Cardiovascular disease is a major cause of morbidity, disability, and mortality in kidney transplant patients. Cumulative reports indicate that the excessive risk of cardiovascular events is not ...entirely explained by the increased prevalence of traditional cardiovascular risk factors. Atherosclerosis is a chronic inflammatory disease, and it has been postulated that posttransplant immune disturbances may explain the gap between the predicted and observed risks of cardiovascular events. Although concordant data suggest that innate immunity contributes to the posttransplant accelerated atherosclerosis, only few arguments plead for a role of adaptive immunity. We report and discuss here consistent data demonstrating that CD8+ T cell activation is a frequent posttransplant immune feature that may have pro-atherogenic effects. Expansion of exhausted/activated CD8+ T cells in kidney transplant recipients is stimulated by several factors including cytomegalovirus infections, lymphodepletive therapy (e.g., antithymocyte globulins), chronic allogeneic stimulation, and a past history of renal insufficiency. This is observed in the setting of decreased thymic activity, a process also found in elderly individuals and reflecting accelerated immune senescence.
The prognosis of patients undergoing kidney tumor resection or kidney donation is linked to many histologic criteria. These criteria notably include glomerular density, glomerular volume, vascular ...luminal stenosis, and severity of interstitial fibrosis/tubular atrophy. Automated measurements through a deep-learning approach could save time and provide more precise data. This work aimed to develop a free tool to automatically obtain kidney histologic prognostic features.
In total, 241 samples of healthy kidney tissue were split into three independent cohorts. The "Training" cohort (
=65) was used to train two convolutional neural networks: one to detect the cortex and a second to segment the kidney structures. The "Test" cohort (
=50) assessed their performance by comparing manually outlined regions of interest to predicted ones. The "Application" cohort (
=126) compared prognostic histologic data obtained manually or through the algorithm on the basis of the combination of the two convolutional neural networks.
In the Test cohort, the networks isolated the cortex and segmented the elements of interest with good performances (>90% of the cortex, healthy tubules, glomeruli, and even globally sclerotic glomeruli were detected). In the Application cohort, the expected and predicted prognostic data were significantly correlated. The correlation coefficients
were 0.85 for glomerular volume, 0.51 for glomerular density, 0.75 for interstitial fibrosis, 0.71 for tubular atrophy, and 0.73 for vascular intimal thickness, respectively. The algorithm had a good ability to predict significant (>25%) tubular atrophy and interstitial fibrosis level (receiver operator characteristic curve with an area under the curve, 0.92 and 0.91, respectively) or a significant vascular luminal stenosis (>50%) (area under the curve, 0.85).
This freely available tool enables the automated segmentation of kidney tissue to obtain prognostic histologic data in a fast, objective, reliable, and reproducible way.
T-lymphocyte activation may contribute to atherosclerosis, the prevalence of which is increased in transplant patients. However, the cardiovascular consequences of polyclonal antithymocyte globulin ...(ATG)-induced immune modifications, which include alterations in T-cell subsets, are unknown. We conducted a retrospective single-center study to assess whether ATG associates with an increased incidence of atherosclerotic events (CVEs) in kidney transplant patients. Propensity score analysis was performed to address potential confounding by indication. We also tested whether ATG use induces a proatherogenic immune status. Sixty-nine (12.2%) CVEs occurred during follow-up (87±31 months). The cumulative incidence of CVEs was higher in ATG-treated patients (14.7% versus 8.2%; P=0.03). Cox regression analysis revealed that ATG use was an independent risk factor for CVEs (hazard ratio HR, 2.36; 95% confidence interval 95% CI, 1.35 to 4.13; P=0.003). Results obtained in the propensity score match analysis recapitulated those obtained from the overall cohort (HR, 2.09; 95% CI, 1.11 to 3.98; P=0.02). Late-stage differentiated CD8(+) T cells increased 1 year after transplantation only in ATG-treated patients. More generally, ATG associated with features of immune activation. These modifications increased markedly in patients exposed to cytomegalovirus (CMV). Subanalyses suggest that the effect of ATG on CVEs is restricted to CMV-exposed patients. However, CMV infection associated significantly with CVEs only in ATG-treated patients (HR, 2.07; 95% CI, 1.16 to 3.70; P=0.01). In conclusion, ATG associated with both immune activation and post-transplant CVEs in this cohort. Further studies should precisely determine whether ATG-induced immune activation is the causal link between ATG and CVEs.
Few data are available concerning immune factors involved in the occurrence of new onset diabetes after transplantation (NODAT). Our objective was to determine an immune profile associated with the ...subsequent development of NODAT. The secondary objective was to build a predictive model of NODAT. We studied a prospective cohort of incident kidney transplant patients to determine whether pre-transplant immune characteristics could be associated with the occurrence of NODAT. 818 patients were included. We observed a significant inverse correlation between BMI and recent thymic emigrants (RTE) % at transplant time (p < 0.001). 177 (17.3%) of 677 non-diabetic patients experienced NODAT in the first year post-transplant. In multivariate analysis, age, body mass index (BMI), use of Tacrolimus, use of anti-thymocyte globulins (ATG), higher B cell count, and lower recent thymic emigrants (RTE) % were associated with NODAT. A differential effect of immune profile was observed in ATG-treated patients and non-ATG-treated patients. B cell count predicts NODAT only in non-ATG-treated patients whereas lower RTE% was associated with NODAT only in ATG-treated patients. Tacrolimus sparing and B cell depletion may efficiently prevent NODAT in selected patients. We identified an immune profile associated with the occurrence of post-transplant diabetes. Further studies should better precise the exact mechanisms involved in this association. Trial registration NCT02843867, registered July 8, 2016 – retrospectively registered https://clinicaltrials.gov/ct2/show/record/NCT02843867.
Apheresis allows the fast removal of autoantibodies in anti-glomerular basement membrane (anti-GBM) disease, and in severe antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis. The ...CINEVAS study tested whether immunoadsorption (IA) allowed a faster removal of ANCA and/or anti-GBM antibodies than plasma exchanges (PEx).
CINEVAS was a prospective multicenter study comparing IA to PEx in consecutive patients with ANCA and/or anti-GBM vasculitides. The primary objective was the reduction rate in autoantibody titers between the beginning of the first and the end of the seventh apheresis session. Secondary objectives were number of sessions needed to obtain desired reduction rates; reduction rates of total Ig levels; tolerance of sessions; and patients’ outcome.
The results of 38 patients (16 treated with IA and 22 with PEx), and 43 autoantibodies, were analyzed. There was no difference in the reduction rates in autoantibody titers between IA and PEx over 7 sessions (respectively 98% vs. 96%, P = 0.39). The numbers of sessions needed to obtain undetectable autoantibodies, or 50%, 75%, or 90% reductions, did not differ between techniques. Greater reduction rates of autoantibodies were observed when plasma was separated by filtration compared to centrifugation, with IA and PEx. IA allowed a greater reduction in total IgG levels, and better preservation of total IgA and IgM levels than PEx. PEx sessions required higher volumes of plasma, IA sessions higher volumes of citrate; IA sessions were longer.
IA and PEx were comparable in ANCA or anti-GBM removal kinetics, despite a faster reduction in total IgG with IA.
Display omitted
Lack of clear identification of patients at high risk of acute rejection hampers the ability to individualize immunosuppressive therapy. Here we studied whether thymic function may predict acute ...rejection in antithymocyte globulin (ATG)-treated renal transplant recipients in 482 patients prospectively studied during the first year post-transplant of which 86 patients experienced acute rejection. Only CD45RA+CD31+CD4+ T cell (recent thymic emigrant RTE) frequency (RTE%) was marginally associated with acute rejection in the whole population. This T-cell subset accounts for 26% of CD4+ T cells. Pretransplant RTE% was significantly associated with acute rejection in ATG-treated patients (hazard ratio, 1.04; 95% confidence interval, 1.01–1.08) for each increased percent in RTE/CD4+ T cells), but not in anti-CD25 monoclonal (αCD25 mAb)-treated patients. Acute rejection was significantly more frequent in ATG-treated patients with high pretransplant RTE% (31.2% vs. 16.4%) or absolute number of RTE/mm3 (31.7 vs. 16.1). This difference was not found in αCD25 monclonal antibody–treated patients. Highest values of both RTE% (>31%, hazard ratio, 2.50; 95% confidence interval, 1.09–5.74) and RTE/mm3 (>200/mm3, hazard ratio, 3.71; 95% confidence interval, 1.59–8.70) were predictive of acute rejection in ATG-treated patients but not in patients having received αCD25 monoclonal antibody). Results were confirmed in a retrospective cohort using T-cell receptor excision circle levels as a marker of thymic function. Thus, pretransplant thymic function predicts acute rejection in ATG-treated patients.
Rituximab is a first-line treatment for membranous nephropathy. Nephrotic syndrome limits rituximab exposure due to urinary drug loss. Rituximab underdosing (serum level <2 μg/ml at month-3) is a ...risk factor for treatment failure. We developed a machine learning algorithm to predict the risk of underdosing based on patients' characteristics at rituximab infusion. We investigated the relationship between the predicted risk of underdosing and the cumulative dose of rituximab required to achieve remission.
Rituximab concentrations were measured at month-3 in 92 sera from adult patients with primary membranous nephropathy, split into a training (75%) and a testing set (25%). A forward-backward machine-learning procedure determined the best combination of variables to predict rituximab underdosing in the training data set, which was tested in the test set. The performances were evaluated for accuracy, sensitivity, and specificity in 10-fold cross-validation training and test sets.
The best variables combination to predict rituximab underdosing included age, gender, body surface area (BSA), anti-phospholipase A2 receptor type 1 (anti-PLA2R1) antibody titer on day-0, serum albumin on day-0 and day-15, and serum creatinine on day-0 and day-15. The accuracy, sensitivity, and specificity were respectively 79.4%, 78.7%, and 81.0% (training data set), and 79.2%, 84.6% and 72.7% (testing data set). In both sets, the algorithm performed significantly better than chance (
< 0.05). Patients with an initial high probability of underdosing experienced a longer time to remission with higher rituximab cumulative doses required to achieved remission.
This algorithm could allow for early intensification of rituximab regimen in patients at high estimated risk of underdosing to increase the likelihood of remission.
Broad T cell depletion by polyclonal anti-thymocyte globulins (ATG) has been used for many years as a part of immunosuppressive treatment in transplantation. Currently, two different ATG are used in ...clinical practice, Thymoglobulin and Grafalon. Due to differences in the immunization source, these products contain different specificities and quantity of antibodies. These differences may have clinical consequences.
We conducted a nested study in a large prospective multicentric cohort of kidney transplant to determine whether Grafalon–treated and Thymoglobulin-treated patients experience different lymphocyte reconstitution and clinical outcomes.
182 patients matched for age, gender, CMV status, CMV prophylaxis, number of previous transplantation, and maintenance immunosuppressive treatment were included (Thymoglobulin, n=91; Grafalon®, n=91). One-year post-transplant, recent thymic emigrants were significantly decreased (12±10% vs 21±12%; p<0.001) in Grafalon-treated patients. By contrast, T cell activation (CD38+DR+Ki67+) and senescence (CD8+CD57+CD28−) was increased in Thymoglobulin-treated patients. Compared to Grafalon, Thymoglobulin was not associated with a significantly different rate of acute rejection. CMV disease (p=0.013) was more frequent in Thymoglobulin-treated patients.
Grafalon and Thymoglobulin seem to be equivalent to prevent acute rejection. CMV disease is more frequent in Thymoglobulin-treated patients. One year post-transplant immune profile profoundly differs according to the type of ATG.
•Two different ATG are compared in a prospective study.•The rate of acute rejection is similar in Thymoglobulin- and Grafalon-treated patients.•CMV disease is more frequent in Thymoglobulin-treated patients.•One year post-transplant, Thymoglobulin use is associated with T cell activation.•One year post-transplant, Grafalon is associated with reduced thymic output.
BACKGROUNDChronic exposure to exogenous antigens causes accumulation of proinflammatory CD57CD28 hyperactivated CD8 T cells that may promote atherosclerosis. We hypothesized that persistent ...alloimmune responses may induce immune activation and contribute to posttransplant atherosclerosis.
METHODSThis hypothesis was tested in a single-center cohort of 577 kidney transplant patients. Propensity score analysis was performed to address potential confounding variables by indication. Immune exhaustion was studied in subcohort of 103 patients.
RESULTSFive hundred seventy-seven consecutive renal transplant recipients were included. Seventy-seven atherosclerotic events (AE) (12.3%) occurred during a mean follow-up of 7 years. The cumulative incidence of AE increased with the number of human leukocyte antigen (HLA) mismatches (18%, 10%, and 5% in patients with 5–6, 3–4, and 0–2 mismatches, respectively; P=0.012). Human leukocyte antigen mismatch number (hazards ratio, 1.35; 95% confidence interval, 1.10–1.66, for each supplementary mismatch; P=0.005) was an independent risk factor for AE. In the propensity score match analysis, having received a well-matched kidney conferred a reduced risk of AE (hazards ratio, 0.22; 95% confidence interval, 0.05–0.95; P=0.044). We observed a significant correlation between HLA mismatch numbers and circulating CD57CD28 CD8 T cells (R=0.31; P=0.017). These CD8 T cells were more frequent in patients with more HLA mismatches (P<0.0001).
CONCLUSIONOverall, our results suggest that chronic allogeneic stimulation participates to accelerated atherosclerosis observed after transplantation.
Design method of CRLH TL inspired phase shifters Vivos, Jonathan; Crepin, Thomas; Foulon, Michel-Francois ...
2016 10th European Conference on Antennas and Propagation (EuCAP),
04/2016
Conference Proceeding
A time-efficient method is described for designing metamaterial transmission lines (TL) with a required phase shift over a given frequency band with rigorous phase accuracy. This time-efficient ...method is proposed to make possible industrial application phase shiftersof Composite Right/Left-Handed (CRLH) TL phase shifter for phase compensation solution. A theoretical model is developed by the use of the TL model and of its Bloch phase and impedance. The extraction method of the technological parameters from this model is also explained. To illustrate this method, two CRLH TLs are presented and compared to a conventional phase shifter transmission line.
PDF
