Cohort Of Transplant Recipients Research Articles

CYP3A4*1B but Not CYP3A5*3 as Determinant of Long-Term Tacrolimus Dose Requirements in Spanish Solid Organ Transplant Patients

Tacrolimus (TAC) is a commonly used immunosuppressive drug in solid organ transplantation. Pharmacogenetics has been demonstrated before to be decisive in TAC pharmacotherapy. The CYP3A5*3 variant has been reported to be the main determinant of TAC dose requirements; however, other polymorphisms have also proven to be influential, especially in CYP3A5 non-expressor patients. The aim of this study is to evaluate the influence of genetic polymorphisms in TAC therapy in a cohort of Spanish transplant recipients. Genetic analysis including ten polymorphic variants was performed, and demographic and clinical data and pharmacotherapy of 26 patients were analyzed. No significant differences were found in weight-adjusted dose between CYP3A5 expressors and non-expressors (0.047 mg/kg vs. 0.044 mg/kg), while they were found for carriers of the CYP3A4*1B allele (0.101 mg/kg; p < 0.05). The results showed that patients with at least one CYP3A4*1B allele had a higher TAC dose and lower blood concentration. Dose-adjusted TAC blood levels were also lower in CYP3A4*1B carriers compared to non-carriers (0.72 ng/mL/mg vs. 2.88 ng/mL/mg). These results support the independence of CYP3A5*3 and CYP3A4*1B variants as determinants of dose requirements despite the linkage disequilibrium present between the two. The variability in genotype frequency between ethnicities may be responsible for the discrepancy found between studies.

Virus-specific Th17 Cells Are Induced by Human Cytomegalovirus after Renal Transplantation.

CMV infection and Th17 cells are independently associated with increased risk for late allograft loss after renal transplantation. Although CMV-specific Th17 cells are detectable in animal models and nontransplant clinical populations, evidence linking CMV and Th17 cells after renal transplantation remains unclear. This prospective observational study evaluated a cohort of renal transplant recipients during 12 mo posttransplant to assess the presence of CMV-specific Th17 cells in peripheral blood and their relationship to pretransplant CMV serostatus and CMV DNAemia. CMV-specific Th17 cells were identified among CMV serostatus donor (D)+ and/or recipient (R)+ recipients and expanded during both primary (D+/R-) and reactivated (D+/R+, D-/R+) CMV DNAemia. A subset of CMV-specific Th17 cells coexpressed IFN-γ, indicating a Th1/17 phenotype. These Th17 and Th1/17 cells expressed CCR6, CCR5, activation and terminal differentiation markers (CD95, OX40, HLA-DR, CD57), and a central/effector memory phenotype. CMV-specific Th1/17 cells expressed activating/inhibitory receptors (CD57, 4-1BB, CD160, CTLA-4, PD-1) at higher frequencies than Th17 cells. In contrast, staphylococcal enterotoxin B-induced Th17 cells did not expand during CMV DNAemia, did not differ between CMV serostatus groups over time, expressed CCR6, predominantly coexpressed TNF-α, and had lower expression of activating and inhibitory receptors than pp65-specific Th17 and Th1/17 cells. These data show that CMV-specific Th17 cells expand during episodes of CMV DNAemia among renal transplant recipients, and that these virus-specific Th17 and Th1/17 cells have distinct phenotypes from global circulating Th(1)/17 cells. These results suggest a potential proinflammatory pathway by which CMV-induced Th17 cells may contribute to allograft injury, increasing risk for late allograft loss.

Association between Respiratory Virus Infection and Development of De Novo Donor-Specific Antibody in Lung Transplant Recipients

Chronic lung allograft dysfunction (CLAD) is the most common cause of long-term lung allograft failure. Several factors, including respiratory virus infection (RVI), have been associated with CLAD development, but the underlying mechanisms of these associations are not well understood. We hypothesize that RVI in lung transplant recipients elicits the development of donor-specific antibodies (DSAs), thus providing a mechanistic link between RVI and CLAD development. To test this hypothesis, we retrospectively evaluated for the presence of HLA antibodies in a cohort of lung transplant recipients with symptomatic RVI within the first four months post-transplant using sera at two time points (at/directly after the transplant and following RVI) and time-matched controls without RVI (post-transplant). We found a trend toward the development of de novo DSAs in those with symptomatic RVI versus controls [6/21 (29%) vs. 1/21 (5%), respectively, p = 0.09]. No cases or controls had DSA at baseline. We also found increased rates of CLAD and death among those who developed class II DSA versus those who did not (CLAD: 5/7 (71.4%) vs. 19/34 (54.3%), death: 5/7 (71.4%) vs. 17/35 (48.6%)). Prospective studies evaluating the temporal development of DSA after RVI in lung transplant patients and the subsequent outcomes are warranted.

High bone fracture risk in a large modern cohort of liver transplant recipients.

Liver transplantation (LT) has historically been associated with a high prevalence of osteoporosis, but most of the available data date back to late 1990s-early 2000s with limited sample size. Our aim was to assess the prevalence of bone fragility fractures and contributing factors in a large modern cohort of liver transplant recipients. Retrospective study of 429 consecutive patients receiving liver transplantation from 1/1/2010 to 31/12/2015. Final cohort included 366 patients. Electronic radiological images (lateral views of spine X-rays or Scout CT abdominal scans) performed within 6months from LT, were blinded reviewed to screen for morphometric vertebral fractures. Symptomatic clinical fragility fractures were recorded from the medical records. Patients with fragility fractures in the cohort were 155/366 (42.3%), with no significant differences between sexes. Most sustained vertebral fractures (145/155, 93.5%), mild or moderate wedges, with severe fractures more frequently observed in women. Multiple vertebral fractures were common (41.3%). Fracture rates were similar across different etiologies of cirrhosis and independent of diabetes or glucocorticoids exposure. Kidney function was significantly worse in women with fractures. Independently of age, sex, alcohol use, eGFR, and etiology of liver disease, low BMI was significantly associated with an increased risk for fractures (adjusted OR 1.058, 95%CI 1.001-1.118, P = 0.046). Our study shows a considerable fracture burden in a large and modern cohort of liver transplant recipients. Given the very high prevalence of bone fractures, a metabolic bone disease screening should be implemented in patients awaiting liver transplantation.

Association of early post-transplant hyperglycaemia and diabetes mellitus on outcomes following heart transplantation.

Early post-transplant hyperglycaemia (EPTH) and post-transplant diabetes mellitus (PTDM) are common following solid organ transplantation and may be associated with adverse outcomes. We studied the prevalence of EPTH and cumulative 5-year prevalence of PTDM in a modern cohort of heart transplant recipients who were free from diabetes at baseline as well as the association of EPTH, PTDM and pre-transplant T2DM with adverse transplant-related outcomes. Retrospective cohort study of heart transplant recipients followed for 5 years at a single centre in Sydney, Australia. A total of 141 patients were included, of whom 25 had pre-existing type 2 diabetes mellitus (T2DM) and 116 were free from diabetes at baseline. In patients without pre-existing T2DM, 88 of 116 (76%) experienced EPTH, which was associated with higher rates of acute rejection and hospitalizations, and lower 5-year survival. PTDM developed in 45 of 116 (39%) patients, all of whom had experienced EPTH. Both PTDM and pre-existing T2DM were associated with increased rates of graft rejection and hospitalization, and greater than three-fold increased likelihood of death compared to patients that remained free from diabetes. EPTH and PTDM are highly prevalent following cardiac transplantation. EPTH develops within days of transplant and is strongly associated with progression to PTDM. Pre-existing T2DM, PTDM and EPTH are associated with greater hospitalization, increased episodes of rejection and worse 5-year survival compared to patients who remained free from diabetes during follow-up.

Outcomes of Older Primary Kidney Transplant Recipients by Induction Agent and High-risk Viral Discordance Status in the United States.

The impact of induction type or high-risk viral discordance on older kidney transplant recipients is unclear. Herein, we analyzed the association between induction type, viral discordance, and outcomes for older recipients. We analyzed the Scientific Registry of Transplant Recipients standard analysis file for all primary kidney transplant recipients older than 55 y who were transplanted between 2005 and 2022. All transplants were crossmatch negative and ABO-compatible. Recipients were discharged on tacrolimus and mycophenolate ± steroids. Recipients were categorized into 3 groups by induction received: rabbit antithymocyte globulin (r-ATG; N = 51 079), interleukin-2 receptor antagonist (IL-2RA; N = 22 752), and alemtuzumab (N = 13 465). Kaplan-Meier curves were generated for recipient and graft survival, and follow-up was censored at 10 y. Mixed-effect Cox proportional hazard models examined the association between induction type, high-risk viral discordance, and outcomes of interest. Models were adjusted for pertinent recipient and donor characteristics. Induction type did not predict recipient survival in the multivariable model, whereas Epstein-Barr virus high-risk discordance predicted 14% higher mortality (1.14 [1.07-1.21], P < 0.01). In the multivariable model for death-censored graft survival, alemtuzumab, but not IL-2RA, was associated with an increased risk of graft loss (1.18 [1.06-1.29], P < 0.01) compared with r-ATG. High-risk cytomegalovirus discordance predicted 10% lower death-censored graft survival (1.10 [1.01-1.19], P < 0.02). Live donor and preemptive transplantation were favorable predictors of survival. In this large cohort of older transplant recipients, alemtuzumab, but not IL-2RA, induction was associated with an increased risk of graft loss compared with r-ATG. Cytomegalovirus and Epstein-Barr virus high-risk viral discordance portended poor graft and recipient survival, respectively.

Radiofrequency Echographic Multi Spectrometry (REMS) Technology for Bone Health Status Evaluation in Kidney Transplant Recipients.

Background: A significant loss in bone density and strength occurs during the post-renal-transplant period with higher susceptibility to fracture. The study aims to compare the performance of the Radiofrequency Echographic Multi Spectrometry (REMS) in the bone mineral density assessment with the conventional dual-energy X-ray absorptiometry (DXA) in a cohort of kidney transplant recipients (KTR). Methods: A cohort of 40 patients underwent both DXA and REMS examinations on the lumbar spine and/or proximal femur. The paired t-test was used to compare DXA and REMS measurements; the chi-square test was used to compare the prevalence of osteoporosis/osteopenia. The agreement between the two techniques was assessed through Spearman's correlation. Results: As expected, most KTR patients were osteopenic or osteoporotic with both REMS and DXA (86.5% and 81% for the femur; 88% and 65% for the lumbar spine p < 0.05). A modest correlation (r = 0.4, p < 0.01) was observed at the lumbar spine between the T-score measured by REMS and DXA. A strong correlation was defined between REMS and DXA in the femoral region (r = 0.7, p < 0.0001). Conclusions: The study demonstrates the exchangeability of the two techniques on the proximal femur in KTR and a higher diagnostic accuracy of REMS at the spine level than DXA.

HLA-DR/DQ eplet mismatch predicts risk of de novo donor-specific antibody development in a multi-ethnic Southeast Asian cohort of kidney transplant recipients

HLA-DR/DQ eplet mismatch predicts risk of de novo donor-specific antibody development in a multi-ethnic Southeast Asian cohort of kidney transplant recipients

Characterization of the Antibody Response to SARS-CoV-2 Infection in COVID-19 Transplant versus Nontransplant Recipients by Ig-MS.

Solid organ transplant recipients with immunosuppressant regimens to prevent rejection are less able to mount effective immune responses to pathogenic infection. Here, we apply a recently reported mass spectrometry-based serological approach known as Ig-MS to characterize immune responses against infection with SARS-CoV-2 in cohorts of transplant recipients and immunocompetent controls, both at a single early time point following COVID-19 diagnosis as well as over the course of one-month postdiagnosis. We found that the antibody repertoires generated by transplant recipients against SARS-CoV-2 do not differ significantly compared to immunocompetent individuals with regard to repertoire titer, clonality, or glycan composition. Importantly, our study is the first to characterize the evolution of antibody glycan profiles in transplant recipients with COVID-19 disease, presenting evidence that the evolution of glycan composition in these immunocompromised individuals is similar to that in immunocompetent people.

Impact of Dialysis Time on Long-term Outcomes in HLA-identical Living Donor Kidney Transplant Recipients.

Dialysis vintage is associated with worse outcomes after kidney transplantation. The reasons behind this observation include immunological and nonimmunological risk factors. To mitigate the influence of immunological factors, we examined the association between time on dialysis and clinical outcomes in a cohort of HLA-identical kidney transplant recipients. This retrospective study included 13 321 kidney transplant recipients between 1999 and 2016, of whom 589 were HLA identical followed for at least 5 y. Patient and graft survivals were compared according to dialysis time (<12 or >12 mo) using the log-rank test and Cox regression analysis. We compared surgical complications, cytomegalovirus infection, acute rejection, disease recurrence, and the trajectories of estimated glomerular filtration rate (eGFR). Median time on dialysis was 15 mo; 9.2% of patients received preemptive transplants, and 55.3% of patients were on dialysis for >12 mo. After a median follow-up time of 154 mo, there were no differences in unadjusted and adjusted patient and graft survivals (1, 5, 10, and 15 y) between the 2 groups. There were no differences in the incidence of surgical complications (6.2% versus 3.1%), acute rejection (6.1% versus 7.7%), cytomegalovirus infection (7.6% versus 4.0%), and disease recurrence (4.2% versus 4.0%), respectively. There were no differences in mean eGFR during 5 y or in the proportion of patients with an eGFR <30 mL/min at 5 y (9.9% versus 9.2%). In this low immunological risk cohort of HLA-identical kidney transplant recipients, we did not observe any association between dialysis vintage on patient survival and graft survival.

The adaptive and innate immune systems coordinate for successful control of CMV infection

Previous studies of the immune control of cytomegalovirus infection have primarily focused on analysis of the traditional adaptive T-cell response. Donadeu etal. bring a new perspective through evaluation of multiple adaptive and innate immune subtypes in parallel with cytomegalovirus-specific cell-mediated immunity in a prospective cohort of kidney transplant recipients with findings validated in 2 independent studies. Identification of a natural killer T-cell subtype associated with cell-mediated immunity and freedom from cytomegalovirus infection demonstrates the importance of the coordinated innate and adaptive immune response for effective viral control.

P.127: Covid-19 infection in a large cohort of kidney transplant recipients from a single center.

P.127: Covid-19 infection in a large cohort of kidney transplant recipients from a single center.

HLA-DR/DQ eplet mismatch predicts de novo donor-specific antibody development in multi-ethnic Southeast Asian kidney transplant recipients on different immunosuppression regimens.

Eplet mismatch has been recognized as a more precise strategy for determining HLA compatibility by analyzing donor-recipient HLA differences at the molecular level. However, predicting post-transplant alloimmunity using single-molecule eplet mismatch categories has not been validated in Asian cohorts. We examined a cohort of Southeast Asian kidney transplant recipients (n = 234) to evaluate HLA-DR/DQ eplet mismatch as a predictor of de novo donor-specific antibody (dnDSA) development. HLA-DR/DQ single-molecule eplet mismatch was quantified using HLA Matchmaker, and we utilized previously published HLA-DR/DQ eplet mismatch thresholds to categorize recipients into alloimmune risk groups and evaluate their association with dnDSA development. Recognizing that the predominance of cyclosporine use (71%) may alter published eplet mismatch thresholds derived from a largely tacrolimus-based (87%) cohort, we evaluated cohort-specific thresholds for HLA-DR/DQ single-molecule eplet mismatch categories. Recipient ethnicities included Chinese (65%), Malays (17%), Indians (14%), and others (4%). HLA-DR/DQ dnDSA developed in 29/234 (12%) recipients after a median follow-up of 5.4 years, including against isolated HLA-DR (n = 7), isolated HLA-DQ (n = 11), or both (n = 11). HLA-DR/DQ single-molecule eplet mismatch risk categories correlated with dnDSA-free survival (p = 0.001) with low-risk recipients having a dnDSA prevalence of 1% over 5years. The cohort-specific alloimmune risk categories improved correlation with HLA-DR/DQ dnDSA-free survival and remained significant after adjusting for calcineurin inhibitor and anti-metabolite immunosuppression (p < 0.001). We validated the performance of single-molecule eplet mismatch categories as a prognostic biomarker for HLA-DR/DQ dnDSA development in a cohort of predominantly Asian kidney transplant recipients after adjusting for different immunosuppression regimens.

HLA topography enforces shared and convergent immunodominant B cell and antibody alloresponses in transplant recipients.

Donor-specific antibody (DSA) responses against human leukocyte antigen (HLA) proteins mismatched between kidney transplant donors and recipients cause allograft loss. The rules governing the immunogenicity of non-self donor HLA are poorly understood. Using single-cell, molecular, structural, and proteomic techniques, we profiled the HLA-specific B cell response in the kidney and blood of a transplant recipient with antibody-mediated rejection (AMR). We observed an immunodominant B cell antibody response focused on topographically exposed, solvent-accessible mismatched HLA residues along the peptide-binding groove - a subregion comprising only 20% of the HLA molecule. We further demonstrated that, even within a diverse cohort of transplant recipients, the B cell alloresponse consistently converges on this same immunodominant subregion on the crown of the HLA molecule. Based on these findings, we propose that B cell immunodominance in transplant rejection relies on antigenic topography, and we suggest that this link could be exploited for organ matching and therapeutics.

SARS-CoV-2 Vaccination Rates and Uptake of Tixagevimab-Cilgavimab Among a Cohort of Pediatric Solid Organ Transplant Recipients.

There is a lack of data regarding SARS-CoV-2 vaccination rates and tixagevimab-cilgavimab (TC) uptake among pediatric solid organ transplant recipients. The purpose of our study was to assess these rates. We reviewed vaccination records of pediatric recipients of heart, kidney, and liver transplants at Mayo Clinic, Rochester, MN, who received a transplant between January 2011 and December 2021. All SARS-CoV-2 vaccines and doses of TC received on or before September 1, 2022, the date of approval of the bivalent SARS-CoV2 vaccine, were included. We also assessed whether patients had been seen by an infectious diseases physician (ID) in the preceding 6 months. Our study included 110 patients: 47 kidney, 36 heart, and 27 liver transplant recipients. All vaccine doses recorded were monovalent SARS-CoV-2 vaccines. Sixty-eight (61.8%) patients received at least one vaccine. This varied by age group, with f of≥12 years olds, 40.9% of 5-11 year olds and 14.3% of under 5 year olds (p=0.001). Seven patients (6.4%) were up-to-date (UTD) for age. There was no difference in UTD status by organ type (p=0.335). Patients who saw ID were significantly more likely to be UTD (13.2% versus 2.8%; p=0.047). Among those eligible, 14 (18.2%) received TC, with rates not different based on transplanted organ type (p=0.158) or whether they saw ID (p=0.273). Despite the availability of vaccines, nearly 40% of pediatric solid organ transplant recipients remained unvaccinated against SARS-CoV-2 at time of the bivalent vaccine release. Less than a fifth of eligible patients received TC. Strategies to increase uptake of SARS-CoV-2 vaccines as well as adjunctive agents among this vulnerable group should be further explored.

Endobiogenic Biology of Function Indices in a Cohort of Kidney Transplant Recipients.

Background and Objectives: Endobiogeny is a global systems approach to human biology based on the concept that the endocrine system manages the metabolism. Biology of function (BoF) indices are diagnostic tools in endobiogenic medicine that reflect the action of the endocrine system on the cells and the metabolic activity of an organism. Kidney transplant recipients are a very specific patient population due to their constant use of immunosuppressive agents such as steroids and anamnesis of chronic kidney disease. The aim of this study was to assess the tendencies of endobiogenic BoF indices in a kidney transplant recipient population and to determine the relationship between BoF index values and histology-proven kidney transplant rejection. Materials and Methods: A total of 117 kidney transplant recipients undergoing surveillance or indication allograft biopsy were included in this study. Endobiogenic BoF indices were calculated from complete blood count tests taken before the kidney biopsy. Histology samples were evaluated by an experienced pathologist according to the Banff classification system. Clinical and follow-up data were collected from an electronic patient medical record system. Results: Overall, <35% of the patients had BoF index values assumed to be normal, according to the general population data. Additionally, >50% of the patients had lower-than-normal adaptation, leucocyte mobilization, genital, and adjusted genital ratio indices, while the Cata-Ana, genito-thyroid ratio, adrenal gland, and cortisol indices were increased in >50% of the transplant recipients. The adaptation index was significantly higher in patients with biopsy-proven transplant rejection and demonstrated an AUC value of 0.649 (95%CI 0.540-0.759) for discriminating rejectors from patients without transplant rejection. Conclusions: Most of the kidney transplant recipients had abnormal BoF index values, reflecting increased corticotropic effects on their cells. The adaptation index distinguished patients with biopsy-proven transplant rejection from those without it.

Molecular epidemiology and risk factors associated with BK and JC polyomavirus urinary shedding after kidney allograft.

Polyomaviruses BK (BKPyV) and JC (JCPyV), belonging to the Polyomaviridae, are responsible for human pathologies. In kidney transplant recipients, BKPyV replication can lead to irreversible nephron damage whereas JCPyV replication remains asymptomatic. Concomitant replication is rare and potential competition between the infections has been described. The aim of this retrospective case-control study was to describe the molecular epidemiology and risk factors associated with BKPyV and JCPyV replication in a cohort of kidney transplant recipients. In total, 655 urine samples from 460 patients were tested for BKPyV and JCPyV DNA. Positive samples were submitted to strain genotyping. Demographic and clinical characteristics were also compared. Isolated JCPyV and BKPyV was found in 16.5% and 23.3% of patients, respectively; co-replication was rare (3.9%). BKPyV strains Ib-2, Ib-1, and IVc-2 were the most prevalent. JCPyV strains mostly belonged to genotypes 4 and 1B. During follow-up, JCPyV shedding significantly reduced the risk of BKPyV DNAuria, with an odds ratio of 0.57 (95% confidence interval: 0.35-0.99), and was associated with better prognosis than BKPyV replication, based on the estimated glomerular filtration rate. Molecular epidemiology of BKPyV and JCPyV strains in our region was similar to previous studies. This study suggests that JCPyV is benign and appears to limit damaging BKPyV replication. JCPyV DNAuria screening could thus be a useful strategy to predict BKPyV-related outcomes.

#2581 Cryptococcosis in kidney transplant recipients: a nationwide multicenter retrospective cohort study—CRITERE study

Abstract Background and Aims Cryptococcosis stands as the third most common invasive fungal infection in solid organ transplant recipients. Clinical management and prognosis of the disease remains largely unexplored in the context of kidney transplant recipients. Our main objective was to describe the natural history of cryptococcosis after kidney transplantation from the graft patterns of kidney injury to the long term outcomes. Method We established a nationwide cohort of adult kidney transplant recipients diagnosed with cryptococcosis between 2002 and 2019 in France. All data were gathered starting from the transplantation date and encompassed up to the latest follow-up consultation. All putative causes of AKI as claimed by the attending clinicians were recorded. Cases were matched (ratio 1:6) with kidney transplant recipients from the French prospective multicenter cohort DIVAT with parameters at time of transplant including immunosuppression and known risk factors of cryptococcosis such as age, history of smoke, history of cancer and HIV status. Transplant outcomes (graft failure and patient death) were then compared between matched patients. Results 88 patients were included. Patients were predominantly male (n = 61, 69.3%), with a mean age of 57.0 years [SD ±13.3]. The majority of patients were primary kidney transplants (n = 71, 80.7%) with a median time from ESRD to transplantation of 2.8 years [IQ 1.25-5]. The majority of patients received ATG as induction therapy for their transplant (n = 50, 69.4%)Acute kidney injury (AKI) at diagnosis involved 37.3% of the patients with 13.3% requiring renal replacement therapy. AKI staging was distributed as follows, AKI grade 1 in 12.5% of patients, grade 2 in 13.3% of patients, and grade 3 in 11.5% of patients. During the induction stage, 39% of patients developed amphotericin B-related AKI. AKI resulting from tacrolimus overdose subsequent to tacrolimus/fluconazole interaction occurred in 25.7% of patients during the consolidation stage. Among the patients alive at 3 months following the diagnosis of cryptococcosis, 33.7% of patients exhibited graft dysfunction. Following cryptococcosis, 5 patients displayed T cell rejection and 4 patients developed antibody-mediated rejection. A total of 41 patients with cryptococcosis were matched to 246 controls (ratio 1:6), after a median follow-up of 52.3 [28.1-90.2] months, patients with cryptococcosis exhibited a higher risk of mortality with 35.9% compared with 9.8% (p &amp;lt; 0.001) and graft failure with 33.3% compared with 15.0% (p = 0.0005). Conclusion This study has shown that kidney injury manifests itself through a sequential, multi-step process that initially includes pre-renal impairment, ATN and iatrogenic mechanisms. Amphotericin B-related AKI, followed by tacrolimus overdose represent common causes of AKI.

#2822 Can KDPI estimate long-term graft survival in a cohort of Portuguese patients?

Abstract Background and Aims The Kidney Donor Profile Index (KDPI) was introduced in the United States in 2014 to support clinicians' decision-making regarding the acceptance or decline of potential donors. In Portugal, there is no valid stratification score to assist physicians in accepting or declining an organ offer. Our study aims to characterize a cohort of Portuguese kidney transplant recipients and donors and evaluate the correlation between KDPI and long-term graft survival. The results are interpreted considering the nuances of the Portuguese allocation system, which favors an age-matched donor-recipient allocation. Method We conducted an observational single-center retrospective cohort study, which included patients who received a deceased donor kidney transplant at our unit between January 2013 and December 2015. We excluded patients for whom the donor KDPI index was unavailable for retrieval. Besides the KDPI index, we collected data regarding the receptor's demographic, clinical, and immunological characteristics, as well as graft and recipient survival. The primary outcome was death-censored survival, and follow-up ended on the 31st of December 2023. The secondary outcome was survival with a functioning graft. Survival estimates were obtained using Kaplan-Meier curves. We performed univariate and multivariate survival analysis with log-rank tests and Cox proportional-hazards regression models. Results We selected 364 deceased-donor kidney recipients and 212 kidney donors. The mean KDPI was 60% and 53.3% of donors were classified as expanded criteria. The kidney recipients were predominantly male (68.4%), with a mean age of 50.16 years and an average of 4 HLA mismatches. Median follow-up was 102 months. Considering recipient characteristics according to pre-defined KDPI strata (≤ 20%, 21-85%, &amp;gt; 85%), recipients from higher KDPI were significantly older, with a mean age of 40.6, 48.8, and 61.1 years, respectively (p &amp;lt; 0.001), and had a higher average body mass index (p = 0.041). There were no significant differences regarding the number of HLA mismatches (p = 0.624) or the proportion of hypersensitized patients (p = 0.253) between classes. During follow-up, 16.8% patients presented graft failure and 9.9% died with a functioning graft. Cumulative death-censored graft survival at 5, 8, and 10 years was 87.7%, 87.1%, and 84.4% respectively. The cumulative percentage of patients living with a functioning graft at 5, 8, and 10 years was 83.6%, 76.7%, and 68.6%. Death-censored graft survival was lower in recipients of donors with higher KDPI (Fig. 1), although it did not reach statistical significance (p-value = 0.166). The number of HLA mismatches (p = 0.592) or the recipient's age (p = 0.513) did not significantly impact death-censored graft survival, whereas delayed graft function (DGF) was the variable with the strongest association in univariate analysis (p &amp;lt; 0.001). In a multivariate Cox regression model, KDPI (HR 1.02, p = 0.005) and DGF (HR 3.2, p &amp;lt; 0.001) correlated with graft loss, while older recipients (HR 0.971, p = 0.019) seemed to have a protective effect over death-censored survival. Patient survival with a functioning graft was significantly associated with KDPI strata (p = 0.008; Fig. 2), the recipient's age (p = 0.006), and DGF (p &amp;lt; 0.001) in univariate analysis. Considering KDPI kidneys ≥ 90%, 10-year cumulative death-censored survival was 67.9%. Conclusion In our sample, despite not reaching statistical significance, there was a trend for improved death-censored graft survival in patients with lower KDPI, which further emulates the results of other European cohorts. Nevertheless, the 10-year cumulative death-censored survival of higher KDPI kidneys (≥ 90%) was remarkable, showing that long-term acceptable outcomes can be achieved. The impact of KDPI on patient survival with a functioning graft is probably overestimated, given the bias introduced by the Portuguese matching system, which rewards an “old-for-old” donor-recipient allocation.

#955 Real-world validation of the mortality box score to predict death following kidney transplantation: an international study

Abstract Background and Aims The mortality box score (mBox) is a validated risk prediction score developed by the Paris Transplant Group (NCT03474003), aimed at predicting mortality after kidney transplantation (KT) using data available at the time of surgery. However, its applicability using data routinely collected in institutions' electronic health records (EHRs), enabling automatic computation, needs to be investigated. Method We assessed the mBox's prediction performance in two EHR-based multicenter cohorts of adult kidney transplant recipients (KTRs) transplanted between 2017 and 2021 from: 1) the Greater Paris University Hospitals (AP-HP); and 2) the University of California San Francisco's Hospitals (UCSF). These cohorts were built using solely structured data, routinely collected in the institutions' EHRs. The mBox's discriminative ability to predict death at 3 years following KT was assessed by computing the AUC. Adequation between predicted and observed risk of death was assessed with calibration. Results Out of 10 367, 191 and 5 885 623 patients, we identified 2 560 and 2 028 consecutive KTRs meeting the inclusion criteria in the AP-HP and UCSF cohorts, respectively. In the AP-HP cohort, 344 (13.4%) patients died, during a median follow-up of 3.1 years (interquartile range [IQR]: 1.8 to 4.1). In the UCSF cohort, 150 (7.4%) patients died, during a median follow-up of 2.7 years (IQR: 1.2 to 4.1). The mBox's AUC to predict death within 3 years following KT was 0.780 (95% confidence interval [CI]: 0.752 to 0.801) in the AP-HP cohort and 0.720 (95% CI: 0.672 to 0.768) in the UCSF cohort. Visual examination of the calibration curves showed that the mBox accurately estimated the actual risk of death in the UCSF cohort, and tended to underestimate the actual risk of death in the AP-HP cohort. Conclusion In this real-world international study, performed on 4 588 kidney transplant recipients, relying solely on data routinely collected in institutions' electronic health records, we demonstrate a fair accuracy of the mBox risk prediction score in predicting patient death following transplantation.