Old studies reported a worse outcome for second transplant recipient (STR) than for first transplant recipient (FTR) mainly due to non-comparable populations with numbers confounding factors. More ...recent analysis, based on improved methodology by using multivariate regressions, challenged this generally accepted idea: the poor prognosis for STR is still under debate.
To assess the long-term patient-and-graft survival of STR compared to FTR, we performed an observational study based on the French DIVAT prospective cohort between 1996 and 2010 (N = 3103 including 641 STR). All patients were treated with a CNI, an mTOR inhibitor or belatacept in addition to steroids and mycophenolate mofetil for maintenance therapy. Patient-and-graft survival and acute rejection episode (ARE) were analyzed using Cox models adjusted for all potential confounding factors such as pre-transplant anti-HLA immunization.
We showed that STR have a higher risk of graft failure than FTR (HR = 2.18, p = 0.0013) but that this excess risk was observed after few years of transplantation. There was no significant difference between STR and FTR in the occurrence of either overall ARE (HR = 1.01, p = 0.9675) or steroid-resistant ARE (HR = 1.27, p = 0.4087).
The risk of graft failure following second transplantation remained consistently higher than that observed in first transplantation after adjusting for confounding factors. The rarely performed time-dependent statistical modeling may explain the heterogeneous conclusions of the literature concerning second transplantation outcomes. In clinical practice, physicians should not consider STR and FTR equally.
Background Corticosteroid-resistant idiopathic nephrotic syndrome (INS) recurs rapidly after transplantation in 30% to 50% of transplant recipients, suggesting the presence of 1 or more circulating ...factors that alter the glomerular filtration barrier. We investigated the possible role in INS recurrence of soluble ST2 (sST2) protein, a marker of T helper type 2 (TH 2) cells and a factor predicted to be regulated by the transcription factor c-Maf; involvement of sST2 protein would be consistent with the observation that both TH 2 cells and c-Maf appear to be activated during INS relapse. Study Design Retrospective observational study. Setting & Participants Patients with biopsy-proven corticosteroid-resistant INS who had undergone kidney transplantation between September 1983 and April 2007 (n = 71). A control group consisting of proteinuric transplant recipients with kidney failure unrelated to INS (n = 34). Predictor Patients who developed INS recurrence after transplantation (n = 31) were compared with those in whom INS did not recur (n = 40) and the control group. Recurrence of INS was defined as urine protein excretion greater than 2 g/d immediately after transplantation that persisted at greater than 1 g/d despite treatment or a kidney graft biopsy showing minimal change glomerulonephritis or focal segmental glomerulosclerosis. Outcomes & Measurements Urine protein excretion in the 3 groups was 5.0 g/d (range, 1.3 to 10.5), 0.14 g/d (range, 0 to 0.46), and 4.3 g/d (range, 3 to 6.2). The sST2 protein was analyzed both quantitatively and qualitatively in patient sera, and its activity was tested in vitro on a mouse podocyte cell line and in vivo in rats. Results sST2 protein levels were significantly increased after transplantation in patients with INS recurrence compared with the 2 other groups (617.5 versus 23 pg/mL; P < 0.001 and 158.5 pg/mL; P < 0.01 respectively). However, patients with recurrence expressed a normal sST2 isoform, and the sST2 protein was unable to induce podocyte injury in vitro or trigger proteinuria in rats. Limitations Pretransplantation and posttransplantation sera do not always represent paired samples. Conclusions These data suggest that sST2 protein is a marker of INS recurrence that does not seem to be involved in the development of INS.
CD8 T cell clonal expansions (TCE) have been observed in elderly, healthy individuals as well in old mice, and have been associated with the ageing process. Both chronic latent and non-persistent ...viral infections have been proposed to drive the development of distinct non-functional and functional TCE respectively. Biases in TCR Vβ repertoire diversity are also recurrently observed in patients that have undergone strong immune challenge, and are preferentially observed in the CD8 compartment. Healthy adults can also exhibit CD8 T cells with strong alterations of their CDR3 length distribution. Surprisingly, no specific investigations have been conducted to analyze the CD8 T cell repertoire in normal adults, to determine if such alterations in TCR Vβ repertoire share the features of TCE. In this study, we characterized the phenotype and function of the CD8 population in healthy individuals of 25-52 years of age. All but one of the EBV-positive HLA-B8 healthy volunteers that were studied were CMV-negative. Using a specific unsupervised statistical method, we identified Vβ families with altered CDR3 length distribution and increased TCR Vβ/HPRT transcript ratios in all individuals tested. The increase in TCR Vβ/HPRT transcript ratio was more frequently associated with an increase in the percentage of the corresponding Vβ(+) T cells than with an absence of modification of their percentage. However, in contrast with the previously described TCE, these CD8(+) T cells were not preferentially found in the memory CD8 subset, they exhibited normal effector functions (cytokine secretion and cytotoxic molecule expression) and they were not reactive to a pool of EBV/CMV/Flu virus peptides. Taken together, the combined analysis of transcripts and proteins of the TCR Vβ repertoire led to the identification of different types of CD8(+) T cell clone expansion or contraction in healthy individuals, a situation that appears more complex than previously described in aged individuals.
Treatment of end stage renal disease has an impact on patients' physical and psychological health, including quality of life (QoL). Nowadays, it is known that reducing the dialysis period has many ...advantages regarding QoL and medical outcomes. Although preemptive transplantation is the preferred strategy to prevent patients undergoing dialysis, its psychological impact is unknown. Moreover, transplantation can be experienced in a completely different manner among patients who were on dialysis and those who still had a functioning kidney at the time of surgery. Longitudinal data are often collected to allow analyzing the evolution of patients' QoL over time using questionnaires. Such data are often difficult to interpret due to the patients' changing standards, values, or conceptualization of what the questionnaire is intended to measure (e.g. QoL). This phenomenon is referred to as response shift and is often linked to the way the patients might adapt or cope with their disease experience. Whether response shift is experienced in a different way among patients who were on dialysis and those who still had a functioning kidney at time of surgery is unknown and will be studied in the PreKit-QoL study (trial registration number: NCT02154815). Understanding the psychological impact of pre-emptive transplantation is an important issue since it can be associated with long-term patient and graft survival.
Adult patients with a pre-emptive transplantation (n = 130) will be prospectively included along with a control group of patients with a pre-transplant dialysis period < 36 months (n = 260). Only first and single kidney transplantation will be considered. Endpoints include: comparison of change between groups in QoL, anxiety and depressive disorders, perceived stress, taking into account response shift. These criteria will be evaluated every 6 months prior to surgery, at hospital discharge, at three and six months, one and two years after transplantation.
The PreKit-QoL study assesses and compares the evolution of QoL and other psychological criteria in preemptive and dialyzed patients taking patients' adaptation into account through response shift analyses. Our study might help to conceive specific, adapted educational programs and psychological support to prevent a possible premature loss of the kidney as a consequence of non-compliance in patients that may be insufficiently prepared for transplantation.
ClinicalTrials.gov identifier NCT02154815 , registered on May 28, 2014.
The state of operational tolerance has been detected sporadically in some renal transplanted patients that stopped immunosuppressive drugs, demonstrating that allograft tolerance might exist in ...humans. Several years ago, a study by Brouard et al. identified a molecular signature of several genes that were significantly differentially expressed in the blood of such patients compared with patients with other clinical situations. The aim of the present study is to analyze the role of one of these molecules over-expressed in the blood of operationally tolerant patients, SMILE or TMTC3, a protein whose function is still unknown.
We first confirmed that SMILE mRNA is differentially expressed in the blood of operationally tolerant patients with drug-free long term graft function compared to stable and rejecting patients. Using a yeast two-hybrid approach and a colocalization study by confocal microscopy we furthermore report an interaction of SMILE with PDIA3, a molecule resident in the endoplasmic reticulum (ER). In accordance with this observation, SMILE silencing in HeLa cells correlated with the modulation of several transcripts involved in proteolysis and a decrease in proteasome activity. Finally, SMILE silencing increased HeLa cell sensitivity to the proteasome inhibitor Bortezomib, a drug that induces ER stress via protein overload, and increased transcript expression of a stress response protein, XBP-1, in HeLa cells and keratinocytes.
In this study we showed that SMILE is involved in the endoplasmic reticulum stress response, by modulating proteasome activity and XBP-1 transcript expression. This function of SMILE may influence immune cell behavior in the context of transplantation, and the analysis of endoplasmic reticulum stress in transplantation may reveal new pathways of regulation in long-term graft acceptance thereby increasing our understanding of tolerance.
Exploitation of the ever-increasing volume of observational data has become a major challenge for real-world evidence (RWE). Causal inference can be viewed as emulations of clinical trials (ECTs) ...from real-world data (RWD). This requires in-depth knowledge of data management and modern statistical models, which evolve considerably. We have developed Plug-Stat
®
to facilitate these analyses. Plug-Stat
®
is a user-friendly graphical interface of R software implemented with JavaScript and VB.net. The implementation of Plug-Stat® for a specific database consists of two main tasks. The first concerns the automatic importation of data to link the software with the data and to avoid the repetition of data management activities for each study. The second is to define the outcomes and the associated possible confounders. To perform an ECT, we proposed the use of inverse probability weighting, flexible parametric estimation of the propensity score model with B-splines, and robust estimation of the variance. The statistical modeling steps are automatized to direct the user toward the correct methodology without data management. We illustrated the usefulness of Plug-Stat
®
with several recently published ECTs. In this paper, we presented the outcome comparison of preemptive deceased-donor kidney transplantations versus transplantations after dialysis. The interactive interfaces assist the user in conducting causal research based on ECT, and tutorials are available, offering self-training opportunities. Plug-Stat
®
reduces the time and, consequently, the cost necessary for different studies from the same cohort.
Abstract Background and Aims One of the most severe complication of type 1 diabetes (D1) is renal injury which can lead to end stage renal disease. Even though improvement have been made to slow the ...progression of the renal disease, some of D1 patients still reach dialysis. Those patients seem to have more comorbidities and poor prognosis compare to patients without diabetes (D0) starting dialysis or patients with type 2 (D2) diabetes. Method The French Renal Epidemiology and Information Network (REIN) registry collects information on all patients starting dialysis in France. We used this cohort to explore survival and access to renal transplantation of D1 on dialysis patients compare to D0 and D2 patients, using Cox proportional hazard models and graphical representation of the variables to explore the pathway from type 1 diabetes to the outcomes of interest. We performed sensitivity analysis on the imputed base obtain by MICE (in order to reduce the influence of missing data) to compare HR. Results From January 1, 2010 to December 31,2016, 1596 D1 patients were compared to 39540 D0 patients and 28170 D2 patients. Excess in all-cause mortality rate were 1.26 1.14-1.40 (p < 0.001) for D1 versus D0 and rises to 1.45 1.32-1.59 (p < 0.001) when considering diabetes-related comorbidities on the pathway from diabetes to death. D1 had a poorer access to kidney transplantation (0.74 0.66-0.82 p < 0.001) adjusting for non-diabetes-related comorbidities. Using the survival model to compare D1 and D2 on the imputed bases, we obtained an HR: 1.11; 95% CI: 1.01-1.21 p = 0.027, in favor of a worse survival of D1 patients in dialysis compare to D2 patients Conclusion These results confirm that D1 patients starting dialysis are severely ill and particular care need to be given to detect and so reduce diabetes-related comorbidities and increase access to kidney transplantation.
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