Biopsy-proven Acute Rejection Rates Research Articles

Impact of transiting from fluorescent polarisation immunoassay to high-performance liquid chromatography–tandem mass spectrometry for immunosuppressant levels analysis in kidney transplant patients

Background: High-performance liquid chromatography–tandem mass spectrometry (HPLC-TMS) is preferred to fluorescent polarisation immunoassay (FPIA) in therapeutic drug monitoring (TDM), as it only measures active drug. Our hospital replaced FPIA with HPLC-TMS for analysis of calcineurin inhibitor (CNI) levels. Preliminary studies demonstrated significantly lower CNI levels with HPLC-TMS versus FPIA in kidney transplant recipients (KTRs). Most studies evaluating CNI exposure in KTRs used FPIA, posing challenges in interpreting HPLC-TMS levels. This study aimed to compare the effectiveness and safety outcomes in the one-year period before (FPIA period) and after (HPLC-TMS period) the switch. Methods: A retrospective cohort study was conducted on KTRs receiving ciclosporin (CsA) or tacrolimus (FK). Primary effectiveness end points were biopsy-proven acute rejection (BPAR) rate and estimated glomerular filtration rate (eGFR); safety end points were viral infections and hospitalisation for infection. The secondary end point was change in CNI levels during the FPIA versus HPLC-TMS periods. Results: A total of 307 patients were analysed (CsA n=182, FK n=125). BPAR only occurred in two patients in the HPLC-TMS period among the CsA cohort ( p=0.50), but it occurred in six patients in the FPIA period and one patient in the HPLC-TMS period ( p=0.13) among the FK cohort. Median eGFR were similar in both periods (CsA: 52.2 mL/min/1.73 m2 (interquartile range (IQR) 39.8–67.6) vs. 52.5 mL/min/1.73 m2 (IQR 37.1–68.0), p=0.65; FK: 57.7 mL/min/1.73 m2 (IQR 39.1–80.0) vs. 56.4 mL/min/1.73 m2 (IQR 33.5–76.7), p=0.08). There were no significant differences in safety outcomes. The median change in CNI levels from the FPIA period to the HPLC-TMS period was –20.5% (IQR –32.5 to –3.9) and –6.9% (IQR –17.7 to 8.0) among CsA and FK cohorts, respectively ( p<0.01). Conclusion: The switch from FPIA to HPLC-TMS for CNI TDM in KTRs did not yield significant changes in clinical end points.

Randomized trial of 3 maintenance regimens (TAC/SRL vs. TAC/MMF vs. CSA/SRL) with low-dose corticosteroids in primary kidney transplantation: 18-year results.

A randomized trial of 150 primary kidney transplant recipients, initiated in May 2000, compared tacrolimus (TAC)/sirolimus (SRL) vs. TAC/mycophenolate mofetil (MMF) vs. cyclosporine microemulsion (CSA)/SRL (N=50/group). All patients received daclizumab induction and maintenance corticosteroids. With current median follow-up of 18years post-transplant, biopsy-proven acute rejection (BPAR) occurred less often in TAC/MMF (26% (13/50)), vs. the TAC/SRL (36% (18/50)) and CSA/SRL (34% (17/50)) arms combined (p=.23), with statistical significance favoring TAC/MMF (p=.05) after controlling for the multivariable (Cox model) effects of recipient age, recipient race/ethnicity, and donor age. First BPAR rate was clearly more favorable for TAC/MMF after stratifying patients by having 0-1 (N=72) vs. 2-3 (N=78) unfavorable baseline characteristics (recipient age <50years, African American or Hispanic recipient, and donor age ≥50years) (p=.02). Mean estimated glomerular filtration rate (eGFR), using the CKD-EPI formula, was consistently higher for TAC/MMF, particularly after controlling for the multivariable effect of donor age, throughout the first 96months post-transplant (p≤.008). These differences were translated into an observed more favorable graft failure due to immunologic cause (CAI/TG) rate for TAC/MMF (p=.06), although no significant differences in overall death-uncensored graft loss were observed. Previously reported significantly higher study drug discontinuation and requirement for antilipid therapy rates in the SRL-assigned arms were maintained over time. Overall, these results at 18years post-transplant more definitively show that TAC/MMF should be the gold standard for achieving optimal, long-term maintenance immunosuppression in kidney transplantation.

Grafalon® vs. Thymoglobulin® as an Induction Agent in Renal Transplantation - A Retrospective Study.

Introduction:Antihuman thymocyte immunoglobulin, used as an induction agent in renal transplantation, is of two types – thymoglobulin and grafalon (formerly ATG-Fresenius). In this study, we compared outcomes with these two agents.Methods:This was a single-center retrospective study of patients transplanted from January 2017 to October 2019, who received either grafalon or thymoglobulin induction. Grafalon or thymoglobulin was given at 6 and 3 mg/kg, respectively, followed by standard triple immunosuppression of tacrolimus, MMF, and prednisolone.Results:Median follow up was 22 (3–36) months. Thymoglobulin was given to 255 patients, whereas 78 patients received grafalon. Baseline demographics were similar between the two groups although significantly more patients in the grafalon group received ABO incompatible transplant (15% vs. 4.3%; P = 0.002). Patient survival was similar between the two groups (99% in grafalon vs. 98.8% in thymoglobulin; P = 1.0). Death censored graft survival was also similar (99% in grafalon vs. 100% in thymoglobulin; P = 0.23). Biopsy proven acute rejection (BPAR) was significantly higher in the grafalon group (12.8% vs. 5.1%, P = 0.04). The significance persisted after multivariable regression analysis (P = 0.02). Other outcomes such as infection rate and estimated glomerular filtration rate on last follow up were comparable between the two groups.Conclusions:Grafalon (6 mg/kg dose) when used as an induction agent was associated with significantly higher rate of BPARs as compared to thymoglobulin (3 mg/kg dose) although with comparable short-term patient and death censored graft survival, graft function, and infection rates.

Two Decades of Deceased Donor Kidney Transplantation at Ahmedabad, India.

Gujarat, Tamil Nadu, Telangana, Maharashtra, Kerala, Chandigarh, and Karnataka are states in India with active programs for deceased donor kidney transplant. We report our experience of 2 decades of deceased donor kidney transplant at the Institute of Kidney Diseases and Research Center, Dr. H. L. Trivedi Institute of Transplantation Sciences, Ahmedabad, Gujarat, India. This single-center retrospective study comprised data from 831 deceased donor kidney transplant recipients between January 1, 1997 and December 31, 2018. Mean recipient age was 38 ± 14 years; 564 were male, and 267 were female. Mean donor age was 45.3 ± 17.13 years; 565 were men, and 266 were women. Between January 1, 1997 and March 15, 2020, 5838 kidney transplants were completed, including 4895 living donor kidney transplants, 943 deceased donor kidney transplants, and 440 kidney paired donation transplants. Over the mean follow-up time of 8 ± 5.4 years, patient survival rate was 70% (n = 581) and death-censored graft survival rate was 84% (n = 698). Delayed graft function was shown in 210 patients (25%) and biopsy-proven acute rejection rate in 180 patients (21%). Our experience of favorable outcomes with deceased donor kidney transplants has expanded the donor pool in many ways, including transplant from expanded criteria donors to younger recipients; transplant from older donors to older recipients; donation after cardiac death; successful intercity organ procurement; dual-kidney transplant; en bloc transplant from a pediatric deceased donor; and transplant from brain death deceased donors who died from neurotoxic snakebite, recurrent primary brain tumor, bacterial meningitis, or head injury, or with disseminated intravascular coagulation and deranged renal functions. The pathway to increase organ donation was investigated. Deceased donor kidney transplant can achieve acceptable graft function with patient/graft survival, which may encourage the use of this approach to increase the number of available organs.

Outcomes and Health Care Utilization After Early Hospital Dismissal in Kidney Transplantation: An Analysis of 1001 Consecutive Cases.

To understand whether reduced lengths of stay after kidney transplantation were associated with excess health care utilization in the first 90 days or long-term graft and patient survival outcomes. Reducing length of stay after kidney transplant has an unknown effect on post-transplant health care utilization. We studied this association in a cohort of 1001 consecutive kidney transplants. We retrospectively reviewed 2011-2015 data from a prospectively-maintained kidney transplant database from a single center. A total of 1001 patients underwent kidney transplant, and were dismissed from the hospital in 3 groups: Early [≤2 days] (19.8%), Normal [3-7 days] (79.4%) and Late [>7 days] (3.8%). 34.8% of patients had living donor transplants (Early 51%, Normal 31.4%, Late 18.4%, P < 0.001). Early patients had lower delayed graft function rates (Early 19.2%, Normal 32%, Late73.7%, P = 0.001). By the hospital dismissal group, there were no differences in readmissions or emergency room visits at 30 or 90 days. Glomerular filtration rate at 12 months and rates of biopsy-proven acute rejection were also similar between groups. The timing of hospital dismissal was not associated with the risk-adjusted likelihood of readmission. Early and Normal patients had similar graft and patient survival. Late dismissal patients, who had higher rates of cardiovascular complications, had significantly higher late mortality versus Normal dismissal patients in unadjusted and risk-adjusted models. Dismissing patients from the hospital 2 days after kidney transplant is safe, feasible, and improves value. It is not associated with excess health care utilization or worse short or long-term transplant outcomes.

Evaluation of Induction Strategies in Heart Transplant at a Single Center

Immunosuppression induction is commonly utilized in heart transplant (HT) to prevent acute rejection and/or delay calcineurin inhibitor (CNI) initiation. However, guidance on whether to use induction and preferred agent(s) are not well defined. This is reflected by high practice variability across centers. According to ISHLT registry data, 54% of adult HT cases utilized induction, 31% with an IL-2R antagonist and 23% with a T-cell depleting agent. Our center has primarily utilized 3 strategies based on rejection risk and need to delay CNI: IL-2R antagonist (basiliximab), T-cell depleting (anti-thymocyte globulin, rabbit (rATG)), or no induction. Our study's objective was to compare these strategies' safety and effectiveness. A retrospective chart review was conducted at a large academic medical center, including HT cases performed between January 2015 and April 2019. Patients were stratified by induction strategy used at the time of transplant. The primary outcomes were rate of biopsy-proven acute cellular rejection (ACR) grade 2R or higher, treated antibody mediated rejection (AMR), and any infection within one year of transplantation. From January 2015 to April 2019, 145 total HTs were included in our study (123 heart, 20 heart-kidney, and 2 heart-liver). rATG was the most common induction strategy used (36%), followed by no induction (35%), and basiliximab (26%). Four patients (3%) received 1 dose of basiliximab but were switched to rATG. ACR rates were not statistically different among induction groups: 22% with no induction, 11% with basiliximab, 17% with rATG, and 0% with combination (p = 0.51). AMR rates were also not statistically different: 6% with no induction, 5% with basiliximab, 4% with rATG, and 0% with combination (p = 0.93). There was no difference detected in donor-specific antibody (DSA) formation at 1 year (p = 0.81). The percentages of patients with any infection were: 53% with no induction, 55% with basiliximab, 62% with rATG, and 75% with combination (p = 0.90). Incidences of ACR, AMR, DSA formation, and infection were not statistically different among induction strategies at one year post-transplant. It may be beneficial to individualize induction strategies based on recipient factors at the time of transplantation. Long term outcomes in this patient cohort are yet to be determined.

Effects of Sofosbuvir-Based Hepatitis C Treatment Regimens on Calcineurin Inhibitor Dosing in Liver and Kidney Transplant Recipients.

Available data have suggested that directacting antivirals for hepatitis C virus may decrease calcineurin inhibitor concentrations. In this study, our aim was to determine the effects of hepatitis C directacting antivirals on calcineurin inhibitor doses and trough levels. This retrospective, singlecenter study included 52 abdominal transplant recipients treated with sofosbuvir-based regimens between 2014 and 2017. The primary outcome was percent change in calcineurin inhibitor troughs and total daily doses between the week before treatment with direct-acting antivirals, days 21 to 35 oftreatment, and days 21 to 35 aftertreatment. Secondary outcomes included sustained virologic response and biopsyproven acute rejection rates. The median percent difference in calcineurin inhibitor troughs from pretreatment to during treatment was -20.5% (interquartile range, -36.2% to 13.1%) and from pretreatment to posttreatment was -13.5% (interquartile range, -33.7% to 10.7%). Corresponding percent changes in calcineurin inhibitor doses were 0% (interquartile range, 0%-0%) and 0% (interquartile range, -10.5% to 33.3%), respectively. Patients on tacrolimus experienced statistically significant changes in troughs but not doses. During treatment, 65% of patients required no dose change, 23% underwent a dose increase, and 12% had a dose decrease. The sustained virologic response rate was 98%, and the biopsy-proven acute rejection rate was 0%. Hepatitis C direct-acting antiviraltherapy may decrease calcineurin inhibitor levels, but this was not associated with clinically different dosing requirements or rejection rates.

A Comparison of Different Valgancyclovir Formulations in the Universal 6-Month Prophylaxis Against CMV Infection in Renal Transplant Recipients: A Randomized Single-Centre Study.

Cytomegalovirus (CMV) is the most common opportunistic infective pathogen in kidney transplant recipients. Valganciclovir (VAL) is commonly used for prophylaxis, especially in high-risk recipients. Generic VAL formulations have become available, but the data about their safety and efficacy are lacking. Consecutive de novo kidney transplant patients were randomized to generic VAL Valganciklovir Teva® (VT group)(24 patients) or Alvanocyte® (A group), Alvogen (19 patients) or to Valcyte® (V group), Roche (23 patients) in a 18-month open-label study. Universal prophylaxis was used for 6 months after the transplantation. CMV DNA levels were measured at 1,3,6,9,12 and 18 months after the transplantation. All positive measurements of CMV DNA were recorded. Groups did not differ regarding the clinical characteristics or the risk for developing CMV infection in the post-transplant period. CMV replications were most common at 9 months after the transplantation with rates of 9% for the V, 13% for the VT and 26% for the A group (p=0.26). At 12 months, positive CMV DNA was recorded in 22%, 8% and 11 % of patients taking V, VT and A, respectively (p=0.37). Rates of biopsy-proven acute rejection, adverse events, and serious adverse events were similar for all formulations. Lymphocele occurred most commonly in the V group (35%) compared to 17% in VT and 17% in the A group (p=0.23). One patient from each of the A and VT groups developed CMV disease. Additionally, they were the only two patients with CMV DNA copies above 656 IU/ml. Glomerular filtration rates were similar in all groups at all time points, while proteinuria was significantly higher at 12 months in patients who received V 0.32 g/day (0.18 - 0.42), compared to patients on VT 0.2 (0.1 - 0.2), or A 0.2 (0.2 - 0.3), p=0.04. Valgancyclovir efficacy and safety in this limited data set is similar with early administration of V, VT and A after kidney transplantation. Additional studies aimed at elucidating the effectiveness of this treatment regimen in patients who are at high risk for developing CMV infection are necessary to draw further conclusions.

Once-daily prolonged-release tacrolimus versus twice-daily tacrolimus in liver transplantation

ObjectiveFor patients who have received a kidney transplant, studies have shown that once-daily prolonged-release tacrolimus (TAC) has similar efficacy and safety to standard twice-daily dosing. The purpose of this study was to perform a meta-analysis to compare the effectiveness and safety of daily TAC (TAC qd) versus standard twice-daily TAC (TAC bid) administration in liver transplantation (LT). DesignMeta-analysis. Setting and participantsWe systematically searched the PubMed/MEDLINE, Web of Science, and Cochrane Library databases for studies comparing outcomes of LT patients who received TAC qd versus TAC bid. Outcome measuresResults were reported as odds ratios (ORs) with 95% CIs. ResultsSix studies, which included 5179 LT recipients (TAC qd = 951; TAC bid = 4228) were included in the analysis. The TAC qd group had a low 1-year graft loss rate (OR 0.70 [95% CI 0.54–0.91], P = 0.008) and lower rate of biopsy-proven acute rejection (BPAR) at 90 days (OR 0.46 [95% CI 0.24–0.89], P = 0.02) compared with the TAC bid group. There was no significant difference in 1-year mortality or the incidence of adverse events after LT between the 2 groups. ConclusionsCurrent evidence suggests that TAC qd is safe and effective for LT patients during the first year after transplantation. Longer-term follow-up studies are necessary to determine if TAC qd is safe and effective beyond the first year after LT.

Clinical Significance of Mycophenolate Mofetil Withdrawal in Kidney Transplant Recipients

IntroductionThe most effective immunosuppressant protocol in kidney transplantation (KT) is the combination of a calcineurin inhibitor, steroid, and mycophenolate mofetil (MMF) until now. However, MMF withdrawal (MW) is performed for many reasons, and the clinical course of the KT recipients after MW is not clearly known. The purpose of this study was to investigate the clinical outcomes of KT after MW. Materials and MethodsWe retrospectively analyzed the medical records of 626 KT recipients between 2000 and 2016. We evaluated the incidence of biopsy-proven acute rejection (BPAR), graft and patient survival rates, and risk factors related with graft failure. ResultsThe proportion of MW was 33.2% (208 of 626 patients). The median time between KT and MW was 6.4 months (range, 3.2–32.1 months). The common causes of MW were infection (70.7%), hematologic abnormalities (9.1%), and gastrointestinal trouble (7.7%). The incidence of BPAR was significantly higher in the MW group compared with the MMF continuation group (27.4% vs 8.9%, respectively, P < .001). Death-censored graft survival and patient survival rates were significantly lower in the MW group compared with the MMF continuation group (P < .001; P < .001, respectively). In the multivariate analysis, BPAR after MW was an independent risk factor for graft failure (hazard ratio 6.058, 95% confidence interval, 3.172–11.569, P < .001). ConclusionsThe incidence of rejection, graft failure, and patient mortality in KT were high after MW. Therefore, MW should be considered carefully.

Once- vs Twice-Daily Tacrolimus: Survival Rates and Side Effects: Single-Center Experience

BackgroundThis study aimed to determine whether de novo, prolonged-release tacrolimus- (PR-tacro) based immunosuppressive regimen affected graft and patient survival when compared to an immediate-release, twice-daily, tacrolimus- (IR-tacro) based regimen in kidney transplant recipients. We also aimed to determine the difference between the frequency of side effects, including diabetes control, in study groups. MethodsA total of 115 standard risk kidney transplant recipients were enrolled in this single center, retrospective study. Fifty-two patients received PR-tacro and 63 patients received IR-tacro as a calcineurin inhibitor. The primary outcome measures included incidence of graft loss and delayed graft function (DGF), biopsy-proven acute rejection , graft and patient survival, and creatinine clearance. Secondary outcome measures included the incidence of non-adherence, drug-induced tremor; post-transplant diabetes mellitus diagnosis rate; and control of diabetes in pre-transplant diabetic patients. ResultsBaseline characteristics and mean tacrolimus trough levels were comparable between groups. Incidence of graft loss, DGF, and graft and patient survival were similar between groups (P > .05). Mean creatinine clearance level was also similar (P > .05). Mean serum levels of fasting glucose (P < .05) and A1C (P < .05) were lower in PR-tacro group when compared to IR-tacro group. Post-transplant diabetes mellitus diagnosis rate was also lower in PR-tacro group when compared to IR-tacro group (P = .040). ConclusionThis study suggests that there is no statistically significant difference between PR-tacro and IR-tacro in terms of patient and graft survival, DGF, and biopsy-proven acute rejection rates in kidney transplant recipients. Post-transplant diabetes mellitus frequency is lower in non-diabetic patients, and glucose metabolism control is better in diabetic patients.

Tacrolimus Concentration-to-Dose Ratios in Kidney Transplant Recipients and Relationship to Clinical Outcomes.

One factor impacting tacrolimus interpatient variability is the presence of CYP3A5 polymorphisms. Low tacrolimus concentration-to-dose ratios (CDRs), or rapid metabolizers (RMs), have been associated with poor graft function outcomes and higher biopsy-proven acute rejection (BPAR) rates in a predominantly white population. Pretransplant CYP genotyping is not routinely conducted, and therefore only a small number of studies have assessed the use of tacrolimus CDRs as a surrogate for metabolism. We explored differences in outcomes between patients with low tacrolimus CDRs and high tacrolimus CDRs (i.e., nonrapid metabolizers [NRMs]) in a diverse patient population. To determine the relationship between tacrolimus CDRs and graft and patient outcomes in kidney transplant recipients at a large transplant center between 2006 and 2016. Inclusion criteria consisted of adult kidney transplant recipients who received rabbit antithymocyte globulin induction followed by a maintenance regimen of tacrolimus, mycophenolate, and prednisone. The primary end point was BPAR at 1year. Secondary end points included graft survival, patient survival, and toxicities. Determination of clusters was conducted using the two-step cluster analysis with a defined two-cluster distribution. Kaplan-Meier survival curves were created using the log-rank test. The NRM cluster consisted of 322 patients with a mean CDR of 2.91ng/ml/mg. The RM cluster consisted of 932 patients with a mean CDR of 1.14ng/ml/mg. The BPAR at 1year posttransplant was 3.7% in the NRM cluster and 3.6% in the RM cluster (p=0.95). Death at 5years was higher in the NRM group compared with the RM group for unknown reasons (p=0.03). Differences in the incidence of posttransplant toxicities were not statistically significant at any time point, except for increased rates of cutaneous cancer at 5years and cardiovascular disease overall in the NRM group. Tailoring tacrolimus therapy early posttransplant based on CDR is not supported by the findings in this study.

Long-Term Outcomes of Patients With Amyloidosis Following Kidney Transplant.

Reported graft and patient survival rates in amyloidosis after renal transplant differ considerably between studies. Group 1 included 24 patients who had end-stage renal disease secondary to amyloidosis. Group 2 (the control group) included 24 consecutive patients who had kidney disease secondary to various causes other than amyloidosis. Comparisons between groups were made for kidney and patient survival rates and other complications following kidney transplant. We also compared survival rates of patients in group 1 versus another control group that included patients with amyloidosis who were treated with hemodialysis (group 3; n = 25). Mean follow-up was 109.5 ± 79.8 months. Biopsy-proven acute rejection and graft failure rates were not significantly different between groups. In group 1 versus group 2, the cumulative 10-year and 20-year patient survival rates were 68.2% versus 86.1% and 36.9% versus 60.3%, respectively (P = .041). Survival was not significantly different in group 1 compared with group 2 and group 3, although patients in group 3 had significantly shorter duration of time to death after the start of renal replacement therapy. Patient survival may be lower in kidney transplant recipients with amyloidosis compared with patients with end-stage renal disease due to other causes. However, graft failure and acute rejection rates seem to be similar.

Comparing everolimus-based immunosuppression with reduction or withdrawal of calcineurin inhibitor reduction from six months after heart transplantation: the randomized MANDELA study.

In the 12-month, open-label MANDELA study, patients were randomized at month 6 after heart transplantation to (i) convert to calcineurin inhibitor (CNI)-free immunosuppression with everolimus (EVR), mycophenolic acid and steroids (CNI-free, n=71), or to (ii) continue reduced-exposure CNI, with EVR and steroids (EVR/redCNI, n=74). Tacrolimus was administered in 48.8% of EVR/redCNI patients and 52.6% of CNI-free patients at radomization. Both strategies improved and stabilized renal function based on the primary endpoint (estimated GFR at month 18 post-transplant post-randomization) with superiority of the CNI-free group versus EVR/redCNI : mean 64.1mL/min/1.73m2 versus 52.9mL/min/1.73m2 ; difference +11.3mL/min/1.73m2 (p<0.001). By month 18, estimated GFR had increased by ≥10mL/min/1.732 in 31.8% and 55.2% of EVR/redCNI and CNI-free patients, respectively, and by ≥25 mL/min/1.73m2 in 4.5% and 20.9%. Rates of biopsy-proven acute rejection (BPAR) were 6.8% and 21.1%; all cases were without hemodynamic compromise. BPAR was less frequent with EVR/redCNI versus the CNI-free regimen (p=0.015); 6/15 episodes in CNI-free patients occurred with EVR concentration <5ng/mL. Rates of adverse events and associated discontinuations were comparable EVR/redCNI from month 6 achieved stable renal function with infrequent BPAR. One-year renal function can be improved by early conversion to EVR-based CNI-free therapy but requires close EVR monitoring. This article is protected by copyright. All rights reserved.

Early Switch to Mammalian Target of Rapamycin Inhibitors Is a Sustainable Treatment Approach in Renal Transplant Recipients: 7-Year Results

ObjectiveThe aim of this study was to investigate the safety and sustainability of mammalian target of rapamycin inhibitor (m-TORi)-based treatment protocols in renal transplant patients. MethodsWe retrospectively evaluated a total of 206 patients who were switched to low-dose calcineurin inhibitors (CNI) + m-TORi or mycophenolate mofetil (MMF) + m-TORi treatment protocols in the first 3 months of renal transplantation between January 2010 and August 2011 in our center. Demographic and laboratory features of the patients were recorded. ResultsOf the patients included in the study, 89 (43.2%) were female and 117 (56.8%) were male. The mean age was 41.9 ± 13.8 years. Panel reactive antibody was negative in 95% of the recipients. One hundred thirty-four (65%) patients received anti-thymocyte globulin induction therapy. Initially, 108 patients were treated with cyclosporine and 98 (47.6%) were treated with tacrolimus-based regimens. One hundred thirty-five patients (65.5%) were switched to low-dose CNI + m-TORi and 71 patients (34.5%) were switched to MMF + m-TORi. The mean switching time was 3 months. At the end of the study, 161 patients (78.2%) were still continuing the m-TORi treatment protocol and 45 patients (21.8%) could not continue for various reasons (11.4% proteinuria, 5.5% edema, 2.9% acute rejection, 1% acne + oral aphthae, 1% neuropathy). The biopsy-proven acute rejection rate was 4.5% (n = 9). The mean duration of sustainability of m-TORi treatment protocol was 84.15 ± 6.79 months. Mean serum creatinine of patients who were still continuing m-TORi was 1.42 ± 1.09 mg/dL. ConclusionSwitching to m-TORi in the early posttransplant period is a safe and sustainable treatment approach.

Liver transplantation for hepatitis C virus (HCV) non-viremic recipients with HCV viremic donors.

In the context of organ shortage, the opioid epidemic, and effective direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV), more HCV-infected donor organs may be used for liver transplantation. Current data regarding outcomes after donor-derived HCV in previously non-viremic liver transplant recipients are limited. Clinical data for adult liver transplant recipients with donor-derived HCV infection from March 2017 to January 2018 at our institution were extracted from the medical record. Ten patients received livers from donors known to be infected with HCV based on positive nucleic acid testing. Seven had a prior diagnosis of HCV and were treated before liver transplantation. All recipients were non-viremic at the time of transplantation. All 10 recipients derived hepatitis C infection from their donor and achieved sustained virologic response at 12weeks posttreatment with DAA-based regimens, with a median time from transplant to treatment initiation of 43days (IQR 20-59). There have been no instances of graft loss or death, with median follow-up of 380days (IQR 263-434) posttransplant. Transplantation of HCV-viremic livers into non-viremic recipients results in acceptable short-term outcomes. Such strategies may be used to expand the donor pool and increase access to liver transplantation.

Short-Term Intensified Dosage Regimen of Mycophenolic Acid is Associated with Less Acute Rejection in Kidney Transplantation from Donation after Circulatory Death

Introduction: Whether an early, short-term, adequate exposure to mycophenolic acid (MPA) under tacrolimus-based immunosuppression regimen in kidney transplantation from donation after circulatory death (DCD) was effective and safe is yet unknown. Material and Methods: The study was a single-center, retrospective, cohort study of DCD transplantation in China. Intensified and standard dosage regimens of enteric-coated mycophenolate sodium (EC-MPS) were week 1, 2,160 vs. 1,440 mg/day. The incidences of biopsy-proven acute rejection (BPAR), delayed graft function, infection, and patient and graft survival were compared between the 2 groups. Results: A total of 209 patients (n = 82 in intensified group and n = 127 in standard group) were enrolled from August 2013 to December 2014. The incidence of BPAR at 12 months was significantly lower in the intensified group as compared to that of the standard group. (2.4 vs. 10.2%, p = 0.035). The mean MPA area under curve (AUC) levels at day 7 was significantly higher in the intensified group than that in the standard group (66.18 ± 35.48 vs. 45.30 ± 23.5 mg·h/L, p < 0.001). MPA AUC levels were significantly decreased in patients with BPAR as compared to those with NO-BPAR. Conclusion: An early, short-term regimen of intensified EC-MPS with tacrolimus increased early MPA exposure and achieved a low rate of BPAR in kidney transplantation from DCD.

Impact of Primary Disease Nature in the Development of De Novo Donor-Specific Antibodies After Kidney Transplant and the Risk of Acute Rejection

In this study, we explored the effect of the primary disease nature on development of de novo donor-specific antibodies after kidney transplant. We retrospectively studied kidney transplant recipients based on their primary disease. Patients were divided according to autoimmune and nonautoimmune diseases. The frequency of de novo donor-specific antibodies posttransplant and the incidence of acute rejection were estimated. De novo donor-specific antibodies were determined by the Luminex (LAB Screen products, One Lambda, Inc., Canoga Park, CA, USA) assay. Our study included 228 patients: 92 with autoimmune diseases and 136 with nonautoimmune diseases. Similar rates of de novo donor-specific antibodies (10.9% vs 11.8%; P = .835) were shown in the 2 groups over a mean (standard deviation) follow-up of 56.5 (27.8) months. In the nonautoimmune group, presence of de novo donor-specific antibodies was associated with higher rates of biopsy-proven acute rejection (37.5% vs 8.3%; odds ratio = 6.6; 95% confidence interval, 1.985-21.945; P = .002) versus that shown in patients of the same group without de novo donor-specific antibodies. In the autoimmune group, biopsy-proven acute rejection rates were similar between patients with and without de novo donor-specific antibodies. Mean fluorescence intensity titers of de novo donor-specific antibodies were significantly higher in patients with nonautoimmune primary disease (P = .003).Overall, graft loss was shown to be significantly higher in patients with autoimmune than in patients with nonautoimmune diseases (P < .001), although not different between patients with de novo donor-specific antibody formation (P = .677). No associations were shown between the frequency of de novo donor-specific antibody development after kidney transplant and the nature of the primary disease (autoimmune vs nonautoimmune). Detection of de novo donor-specific antibodies was associated with higher rates of biopsy-proven acute rejection among patients with nonautoimmune primary disease.

Efficacy and Safety of a Tofacitinib-based Immunosuppressive Regimen After Kidney Transplantation: Results From a Long-term Extension Trial.

BackgroundTofacitinib is an oral Janus kinase inhibitor. This open-label, long-term extension (LTE) study (NCT00658359) evaluated long-term tofacitinib treatment in stable kidney transplant recipients (n = 178) posttransplant.MethodsPatients who completed 12 months of cyclosporine (CsA) or tofacitinib treatment in the phase IIb parent study (NCT00483756) were enrolled into this LTE study, evaluating long-term tofacitinib treatment over months 12 to 72 posttransplant. Patients were analyzed by tofacitinib less-intensive (LI) or more-intensive (MI) regimens received in the parent study. For both groups, tofacitinib dose was reduced from 10 to 5 mg twice daily by 6 months into the LTE. Patients were followed up through month 72 posttransplant, with a focus on month 36 results.ResultsTofacitinib demonstrated similar 36-month patient and graft survival rates to CsA. Biopsy-proven acute rejection rates at month 36 were 11.2% for CsA, versus 10.0% and 7.4% (both P > 0.05) for tofacitinib LI and MI, respectively. Least squares mean estimated glomerular filtration rates were 9 to 15 mL/min per 1.73 m2 higher for tofacitinib versus CsA at month 36. The proportions of patients with grade 2/3 interstitial fibrosis and tubular atrophy in month 36 protocol biopsies were 20.0% for LI and 18.2% for MI (both P > 0.05) versus 33.3% for CsA. Kaplan-Meier cumulative serious infection rates at month 36 were numerically higher for tofacitinib LI (43.9%; P = 0.45) and significantly higher for MI (55.9%; P < 0.05) versus CsA (37.1%).ConclusionsLong-term tofacitinib continued to be effective in preventing renal allograft acute rejection and preserving renal function. However, long-term tofacitinib and mycophenolic acid product combination was associated with persistent serious infection risk.

Preformed C1q-binding Donor-specific Anti-HLA Antibodies and Graft Function After Kidney Transplantation

BackgroundDe novo complement-binding donor-specific anti-human leukocyte antigen antibodies (DSAs) are reportedly associated with an increased risk of kidney graft failure, but there is little information on preformed complement-binding DSAs. This study investigated the correlation between preformed C1q-binding DSAs and medium-term outcomes in kidney transplantation (KT). MethodsWe retrospectively studied 44 pretransplant DSA-positive patients, including 36 patients who underwent KT between April 2010 and October 2016. There were 17 patients with C1q-binding DSAs and 27 patients without C1q-binding DSAs. Clinical variables were examined in the 2 groups. ResultsPatients with C1q-binding DSAs had significantly higher blood transfusion history (53.0% vs 18.6%; P = .0174), complement-dependent cytotoxicity crossmatch (CDC-XM)-positivity (29.4% vs 0%; P = .0012), and DSA median fluorescence intensity (MFI) (10,974 vs 2764; P = .0009). Among patients who were not excluded for CDC-XM-positivity and underwent KT, there was no significant difference in cumulative biopsy-proven acute rejection rate (32.5% vs 33.5%; P = .8354), cumulative graft survival, and 3-month and 12-month protocol biopsy results between patients with and without C1q-binding DSAs. Although patients with C1q-binding DSAs showed a higher incidence of delayed graft function (54.6% vs 20.0%; P = .0419), multivariate logistic regression showed that DSA MFI (P = .0124), but not C1q-binding DSAs (P = .2377), was an independent risk factor for delayed graft function. ConclusionsIn patients with CDC-XM-negativity, preformed C1q-binding DSAs were not associated with incidence of antibody-mediated rejection and medium-term graft survival after KT. C1q-binding DSAs were highly correlated with DSA MFI and CDC-XM-positivity.