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Successful reduction of immunosuppression in older renal transplant recipients who exhibit donor-specific regulation.

ABSTRACT: We hypothesized that T-regulatory cells specific for donor alloantigens would protect a renal transplant during partial withdrawal of immunosuppression.To test this hypothesis, 32 renal transplant recipients aged 55 years and older with excellent renal function were tested for donor-specific regulation (DSR) by trans-vivo delayed type hypersensitivity assay at the time of enrollment (T=0) and 6 months later (T=6). Twenty-two patients had prednisone withdrawn during a 3-month period, whereas 10 controls were maintained on triple therapy (prednisone, cyclosporine, and mycophenolate).Of 22 patients in the steroid withdrawal group, 10 were DSR+ and 12 were DSR- at the time of enrollment (T=0). None of the DSR+ patients experienced acute rejection, nor did any have donor-specific human leukocyte antigen (HLA) antibody during or after withdrawal. Of 12 DSR- patients, three developed acute rejection, which were reversed with bolus steroid treatment, and four were donor-specific antibody+ at T=0 or T=6. Two years later, 80% (8 of 10) of DSR+ patients in the withdrawal group remain steroid free while maintaining excellent renal function, as compared with only 58% (7 of 12) DSR- patients. Patient survival at 4 years was similar for DSR+ (9 of 10) and DSR- (11 of 12) patients in the withdrawal group. Patients maintained on triple therapy remained rejection free during the 4-year follow-up regardless of initial DSR status, with patient survival rate of 70% (7 of 10).DSR before steroid withdrawal may identify a subset of transplant patients who could benefit from reduction of immunosuppression without elevated risk of rejection or deteriorating renal function.

SUBMITTER: Jankowska-Gan E

PROVIDER: S-EPMC2747510 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Successful reduction of immunosuppression in older renal transplant recipients who exhibit donor-specific regulation.

Jankowska-Gan Ewa E Sollinger Hans W HW Pirsch John D JD Cai Junchao J Pascual Julio J Haynes Lynn D LD Munoz del Rio Alenjandro A Burlingham William J WJ

Transplantation 20090801 4

<h4>Background</h4>We hypothesized that T-regulatory cells specific for donor alloantigens would protect a renal transplant during partial withdrawal of immunosuppression.<h4>Methods</h4>To test this hypothesis, 32 renal transplant recipients aged 55 years and older with excellent renal function were tested for donor-specific regulation (DSR) by trans-vivo delayed type hypersensitivity assay at the time of enrollment (T=0) and 6 months later (T=6). Twenty-two patients had prednisone withdrawn du ...[more]

PMID: 19696637

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Project description:BackgroundThe efficacy and safety of minimisation of immunosuppression including early steroid withdrawal in kidney transplant recipients treated with Basiliximab induction remains unclear.MethodsThis retrospective cohort study reports the outcomes from 298 consecutive renal transplants performed since 1st July 2010-June 2013 treated with Basiliximab induction and early steroid withdrawal in low immunological risk patients using a simple immunological risk stratification and 3-month protocol biopsy to optimise therapy. The cohort comprised 225 low-risk patients (first transplant or HLA antibody calculated reaction frequency (CRF ≤50% with no donor specific HLA antibodies) who underwent basiliximab induction, steroid withdrawal on day 7 and maintenance with tacrolimus and mycophenolate mofetil (MMF), and 73 high-risk patients who received tacrolimus, MMF and prednisolone for the first 3 months followed by long term maintenance immunosuppression with tacrolimus and prednisolone. High-risk patients not undergoing 3-month protocol biopsy were continued on triple immunosuppression.ResultsSteroid withdrawal could be safely achieved in low immunological risk recipients with IL2 receptor antibody induction. The incidence of biopsy-proven acute rejection was 15.1% in the low-risk and 13.9% in the high-risk group (including sub-clinical rejection detected at protocol biopsy). One- year graft survival was 93.3% and patient survival 98.5% in the low-risk group, and 97.3 and 100% respectively in the high-risk group. Graft function was similar in each group at 1 year (mean eGFR 61.2 ± 23.4 mL/min low-risk and 64.6 ± 19.2 mL/min high-risk).ConclusionsImmunosuppression regimen comprising basiliximab induction, tacrolimus, MMF and prednisolone with early steroid withdrawal in low risk patients and MMF withdrawal in high risk patients following a normal 3-month protocol biopsy is effective in limiting acute rejection episodes and produces excellent rates of patient survival, graft function and complications.

Project description:Background and aimsAs conversion from calcineurin inhibitor to sirolimus (SRL), a mechanistic target of rapamycin inhibitor (mTOR-I), has been shown to enhance immunoregulatory profiles in liver transplant (LT) recipients (LTRs), mTOR-I therapy might allow for increased success of immunosuppression (IS) withdrawal. Our aim was to determine if operational tolerance could be observed in LTRs withdrawn from SRL and if blood/graft tolerance biomarkers were predictive of successful withdrawal.Approach and resultsWe performed a prospective trial of SRL monotherapy withdrawal in nonimmune, nonviremic LTRs > 3 years post-LT. SRL was weaned over ~6 months, and biopsies were performed 12 months postweaning or at concern for acute rejection. Twenty-one LTRs consented; 6 were excluded due to subclinical acute rejection on baseline biopsy or other reasons, and 15 underwent weaning (age 61.3 ± 8.8 years; LT to SRL weaning 6.7 ± 3 years). Eight (53%) achieved operational tolerance (TOL). Of the 7 who were nontolerant (non-TOL), 6 had mild acute rejection on biopsy near the end of weaning or at study end; 1 was removed from the trial due to liver cancer recurrence. At baseline preweaning, there were statistically increased blood tolerogenic dendritic cells and cell phenotypes correlating with chronic antigen presentation in the TOL versus non-TOL groups. A previously identified biopsy gene signature accurately predicted TOL versus non-TOL in 12/14 LTRs before weaning. At study end, biopsy staining revealed statistically significant increases in antigen-presenting cell:leukocyte pairings, FOXP3+ /CD4+ T cells, Tbet+ /CD8+ T cells, and lobular dendritic cells in the non-TOL group.ConclusionsThis study evaluated IS withdrawal directly from mTOR-I therapy in LTRs and achieved > 50% operational tolerance. Preweaning gene expression and peripheral blood mononuclear cell profiling may be useful as predictors of successful mTOR-I therapy withdrawal. NCT02062944.

Project description:Background3% of kidney transplant recipients return to dialysis annually upon allograft failure. Development of antibodies (Ab) against human leukocyte antigens (HLA) is a validated prognostic biomarker of allograft failure. We tested whether screening for HLA Ab, combined with an intervention to improve adherence and optimization of immunosuppression could prevent allograft failure.MethodsProspective, open-labelled randomised biomarker-based strategy (hybrid) trial in 13 UK transplant centres [EudraCT (2012-004308-36) and ISRCTN (46157828)]. Patients were randomly allocated (1:1) to unblinded or double-blinded arms and screened every 8 months. Unblinded HLA Ab+ patients were interviewed to encourage medication adherence and had tailored optimisation of Tacrolimus, Mycophenolate mofetil and Prednisolone. The primary outcome was time to graft failure in an intention to treat analysis. The trial had 80% power to detect a hazard ratio of 0.49 in donor specific antibody (DSA)+ patients.FindingsFrom 11/9/13 to 27/10/16, 5519 were screened for eligibility and 2037 randomised (1028 to unblinded care and 1009 to double blinded care). We identified 198 with DSA and 818 with non-DSA. Development of DSA, but not non-DSA was predictive of graft failure. HRs for graft failure in unblinded DSA+ and non-DSA+ groups were 1.54 (95% CI: 0.72 to 3.30) and 0.97 (0.54-1.74) respectively, providing no evidence of an intervention effect. Non-inferiority for the overall unblinded versus blinded comparison was not demonstrated as the upper confidence limit of the HR for graft failure exceeded 1.4 (1.02, 95% CI: 0.72 to 1.44). The only secondary endpoint reduced in the unblinded arm was biopsy-proven rejection.InterpretationIntervention to improve adherence and optimize immunosuppression does not delay failure of renal transplants after development of DSA. Whilst DSA predicts increased risk of allograft failure, novel interventions are needed before screening can be used to direct therapy.FundingThe National Institute for Health Research Efficacy and Mechanism Evaluation programme grant (ref 11/100/34).

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Successful reduction of immunosuppression in older renal transplant recipients who exhibit donor-specific regulation.

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Successful reduction of immunosuppression in older renal transplant recipients who exhibit donor-specific regulation.

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