Post-transplant Rejection Research Articles

Donor Characteristics and Outcomes of Pediatric Heart Transplantation in South Korea.

Heart transplantation is often limited by the availability of transplantable donor heart and understanding of donor aspects that would influence transplant outcomes becomes important. In this study, donor characteristics and their impact on the outcomes of pediatric heart transplantations performed in South Korea were investigated. We reviewed the medical records of patients less than 18 years old who received heart transplantation between 2002 and 2022 in three tertiary hospitals located in South Korea. A total of 139 cases were enrolled. One-year mortality was 10.4% and total mortality was 33.8%. Forty-nine recipients (35.3%) showed biopsy-proven rejections and 20 (14.4%) showed cardiac allograft vasculopathy during mean follow-up of 6.4 ± 4.9 years. Six recipients (4.5%) showed left ventricle ejection fraction of less than 55% post-transplantation. The mean age of the donors was 23.0 ± 15.4 years. The most common cause of death of the donors was unspecified illness (46.4%). Donors with a history of diabetes, hypertension, smoking, and alcohol consumption were 0%, 3.1%, 32.1%, and 34.4%, respectively. Mean total ischemic time was 191.6 ± 72.7 min, while total ischemic time was over 4 h in 37 patients (26.6%). There were no significant relationship between donor factors and survival. However, donor's history of drinking or cardiopulmonary resuscitation was significantly associated with acute rejection and donor's age with cardiac allograft vasculopathy. Donor factors did not show significant impact on post-transplant survival but some factors were predictive of post-transplant rejection and cardiac allograft vasculopathy.

Assessment of the Therapeutic Potential of Enhancer of Zeste Homolog 2 Inhibition in a Murine Model of Bronchiolitis Obliterans Syndrome.

Bronchiolitis obliterans syndrome (BOS) is a chronic complication following lung transplantation that limits the long-term survival. Although the enhancer of zeste homolog 2 (EZH2) is involved in post-transplantation rejection, its involvement in BOS pathogenesis remains unclear. We aimed to investigate the therapeutic potential of EZH2 inhibition in BOS. 3-deazaneplanocin A (DZNep) was administered intraperitoneally to heterotopic tracheal transplant recipient model mice. Tracheal allografts were obtained on days 7, 14, 21, and 28 after transplantation. The obstruction ratios of the DZNep and control groups on days 7, 14, 21, and 28 were 15.1% ± 0.8% vs. 20.4% ± 3.6% (p = 0.996), 16.9% ± 2.1% vs. 67.7% ± 11.5% (p < 0.001), 47.8% ± 7.8% vs. 92.2% ± 5.4% (p < 0.001), and 60.0% ± 9.6% vs. 95.0% ± 2.3% (p < 0.001), respectively. The levels of interleukin (IL)-6 and interferon-γ on day 7 and those of IL-2, tumor necrosis factor, and IL-17A on days 14, 21, and 28 were significantly reduced following DZNep treatment. DZNep significantly decreased the number of infiltrating T-cells on day 14. In conclusion, DZNep-mediated EZH2 inhibition suppressed the inflammatory reactions driven by pro-inflammatory cytokines and T cell infiltration, thereby alleviating BOS symptoms.

Neoadjuvant atezolizumab plus bevacizumab prior liver transplantation for hepatocellular carcinoma☆

Background & AimsThe combination of atezolizumab and bevacizumab offers a novel approach to immunomodulation, showing efficacy as a primary treatment in advanced hepatocellular carcinoma (HCC). Concerns about graft safety and rejection have limited its exploration in the neoadjuvant setting of liver transplantation (LT).This study investigates the clinical efficacy and the safety profile related to the pre-transplant administration of atezolizumab and bevacizumab for HCC. MethodsProspective assessment of 17 patients with HCC treated with neoadjuvant preoperative atezolizumab and bevacizumab prior to LT for HCC, obtained from December 2020 and December 2023 at seven Western transplant centers. ResultsAmong the 17 patients with HCC included in the study, 16 (94.1%) had a tumor burden outside of Milan Criteria (MC). Neoadjuvant loco-regional therapies along with the administration of atezolizumab plus bevacizumab (median:5 months; discontinued at least 4 weeks prior LT), achieved an ORR 94% (Complete response: 59%), downstaging to within MC (82%) and a pathological response at explant examination of 88%. Grade 3-4 TRAE accounted for 17.6% of cases and were manageable. During the 25 months median follow-up period, 2 cases of mild (RAI ≤ 4), biopsy-proven rejection were reported but no instances of severe allograft rejection or graft loss. The 1-year and 3-year post-LT survival rates were 94.2% and 88.2%, respectively. ConclusionsThis study highlights the favorable oncological and survival outcomes from a multicentric cohort of HCC patients treated with atezolizumab and bevacizumab in the pre-LT setting. This immune-based combination was safe in terms of TRAE, and absence of severe post-transplant rejection or graft loss. These preliminary results could pave the way for expanding transplant eligibility criteria in patients at more advanced HCC stages. Impact and Implications•The combination of atezolizumab and bevacizumab in the neoadjuvant setting prior to liver transplantation for hepatocellular carcinoma (HCC) has been limitedly explored despite its potential to enhance anti-tumor response and downstaging due to raising concerns about its safety profile.•Among 17 patients who underwent successful liver transplantation following neoadjuvant atezolizumab/bevacizumab, 82% achieved downstaging to within MC, 94% radiological objective response and 88% pathology response, without drop-outs due to TRAEs or graft loss.•The neoadjuvant combination of atezolizumab plus bevacizumab prior liver transplantation in HCC shows an encouraging safety profile and stands out as a promising pre-transplant optimization treatment adjunct, leading to improved oncological outcomes

Urinary Metabolite Constellation Also Detects Very Early Post-transplant Rejection in Living Donor Kidney Recipients

Urinary Metabolite Constellation Also Detects Very Early Post-transplant Rejection in Living Donor Kidney Recipients

Short-term alcohol abstinence prior to liver transplantation and impact on rejection

Background & AimsAlcohol-associated liver disease (ALD) is a leading indication for liver transplant (LT). Historically, centers implemented 6-month abstinence periods prior to LT listing; however, the impact of this abstinence time on post-transplant rejection outcomes is unclear. This study evaluated if short-term abstinence is associated with increased rejection post-LT. MethodsThis single-center, retrospective, cohort included adult LT recipients from 11/1/2015 to 7/21/2021 with a primary indication of ALD. Patients were grouped by pre-transplant abstinence time of <6 or ≥6-months. The primary endpoint was biopsy proven acute rejection (BPAR) at 12-months post-LT. Secondary endpoints were infection, alcohol relapse, patient and graft survival at 12-months. ResultsOverall, 228 LT recipients met inclusion criteria (<6-months: n = 130; ≥6-months: n = 98). Patients with <6-months of abstinence were younger, had higher MELD scores, and more renal replacement therapy needs. Incidence of BPAR within 12 months of LT was 28 % in the <6-month group vs. 18 % in the ≥6-month group (p = 0.078). Tacrolimus initiation was lower at 7 days post-LT in the <6-month group (77% vs. 89 %; p = 0.029). Delay in tacrolimus initiation past 7 days post-LT was associated with greater BPAR (35% vs. 12 %; p = 0.0001). Increased bloodstream infections (21% vs. 7 %; p = 0.04) and CMV DNAemia (31% vs. 7 %; p = 0.0008) were seen in the <6-month group. Patient and graft survival was similar between groups. ConclusionsAbstinence time of <6-months was not associated with more BPAR within 12-months post-LT. The <6-month group was sicker at time of LT, which correlates to lower tacrolimus exposure early post-LT and heightened incidence of bacteremia and CMV viremia. Given the high acuity of the <6-month abstinence group, the risk of BPAR must be closely balanced with infection risk.

Donor-derived Cell-free DNA Evaluation in Pediatric Heart Transplant Recipients: A Single-center 12-mo Experience.

Endomyocardial biopsy (EMB) is considered the gold-standard method to diagnose rejection after heart transplantation. However, the many disadvantages and potential complications of this test restrict its routine application, particularly in pediatric patients. Donor-derived cell-free DNA (dd-cfDNA), released by the transplanted heart as result of cellular injury, is emerging as a biomarker of tissue damage involved in ischemia/reperfusion injury and posttransplant rejection. In the present study, we systematically evaluated dd-cfDNA levels in pediatric heart transplant patients coming for follow-up visits to our clinic for 12 mo, with the aim of determining whether dd-cfDNA monitoring could be efficiently applied and integrated into the posttransplant management of rejection in pediatric recipients. Twenty-nine patients were enrolled, and cfDNA was obtained from 158 blood samples collected during posttransplant follow-up. dd-cfDNA% was determined with a droplet-digital polymerase chain reaction assay. EMB scores, donor-specific antibody measurements, and distress marker quantification were correlated with dd-cfDNA, together with echocardiogram information. The percentage of dd-cfDNA increased when EMBs scored positive for rejection (P = 0.0002) and donor-specific antibodies were present (P = 0.0010). N-terminal pro-B-type natriuretic peptide and high-sensitive troponin I elevation were significantly associated with dd-cfDNA release (P = 0.02 and P < 0.0001, respectively), as were reduced isovolumetric relaxation time (P = 0.0031), signs of heart failure (P = 0.0018), and treatment for rejection (P = 0.0017). By determining a positive threshold for rejection at 0.55%, the test had a negative predictive value maximized at 100%. Collectively, results indicate that dd-cfDNA monitoring has a high negative prognostic value, suggesting that in heart transplanted children with dd-cfDNA levels of <0.55% threshold, protocol EMBs may be postponed.

Interleukin 6 and interleukin 17A serum levels and gene- polymorphisms in the development of early allograft rejection in living donor liver transplant recipients

The aim of this study is to evaluate the role of serum level of Interleukin 6(IL-6) and Interleukin 17 (IL-17) in liver transplantation outcome for living recipients, Analyze the relation between the gene polymorphism and the occurrence of rejection after liver transplantation and Study the relation between the gene polymorphism and the occurrence of different infectious complications. The study was conducted in March 2023 and included 60 healthy volunteers from the National Liver Institute (NLI) blood bank at Menoufia University and 120 live donation liver recipient patients at NLI. During one month of liver transplantation, the cytokine levels (IL-17, IL-6 proteins, IL-6 G-174C, and IL-17 A rs2275913 gene polymorphism) and CD4 levels for 60 patients of 120 live donation liver recipient patients whom early reject transplanted tissue and the same parameters were measured after 6 months follow up for non-reject group. The main finding of this study was that the post-transplant rejection group and the post-transplant non-rejection and control groups differed significantly in the genotype frequency (CC, CG, and GG) or alleles of IL-6 G-174C (p = 0.011). On the other hand IL-17A rs2275913 gene polymorphism and its alleles (p = 0.71) showed no statistically significant difference. We also observed that serum IL-17 levels, with 100% specificity and 100% sensitivity threshold, will be more sensitive and specific than serum IL-6 and CD4 count in differentiating post-transplant rejection from non-rejection patients. The results showed that there was no significant relationship between the genotypes and serum levels of interleukins and the type and degree of rejection. Proinflammatory cytokines might be useful indicators for distinguishing and early identifying unfavorable outcomes after transplantation, allowing for prompt and effective treatment intervention. To evaluate these findings, prospective clinical trials are required.

Cytokine Dynamics and Herpesvirus Interactions in Pediatric Liver and Kidney Transplant Recipients: The Distinct Behavior of HCMV, HHV6, HHV7 and EBV.

Pediatric solid organ transplant (SOT) recipients face a challenging balance between immunosuppression and graft rejection. While Epstein-Barr Virus (EBV) and cytomegalovirus (HCMV) are known contributors to post-transplant lymphoproliferative disease and graft rejection, respectively, the roles of herpesvirus 6 and 7 (HHV6 and HHV7) and the impact of these herpesviruses on cytokine levels remain unclear, leading to gaps in clinical practice. In this associative study, we measured 17 cytokines using a Bio-Plex assay in a meticulously curated plasma sample pool (N = 158) from pediatric kidney and liver transplant recipients over a one-year follow-up period. The samples included virus-negative and virus-positive cases, either individually or in combination, along with episodes of graft rejection. We observed that the elevation of IL-4, IL-8, and IL-10 correlated with graft rejection. These cytokines were elevated in samples where HCMV or HHV6 were detected alone or where EBV and HHV7 were co-detected. Interestingly, latent EBV, when detected independently, exhibited an immunomodulatory effect by downregulating cytokine levels. However, in co-detection scenarios with β-herpesviruses, EBV transitioned to a lytic state, also associating with heightened cytokinemia and graft rejection. These findings highlight the complex interactions between the immune response and herpesviruses in transplant recipients. The study advocates for enhanced monitoring of not only EBV and HCMV but also HHV6 and HHV7, providing valuable insights for improved risk assessment and targeted interventions in pediatric SOT recipients.

Transbronchial Cryobiopsy Versus Transbronchial Forceps Biopsy for Acute Cellular Rejection Detection in Lung Transplantation: A Meta-Analysis

BackgroundTransbronchial cryobiopsy (TBCB) provides larger tissue samples and improved sampling depth, but its role in diagnosing acute cellular rejection (ACR) in lung transplant patients is unclear due to limitations in existing studies. To address this, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of TBCB. MethodsA thorough literature review was conducted to evaluate TBCB in post-lung transplant surveillance, assessing the quality of studies and conducting a meta-analysis comparing diagnostic yields of TBCB and transbronchial forceps biopsy (TBFB), as well as evaluating procedural complications. ResultsOur meta-analysis, incorporating 11 studies with a total of 915 patients, showed that TBCB had a diagnostic rate of 38.27% (225/588) for ACR post-lung transplantation, notably higher than the 35.65% (251/704) for TBFB. The inverse-variance weighted odds ratio was calculated at 2.32 (95% confidence interval: 1.24–4.32; p=0.008). Funnel plot analysis indicated no major publication bias. Meta-analysis of 6 studies demonstrated that TBCB, compared to TBFB, significantly increased the diagnostic rate for chronic rejection post-transplantation (25.00% vs 10.93%, p=0.005). Our meta-analysis comparing the safety of TBCB and TBFB in post-lung transplant surveillance found no significant differences in moderate to severe bleeding (5.99% vs 6.31%, p=0.98), or pneumothorax incidence (3.90% vs 3.29%, p=0.75). ConclusionsOur study indicates that TBCB may enhance the diagnosis of acute and chronic rejection post-lung transplantation with a safety profile comparable to TBFB. Further research and the development of standardized procedures are warranted to ensure the safe and effective application of TBCB in broader clinical practice.

Hepatitis C viremic lung transplantation to aviremic recipients: Comprehensive outcomes and post-transplant viremia.

Direct-acting antiviral (DAA) therapy has revolutionized solid organ transplantation by providing an opportunity to utilize organs from HCV-viremic donors. Though transplantation of HCV-viremic donor organs into aviremic recipients is safe in the short term, midterm data on survival and post-transplant complications is lacking. We provide a midterm assessment of complications of lung transplantation (LT) up to 2 years post-transplant, including patient and graft survival between HCV-viremic transplantation (D+) and HCV-aviremic transplantation (D-). This is a retrospective cohort study including 500 patients from 2018 to 2022 who underwent LT at our quaternary care institution. Outcomes of patients receiving D+ grafts were compared to those receiving D- grafts. Recipients of HCV antibody+ but PCR- grafts were treated as D- recipients. We identified 470 D- and 30 D+ patients meeting inclusion criteria. Crude mortality did not differ between groups (p=.43). Patient survival at years 1 and 2 did not differ between D+ and D- patients (p=.89, p=.87, respectively), and graft survival at years 1 and 2 did not differ between the two groups (p=.90, p=.88, respectively). No extrahepatic manifestations or fibrosing cholestatic hepatitis (FCH) occurred among D+ recipients. D+ and D- patients had similar rates of post-transplant chronic lung allograft rejection (CLAD) (p=6.7%vs. 12.8%, p=.3), acute cellular rejection (60.0%vs. 58.0%, p=.8) and antibody-mediated rejection (16.7%vs. 14.2%, p=.7). There is no difference in midterm patient or graft survival between D+ and D-LT. No extrahepatic manifestations of HCV occurred. No differences in any type of rejection including CLAD were observed, though follow-up for CLAD was limited. These results provide additional support for the use of HCV-viremic organs in selected recipients in LT.

Disulfiram, an Anti-alcoholic Drug, Targets Macrophages and Attenuates Acute Rejection in Rat Lung Allografts.

Macrophages contribute to post-transplant lung rejection. Disulfiram (DSF), an anti-alcoholic drug, has an anti-inflammatory effect and regulates macrophage chemotactic activity. Here, we investigated DSF efficacy in suppressing acute rejection post-lung transplantation. Male Lewis rats (280-300g) received orthotopic left lung transplants from Fisher 344 rats (minor histocompatibility antigen-mismatched transplantation). DSF (0.75mg/h) monotherapy or co-solvent only (50% hydroxypropyl-β-cyclodextrin) as control was subcutaneously administered for 7 days (n = 10/group). No post-transplant immunosuppressant was administered. Grades of acute rejection, infiltration of immune cells positive for CD68, CD3, or CD79a, and gene expression of monocyte chemoattractant protein and pro-inflammatory cytokines in the grafts were assessed 7 days post-transplantation. The DSF-treated group had significantly milder lymphocytic bronchiolitis than the control group. The infiltration levels of CD68+ or CD3+ cells to the peribronchial area were significantly lower in the DSF than in the control groups. The normalized expression of chemokine ligand 2 and interleukin-6 mRNA in allografts was lower in the DSF than in the control groups. Validation assay revealed interleukin-6 expression to be significantly lower in the DSF than in the control groups. DSF can alleviate acute rejection post-lung transplantation by reducing macrophage accumulation around peripheral bronchi and suppressing pro-inflammatory cytokine expression.

Nanoparticle-assisted Targeting Delivery Technologies for Preventing Organ Rejection.

Although organ transplantation is a life-saving medical procedure, the challenge of posttransplant rejection necessitates safe and effective immune modulation strategies. Nanodelivery approaches may have the potential to overcome the limitations of small-molecule immunosuppressive drugs, achieving efficacious treatment options for transplant tolerance without compromising overall host immunity. This review highlights recent advances in biomaterial-assisted formulations and technologies for targeted nanodrug delivery with transplant organ- or immune cell-level precision for treating graft rejection after transplantation. We provide an overview of the mechanism of transplantation rejection, current clinically approved immunosuppressive drugs, and their relevant limitations. Finally, we discuss the targeting principles and advantages of organ- and immune cell-specific delivery technologies. The development of biomaterial-assisted novel therapeutic strategies holds considerable promise for treating organ rejection and clinical translation.

Impact of age over 70 years in the new allocation system on the outcomes of heart transplantation in the US.

United Network for Organ Sharing (UNOS) allocation criteria changed in 2018 to accommodate the increased prevalence of patients on a ventricular assist device as a bridge to heart transplant and prioritize sicker people in anticipation of a heart graft. We aimed to assess the impact of patient age in the new allocation policy on mortality following heart transplantation. Secondary outcomes included the effect of age ≥70 on post-transplant events, including stroke, dialysis, pacemaker, and rejection requiring treatment. The UNOS Registry was queried to identify patients who underwent heart transplants alone in the US between 2000 and 2021. Patients were divided into groups according to their age (over 70 and under 70 years old). Patients aged over 70 were more likely to require dialysis during follow-up, but less likely to experience rejection requiring treatment, compared with patients aged <70. Age ≥70 in the new allocation system was a significant predictor of 1-year mortality (adjusted HR: 1.41; 95% CI: 1.05-1.91; p=.024), but its effect on 5-year mortality was not significant after adjusting for potential confounders (adjusted HR: 1.27; 95% CI:.97-1.66; p=.077). Undergoing transplantation under the new allocation policy vs the old allocation policy was not a significant predictor of mortality in patients over 70 years old. Age ≥70 is a significant predictor of 1-year mortality following heart transplantation, but not at 5 and 10 years; however, the new allocation does not seem to have changed the outcomes for this group of patients.

Therapeutic apheresis: is it safe in children with kidney disease?

BackgroundTherapeutic apheresis (TA) is already used to treat various diseases in the field of nephrology. The aim of this study was to evaluate the frequency and types of complications that occur during TA in children with kidney disease.MethodsRecords of children (≤ 18 years) who underwent TA between 2007 and 2022 were retrospectively reviewed. Children with missing data and those with a diagnosis of nonnephrological disease were excluded.ResultsA total of 1214 TA sessions, including 1147 therapeutic plasma exchange (TPE) sessions and 67 immunoadsorption (IA) sessions, were performed on the 108 patients enrolled in the study. Forty-seven percent of the patients were male, and the mean age was 12.22 ± 4.47 years. Posttransplant antibody-mediated rejection (64.8%) and hemolytic uremic syndrome (14.8%) were the most common diagnoses indicating TA. Overall, 17 different complications occurred in 58 sessions (4.8%), and 53 sessions (4.6%) were not completed because of these complications. The distribution of complications among the patients was as follows: 41.4% had technical complications, 25.9% had allergic complications, and 32.7% had others. The most common technical complication was insufficient flow (37.5%). The incidence of complications was greater in patients aged 3–6 years than in patients in the other age groups (p = 0.031). The primary disease, type of vascular access, and rate of fresh frozen plasma/albumin use were similar between patients with and without complications (p values of 0.359 and 0.125 and 0.118, respectively).ConclusionsOur study showed that complications occurred in only 4.8% of TA sessions. The most common complication was technical problems.Graphical A higher resolution version of the Graphical abstract is available as Supplementary information

A retrospective analysis of anticoagulant safety among heart transplant recipients undergoing endomyocardial biopsy.

Transvenous endomyocardial biopsy is an invasive procedure which is used to diagnose rejection following an orthotopic heart transplant. Endomyocardial biopsy is widely regarded as low risk with all-cause complication rates below 5% in most safety studies. Following transplant, some patients require therapeutic anticoagulation. It is unknown whether anticoagulation increases endomyocardial biopsy bleeding risk. Records from 2061 endomyocardial biopsies performed for post-transplant rejection surveillance at our institution between November 2016 and August 2022 were reviewed. Bleeding complications were defined as vascular access-related hematoma or bleeding, procedure-related red blood cell transfusion, and new pericardial effusion. Relative risk and small sample-adjusted 95% confidence interval was calculated to investigate the association between bleeding complications and anticoagulation. The overall risk of bleeding was 1.2% (25/2061 cases). There was a statistically significant increase in bleeding among patients on intravenous (RR 4.46, CI 1.09-18.32) but not oral anticoagulants (RR .62, CI .15-2.63) compared to patients without anticoagulant exposure. There was a trend toward increased bleeding among patients taking warfarin with INR ≥ 1.8 (RR 3.74, CI .90-15.43). Importantly, no bleeding events occurred in patients taking direct oral anticoagulants such as apixaban. Based on these results, intravenous rather than oral anticoagulation was associated with a significantly higher risk of bleeding complications following endomyocardial biopsy.

Association between CYP3A5 Gene Polymorphism and Post-Transplant Acute Immune Rejection in Renal Transplant Recipients Receiving Tacrolimus Therapy: A Correlation Study.

Acute immune rejection remains a challenge in the post-transplant period, with approximately 7.8% of renal transplant recipients experiencing rejection episodes within the first year. Genetic polymorphisms in the CYP3A5 gene, which influences tacrolimus metabolism, have garnered interest regarding their association with clinical outcomes in renal transplantation. This retrospective correlation study analysed clinical data from kidney transplant patients who received tacrolimus treatment at our hospital from June 2015 to June 2023. The presence of CYP3A5 gene polymorphisms, tacrolimus trough levels, and demographic and clinical data were collected and analysed. A total of 105 kidney transplant patients were included. Patients were divided into acute immune rejection (n = 56) and non-acute immune rejection (n = 49) groups. The distribution of CYP3A5 gene polymorphisms differed significantly between the acute rejection and non-acute rejection groups (p = 0.037). The acute rejection group exhibited a higher frequency of CYP3A5 *1/*1 or *1/*3 genotypes than the non-acute rejection group. No statistically significant differences were found in the tacrolimus trough levels between the two groups. Correlation analysis revealed a statistically significant correlation between CYP3A5 gene polymorphism and post-transplant acute immune rejection (r = 0.223, p < 0.05). This study demonstrated a significant association between CYP3A5 gene polymorphism and the risk of post-transplant acute immune rejection in renal transplant recipients receiving tacrolimus therapy. These findings highlighted the importance of genetic variability in tacrolimus metabolism when managing immunosuppressive therapy in transplant recipients.

Peak insulin drip rate associated with decreased infections post-solid organ transplant.

Infection and rejection outcomes were retrospectively analyzed in patients following liver transplant and separately following heart transplant with patients being stratified by their severity of immediate postoperative insulin resistance as measured by the peak insulin drip rate that was required to reduce glucose levels. For each group, these peak insulin drip rates were divided into quartiles (Q). In liver transplant patients (n=207), those in Q4 (highest infusion rate) had significantly fewer infections up to 6 months post-transplant (42.3%vs. 60.0%, p=.036) and borderline fewer rejection episodes (25.0%vs. 40.0%, p=.066) compared to Q1-Q3 patients. To confirm these unexpected results, a subsequent similar analysis in heart transplant (n=188) patients again showed that Q4 patients had significantly fewer infections up to 6 months (19.1%vs. 53.9%, p<.0001) compared to Q1-Q3 patients. Logistic regression in a subset of 103 cardiac transplant patients showed that the maximum glucose during surgery, prior MI, and hypertension were associated with severe insulin resistance (SIR) status, while the presence of pre-existing diabetes and BMI were not. We hypothesize that patients are who are able to mount a more robust counter-regulatory response that causes the insulin resistance may be healthier and thus able to mount a better response to infections.

T-cell receptor sequencing reveals selected donor-reactive CD8+ T cell clones resist antithymocyte globulin depletion after kidney transplantation

High frequencies of donor-reactive memory T cells in the periphery of transplant candidates prior to transplantation are linked to the development of posttransplant acute rejection episodes and reduced allograft function. Rabbit antithymocyte globulin (rATG) effectively depletes naïve CD4+ and CD8+ T cells for >6 months posttransplant, but rATG’s effects on human donor-reactive T cells have not been carefully determined. To address this, we performed T cell receptor β-chain sequencing on peripheral blood mononuclear cells aliquots collected pretransplant and serially posttransplant in 7 kidney transplant recipients who received rATG as induction therapy. We tracked the evolution of the donor-reactive CD4+ and CD8+ T cell repertoires and identified stimulated pretransplant, CTV-(surface dye)-labeled, peripheral blood mononuclear cells from each patient with donor cells or third-party cells. Our analyses showed that while rATG depleted CD4+ T cells in all tested subjects, a subset of donor-reactive CD8+ T cells that were present at high frequencies pretransplant, consistent with expanded memory cells, resisted rATG depletion, underwent posttransplant expansion and were functional. Together, our data support the conclusion that a subset of human memory CD8+ T cells specifically reactive to donor antigens expand in vivo despite induction therapy with rATG and thus have the potential to mediate allograft damage.

Quick, Safe, Effective: Ultrasound-Guided Percutaneous Liver Biopsy in the Pediatric Patient

BackgroundPercutaneous liver biopsy has proven to be a valuable tool in the workup of pediatric acute liver failure and the management of post-transplant rejection. However, consensus regarding pre-procedure laboratory values and post-procedure monitoring is lacking.ObjectiveTo characterize the incidence of complications, procedural time, and specimen adequacy for percutaneous liver biopsy in the pediatric patient.MethodsRetrospective review of percutaneous liver biopsies at a single institution was performed for a 5-year span. Procedural notes and anesthesia records were sampled for patient weight and procedural factors across a continuous 6-month period, as well as for the subgroup of patients under 24 months of age. A representative continuous subset of pathology reports comprising 376 patients were reviewed for estimation of specimen adequacy.ResultsEight hundred and sixty-seven ultrasound-guided percutaneous liver biopsies were performed in a 5-year period, 450 of which were in the post-transplant setting with about a 3:1 ratio of split: whole liver transplant. Patient ages ranged from 1 month to 21 years old, with weight ranging from 2.7 to 125 kg. Of the 376 pathology reports available, none were found to be inadequate for evaluation. Two major complications occurred, both of which were biliary leaks in the setting split-liver transplant. There were no incidences of post-procedure hemorrhage. Of the sample reviewed, mean “skin-to-skin” procedure time was under 8.5 min (median of 7 min). Solely among transplant patients, biopsies for split livers averaged 9.2 min, biopsies for whole livers averaged 6.2 min (two-tailed independent t test, p = 0.0426).ConclusionUltrasound guided percutaneous liver biopsy is fast, useful, and safe in pediatric patients on an outpatient basis with same day discharge.Level of Evidence IVThis journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Detrimental impact of early biopsy-proven rejection in liver transplantation.

Existing literature offers conflicting conclusions about whether early acute cellular rejection influences long-term outcomes in liver transplantation. We retrospectively collected donor and recipient data on all adult, first-time liver transplants performed at a single center between 2008 and 2020. We divided this population into two cohorts based on the presence of early biopsy-proven acute cellular rejection (EBPR) within the first 90 days post-transplant and compared outcomes between the groups. There were 896 liver transplants that met inclusion criteria with 112 cases (12.5%) of EBPR. Recipients who developed EBPR had higher biochemical Model for End-Stage Liver Disease scores (28vs. 24, p<.01), but other donor and recipient characteristics were similar. Recipients with EBPR had similar overall survival compared to patients without EBPR (p=.09) but had decreased graft survival (p<.05). EBPR was also associated with decreased time to first episode of late (>90 days post-transplant) rejection (p<.0001) and increased vulnerability to bacterial and viral infection (p<.05). In subgroup analysis of recipients with autoimmune indications for liver transplantation, EBPR had a more pronounced association with patient death (hazard ratio [HR] 3.9, p<.05) and graft loss (HR 4.0, p<.01). EBPR after liver transplant is associated with inferior graft survival, increased susceptibility to late rejections, and increased vulnerability to infection.