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Transcription profiling by array of human positive crossmatch kidney transplant recipients who develop transplant gloerulopathy

ABSTRACT: We studied intragraft gene expression profiles of positive crossmatch (+XM) kidney transplant recipients who develop transplant glomerulopathy (TG) and those who do not. Whole genome microarray analysis and quantitative rt-PCR for 30 transcripts were performed on RNA from protocol renal allograft biopsies in 3 groups: 1) +XM/TG+ biopsies before and after TG; 2) +XM/NoTG; and 3) negative crossmatch kidney transplants (control). Microarray comparisons showed few differentially expressed genes between paired biopsies from +XM/TG+ recipients before and after the diagnosis of TG. Comparing +XM/TG+ and control groups, significantly altered expression was seen for 2,447 genes (18%) and 3,200 genes (24%) at early and late time points, respectively. Canonical pathway analyses of differentially expressed genes showed inflammatory genes associated with innate and adaptive immune responses. Comparing +XM/TG+ and +XM/NoTG groups, 3,718 probe sets were differentially expressed but these were over-represented in only 4 pathways. A classic accommodation phenotype was not identified. Using rt-PCR, the expression of inflammatory genes was significantly increased in +XM/TG+ recipients compared to control biopsies and to +XM/NoTG biopsies. In conclusion, pre-transplant DSA results in a gene expression profile characterized by inflammation and cellular infiltration and the majority of XM+ grafts are exposed to chronic injury. We analyzed gene expression from 2 groups of positive crossmatch kidney transplant recipients (+XM/TG+ and +XM/TG-). Patients in the +XM/TG+ group had 2 biopsies - prior to the development of transplant glomerulopathy on biopsy (Biopsy 1; cg=0; n=10) and after development of transplant glomerulopathy (Biopsy 2; cg>0; n=10). The +XM/TG- patients had only a Biopsy 2 (cg=0; n=11). A third patient group served as controls (n=10) and were from -XM recipients.

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PROVIDER: S-DIXA-D-1115 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:Survival of solid organ grafts depends on life-long immunosuppression, which results in increased rates of infection and malignancy. Induction of tolerance to allografts would represent the optimal solution for controlling both chronic rejection (CR) and side effects of immunosuppression. Although spontaneous ‘‘operational tolerance’’ can occur in human kidney transplantation, the lack of noninvasive peripheral blood biological markers of this rare phenomenon precludes the identification of potentially tolerant patients in whom immunosuppression could be tapered as well as the development of new tolerance inducing strategies. Here, the potential of high throughput microarray technology to decipher complex pathologies allowed us to study the peripheral blood specific gene expression profile and corresponding EASE molecular pathways associated to operational tolerance in a cohort of human kidney graft recipients. In comparison with patients with CR, tolerant patients displayed a set of 343 differentially expressed genes, mainly immune and defense genes, in their peripheral blood mononuclear cells (PBMC), of which 223 were also different from healthy volunteers. Using the expression pattern of these 343 genes, we were able to classify correctly >80% of the patients in a cross-validation experiment and classified correctly all of the samples over time. Collectively, this study identifies a unique PBMC gene signature associated with human operational tolerance in kidney transplantation. 250 samples were analyzed, replicates included: some patients from the TOL and CR groups were sampled twice with an interval between the two different time points of at least 16 months (mean 25.8 months, range 16–31 months). All the samples were analyzed in duplicate or quadruplicate. 1. TOL (n = 21). patients with stable graft function (blood creatinemia<150 mmol/L, proteinuria<1 g/24 h) for at least 1 year (mean 6.4 years,range 1.6–17.2 years) after complete interruption of immunosuppressive therapy. 2. STA (n = 190). Patients with stable kidney graft function under immunosuppressive therapy. 3. CR (n = 31). Patients having a progressive degradation of their renal function (blood creatinemia ≥150 mmol/L, proteinuria ≥1 g/24 h). CR was diagnosed on a graft biopsy according to the updated Banff criteria. CR was defined by histological signs of chronic allograft arteriopathy (arterial intimal fibrosis with mononuclear cell infiltration) and/or transplant glomerulopathy with glomerular double contours. 4. HV (n = 8). Subjects having normal blood formulae and no infectious or other concomitant pathology for at least 6 months before the study.

Project description:Older kidney transplant recipients are susceptible to cognitive impairment, frailty, comorbidities, immunosuppression-related complications, and chronic graft failure, however, there has been limited focus on their concerns and expectations related to transplantation. This study aims to describe the perspectives of older kidney transplant recipients about their experience of kidney transplantation, self-management, and treatment goals to inform strategies and interventions that address their specific needs.Face-to-face semistructured interviews were conducted with 30 kidney transplant recipients aged 65-80 years from five renal units in Australia. Transcripts were analyzed thematically.Six themes were identified: restoring vitality of youth (with subthemes of revived mindset for resilience, embracing enjoyment in life, drive for self-actualization); persisting through prolonged recovery (yielding to aging, accepting functional limitations, pushing the limit, enduring treatment responsibilities); imposing sicknesses (combatting devastating comorbidities, painful restrictions, emerging disillusionment, anxieties about accumulating side effects, consuming treatment burden); prioritizing graft survival (privileged with a miracle, negotiating risks for longevity, enacting a moral duty, preserving the last opportunity); confronting health deterioration (vulnerability and helplessness, narrowing focus to immediate concerns, uncertainty of survival); and value of existence (purpose through autonomy, refusing the burden of futile treatment, staying alive by all means).Older kidney transplant recipients felt able to enjoy life and strived to live at their newly re-established potential and capability, which motivated them to protect their graft. However, some felt constrained by slow recuperation and overwhelmed by unexpected comorbidities, medication-related side effects, and health decline. Our findings suggest the need to prepare and support older recipients for self-management responsibilities, clarify their expectations of post-transplant risks and outcomes, and provide assistance through prolonged recovery after kidney transplantation.

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Transcription profiling by array of human positive crossmatch kidney transplant recipients who develop transplant gloerulopathy

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