Previous Kidney Transplantation Research Articles

#2955 Incidental findings in a renal magnetic resonance imaging study for evaluation of chronic kidney disease in type 2 diabetes population

Abstract Background and Aims Novel Magnetic Resonance Imaging (MRI) techniques are potential methods to non-invasively assess and quantify functional, structural and pathophysiological changes in chronic kidney disease (CKD) that may improve diagnosis, prognosis and treatment of these patients. Advances in imaging techniques are also likely to result in the detection of unexpected and asymptomatic incidental findings. We retrospectively analyzed the overall prevalence of incidental findings in the participants of our previously reported study utilizing a non-contrast multiparametric MRI protocol in patients with type 2 DM (T2DM) as compared to healthy controls. Method The subjects of this sub-study were participants of our original prospective, single-center, observational study, in which several MRI biomarkers were evaluated to differentiate diabetic versus healthy kidneys, and various stages of CKD. A complete medical history and physical examination were performed. The inclusion criteria for the T2DM cohort were: Age 18-70 years, type II DM with CKD staged 3-4 (estimated glomerular filtration rate [eGFR] 15-60 ml/min/1.73 m2, body mass index (BMI) 18-35 and provision of written informed consent. The control group comprised of healthy volunteers who were age- and sex-matched and had the following inclusion criteria: Age 18-70 years, eGFR >80 ml/min/1.73 m2, UACR <30 mmol/g, BMI 18-35 and provision of written informed consent. Exclusion criteria for the diabetic group were any apparent cause/s of CKD other than diabetes, previous kidney transplantation, pregnancy, contraindication for MRI examination, heart failure (NYHA class III or IV), allergies to iodine-based contrast agents. Factors that excluded healthy participants were pregnancy, contraindication for MRI examination, allergy to iodine-based contrast agents and any active or chronic disease/diagnosis. Measured GFR (mGFR) was assessed in all participants using iohexol clearance. An MRI scan using a wide range of non-contrast techniques was performed at baseline. Total scan time for patients did not exceed 45 min per session and no gadolinium-based contrast agents were used in any of the MRI examinations. All patients with incidental findings on MRI were further evaluated and referred to appropriate specialists for management. Results A total of 38 T2DM patients with CKD and 20 age- and gender-matched healthy volunteers who completed the study were included in the analysis. Of the T2DM patients, 2 were found to have CKD stage 2 by mGFR and 36 CKD stages 3–4. Clinically significant incidental findings (excluding 4 cases of renal cysts requiring only follow-up without further intervention) were found in 13 of the 38 (34%) T2DM patients. The most frequent findings were intraductal papillary mucinous neoplasm (IPMN) in 7 patients, followed by 3 cancers (1 case of kidney cancer, 1 bladder cancer and 1 lymphoma) and 3 cases of adrenal gland mass later diagnosed to be benign adenoma on further investigation. In contrast, of the 20 healthy volunteers, 2 (10%) were found to have significant incidental findings, which were IPMN in both. The follow-up duration varied between 2-6 years. The patient with bladder cancer had metastatic disease and died shortly after the diagnosis, the one with kidney cancer is under observation and the one with lymphoma underwent adequate treatment and is under remission. The cases of IPMN are being followed up regularly at our surgical department. Conclusion Clinically important incidental findings on renal MRI appear to be more common in T2DM patients than in healthy volunteers, which would have been missed without MRI examination. Mechanisms for reporting and strategies for dealing with incidental findings need to be taken into account in such investigational imaging studies. The detection of incidental findings also poses various practical and ethical issues. Further larger studies with long-term follow-up are needed to delineate the clinical relevance, natural course and management of such incidental findings.

#1467 Pegcetacoplan for post-transplant recurrent C3 glomerulopathy or immune complex membranoproliferative glomerulonephritis in NOBLE: 12-week evolution

Abstract Background and Aims C3 glomerulopathy (C3G) and primary immune complex membranoproliferative glomerulonephritis (IC-MPGN) are rare diseases caused by uncontrolled complement activation, resulting in excess deposition of C3 breakdown products in the kidneys, which leads to kidney damage and eventually kidney failure. Kidney transplantation is an option for end-stage kidney disease, but disease recurrence is common (up to 67% of patients), and up to 50% of transplant recipients lose renal allografts due to recurrence. Pegcetacoplan is a targeted C3 and C3b inhibitor that may prevent excess deposition of C3 and C5 breakdown products and subsequent glomerular inflammation and kidney damage in patients with C3G or IC-MPGN, potentially improving clinical outcomes. NOBLE (NCT04572854) was the first prospective randomized controlled trial of pegcetacoplan vs standard of care (SOC) in post-transplant patients with recurrent C3G or IC-MPGN. Method Adult patients were randomized 3:1 to subcutaneous pegcetacoplan 1080 mg twice weekly plus SOC (n = 10) or SOC only (n = 3) for 12 weeks followed by a 40-week non-controlled period in which all patients received pegcetacoplan. Primary and secondary endpoint results for Week-12 data have been reported. We conducted a patient-level post hoc analysis to describe key histology changes from renal biopsy (C3c staining, C3G histologic index activity score), clinical parameters (urine protein-to-creatinine ratio [uPCR; calculated from triplicate first-morning spot urine], estimated glomerular filtration rate [eGFR]), and biomarkers (serum C3, plasma sC5b-9) through Week 12. The C3G histologic index uses a semiquantitative scale of 0–3 for 7 markers of activity (mesangial hypercellularity, endocapillary proliferation, membranoproliferative morphology, leukocyte infiltration, cellular and/or microcellular crescent formation, fibrinoid necrosis, and interstitial inflammation), for a total activity score of 0–21. eGFR stability was defined as a decrease of no more than 25% versus baseline. Results Among the 10 pegcetacoplan-treated patients, 7 (70%) had 1 previous kidney transplant, 2 (20%) had 2, and 1 (10%) had 3. The mean (range) time to disease recurrence after most recent transplant was 10.8 (0.4–31.8) months and from most recent recurrence to randomization was 12.2 (2.1–37.7) months, with 60% randomized >6 months post-disease recurrence. Among the 3 SOC-only patients, 2 (66.7%) had 1 transplant and 1 (33.3%) had 2. Mean (range) time to recurrence was 32.8 (4.6–63.8) months and to randomization was 33.9 (7.0–65.4) months. At Week 12, 8 (80%) pegcetacoplan-treated patients had a reduction in C3c staining of at least 1 order of magnitude. Of these 8, 7 (70%) had a decrease in activity score, and 6 of these 7 (60%) had a decrease in proteinuria. Four (40%) patients had reduced C3c staining, decreased activity score, and cleared electron microscopy deposits at Week 12. eGFR remained stable in 9 (90%) patients. Six of 9 (67%) patients with available Week-12 data (4 of 5 patients with >1 g/g uPCR at baseline) had a reduction in uPCR with 5 of the 6 achieving ≥50% uPCR reduction (Table). All pegcetacoplan-treated patients had increased serum C3, as expected, and 9 (90%) had decreased sC5b-9. At Week 12, no TEAEs led to study discontinuation, treatment withdrawal, or death. No encapsulated bacterial infections or events of rejection/graft loss related to the study drug were reported. Conclusion As early as Week 12, more than half (6/10 [60%]) of post-transplant patients with recurrent C3G or IC-MPGN treated with pegcetacoplan achieved reductions in C3c staining, activity score of C3G histology index, and proteinuria, suggesting that pegcetacoplan targets the underlying pathophysiology of the C3G/IC-MPGN in kidney transplant recipients. The safety and efficacy of pegcetacoplan will be further evaluated at Week 52 of the NOBLE study and as part of the Phase 3 VALIANT (NCT05067127) trial, which enrolled patients with C3G or primary IC-MPGN who have native kidney or post-transplant disease.

Pancreas Transplantation Outcome Predictions-PTOP: A Risk Prediction Tool for Pancreas and Pancreas-Kidney Transplants Based on a European Cohort.

For patients with complicated type 1 diabetes having, for example, hypoglycemia unawareness and end-stage renal disease because of diabetic nephropathy, combined pancreas and kidney transplantation (PKT) is the therapy of choice. However, the shortage of available grafts and complex impact of risk factors call for individualized, impartial predictions of PKT and pancreas transplantation (PT) outcomes to support physicians in graft acceptance decisions. Based on a large European cohort with 3060 PKT and PT performed between 2006 and 2021, the 3 primary patient outcomes time to patient mortality, pancreas graft loss, and kidney graft loss were visualized using Kaplan-Meier survival curves. Multivariable Cox proportional hazards models were developed for 5- and 10-y prediction of outcomes based on 26 risk factors. Risk factors associated with increased mortality included previous kidney transplants, rescue allocations, longer waiting times, and simultaneous transplants of other organs. Increased pancreas graft loss was positively associated with higher recipient body mass index and donor age and negatively associated with simultaneous transplants of kidneys and other organs. Donor age was also associated with increased kidney graft losses. The multivariable Cox models reported median C-index values were 63% for patient mortality, 62% for pancreas loss, and 55% for kidney loss. This study provides an online risk tool at https://riskcalc.org/ptop for individual 5- and 10-y post-PKT and PT patient outcomes based on parameters available at the time of graft offer to support critical organ acceptance decisions and encourage external validation in independent populations.

Bridging the gap: assessing CMV DNAemia in kidney transplant recipients with previous solid organ transplants

Cytomegalovirus (CMV) infection poses a significant threat to solid organ transplant (SOT) recipients and can lead to various complications and adverse outcomes. In an effort to prevent CMV infection, it is common to utilize prophylactic strategies, including antiviral medications such as valganciclovir, especially for high-risk patients. Risk factors for CMV infection in kidney transplant recipients (KTRs) include CMV mismatch between donor and recipient (i.e., donor positive, recipient negative), and intensity of immunosuppression, such as the use of T-cell depleting agents. However, little attention has been given to KTRs with a history of prior SOTs, despite their prolonged exposure to immunosuppressive regimens. The aim of this retrospective single-center study was to investigate the incidence and implications of CMV DNAemia in KTRs with prior SOTs. The study included 97 KTRs with prior SOTs and 154 KTRs with no prior transplants as a control group. In the study group, the most common SOT before the current kidney transplantation (KT), was a previous KT. Patients in the KTR group with prior SOTs were more sensitized than those in the control group [calculated panel-reactive antibody > 30%: 49 (50.5%) vs. 30 (19.45%) patients, p = 0.001]. There was a 39.2% incidence of CMV DNAemia in the previous SOT group compared to 48.7% in the control group [non-significant (NS)]. Patients with prior SOTs demonstrated a shorter post-transplant time to CMV DNAemia [median time 1.6 months (interquartile range, IQR 0.7–5.8) in the KTRs with prior SOTs vs. 2.6 months (IQR 1.5–8.1) in the control group (p = 0.001)]. Although the study highlights the need for tailored prophylaxis strategies and vigilant monitoring in KTRs with prior SOTs, its limitations, such as its retrospective nature and single-center design, call for further multicenter research to establish comprehensive guidelines for managing CMV DNAemia in this unique patient population. Despite these limitations, this study underscores the importance of recognizing the heightened risk of CMV infection or reactivation in KTRs overall and the potential benefits of proactive intervention to mitigate associated morbidity and mortality.

Nedosiran Safety and Efficacy in PH1: Interim Analysis of PHYOX3

Primary hyperoxaluria (PH) is a rare genetic disorder of hepatic glyoxylate metabolism. Nedosiran is an RNA interference (RNAi) therapeutic that the US Food and Drug Administration has approved for treatment of PH1. PHYOX3 is a trial evaluating monthly nedosiran in patients with PH. In this PHYOX3 interim analysis, participants with PH1 who continued from a single-dose nedosiran trial (PHYOX1), with no previous kidney or liver transplantation, dialysis, or evidence of systemic oxalosis were eligible. The safety and efficacy of once-monthly nedosiran was assessed over 30 months. Thirteen participants completed PHYOX1 and continued into PHYOX3. At baseline, the mean (SD) and median (range) age was 24.2 (6.6) years and 23.0 (14-39) years, respectively; 53.8% were female and 61.5% were White. Mean estimated glomerular filtration rate (eGFR) remained stable (62-84.2 mL/min per 1.73 m2) to month 30. Mean 24-hour urinary oxalate (Uox) excretion showed a sustained reduction from baseline of≥60% at every visit (months 2-30). From month 2, at least 10 of 13 (76.9%) participants achieved normal (<0.46 mmol/24h; upper limit of assay-normal [ULN]) or near-normal (≥0.46 to<0.60 mmol/24h;≥ULN to<1.3× ULN) 24-hour Uox excretion. All participants experienced≥1 adverse event (AE), mostly mild or moderate in severity (primarily, injection site events). Three serious, not treatment-related AEs were reported; there were no deaths or study discontinuations due to AEs. Nedosiran was well-tolerated in patients with PH1, and treatment resulted in a sustained, substantial reduction in Uox excretion for at least 30 months in this long-term study. No safety signals have been identified to date. The PHYOX3 study is ongoing.

A tool to predict the risk of lower extremity amputation in patients starting dialysis.

Non-traumatic lower extremity amputation (LEA) is a severe complication during dialysis. To inform decision-making for physicians, we developed a multivariable prediction model for LEA after starting dialysis. Data from the Swedish Renal Registry (SNR) between 2010 and 2020 were geographically split into a development and validation cohort. Data from NECOSAD between 1997 and 2009 were used for validation targeted at Dutch patients. Inclusion criteria were no previous LEA and kidney transplant and age≥40 years at baseline. A Fine-Gray model was developed with LEA within 3 years after starting dialysis as outcome of interest. Death and kidney transplant were treated as competing events. One coefficient, ordered by expected relevance, per 20 events was estimated. Performance was assessed with calibration and discrimination. SNR was split into an urban development cohort with 4771 individuals experiencing 201 (4.8%) events and a rural validation cohort with 4.876 individuals experiencing 155 (3.2%) events. NECOSAD contained 1658 individuals experiencing 61 (3.7%) events. Ten predictors were included: female sex, age, diabetes mellitus, peripheral artery disease, cardiovascular disease, congestive heart failure, obesity, albumin, haemoglobin and diabetic retinopathy. In SNR, calibration intercept and slope were -0.003 and 0.912 respectively. The C-index was estimated as 0.813 (0.783-0.843). In NECOSAD, calibration intercept and slope were 0.001 and 1.142 respectively. The C-index was estimated as 0.760 (0.697-0.824). Calibration plots showed good calibration. A newly developed model to predict LEA after starting dialysis showed good discriminatory performance and calibration. By identifying high-risk individuals this model could help select patients for preventive measures.

Long-term patency of arteriovenous fistulas for hemodialysis: A decade's experience in a transplant unit.

The heterogeneous quality of studies on arteriovenous fistulas outcome, with variable clinical settings and large variations in definitions of patency and failure rates, leads to frequent misinterpretations and overestimation of arteriovenous fistula patency. Hence, this study aimed to provide realistic and clinically relevant long-term arteriovenous fistula outcomes. We retrospectively analyzed all autologous arteriovenous fistulas at our center over a 10-year period (2012-2022). Primary and secondary patency analysis was conducted using the Kaplan-Meier method; multivariate analysis of variance was used to detect outcome predictors. Vascular access-specific endpoints were defined according to the European guidelines on vascular access formation. Of 312 arteriovenous fistulas, 57.5% (n = 181) were radio-cephalic (RC_AVF), 35.2% (n = 111) brachio-cephalic (BC_AVF), and 6.3% (n = 20) brachio-basilic (BB_AVF). 6, 12, and 24 months follow-up was available in 290 (92.1%), 282 (89.5%), and 259 (82.2%) patients, respectively. Primary patency rates at 6, 12, and 24 months were 39.5%, 34.8%, and 27.2% for RC_AVF, 58.3%, 44.4%, and 27.8% for BC_AVF, and 40.0%, 42.1%, and 22.2% for BB_AVF (p = 0.15). Secondary patency rates at 6, 12, and 24 months were 65.7%, 63.8%, and 59.0% for RC_AVF, 77.7%, 72.0%, and 59.6% for BC_AVF, and 65.0%, 68.4%, and 61.1% for BB_AVF (p = 0.29). Factors associated with lower primary and secondary patency were hemodialysis at time of arteriovenous fistula formation (p = 0.037 and p = 0.024, respectively) and higher Charlson Comorbidity Index (p = 0.036 and p < 0.001, respectively). Previous kidney transplant showed inferior primary patency (p = 0.005); higher age inferior secondary patency (p < 0.001). Vascular access care remains challenging and salvage interventions are often needed to achieve maturation or maintain patency. Strict adherence to standardized outcome reporting in vascular access surgery paints a more realistic picture of arteriovenous fistula patency and enables reliable intercenter comparison.

Role of standard HLA mismatch in modifying associations between non-pharmacologic risk factors and solid organ malignancy after kidney transplantation

BackgroundHuman leukocyte antigen mismatch(es) (HLA-mm) between donors and recipients has not been extensively studied either as a risk factor for solid organ malignancy (SOM) or as a modifier of associations between nonpharmacologic risk factors and SOM in kidney transplant recipients (KTRs). MethodsIn a secondary analysis from a previous study, 166,256 adult KTRs in 2000–2018 who survived the first 12 months post-transplant free of graft loss or malignancy were classified into 0, 1–3, and 4–6 standard HLA-mm cohorts. Multivariable cause-specific Cox regressions analyzed the risks of SOM and all-cause mortality (ac-mortality) in 5 years following the first KT year. Comparisons of associations between SOM and risk factors in HLA mismatch cohorts were made by estimating the ratios of adjusted hazard ratios. ResultsCompared with 0 HLA-mm, 1–3 HLA-mm was not associated, and 4–6 HLA-mm was equivocally associated with increased risk of SOM [hazard ratio, (HR) = 1.05, 95%, confidence interval (CI) = 0.94–1.17 and HR = 1.11, 95% CI = 1.00–1.34, respectively]. Both 1–3 HLA-mm and 4–6 HLA-mm were associated with increased risk of ac-mortality compared with 0 HLA mm [hazard ratio (HR) = 1.12, 95%, Confidence Interval (CI) = 1.08–1.18) and (HR = 1.16, 95% CI = 1.09–1.22), respectively]. KTR's history of pre-transplant cancer, age 50–64, and >/=65 years were associated with increased risks of SOM and ac-mortality in all HLA mismatch cohorts. Pre-transplant dialysis >2 years, diabetes as the primary renal disease, and expanded or standard criteria deceased donor transplantation were risk factors for SOM in the 0 and 1–3 HLA-mm cohorts and of ac-mortality in all HLA-mm cohorts. KTRs male sex or history of previous kidney transplant was a risk factor for SOM in the 1–3 and 4–6 HLA-mm cohorts and of ac-mortality in all HLA-mm cohorts. ConclusionDirect association between SOM and the degree of HLA mismatching is equivocal and limited to the 4–6 HLA-mm stratum; however, the degree of HLA mismatching has significant modifying effects on the associations between specific nonpharmacologic risk factors and SOM in KTRs.

#5887 RESULTS OF KIDNEY TRANSPLANTATION IN VERY-HIGHLY SENSITIZED PATIENTS INCLUDED IN AN EXCHANGE PROGRAM BASED ON VIRTUAL CROSSMATCH

Abstract Background and Aims In 2012, a kidney transplant (KT) exchange program for very-highly sensitized patients (panel reactive antibody [PRA] ≥95%) began in Andalusia between the 5 KT centers based on virtual crossmatch. Method Retrospective cohort study of KT recipients within the Andalusian very-highly sensitized patients’ program from 2012 to December 2021. Survival was analyzed using Kaplan-Meier. We performed a multivariable analysis using Cox regression for pre-KT risk factors for graft survival. Results During the study period, 213 KT were performed. The median PRA was 98%. of them, 18.7% were KT from type-III non-heart-beating donors and 69.5% were retransplanted patients. The median time on renal replacement therapy until KT was 1509 days and, from their inclusion in the very-highly sensitized patients’ program, 334 days. The median post-KT follow-up time was 1103 days. Patient/graft survival was 97.5%/91.7% and 82%/76.5% at one year and 5 years, respectively. Graft survival was lower in patients who had received more than one KT (P = .029). However, we found no differences when comparing PRA (&amp;lt; or ≥98%) or type of donor. In the multivariable analysis, the number of previous KT was a predictor of graft loss. We had more detailed information on renal function and post-KT complications in patients from 3 centers (n=104). Six patients (5.7%) developed donor-specific antibodies (DSA) (1 class I, 3 class II, 2 class I and II) after a median of 267.5 days post-KT. Ten patients (9.3%) presented acute rejection (AR) diagnosed by biopsy: 4 T-cell-mediated rejection (3.7%) and 6 antibody-mediated rejection (5.6%). Active antibody-mediated chronic rejection (CR) was diagnosed in 5 patients and BK nephropathy in 2. Three graft losses were due to immunological causes (1 RA, 2 RC). Median renal function at one year was: Crp 1.3 mg/dl and glomerular filtration rate 55.1 ml/min. Conclusion Despite being a high-risk group, the survival results have been very satisfactory. The number of previous KT is a risk factor for graft survival.

#4251 KIDNEY TRANSPLANTATION WITH DONOR-SPECIFIC ANTIBODIES: A GROWING NEED

Abstract Background and Aims Preformed donor specific antibodies in kidney transplant (KT) recipients are associated with higher risk of antibody mediated rejection (ABMR) and poorer graft survival. However, remaining a long time on the waiting list is strongly related to worse patient outcomes. We aimed to analyze KT recipients with preformed DSA with mean intensity fluorescence (MFI) who received induction therapy adapted to their higher immunological risk. Method We conducted a cohort retrospective study. All KT with preformed DSA performed in our center since May 2010 until March 2021 were included in the analysis. The presence of DSA was evaluated through Luminex Single Antigen (SA®) technology. All KT were performed with cadaveric kidney donor and with previous negative test by CDC crossmatch. The induction therapy in the presence of DSA included steroids, thymoglobulin, rituximab, plasmapheresis and standard treatment with tacrolimus and mycophenolate. Results During the study period 27 KT with preformed DSA were carried out. Recipient median age was 49 (IQR 40-62) years and 70,2% were women. Dialysis vintage was 5.8 (IQR 2.3-10.2) years. 63% were blood group A and 29,5% blood group 0. 29.6% were also included in the Hypersensitized National Programme (PATHI). The main causes of sensitization were previous KT (55.6%), pregnancy (29.6%) and blood transfusions (3.7%). 63% received KT with preformed DSA class I (median MFI 2218) and 37% with preformed DSA class II (median MFI 1900). Median calculated PRA was 90.5% (IQR 80.6-98.3). Median follow up time was 32.5 (IQR 12.3-61.2) months. Seventeen kidney biopsies were carried out. The most frequent findings were acute tubular necrosis (35.3%) and active ABMR (23.5%). DSA disappeared in most of the cases in successive analysis (81%) without any differences between both DSA classes. Median serum creatinine was 1.25 (IQR 0.97-1.75) mg/dl at 12 months and 1.65 (IQR 1.1-1.81) mg/dl at 24 months. In the post-transplantation period 2 patients were diagnosed with malignant solid organ tumors, 3 developed BK nephropathy, 5 CMV asymptomatic reinfection, and 9 recurrent urinary tract infections. During the observation time, 8 grafts were lost (29.6%): 3 due to patient deaths with functioning grafts and 5 due to graft failure (3 chronic ABMR, 1 active ABMR and 1 BKV nephropathy). Graft survival was 98% and 12 months and 92% at 24 months, respectively. Conclusion DSA with MFI low levels must be considered as a risk factor of ABMR and not as a contraindication to perform KT. A reinforced induction immunosuppression therapy enables KT to patients with high immunological risk and avoid prolonged time on the waiting list.

#5256 REACTIVATION OF HEPATITIS B VIRUS IN KIDNEY TRANSPLANT RECIPIENTS WITH RESOLVED INFECTION: A SINGLE-CENTER EXPERIENCE

Abstract Background and Aims Patients with end-stage renal disease (ESRD) frequently present serologic evidence of previous contact with hepatitis B virus (HBV). Although uncommon, HBV reactivation after kidney transplantation (KT) may cause serious complications and adverse outcomes in these patients. However, data regarding risk factors for reactivation are still scarce. This study aims to describe a cohort of patients with resolved HBV infection who showed reactivation of the virus after KT. Method Retrospective cohort study including patients with resolved HBV infection who underwent KT between August 2007 and December 2021. Resolved HBV infection was defined as being seronegative to HB surface antigen (HBsAg) and seropositive to HB core antibody (HBcAb), regardless of HB surface antibody (HBsAb) status. HBV reactivation after KT was defined as seropositivity to HBsAg or presence of HBV-DNA in the serum (viraemia). Preemptive prophylactic entecavir was not used. Demographic and clinical data were collected from the electronic records. Results A total of 104 patients (70.2% male) were included with a mean age of 52±10 years. Prior to KT, 93.3% were seropositive to HBsAb. Seropositivity to other viruses was present in 18 patients: human immunodeficiency virus (HIV) alone in 5 patients, hepatitis C virus (HCV) alone in 11 patients and coinfection in 2 patients. Deceased-donor KT was performed in 94.2% and only 9 patients had had a previous KT. Rituximab was used as induction immunosuppressive therapy in 13 patients. Median follow-up time after KT was 75 months (IQR 37-115). HBV reactivation occurred in 6 patients with a median time after KT of 5 months (IQR 3-11.5). At reactivation diagnosis, median HBsAg titer was 83.2 (IQR 34-784.5; reference range &amp;lt; 1) and median viral load was 6.7 × 106 copies/mL (IQR 0.4 × 106-378 × 106). Only one patient presented seropositivity to HBsAg without viraemia. Half of these patients were seropositive to HBsAb prior to KT and became seronegative at reactivation diagnosis. No liver enzyme elevation was registered at reactivation diagnosis. Donor HBcAb status, coinfection with HIV or HCV, Rituximab use and recipient HBsAb status were not associated to HBV reactivation after KT. Two patients with HBV reactivation lost kidney graft function and 2 died during follow-up. Conclusion Hepatitis B virus reactivation is possible after kidney transplantation and may pose major adjustments to the treatment, namely the immunosuppressive therapy. Careful monitoring of hepatitis B virus serology and viraemia could be particularly useful in early diagnosis and prompt approach to its reactivation. Larger and multi-center studies are warranted to identify specific risk factors in this population and prevent reactivation.

#6858 GRAFT SURVIVAL IN MULTIPLE KIDNEY TRANSPLANT RECIPIENTS FROM CHILDHOOD TO ADULTHOOD: AN ERA STUDY FROM 1978 UNTIL 2019

Abstract Background and Aims Knowledge regarding graft survival after transplantation in European children with multiple kidney transplants followed from childhood into adulthood including factors affecting these outcomes is lacking. Method Using ERA Registry data, we investigated all patients on kidney replacement therapy (KRT) who received their first kidney transplant (KT) before 20 years of age between 1978 and 2019. Graft survival after first, second and third KT were studied alongside their risk factors, using Kaplan-Meier survival analysis and multivariable Cox regression models. Results Among 10012 paediatric KT candidates, 8601, 1962 and 412 received at least one, two and three KTs. Graft survival at 5 and 10 years was 80.6% and 65.7% for first KTs, 71.3% and 53.7% for second KTs and 67.1 and 49.5% for third KTs. Factors associated with increased graft failure risk were having glomerulonephritis or a recurrent disease as cause of kidney failure for first KT recipients (aHR 1.24, 95%CI 1.12-1.37 and aHR 1.24, 95%CI 1.13-1.37, respectively). Patients whose first KT lifespan was between 0–30 days or more than 5 years presented lower graft failure risks regarding their second KT compared to patients whose KT survived between 1–5 years (aHR 0.79, 95%CI 0.64-0.98 and aHR 0.73, 95%CI 0.61-0.88, respectively). Similar results were found for third KT recipients whose second KT lived for more than 5 years (aHR 0.61, 95%CI 0.41-0.92). Patients who were transplanted for the first and second time before 2007 presented a higher graft failure risk compared to patients who received their KT between 2016–2019 (aHR 2.09, 95%CI 1.65-2.65 and aHR 1.63 95%CI 1.29-2.06 for the transplantation era before 2000 and between 2000–2007 concerning the first KT; and aHR 1.69, 95%CI 1.15-2.47 and aHR 1.51, 95%CI 1.06-2.16, respectively for the era before 2000 and between 2000–2007 concerning the second KT). Pre-emptive KTs presented less graft failure compared to patients who received dialysis &amp;gt; 1 year for first and second KT (aHR 0.89, 95%CI 0.81-0.98 and aHR 0.63, 95%CI 0.51-0.78,respectively). Patients having received a LD KT had less chances for graft failure for first and second KT (aHR 0.77, 95%CI 0.7-0.84 and aHR 0.71 (0.6-0.85, respectively). Having a second LD KT (no matter the donor type for first KT) was advantageous compared to having a second DD. Conclusion Graft outcomes after pediatric kidney (re)transplantation have improved significantly over time for all recipient subgroups, especially for patients with LD KT, longer previous KT lifespan and pre-emptive KT. Patients with GN and recurrent diseases as causes of their kidney failure showed the poorest outcomes, highlighting the need for continued progress in this field.

#4264 PERITONEAL DIALYSIS AFTER FAILED KIDNEY TRANSPLANT: A SUITABLE OPTION

Abstract Background and Aims Despite great advances in graft survival, kidney transplant (KT) recipients frequently return to dialysis. The aim of this study was to perform an analysis of peritoneal dialysis (PD) outcomes of patients with a failed KT. Method Single-center retrospective cohort study with end-stage renal disease (ESRD) patients who started PD from 1st January 2010 to 31st December 2017. Two groups were analyzed - patients who started PD with no previous renal replacement therapy (RRT) - PD first -, and patients who transitioned directly from a failed kidney transplant. Results Among 152 patients who started PD, 115 were PD first and 15 transitioned from KT. The population included 63,1% of male gender, with a mean age of 52,4 ± 15,5 years and had PD median vintage of 30 months (IQR 20,6). Patients who transitioned from KT were significantly younger (mean age 42,8 ± 14,3 vs. 53,7 ± 15,3, p = 0,015) and had lower prevalence of diabetes mellitus (13,3% vs. 40,0%, p = 0,044). In KT patients, glucocorticoids were continued until there was residual diuresis and non-glucocorticoid immunosuppression was maintained for a median of 180 days (± 176) after PD start. Nearly a third (30,0%) of patients had no hospitalizations and 35,5% had more than 2 hospital admissions. Annual hospitalization rate was higher in prior KT group (1,40 vs. 0,48, p = 0,002). Prior KT associated with higher annual peritonitis rate (0,70 vs. 0,20, p = 0,017). A higher number of MACE was also observed in prior KT group (33,3% vs. 7,9%, p = 0,004). Residual diuresis was significantly lower in the group with previous KT. Neither ultrafiltration failure (6,7% vs. 9,9%, p = 0,974), nor technique survival (death or hemodialysis transfer 53,3% vs. 54,8%, p = 0,917; logrank 0,354) were different between groups. Conclusion Although higher incidence of diabetes mellitus was observed in PD first group, no differences were identified in ultrafiltration failure rates between groups. Despite significantly lower diuresis in prior KT group, both groups had adequate dialysis efficacy (mean Kt/V&amp;gt;1,7) and similar technique survival. Higher peritonitis rate and MACE incidence was observed in prior KT group, possibly associated with maintenance immunosuppression. Nevertheless, PD is a valid choice for RRT after a failed KT and should be offered to these patients.

#4445 ANAEMIA MANAGEMENT IN PERITONEAL DIALYSIS: FROM GUIDELINES TO ROUTINE CLINICAL PRACTICE

Abstract Background and Aims The evidence on the management of renal anemia in peritoneal dialysis (PD) is much weaker than in hemodialysis (HD). Current guidelines establish the same haemoglobin (Hb) target for patients under eritropoietin stimulating agents (ESAs) in both dialysis techniques (PD, HD), although patients in PD are usually younger, more active and lesss comorbid. Unfortunately, there is not randomized controlled trials evaluating the efficacy and safety the effect of different Hb target on clinical outcomes. The aim is to describe the current situation of anaemia prevalence, treatments, and achievement of clinical guidelines recommendations in this population. Method Retrospective nationwide multicenter study including patients from 19 PD units. All prevalent PD patients that were active in the technique in November 2019 for at least 3 months was included (to avoid COVID pandemic interferences). Exclusion criteria were a previous kidney transplant failure and being on PD due to a cardiorenal syndrome with a residual renal function over 20 ml/min/1.73 m2. The nephrologists collected baseline data, demographics, comorbidities, and data related to anemia management (ie, laboratory values, previously prescribed treatments, and subsequent adjustments) from electronic medical records. The European adaptation of KDIGO guidelines was the reference for iron and Hb limits, prescriptions and targets. Results A total of 343 patients (mean age 62.9 years, 61.2% male) were included. Regarding anaemia-treatment prescription, 72.9% were receiving ESAs and 33.2% iron therapy (20.7% intravenously-IV and 12.5% orally). Eighty-two (32.8%) patients were receiving ESA without iron therapy, despite to have an indication to do it according ERBP guidelines in 53 out of them. After knowing lab results, iron therapy was only started in 8 (15%) patients. Among ESA-treated patients, 58.8% had an optimal control (Hb 10–12 g/dl). Seventeen patients had haemoglobin over 13 g/dl, and 12 of them continued receiving ESA after knowing lab results. Only three patients had persistent haemoglobin &amp;lt;10 g/dl. Seven patients (2%) met criteria for ESA resistance (epoetin dose &amp;gt;300 IU/kg/week). Patients in the highest tertile of erythropoietin resistance index (ERI) (&amp;gt;6.3 UI/kg/week/g/dl) were more inflamed, had lower albumin levels and lower residual renal function. Conclusion Anaemia prevalence is high in this population and its management in PD Units could be improved according to the ERBP guidelines. The lack of iron therapy in patients who should have received it and the excessive tolerance to high Hb levels are the most relevant opportunities to improve compliance with clinical guidelines.

Patient level factors increase risk of acute kidney disease in hospitalized children with acute kidney injury.

Studies in adults have shown that persistent kidney dysfunction ≥7-90 days following acute kidney injury (AKI), termed acute kidney disease (AKD), increases chronic kidney disease (CKD) and mortality risk. Little is known about the factors associated with the transition of AKI to AKD and the impact of AKD on outcomes in children. The aim of this study is to evaluate risk factors for progression of AKI to AKD in hospitalized children and to determine if AKD is a risk factor for CKD. Retrospective cohort study of children age ≤18 years admitted with AKI to all pediatric units at a single tertiary-care children's hospital between 2015 and 2019. Exclusion criteria included insufficient serum creatinine values to evaluate for AKD, chronic dialysis, or previous kidney transplant. A total of 528 children with AKI were included in the study. There were 297 (56.3%) hospitalized AKI survivors who developed AKD. Among children with AKD, 45.5% developed CKD compared to 18.7% in the group without AKD (OR 4.0, 95% CI 2.1-7.4, p-value <0.001 using multivariable logistic regression analysis including other covariates). Multivariable logistic regression model identified age at AKI diagnosis, PCICU and NICU admission, prematurity, malignancy, bone marrow transplant, previous AKI, mechanical ventilation, AKI stage, duration of kidney injury, and need for kidney replacement therapy during day 1-7 as risk factors for AKD after AKI. AKD is common among hospitalized children with AKI and multiple risk factors are associated with AKD. Children that progress from AKI to AKD are at higher risk of developing CKD. A higher resolution version of the Graphical abstract is available as Supplementary information.

Risk Factors for a Failed Transmetatarsal Amputation in Patients with Diabetes.

Transmetatarsal amputation (TMA) is a well-recognized limb-salvage procedure, often indicated for the treatment of diabetic foot infections. Currently, there is no widespread agreement in the literature with regard to the factors associated with failure of TMA. This study aimed to define risk factors for the failure of TMA, defined as below-the-knee or above-the-knee amputation, in patients with diabetes. This retrospective cohort study included 341 patients who underwent primary TMA. Patients who had a revision to a higher level (the failed TMA group) were compared with those who did not have failure of the initial amputation (the successful TMA group). This study showed a higher frequency of renal impairment, defined as a high creatinine level and/or a previous kidney transplant or need for dialysis, in the failed TMA group (p = 0.002 for both). Furthermore, a Charlson Comorbidity Index (CCI) threshold value of 7.5 was identified as the optimal predictive value for failure of TMA (p = 0.002), and patients with a CCI of >7.5 had a median time of 1.13 months until the initial amputation failed. TMA is associated with a high risk of revision. CCI may be used as a preoperative selection criterion, as 71.8% of patients with a CCI of >7.5 had failure of the TMA. Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Pyogenic liver abscesses in liver transplant recipients versus non-transplant population. Outcome and risk factors of patient survival.

Pyogenic liver abscess (PLA) is a life-threatening infection in both liver transplant (LT) and non-LT patients. Several risk factors, such as benign and malignant hepatopancreatobiliary diseases and colorectal tumors have been associated with PLA in the non-LT population, and hepatic artery stricture/thrombosis, biliary stricture, and hepaticojejunostomy in the LT patients. The objective of this study is to compare the outcomes of patients with PLA in LT and non-LT patients and to determine the risk factors associated with patient survival. From January 2000 to November 2020, a total of 296 adult patients were diagnosed of PLA in our institution, of whom 26 patients had previously undergone liver transplantation (LTA group), whereas 263 patients corresponded to the non-LTA population. Seven patients with PLA who had undergone previous kidney transplantation were excluded from this retrospective study. Twenty-six patients out of 1503 LT developed PLA (incidence of 1.7%). Median age was significantly higher in non-LTA patients (p=.001). No significant differences were observed in therapy. PLA recurrence was significantly higher in LTA than in non-LTA (34.6% vs. 14.8%; p=.008). In-hospital mortality was greater in the LT group than in the non-LT group (19.2%vs. 9.1% p=.10) and was identified in multivariable analysis as a risk factor for mortality (p=.027). Mortality rate during follow-up did not show significant differences between the groups: 34.6% in LTA patients versus 26.2% in non-LTA patients (p=.10). The most common causes of mortality during follow-up were malignancies, Covid-19 infection, and neurologic disease. 1-, 3-, and 5-year actuarial patient survival rates were 87.0%, 64.1%, and 50.4%, respectively, in patients of LTA group, and 84.5%, 66.5%, and 51.0%, respectively, in patients with liver abscesses in non-LTA population (p=.53). In conclusion, LT was a risk factor for in hospital mortality, but not during long-term follow-up.

Immune Response to COVID-19 mRNA Vaccination in Previous Nonresponder Kidney Transplant Recipients After Short-term Withdrawal of Mycophenolic Acid 1 and 3 Months After an Additional Vaccine Dose.

The impaired immune response to coronavirus disease 2019 (COVID-19) vaccination in kidney transplant recipients (KTRs) leads to an urgent need for adapted immunization strategies. Sixty-nine KTRs without seroconversion after ≥3 COVID-19 vaccinations were enrolled, and humoral response was determined after an additional full-dose mRNA-1273 vaccination by measuring severe acute respiratory syndrome coronavirus 2-specific antibodies and neutralizing antibody activity against the Delta and Omicron variants 1 and 3 mo postvaccination. T-cell response was analyzed 3 mo postvaccination by assessing interferon-γ release. Mycophenolic acid (MPA) was withdrawn in 41 KTRs 1 wk before until 4 wk after vaccination to evaluate effects on immunogenicity. Graft function, changes in donor-specific anti-HLA antibodies, and donor-derived cell-free DNA were monitored in KTRs undergoing MPA withdrawal. Humoral response to vaccination was significantly stronger in KTRs undergoing MPA withdrawal 1 mo postvaccination; however, overall waning humoral immunity was noted in all KTRs 3 mo after vaccination. Higher anti-S1 immunoglobulin G levels correlated with better neutralizing antibody activity against the Delta and Omicron variants, whereas no significant association was detected between T-cell response and neutralizing antibody activity. No rejection occurred during study, and graft function remained stable in KTRs undergoing MPA withdrawal. In 22 KTRs with Omicron variant breakthrough infections, neutralizing antibody activity was better against severe acute respiratory syndrome coronavirus 2 wild-type and the Delta variants than against the Omicron variant. MPA withdrawal to improve vaccine responsiveness should be critically evaluated because withdrawing MPA may be associated with enhanced alloimmune response, and the initial effect of enhanced seroconversion rates in KTRs with MPA withdrawal disappears 3 mo after vaccination.

Patient and graft survival in pancreas transplant recipients: The EFISPAN study

Introduction and objectivesGraft outcomes in pancreas transplantation have improved in recent decades, but data are mainly derived from registries or prospective single-centre studies. This large epidemiological study was undertaken to investigate the impact of clinical and demographic factors on graft and patient survival in pancreas transplant recipients in Spain, and to provide robust, country-wide, practice-based data to complement registry findings. Patients and methodsWe conducted a retrospective, longitudinal, epidemiological study to assess risk factors impacting patient and graft survival in pancreas transplant recipients in eight centres in Spain. All patients transplanted between 1 January 2008 and 31 December 2012 were included; data were collected until 31 December 2015. The Kaplan–Meier method was used for all time-to-event analyses, including patient survival, graft survival, acute rejection, and BPAR. For graft survival analysis, in cases of death with functioning graft, patients were censored without any event on the date of death. For acute rejection and BPAR, patients were censored without any event on the date of death or graft loss. Univariable and multivariable analyses (Cox proportional hazards model) were conducted to assess the association between baseline clinical and demographic characteristics and patient/graft survival. ResultsData were included for 241 (80.1%) simultaneous pancreas-kidney transplants, 56 (18.6%) pancreas-after-kidney transplants and 4 (1.3%) pancreas transplants alone. Mean±standard deviation time from diagnosis until transplantation was 26.1±7.5 years. Nineteen patients died, mainly due to infections (n=10); the remaining 282 patients (93.7%) survived from transplantation until the end of the study. Among 55 patients (18.3%) with pancreas graft loss, the main reasons were vascular thrombosis (n=19), chronic rejection (n=10), acute rejection (n=6) and death with a functioning graft (n=5). The overall rate of vascular-related death was 1.3% at 5 years post transplant. Univariable analysis showed that patient age and weight, donor age, previous kidney transplantation, previous cardiovascular events and need for insulin more than 48h post transplantation were significantly associated with pancreas graft survival. Of these, in multivariable analyses pancreas graft survival was inferior in patients who had received a previous kidney transplant prior to pancreas transplantation (log-rank test, p=0.0002). Glucose metabolism, renal function and cardiovascular risk factors were generally stable following transplantation. ConclusionsThe results of this multicentre study highlight the excellent patient and graft outcomes following pancreas transplantation, with a notably low incidence of cardiovascular events.

Naïve T Cell-Depleted Hematopoietic Graft Combined with Solid Organ Transplantation As Strategy to Induce Tolerance By Transient Mixed Chimerism

BACKGROUND The major challenge of solid organ transplantation (SOT) is to prevent graft rejection. The chronic use of pharmacological immunosuppression has been associated with increased rates of infection, cardiovascular, metabolic, endocrine disorders, and cancer. The induction of chimerism by donor hematopoietic stem cell transplantation (HSCT) together with SOT is an active tolerance induction approach. Here, we present a new model for inducing transient mixed chimerism in 2 patients undergoing SOT employing a non-myeloablative conditioning (NMA) regimen and a partially T cell-depleted (TCD) graft consisting of CD34+ hematopoietic progenitor cells and CD45RA− memory lymphocytes. METHODS SOT and HSCT were performed at University Hospital La Paz, Madrid. Bone marrow harvesting was performed on the iliac crest and lumbar and dorsal vertebrae of the deceased donor for patient#1 and mobilized leukoapheresis from sibling donor for patient#2. First we obtained the enriched by CD34+ selection using the CliniMACS system (Miltenyi Biotec) and afterwards the CD45RA− cells were purified. Lineage-specific chimerism analysis was analyzed using quantitative real-time polymerase chain reaction. Immune cell recovery was monitored by multiparametric flow cytometry. We obtained the permission of the Organización Nacional de Trasplantes and the informed consent was obtained from the patient and donor and/or caregivers. RESULTSPatient 1 A 15-year-old boy was diagnosed with intestinal epithelial dysplasia in 2008. After two previous intestinal and multivisceral acute cellular rejections forced a third MVT. With the imptemption to induce donor tolerance, a T cell-depleted bone marrow graft from the same deceased donor was employed. Bone marrow harvesting was performed obtaining a total volume of 141 ml with 4x109 total nucleated cells. Peripheral blood was obtained after unclasping the thoracic aorta. The stem cell fraction from bone marrow was enriched by CD34+ selection, obtaining 8.75x105/kg CD34+cells/kg. Memory lymphocytes were purified and aliquots containing 1x106/kg CD3+CD45RO+ and 2.1x104/kg CD3+CD45RA+ T cells. Both products were cryopreserved. The conditioning regimen before HSCT included fludarabine and cyclophosphamide. On day 88 after MVT, we infused all the CD34+ cells and 1x106/Kg CD3+CD45RO+ T cells. The CD3+CD45RO+ T cells were also infused periodically on a monthly basis for 1 year. Donor chimerism in CD3+ T cells ranged from 0.05 to 5.1 during the first year after HSCT. We observed a peak of the percentage of regulatory T cells (Tregs). No degree of graft-versus-host disease (GvHD) was observed, and the patient became independent of total parenteral and enteral nutrition. Serial follow-up intestinal biopsies did not show any sign of immune rejection. The patient continued to receive sirolimus to maintain drug concentrations at 6 ng/ml as the only immunosuppression treatment. No signs of rejection were detected after 27 months of follow-up. Patient 2 A 49-year-old woman was diagnosed with chronic kidney failure secondary to rapidly progressive glomerulonephritis. The patient had received 3 previous kidney transplants from deceased donors. A kidney transplant from her sibling was performed in March 2021. Hematopoietic progenitor cells were obtained from mobilized peripheral blood leukapheresis. A NMA conditioning regimen employing total lymphoid irradiation (8 Gy) with antithymocyte globulin (7.5 mg/kg). Two weeks after the kidney transplantation, we infused a graft consisting of 1.27x107/kg CD34+, 4.43x106/kg CD3+CD45RO+, and 5x104/kg CD3+CD45RA+ cells. Controls for hematopoietic chimerism demonstrated the presence of transient mixed hematopoietic chimerism during the first 2 months after SOT of between 0.1% and 40% CD3+ cells. The patient continued on monotherapy with tacrolimus. Immune reconstitution analysis showed a Treg peak. The patient did not have acute rejection, GvHD, viral reactivations or episodes of bacterial infection during the 17 months of follow-up. CONCLUSIONS We describe for the first time the use of non-myeloablative conditioning and a CD45RA− T cell-depleted graft to induce transitory mixed chimerism using both hematopoietic progenitors and a solid organ coming from the same donor, for tolerance induction purposes. The patients continue to progress favorably 17 months or more after SOT, receiving immunosuppressive monotherapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal