellar graft and the recipient's cornea, ocular hypertension during anterior chamber air tamponade. Persistent epithelial defect can be a sign of primary graft failure in DALK, DSAEK and DMEK. Selective keratoplasty is characterized by a lower incidence of immune rejection than PK. In some cases, DALK can be complicated by corneal changes related to suture fixation of the graft. Long-term postoperative use of topical glucocorticoids can cause ocular hypertension and cataracts.

Computational Analysis of Routine Biopsies Improves Diagnosis and Prediction of Cardiac Allograft Vasculopathy.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is a leading cause of morbidity and mortality for heart transplant recipients. Although clinical risk factors for CAV have been established, no personalized prognostic test exists to confidently identify patients at high versus low risk of developing aggressive CAV. This investigation aimed to leverage computational methods for analyzing digital pathology images from routine endomyocardial biopsies (EMBs) to develop a precision medicine tool for predicting CAV years before overt clinical presentation. METHODS: Clinical data from 1 year after transplant were collected on 302 transplant recipients from the University of Pennsylvania, including 53 patients with early-onset CAV and 249 no early-onset CAV controls. These data were used to generate a clinical model (Clinical Risk Factor Future Cardiac Allograft Vasculopathy Prediction Model [ClinCAV-Pr]) for predicting future CAV development. From this cohort, 183 archived EMBs were collected for CD31 and modified trichrome staining and then digitally scanned. These included 1-year posttransplant EMBs from 50 patients with early-onset CAV and 82 patients with no early-onset CAV, as well as 51 EMBs from disease control patients obtained at the time of definitive coronary angiography confirming CAV. Using biologically inspired, handcrafted features extracted from digitized EMBs, quantitative histological models for differentiating no early-onset CAV from disease controls (Histological Cardiac Allograft Vasculopathy Diagnostic Model [HistoCAV-Dx]) and for predicting future CAV from 1-year posttransplant EMBs were developed (Histological Future Cardiac Allograft Vasculopathy Prediction Model [HistoCAV-Pr]). The performance of histological and clinical models for predicting future CAV (ie, HistoCAV-Pr and ClinCAV-Pr, respectively) were compared in a held-out validation set before being combined to assess the added predictive value of an integrated predictive model (Integrated Histological/Clinical Risk Factor Future Cardiac Allograft Vasculopathy Prediction Model [iCAV-Pr]). RESULTS: ClinCAV-Pr achieved modest performance on the independent test set, with an area under the receiver operating curve (AUROC) of 0.70. The HistoCAV-Dx model for diagnosing CAV achieved excellent discrimination, with an AUROC of 0.91, whereas the HistoCAV-Pr model for predicting CAV achieved good performance with an AUROC of 0.80. The integrated iCAV-Pr model achieved excellent predictive performance, with an AUROC of 0.93 on the held-out test set. CONCLUSIONS: Prediction of future CAV development is greatly improved by incorporation of computationally extracted histological features. These results suggest morphological details contained within regularly obtained biopsy tissue have the potential to enhance precision and personalization of treatment plans for patients after heart transplant.

The impact of donor diabetes on corneal transplant immunity.

Corneal transplantation is the most common form of solid tissue grafting, with an approximately 80% to 90% success rate. However, success rates may decline when donor tissues are derived from patients with a history of diabetes mellitus (DM). To evaluate the underlying immunopathologic processes that cause graft rejection, we used streptozotocin-induced type 1 DM (DM1) and transgenic Lepob/ob type 2 DM (DM2) diabetic murine models as donors and nondiabetic BALB/c as recipients. DM resulted in an increased frequency of corneal antigen-presenting cells (APCs) with an acquired immunostimulatory phenotype. Following transplantation, recipients that received either type of diabetic graft showed increased APC migration and T helper type 1 alloreactive cells, impaired functional regulatory T cells, and graft survival. Insulin treatment in streptozotocin-induced diabetic mice led to an increased tolerogenic profile of graft APC, lower T helper type 1 sensitization, and a higher frequency of functional regulatory T cells with high suppressive capacity, reflected in increased graft survival. We conclude that both DM1 and DM2 in donors can impact corneal APC functional phenotype, rendering the tissue more immunogenic and thereby increasing the risk of graft failure.

Importance of social vulnerability on long-term outcomes after heart transplantation.

The relationship between social determinants of health and outcomes after heart transplantation has not been examined. The social vulnerability index (SVI) uses United States census data to determine the social vulnerability of every census tract based on 15 factors. This retrospective study seeks to examine the impact of SVI on outcomes after heart transplantation. Adult heart recipients who received a graft between 2012 and 2021 were stratified into SVI percentiles of <75% and SVI of ≥75%. The primary endpoint was survival. The median SVI was 48% (interquartile range: 30%-67%) among 23 700 recipients. One-year survival was similar between groups (91.4 vs 90.7%, log-rank P = .169); however, 5-year survival was lower among individuals living in vulnerable communities (74.8% vs 80.0%, P < .001). This finding persisted despite risk adjustment for other factors associated with mortality (survival time ratio 0.819, 95% confidence interval: 0.755-0.890, P < .001). The incidences of 5-year hospital readmission (81.4% vs 75.4%, P < .001) and graft rejection (40.3% vs 35.7%, P = .004) were higher among individuals living in vulnerable communities. Individuals living in vulnerable communities may be at increased risk of mortality after heart transplantation. These findings suggest there is an opportunity to focus on these recipients undergoing heart transplantation to improve survival.

Advances in Human Lung Transplantation.

Lung transplantation improves survival and quality of life in patients with advanced pulmonary disease. Over the past several decades, the volume of lung transplants has grown substantially, with increasing transplantation of older and acutely ill individuals facilitated by improved utilization and preservation of available donor organs. Other advances include improvements in the diagnosis and mechanistic understanding of frequent post-transplant complications, such as primary graft dysfunction, acute rejection, and chronic lung allograft dysfunction (CLAD). CLAD occurs as a result of the host immune response to the allograft and is the principal factor limiting long-term survival after lung transplantation. Two distinct clinical phenotypes of CLAD have emerged, bronchiolitis obliterans syndrome and restrictive allograft syndrome, and this distinction has enabled further understanding of underlying immune mechanisms. Building on these advances, ongoing studies are exploring novel approaches to diagnose, prevent, and treat CLAD. Such studies are necessary to improve long-term outcomes for lung transplant recipients.

Long-term survival from progressive multifocal leukoencephalopathy in living-donor liver transplant recipient with preformed donor-specific antibody.

Intensive immunosuppression has enabled liver transplantation even in recipients with preformed donor-specific antibodies (DSA), an independent risk factor for graft rejection. However, these recipients may also be at high risk of progressive multifocal encephalopathy (PML) due to the comorbid immunosuppressed status. A 58-year-old woman presented with self-limited focal-to-bilateral tonic-clonic seizures 9 months after liver transplantation. She was desensitized using rituximab and plasma exchange before transplantation and was subsequently treated with steroids, tacrolimus, and everolimus after transplantation for her preformed DSA. Neurological examination revealed mild acalculia and agraphia. Cranial MRI showed asymmetric, cortex-sparing white matter lesions that increased over a week in the left frontal, left parietal, and right parieto-occipital lobes. Polymerase chain reaction (PCR) of the cerebrospinal fluid for the JC supported the diagnosis of PML. Immune reconstitution by reducing the immunosuppressant dose stopped lesion expansion, and PCR of the cerebrospinal fluid for the JC virus became negative. Graft rejection occurred 2 months after immune reconstitution, requiring readjustment of immunosuppressants. Forty-eight months after PML onset, the patient lived at home without disabling deficits. Intensive immunosuppression may predispose recipients to PML after liver transplantation with preformed DSA. Early immune reconstitution and careful monitoring of graft rejection may help improve outcomes.

Quantitative ultrasound for non-invasive evaluation of subclinical rejection in renal transplantation.

OBJECTIVES: This study aimed to investigate the predictive efficacy of shear-wave elastography, superb microvascular imaging (SMI), and CEUS for allograft rejection in kidney transplants without graft dysfunction. METHODS: From January 2021 to November 2021, 72 consecutive patients who underwent both allograft biopsy and ultrasound were evaluated. Blood test results were obtained within a week of the ultrasound examinations, which were performed before the protocol biopsy. Resistive index (RI), tissue viscoelasticity, vascular index, and quantitative CEUS parameters were measured. Patients were divided based on biopsy results into the rejection and non-rejection groups. RESULTS: Among the 72 patients, 21 patients had pathological characteristics of acute rejection. RI of allograft was significantly higher in the rejection group (p = 0.007), compared to the non-rejection group. There were no significant between-group differences in vascular indices of SMI, mean elasticity, and mean viscosity. Meanwhile, among the parameters obtained by the time-intensity curve on CEUS, the cortical and medullary ratios of average contrast signal intensity, peak enhancement, wash-in area AUC, wash-in perfusion index, wash-out AUC, and wash-in and wash-out AUC were significantly different between the two groups (p < 0.05). In the receiver operating characteristic curve analysis for predicting allograft rejection, the AUC was 0.853 for the combination of six CEUS parameters, RI, and blood urea nitrogen. CONCLUSIONS: Among non-invasive quantitative ultrasound measurements, CEUS parameters are the most useful for diagnosing subclinical allograft rejection. Furthermore, the combination of CEUS parameters, RI, and blood urea nitrogen may be helpful for the early detection of renal allograft rejection. KEY POINTS: • Among non-invasive quantitative ultrasound measurements, CEUS parameters are the most useful for the diagnosis of subclinical allograft rejection. • On CEUS, the C/M ratios of MeanLin, PE, WiAUC, WiPI, WoAUC, and WiWoAUC are significantly lower in the rejection group; the combination of these showed reliable predictive performance for rejection. • The combination of CEUS parameters, RI, and BUN has a high predictive capability for subclinical allograft rejection.