Biopsy-proven Acute Rejection Research Articles

Avoiding Tacrolimus Underexposure and Overexposure with a Dosing Algorithm for Renal Transplant Recipients: A Single Arm Prospective Intervention Trial.

Bodyweight‐based tacrolimus dosing followed by therapeutic drug monitoring is standard clinical care after renal transplantation. However, after transplantation, a meager 38% of patients are on target at first steady‐state and it can take up to 3 weeks to reach the target tacrolimus predose concentration (C0). Tacrolimus underexposure and overexposure is associated with an increased risk of rejection and drug‐related toxicity, respectively. To minimize subtherapeutic and supratherapeutic tacrolimus exposure in the immediate post‐transplant phase, a previously developed dosing algorithm to predict an individual’s tacrolimus starting dose was tested prospectively. In this single‐arm, prospective, therapeutic intervention trial, 60 de novo kidney transplant recipients received a tacrolimus starting dose based on a dosing algorithm instead of a standard, bodyweight‐based dose. The algorithm included cytochrome P450 (CYP)3A4 and CYP3A5 genotype, body surface area, and age as covariates. The target tacrolimus C0, measured for the first time at day 3, was 7.5–12.5 ng/mL. Between February 23, 2019, and July 7, 2020, 60 patients were included. One patient was excluded because of a protocol violation. On day 3 post‐transplantation, 34 of 59 patients (58%, 90% CI 47–68%) had a tacrolimus C0 within the therapeutic range. Markedly subtherapeutic (< 5.0 ng/mL) and supratherapeutic (> 20 ng/mL) tacrolimus concentrations were observed in 7% and 3% of the patients, respectively. Biopsy‐proven acute rejection occurred in three patients (5%). In conclusion, algorithm‐based tacrolimus dosing leads to the achievement of the tacrolimus target C0 in as many as 58% of the patients on day 3 after kidney transplantation.

Cell-free DNA in the surveillance of heart transplant rejection.

Circulating cell-free deoxyribonucleic acid (cfDNA) is promptly materializing as a highly useful tool for the surveillance of solid-organ transplant rejection. Donor-specific fraction (DF) cfDNA is a potential marker of selective donor organ injury. It is emerging as a promising analytical target in the near future. The aim of this systematic review is to throw light on the importance of cfDNA and future perspective in detecting acute rejection in heart transplantation. An exhaustive search was carried out for this review article on the basis of literature available including scientific databases of PubMed, Embase, and ClinicalTrials.gov. The search engines were systematically explored using the search terms "cell free DNA," "Heart transplant," and "Rejection" from inception until August 2020, and narrative analysis was accomplished. Majority of the studies described endomyocardial biopsy-proven acute rejection as reference standard. After initial screening of 331 articles, 11 studies were included and discussed in detail in the present review article. Majority of the studies showed prospective designs. A firm correlation was noted between acute rejection (identified on endomyocardial biopsy) and cfDNA levels by most of the studies. cfDNA is a promising tool to replace repeated biopsies to detect rejection. The development in the area of digital droplet polymerase chain reaction and massive parallel sequencing, along with the overall reduction in cost of sequencing with its automation, has helped establish its role in the transplant population.

Predicting acute rejection in children, adolescents, and young adults with a kidney transplant by assessing barriers to taking medication.

Nonadherence to immunosuppression is common among pediatric, adolescent, and young adult kidney transplant recipients and a leading cause of graft loss. Assessing barriers to medication adherence in clinical practice may identify patients at risk for rejection and provide therapeutic targets. Kidney transplant patients and/or their caregivers were assessed for 14 barriers to medication adherence using the barriers assessment tool. We compared rejection rates between patients with at least one reported adherence barrier to those without reported adherence barriers using a Kaplan-Meier estimator and Cox proportional hazard models to adjust for other mediators of acute rejection at 2 years following barriers assessment. Ninety-eight patients were assessed for barriers to adherence. Over the 2-year observation period, 22 patients developed biopsy-proven acute rejection (BPAR). Kaplan-Meier estimates show that patients with an identified barrier to adherence were more likely to have BPAR (p = 0.02) than patients without an identified barrier in the 24 months following barriers assessment. The median time to rejection for patients who experienced acute rejection was 175.5 days (IQR 63-276 days) from the time of barriers assessment. An identified barrier to adherence remained the only statistically significant predictor of BPAR with Cox modeling (HR 2.6, p = 0.04), after accounting for age, sex, and race. Pediatric and adolescent kidney transplant recipients with identified adherence barriers are at increased risk for acute rejection. Barriers to adherence provide a potentially modifiable therapeutic target that can be assessed in clinic to guide targeted interventions.

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.

Early Posttransplant Blood Transfusion and Risk for Worse Graft Outcomes

IntroductionBlood transfusion is a risk factor for allosensitization. Nevertheless, blood transfusion posttransplant remains a common practice. We evaluated the effect of posttransplant blood transfusion on graft outcomes.MethodsWe included nonsensitized, first-time, kidney-alone recipients transplanted between 1 July 2015 and 31 December 2017. Patients were grouped based on receiving blood transfusion in the first 30 days posttransplant. The primary end point was a composite outcome of biopsy-proven acute rejection, death of any cause, or graft failure in the first year posttransplant. Secondary outcomes included the individual components of the primary outcome and the cumulative incidence of de novo donor-specific antibodies (DSAs).ResultsTwo hundred seventy-three patients were included. One hundred twenty-seven (47%) received blood transfusion. Patients in the transfusion group were more likely to be older, have had a deceased donor, and have received induction with basiliximab. There was no difference between groups in the composite primary outcome (adjusted hazard ratio = [HR] 1.34; 95% confidence interval [CI], 0.83–2.17; P = 0.23). The cumulative incidence of de novo DSAs during the first year posttransplant was similar between groups (12.8% transfusion vs. 10.9% no transfusion, P = 0.48).ConclusionEarly transfusion of blood products in kidney transplant recipients receiving induction with lymphocyte depletion was not associated with an increased hazard of experiencing acute rejection, death from any cause, or graft loss.

Outcomes of Kidney Transplantation in the Elderly Recipients.

Introduction:In a developing country with a predominantly young population, the valid assumption is directed toward medical care toward the young. However, as medical technology has advanced, quality care has ensured better survival for the elderly population also. The aim of this study was to determine the clinical outcomes in elderly patients undergoing kidney transplantation.Materials and Methods:A retrospective analysis of 1150 patients who had undergone live related renal transplantation was done from January 2006 to December 2014. These patients were divided into two groups; Group 1: age >60 years (N = 150), Group 2: age 18–60 years (N = 1000). The clinical outcomes were compared.Results:The mean age in Group 1 was 69 ± 7.5 years (SD ± 7.5), and group 2 was 41 ± 8 years. In groups 1 and 2, males were 80% and 82%; death censored graft survival at 5 years was 82% and 87%; patient survival at 5 years was 86% and 94%, respectively. The incidence of biopsy-proven acute rejection was similar in both groups (11.3 vs. 10.2%, P = 0.12). Urinary tract infection was the most common infectious complication. Sepsis was the primary cause of death in both groups.Conclusion:In the elderly patients who underwent kidney transplantation, satisfactory graft function, and patient survival were maintained over a period of 60 months. Urinary tract infections were common, and sepsis was the most common cause of death with a surviving allograft. The acute rejection and mortality rates were comparable to the literature published from India so far.

Outcomes of ABO-incompatible kidney transplantation in older patients: a national cohort study.

Outcomes of ABO-incompatible living donor kidney transplantation (ABOi LDKT) in older individuals have not been established. This multicentric observational study, using data from the Korean Organ Transplantation Registry database, included 634 older patients (≥60years) undergoing kidney transplantation. We compared clinical outcomes of ABOi LDKT (n=80) with those of ABO-compatible LDKT (ABOc LDKT, n=222) and deceased donor kidney transplantation (DDKT, n=332) in older patients. Death-censored graft survival was similar between the three groups (P=0.141). Patient survival after ABOi LDKT was similar to that after ABOc LDKT (P=0.489) but higher than that after DDKT (P=0.038). In multivariable analysis, ABOi LDKT was not risk factor (hazard ratio [HR] 1.73, 95% confidence interval [CI] 0.29-10.38, P=0.548), while DDKT was significant risk factor (HR 3.49, 95% CI 1.01-12.23, P=0.049) for patient survival. Although ABOi LDKT showed higher biopsy-proven acute rejection than ABOc LDKT, the difference was not significant after adjustment with covariates. However, ABOi LDKT was significant risk factor for infection (HR 1.66, 95% CI 1.12-2.45, P=0.012). In older patients, ABOi LDKT was not inferior to ABOc LDKT and was superior to DDKT for patient survival. ABOi LDKT can be recommended for older patients, rather than waiting for DDKT.

FKBP-CaN-NFAT pathway polymorphisms selected by in silico biological function prediction are associated with tacrolimus efficacy in renal transplant patients

AimThe aim of the present study was to investigate the potential effects of genetic variations in the FKBP-CaN-NFAT pathway on clinical events associated with tacrolimus efficacy in Chinese renal transplant patients. MethodsOne hundred and forty Chinese renal transplant patients of Han ethnicity with over five years of follow-up were enrolled in our study. A pool of single nucleotide polymorphisms (SNPs) (1284 SNPs) was extracted from the Ensembl database according to chromosomal regions of the candidate genes. Next, 109 SNPs were screened out from this pool using multiple bioinformatics tools for subsequent genotyping using the MALDI-TOF-MS method. The associations of these candidate SNPs with acute rejection, nephrotoxicity, pneumonia and post-transplant estimated glomerular filtration rate (eGFR) were explored. ResultsFourty-four SNPs were found to be associated with tacrolimus-related clinical drug response. Specifically, eight SNPs were associated with the incidence of biopsy-proven acute rejection, four SNPs were associated with the rate of nephrotoxicity, 16 SNPs were correlated with the onset of pneumonia, and 26 SNPs were found to significantly influence post-transplant eGFR trend. An elaborate scoring system was implemented to prioritize the validation of these potentially causal SNPs. In particular, NFATC2 rs150348438 (G>T) performed well during integrative scoring (Ptotal=23.8) and was significantly associated with the occurrence of pneumonia (P = 0.0035, HR=0.91, 95% CI=0.85–0.97) and post-transplant eGFR levels (P = 0.000003). ConclusionsNFATC2 rs150348438, rs6013219, rs1052653, and NFATC1 rs754093, ranking high in scoring, significantly affected the post-transplant eGFR and the incidence of pneumonia, acute rejection, and nephrotoxicity in renal transplant patients taking tacrolimus. Those SNPs may alter the expression and regulation of FKBP-CaN-NFAT pathway by influencing transcription regulation, mature mRNA degradation and RNA splicing, or protein coding. Critical SNPs of high ranking may serve as PD-associated pharmacogenetic biomarkers indicating individual response variability of TAC, and thus aid the clinical management of renal transplant patients.

Sirolimus in renal transplant recipients with malignancies in Germany.

BackgroundRenal transplant recipients have an increased cancer risk. The mammalian target of rapamycin inhibitor sirolimus (SRL) has immunosuppressive and antitumour activities but knowledge about its use in recipients with cancer is limited.MethodsWe retrospectively analysed 726 renal allograft recipients converted to SRL from 10 German transplant centres. Patient and graft survival were analysed depending on malignancy status prior to conversion and tumour entity.ResultsMalignancy before conversion to SRL was reported in 230 patients, with 137 patients having skin cancers and 101 having solid cancers. Cancer occurred 4.6 ± 9.4 (median 3.0) years after transplantation. Basal cell carcinoma, squamous cell carcinoma and Bowen’s disease were the most prevalent skin cancers, while carcinomas of the kidney, colon and breast were the most prevalent solid cancers before conversion. Patients with prior malignancy were older and had better renal function at conversion compared with patients without a history of cancer. After conversion to SRL, cancer incidence rates (IRs) of all tumours were lower compared with rates before conversion. Cancer IRs after conversion were higher in patients with malignancy before conversion compared with those without. Patient survival was worse in patients with solid cancers compared with patients with skin cancers or without malignancies. Biopsy-proven acute rejections in the first year after conversion were less frequent in patients with malignancy compared with those without. Graft survival and renal function in all cancer types were better than in patients converted to SRL without cancers.ConclusionsConversion to SRL in patients with a history of cancer is safe regarding renal function and graft survival, while patient survival is largely dependent on tumour entity.

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&lt;0.01). Conclusion: The switch from FPIA to HPLC-TMS for CNI TDM in KTRs did not yield significant changes in clinical end points.

Combined impact of pre-sensitization and delayed graft function on the development of allograft rejection in deceased donor kidney transplantation: nationwide cohort study

Background: Both pre-sensitization to human leukocyte antigen and delayed graft function (DGF) is well documented to be asso ciated with poor allograft outcome. The aim of this study is to investigate whether development of DGF and pre-transplant highly sensitization has synergistic adverse effect on the allograft outcome after deceased donor kidney transplantation (DDKT) using Korean Transplant Registry (KOTRY) database, the nationwide prospective cohort. Methods: Between May 2014 and June 2019, total 1,945 DDKT were registered in KOTRY database and out of them, 1,370 cases were included in this study. According to pre-sensitization status and development of DGF post-transplant, they were divided into four groups: non-pre-sensitized-DGF(-) (n=1,100), non-pre-sensitized-DGF(+) (n=133), pre-sensitized-DGF(-) (n=116), and pre-sen sitized-DGF(+) (n=21). We compared allograft rejection, the change of allograft function, allograft survival, patient survival, and post-transplant complications across four groups. Results: The incidence of overall biopsy-proven rejection and acute antibody-mediated rejection (ABMR) was significantly higher in the pre-sensitized-DGF(+) group than the other three groups. In addition, multivariable analysis demonstrated that pre-sensi tization combined with DGF is an independent risk factor for both overall rejection and ABMR compared to non-pre-sensitized- DGF(-) group (hazard ratio, 10.769; 95% confidence interval, 3.717-31.198; P<0.001). Moreover, DGF and pre-sensitization showed statistically significant interaction each other (P for interaction <0.001). Pre-sensitization combined with DGF did not show a significant impact on allograft function and allograft or patient survival in this study. Conclusions: In conclusion, pre-sensitization and DGF show a synergistic adverse impact on the post-transplant allograft out come in terms of allograft rejection after DDKT. Therefore, we suggest when DGF occurred in DDKT with pre-sensitization, more careful monitoring or surveillance for allograft rejection is required.

Impact of kidney and recipient weight incompatibility on the allograft outcomes in kidney transplant recipients with pre-transplant diabetes mellitus: a single center retrospective cohort study

Background: The aim of this study was to analyze the impact on the adverse allograft outcome of transplanting relatively small kidneys in patients with pre-transplant diabetes mellitus (DM). Methods: From January 2010 to December 2018, 1,290 kidney transplants (KTs) were performed in Seoul St. Mary’s Hospital. Of these, 793 cases of non-sensitized living donor KT recipients were enrolled. They were divided into four groups (non-DM large kidney, non-DM small kidney, DM large kidney, and DM small kidney) according to the median kidney weight and recipient weight ratio (2.9 g/kg) and presence or absence of pre-transplant DM. The primary outcome of this study was death censored graft loss (DCGL) rate. Results: There was no significant difference in the biopsy-proven acute rejection rate among the four groups. DM small kidney group showed the highest DCGL rate (18/131 [13.7%], P=0.004) and was to be the independent risk factor for DCGL (adjusted haz ard ratio, 2.829; P=0.003). Moreover, renal function after 4 years of transplantation worsened faster in the DM small kidney group compared to other groups, and allograft survival decreased after 1 year of transplantation. Conclusions: Our results suggest that transplanting large kidneys rather than small kidneys is considered to have an advantage in terms of allograft outcome in pre-transplant DM patients, and this should be considered in donor selection.

Abstract 16060: Cardiac Magnetic Resonance Imaging Diastolic Indices Correlate With Cardiac Catheterization Filling Pressures in Pediatric Heart Transplant Recipients

Background: Atrial and ventricular filling pressures are routinely used in pediatric heart transplant (HTx) recipients to assess graft function. Cardiac magnetic resonance (CMR) can provide a non-invasive assessment of diastolic function, but data are lacking in pediatric HTx. We hypothesized that CMR indices of diastolic function correlate with filling pressures, providing a non-invasive approach to assessment of ventricular dysfunction. Method: Pediatric HTx recipients were prospectively enrolled at the time of cardiac catheterization. Pulmonary capillary wedge pressure (PCWP) and right atrial pressure (RAP) were measured. CMR included standard volumetric analysis and T1 and extracellular volume (ECV) mapping in the short axis at the mid-left ventricle (LV) to evaluate extracellular matrix expansion. Filling curves were calculated by contouring every phase in the short axis stack and global longitudinal and circumferential strain (GLS, GCS) were calculated using feature tracking. Correlations were analyzed using Spearman’s correlation. Results: A total of 31 patients with a mean age of 16.2 y/o were included, 9 with biopsy-proven acute rejection. The median time from transplant was 6.9 years and the mean LVEF was 58%. Peak LV ejection rate/end-diastolic volume (PER/EDV) correlated with PCWP (rho=-0.43, p=0.02, Fig 1) and RAP (rho=-0.40, p=0.03). GLS and GCS correlated with RAP (rho=0.51 p=0.007, and rho=0.38 p=0.05, respectively); GLS also correlated with PCWP (rho=0.46, p=0.02). Native T1 time-correlated with PCWP (rho=0.54, p=0.003), while the correlation between ECV and PCWP did not reach statistical significance (rho=0.37, p=0.06). Conclusion: CMR can be a useful non-invasive modality to assess for early signs of diastolic dysfunction in patients after pediatric HTx. Further research is needed to describe the clinical significance of these associations.

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.

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.

Pre-emptive immunosuppression using tacrolimus monotherapy does not reduce the rate of early acute rejection in renal transplantation from live donors: a comparative cohort study.

The planned nature of live donor kidney transplantation allows for immunosuppression to be initiated in the pretransplant period. The aim of this study was to determine the effect of pre-emptive immunosuppression on acute rejection rates after live donor kidney transplantation. In two consecutive cohorts of live donor kidneys transplants, 99 patients received pre-emptive immunosuppression with tacrolimus monotherapy for 2weeks prior to transplantation (PET group - first era) and 100 patients received tacrolimus-based immunosuppression commencing on the day of transplantation (control group - second era). The main outcome measure was the incidence of biopsy-proven acute rejection (BPAR) in the first 3months post-transplantation. Tacrolimus levels were significantly higher in the PET group at day 4 post-transplant (PET 9.08±4.57 vs. control 5.92±3.64ng/ml; P<0.0001), but there were no significant differences in tacrolimus levels at day 7 (PET 8.22±3.58 vs. control 7.63±3.56ng/ml; P=0.2452). BPAR was numerically higher in the PET group, but this difference did not reach statistical significance (PET 13/99 vs. control 6/100; P=0.097). There were no differences in allograft function measured by serum creatinine at 1year (PET 130±36 vs. control 142±69μmol/l; P=0.6829). Graft survival at 1year was equivalent in both groups (PET 96.9 vs. control 97.0%; P=0.9915). This study suggests that there is little role for the use of pre-emptive tacrolimus monotherapy in ABO blood group and HLA-compatible live donor kidney transplantation in patients on triple maintenance immunosuppression.

Increasing net immunosuppression after BK polyoma virus infection.

Reducing immunosuppression can effectively treat BK viremia (BKV) and BK nephropathy, but has been associated with increased risks for acute rejection and development of donor-specific antibodies (DSA). To date there have been no systematic evaluations of re-escalating immunosuppression in transplant patients with resolving BKV. Importantly, the safety of this approach and impact on graft survival is unclear. We performed a single-center retrospective review of kidney transplant recipients between July 2011 and June 2013 who had immunosuppression reduction after developing BKV (plasma PCR≥1000copies/ml). Changes in immunosuppression and patient outcomes were tracked until occurrence of a complication event: biopsy-proven acute rejection (BPAR), detection of de novo DSA, or recurrent BKV. Patients were grouped according to whether or not net immunosuppression was eventually increased. Out of 88 patients with BKV, 44 (50%) had net immunosuppression increased while the other 44 did not. Duration of viremia, peak viremia, induction, and sensitization status were similar between the two groups. In a Kaplan-Meier analysis, increasing immunosuppression was associated with less BPAR (P=.001) and a trend toward less de novo DSA development (P=.06). Death-censored graft survival (P=.27) was not different between the two groups. In the net immunosuppression increase group, recurrent BKV occurred in 22.7% without any BKV-related graft losses. These findings support potential benefits of increasing immunosuppression in patients with low-level or resolved BKV, but prospective trials are needed to better understand such an approach.

A noninferiority design for a delayed calcineurin inhibitor substitution trial in kidney transplantation.

Improving long‐term kidney transplant outcomes requires novel treatment strategies, including delayed calcineurin inhibitor (CNI) substitution, tested using informative trial designs. An alternative approach to the usual superiority‐based trial is a noninferiority trial design that tests whether an investigational agent is not unacceptably worse than standard of care. An informative noninferiority design, with biopsy‐proven acute rejection (BPAR) as the endpoint, requires determination of a prespecified, evidence‐based noninferiority margin for BPAR. No such information is available for delayed CNI substitution in kidney transplantation. Herein we analyzed data from recent kidney transplant trials of CNI withdrawal and “real world” CNI‐ based standard of care, containing subjects with well‐documented evidence of immune quiescence at 6 months posttransplant—ideal candidates for delayed CNI substitution. Our analysis indicates an evidence‐based noninferiority margin of 13.8% for the United States Food and Drug Administration's composite definition of BPAR between 6 and 24 months posttransplant. Sample size estimation determined that ~225 randomized subjects would be required to evaluate noninferiority for this primary clinical efficacy endpoint, and superiority for a renal function safety endpoint. Our findings provide the basis for future delayed CNI substitution noninferiority trials, thereby increasing the likelihood they will provide clinically implementable results and achieve regulatory approval.

Randomized trial of steroid free immunosuppression with basiliximab induction in adult live donor liver transplantation (LDLT)

BackgroundCorticosteroids are an integral part of immunosuppression following solid organ transplantation, despite their metabolic complications. We conducted a randomized trial to evaluate the efficacy of steroid-free immunosuppression following live donor liver transplantation (LDLT). MethodsWe randomized 104 patients stratified based on pre-transplant diabetic status to either a steroid-free arm (SF-arm) (Basiliximab + Tacrolimus and Azathioprine,n = 52) or Steroid arm (S-Arm) (Steroid + Tacrolimus + Azathioprine,n = 52). The primary endpoint was the occurrence of metabolic complications (new-onset diabetes after transplant (NODAT), new-onset systemic hypertension after transplant (NOSHT), post-transplant dyslipidemia) within 6 months after transplant. Secondary endpoints included biopsy-proven acute rejection (BPAR) within six months, patient and graft survival at 6 months. ResultsThe incidence NODAT was significantly higher in S-arm at 3 months (64.5%vs. 28.1%,p-0.004) and 6 months (51.6% vs. 15.6%,p-0.006). Likewise, the incidence of NOSHT (27.8% vs. 4.8%,p-0.01) and hypertriglyceridemia (26.7% vs. 8%,p-0.03) at six months was significantly higher in S-arm. However, there were no differences in BPAR (19.2% vs. 21.2%, p-0.81), time to first rejection (58 vs. 53 days, p-0.78), patient and graft survival (610 vs. 554 days,p- 0.22). ConclusionFollowing LDLT, basiliximab induction with tacrolimus and azathioprine maintenance resulted in significantly lower metabolic complications compared to the triple-drug regimen of steroid, tacrolimus, and azathioprine.

Evidence of potent humoral immune activity in COVID-19-infected kidney transplant recipients.

Whether kidney transplant recipients are capable of mounting an effective anti‐severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) adaptive immune response despite chronic immunosuppression is unknown and has important implications for therapy. Herein, we analyzed peripheral blood cell surface and intracellular cytokine phenotyping by flow cytometry along with serum antibody testing in 18 kidney transplant recipients with active coronavirus disease 2019 (COVID‐19) infection and 36 matched, transplanted controls without COVID‐19. We observed significantly fewer total lymphocytes and fewer circulating memory CD4+ and CD8+ T cells in the COVID‐19 subjects. We also showed fewer anergic and senescent CD8+ T cells in COVID‐19 individuals, but no differences in exhausted CD8+ T cells, nor in any of these CD4+ T cell subsets between groups. We also observed greater frequencies of activated B cells in the COVID‐19 patients. Sixteen of 18 COVID‐19 subjects tested for anti‐SARS‐CoV‐2 serum antibodies showed positive immunoglobulin M or immunoglobulin G titers. Additional analyses showed no significant correlation among immune phenotypes and degrees of COVID‐19 disease severity. Our findings indicate that immunosuppressed kidney transplant recipients admitted to the hospital with acute COVID‐19 infection can mount SARS‐CoV‐2‐reactive adaptive immune responses. The findings raise the possibility that empiric reductions in immunosuppressive therapy for all kidney transplant recipients with active COVID‐19 may not be required.