Higher Incidence Of Acute Rejection Research Articles

Interactions of TTV with BKV, CMV, EBV, and HHV-6A and their impact on post-transplant graft function in kidney transplant recipients.

Mono and combined reactivation of latent viruses occurs frequently under immunosuppressive therapy in kidney transplant patients. Recently, monitoring torque teno virus (TTV) reactivation came more into focus as a potential biomarker for immune status. The surrogate characteristics of TTV reactivation on acute rejection, and the combined reactivation with other latent viruses such as cytomegalovirus (CMV), human BK virus (BKV), Epstein-Barr virus (EBV), and human herpes virus-6A (HHV-6A) on allograft function, are unknown so far. Blood samples from 93 kidney transplant recipients obtained during the first post-transplant year were analyzed for TTV/BKV/CMV/EBV/HHV-6A load. Clinical characteristics, including graft function [glomerular filtration rate (GFR)], were collected in parallel. TTV had the highest prevalence and viral loads at 100% and a mean of 5.72 copies/ml (cp/ml) (log10). We found 28.0%, 26.9%, 7.5%, and 51.6% of simultaneous reactivation of TTV with BKV, CMV, EBV, and HHV-6, respectively. These combined reactivations were not associated with a significantly reduced estimated GFR at month 12. Of interest, patients with lower TTV loads <5.0 cp/ml (log10) demonstrated not only a higher incidence of acute rejection, but also an unexpected significantly earlier occurrence and higher incidence of BKV and HHV-6A reactivation. Correlations between TTV loads, other latent viruses, and immunosuppressive medication were only significant from 6 months after transplant. We were able to observe and support previously introduced TTV load thresholds predicting kidney allograft rejection. However, due to a possible delayed relation between immunosuppressive medication and TTV viral load adaptation, the right time points to start using TTV as a biomarker might need to be further clarified by other and better designed studies.

#2390 Does incompatible kidney transplantation provide a reliable alternative? An updated meta-analysis

Abstract Background and Aims The ABO system often poses one of the challenges to kidney transplantation, but due to the scarcity of organs, ABO incompatible kidney transplantation (ABOi-kTx) has gained the clinical attention. So, we aim in this study to evaluate the impact of ABO incompatible kidney transplantation on patients' clinical outcomes in comparison with ABO compatible kidney transplantation (ABOc-kTx). Method We searched six electronic databases: PubMed, Scopus, WOS, Cochrane, Embase, and Medline to identify relevant studies published until October 8th 2023, with no filters applied during the research process. After screening of 8562 studies, we included observational studies that compared any clinical outcomes of ABO incompatible kidney transplantation with ABO compatible kidney transplantation across various age groups. Synthesized odds ratios (ORs) with 95% confidence intervals (CIs) are used to present the differences between the two groups based on random-effects models. Results Our comprehensive search according to the eligible criteria of this study resulted in 102 studies including 254 496 patients in both groups. Due to the clinical heterogeneity, we used random effects models for quantitative synthesis of the eligible studies. Our meta-analysis showed that there was a statistically significant higher mortality ratio after one year, 3 years and 5 years (odds ratio [OR] 2.21 [95% CI 1.56–3.14], P &amp;lt; .00001; I² = 53%), (OR 1.86 [1.35–2.75], P = .0001; I² = 61%), (OR 1.69 [1.20–2.40], P = .003; I² = 75%), respectively. While there was no statistically significant difference at 8-years after transplantation (OR 1.05 [0.76–1.46], P = .77; I² = 58%). Pooled data of graft failure from our studies revealed higher incidence in ABOi-kTx group after one year (OR 2.44 [1.81–3.28], P &amp;lt; .00001; I² = 64%), 3 years (OR 1.57 [1.24–1.98], P &amp;lt; .00001; I² = 54%) and after 5 years (OR 1.57 [1.23–2.01], P = .0003; I² = 76%), There was not any statistically significant difference between both groups after 8 years. Acute anti-body mediated rejections were noticed to be statistically higher in ABOi-kTx group (OR 2.51 [2.12–2.97], (P &amp;lt; .00001); I² = 20%). Also, there was a significantly higher incidence of CMV infection in ABOi-kTx group (OR 1.27 [1.08–1.48], (P = .003); I² = 58%). Conclusion Although that ABOi-kTx is inferior to ABOc-kTx in the first 5 years after the transplantation in patient and graft mortality. Both groups are similar in both outcomes after 8 years post transplantation. Considering the higher incidence of acute rejection in the ABOi-kTx group and increased infection rate, desensitization techniques should be furtherly developed for better survival and complication outcomes.

The impact of colonic allograft inclusion on intestinal transplantation outcomes: Results from UNOS/OPTN database analysis.

Outcomes of intestinal transplantation with colon allograft (ICTx) remain controversial. We aimed to assess the outcomes of ICTx in comparison to intestinal transplantation without colon (ITx) using the UNOS/OPTN registry database. We retrospectively reviewed 2612 patients who received primary intestinal transplants from 1998 to 2020. The rates of acute rejection (AR) within 6 months after transplant were compared between ICTx and ITx. Risk factors of 6-month AR were examined using logistic regression model by era. Furthermore, conditional graft survival was analyzed to determine long-term outcomes of ICTx. Of 2612 recipients, 506 (19.4%) received ICTx. Graft and patient survival in ICTx recipients were comparable to those in ITx recipients. White ICTx recipients had a higher incidence of AR within 6 months compared to ITx during the entire study period (p=.002), colonic inclusion did not increase the risk of 6-month AR in the past decade. ICTx recipients who experienced 6-month AR had worse graft and patient survival compared to those who did not (p<.001 and p=.004, respectively). Among patients who did not develop 6-month AR, Cox proportional hazard model analysis revealed that colonic inclusion was independently associated with improved conditional graft survival. In the recent transplant era, colonic inclusion is no longer associated with a heightened risk of 6-month AR and may provide better long-term survival compared to ITx when AR is absent. Risk adjustment for rejection and proper immunosuppressive therapy are crucial to maximize the benefits of colonic inclusion.

Prevalence and significance of clonal hematopoiesis of indeterminate potential in lung transplant recipients

BackgroundClonal hematopoiesis of indeterminate potential (CHIP), the age-related acquisition of somatic mutations that leads to an expanded blood cell clone, has been associated with development of a pro-inflammatory state. An enhanced or dysregulated inflammatory response may contribute to rejection after lung transplantation, however the prevalence of CHIP in lung recipients and influence of CHIP on allograft outcomes is unknown.MethodsWe analyzed whole-exome sequencing data in 279 lung recipients to detect CHIP, defined by pre-specified somatic mutations in 74 genes known to promote clonal expansion of hematopoietic stem cells. We compared the burden of acute rejection (AR) over the first post-transplant year in lung recipients with vs. without CHIP using multivariable ordinal regression. Multivariate Cox proportional hazards models were used to assess the association between CHIP and CLAD-free survival. An exploratory analysis evaluated the association between the number of CHIP-associated variants and chronic lung allograft dysfunction (CLAD)-free survival.ResultsWe detected 64 CHIP-associated mutations in 45 individuals (15.7%), most commonly in TET2 (10.8%), DNMT3A (9.2%), and U2AF1 (9.2%). Patients with CHIP tended to be older but did not significantly differ from patients without CHIP in terms of race or native lung disease. Patients with CHIP did not have a higher incidence of AR over the first post-transplant year (p = 0.45) or a significantly increased risk of death or CLAD (adjusted HR 1.25, 95% CI 0.88–1.78). We did observe a significant association between the number of CHIP variants and CLAD-free survival, specifically patients with 2 or more CHIP-associated variants had an increased risk for death or CLAD (adjusted HR 3.79, 95% CI 1.98–7.27).ConclusionsLung recipients have a higher prevalence of CHIP and a larger variety of genes with CHIP-associated mutations compared with previous reports for the general population. CHIP did not increase the risk of AR, CLAD, or death in lung recipients.

Calcineurin and mTOR inhibitors in kidney transplantation: integrative metamodeling on transplant survival and kidney function.

In our study, we examined the efficacy of mTOR (mammalian target of rapamycin) inhibitors, specifically rapamycin (Rap), compared to calcineurin inhibitors (CNIs) in kidney transplantation. By conducting a comprehensive search across reputable databases (EMBASE, Scopus, PubMed, Cochrane, and Crossref), we gathered data for a six-month post-transplantation period. Our analysis revealed that mTOR inhibitor administration resulted in improved glomerular filtration rate (GFR) and serum creatinine levels. However, it is important to note that the mTOR inhibitor group had a higher incidence of acute rejection after biopsy. Through molecular modeling, we observed that Rap exhibited a superior binding affinity for mTOR compared to CNIs' binding to calcineurin, probably contributing to the transplant rejection. Our meta-analysis supports the cautious use of an optimal mTOR inhibitor in conjunction with careful consideration of clinical features when minimizing CNIs early in the transplantation process. This is because mTOR inhibitors have complementary mechanisms of action, a low nephrotoxicity profile, and favorable outcomes in serum creatinine and GFR, which contribute to improved transplant survival.

Unrelated versus related living-donor kidney transplantation is associated with higher acute rejection rate but similar graft survival Running title: Outcomes in living-donor kidney transplantation

Kidney transplantation (KT) from living donors has been shown to have multiple benefits compared with that from deceased donors. We sought to compare significant graft outcomes, namely acute rejection (AR), graft function, and survival, between transplant recipients who received a kidney from a living-related donor (LRD) and from a living unrelated donor (LURD). Our cohort comprised 198 donor and recipient pairs undergoing living-donor KT at our center over 10 years. LRD recipients were compared with LURD recipients according to demographic and clinical characteristics, transplant variables (including immunosuppression), graft function, survival, and AR rate. The estimated glomerular filtration rate (eGFR) was similar in both groups over the follow-up time, of 60-65 mL/min (p&lt;0.05 over a 10-year period). Censored graft survival was similar between LRD and LURD recipients (96.9% vs. 98.0% at 5 years and 87.8% vs. 79.4% at 10 years, respectively; p=0.837). LURD recipients had a higher incidence of AR, although LURD recipient status was not an independent risk factor for AR. Multivariate analysis showed that human leukocyte antigen (HLA) -DR mismatch (MM) was an independent predictor of AR (hazard ratio [HR] 2.256, p&lt;0.05). HLA-A and HLA-B MM did not affect the AR HR between the groups. Graft function and censored-death survival rates were similar between the LURD and LRD KT recipients. HLA-DR MM was an independent risk factor for AR.

Biologically Unrelated Living Donor for Kidney Transplantation Associated With Higher Acute Rejection Rate but With Similar Graft Survival of a Related Living Donor.

Kidney transplantation (KT) from living donors has been shown to have multiple benefits compared to those from deceased donors. We sought to compare significant graft outcomes, namely acute rejection (AR), graft function, and survival between transplant recipients who received a kidney from living related donor (LRD) and living unrelated donor (LURD). Our cohort comprised 198 donor and recipient pairs undergoing living-donor KT at our center over 10 years. The LRD recipients were compared with LURD recipients according to demographic and clinical characteristics, transplant variables (including immunosuppression), graft function, survival, and AR rate. The estimated glomerular filtration rate (eGFR) was similar in both groups over the follow-up time i.e.,60-65 mL/min (p>0.05 over 10 years). Censored graft survival was similar between LRD and LURD recipients (96.9% vs. 98.0% at five years and 87.8% vs. 79.4% at 10 years, respectively; p=0.837). The LURD recipients had a higher incidence of AR, although LURD recipient status was not an independent risk factor for AR.Multivariate analysis showed that human leukocyte antigen (HLA)-DR mismatch (MM) was an independent predictor of AR (hazard ratio (HR) 2.256, p<0.05). Both HLA-A and HLA-B MM did not affect the AR HR between the groups. Graft function and censored graft survival rates were similar between LURD and LRD KT recipients in our study. The AR was higher in LURD recipients, although the LURD recipient status was not an independent risk factor for AR. The HLA-DR MM was an independent predictor of AR, while HLA-A and HLA-B MM did not affect AR HR between groups of patients.

316.1: Incidence and Effect on Survival of Delayed Graft Function in Donor-Deceased Kidney Transplants in Argentina: A Multicenter Analysis

Introduction: Delayed graft function (DGF) is a manifestation of acute kidney injury with attributes unique to the transplant process. DGF is associated with negative outcomes such as higher incidence of acute rejection, worse graft function and lower grafts and patients´ survival. Although the worldwide incidence of DGF is variable, a previous study showed that the incidence in Argentina is higher than the US and most countries in Europe. Therefore, the aim of our study was to identify the risk factors associated with DGF in Argentina and to evaluate the impact of DGF on grafts´ and patients´ survival. Methods: Retrospective multicenter cohort study of deceased-donor kidney transplant from 33 transplant centers in Argentina between 2015 and 2017. Demographic data and donor and recipient related variables were analyzed at baseline and at 3 and 5 years of follow-up. Data were obtained from SINTRA/ INCUCAI, the Argentinian procurement organization and from the transplant centers. Results: Between 2015 and 2017, 1886 single kidney transplants were performed in 33 centers. Recipient and donor characteristics are shown in Table 1. In the current study, the incidence of DGF was 62%. Univariate analysis demonstrated that higher donor creatinine, donor age, recipient time on dialysis, donor BMI, absence of induction and cold ischemia time were risk factors associated with DGF. Multiple organ donation and cause of death other than stroke were associated with reduced risk DGF. In the multivariable analysis donor age (0.02), higher donor creatinine (0.02), recipient time on dialysis (<0.01), cold ischemia time (<0.01), monorganic donor (<0.01)) were risk factors of DGF. Renal function was significatively better in patients without DGF throughout the 5 years follow -up (p<0.05). Patients with DGF had higher incidence of acute rejection in the first three months of follow-up, with T-cell mediated rejection being the most frequent. At 3 and 5 years of follow up there was no increased risk of rejection when both groups were compared. Graft survival and patient survival were lower in the group that developed DGF at 1, 3 and 5 years of follow-up (<0.01) (Figure 1). Conclusion: We confirmed the high incidence of DGF in our country. Furthermore, the analysis on the risk factors associated with DGF were not as much as different as in other countries where the incidence of DGF were lower. Further studies should be done to unravel the cause of this high incidence of DGF in Argentina. Heads of Transplant Centers: WalterJ, Raffaele P, Ciappa M, Paladini J, De la Fuente J, Novoa P, Soler Pujol G, Toselli L, Suso E, Ferreyra M, Fragale G, Reinoso S, Acosta F, Sgrosso J, Arriola M, Maldonado R, Acosta M, Prado R, Sedevich A, Martinez I, Di Pietrantonio S, Oddino J, Trimarchi H, Raimondi C, Gómez M, Dorado E, Palti G, Mele P, Maggiora E, Papaginovic Leiva M. Kidney Commitee: Ibañez J, Benitez ML, Leon L, Mesias M, Osella F.

Outcomes in AB0 Incompatible Living Donor Kidney Transplantation: A Case - Control Study.

BackgroundPatients waiting for a kidney transplant by far exceed available organs. AB0 incompatible living donor kidney transplantation (AB0i LDKT) represents an additional therapeutic strategy, but with higher risk for complications. We aimed at evaluating outcomes of AB0i LDKTs compared to compatible (AB0c) controls at our Institution.MethodsRetrospective matched case – control study (1:2) comparing AB0i vs. AB0c LDKTs from March 2012 to September 2021. Considered outcomes: graft function, acute rejection, sepsis, CMV infection, BK virus reactivation, death-censored graft survival, patient survival.ResultsSeventeen AB0i LDKTs matched to 34 AB0c controls. We found excellent graft function, comparable in the two groups, at all considered intervals, with an eGFR (ml/min/1.73 m2) of 67 vs. 66 at 1 year (p = 0.41), 63 vs. 64 at 3 years (p = 0.53). AB0i recipients had a statistically significant higher incidence of acute rejection, acute antibody-mediated rejection and sepsis within 30 days (p = 0.016; p = 0.02; p = 0.001), 1 year (p = 0.012; p = 0.02; p = 0.0004) and 3 years (p = 0.004; p = 0.006; p = 0.012) after surgery. There was no difference in CMV infection, BK virus reactivation, death-censored graft survival between the two groups. Patient survival was inferior in AB0i group at 1 and 3 years (88.2 vs. 100%; log-rank p = 0.03) due to early death for opportunistic infections. AB0i LDKTs spent longer time on dialysis (p = 0.04) and 82.3 vs. 38.3% controls had blood group 0 (p = 0.003).ConclusionsAB0i LDKT is an effective therapeutic strategy with graft function and survival comparable to AB0c LDKTs, despite higher rates of acute rejection and sepsis. It is an additional opportunity for patients with less chances of being transplanted, as blood group 0 individuals.

Donor Metabolic Risk Score Predicts Graft-Related Outcome After Heart Transplantation

<h3>Purpose</h3> Brain death may trigger profound metabolic and molecular changes that significantly affect the function of the heart transplant. We investigated the effect of brain death on the metabolomics of heart transplant donors, addressed the impact of the donor metabolomics to transplant outcome, and designed and validated a heart donor metabolomic risk score to predict the risk of allograft failure. <h3>Methods</h3> We analyzed plasma samples from 84 brain-dead heart transplant donors, and from 20 healthy blood donors. We profiled over 100 metabolites using targeted UPLC mass spectrometry. We carried out bioinformatic and statistical analysis on the identified altered metabolites, biological pathways, and their impact on graft-related outcome after transplantation. <h3>Results</h3> Brain death significantly altered the donor plasma metabolome profiles of 30 metabolites, of which 12 were upregulated and 18 were downregulated compared to the healthy controls. Major changes in mitochondrial energy metabolism occurred during brain death with significant alteration in nucleotide metabolism suggesting probable effect of mitochondrial dysfunction. Assessment of donor plasma metabolites revealed that mitochondrial pathways related metabolites such as serine, 4-pyridoxic acid, cytidine, inosine, aspartate, glutamine, niacinamide, taurine and tryptophan metabolites could serve as key biomarkers for transplant outcomes. Interestingly, the donor metabolic high-risk scores generated using these 9 metabolites were associated with a higher incidence of acute rejection and increased graft-related mortality after heart transplantation (Figure 1). <h3>Conclusion</h3> In this study, we demonstrate that brain-dead heart transplant donors had unique but heterogenous plasma metabolome. Furthermore, our result show that brain-death induces mitochondria-related metabolic alterations that may affect the recipient outcome suggesting new therapeutic strategies for donor treatment.

Long-term Outcomes Following Kidney and Liver Transplant in Recipients With HIV

Kidney transplant (KT) and liver transplant (LT) in HIV-positive patients have become more widely adopted. Data looking at long-term outcomes of patient and graft survival are lacking. To compare the long-term outcomes of KT and LT in HIV-positive recipients with matched HIV-negative recipients. Retrospective, single-center, cohort, study using data from 2000 to 2019. Patients were observed until death, or graft failure requiring retransplant. All HIV-positive patients who underwent KT and/or LT between 2000 and 2019 were included. Propensity matching was performed to the corresponding HIV-negative cohort, which was obtained from the University of California, San Francisco's transplant recipient registry. The data were analyzed from 2020 to 2021. HIV infection. Patient and graft survival for KT and patient survival for LT. Incidence of acute rejection and its association with KT graft survival. For KT, 655 HIV-negative recipients (mean [SD] age, 52.3 [13.6] years; 450 [68.7%] were men) and 119 HIV-positive recipients (mean [SD] age, 51.7 [9.4] years; 86 [72.3%] were men) were included. Patient survival was 79.6% (95% CI, 73.6%-86.1%) and 53.6% (95% CI, 38.9%-74.0%) at 15 years posttransplant, respectively. Graft survival was 57.0% (95% CI, 47.8%-68.0%) and 75.0% (95% CI, 65.3%-86.2%) at 15 years posttransplant, respectively. Diagnosis of HIV was not associated with worse graft survival (hazard ratio, 1.09; 95% CI, 0.61-1.97; P = .77). For LT, 80 HIV-positive recipients (mean [SD] age, 52.6 [8.2] years; 53 [66.3%] were men) and 440 HIV-negative recipients (mean [SD] age, 54.6 [12.8] years; 291 [66.1%] were men) were included. Patient survival was 75.7% (95% CI, 71.8%-79.8%) for HIV-negative LT recipients and 70.0% (95% CI, 60.6%-80.8%) for HIV-positive LT recipients at 15 years posttransplant. Diagnosis of HIV was not a statistically significant predictor of patient survival (hazard ratio, 1.36; 95% CI, 0.83-2.24; P = .22). In KT, HIV-positive patients with at least 1 episode of acute rejection had a graft survival of 52.8% (95% CI, 38.4%-72.5%; P < .001) at 15 years posttransplant, compared with 91.8% in those without AR. In this single-center cohort study, KT and LT in HIV-positive patients had comparable long-term outcomes with those in matched HIV-negative patients. The high incidence of acute rejection was associated with reduced graft survival. The findings support providing transplant to HIV-positive patients, which may be an appropriate use of transplant resources and provides equitable access for HIV-positive patients.

New Insights in Mechanisms and Therapeutics for Short- and Long-Term Impacts of Hepatic Ischemia Reperfusion Injury Post Liver Transplantation.

Liver transplantation has been identified as the most effective treatment for patients with end-stage liver diseases. However, hepatic ischemia reperfusion injury (IRI) is associated with poor graft function and poses a risk of adverse clinical outcomes post transplantation. Cell death, including apoptosis, necrosis, ferroptosis and pyroptosis, is induced during the acute phase of liver IRI. The release of danger-associated molecular patterns (DAPMs) and mitochondrial dysfunction resulting from the disturbance of metabolic homeostasis initiates graft inflammation. The inflammation in the short term exacerbates hepatic damage, leading to graft dysfunction and a higher incidence of acute rejection. The subsequent changes in the graft immune environment due to hepatic IRI may result in chronic rejection, cancer recurrence and fibrogenesis in the long term. In this review, we mainly focus on new mechanisms of inflammation initiated by immune activation related to metabolic alteration in the short term during liver IRI. The latest mechanisms of cancer recurrence and fibrogenesis due to the long-term impact of inflammation in hepatic IRI is also discussed. Furthermore, the development of therapeutic strategies, including ischemia preconditioning, pharmacological inhibitors and machine perfusion, for both attenuating acute inflammatory injury and preventing late-phase disease recurrence, will be summarized in the context of clinical, translational and basic research.

Endogenous memory T cells with donor-reactivity: early post-transplant mediators of acute graft injury in unsensitized recipients.

The pretransplant presence of endogenous donor-reactive memory T cells is an established risk factor for acute rejection and poorer transplant outcomes. A major source of these memory T cells in unsensitized recipients is heterologously generated memory T cells expressing reactivity to donor allogeneic MHC molecules. Multiple clinical studies have shown that the pretransplant presence of high numbers of circulating endogenous donor-reactive memory T cells correlates with higher incidence of acute rejection and decreased graft function during the first-year post-transplant. These findings have spurred investigation in preclinical models to better understand mechanisms underlying endogenous donor-reactive memory T-cell-mediated allograft injury in unsensitized graft recipients. These studies have led to the identification of unique mechanisms underlying the activation of these memory T cells within allografts at early times after transplant. In particular, optimal activation to mediate acute allograft injury is dependent on the intensity of ischaemia-reperfusion injury. Therapeutic strategies directed at the recruitment and activation of endogenous donor-reactive memory T cells are effective in attenuating acute injury in allografts experiencing increased ischaemia-reperfusion injury in preclinical models and should be translatable to clinical transplantation.

The Presence of a Marked Imbalance Between Regulatory T Cells and Effector T Cells Reveals That Tolerance Mechanisms Could Be Compromised in Heart Transplant Children.

Background.Regulatory T cells (Treg) are crucial for the induction and maintenance of graft tolerance. In pediatric heart transplant procedures, the thymus is routinely excised, removing the primary source of T-cell replenishment. Consequently, thymectomy joined to the effects of immunosuppression on the T-cell compartment may have a detrimental impact on Treg values, compromising the intrinsic tolerance mechanisms and the protective role of Treg preventing graft rejection in heart transplant children.Methods.A prospective study including 7 heart transplant children was performed, and immune cell populations were evaluated periodically in fresh peripheral blood at different time points before and up to 3 y posttransplant.Results.Treg counts decreased significantly from the seventh-month posttransplant. Furthermore, there was a significant increase in effector memory and terminally differentiated effector memory T cells coinciding with the fall of Treg counts. The Treg/Teffector ratio, a valuable marker of the tolerance/rejection balance, reached values around 90% lower than pretransplant values. Additionally, a negative correlation between Treg count and T effector frequency was observed. Particularly, when Treg count decreases below 50 or 75 cells/μL in the patients, the increase in the frequency of T effector CD4+ and CD8+, respectively, experiences a tipping point, and the proportion of T-effector cells increases dramatically.Conclusions.These results reveal that interventions employed in pediatric heart transplantation (immunosuppression and thymectomy) could induce, as an inevitable consequence, a dysregulation in the immunologic status characterized by a marked imbalance between Treg and T effector, which could jeopardize the preservation of tolerance during the period with the higher incidence of acute rejection.

Sex-Associated Differences in Cytomegalovirus Prevention: Prophylactic Strategy is Potentially Associated With a Strong Kidney Function Impairment in Female Renal Transplant Patients.

Post-transplantation cytomegalovirus (CMV) syndrome can be prevented using the antiviral drug (val)ganciclovir. (Val)ganciclovir is typically administered following a prophylactic or a pre-emptive strategy. The prophylactic strategy entails early universal administration, the pre-emptive strategy, early treatment in case of infection. However, it is not clear which strategy is superior with respect to transplantation outcome; sex-specific effects of these prevention strategies are not known. We have retrospectively analyzed 540 patients from the multi-centre Harmony study along eight pre-defined visits: 308 were treated according to a prophylactic, 232 according to a pre-emptive strategy. As expected, we observed an association of prophylactic strategy with lower incidence of CMV syndrome, delayed onset and lower viral loads compared to the pre-emptive strategy. However, in female patients, the prophylactic strategy was associated with a strong impairment of glomerular filtration rate one year post-transplant (difference: −11.8 ± 4.3 ml min−1·1.73 m−2, p = 0.006). Additionally, we observed a tendency of higher incidence of acute rejection and severe BK virus reactivation in the prophylactic strategy group. While the prophylactic strategy was more effective for preventing CMV syndrome, our results suggest for the first time that the prophylactic strategy might lead to inferior transplantation outcomes in female patients, providing evidence for a strong association with sex. Further randomized controlled studies are necessary to confirm this potential negative effect.

“FIRST-IN-HUMAN” CLINICAL TRIAL EMPLOYING ADOPTIVE TRANSFER OF AUTOLOGOUS THYMUS-DERIVED TREG CELLS (THYTREG) TO PREVENT GRAFT REJECTION IN HEART-TRANSPLANTED CHILDREN

Introduction: Immune allograft rejection remains the main obstacle to successful transplants. Due to their suppressive capacity, adoptive transfer of regulatory T cells (Treg) has acquired growing interest in achieving indefinite graft survival. Limited Treg recovery and reduced quality remain the main obstacles in current protocols where Treg are obtained from adult peripheral blood. We have developed a novel GMP-compatible protocol using the thymus routinely discarded during pediatric cardiac surgeries as Treg source, obtaining massive Treg counts with very high purity and suppressive capacity (Figure 1). Our Treg product has been approved by the Spanish Drug Agency (AEMPS) and is being used to treat transplanted children. Materials and Methods: We initiated the recruitment of patients last February for the first clinical trial worldwide (phase I/IIa) that evaluates the safety and efficacy of employing autologous thyTreg in 10 children (< 2 years old) undergoing heart transplantation. A single dose of thyTreg, manufactured under GMP conditions, is infused back into the patient at day +7 post-transplant and the remaining cells are cryopreserved for potential future reinfusions. The children are receiving as immunosuppressive therapy: tacrolimus, mofetil mycophenolate and short-term corticoids; without induction therapy with basiliximab (Figure 2). As a control cohort, we have performed a prospective study of 7 heart-transplanted children that were also thymectomiced and receive the same immunosuppressive therapy but not the thyTreg therapy, performing a comprehensive immune analysis at different time points before and up to 2 years post-transplant. Results and Discussion: The prospective study of our control cohort showed that the Treg to T effector CD4+ and CD8+ ratio significantly decreased after transplant until reaching values of -89,47% and -93,15% lower, respectively, at 2 years post-transplant (Figure 3). The marked decrease in the Treg/Teff ratio reveals that tolerance mechanisms are compromised in heart-transplanted children, just in the period with higher incidence of acute rejection. Due to this fact, the main parameters of efficacy in the clinical trial are to evaluate the recovery of circulating Treg, the Treg/Teff ratio, and determine changes in the incidence of acute rejection during the 2-year follow-up. Preliminary results about the evolution of patients treated with thyTreg will be available at the date of the congress. Conclusion: The clinical use of a cell therapy with thyTreg is a new therapeutic strategy to induce graft tolerance that could establish a new paradigm in the context of solid organ transplantation. The improved quality and amount of thyTreg obtained with this protocol allow to prepare hundreds of doses that could be administered periodically to induce indefinite immunological tolerance and thus achieve the indefinite survival of the transplanted organ.This work was supported by grants from Fundación Familia Alonso (FFA-19), grants from ISCIII co-founded by FEDER funds (PI18/00495; PI18/00506; DTS18/00038) and EXOHEP-CM Program (B2017/BMD3727).

P1715CORRELATION OF DONATED KIDNEY MASS AND GRAFT FUNCTION IN RECIPIENTS OF LIVING DONOR KIDNEY TRANSPLANTATION

Abstract Background and Aims Kidney volume has been proven to be a surrogate marker of nephron mass and renal function in living donors. Although many studies correlate the kidney mass with renal donors’ function after donation, few studies have compared the donated kidney mass with estimated glomerular filtration rate (eGFR) in the kidneýs recipients. The purpose of this study is to examine the relationship between donor kidney volume and post-transplantation graft function by using computerized tomography to obtain renal volumes. Method Clinical data off all donor and recipient pairs undergoing live donor kidney transplantation (KT) at our institution between January 2008 and December 2017 (n=195) were reviewed. The volume of the kidney selected for transplant was determined using volume calculating software and correlate to transplant recipient eGFR. Results All metrics of donor kidney volume (DKV): DKV alone, ADK adjusted for weight, body mass index (BMI) or body surface area (BSA), correlated significantly with eGFR (all with p&amp;lt;0,001) at 1 year after KT, with DKV/BSA having the highest correlation (r=0,431). Hence, recipients were divided into terciles according their DKV/BSA (cm3/m2): tercile 1 (DKV/BSA between 49,7-77,5, n=64), tercile 2 (78-95,2, n=63) and tercile 3 (95,4-176, n=63). eGFR differences between groups at each time point were all significant (P&amp;lt;0.05), except for the comparison between T1 and T2 at month 6 (figure 1) Significant risk factors for eGFR&amp;lt;60 ml/min at 1-year were: acute rejection (AR) at 1-year (OR=4.116, P=0.018); calculated PRA&amp;gt;0% (OR=2.075, P=0.039); higher donor age (OR per unit=1.033, P=0.047); and peritoneal dialysis modality (in comparison with preemptive KT: OR=3.232, P=0.013). Higher (T3) DKV/BSA tercile (in comparison with T1: OR=0.306, P=0.004) was protective of this outcome. Patients that experienced AR at 1-year had significantly lower DKV/BSA, particularly those with acute cellular rejection (ACR). The median follow-up was 4,8 years (IQR: 3.2-7.5). The censored graft survival by DKV/BSA terciles at 10 years were 59,3% for group 1, 91.3% for group 2 and 91.1% for group 3 (figure 3). Conclusion Our study demonstrates that transplantation of donor-recipient pairs with lower DKV/BSA ratio were associated with significantly worse graft function and higher incidence of AR. This data suggests that a larger mass of nephrons remaining adjusted to recipient’s weight seems to predict a better long-term eGFR. This method can be useful in order to identify patients at risk for a low eGFR after KT and, in cases of multiple potential donors, optimize donor selection.

Transplanting the Elderly: Mandatory Age- and Minimal Histocompatibility Matching.

Worldwide over 40% of patients receiving renal replacement therapy (RRT) are aged 65 years or older, a number that is still increasing. Renal transplantation is the preferred RRT, providing substantial survival benefit over those remaining on dialysis, including the elderly. Only 3% of patients aged 65 years or older accepted on the waiting list actually received a kidney transplant offer within the Eurotransplant allocation region. To increase the chance for elderly to receive a timely kidney transplant, the Eurotransplant Senior Program was introduced. The ESP supports local allocation of older kidneys to older donors in order to decrease cold ischemia time, while disregarding former exchange principles based on matching for HLA antigens. As a consequence, more elderly received a kidney transplant and a relative higher incidence of acute rejection resulted in additional courses of high steroids and/or depleting antibody therapy. Since death with a functioning graft due to infections is the dominant reason of graft loss in elderly, more intense clinical immunosuppression to prevent or treat acute rejection is not a very attractive option. Therefore in elderly kidney transplant candidates, we advocate reintroduction of minimal histocompatibility criteria (i.e., HLA-DR matching) followed by age-matching with mandatory local/regional allocation to also facilitate short cold ischemia.

Acute Rejection (AR) and Lymphocytic Bronchiolitis (LB) in a Multicenter Lung Transplant Cohort

Purpose Despite the importance of AR and LB in lung recipients, the incidence and associated clinical factors have not been prospectively studied in a contemporary cohort. We used a multicenter lung transplant cohort to describe the incidence of AR and LB over the first posttransplant year, examine concurrent histology at the time of an AR/LB event, and determine recipient factors associated with AR or LB. Methods The cohort was drawn from CTOT-20 (NCT02631720), an observational study collecting prospective clinical outcome data on lung recipients at 5 North American centers. The first 200 enrolled, transplanted subjects with ≥1 lung biopsy within the first posttransplant year were included. Recipients were managed according to center-specific clinical care practices. Descriptive statistics were used to summarize AR or LB events and concurrent histology. Univariate Cox modeling was used to evaluate the impact of select recipient factors on the time to first occurrence of AR or LB. Results 1007 biopsies were performed over the first posttransplant year in this cohort. 56% and 17% of patients experienced at least one AR or LB episode, respectively. Rates of minimal and mild AR and minimal LB were similar on for cause vs. surveillance biopsies. While a majority of LB events were concurrent with AR, AR events generally occurred in isolation or were concurrent with non-rejection histopathology. Univariate analyses suggested a protective effect of induction immunosuppression on the risk for AR. We also observed a significant decrease in the hazard of AR and LB in bilateral, as compared to single, lung recipients (Figure). Conclusion We observed a higher incidence of AR than that reported by the ISHLT registry. This may, in part, be attributed to the practice of surveillance biopsies in all CTOT-20 centers. While the impact of induction on AR risk is consistent with ISHLT data, the novel association between transplant type and AR/LB will be further validated over extended cohort follow up using multivariable approaches.

High Calcineurin Inhibitor Intrapatient Variability Is Associated With Renal Allograft Inflammation, Chronicity, and Graft Loss.

High calcineurin inhibitor (CNI) intrapatient variability (IPV) has been associated with poor kidney allograft outcomes. However, the relationship between early allograft histological changes, their progression, and CNI-IPV is less well studied. Hence, we evaluated effect of CNI-IPV defined by the degree of fluctuation of CNI levels in all kidney transplant patients over 2 to 12 months posttransplant on early allograft inflammation, subsequent chronicity, and later clinical outcomes. Two hundred eighty-six patients transplanted from January 2013 to November 2014 were enrolled with protocol and indication biopsies. The mean CNI-IPV was 28.5% and a quarter of our cohort had IPV of 35% or greater (high CNI IPV). Baseline demographic differences were similar between high and low CNI IPV groups. High CNI-IPV was associated with a higher incidence of acute rejection (AR) within 1 year (52% vs 31% P < 0.001), more persistent/recurrent AR by 1 year (18.2% vs 6.2%, P = 0.002), higher-grade AR (≥Banff 1B, 27.5% vs 7.3%, P < 0.001), and worse interstitial fibrosis/tubular atrophy (P = 0.005). High CNI-IPV was associated with increased graft loss (GL) and impending graft loss (iGL, defined as eGFR<30 ml/min and >30% decline in eGFR from baseline), regardless of donor-specific antibody, delayed graft function, rejection, or race. In a multivariate Cox Proportional Hazards Model, high CNI-IPV was independently associated with GL + iGL (hazard ratio, 3.1; 95% confidence interval, 1.6-5.9, P < 0.001). High CNI-IPV within 1 year posttransplant is associated with higher incidence of AR, severe AR, allograft chronicity, GL, and iGL. This represents a subset of patients who are at risk for poor kidney transplant outcomes and potentially a modifiable risk factor for late allograft loss.