Dataset Information

Transcription profiling of human kidneys from chronic allograft nephropathy patients treated with either cyclosporin or sirolimus immunosuppression regimes

ABSTRACT: Background: Despite significant improvements in short-term kidney transplant survival, comparable increases in 5 and 10-year outcomes have not been achieved. Chronic allograft nephropathy (CAN) is a major cause of late graft loss. Toxic nephropathy and inadequate long-term immunosuppression are possible factors. We performed a randomized prospective trial comparing calcineurin inhibitor (CNI)-free to CNI-based immunosuppression to determine the impact on renal function, structure, and gene expression. Methods: Sixty-one kidney recipients received mycophenolate mofetil (MMF), and prednisone (P). Randomized patients received concentration-controlled sirolimus or cyclosporine. Two years post-transplant 55 patients underwent renal function studies, 48 (87%) underwent transplant biopsies; all classified by Banff scoring and 41 by DNA microarrays. Findings: Comparing sirolimus/MMF/P to cyclosporine/MMF/P at two years, there was a significantly lower serum creatinine (1.35 vs. 1.81 mg/dl; p=0.008), significantly higher Cockroft-Gault glomerular filtration rate (GFR) (80.4 vs. 63.4 cc/min; p=0.008), iothalamate GFR (60.6 vs. 49.2 cc/min; p= 0.018), and Banff 0 (normal) biopsies (66.6 vs. 20.8%; p=0.013). Regression analysis of calculated GFRâs from 1 to 36 months yielded a positive slope for sirolimus of 3.36 ml/min/year, and a negative slope for cyclosporine of â1.58 ml/min/year (p=0.008). Gene expression profiles of kidney biopsies with higher Banff CAN scores confirmed significant up regulation of genes responsible for immune/inflammation and fibrosis/tissue remodeling. Interpretation: At two years the sirolimus-treated patients have better renal transplant function, a diminished prevalence of CAN, and down regulated expression of genes responsible for the progression of CAN. All may provide for an alternative natural history with improved graft survival.

ORGANISM(S): Homo sapiens

SUBMITTER:

PROVIDER: S-DIXA-D-1039 | biostudies-other |

REPOSITORIES: biostudies-other

ACCESS DATA

Similar Datasets

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.

Dataset Information

Transcription profiling of human kidneys from chronic allograft nephropathy patients treated with either cyclosporin or sirolimus immunosuppression regimes

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets