Intravenous immunoglobulins (IVIG) are commonly used in peri-transplant desensitization, but evidence supporting their efficacy is limited. We conducted a prospective, randomized single-center, open-label, Phase IIIb non-inferiority clinical pilot trial to compare the efficacy of IVIG (administered at a dose of 3 × 0.5 g/kg) versus no IVIG, in conjunction with rabbit anti-thymocyte globulin (5–7 mg/kg) induction, in pre-sensitized patients with donor-specific antibodies who had negative pre-transplantation Flow- and CDC-crossmatches, between July 2020 and November 2022. The primary endpoint was the rate of efficacy failure, defined as biopsy-proven rejection within 12-month post-transplant. Secondary endpoints included the incidence of rejection at protocol biopsies, evaluated by histology and biopsy-based transcripts diagnostics. Of the screened patients, 53 (72.6%) were excluded due to crossmatch positivity. Ten patients were randomized to the IVIG+, and 7 to the IVIG-arm. The trial was prematurely terminated due to futility at interim analysis. In the IVIG-arm, 3 patients (43%) experienced the primary endpoint compared to none in the IVIG+ arm (p = 0.026). MMDx identified one molecular ABMR in the IVIG+ and 2 in the IVIG-arm in 12-month protocol biopsies. There was one graft loss in the IVIG-arm. The results of this pilot study, although not definitive, do not support the use of IVIG-sparing regimens in HLA-incompatible kidney transplantation (NCT04302805).This study is registered on ClinicalTrials.gov under the identifier NCT04302805.

BACKGROUND: Despite a sharp rise in kidney graft short-term survival rates and better donor-recipient HLA matching, mid- and long-term survival have not sufficiently improved over the past decades. Several studies suggest that non-HLA factors could be involved in kidney allograft injury, but no validated marker has yet been identified. Here, we aimed at finding genetic variations and mismatches associated with graft function and survival. METHODS: Using genome-wide strategies, we tested the recipients' and donors' common variations (SNPs and CNVs), and the donor-recipient genetic mismatches for association with 1-year kidney graft function and with time-to-death-censored kidney graft failure in a monocentric European cohort of 1,482 complete donor-recipient pairs. We validated our findings through a meta-analysis in two independent European cohorts gathering a total of 1,842 additional complete pairs. RESULTS: We did not identify any significant association with 1-year graft function. However, we discovered four non-HLA mismatches (3 SNPs and 1 CNV) associated with time-to-kidney graft failure. One signal in a regulatory region upstream the TOM1L1 gene (p = 6.3 × 10−9, HR = 4.1) was successfully replicated in the validation cohorts (pmeta-analysis = 6.7 × 10−9, HR = 2.9) and ranked among the top 50 rejection-specific genes in a pan-organ transcriptomics study. This locus was also associated with time-to-cellular and humoral rejection (p = 0.02) in the discovery cohort in patients achieving primary graft function. CONCLUSIONS: By running one of the largest ever performed kidney transplantation genomic analyses, we identified and confirmed a novel donor-recipient genetic mismatch in a biologically relevant non-HLA locus associated with kidney allograft failure. ### Competing Interest Statement PA Gourraud is the founder of Methodomics (2008) and the co-founder of Big data Santé (2018). He consults for major pharmaceutical companies, and start-ups, all of which are handled through academic pipelines (AstraZeneca, Biogen, Boston Scientific, Cook, Docaposte, Edimark, Ellipses, Elsevier, Janssen, IAGE, Lek, Methodomics, Merck, Mérieux, Octopize, Sanofi-Genzyme, Lifen, Aspire UAE). PA Gourraud is a volunteer board member at AXA not-for-profit mutual insurance company (2021). He has no prescription activity with either drugs or devices. He receives no wages from these activities. ### Funding Statement The KiT-GENIE cohort has been funded by several entities: (1) The Étoiles Montantes funding by the Pays de la Loire region (n°2018-09998), (2) The IRCT Dialyse research project by the Société Francophone de Néphrologie, Dialyse et Transplantation (SFNDT), (3) The Greffe research project by French Agence de la Biomédecine (ABM, n°18GREFFE014). In addition, this work has benefited from government support through the National Research Agency (ANR) under the future investment program (n°ANR-17-RHUS-0010) and from the European Union’s Horizon 2020 Research and Innovation Programme (n°754995). This work was supported by Nantes Métropole, Région des Pays de la Loire and European Union (FEDER) via the Programme d'investissements d'Avenir (NExT, SHLARC Project, Nantes Université). Finally, we thank the Roche Pharma, Novartis, Astellas, Chiesi, Sandoz and Sanofi laboratories for supporting the DIVAT cohort as the CENTAURE Foundation (http://www.fondation-centaure.org). This research has been conducted as part of the AIby4 project (AI by/for Human, Health and Industry), funded by Centrale Nantes and the French Ministry of Education and Research and the French National Research Agency (ANR-20-THIA-0011). The UKIRTC was supported by grants awarded from the Wellcome Trust (090355/A/09/Z, 090355/B/09/Z and 088849/Z/09/Z, “WTCCC3”), the Medical Research Council (grants G0600698 and MR/J006742/1 to S.H.S.; G0802068 to G.M.L. and MR/K002996/1 to G.M.L; grants G0801537/ID: 88245), Guy's and St Thomas' Charity (grants R080530 and R090782) to M.H.F. and G.M.L., from the European Union FP7 (grant agreement no HEALTHF5–2010–260687 to M.H.F. and project number 305147: BIO-DrIM to M.H.F. and I.R.M.); and by the National Institute for Health Research Biomedical Research Centre at Guy's and St Thomas' and King's College London. The Prague cohort was co-funded by the Ministry of Health of the Czech Republic under grant NU21-06-00021. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Written consent was obtained from each participant for access to clinical data and participation to DNA analyses (DIVAT nb CNIL 914184). Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research. The UKIRTC was approved (or granted exemption) by the appropriate institutional and/or national research ethics committee which was the Hammersmith and Queen Charlotte′s & Chelsea Research Ethics Committee REC No 08/H0707/1. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The GWAS aggregated data analyzed during the current study will be available for scientific review from the corresponding author upon reasonable request from the GWAS Catalog (GCP001044). Regarding subjects′ personal data under the responsibility of the sponsor, those data will be available for scientific review under the conditions defined by the EU General Data Protection Regulation. A data transfer agreement shall be signed with the sponsor defining the scope of the data transfer, as required by the GDPR and including an obligation to use the data for the sole purpose of the scientific review and forbidding their disclosure to third parties.

Background. Booster doses of SARS-CoV-2 mRNA vaccines are commonly used in kidney transplant recipients (KTRs). However, there is uncertainty regarding the waning of vaccination responses and immunological safety in KTRs. Methods. A total of 123 KTRs were included in the final analysis of this prospective observational cohort study. The aim was to evaluate the immunogenicity and immunological safety. SARS-CoV-2 antispike IgG antibodies and anti-HLA antibodies were measured at baseline and then at months 3, 6, and 12 after vaccination with the first booster dose (ie, the third vaccine dose). Antibodies against S1 and S2 subunits of SARS-CoV-2 were evaluated using an immunochemiluminescent assay (cutoff 9.5 AU/mL, sensitivity 91.2%, and specificity 90.2%). Anti-HLA antibodies were analyzed using single-antigen bead technology. Results. Seroconversion was reached in 65% of KTRs previously nonresponding to 2-dose mRNA vaccination; the overall seroconversion rate 3 mo after the first booster dose was 83%. Vaccination induced a durable humoral response, and the antibody levels were stable during the 12-mo study follow-up. Higher age (exponentiated beta coefficient [eβ] 0.97; 95% confidence interval [CI], 0.943-0.997) and a full dose of mycophenolate (eβ 0.296; 95% CI, 0.089-0.984) were negatively associated with SARS-CoV-2 IgG antibody levels, whereas better graft function (eβ1.021; 95% CI, 1.005-1.037) was associated positively. There were no systematic signs of anti-HLA antibody development after vaccination. However, during the follow-up, there was a nonsignificant signal of an increase in anti-HLA antibodies in those who developed COVID-19. Conclusions. Additional booster doses of SARS-CoV-2 mRNA vaccines induce durable antibody response even in a large subset of previous nonresponders and are not associated with the risk of allosensitization. Furthermore, a signal linking COVID-19 to the development of anti-HLA antibodies was observed, and this should be confirmed and further examined (NCT05483725).

Presensitized patients with donor-specific antibodies (DSAs) are at increased risk of antibody-mediated rejection (AMR) of kidney allografts.1 The long-term consequences of AMR are serious because currently available therapeutic options lack lasting effectiveness.2 Targeting plasma cells to counter antibody production may hold promise for treating AMR.3 Daratumumab is a fully humanized monoclonal antibody directed against CD38, a glycoprotein expressed at high levels on plasma cells and, in addition, natural killer cells, which are suggested to act as effector cells in AMR.4,5 Several case reports suggested its efficacy in the treatment of AMR in patients with and without multiple myeloma.6-8 Timing of such therapy is of significant concern because serum creatinine alone cannot distinguish subclinical injury, and innovative tools are necessary for more precise diagnostics. Here, we describe a case of severe DSA rebound associated with subclinical AMR by histology and molecular assessments effectively reversed by a 6-mo course of daratumumab. CASE DESCRIPTION The patient is a 55-y-old man who has undergone fourth kidney transplantation in November 2022. The deceased brain death donor was a 61-y-old man with well-preserved kidney function (estimated glomerular filtration rate [eGFR]: 2.4 mL/s). Despite a high level of sensitization (calculated panel-reactive antibody 91%), there was only a single anti-HLA class II DSA present (specificity: DQA1*01:02/DQB1*06:02; mean fluorescence intensity [MFI]: 4200). Both actual cytotoxic and flow T and B crossmatch were negative. A detailed description of the HLA typing of all donors and recipient is given in Table S1 (SDC,https://links.lww.com/TXD/A680). A single plasma exchange immediately before surgery was performed for desensitization. A single intravenous dose of alemtuzumab (30 mg) was applied perioperatively as induction (Figure 1A). Peritransplant desensitization included 5 plasma exchanges every other day, along with a high dose of IVIG (2 g/kg in total).9 For maintenance immunosuppression, tacrolimus (target trough level 8–12 µg/L), mycophenolate mofetil (2000 mg), and tapered prednisone were administered. Infection prophylaxis consisted of valganciclovir and trimethoprim/sulfamethoxazole. Graft function developed immediately (Figure 1B).FIGURE 1.: Clinical course of the case. A, Therapy during the follow-up. B, Renal function. C, DSAs. DSA, donor-specific antibody; eGFR, estimated glomerular filtration rate; MFI, mean fluorescence intensity.At postoperative day (POD) 9, Luminex-based single antigen testing revealed a substantial increase in anti-HLA reactivity. Specifically, a significant rebound of the preformed donor-specific anti-DQA1*01:02/DQB1*06:02 (16 000 MFI) was noticed along with the presence of 3 different DSA-targeting DR antigens (DRB1*12:02, DRB5*01:01 and DRB3*02:02, maximum MFI 4600; Figure 1C). Tacrolimus trough levels exceeded the target range (18.4 µg/L). On POD 12, acute tubular necrosis without microvascular inflammation (MVI) or capillary C4d staining was present in the graft biopsy (Figure 2A1). However, Molecular Microscope Diagnostic System (MMDx) assessment showed a finding of moderate early stage AMR (Figure 2A2 and A3). Serum creatinine at the time of biopsy was 210 µmol/L and tacrolimus trough levels 12 µg/L. Donor-derived cell-free DNA (dd-cfDNA; Prospera) testing revealed a profound level of graft injury, with fractions increasing to 3.21% (negative result defined as <1%). Clearly, early after transplantation, the dd-cfDNA assessment cannot rule out other peritransplant injuries. However, considering the presence of molecular AMR and DSA rebound, we planned the administration of rituximab (1 g) on top of the induction protocol. However, its administration was complicated by a serious allergic reaction, and patient thus received a steroid bolus. The patient was discharged home with a serum creatinine of 165 µmol/L (eGFR of 0.66 mL/s). Another dd-cfDNA assessment at POD 30 revealed an ongoing allograft injury (7.97%) despite stable kidney graft function.FIGURE 2.: Histologic (A1, B1, C1) and MMDx results (A2, A3, B2, B3, C2, C3, D1, and D2) of index and surveillance biopsies. Histopathologic examination revealed acute tubular necrosis in the first biopsy, active AMR in the second biopsy (glomerulitis shown by red circles), and resolution of g and remaining mild ptc only (shown by a red circle) in the third biopsy. Biopsies assignments to specific rejection and injury archetypal phenotypes, as defined by MMDx-based analysis, are depicted (yellow triangles) in PC plots (PC1 vs PC2) based on a reference set of 5087 biopsies.10 Colored circles indicate the locations of 6 rejection archetype centers: R1: no rejection; R2: TCMR1; R3: TCMR2; R4: early-stage AMR; R5: fully developed AMR; R6: late-stage AMR; R7, minor AMR and 6 injury archetype centers—R1: normal; R2: AKI1; R3: AKI2; R4: CKD; R5: CKD/AKI; and R6: Minor CKD. The development of molecular scores between index and follow-up biopsies. D1, Rejection classifier scores. D2, Injury scores. Dashed lines, molecular scores for particular Banff histologic lesions. AKI, acute kidney injury; AMR, antibody-mediated rejection; cg, transplant glomerulopathy; CKD, chronic kidney disease; g, glomerulitis; i, interstitial inflammation; MMDx, Molecular Microscope Diagnostic System; PC, principal component; ptc, peritubular capillaritis; t, tubulitis; TCMR, T cell–mediated rejection.At POD 90, a surveillance biopsy revealed considerable MVI (glomerulitis [g2] and peritubular capillaritis [ptc2]), suggesting morphologic AMR activity (Figure 2B1). MMDx showed severe fully developed AMR (Figure 2B2 and B3). The immunodominant DSAs against DQA1*01:02/DQB1*06:02 remained consistently elevated (15 000 MFI). Tacrolimus level was 10.5 µg/L, and virology screening revealed BK virus replication (23 000 copies/ mL); however, the biopsy did not show features of polyomavirus nephropathy and graft function remained stable. As a consequence, mycophenolate mofetil was transiently reduced to 500 mg/d. Based on the ongoing presence of class II DSAs, worsening of histological and molecular features of AMR, and positive dd-cfDNA, we initiated rescue treatment with daratumumab at POD 115 when the BK virus plasma load decreased. Daratumumab was given subcutaneously (1800 mg/dose) 11 times during a period of 6 mo. Initially, the daratumumab dose was given every week 4 times, followed by every other week 5 times and finally monthly 2 times (Figure 1A). A second surveillance biopsy was performed at POD 282, coinciding with the last daratumumab dose. The extent of MVI (g0, ptc1) was below the diagnostic criteria for definite AMR (Figure 2C1). MMDx analysis indicated complete resolution of rejection-related scores (Figure 2C2 and C3). The current graft function is stable (eGFR of 0.8 mL/s), and the dd-cfDNA test performed 1 y after transplantation yielded a negative result (0.08%). There were no rehospitalizations for infection complications, but 1 month after completion of treatment, the patient did experience a mild COVID-19 disease treated with remdesivir. During daratumumab treatment, DSA levels declined, eventually reaching positivity thresholds, and remained negative until the last measurement at POD 421 (Figure 1C). The changes in DSA levels were accompanied by a substantial decrease in levels of non-DSA HLA antibodies. Detailed descriptions of molecular assessments of kidney allograft on days 12, 90 and 285 are given in Figure 2A–D. DISCUSSION Despite the high risk of AMR, HLA-incompatible transplantation may remain the only chance for transplantation for some patients if acceptable mismatch programs are not available or a long waiting time for a compatible graft is not realistic. Our case suggests the efficacy of targeting CD38 to counter active AMR and points out the critical role innovative diagnostic methods have in HLA-incompatible transplantation. The kidney transplantation was performed across low levels of preformed anti-HLA DQ reactivity associated with the negative flow and cytotoxic crossmatches before surgery. Despite desensitization, we detected molecular features of AMR, which were associated with DSA rebound early posttransplantation. In AMR, molecular assessment may be a more precise diagnostic option than conventional histology,11,12 particularly in HLA-incompatible kidney transplantation when patients receive profound induction immunosuppression, which mitigates but does not definitely alter the alloimmune response. MMDx has been implemented in US transplant centers and is currently available in our center for routine assessments. Daratumumab was given as a salvage therapy at 3 mo when DSA levels persisted unchanged, surveillance biopsy confirmed AMR by both histology and MMDx, and dd-cfDNA indicated profound injury. The prognosis of such a graft was considered to be poor despite a mostly subclinical presentation of rejection. A total daratumumab dose was given over a limited course of 6 mo, primarily to mitigate infection risks and limit treatment costs. This approach was successful because it led to DSA elimination achieved after only 6 doses, and, notably, a second surveillance biopsy after 6 mo showed normalization of histology and molecular assessments. Current follow-up has been uneventful, with no evidence of DSA rebound, stable kidney graft function and negative dd-cfDNA. In conclusion, a 6-mo course of daratumumab was well tolerated and demonstrated efficacy in converting DSA rebound and normalizing histology, molecular microscope, and dd-cfDNA assessments. Future systematic interventional trials are needed to establish the efficacy and safety of this approach in larger cohorts.

As the protection provided by 2 doses of an mRNA vaccine substantially wanes over time and with the emergence of new viral variants,1 administration of booster doses was recommended for kidney transplant recipients (KTRs).2–4 Vaccination-associated immune activation might be associated with allorecognition and graft injury,5 and safety data in KTRs are insufficient. This prospective, observational study aims to evaluate vaccine safety, the dynamics of anti-HLA antibodies and donor-derived cell-free DNA (dd-cfDNA),6–9 and seroconversion rates following the first booster dose of an mRNA vaccine. The 3-mo follow-up of 108 SARS-CoV-2 naive KTRs is reported. Anti-HLA antibodies, SARS-CoV-2 IgG S1/S2 antibodies, kidney graft function were measured at baseline (D0) and at 3 mo (M3); dd-cfDNA was analyzed in 79 KTRs. Anti-HLA antibodies were measured with the single-antigen bead technology (LabScreen Mixed and LabScreen Single Antigen Luminex). The presence of donor-specific antibodies (DSAs) was assessed using HLA fusion 4.6.0 software (all One Lambda, Inc). The cutoff of 500 mean fluorescent intensity (MFI) was set as a threshold for DSA/anti-HLA antibody positivity.10 A significant increase in anti-HLA antibodies or DSAs was defined with the emergence of a de novo antibody with MFI >500 and a >50% increase in MFI of a preformed antibody. Calculated virtual panel-reactive antibodies were computed using the Eurotransplant Reference Laboratory calculator.11 The dd-cfDNA was measured with the Prospera test, with 1% cutoff.6 After vaccination, all study participants were contacted and asked about any reactions. SARS-CoV-2 S1/S2 IgG was tested using the LIAISON SARS-CoV-2 S1/S2 IgG chemiluminescence immunoassay (DiaSorin S.p.A., Italy). Cutoff of 9.5 arbitrary units (kAU/ml) was used to define seroconversion. One-sided, paired Wilcoxon test was used to compare the differences in MFI, dd-cfDNA, anti-SARS-CoV-2 IgG, and estimated glomerular filtration rate at D0 and M3. Anti-HLA antibodies at the D0 visit were found in 27% of KTRs (sensitized KTRs); 4 became negative by the M3 visit. One KTR developed de novo anti-HLA antibodies. DSAs at the D0 visit were found in 6 KTRs; by the M3 visit' 2 became negative; in 4 KTRs' MFI remained stable. One KTR developed de novo DSAs with a low MFI. No increases in the average MFI nor in up to 2 immunodominant anti-HLA MFIs were found (Figure 1A–D). No increase in calculated virtual panel-reactive antibodies was found (Figure 1E–F).FIGURE 1.: Dynamics of HLA specific antibodies after vaccination. In box plots, the bold horizontal lines represent the median; upper and lower box boundaries are 25th and 75th quantiles; individual participants are denoted as points. A, Average MFI of anti-HLA antibodies in class I between D0 and M3. B, Average MFI of anti-HLA antibodies in class II between D0 and M3. C, MFI of up to 2 immunodominant anti-HLA antibodies in class I between D0 and M3. D, MFI of up to 2 immunodominant anti-HLA antibodies in class II between D0 and M3. E, Calculated virtual panel-reactive antibodies (cPRA) change between D0 and M3 in the whole cohort. F, cPRA change between D0 and M3 in anti-HLA Ab positive KTRs only. A 1-sided paired Wilcoxon test was used to calculate the P values. Ab, antibody; cPRA, calculated panel-reactive antibodies; D0 visit, day of administration of third vaccine dose; KTR, kidney transplant recipient; M3 visit, 3 mo after third dose of vaccine; MFI, mean fluorescence intensity.There was no KTR with a new increase of dd-cfDNA above 1% at M3, nor with any overall increase in dd-cfDNA in the whole cohort including sensitized KTRs (Figure 2A,B). The dd-cfDNA at M3 increased in nonsensitized KTRs (Figure 2C); however, this increase was mild and far below the 1% threshold. Sensitized KTRs presented higher dd-cfDNA (Figure 2D).FIGURE 2.: Donor-derived cell-free DNA dynamics and eGFR dynamics. In boxplots, the bold horizontal lines represent the median; upper and lower box boundaries are 25th and 75th quantiles; individual participants are denoted as points; the dashed line leveled at 1% represents the cutoff for positivity. A' dd-cfDNA in all participants between D0 and M3. B' dd-cfDNA in participants without anti-HLA antibodies between D0 and M3. C' dd-cfDNA in participants with anti-HLA antibodies between D0 and M3. D' dd-cfDNA compared between participants with and without anti-HLA antibodies at D0 and M3. E' eGFR in all participants between D0 and M3. F' eGFR in participants without anti-HLA antibodies between D0 and M3. G' eGFR in participants with anti-HLA antibodies between D0 and M3, (F, G). A 1-sided paired Wilcoxon test was used to calculate the P value for plots (A–C) and (E–G); a 2-sided Wilcoxon test was used to calculate the P value for plot (D). Ab, antibody; dd-cfDNA, donor-derived cell-free DNA; D0 visit, day of administration of third vaccine dose; eGFR, estimated glomerular filtration rate; M3 visit, 3 mo after third dose of vaccine.No difference in estimated glomerular filtration rate was found (Figure 2E–G); no for cause graft biopsy was performed. Seroconversion was detectable in 52 (48%) at D0 and in 85 (81%) KTRs at M3, respectively. In conclusion, we found no evidence of allosensitization or subclinical kidney allograft injury following the first booster dose. ACKNOWLEDGMENTS We wish to thank the outpatient clinic nursing staff for obtaining patient samples; Transplant Laboratory technicians for sample handling; Petr Raska, MSc, and Michal Hojny, PharmD, for organizing the booster dose campaign at IKEM; Hedvika Cacarova for English proofreading; Cesar Escrig for fruitful discussion; and Natera Inc for blood sample processing and Prospera results.

AIM:To evaluate risk factors for primary sclerosing cholangitis (PSC) recurrence (rPSC) after orthotopic liver transplantation (OLT) in patients with well-preserved colons.METHODS:We retrospectively evaluated the medical records of all patients transplanted for PSC in our center between July 1994 and May 2015 and selected 47 with follow-up of at least 60 mo for further analysis based on strict inclusion and exclusion criteria. rPSC was confirmed by magnetic resonance or endoscopic retrograde cholangiopancreatography and liver biopsy. All patients were evaluated by protocolary pre-OLT colonoscopy with randomized mucosal biopsies. Colonoscopy was repeated annually after OLT. Both organ donors and recipients were human leukocyte antigen (HLA) typed by serological and/or DNA methods. All input data were thoroughly analyzed employing relevant statistical methods.RESULTS:Altogether, 31 men and 16 women with a median (range) age of 36 (15-68) years at the time of OLT and a median follow-up of 122 (60-249) mo were included. rPSC was confirmed in 21/47 (44.7%) of patients, a median 63 (12-180) mo after transplantation. De novo colitis [rPSC in 11/12, P ≤ 0.05, hazard ratio (HR): 4.02, 95% confidence interval (CI): 1.58-10.98] and history of acute cellular rejection (rPSC in 14/25, P ≤ 0.05; HR: 2.66, 95%CI: 1.03-7.86) showed strong positive associations with rPSC. According to the univariate analysis, overlapping features of autoimmune hepatitis (rPSC in 5/5, P ≤ 0.05) and HLA-DRB1*07 in the donor (rPSC in 10/15, P ≤ 0.05) represent other potential risk factors for rPSC, while the HLA-DRB1*04 (rPSC in 0/6, P ≤ 0.05), HLA-DQB1*03 (rPSC in 1/11, P ≤ 0.05), and HLA-DQB1*07 (rPSC in 0/7, P ≤ 0.05) recipient alleles may have protective roles.CONCLUSION:De novo colitis and acute cellular rejection are clinical conditions significantly predisposed towards recurrence of PSC after liver transplantation.