Biopsy-proven Acute Rejection Episodes Research Articles

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.

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

Conversion from twice-daily everolimus to once-daily sirolimus in long-term stable liver transplant recipients

BackgroundAfter organ transplantation, strategies for simplifying the therapeutic regimen may improve adherence and prevent acute organ rejection and/or late graft loss. The present study aimed to evaluate the safety and efficacy of conversion from everolimus (EVR) twice daily to sirolimus (SIR) once daily in a large cohort of liver transplantation (LT) patients. MethodsWe included 108 LT patients with at least 12 months of post-transplant follow-up and no rejection episodes in the last year. Conversion was based on a 1:1 ratio (but eventually adapted to available formulations of SIR). ResultsThe median age at the time of conversion was 68.9 years (range: 26.1–83.6); 75.0% were men. The main indications for mTOR inhibitor use were renal failure (38.9%) and/or a history of malignancy (37.0%). Median conversion time after LT was 14.8 years (range: 2.3–31.5). The median dose of EVR and SIR (initially) was 1.50 mg/day (range: 0.5–4.5). The mean follow-up after conversion was 15.8±4.4 months. Median serum EVR/SIR trough levels before/after conversion were 3.85 ng/mL vs. 6.32 ng/mL (p < 0.05), i.e. a 1:1.64 ratio. At the end of follow-up after conversion, the median dose of SIR was 1.25 mg/day (range: 0.5–3.5), and the mean serum SIR trough level was 5.23 ng/mL; 9 patients (8.3%) had returned to EVR, because of side effects (mainly digestive), that resolved thereafter. No biopsy-proven acute rejection episode was observed. Finally, 87.1% of patients considered the conversion beneficial and the cost was reduced by 50.3%. ConclusionThe results of our study indicate that conversion from once-daily EVR to once-daily SIR in stable LT patients is safe, but needs dose adaptations and careful monitoring.

Safety and efficacy of everolimus initiation from the first month after liver transplantation: A systematic review and meta-analysis.

Everolimus, a selective inhibitor of mamalian target of rapamycin (mTORi), is considered to be an alternative immunosuppressive regimen in the liver transplantation (LT) setting. However, most of the transplant centers avoid its early use (i.e., during the first month) after LT mainly due to safety issues. We searched for all articles published between 01/2010 and 7/2022 to evaluate the effectiveness and safety ofinitial/early administration of everolimus after LT. Seven studies (three randomized controlled trials and four prospective cohort studies) were included:initial/early everolimus-including therapy (group 1) was used in 512 (51%) and calcineurin inhibitor (CNI) based therapy (group 2) in 494 (49%) patients. No significant difference was found between group 1 and group 2 patients regarding the rates of biopsy-proven acute rejection episodes (Odds Ratio [OR]: 1.27, 95% CI: .67-2.41, p=.465) and hepatic artery thrombosis (OR: .43, 95% CI: .09-2.02, p=.289). Everolimus was associated with higher rates of dyslipidemia (14.2%vs. 6.8%, p=.005) and incisional hernia (29.2%vs. 10.1%, p<.001). Finally, no difference was found between the two groups regarding recurrence of hepatocellular carcinoma (Risk Rates [RR]: 1.22 95%CI: .66-2.29, p=.524) and mortality (RR: .85 95%CI: .48-1.50, p=.570). Use ofinitial/early everolimus seems to be effective withasatisfactory safety profile,making its administration a reasonable therapeutic option in the LT setting.

Very Low Dose Anti-Thymocyte Globulins Versus Basiliximab in Non-Immunized Kidney Transplant Recipients.

The choice between Basiliximab (BSX) or Anti-Thymocyte Globulin (ATG) as induction therapy in non-immunized kidney transplant recipients remains uncertain. Whilst ATG may allow steroid withdrawal and a decrease in tacrolimus, it also increases infectious complications. We investigated outcomes in non-immunized patients receiving a very low dosage of ATG versus BSX as induction. Study outcomes were patient/graft survival, cumulative probabilities of biopsy proven acute rejection (BPAR), infectious episode including CMV and post-transplant diabetes (PTD). Cox, logistic or linear statistical models were used depending on the studied outcome and models were weighted on propensity scores. 100 patients received ATG (mean total dose of 2.0mg/kg) and 83 received BSX. Maintenance therapy was comparable. Patient and graft survival did not differ between groups, nor did infectious complications. There was a trend for a higher occurrence of a first BPAR in the BSX group (HR at 1.92; 95%CI: [0.77; 4.78]; p = 0.15) with a significantly higher BPAR episodes (17% vs 7.3%, p = 0.01). PTD occurrence was significantly higher in the BSX group (HR at 2.44; 95%CI: [1.09; 5.46]; p = 0.03). Induction with a very low dose of ATG in non-immunized recipients was safe and associated with a lower rate of BPAR and PTD without increasing infectious complications.

410.2: Outcomes of Living Donor Kidney Transplantation After SARS-CoV-2 Infection in Both the Donor and the Recipient: A Multicenter Study Running Title - LDKT in COVID-19 Survivors

Introduction: The evidence for living donor kidney transplantation (LDKT) when both donor-recipient (D-R) pair had a history of COVID-19 infection is scarce. Methods: We explored the protocol, outcome, and follow-up of 64 LDKT when D-R pair had recovered from COVID-19 in a retrospective, multicentre (n = 12) study from India between October 29, 2020, to December 1, 2021. There was no change in induction/ immunosuppression regimen in the study among different COVID-19 severity and is similar to standard practice. Results: Clinical severity in patients and donors was asymptomatic/ mild without requiring oxygen therapy in 77%(n=49), 95.4%(n=63) and moderate/ severe 4.6%(n=1) illness requiring oxygen therapy in 23%(n=15) and 4.6%(n=1), respectively. The mean ± SE(SD) waiting time from first documented RT-PCR negative to surgery for recipient and donor was 90.9 ± 9.27(74.1) and 47±4.5 (29.2) days respectively. Six (9.3%) episodes of biopsy-proven acute rejection (BPAR) were reported at follow-up of 214 ± 14.8(119) days and median (IQR) of 227(109-309) days. The locally weighted scatter plot smoothing curve for creatinine during follow-up in the D-R pair showed no trends of raised creatinine in the context of waiting time from COVID-19 to surgery. No graft loss, death, reactivation/reinfection, and any complications relating to surgery or COVID-19 were reported in the study. Conclusions: Our report shows excellent outcomes and follow-up data of LDKT in recovered D-R pairs with the standard immunosuppression protocol. To date, this remains the first and the largest study of LDKT when D-R pair had prior COVID-19.

Kidney Retransplantation Outcomes: A Paired Recipient Control Study

Despite progressive improvements in graft and patient survival after kidney transplantation over the last decades, an increasing number of patients are waitlisted for retransplantation. Identifying the risk factors for second graft failure can help us improve management for such patients. The aim of this study was to compare the outcomes of kidney retransplantation with those of first transplantation. This retrospective study included all the recipients of a second kidney transplant between January 2008 and December 2019. For each patient with a second kidney transplant, we selected the paired recipient from the same donor. We excluded recipients of donations from living donors, patient-and-donor pairs with more than 1 transplant, and patients without a pair. The follow-up took place December 31, 2020. We included 152 patients, corresponding to 76 pairs of recipients. Patients who underwent a second transplant had significantly higher panel reactive antibody values and longer waiting time for retransplantation. Biopsy-proven acute rejection episodes were doubled in patients undergoing a second transplant (P=.12). There was a lower survival of second grafts at the first, fifth, and 10th year (P < .05). The main factor influencing graft loss for both groups was acute rejection, and, in patients, with a second transplant, acute rejection increased the risk of graft loss by 17 times (odds ratio, 17.5; 95% confidence interval, 4.19-98). The clinical results of second kidney transplants still fall short of first transplants, with the main factor of poor prognosis being acute rejection. In young patients, allocation and immunosuppression management should consider this risk to improve long-term outcomes.

POS-809 INFERIOR GRAFT SURVIVAL FOLLOWING BIOPSY-PROVEN ACUTE REJECTION IN ABO INCOMPATIBLE TRANSPLANT RECIPIENTS WHEN COMPARED WITH ABO COMPATIBLE TRANSPLANT - PROPENSITY SCORE MATCHED CASE CONTROL STUDY

ABO-incompatible kidney transplants (ABOi KTx) increased the pool of living donations. Although available outcome data in ABOi KTx is equivocal for its non-inferiority when compared to ABO compatible transplant recipients (ABOc KTx), the data on graft survival after a biopsy-proven acute rejection (BPAR) episode are scarce in ABOi KTx.

Impact of the Mayo Adhesive Probability Score on Donor and Recipient Outcomes After Living-donor Kidney Transplantation: A Retrospective, Single-center Study of 782 Transplants.

This study was performed to assess the impact of the Mayo Adhesive Probability (MAP) score on donor and recipient outcomes after living-donor kidney transplantation (LDKT). We retrospectively analyzed 782 transplants involving LDKT between February 2008 and October 2019 to assess the correlation between the MAP score and outcome after LDKT. We divided the transplants into 2 groups according to the donor MAP score: 0 (MAP0) and 1-5 (MAP1-5). Compared with the MAP0 group, donors in the MAP1-5 group were significantly older, had higher body mass index, and were more likely to be men. The prevalences of hypertension, hyperlipidemia, and diabetes were also higher among donors in the MAP1-5 group than among donors in the MAP0 group. Operative time, estimated blood loss during donor nephrectomy, and percentage of glomerular sclerosis were significantly greater in the MAP1-5 group than in the MAP0 group. Donor and recipient perioperative complications were comparable between the 2 groups; death-censored graft survival rates also did not significantly differ between groups. Although the recipient mean estimated glomerular filtration rate (eGFR) from postoperative d 1 to 7 was significantly higher in the MAP0 group than in the MAP1-5 group (P = 0.007), eGFR reductions within 5 y after transplantation were similar between groups. There were no significant differences between groups in recipient mortality and biopsy-proven acute rejection episodes within 1 y after transplantation. Additionally, multivariate analysis showed that the only factors affecting recipient eGFR at postoperative d 7 were donor age, recipient age, and female sex (P < 0.001, <0.001, and =0.004, respectively). The MAP score did not influence surgical complications or graft survival; therefore, it should not affect donor selection.

A Prospective Controlled Trial to Evaluate Safety and Efficacy of in vitro Expanded Recipient Regulatory T Cell Therapy and Tocilizumab Together With Donor Bone Marrow Infusion in HLA-Mismatched Living Donor Kidney Transplant Recipients (Trex001).

Background: The induction of donor-specific immunological tolerance could improve outcome after kidney transplantation. However, no tolerance protocol is available for routine clinical use. Chimerism-based regimens hold promise, but their widespread application is impeded in part by unresolved safety issues. This study tests the hypothesis that therapy with polyclonal recipient regulatory T cells (Tregs) and anti-IL6R (tocilizumab) leads to transient chimerism and achieves pro-tolerogenic immunomodulation in kidney transplant recipients also receiving donor bone marrow (BM) without myelosuppressive conditioning of the recipient.Methods/design: A prospective, open-label, controlled, single-center, phase I/IIa academic study is performed in HLA-mismatched living donor kidney transplant recipients.Study group: Recipients of the study group receive in vitro expanded recipient Tregs and a donor bone marrow cell infusion within 3 days after transplantation and tocilizumab for the first 3 weeks post-transplant. In addition they are treated with thymoglobulin, belatacept, sirolimus, and steroids as immunosuppression. Starting 6 months post-transplant, sirolimus and steroids are withdrawn in a step-wise manner in stable patients.Control group: Recipients of the control group are treated with thymoglobulin, belatacept, sirolimus, and steroids as immunosuppression. Co-primary endpoints of safety (impaired graft function [eGFR <35 mL/min/1.73 m2], graft-vs.-host disease or patient death by 12 months) and efficacy (total leukocyte donor chimerism within 28 days post-transplant) are assessed. Secondary endpoints include frequency of biopsy-proven acute rejection episodes and subclinical rejection episodes on surveillance biopsies, assessment of kidney graft function, and the evaluation whether the study protocol leads to detectable changes in the immune system indicative of pro-tolerogenic immune modulation.Discussion: The results of this trial will provide evidence whether treatment with recipient Tregs and donor BM is feasible, safe and efficacious in leading to transient chimerism. If successful, this combination cell therapy has the potential to become a novel treatment option for immunomodulation in organ transplantation without the toxicities associated with myelosuppressive recipient conditioning.Trial registration: European Clinical Trials Database EudraCT Nr 2018-003142-16 and clinicaltrials.gov NCT03867617.

Hepatitis E Is a Rare Finding in Liver Transplant Patients With Chronic Elevated Liver Enzymes and Biopsy-Proven Acute Rejection

BackgroundIn past decades, liver transplant (LT) patients were not routinely screened for hepatitis E virus (HEV) infection, and thus it might have been misdiagnosed as an acute rejection episode. Our aim was to analyze a real-world cohort of LT patients who presented with at least 1 episode of biopsy-proven acute rejection (BPAR) and suffered from persistent elevated transaminases, to evaluate the frequency of HEV infection misdiagnosed as a rejection episode. MethodsData from 306 patients transplanted between 1997 and 2017, including 565 liver biopsies, were analyzed. Biopsies from patients suffering from hepatitis C (n = 79; 25.8%) and from patients who presented with a Rejection Activity Index <5 (n = 134; 43.8%) were excluded. A subgroup of 74 patients (with 134 BPAR) with persistently elevated liver enzymes was chosen for further HEV testing. ResultsPositive HEV IgG was detectable in 18 of 73 patients (24.7%). Positive HEV RNA was diagnosed in 3 of 73 patients with BPAR (4.1%). Patients with HEV infection showed no difference in etiology of the liver disease, type of immunosuppression, or median Rejection Activity Index. ConclusionFew HEV infections were misdiagnosed as acute rejection episodes in this real-world cohort. Thus, HEV infection is an infrequent diagnosis in cases with persistent elevated liver enzymes and BPAR after LT.

An intronic polymorphism of NFATC1 gene shows a risk association with biopsy-proven acute rejection in renal transplant recipients.

BackgroundWe aimed to explore the influence of single nucleotide polymorphisms (SNPs) in NFATC1 gene on the occurrence of biopsy-proven acute rejection (BPAR) in renal transplant recipients.MethodsBlood samples from 131 subjects with stable allograft function (STA) and 69 with BPAR episodes were collected and analyzed using target sequencing (TS) with an established panel. Odds ratios (OR) and 95% confidence intervals (95% CIs) were calculated for logistic regression models adjusted for confounding factors. Pathological changes were extracted and the relationship with tagger SNPs was calculated. Moreover, the CCK-8 assay was performed to explore the proliferation of T lymphocytes, and PCR, Western blotting and enzyme-linked immunosorbent assay were applied to identify the effect of mutant on the activation of T cells.ResultsHigh-quality readouts were obtained for 55 NFATC1 SNPs and 14 tagger SNPs were remained for further analysis. After adjusting for clinical confounding factors, the distribution of four NFATC1 SNPs, including rs2290154, rs2304738, rs754093 and rs754096, were statistically significant between STA and BPAR groups. Pathological association analysis indicated one SNP, rs2290154, was significantly related with the Banff score and renal tubulitis. Our in vitro study suggested that NFATC1 rs2290154 mutant could remarkably promote the T cell proliferation, increase the transcription of NFATC1 mRNA and expression of NFATC1 protein, as well as the interleukin-2 (IL-2) secretion.ConclusionsWe reported the crucial association of NFATC1 gene with the occurrence of acute rejection (AR) episodes. Moreover, in vitro NFATC1 rs2290154 was significantly involved in the T lymphocytes activation and proliferation through increasing the translation of NFATC1 mRNA and expression of NFATC1 protein, along with the secretion of IL-2.

Sequential Cohort Analysis After Liver Transplantation Shows de Novo Extended Release Tacrolimus Is Safe, Efficacious, and Minimizes Renal Dysfunction

We conducted a single-center, prospective sequential cohort analysis of adult patients undergoing LT during a change in protocol from de novo BDT to ERT, with a 6-month post-LT follow-up. A total of 160 transplanted patients were evaluated; 82 were in the BDT group and 78 were in the ERT group. The cohorts were matched for standard variables and a similar proportion in each group received induction interleukin-2 receptor antibody (36% and 31%). There were no significant differences in the measured outcomes of patient and graft survival, biopsy-proven acute rejection episodes, post LT diabetes, and toxicity. A significantly lower number of patients developed chronic kidney disease Stage3-4 in the ERT cohort compared with BDT cohort. In patients with pre-LT renal dysfunction who received antibody induction, estimated glomerular filtration rate decreased significantly in the BDT but not the ERT group. We show that once-daily ERT is as safe and efficacious as BDT in de novo LT but optimally conserves renal function post-LT.

Extended Efficacy of Low-Dose Valganciclovir for Prevention of Cytomegalovirus Disease in Intermediate-Risk Kidney Transplant Recipients: Two-Year Follow-Up.

In a previous study, we evaluated 1-year outcomes of using low-dose valganciclovir prophylaxis for cytomegalovirus infection in intermediate-risk kidney transplant recipients. Whether this effect persists in the long term is unknown. We aimed to evaluate the 2-year follow up of such adopted prophylaxis. We randomized 2 matched groups of kidney transplant recipients (1:1) to receive valganciclovir as 450 mg daily (group 1) or 900 mg daily (group 2) for the first 6 months after kidney transplant. The final analysis included 196 patients as intermediate-risk patients (98 in each treatment group) after exclusion of 5 high-risk patients. Serologically, all patients were at moderate risk for cytomegalovirus infection. Long-term outcomes including cytomegalovirus disease, acute rejection, new-onset diabetes after transplant, graft loss, and patient survival were assessed. Through year 2 of follow-up, cytomegalovirus infection was reported in only 1 patient in group 1 (at month 13) and 1 patient in group 2 (at month 19) (not significant). Biopsy-proven acute rejection episodes were not statistically different between the groups (2 episodes in group 1 and 6 in group 2; P = .431). New-onset diabetes posttransplant was reported in 8.1% in group 1 and 13.2% in group 2 (P = .535). Graft failure was equal in both groups (1 in each group) at 2 years of follow up (not significant). Patient survival was comparable in both groups (100% in group 1 versus 97.9% in group 2; P = .661). The total number of cytomegalovirus infections at 2 years was numerically less in group 1 (P = .128). Low-dose valganciclovir prophylaxis for 6 months was associated with sustained reduction of cytomegalovirus infection up to 2 years after kidney transplant without significant impact on the acute rejection, new-onset diabetes posttransplant, or patient and graft outcomes.

Association of posttransplant donor-specific HLA antibody with liver fibrosis after pediatric liver transplantation

Introduction: Although the short-term outcomes of pediatric liver transplantation (LT) have improved, the long-term outcomes, which are especially important in pediatric LT, have not improved to the same extent. This is partly caused by immunological progression of liver graft fibrosis. However, liver function test results are commonly normal even among patients with liver fibrosis; therefore, the indication and timing of liver graft biopsy have not been established. The aim of this study was to evaluate the significance of posttransplant donor-specific antibody (DSA) as a predictor of liver fibrosis during long-term follow-up after pediatric LT. Method: A retrospective analysis of liver graft fibrosis was performed in 34 LT recipients. Patients were divided into two groups based on histological findings, and clinical characteristics among patients with immunological graft fibrosis were assessed. The fibrosis group included patients with fibrosis of F2 or more. Result: Of the 34 patients included in this study, 11 (32%) were included in the fibrosis group and 23 in the non-fibrosis group. No significant between-group differences were found regarding pretransplant characteristics, including age, sex, ABO incompatibility, and immunosuppressive regimen. Episodes of biopsy-proven acute rejection and non-adherence to immunosuppressive drugs were comparable between the two groups. The mean fluorescence intensity (MFI) for anti-DR donor-specific antibodies was significantly higher among the patients with immunological fibrosis than among those without (1655 vs. 389; p = 0.009), and significantly more patients tested positive in the fibrosis group than in the non-fibrosis group (73% vs. 30%; p = 0.03). Conclusion: Posttransplant development of anti-DR DSA is a risk factor of liver fibrosis during long-term follow-up. This finding provides useful information for the implementation of valid histological examinations of liver grafts for patients with higher MFI, especially for anti-DR DSA, after pediatric LT.

Risk of hepatitis B reactivation in hepatitis B surface antigen seronegative and core antibody seropositive kidney transplant recipients

Previous contact with Hepatitis B virus (HBV) is common in patients undergoing hemodialysis. Literature has shown conflicting results on the risk of HBV reactivation in kidney transplant (KT) recipients with serologic evidence of past HBV infection. We reviewed 631 consecutive KT recipients and selected 70 patients simultaneously HBsAg negative and anti-HBc positive before KT, regardless of hepatitis B surface antibody (anti-HBs) status. Demographic characteristics, coinfection with other viruses, the presence of a previous KT, induction and maintenance immunosuppression, length of follow up, biopsy-proven acute rejection episodes, incidence of impaired liver function, and causes of graft loss and mortality were collected. Hepatitis B virus reactivation was defined as detection of HBV DNA viral load >2000IU/mL during follow up. Outcome data included HBV reactivation episodes, graft function, and patient survival. Median follow-up was 151months; 91.4% of patients were positive to anti-HBs prior to KT. No patient received HBV prophylaxis and 11 patients (15.7%) received rituximab as part of induction therapy. Anti-HBs titers remained stable in all patients throughout the observation period but two patient showed evidence of HBV reactivation after KT. Hepatitis B virus reactivation in HBsAg-negative and anti-HBc-positive after KT is rare but possible. We suggest evaluating HBV serologies, HBV DNA viral load, and liver enzymes before KT and routinely monitoring serologic HBV markers after KT. As only two patients experienced HBV reactivation, it is neither possible to define risk factors for HBV reactivation nor to evaluate the impact of different immunosuppressants or the benefit of prophylactic regimens. Further studies regarding HBV reactivation in solid organ transplant recipients are necessary.

Favorable Outcomes of Elderly ABO-Incompatible Kidney Transplantation-Pilot Single Center Experience

Background: The growth in the end-stage kidney disease (ESKD) population has been predominantly in the older adult population. In Japan, ABO-incompatible kidney transplantation has become an acceptable treatment option. However, few studies have been conducted on elderly ABO-incompatible kidney transplantation. Patients and Methods: Seventeen patients aged 60 years and older who received their grafts from ABO-incompatible living donors at our institution between December 2006 and September 2016 were enrolled in this study, and the outcome of these recipients was evaluated. Results: All 17 patients underwent successful kidney transplantation. Both overall patient and graft survival rates were 100, 100, and 83.3% at posttransplant 1, 3, and 5 years respectively. Six of the 17 patients (35.3%) had an episode of biopsy-proven acute cellular rejection. Two patients who developed steroid- and deoxyspergualin-resistant acute rejection required anti-human thymocyte immunoglobulin. Conclusion: ABO-incompatible kidney transplantation may be an effective radical renal replacement therapy for elderly patients with ESKD, although it could be a high-risk procedure.

Analysis of the Association of Posttransplant Donor-Specific HLA Antibody with Liver Fibrosis After Pediatric Liver Transplantation

Objectives Although the short-term outcomes of pediatric liver transplantation (LT) have improved, the long-term outcomes, which are especially important in pediatric LT, have not improved to the same extent. This is partly caused by immunological progression of liver graft fibrosis. However, liver function test results are commonly normal even among patients with liver fibrosis; therefore, the indication and timing of liver graft biopsy have not been established. The aim of this study was to identify predictive factors of immunological graft fibrosis during long-term follow-up after pediatric LT. Methods We retrospectively identified 90 patients who underwent pediatric living donor LT (LDLT) at our institution between July 1991 and October 2013. Out of 90 LDLT patients, donor-specific antibody (DSA) screening was performed for 71 patients. After the DSA screening, liver biopsies were subsequently performed and graft fibrosis plus findings of chronic rejection were evaluated for 18 patients. Patients were divided into two groups based on histological findings, and clinical characteristics among patients with immunological graft fibrosis were assessed. The degree of fibrosis was diagnosed based on the Metavir fibrosis staging, and the fibrosis group included patients with fibrosis of F2 or more and patients with F1 fibrosis plus findings of chronic rejection, especially including C4d deposition. The cut-off for a positive reaction of Single Antigen Beads assay was set at a mean fluorescence intensity (MFI) of 1,000 or more. Results Of 18 patients, seven were included in the fibrosis group. No significant between-group differences were found regarding pretransplant characteristics, including age, sex, primary disease, ABO incompatibility, and immunosuppressive regimen. Episodes of biopsy-proven acute rejection and non-adherence to immunosuppressive drugs were comparable between the two groups. The mean fluorescence intensity (MFI) for anti-DR DSAs was significantly higher in the fibrosis group than the non-fibrosis group (1655 vs. 216; p = 0.019). There were significant between-group differences regarding the positive rate of anti-DR DSAs (86% vs. 28%; p = 0.012). The MFI for anti-DQ DSA was higher among patients with liver fibrosis, although this between-group difference did not reach statistical significance. The immunosuppression minimization rate was more prevalent among patients with liver fibrosis, although this between-group difference did not reach statistical significance (71% vs. 45%; p = 0.37). Conclusion Posttransplant development of anti-DR DSA is a risk factor of liver fibrosis during long-term follow-up. This finding provides useful information for the implementation of valid histological examinations of liver grafts for patients with higher MFI, especially for anti-DR DSA, after pediatric LT. JSPS KAKENHI Grant Numbers JP17K16502. JSPS KAKENHI Grant Numbers JP26861036.

Detection of Hepatis C Virus-Related Immunologic Markers and Their Impact on Outcomes of Living-Donor Kidney Transplant Recipients.

Liver disease is an important cause of morbidity and mortality among recipients of transplanted organs. In addition to the liver, hepatitis C virus infection has a significant prevalence among recipients of kidney transplant and is related to worse graft and recipient survival as the kidney is an important component of the hepatitis C virus clinical syndrome. This retrospective single center study included 336 patients with end-stage renal disease who received a kidney transplant at the Mansoura Urology and Nephrology Center from January 1992 to December 1995. Of 336 patients, 63 were excluded, and the remaining 273 patients were divided into 3 groups: viremic active (72 patients), viremic inactive (108 patients), and nonviremic (93 patients). Division of patients was based on hepatitis C virus RNA complement level (C3 and/or C4 consumption), circulating cryoglobulins, and rheumatoid factor detection. Our study showed insignificant differences regarding patient characteristics and demographic data among the study groups but significantly higher incidence of transaminitis in viremic (active and inactive) patients. Nonsignificant differences were found regarding proteinuria among the 3 groups, including among those who had levels in either nephrotic or nonnephrotic ranges. Biopsy-proven acute rejection episodes among the 3 groups of recipients were statistically comparable, with significantly higher frequency of chronic rejection episodes among viremic active patients. Nonviremic recipients had significantly lower serum creatinine levels than viremic (active and inactive) recipients. Patient and graft survival results were comparable among the groups. Presence of hepatitis C virus immunologic markers does not have a significant effect on patient and graft survival; however, it may be a clue for long-term incidence of chronic rejection.

Graft-derived cell-free DNA, a noninvasive early rejection and graft damage marker in liver transplantation: A prospective, observational, multicenter cohort study.

BackgroundGraft-derived cell-free DNA (GcfDNA), which is released into the blood stream by necrotic and apoptotic cells, is a promising noninvasive organ integrity biomarker. In liver transplantation (LTx), neither conventional liver function tests (LTFs) nor immunosuppressive drug monitoring are very effective for rejection monitoring. We therefore hypothesized that the quantitative measurement of donor-derived cell-free DNA (cfDNA) would have independent value for the assessment of graft integrity, including damage from acute rejection.Methods and findingsTraditional LFTs were performed and plasma GcfDNA was monitored in 115 adults post-LTx at three German transplant centers as part of a prospective, observational, multicenter cohort trial. GcfDNA percentage (graft cfDNA/total cfDNA) was measured using droplet digital PCR (ddPCR), based on a limited number of predefined single nucleotide polymorphisms, enabling same-day turn-around. The same method was used to quantify blood microchimerism. GcfDNA was increased >50% on day 1 post-LTx, presumably from ischemia/reperfusion damage, but rapidly declined in patients without graft injury within 7 to 10 d to a median <10%, where it remained for the 1-y observation period. Of 115 patients, 107 provided samples that met preestablished criteria. In 31 samples taken from 17 patients during biopsy-proven acute rejection episodes, the percentage of GcfDNA was elevated substantially (median 29.6%, 95% CI 23.6%–41.0%) compared with that in 282 samples from 88 patients during stable periods (median 3.3%, 95% CI 2.9%–3.7%; p < 0.001). Only slightly higher values (median 5.9%, 95% CI 4.4%–10.3%) were found in 68 samples from 17 hepatitis C virus (HCV)–positive, rejection-free patients. LFTs had low overall correlations (r = 0.28–0.62) with GcfDNA and showed greater overlap between patient subgroups, especially between acute rejection and HCV+ patients. Multivariable logistic regression modeling demonstrated that GcfDNA provided additional LFT-independent information on graft integrity. Diagnostic sensitivity and specificity were 90.3% (95% CI 74.2%–98.0%) and 92.9% (95% CI 89.3%–95.6%), respectively, for GcfDNA at a threshold value of 10%. The area under the receiver operator characteristic curve was higher for GcfDNA (97.1%, 95% CI 93.4%–100%) than for same-day conventional LFTs (AST: 95.7%; ALT: 95.2%; γ-GT: 94.5%; bilirubin: 82.6%). An evaluation of microchimerism revealed that the maximum donor DNA in circulating white blood cells was only 0.068%. GcfDNA percentage can be influenced by major changes in host cfDNA (e.g., due to leukopenia or leukocytosis). One limitation of our study is that exact time-matched GcfDNA and LFT samples were not available for all patient visits.ConclusionsIn this study, determination of GcfDNA in plasma by ddPCR allowed for earlier and more sensitive discrimination of acute rejection in LTx patients as compared with conventional LFTs. Potential blood microchimerism was quantitatively low and had no significant influence on GcfDNA value. Further research, which should ideally include protocol biopsies, will be needed to establish the practical value of GcfDNA measurements in the management of LTx patients.