Rapid Steroid Withdrawal Research Articles

Alemtuzumab versus anti‐thymocyte globulin in kidney transplant recipients receiving a rapid steroid withdrawal regimen

AbstractIntroductionIn kidney transplant recipients (KTRs), steroid‐free maintenance regimens are used to minimize the negative impact of steroid use. Studies comparing alemtuzumab (ALZ) and anti‐thymocyte globulin (ATG) with rapid steroid withdrawal are limited. The aim of this study was to assess a composite outcome of incidence of de novo donor specific antibodies (dnDSAs), biopsy proven rejection (BPAR), graft failure, or death in KTRs receiving ALZ or ATG with a steroid‐free maintenance regimen.MethodsA single‐center, retrospective cohort study was conducted in adult KTRs who underwent rapid steroid withdrawal. There were two cohorts, KTRs who received induction with ALZ compared to ATG. The primary composite outcome was incidence of dnDSAs, BPAR, graft failure, or death. Secondary outcomes included renal function, cytomegalovirus (CMV) and BK viremia, and leukopenia.ResultsTwo hundred twenty‐five KTRs were included where 146 received ALZ and 79 received ATG. The Cox proportional hazard of the primary composite outcome in the ALZ compared to ATG group was not significant (unadjusted model HR 1.37, 95% CI .74–2.55). Individual incidences of composite outcome were similar. There was a difference in estimated glomerular filtration rate at 12 months post‐transplant (55.7 vs. 62.3 mL/min/1.73m2, p = .03) and leukopenia at 3 months (3.7 vs. 4.2 × 109/L, p = .03). Other secondary outcomes were similar.ConclusionsThere was no difference in composite outcome for dnDSAs, BPAR, graft failure, and death.

Excellent efficacy and beneficial safety during observational 5-year follow-up of rapid steroid withdrawal after renal transplantation (Harmony FU study).

We previously reported excellent efficacy and improved safety aspects of rapid steroid withdrawal (RSWD) in the randomized controlled 1-year "Harmony" trial with 587 predominantly deceased-donor kidney transplant recipients randomized either to basiliximab or rabbit antithymocyte globulin induction therapy and compared with standard immunosuppressive therapy consisting of basiliximab, low tacrolimus once daily, mycophenolate mofetil and corticosteroids. The 5-year post-trial follow-up (FU) data were obtained in an observational manner at a 3- and a 5-year visit only for those Harmony patients who consented to participate and covered clinical events that occurred from the second year onwards. Biopsy-proven acute rejection and death-censored graft loss rates remained low and independent of RSWD. Rapid steroid withdrawal was an independent positive factor for patient survival (adjusted hazard ratio 0.554, 95% confidence interval 0.314-0.976; P=.041).The reduced incidence of post-transplantation diabetes mellitus in RSWD patients during the original 1-year study period was not compensated by later incidences during FU. Incidences of other important outcome parameters such as opportunistic infections, malignancies, cardiovascular morbidity/risk factors, donor-specific antibody formation or kidney function did not differ during FU period. With all the limitations of a post-trial FU study, the Harmony FU data confirm excellent efficacy and beneficial safety aspects of RSWD under modern immunosuppressive therapy over the course of 5 years after kidney transplantation in an immunologically low-risk, elderly population of Caucasian kidney transplant recipients. Trial registration: Clinical trial registration number: Investigator Initiated Trial (NCT00724022, FU study DRKS00005786).

#3973 EXCELLENT EFFICACY AND BENEFICIAL SAFETY DURING FIVE YEAR FOLLOW-UP OF RAPID STEROID WITHDRAWAL AFTER RENAL TRANSPLANTATION (HARMONY STUDY)

Abstract Background and Aims We previously reported excellent efficacy and improved safety aspects of rapid steroid withdrawal in the randomized controlled one year “Harmony” trial with 587 predominantly deceased-donor kidney transplant recipients randomized either to basiliximab or rabbit antithymocyte globulin induction therapy and compared to standard immunosuppressive therapy consisting of basiliximab, low tacrolimus once daily, mycophenolate mofetil, and corticosteroids. The five-year post-trial follow-up (FU) data reported here were obtained in an observational manner to evaluate, how these excellent short-term surrogate parameters will translate into hard long-term outcome parameters like patient death/graft loss. Method The five-year post-trial follow-up data were obtained in an observational manner at a three and a five-year visit for patients who consented to participate and covered clinical events that occurred from the second year onwards. Results Biopsy-proven acute rejection and death-censored graft loss rates remained low and independent of rapid steroid withdrawal (see Figure 1). Rapid steroid withdrawal was an independent positive factor for patient survival (adjusted hazard ratio 0.554, 95 % confidence interval 0.314 to 0.976; p = 0.041, see Table 1). The reduced incidence of post-transplantation diabetes mellitus in rapid steroid withdrawal patients during the original one-year study period was not compensated by later incidences during follow-up. Incidences of other important outcome parameters such as opportunistic infections, malignancies, cardiovascular morbidity/risk factors, donor specific antibody formation, or kidney function did not differ during follow-up period. Conclusion The Harmony follow-up trial confirms excellent efficacy and beneficial safety aspects of rapid steroid withdrawal under modern immunosuppressive therapy demonstrating for the first time increased patient survival in an immunologically low-risk, elderly population of Caucasian kidney transplant recipients.

Belatacept for Simultaneous Calcineurin Inhibitor and Chronic Corticosteroid Immunosuppression Avoidance: Two-Year Results of a Prospective, Randomized Multicenter Trial.

Immunosuppressive therapy in kidney transplantation is associated with numerous toxicities. CD28-mediated T-cell costimulation blockade using belatacept may reduce long-term nephrotoxicity, compared with calcineurin inhibitor-based immunosuppression. The efficacy and safety of simultaneous calcineurin inhibitor avoidance and rapid steroid withdrawal were tested in a randomized, prospective, multicenter study. This study reports the 2-year results of a randomized clinical trial of 316 recipients of a new kidney transplant. All kidney transplants were performed using rapid steroid withdrawal immunosuppression. Recipients were randomized in a 1:1:1 ratio to receive belatacept with alemtuzumab induction, belatacept with rabbit anti-thymocyte globulin (rATG) induction, or tacrolimus with rATG induction. The composite end point consisted of death, kidney allograft loss, or an eGFR of <45 ml/min per 1.73 m2 at 2 years. The composite end point was observed for 11 of 107 (10%) participants assigned to belatacept/alemtuzumab, 13 of 104 (13%) participants assigned to belatacept/rATG, and 21 of 105 (21%) participants assigned to tacrolimus/rATG (for belatacept/alemtuzumab versus tacrolimus/rATG, P=0.99; for belatacept/rATG versus tacrolimus/rATG, P=0.66). Patient and graft survival rates were similar between all groups. An eGFR of <45 ml/min per 1.73 m2 was observed for nine of 107 (8%) participants assigned to belatacept/alemtuzuab, eight of 104 (8%) participants assigned to belatacept/rATG, and 20 of 105 (19%) participants assigned to tacrolimus/rATG (P<0.05 for each belatacept group versus tacrolimus/rATG). Biopsy sample-proven acute rejection was observed for 20 of 107 (19%) participants assigned to belatacept/alemtuzuab, 26 of 104 (25%) participants assigned to belatacept/rATG, and seven of 105 (7%) participants assigned to tacrolimus/rATG (for belatacept/alemtuzumab versus tacrolimus/rATG, P=0.006; for belatacept/rATG versus tacrolimus/rATG, P<0.001). Gastrointestinal and neurologic adverse events were less frequent with belatacept versus calcineurin-based immunosuppression. Overall 2-year outcomes were similar when comparing maintenance immunosuppression using belatacept versus tacrolimus, and each protocol involved rapid steroid withdrawal. The incidence of an eGFR of <45 ml/min per 1.73 m2 was significantly lower with belatacept compared with tacrolimus, but the incidence of biopsy sample-proven acute rejection significantly higher. Belatacept Early Steroid Withdrawal Trial, NCT01729494.

UNOS/OPTN Data-guided Assessment of Focal Segmental Glomerulosclerosis After Kidney Transplantation and Evaluation of Immunosuppressive Protocols in a Steroid-free Center.

Background.Focal segmental glomerulosclerosis (FSGS) is a common recurrent glomerulopathy associated with graft loss and patient survival after kidney transplantation (KT). However, its natural history, clinical predictors, and treatment response are still poorly understood. Steroid withdrawal regimens in KT have been associated with improvements in cardiovascular risk and patient outcomes. The Scripps Center for Organ Transplantation (SCOT) uses a rapid low-dose steroid withdrawal immunosuppression (IS) protocol for KT maintenance.Methods.We assessed the impact of our protocol on FSGS disease recurrence over a 10-y period to reassess our steroid and IS protocols and to evaluate if our patient outcomes diverge from published data. We compared 4 groups: steroids always, steroid free, steroid switch on, and steroid weaned off. We used IS and induction-matched retrospective data from United Network for Organ Sharing (UNOS) to investigate patient and graft survival for FSGS at SCOT.Results.Our analysis results differ from earlier studies showing that FSGS was associated with a higher risk of graft loss, perhaps because of selection of a UNOS data set filtered to match the SCOT IS protocol for making direct comparisons. Overall outcomes of graft failure and recipient death did not differ between SCOT patients and steroid-free transplant patient data from the UNOS data for FSGS. SCOT recurrence rate for FSGS was 7.5%, which was lower than in most published single-center studies.Conclusions.Based on our results, we believe that it is safe to continue the steroid avoidance protocols at SCOT and the steroid-free protocol may not be detrimental when the adverse effects and toxicities associated with steroid use are considered.

Rapid Steroid Withdrawal after Renal Transplantation Reduces Mortality: Five Year Follow-Up of a Randomized Controlled Trial (Harmony Study) Confirms Long Term Efficacy and Safety

Background: We previously reported excellent efficacy and improved safety aspects of rapid steroid withdrawal (RSWD) in the randomized controlled one year “Harmony” trial, in which 587 predominantly deceased-donor kidney transplant recipients were randomized either to basiliximab or rabbit ATG induction therapy and compared to standard immunosuppressive therapy consisting of basiliximab, low tacrolimus once daily, mycophenolate mofetil, and corticosteroids. Methods: Following the end of the original one-year study period, patients were asked to participate in the observational follow-up (FU) study examining most of the end points of the original study. Hereby, de novo incidences between year one and three as well as year three and five were assessed at the three-/five-year visits, respectively. Findings: Biopsy-proven acute rejection and death-censored graft survival rates remained low and independent of RSWD. RSWD was an independent positive factor for patient survival (adjusted hazard ratio 0·554, 95% confidence interval 0·314 to 0·976; p=0·041). Survival rate was increased with 89·4 % or 90·4 % in RSWD patients (basiliximab or rabbit ATG) compared to 84·7 % in control patients (p = 0·064). The reduced incidence of post-transplantation diabetes mellitus in RSWD patients during the original one-year study period was not compensated by later incidences during FU. Also, incidences of other important outcome parameters such as opportunistic infections, malignancies, cardiovascular morbidity/risk factors, donor specific antibody formation, or kidney function did not differ during FU period. Unexpectedly, patient incidences of bacterial infections requiring hospitalization was reduced in the rabbit ATG group. Interpretation: The Harmony FU trial confirms excellent efficacy and beneficial safety aspects of RSWD under modern immunosuppressive therapy. This is the first randomized study demonstrating increased patient survival in RSWD patients. The results shown here support that RSWD should become the new gold standard approach in an immunologically low-risk, elderly, and severely diseased population of Caucasian kidney transplant recipients. Trial Registration: Follow-up study DRK5786; Original trial NCT 00724022). Funding: The FU trial was designed and run by the first and last author who received financial support from Astellas Pharma GmbH and Sanofi (Investigator Initiated Trial (NCT 00724022, follow up study DRK5786). Neither of the funders had any role in data collection, data analysis, data interpretation, or writing of the manuscript. An independent contract research organization (Coordination Center for Clinical Studies of the Technical University of Dresden, Dresden, Germany) was responsible for data collection, monitoring and statistical analyses. Declaration of Interest: CH received grant support, consulting fees, and lecture fees from Astellas, Sanofi, Genzyme, Roche Pharma, Novartis, and Wyeth/Pfizer. CK received consulting fees and lecture fees from Astellas, Chiesi, Novartis, Sanofi-Genzyme. JWM received grant support, consulting fees, and lecture fees from Vifor, GSK, Novartis, Astra-Zeneca and Boehringer Ingelheim. OW has received research grants for clinical studies, speaker’s fees, honoraria and travel expenses from Amgen, Alexion, Astellas, Basilea, Biotest, Bristol-Myers Squibb, Correvio, Chiesi, Gilead, Hexal, Janssen, Dr. F. Kohler Chemie, MSD, Novartis, Roche, Pfizer, Sanofi, Takeda, TEVA and UCB. BB received grant support, consulting fees and lecture fees from Astellas, Bayer, Chiesi and Novartis. All other authors declare no competing interests. Ethical Approval: The study was approved by the institutional review boards of all sites participating in the follow-up period.

Kidney allograft rejection: Diagnosis and treatment practices in USA- A UNOS survey.

We studied diverse rejection management strategies across centers by conducting a UNOS survey of kidney transplant program directors in 2017. There were 104 total responses from 235 kidney transplant programs representing 88 unique transplant programs (response rate 37%). Information was collected on center-specific management practices. Pertinent center-specific data were obtained from the OPTN database. Of the respondents, 33% were considered large centers (>100 transplants/year). Thymoglobulin was the most commonly used induction agent at 84%, 72% responders do rapid steroid withdrawal, and mycophenolic acid (MPA) is the major antimetabolite (100%). For diagnosing TCMR, 100% used indication biopsy, 28% used protocol biopsy, 2% used serum biomarkers, and none used urine cytokines. For ABMR, 99% used indication biopsy, 34% used protocol biopsy, 72% used DSA, 21% used C1q positive DSA, and none used gene profiling (ENDATS). The treatment of subclinical and clinical TCMR included iv/PO steroids. PP/IVIG were the commonest treatments for ABMR. The use of rituximab, bortezomib, and eculizumab increased from C4D-ABMR to recurrent ABMR. There are diverse management practices for diagnosing and treating rejection. An effort to harmonize these diverse practices for management of TCMR and ABMR will give an opportunity to pool data for evaluating clinical outcomes.

Antithymocyte induction dosing and incidence of opportunistic viral infections using steroid-free maintenance immunosuppression.

Currently, there is limited literature evaluating rATG induction dosing and incidence of opportunistic viral infections when using steroid-free maintenance immunosuppression. This single-center, retrospective, study compared high rATG (>4.5mg/kg) versus low (<4.5mg/kg) induction dosing and the overall incidence of early opportunistic viral infection at 180days in the setting of maintenance immunosuppression consisting of tacrolimus, mycophenolate, rapid steroid withdrawal, and a tiered antiviral prevention strategy based on donor-recipient Cytomegalovirus (CMV) serostatus. A total of 209 patients were included; 76 patients received low-dose and 133 patients received high-dose rATG. Incidence of overall opportunistic viral infection occurred more frequently in patients who received high compared to low dose (29.8% vs 25% p=.030). Incidence of CMV infection was also significantly increased in the high-dose group (31.6% vs 18.4% p=.039). In a multivariable model, rATG dose, as a continuous variable, remained a significant independent predictor of infection along with CMV risk (OR 1.46, 95% CI 1.02-2.09) controlling for age and CMV risk. There were no differences in graft-related outcomes at 180days. Higher cumulative rATG induction dose was associated with increased incidence of opportunistic viral infections, in the setting of a steroid-free maintenance immunosuppression in the early post-transplant period.

UNOS/OPTN data guided assessment of IgA nephropathy recurrence after kidney transplantation and evaluation of immunosuppressive protocols in a steroid free center

Immunoglobulin A (IgA) Nephropathy (IgAN) is one of the most common recurrent glomerulopathies associated with graft loss and patient survival after kidney transplantation (KT). Steroid withdrawal regimens in KT have been associated with improvements of patient outcomes. The Scripps Center for Organ Transplantation (SCOT) utilizes a rapid low-dose steroid withdrawal immunosuppression (IS) protocol for KT maintenance. We assessed the impact of our protocol on IgAN recurrence over a 10-year period to reassess our steroid withdrawal and IS protocols to see if outcomes diverged from available UNOS data. Therefore, we used IS and induction matched retrospective data from UNOS to investigate patient and graft survival for IgAN. SCOT recurrence rates for IgAN was 13.6%. Overall outcomes of graft failure and recipient death did not differ between SCOT patients and data obtained from steroid free transplants from UNOS. Our results differ from earlier studies showing IgAN was associated with a higher risk of graft loss, perhaps due to selection of a SCOT IS matched dataset. Based on our analysis, we believe that it is safe to continue the steroid avoidance protocols at SCOT and think that it may be beneficial, given the adverse effects and toxicities associated with steroid use.

Evidence for the alloimmune basis and prognostic significance of Borderline T cell-mediated rejection.

Prognostic biomarkers of T cell–mediated rejection (TCMR) have not been adequately studied in the modern era. We evaluated 803 renal transplant recipients and correlated HLA‐DR/DQ molecular mismatch alloimmune risk categories (low, intermediate, high) with the severity, frequency, and persistence of TCMR. Allograft survival was reduced in recipients with Banff Borderline (hazard ratio [HR] 2.4, P = .003) and Banff ≥ IA TCMR (HR 4.3, P < .0001) including a subset who never developed de novo donor‐specific antibodies (P = .002). HLA‐DR/DQ molecular mismatch alloimmune risk categories were multivariate correlates of Banff Borderline and Banff ≥ IA TCMR and correlated with the severity and frequency of rejection episodes. Recipient age, HLA‐DR/DQ molecular mismatch category, and cyclosporin vs tacrolimus immunosuppression were independent correlates of Banff Borderline and Banff ≥ IA TCMR. In the subset treated with tacrolimus (720/803) recipient age, HLA‐DR/DQ molecular mismatch category, and tacrolimus coefficient of variation were independent correlates of TCMR. The correlation of HLA‐DR/DQ molecular mismatch category with TCMR, including Borderline, provides evidence for their alloimmune basis. HLA‐DR/DQ molecular mismatch may represent a precise prognostic biomarker that can be applied to tailor immunosuppression or design clinical trials based on individual patient risk.

Randomized Controlled Trial Assessing the Impact of Tacrolimus Versus Cyclosporine on the Incidence of Posttransplant Diabetes Mellitus

IntroductionDespite the high incidence of posttransplant diabetes mellitus (PTDM) among high-risk recipients, no studies have investigated its prevention by immunosuppression optimization.MethodsWe conducted an open-label, multicenter, randomized trial testing whether a tacrolimus-based immunosuppression and rapid steroid withdrawal (SW) within 1 week (Tac-SW) or cyclosporine A (CsA) with steroid minimization (SM) (CsA-SM), decreased the incidence of PTDM compared with tacrolimus with SM (Tac-SM). All arms received basiliximab and mycophenolate mofetil. High risk was defined by age >60 or >45 years plus metabolic criteria based on body mass index, triglycerides, and high-density lipoprotein–cholesterol levels. The primary endpoint was the incidence of PTDM after 12 months.ResultsThe study comprised 128 de novo renal transplant recipients without pretransplant diabetes (Tac-SW: 44, Tac-SM: 42, CsA-SM: 42). The 1-year incidence of PTDM in each arm was 37.8% for Tac-SW, 25.7% for Tac-SM, and 9.7% for CsA-SM (relative risk [RR] Tac-SW vs. CsA-SM 3.9 [1.2–12.4; P = 0.01]; RR Tac-SM vs. CsA-SM 2.7 [0.8–8.9; P = 0.1]). Antidiabetic therapy was required less commonly in the CsA-SM arm (P = 0.06); however, acute rejection rate was higher in CsA-SM arm (Tac-SW 11.4%, Tac-SM 4.8%, and CsA-SM 21.4% of patients; cumulative incidence P = 0.04). Graft and patient survival, and graft function were similar among arms.ConclusionIn high-risk patients, tacrolimus-based immunosuppression with SM provides the best balance between PTDM and acute rejection incidence.

Short-term adverse effects of early subclinical allograft inflammation in kidney transplant recipients with a rapid steroid withdrawal protocol.

The impact of subclinical inflammation (SCI) noted on early kidney allograft biopsies remains unclear. This study evaluated the outcome of SCI noted on 3-month biopsy. A total of 273/363 (75%) kidney transplant recipients with a functioning kidney underwent allograft biopsies 3-months posttransplant. Among those with stable allograft function at 3months, 200 biopsies that did not meet the Banff criteria for acute rejection were identified. These were Group I: No Inflammation (NI, n=71) and Group II: Subclinical Inflammation (SCI, n=129). We evaluated differences in kidney function at 24-months and allograft histology score at 12-month biopsy. SCI patients had a higher serum creatinine (1.6±0.7 vs 1.38±0.45; P=.02) at 24-months posttransplant, and at last follow-up at a mean of 42.5months (1.69±0.9 vs 1.46±0.5mg/dL; P=.027). The allograft chronicity score (ci+ct+cg+cv) at 12-months posttransplant was higher in the SCI group (2.4±1.35 vs 1.9±1.2; P=.02). The incidence of subsequent rejections within the first year in SCI and NI groups was 24% vs 10%, respectively (P=.015). De novo donor-specific antibody within 12months was more prevalent in the SCI group (12/129 vs 1/71, P=.03). SCI is likely not a benign finding and may have long-term implications for kidney allograft function.

Efficacy of rapid steroid withdrawal after induction therapy

Efficacy of rapid steroid withdrawal after induction therapy

Infliximab and Low Dose Alemtuzumab in Patients with Steroid-Refractory Acute Graft-Versus-Host Disease

Introduction:Steroid-refractory grade IV acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) carries a mortality rate of approximately 80%. Trials of novel therapies including antibodies directed against the T-cell immune response have generally failed to improve outcomes although may lead to responses. Infliximab, a chimeric monoclonal antibody to TNF alpha, and alemtuzumab another monoclonal antibody targeting CD52, an antigen expressed on T and B lymphocytes and other antigen presenting cells (APCs) both have produced response rates in the 50-75% range. However, few are long-term survivors as the majority die of opportunistic infections (OI). While steroids are ineffective in many series, they are continued when novel agents are employed. We have approached steroid-refractory aGVHD with a combination of rapid steroid discontinuation, standard doses of infliximab and short course low dose alemtuzumab with the hope for aGVHD control without early deaths from OIs.Methods:We identified all patients who were treated for steroid-refractory aGVHD between January 1, 2014 and March 1, 2016 at Loyola University Medical Center. The diagnosis of aGVHD was made by clinical criteria per the National Institutes of Health guidelines. The diagnosis was confirmed by endoscopic evaluation and biopsy of the affected organ. All patients received methylprednisolone 2 mg/kg/day IV given in twice daily dosing for at least 7 days prior to being considered steroid-refractory. Patients received infliximab 10 mg/kg IV infusion weekly x 2 then every other week until remission and alemtuzumab 3 mg IV test dose on day 1, followed by 10 mg IV daily for 4 days. At the same time steroids were reduced by 50% and further reductions of 50% were made every 4 days. Responses were assessed by daily grading of aGVHD per Glucksberg criteria after dosing of infliximab and alemtuzumab. A complete response (CR) was defined as full resolution of abdominal pain, diarrhea, rectal bleeding, liver function test abnormalities, or skin involvement. A partial response (PR) was defined as a 50% improvement in diarrhea, liver function abnormalities, or skin involvement with a decrease in 1 or more grade levels of aGVHD per Glucksberg criteria.Results:To date 6 patients have been treated for steroid-refractory aGVHD after matched related donor (MRD) or matched unrelated donor (MUD) HSCT. Patient characteristics are shown in Table 1. There were 5 patients who underwent a MRD or MUD HSCT for myelodysplastic syndrome (MDS), and 1 patient who underwent a MUD HSCT for B-cell acute lymphoblastic leukemia (B-ALL). Median age at treatment was 64 years. All patients had Glucksberg grade 4 aGVHD (Table 1). The overall response rate (ORR) was 83% with 4 patients achieving a PR, 1 patient achieving CR, and 1 patient with no response to treatment. Day 100 survival after dosing of alemtuzumab was 50% with deaths due to aGVHD in 2 patients and death due to septic shock in 1 patient. CMV reactivation occurred in 4 patients and EBV reactivation occurred in 1 patient.Conclusion:In our single institution analysis, the combination of infliximab and alemtuzumab with rapid steroid withdrawal achieved a high ORR of 83% in treatment of steroid-refractory aGVHD after MRD or MUD HSCT with an encouraging 50% survival at day 100. This approach will be continued to further define its efficacy and safety for the treatment of steroid-refractory aGVHD. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Rabbit-ATG or basiliximab induction for rapid steroid withdrawal after renal transplantation (Harmony): an open-label, multicentre, randomised controlled trial

Standard practice for immunosuppressive therapy after renal transplantation is quadruple therapy using antibody induction, low-dose tacrolimus, mycophenolate mofetil, and corticosteroids. Long-term steroid intake significantly increases cardiovascular risk factors with negative effects on the outcome, especially post-transplantation diabetes associated with morbidity and mortality. In this trial, we examined the efficacy and safety parameters of rapid steroid withdrawal after induction therapy with either rabbit antithymocyte globulin (rabbit ATG) or basiliximab in immunologically low-risk patients during the first year after kidney transplantation. In this open-label, multicentre, randomised controlled trial, we randomly assigned renal transplant recipients in a 1:1:1 ratio to receive either basiliximab induction with low-dose tacrolimus, mycophenolate mofetil, and steroid maintenance therapy (arm A), rapid corticosteroid withdrawal on day 8 (arm B), or rapid corticosteroid withdrawal on day 8 after rabbit ATG (arm C). The study was done in 21 centres across Germany. Only participants aged between 18 and 75 years with a low immunological risk who were scheduled to receive a single-organ renal transplant from either a living donor or a deceased donor were considered for enrolment. Patients receiving a second renal transplant were eligible, provided that the first allograft was not lost due to acute rejection within the first year after transplantation. Donor and recipient had to be ABO compatible. Grafts with pre-transplant existing donor-specific human leukocyte antigen (HLA) antibodies were not eligible and the recipients had to have a panel-reactive antibody concentration of 30% or less. Pregnant women and nursing mothers were excluded from the study. The primary endpoint was the incidence of biopsy-proven acute rejection (BPAR) at 12 months. All analyses were done by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00724022. Between Aug 7, 2008, and Nov 30, 2013, 615 patients were randomly assigned to arm A (206), arm B (189), and arm C (192). BPAR rates were not reduced by rabbit ATG (9·9%) compared with either treatment arm A (11·2%) or B (10·6%; A versus C: p=0·75, B versus C p=0·87). As a secondary endpoint, rapid steroid withdrawal reduced post-transplantation diabetes in arm B to 24% and in arm C to 23% compared with 39% in control arm A (A versus B and C: p=0·0004). Patient survival (94·7% in arm A, 97·4% in arm B, and 96·9% in arm C) and censored graft survival (96·1% in arm A, 96·8% in arm B, and 95·8% in arm C) after 12 months were excellent and equivalent in all arms. Safety parameters such as infections or the incidence of post-transplantation malignancies did not differ between the study arms. Rabbit ATG did not show superiority over basiliximab induction for the prevention of BPAR after rapid steroid withdrawal within 1 year after renal transplantation. Nevertheless, rapid steroid withdrawal after induction therapy for patients with a low immunological risk profile can be achieved without loss of efficacy and is advantageous in regard to post-transplantation diabetes incidence. Investigator Initiated Trial; financial support by Astellas Pharma GmbH, Sanofi, and Roche Pharma AG.

Rapid steroid withdrawal in kidney transplantation: living in HARMONY?

Rapid steroid withdrawal in kidney transplantation: living in HARMONY?

Impact of Maintenance Steroids versus Rapid Steroid Withdrawal in African-American Kidney Transplant Recipients: Comparison of Two Urban Centers.

BackgroundRapid steroid withdrawal (RSW) is used increasingly in kidney transplantation but long-term outcomes in African-American (AA) recipients are not well known. We compared 1 and 5 year transplant outcomes in a large cohort of AA patients who were maintained on continued steroid therapy (CST) to those who underwent RSW.MethodsPost-transplant courses of A as receiving kidney allografts from 2003–2011 at two urban transplant centers in Chicago were followed. Prior to outcome analysis, we used Inverse Probability of Treatment Weights (IPTW) to match the two groups on a set of baseline risk factors. Graft and patient survival, GFR at 1 and 5 years, incidence and type of rejection, incidence of post-transplant diabetes mellitus (PTDM), delayed graft function, CMV and BK viremia were compared.ResultsThere were 150 AA recipients in the CST analytic group and 157 in the RSW analytic group. Graft and patient survival was similar between the two groups. Rates of CMV viremia were higher in the RSW compared to the CST analytic group at 1 year. Biopsy-proven acute rejection and PTDM were similar between the RSW and CST groups.ConclusionsIn AA recipients, RSW has similar long-term outcomes to CST.

A Prospective Study of Acute Clinical and Subclinical Rejection in a Rapid Steroid Withdrawal Protocol.

Purpose: To estimate the incidence and risk factors for acute clinical rejection (CR) and subclinical rejection (SCR) and evaluate response to therapy. Methods: We prospectively followed all adults who underwent kidney transplantation between 1/1/2013 - 9/30/2013 at our center. All received thymoglobulin(94%) or simulect(6%) induction, CNI/MPA maintenance therapy and rapid steroid withdrawal by day 7. Protocol biopsy was performed at 3 months post transplant. Five pts expired within 3 months of transplant and were excluded. Remaining 138 were divided into 4 groups. Gr I (N=15) had SCR on protocol biopsy and received therapy. Gr II (N=62) no rejection. Gr III (n=16) had acute CR on indication biopsy. Gr IV (n=45) did not undergo biopsy. Banff classification was followed for biopsy grading. Steroids and/or thymoglobulin were used for acute T-cell rejection and PP/IVIG for acute AMR. Recipient demographics, transplant and post-transplant variables, serum creatinine (1, 3 and 6 months) were compared using t-test and chi-square test. Results: The incidence of SCR was 16%(15/93) and CR was 11.6%(16/138). The distribution of variables are as shown.Table: No Caption available.No statistical difference was noted for all variables among the groups. Creatinine was higher in patients with CR at the time of the biopsy. There was a trend towards decline in creatinine from 1 to 6 months in Gr 1 and 3 (p = NS). Conclusion: This prospective study revealed the incidence of acute CR to be 11.6% and SCR to be 16% with mainly thymoglobulin induction and CNI/MPA based maintenance therapy with rapid steroid withdrawal. This immunosuppressive regimen was associated with high incidence of combined CR and SCR (at 3 months post-transplant). Protocol biopsy helps identify early acute rejection and optimize therapy to stabilize short-term renal function. Longer follow up with larger cohort size is required to estimate long-term outcome.

Impact of Early Conversion From Tacrolimus to Sirolimus on Chronic Allograft Changes in Kidney Recipients on Rapid Steroid Withdrawal

Calcineurin-inhibitor therapy is a contributing factor to the origin of interstitial fibrosis and tubular atrophy (IFTA). We conducted a prospective randomized trial of conversion of tacrolimus to sirolimus at 1-month posttransplant in kidney transplant recipients on rapid steroid withdrawal. We compared the chronic changes (IFTA and sum of Banff chronic scores--Total Score) on protocol biopsies at 1 month, 1 year, and 2 years in all randomized patients. We compared the outcomes between treatment groups and analyzed the impact of previous rejection on the chronic changes. We randomized 122 patients, 62 to sirolimus and 60 to tacrolimus. The 1-year biopsy was performed in 54 patients (90%) of the tacrolimus group and 56 patients (90%) of the sirolimus group. The proportion of biopsies with IFTA more than or equal to 2 and the Total Score more than 2 increased over the 2 years but were not different between the study groups at any time point. On the 1-year biopsy, there was more IFTA, and the fraction with Total Score more than 2 was higher in the tacrolimus group with previous rejection. In the cohort without rejection, there was a significant progression of the IFTA and Total Score between 1 and 2 years in both the sirolimus and tacrolimus groups. Conversion from tacrolimus to sirolimus at 1-month posttransplant in kidney transplant recipients on rapid steroid withdrawal does not decrease the progression of chronic changes on protocol biopsies during the first 2 years even in those patients without previous acute rejection.

Results of a Prospective Randomized Trial of Sirolimus Conversion in Kidney Transplant Recipients on Early Corticosteroid Withdrawal

The use of calcineurin inhibitors is associated with chronic nephrotoxicity and lower glomerular filtration rate (GFR). As a result, one strategy of transplant immunosuppression is calcineurin inhibitor elimination. The aim of this study was to determine the outcome of a prospective randomized trial of kidney transplant recipients receiving rapid corticosteroid withdrawal, tacrolimus and mycophenolate mofetil (MMF) for 1 month followed by randomization to switch to sirolimus-MMF or to stay on tacrolimus-MMF. The primary outcome was the difference in measured GFR at 1 year using intention-to-treat analysis. Sixty patients were randomized to stay on tacrolimus-MMF and 62 to sirolimus-MMF. Actual graft survival (including death) at 2 years was 98.4% in the sirolimus group, 96.7% in the tacrolimus group. Sixty-three percentage of the patients in the sirolimus group withdrew during the 2-year period of the study compared with 18% of the tacrolimus group (P<0.0001), primarily related to rejection or medication side effects. Rejection during the first year occurred in 5% of the tacrolimus group and 13% of the sirolimus group (P=0.15). Measured GFR at 1 year (mean±SD) was 57.4±20.7 mL/min/1.73 m in the sirolimus group and 62.7±26.5 mL/min/1.73 m in the tacrolimus group (95% CI of difference -3.7-14.4). We conclude that conversion from tacrolimus-MMF to sirolimus-MMF at 1 month posttransplant in kidney recipients on rapid steroid withdrawal is poorly tolerated and does not improve GFR at 1 year.