Biopsy-proven Acute Rejection Research Articles

A comparative study on outcomes of ABO-incompatible kidney transplants between robot-assisted vs. open surgery-propensity score-matched analysis: a retrospective cohort study

BackgroundRobot-assisted kidney transplantation (RAKT) is increasingly being adopted worldwide. Despite this growing interest, there remains a notable gap in the literature, especially concerning its effectiveness in immunologically high-risk patients compared to conventional open kidney transplantation (OKT). This study investigates the viability and success of RAKT in comparison with OKT, particularly for recipients with ABO incompatibility (ABOi).MethodsThis retrospective, single-center study included 239 living-donor transplants between October 2020 and February 2023, with 210 patients undergoing ABOi-OKT and 29 undergoing ABOi-RAKT. A composite of biopsy-proven acute rejection (BPAR), graft failure, and the development of de novo donor-specific antibodies was analyzed through univariate and multivariate models. Propensity score matching (PSM) was utilized to ensure a balanced comparison between the two groups. Following PSM, a total of 131 cases in the OKT group and 26 cases in the RAKT group were analyzed.ResultsAfter PSM, the mean recipient age was 48.56 years for OKT and 47.96 years for RAKT. Both groups had comparable one-year (RAKT: 92.4%, OKT: 93.1%) and two-year BPAR-free survival rates (RAKT: 92.4%, OKT: 91.9%). Mean estimated glomerular filtration rate values were similar at 12 months post-transplant (RAKT: 62.15 ml/min/1.73 m², OKT: 64.53 ml/min/1.73 m²). Operative times were significantly longer for RAKT (291.42 vs. 150.81 min, p < 0.001), while cold ischemic time was also longer for RAKT (119.77 vs. 47.22 min, p < 0.001). Hospital stays were shorter for RAKT (median 6 vs. 8 days, p < 0.001). There was no significant difference in the composite outcome of BPAR, graft failure, and de novo donor-specific antibodies between the two groups (HR 0.858, 95% CI: 0.180–4.096, p = 0.848).ConclusionsRAKT is a safe and effective alternative to OKT in ABOi patients, demonstrating similar perioperative outcomes, graft survival rates, and renal function. The application of ropensity score matching analysis strengthens the reliability of these findings, confirming RAKT’s viability for high-risk kidney transplant recipients.Trial registrationThe clinical trial associated with this study was registered on 2024-02-24 with the Clinical Trial Number NCT06287008||https://www.clinicaltrials.gov/)

BK Polyomavirus DNAemia With a High DNA Load Is Associated With De Novo Donor-Specific HLA Antibodies in Kidney Transplant Recipients.

BK polyomavirus-associated nephropathy (BKPyVAN) is a well-known complication of kidney transplantation (KTx). The mainstay of prevention is the reduction of immunosuppression upon detection of BK polyomavirus (BKPyV) DNAemia, which precedes BKPyVAN. However, this reduction may inadvertently increase the risk of alloimmunity particularly in patients with a high BKPyV DNA load, where significant immunosuppression reduction is often necessary. This single-center, retrospective cohort study assesses the risk of de novo donor-specific antibodies (dnDSA) development and biopsy-proven acute rejection (BPAR) following high and low BKPyV DNAemia. All patients who underwent KTx at Leiden University Medical Center between 2011 and 2020 were included. Patients were grouped according to high (maximum BKPyV DNA load > 4log10 copies/mL), low (maximum serum BKPyV DNA load ≤ 10E4 copies/mL), and absent BKPyV DNAemia, and analyzed for the development of dnDSA and BPAR, using Cox regression. Of 1076 KTx recipients included, 108 (10%) developed a BKPyV DNAemia with a maximum DNA load below 4log10 copies/mL, whereas 121 (11.2%) developed a BKPyV DNAemia exceeding 4log10 copies/mL. The risk of dnDSA development was higher in patients with a high BKPyV DNAemia, compared to patients without DNAemia (adjusted hazard ratio of 1.9 (95% CI 1.1-3.2, p = 0.017). No significant difference in dnDSA risk was observed between patients with low and absent BKPyV DNAemia. Risk of BPAR did not differ between groups. Our study shows that higher BKPyV DNA loads in KTx patients are associated with a higher risk for dnDSA development, highlighting the importance of exploring additional strategies for the prevention and treatment of BKPyV infections in KTx 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.

Matched pair analysis of the effect of longer hypothermic machine perfusion time on kidney transplant outcomes.

Hypothermic machine perfusion (HMP) has demonstrated benefits in terms of early kidney transplant function compared to static cold storage. While longer preservation times have shown detrimental effects, a previous paired study indicated that longer pump times (the second kidney in a pair) might lead to improved outcomes. To revisit the prior paired study's somewhat unexpected results by reviewing our program's experience. A total of 61 pairs of transplant recipients who received kidneys from the same donor (2012-2021) were analyzed. Patients were divided into two groups depending on whether they were transplanted first (K1) or second (K2). Therefore, the patients in each pair had identical donor characteristics, except for time on the pump. Statistical analyses included Kaplan-Meyer analysis and paired tests, including McNemar's test, student's paired t-test, or Wilcoxon's test, as appropriate. The two groups of recipients had similar demographics (age, body mass index, diabetes, time on dialysis, sensitization and retransplants). Cold ischemic times for K1 and K2 were 8.9 (95%CI: 7.9, 9.8) and 14.7 hours (13.7, 15.8) (P < 0.0001), respectively. Overall, K2 had a higher rate of freedom from biopsy-proven acute rejection at 1 year (P = 0.015). Delayed graft function was less common in K2, 12/61 (20%) than in K1, 20/61 (33%) (P = 0.046). Finally, K2 showed a higher graft survival than K1 (P = 0.023). Our results agree with a previous study that suggested possible advantages to longer pump times. Both studies should encourage further research into HMP's potential anti-inflammatory effect.

Age-Related Differences in Rejection Rates, Infections, and Tacrolimus Exposure in Pediatric Kidney Transplant Recipients in the CERTAIN Registry

IntroductionData on age-related differences in rejection rates, infectious episodes and tacrolimus exposure in pediatric kidney transplant recipients (pKTR) on a tacrolimus-based immunosuppressive regimen are scarce. MethodsWe performed a large-scale analysis of 802 pKTR from the CERTAIN registry from 40 centers in 14 countries. Inclusion criteria were a tacrolimus-based immunosuppressive regimen and at least two years of follow-up. The patient population was divided into three age groups (infants and young children <6 years, school-aged children 6-12 years, and adolescents >12 years) to assess age-related differences in outcome. ResultsMedian follow-up was 48 months (IQR, 36-72). Within the first 2 years post-transplant, infants and young children had a significantly higher incidence of infections (80.6% vs. 55.0% in adolescents, P<0.001) and a significantly higher number of cumulative hospital days (median 13 days vs. 7 days in adolescents, P < 0.001). Adolescents had a significantly higher rate of biopsy-proven acute rejection episodes in the first year post-transplant (21.7%) than infants and young children (12.6%, P=0.007). Infants and young children had significantly lower tacrolimus trough levels, lower tacrolimus concentration-to-dose ratios as an approximation for higher tacrolimus clearance, and higher tacrolimus intra-patient variability (all P < 0.01) than adolescents. ConclusionsThis largest study to date in European pKTR on a tacrolimus-based immunosuppressive regimen shows important age-related differences in rejection rates, infection episodes, tacrolimus exposure and clearance. These data suggest that immunosuppressive therapy in pKTR should be tailored and personalized according to the age-specific risk profiles of this heterogeneous patient population. The data may also serve as a benchmark for future studies with novel immunosuppressive drugs.

P.487: Alloactivation has a key role in biopsy-proven acute rejection in pediatric liver transplant.

P.487: Alloactivation has a key role in biopsy-proven acute rejection in pediatric liver transplant.

204.1: Identification of patients with low likelihood of biopsy-proven acute rejection by donor-derived cell-free DNA and liver function tests in pediatric liver transplant.

204.1: Identification of patients with low likelihood of biopsy-proven acute rejection by donor-derived cell-free DNA and liver function tests in pediatric liver transplant.

Clinical Value of Peripheral Blood Gene Expression Profile and Donor-Derived Cellfree DNA for Identifying Persistent Rejection.

Persistent rejection is an increasingly recognized barrier to long-term kidney allograft survival. A noninvasive method to help identify patients with persistent rejection in need of biopsy would be valuable. This was a post-hoc analysis of a multicenter observational study. Subjects that had a biopsy-proven acute rejection and had another biopsy within 9 months (270 days) and had a biopsy-paired biomarker sample were included. A total of 64 "index" rejections in 58 subjects with repeat biopsies were identified with a median time to repeat biopsy of 100 days. Persistent rejection was present in 61%; 69% of follow-up biopsies were performed in clinically stable patients. Peripheral blood gene expression profile (GEP) demonstrated 59% sensitivity, 76% specificity, PPV of 79%, and NPV of 54%. Donor-derived cell-free DNA (dd-cfDNA) demonstrated sensitivity of 62%, specificity of 86%, PPV of 88%, and NPV of 56%. For repeat biopsies within 90 days of rejection in clinically stable patients (63% of repeat biopsies), both GEP and dd-cfDNA had specificities and PPVs of 100%. GEP was more likely to be positive in TCMR, while dd-cfDNA was more likely to be positive in AMR. Both GEP and dd-cfDNA may have utility at identifying clinically stable patients with persistent rejection in need of biopsy, however they identify different types of rejection.

Molecular screening of transitional B cells as a prognostic marker of improved graft outcome and reduced rejection risk in kidney transplant.

Understanding immune cell dynamics in kidney transplantation may provide insight into the mechanisms of rejection and improve patient management. B cells have gained interest with a special relevance of the "regulatory" subsets and their graft outcome prognostic value. In this study, we aimed to prove that the direct immunophenotyping and target gene expression analysis of kidney transplant patients' fresh whole blood will help to identify graft rejection risk and assist in the monitoring of kidney transplanted patients. We employed flow cytometry and qPCR techniques to characterize B and T cell subsets within fresh whole blood samples, with particular emphasis on transitional B cells (TrB) identified as CD19+CD24hiCD38hi. TrB are a relevant population in the context of kidney transplantation and are closely associated with regulatory B cells (Bregs) in humans. Patients were monitored, tracking pertinent clinical parameters and kidney-related events, including alterations in graft function and episodes of biopsy proven rejection. Higher percentages of TrB cells at 3 months after transplantation were positively associated with better graft outcomes and lower biopsy-proven acute rejection risk. Furthermore, a novel panel of B cell regulatory associated genes was validated at 3 months post-transplantation by qPCR analysis of peripheral blood mononuclear cell (PBMC) mRNA, showing high predictive power of graft events and prognostic value. These findings suggest that monitoring TrB may provide interesting patient management information, improve transplant outcomes, and allow for personalized drug regimens to minimize clinical complications.

Kidney transplantation in children and adolescents with C3 glomerulopathy or immune complex membranoproliferative glomerulonephritis: a real-world study within the CERTAIN research network

BackgroundComplement 3 glomerulopathy (C3G) and immune complex membranoproliferative glomerulonephritis (IC-MPGN) are ultra-rare chronic kidney diseases with an overall poor prognosis, with approximately 40–50% of patients progressing to kidney failure within 10 years of diagnosis. C3G is characterized by a high rate of disease recurrence in the transplanted kidney. However, there is a lack of published data on clinical outcomes in the pediatric population following transplantation.MethodsIn this multicenter longitudinal cohort study of the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry, we compared the post-transplant outcomes of pediatric patients with C3G (n = 17) or IC-MPGN (n = 3) with a matched case–control group (n = 20).ResultsEleven of 20 children (55%) with C3G or IC-MPGN experienced a recurrence within 5 years post-transplant. Patients with C3G or IC-MPGN had a 5-year graft survival of 61.4%, which was significantly (P = 0.029) lower than the 5-year graft survival of 90% in controls; five patients with C3G or IC-MPGN lost their graft due to recurrence during this observation period. Both the 1-year (20%) and the 5-year (42%) rates of biopsy-proven acute rejection episodes were comparable between patients and controls. Complement-targeted therapy with eculizumab, either as prophylaxis or treatment, did not appear to be effective.ConclusionsThese data in pediatric patients with C3G or IC-MPGN show a high risk of post-transplant disease recurrence (55%) and a significantly lower 5-year graft survival compared to matched controls with other primary kidney diseases. These data underscore the need for post-transplant patients for effective and specific therapies that target the underlying disease mechanism.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

LCP-Tacrolimus Extended-Release (Envarsus XR) Use in Adolescent and Young Adult Solid Organ Transplant Recipients.

Limited published experience describes once daily, extended-release tacrolimus (LCP-Tac) use in pediatric solid organ transplantation (SOT), particularly nonrenal SOT. LCP-Tac can simplify immunosuppression (IS) regimens, minimize immediate release-tacrolimus (IR-Tac)-associated adverse effects, and promote adherence. This study describes the successful use of LCP-Tac in adolescent and young adult (AYA) SOT populations. A single-center, retrospective chart review of AYA SOT recipients (age < 25 years) converted from IR-Tac to LCP-Tac. Graft survival, biopsy-proven acute rejection (BPAR), infection rates, estimated glomerular filtration rate (eGFR), and pill burden were assessed at five time points postconversion (1, 3, 6, 12, and 24 months). Intrapatient variability of tacrolimus, as assessed by coefficient of variability (CV%), was also analyzed. Twenty-nine AYA SOT recipients (19 heart, 6 kidney, and 4 liver) were converted to LCP-Tac, with a median age of 17.4 years at conversion. Conversion, mainly due to perceived or identified medication nonadherence, occurred at a median of 5.4 years posttransplant. No graft loss occurred within 24 months of conversion, and BPAR incidence rate was consistent with previous reports for these populations. Only one patient experienced CMV infection. Renal function remained stable postconversion. Successful conversion from IR-Tac to LCP-Tac was demonstrated in AYA heart, kidney, and liver transplant recipients. These AYA SOT recipients experienced reduced pill burden and improved tacrolimus trough concentration variability. However, the impact on medication adherence warrants further investigation. Future research should explore the targeted use of LCP-Tac to enhance IS tolerability and medication adherence in young SOT populations.

Immunosuppressive Induction Therapy Using the Antithymocyteglobulin Grafalon: A Single-Center Non-Interventional Study.

Background: Induction therapy with depleting antibodies in the setting of liver transplantation (LT) is discussed controversially to this day. The rabbit antithymocyteglobulin (ATG) Thymoglobulin (rATG) was introduced as early as 1984 and was frequently used as a standard regime for induction therapy after LT. There are no public reports characterizing Grafalon (ATG-F), a novel ATG, as an induction agent after LT. Objectives: The aim of this observational non-interventional study was to investigate the safety and efficacy of Grafalon induction therapy and characterize its clinical effects in the setting of LT. Methods: A cohort of 80 patients undergoing deceased donor LT at the Medical University of Vienna and receiving Grafalon as part of the clinical standard immunosuppressive regimen was prospectively included between March 2021 and November 2022. Patients were monitored closely for leukocytopenia and thrombocytopenia during the first postoperative week and followed up for incidence and severity of biopsy-proven acute rejection (BPAR), overall survival, and bacterial infections in the first year after LT. Results: The incidences of thrombocytopenia and leukocytopenia following Grafalon treatment peaked on postoperative day four, with 64% and 31%, respectively. However, there were no cases of severe leukocytopenia after the first postoperative week. Induction therapy with Grafalon resulted in a rate of localized bacterial infections and bacteremia of 28% and 21%, respectively. The rate of BPAR was 12.5% in the first year after LT; the one-year survival rate in this cohort was 90%. Conclusions: Overall, this study provides evidence of the safety and efficacy of Grafalon as an induction agent. Further studies investigating the potential long-term effects of Grafalon, as well as comparison studies with different immunosuppressive regimens, are needed in order to draw further conclusions.

Early Conversion to Everolimus Within 180 Days of Living Donor Liver Transplantation.

Early conversion to Everolimus (EVR) post deceased donor liver transplant has been associated with improved renal function but increased rejection. Early EVR conversion has not been evaluated after living donor liver transplant (LDLT). A retrospective cohort study was conducted to compare the rate of rejection and renal function in patients converted to EVR early post-LDLT to patients on calcineurin inhibitors (CNIs). This was a single center retrospective cohort study of adult LDLT recipients between January 2012 and July 2019. Patients converted to EVR within 180 days of transplant were compared to patients on CNIs. The primary endpoint was biopsy proven acute rejection (BPAR) at 24 months posttransplant. Key secondary endpoints included eGFR at 24 months, change in eGFR, adverse events, and all-cause mortality. From a total of 173 patients involved in the study: 58 were included in the EVR group and 115 in the CNI group. Median conversion to EVR was 26 days post-LDLT. At 24 months, there was no difference in BPAR (22.7% EVR vs. 19.1% CNI, p = 0.63). Median eGFR at 24 months posttransplant was not significantly different (68.6 [24.8 to 112.4] mL/min EVR vs. 75.9 [35.6-116.2] mL/min CNI, p = 0.103). Change in eGFR from baseline was worse in the EVR group (-13.0 [-39.9 to 13.9] mL/min EVR vs. -5.0 [-31.2 to 21.2] mL/min CNI, p = 0.047). Median change from conversion to 24 months posttransplant (EVR group only) was -3.43mL/min/1.73 m2 (-21.0 to 9.6). Early EVR conversion was not associated with increased risk of rejection among LDLT recipients. Renal function was not impacted. EVR may be considered as an alternative after LDLT in patients intolerant of CNIs.

A comparative analysis of clinical outcomes between conversion to mTOR inhibitor and calcineurin inhibitor reduction in managing BK viremia among kidney transplant patients

BK virus-associated nephropathy (BKVAN) exerts a substantial impact on allograft survival, however, the absence of robust clinical evidence regarding treatment protocols adds to the complexity of managing this condition. This study aimed to compare the two treatment approaches. The study population consisted of patients who underwent kidney transplantation between January 2016 and June 2020 at two tertiary hospitals in Korea. Patients diagnosed with BK viremia were evaluated based on their initial viral load and the treatment methods. The ‘Reduction group’ involved dose reduction of tacrolimus while the ‘Conversion group’ included tacrolimus discontinuation and conversion to sirolimus. A total of 175 patients with an initial viral load (iVL) ≥ 3 on the log10 scale were evaluated within two iVL intervals (3–4 and 4–5). In the iVL 4–5 interval, the Reduction group showed potential effectiveness in terms of viral clearance without statistically significant differences. However, within the iVL 3–4 interval, the Reduction group demonstrated superior viral clearance and a lower incidence of biopsy-proven acute rejection (BPAR) than the Conversion group. The renal function over 12 months after BKV diagnosis showed no statistically significant difference. Reducing tacrolimus compared to converting to mTORi would be a more appropriate treatment approach for BK viral clearance in kidney transplantation. Further research is warranted in a large cohort of patients.

#2859 Clinical and morphological characteristics of biopsy-proven kidney graft rejection in Latvia

Abstract Background and Aims Kidney transplantation is a treatment for many patients with end stage renal disease leading to increased quality of life. In last decades results in kidney transplantation have been improving, but allograft rejection remains an important clinical problem. Graft biopsy remains the gold standard to assess the cause of kidney transplant status. This study aimed to determine clinical and histopathological characteristics, treatment and short-term outcomes of biopsy-proved kidney graft rejection in Latvia. Method In this retrospective observational study all kidney allograft biopsies performed in Pauls Stradins Clinical University Hospital from January 2014 till December 2022 was reviewed. Biopsies with rejection, ≥7 glomeruli, patients ≥18 years old were included. Acute rejection was diagnosed according to clinical, laboratory and biopsy-proven acute rejection (BPAR) histological criteria. BPAR was classified and subdivided using Banff criteria. All recipients universally received either depleting or non-depleting induction therapy. Most of the patient (82%) for maintenance immunosuppression (MI) received triple therapy with calcineurin inhibitor, mycophenolate mofetil, and prednisone, others—in different combinations with above and mammalian target of rapamycin (mTOR), azathioprine. Graft function was evaluated according to glomerular filtration rate (GFR), calculated with the CKD-EPI Creatinine, 2021 equation. Treatment strategies, laboratory data at the time of biopsy and after 1 year follow-up were analysed. Repeated-control biopsies after receiving therapy were excluded. Data were analysed using descriptive statistics and T-test. Results From all 523 biopsies, further included and analysed were 153 (total 146 patients). 58% were males, average patient age was 45.5 years. Most 84% of the grafts were from deceased, 8%—living donors. Mean time from transplantation to biopsy was 32 months. Acute antibody-mediated rejection (AAMR) was diagnosed in 41% cases, chronic-active antibody mediated (CAAMR)—25%, followed by mixed 16%, acute cellular (ACR) 10% and borderline 8% rejection. Besides augmented MI for almost all patients, pulse steroids (GCS) were the most commonly 70% administered treatment, followed by plasma exchange 59% (PEX), rituximab (RTX) 50%, immunoglobulins (IG) 24% and anti-thymocyte globulin (ATG) 10% in different, mostly non-homogenous combinations. Non adherence, advanced fibrotic changes in biopsy and serious comorbidities were the main reasons patients did not receive specific treatment besides intensified MI. The most favourable outcomes were in ACR where mean allograft GFR increased +20.7 ml/min after one year, compared to the worst outcome CAAMR group where GFR decreased −4.7 ml/min (p = 0.03). In ACR group 92% graft function stayed the same or improved, moreover 54% graft function increased ≥20% from baseline; similarly in mixed and AAMR group GFR increase ≥20% were for 45% and 48%, compared to CAAMR where it was only for 6% of patient. Furthermore, the CAAMR group was with the most patients (48%) who returned to dialysis or died. In AAMR and mixed rejection groups mean GFR changes were close +13.4 ml/min and +12.9 ml/min (p = 0.95). There were no statistically significant associations between treatment outcomes in PEX+RTX+GCS vs PEX+RTX+GCS+IG in the AAMR group (p = 0.382). Overall, 3.9% of patients died. Conclusion Overall BPAR prevalence between kidney graft biopsies was high (29%). Antibody mediated rejection was diagnosed most often with least favourable short-term outcomes in CAAMR group. Despite various improvements in immunosuppression, CAAMR remains a serious cause of transplant dysfunction or loss.

#3036 The influence of first renal graft on second graft rejection and survival: the importance of revisiting histocompatibility and clinical outcomes

Abstract Background and Aims Kidney retransplantation confers a robust survival benefit over dialysis and recent data has shown similar outcomes to first kidney transplant. The number of HLA mismatches is an important predictor of graft loss and sensitization and the presence of donor specific antibodies (DSA) -pre and -post transplant is a major risk factor for rejection and worst outcomes. However, the importance of HLA matching of first graft and the relevance of first donor DSAs on second graft outcomes is less known. Our aim was to identify risk factors to second graft acute rejection and graft loss, related to second and first graft features. Method We performed a retrospective, longitudinal study including all patients submitted to a 2nd kidney transplant between January 2008 and December 2021, excluding patients with more than 2 grafts or multi-organ transplant. Clinical and histocompatibility data from the first and second donor and recipient were collected. HLA antibodies were detected by solid phase assays and considered if MFI &amp;gt;2500. For subsequent kidney transplants, repeated mismatches are not allowed and unacceptable antigens are those for which the patient has pre-formed -A, -B and -DR antibodies, with MFI&amp;gt;1000. Biopsy proven acute rejection was defined according to Banff 2017 criteria. Follow-up was 31st December 2023 for functioning grafts or time to graft failure, with a mean time of 92 ± 53 months. Results We included 114 patients, 73 (64%) males, mostly Caucasians (96%), with a mean age of 43.9 ± 13 years at 2nd transplant. First kidney transplant was performed before 2010 for 99 patients (87%), with a median first graft survival of 82.5 [12.5-144] months and 19 patients (16.7%) presented primary disfunction due to surgical/vascular complications. After graft loss, 43 patients (37.7%) had their graft removed. For second transplant, 11 (9.6%) patients had a living donor. Induction therapy with thymoglobulin occurred in 94 patients (83%) and maintenance therapy with mycophenolic acid, calcineurin inhibitors and steroids was prescribed in 83 patients (73%). During follow-up, 20 patients (17.5%) presented biopsy proven acute rejection, 13 (65%) T cell mediated and 7 (35%) antibody-mediated, the majority during the first-year post-transplant (N = 17, 85%). The risk factors for second graft rejection are summarized in Table 1. Patients with a first graft nephrectomy had a higher risk of acute rejection (OR 3.9, 95% CI [1.4-10.9], p &amp;lt; 0.006) and were more susceptible to the development of second donor post-transplant DSA (58% vs 35%, p = 0.02). Death censored second allograft loss occurred in 24 patients (21%) at follow up and acute rejection was an important risk factors (OR 4.3, 95% CI [1.5-12.1], p = 0.004). First-year graft survival was 93% and a survival at follow up was 79%. On survival analysis the presence of second graft DSA was a major risk factor for graft loss, especially class 2 -DQ and -DR. First transplant total mismatch load, especially on class 1 contributed to worst graft survival. Conclusion Worst outcomes in first kidney transplant were related with an increased risk of acute rejection in second graft and 1st graft nephrectomy increases the risk of the development of 2nd graft DSA and acute rejection. First transplant mismatch load decreased second graft survival.

#1327 mTOR inhibitors in kidney transplant recipients: long-term efficacy and discontinuation causes

Abstract Background and Aims mTOR inhibitors use in kidney transplantation showed conflicting results, but their use as add-on treatment to calcineurin inhibitors (CNI) is still considered a valuable option. High frequency of drug discontinuation hinders their use in clinical practice. We present a real-life study on long term efficacy of mTOR inhibitors use vs mycophenolic acid (MPA) and the causes of drug discontinuation. Method This is an observational retrospective monocentric study. We analyzed data from 773 patients that underwent kidney transplantation at Hospital Clinic between 2013 and 2019. Induction treatment was based either on basiliximab or a lymphocyte-depleting agent together with methylprednisolone. Maintenance treatment was based either on MPA or mTORi with a CNI. Baseline differences were accounted for with the Inverse Propensity of Treatment Weighting (IPTW). Outcomes explored were death with a functioning graft, graft loss or biopsy-proven rejection. Predictors of outcome were explored through logistic regression or Cox-regression as appropriate. Results 335/773 (43.3%) of the patients received MPA as maintenance treatment, whereas 438/773 (56.6%) received an mTOR inhibitor. Average follow-up was 3.36 years (SD ± 2.04 years). No outcome resulted statistically significant at the logistic regression weighted with IPTW in the subgroup mTORi vs MPA: odds ratio was 1.16 (0.75-1.63, p = 0.57) for death, 0.87 (0.54-1.41, p = 0.59) for graft loss and 1.15 (0.79-1.67, p = 0.45) for biopsy-proven acute rejection. The per-protocol analysis confirmed these results as not statistically significant. Strongest predictors of death resulted having a deceased donor of cardiac death (HR 2.17 (1.06-4.40, p = 0.03), having a delayed graft function (HR 1.9 (1.26-2.87, p = 0.002) and being readmitted within three months from the surgery (HR 1.76 (1.21-2.55, p = 0.003). Diabetic nephropathy as cause of kidney disease was significant as well (HR 2.01 (1.24-3.26, p = 0.004). Proportion of patients with a CMV infection were significantly lower in the mTORi than MPA subgroups (33.5% vs 41.5%, p = 0.02). Proportion of patients developing neoplasias were not significantly different (10% vs 11.3%, p = 0.55). A total of 307/773 (39.7%) of patients changed their immunosuppressive treatment at a median time of 110 days (26.5-375.5). In the MPA subgroup 77/335 (22.9%) changed treatment, whereas in the mTORi subgroup 230/438 (52.5%). The causes of change due to drug-related events were the most represented and related to mTOR treatment: lymphocele in 36/773 (4.6%), complications of the surgical wound in 31/773 (4.1%) and edemas in 23/773 (2.9%) were the most common. Of note, unspecific physician preference was cause of discontinuation in a total of 66/773 (8.5%) patients. Conclusion Our data from a tertiary-center, real-life experience show that mTOR inhibitors are a solid alternative to MPA based protocols, with effectiveness proven at the multivariate and weighted analysis. mTOR treatment has a high rate of discontinuation, with most of the causes represented by post-intervention complications; interestingly, physician preference represent a frequent cause. Further experience and research is needed to optimize mTORi treatment, in order to maintain a therapeutic option for transplanted patients.

Evaluation of Tacrolimus Concentrations and Clinical Outcomes Between Extended and Immediate Release Formulations in Kidney Transplant

Objectives: Tacrolimus remains the mainstay of immunosuppression in kidney transplantation. Understanding the relationship between therapeutic tacrolimus levels and outcomes of acute rejection, patient/graft survival, and tolerability are important. The relationship between time to therapeutic tacrolimus levels and outcomes has not been well established, specifically with the use of extended release tacrolimus formulation (LCP-Tac). This study investigated time to therapeutic tacrolimus levels of 2 tacrolimus formulations, LCP-Tac and immediate release tacrolimus (IR-Tac), as a predictor of clinical outcomes. Methods: This was a single-center, retrospective, cohort study of kidney transplant recipients at Duke Hospital between 2013-2021. The primary objective evaluated the difference in time to therapeutic tacrolimus levels with LCP-Tac vs IR-Tac regimens. Secondary endpoints included time within therapeutic range during the first 3 months post-transplant, incidence of biopsy-proven rejection, development of de novo donor specific antibodies, and patient and allograft survival at 12 months post-transplant. Results: 128 patients were included (63 in LCP-Tac group and 65 in IR-Tac group). The time to therapeutic tacrolimus level was similar between formulations (7.2 days with LCP-Tac compared to 6.7 days with IR-Tac, P = .63). The time within therapeutic range during the first 3 months post-transplant, via modified Rosendaal, was similar with LCP-Tac and IR-Tac (56.1% vs 64.8%, respectively). Rates of biopsy-proven acute rejection at 12 months were similar (7/63 (11.1%) compared to 4/65 (6.2%)). There was no difference in patient/graft survival between groups. Conclusions: The time to therapeutic tacrolimus levels did not differ based on tacrolimus formulation and was not correlated with clinical outcomes.

Incidence, epidemiology, and outcomes of acute allograft rejection following liver transplantation in Australia.

Acute allograft rejection is a well-known complication of liver transplantation (LT). The incidence, epidemiology, and outcomes of acute rejection have not been well described in Australia. We retrospectively studied consecutive adults who underwent deceased donor LT at a single center between 2010 and 2020. Donor and recipient data at the time of LT and recipient outcomes were collected from a prospective LT database. Liver biopsy reports were reviewed, and only a graft's first instance of biopsy-proven acute rejection was analyzed. During the study period, 796 liver transplants were performed in 770 patients. Biopsy-proven rejection occurred in 34.9% of transplants. There were no significant changes in the incidence of rejection over time (linear trend p =0.11). The median time to the first episode of rejection was 71 days after LT: 2.2% hyperacute, 50.4% early (≤90d), and 47.5% late rejection (>90d). Independent risk factors for rejection were younger recipient age at transplant (aHR 0.98 per year increase, 95% CI: 0.97-1.00, p =0.01), and ABO-incompatible grafts (aHR 2.55 vs. ABO-compatible, 95% CI: 1.27-5.09, p <0.01) while simultaneous multiorgan transplants were protective (aHR 0.21 vs. LT only, 95% CI: 0.08-0.58, p <0.01). Development of acute rejection (both early and late) was independently associated with significantly reduced graft (aHR 3.13, 95% CI: 2.21-4.42, p <0.001) and patient survival (aHR 3.42, 95% CI: 2.35-4.98, p <0.001). In this 11-year Australian study, acute LT rejection occurred in 35%, with independent risk factors of younger recipient age and ABO-incompatible transplant, while having a simultaneous multiorgan transplant was protective. Acute rejection was independently associated with reduced graft and patient survival after adjustment for other factors.

Comparing the prognostic performance of iBOX and biopsy-proven acute rejection for long-term kidney graft survival

Biopsy-proven acute rejection (BPAR) occurs in approximately 10% of kidney transplant recipients in the first year, making superiority trials unfeasible. iBOX, a quantitative composite of estimated glomerular filtration rate, proteinuria, antihuman leukocyte antigen donor-specific antibody, and + full/− abbreviated kidney histopathology, is a new proposed surrogate endpoint. BPAR’s prognostic ability was compared with iBOX in a pooled cohort of 1534 kidney transplant recipients from 4 data sets, including 2 prospective randomized controlled trials. Discrimination analyses showed mean c-statistic differences between both iBOX compared with BPAR of 0.25 (95% confidence interval: 0.17-0.32) for full iBOX and 0.24 (95% confidence interval: 0.16-0.32) for abbreviated iBOX, indicating statistically significantly higher c-statistic values for the iBOX prognosis of death-censored graft survival. Mean (± standard error) c-statistics were 0.81 ± 0.03 for full iBOX, 0.80 ± 0.03 for abbreviated iBOX, and 0.57 ± 0.03 for BPAR. In calibration analyses, predicted graft loss events from both iBOX models were not significantly different from those observed. However, for BPAR, the predicted events were significantly (P < .01) different (observed: 64; predicted: 70; full iBOX: 76; abbreviated iBOX: 173 BPAR). IBOX at 1-year posttransplant is superior to BPAR in the first year posttransplant in graft loss prognostic performance, providing valuable additional information and facilitating the demonstration of superiority of novel immunosuppressive regimens.