Project description:Immunosuppression is needed in HLA identical sibling renal transplantation. We conducted a tolerance trial in this patient cohort using Alemtuzumab induction, donor hematopoietic stem cells, tacrolimus/mycophenolate immunosuppression converted to sirolimus, planning complete drug withdrawal by 24 months post-transplantation. After an additional 12 months with no immunosuppression, normal biopsies and renal function, recipients were considered tolerant. Twenty recipients were enrolled. Of the first 10 (>36 months post-transplantation), 5 had immunosuppression successfully withdrawn for 16-36 months (tolerant), 2 had disease recurrence and 3 had subclinical rejection in protocol biopsies (non-tolerant). Microchimerism disappeared after 1 year, and CD4+CD25highCD127-FOXP3+ T cells and CD19+IgD/M+CD27- B cells increased to 5 years post-transplantation in both groups, whereas immune/inflammatory gene expression pathways in the peripheral blood and urine were differentially downregulated in tolerant compared to non-tolerant recipients. Therefore, in this HLA identical renal transplant tolerance trial, absent chimerism, Treg and Breg immunophenotypes were indistinguishable between tolerant and non-tolerant recipients, but global genomic changes indicating immunomodulation were observed only in tolerant recipients. A total of 46 PBMC samples representing blood draws from four time points in the first 9 recipients were processed for microarray analysis (The Scripps Research Institute, La Jolla, CA). The analyzed time points were: immediately pre-operatively in the absence of immunosuppression (n=9); post-operatively at 1 year (n=8, range 11-13 months); at 2 years (n=12, range 18-25 months); >3 years (n=17, range 32-48 months). (At year 2 and at > 3 years, repeated samples were obtained from individual subjects, and at one year, one subject had a technically unsatisfactory sample.) To discount the effects of immunosuppression on gene expression, microarray data were included on whole blood from 18 healthy human subjects (controls: GSE40586; NCBI Gene Expression Omnibus [GEO] repository).
Project description:Immunosuppression is needed in HLA identical sibling renal transplantation. We conducted a tolerance trial in this patient cohort using Alemtuzumab induction, donor hematopoietic stem cells, tacrolimus/mycophenolate immunosuppression converted to sirolimus, planning complete drug withdrawal by 24 months post-transplantation. After an additional 12 months with no immunosuppression, normal biopsies and renal function, recipients were considered tolerant. Twenty recipients were enrolled. Of the first 10 (>36 months post-transplantation), 5 had immunosuppression successfully withdrawn for 16-36 months (tolerant), 2 had disease recurrence and 3 had subclinical rejection in protocol biopsies (non-tolerant). Microchimerism disappeared after 1 year, and CD4+CD25highCD127-FOXP3+ T cells and CD19+IgD/M+CD27- B cells increased to 5 years post-transplantation in both groups, whereas immune/inflammatory gene expression pathways in the peripheral blood and urine were differentially downregulated in tolerant compared to non-tolerant recipients. Therefore, in this HLA identical renal transplant tolerance trial, absent chimerism, Treg and Breg immunophenotypes were indistinguishable between tolerant and non-tolerant recipients, but global genomic changes indicating immunomodulation were observed only in tolerant recipients.
Project description:Histological analysis of biopsy is the gold standard to assess renal allograft status. Furthermore, 1-year protocol biopsy is often performed to evaluated graft outcome. However, since biopsy cannot be performed in a time serial basis, we decided to investigate whether blood can be a good compartment to predict allograft outcome. Gene expression microarrays and a large phenotype have been performed in peripheral blood mononuclear cells from 79 renal transplanted patients taken 3 months after transplantation. We evaluated the association of biological parameters with 4 histological groups defined on renal biopsy taken at 1-year post-transplantation: patients which display normal biopsy (n=45), patients with signs of tubular atrophy and interstitial fibrosis (IFTA) (n=14), with IFTA with inflammation (i-IFTA) (n=14) and patients with alloimmune lesions (n=6)
Project description:Histological analysis of biopsy is the gold standard to assess renal allograft status. Furthermore, 1-year protocol biopsy is often performed to evaluated graft outcome. However, since biopsy cannot be performed in a time serial basis, we decided to investigate whether blood can be a good compartment to predict allograft outcome. Gene expression microarrays and a large phenotype have been performed in peripheral blood mononuclear cells from 79 renal transplanted patients taken 3 months after transplantation. We evaluated the association of biological parameters with 4 histological groups defined on renal biopsy taken at 1-year post-transplantation: patients which display normal biopsy (n=45), patients with signs of tubular atrophy and interstitial fibrosis (IFTA) (n=14), with IFTA with inflammation (i-IFTA) (n=14) and patients with alloimmune lesions (n=6) Transcriptomic profile using PBMC from patients showing normal biopsy (n=45), patients with signs of tubular atrophy and interstitial fibrosis (IFTA) (n=14), with IFTA with inflammation (i-IFTA) (n=14) and patients with alloimmune lesions (n=6).
Project description:We aimed to investigate the effect of increased cold ischemia time (CIT) on gene expression profiles of implantation and clinically indicated biopsies early after transplantation and the impact of basiliximab (BAS) versus rabbit antithymocyte globulin (rATG) induction therapies on clinical outcomes and intragraft molecular features A retrospective, single-centered cohort study was designed to compare the safety and efficacy of rATG versus BAS for induction in patients who received a renal transplantation from a deceased donor between January 2007 and December 2012. Recipients with CIT greater than 20 hours were included in this study. Patients were excluded if they had received a prior transplantation or dual organ transplantation. Patients were followed for 12 months post-transplantation or until patient death, graft lost or lost to follow up. Patients in the rATG group received 1.5 mg per kilogram of body weight given intravenously with the initial dose given intraoperatively. Subsequent doses were given daily through post-operative day 3, for a total dose of 4.5-6.0 mg per kilogram. Dosing was adjusted based on daily white blood cell and platelet counts. BAS (20 mg given intravenously) was administered intraoperatively and the subsequent dose on day 3 post-transplantation. All patients received maintenance immunosuppression with tacrolimus, prednisone and mycophenolate mofetil. In total. 230 patients were transplanted with a CIT > 20 hours; 174 and 56 patients received rATG and BAS induction, respectively. Gene expression profiling ws carried out on a subset (n=28) of these patients' post transplant biopsies. Of those 28 patients, 16 received rATG and 12 received BAS induction treatment.
Project description:We investigated blood miRNAs as potential non-invasive biomarkers in kidney transplantation as part of the BIOMARGIN consortium (ClinicalTrials.gov, number NCT02832661). Blood samples were collected at time of the 717 renal allograft biopsies, in four European transplant centers. Profiling of mIR transcriptomes was performed in a multistage discovery-to-validation study. Antibody-mediated rejection (ABMR) is the most common cause of allograft failure after kidney transplantation. The revised Banff 2017 classification defines ABMR as conditions in which histologic evidence of acute and chronic injury is associated with evidence of current/recent antibody interaction with vascular endothelium and serologic evidence of donor-specific antibodies (DSA) to human leukocyte antigen (HLA) or non-HLA antigens
Project description:Kidney transplantation is the preferred treatment for kidney failure, offering improved survival, quality of life and cost-effectiveness compared to dialysis. However, post-transplant management is challenging due to the limited lifespan of transplanted organs, often requiring repeat transplants. Current methods for monitoring post-transplant complications are invasive and have limitations. Therefore, there is an urgent need for novel non-invasive biomarkers. This study investigates the proteomic composition of full urine as a source of information to understand renal biology during the process of transplantation and to identify potential markers for outcome prediction. Urine samples were collected from donors before transplantation and from recipients 4 weeks and 1 year after transplantation. Proteomic analysis was performed using mass spectrometry and label-free quantification. This study underscores the potential of non-invasive urine proteomics for identifying biological processes involved in the response of a kidney to transplantation and for enhancing post-transplant monitoring and outcome prediction.
Project description:Kidney transplantation is the preferred treatment for kidney failure, offering improved survival, quality of life and cost-effectiveness compared to dialysis. However, post-transplant management is challenging due to the limited lifespan of transplanted organs, often requiring repeat transplants. Current methods for monitoring post-transplant complications are invasive and have limitations. Therefore, there is an urgent need for novel non-invasive biomarkers. This study investigates the proteomic composition of full urine as a source of information to understand renal biology during the process of transplantation and to identify potential markers for outcome prediction. Urine samples were collected from donors (timepoint A) before transplantation and from recipients 4 weeks (timepoint B) and 1 year (timepoint C) after transplantation. Proteomic analysis was performed using mass spectrometry and label-free quantification. This study underscores the potential of non-invasive urine proteomics for identifying biological processes involved in the response of a kidney to transplantation and for enhancing post-transplant monitoring and outcome prediction.
Project description:This study represents the first quantitative analysis of the temporal changes in the small urinary extracellular vesicle proteome throughout living donor kidney transplantation identifying PCK2 abundance as a biomarker for renal function 12 months after transplantation
Project description:The Australian Chronic Allograft Dysfunction (AUSCAD) study is an ongoing single centre cohort study at Westmead hospital in Australia. In this section of the study, we aimed to identify biomarkers for allograft rejection in kidney transplant recipients, 3-months after their transplant. Our study recruited 123 patients, each having protocol renal allograft biopsies taken 3-months post transplantation.