Kidney allograft rejection is associated with an imbalance of B cells, regulatory T cells and differentiated CD28-CD8+ T cells: analysis of a cohort of 1095 graft biopsies.

Introduction: The human immune system contains cells with either effector/memory or regulatory functions. Besides the well-established CD4+CD25hiCD127lo regulatory T cells (Tregs), we and others have shown that B cells can also have regulatory functions since their frequency and number are increased in kidney graft tolerance and B cell depletion as induction therapy may lead to acute rejection. On the other hand, we have shown that CD28-CD8+ T cells represent a subpopulation with potent effector/memory functions. In the current study, we tested the hypothesis that kidney allograft rejection may be linked to an imbalance of effector/memory and regulatory immune cells. Methods: Based on a large cohort of more than 1000 kidney graft biopsies with concomitant peripheral blood lymphocyte phenotyping, we investigated the association between kidney graft rejection and the percentage and absolute number of circulating B cells, Tregs, as well as the ratio of B cells to CD28-CD8+ T cells and the ratio of CD28-CD8+ T cells to Tregs. Kidney graft biopsies were interpreted according to the Banff classification and divided into 5 biopsies groups: 1) normal/subnormal, 2) interstitial fibrosis and tubular atrophy grade 2/3 (IFTA), 3) antibody-mediated rejection (ABMR), 4) T cell mediated-rejection (TCMR), and 5) borderline rejection. We compared group 1 with the other groups as well as with a combined group 3, 4, and 5 (rejection of all types) using multivariable linear mixed models. Results and discussion: We found that compared to normal/subnormal biopsies, rejection of all types was marginally associated with a decrease in the percentage of circulating B cells (p=0.06) and significantly associated with an increase in the ratio of CD28-CD8+ T cells to Tregs (p=0.01). Moreover, ABMR, TCMR (p=0.007), and rejection of all types (p=0.0003) were significantly associated with a decrease in the ratio of B cells to CD28-CD8+ T cells compared to normal/subnormal biopsies. Taken together, our results show that kidney allograft rejection is associated with an imbalance between immune cells with effector/memory functions and those with regulatory properties.

Timing of Kidney Clamping and Deceased Donor Kidney Transplant Outcomes.

BACKGROUND AND OBJECTIVES: The fact that metabolism and immune function are regulated by an endogenous molecular clock that generates circadian rhythms suggests that the magnitude of ischemia reperfusion, and subsequent inflammation on kidney transplantation, could be affected by the time of the day. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We evaluated 5026 individuals who received their first kidney transplant from deceased heart-beating donors. In a cause-specific multivariable analysis, we compared delayed graft function and graft survival according to the time of kidney clamping and declamping. Participants were divided into those clamped between midnight and noon (ante meridiem [am] clamping group; 65%) or clamped between noon and midnight (post meridiem [pm] clamping group; 35%), and, similarly, those who underwent am declamping (25%) or pm declamping (75%). RESULTS: Delayed graft function occurred among 550 participants (27%) with am clamping and 339 (34%) with pm clamping (adjusted odds ratio, 0.81; 95% confidence interval, 0.67 to 0.98; P=0.03). No significant association was observed between clamping time and overall death-censored graft survival (hazard ratio, 0.92; 95% confidence interval, 0.77 to 1.10; P=0.37). No significant association of declamping time with delayed graft function or graft survival was observed. CONCLUSIONS: Clamping between midnight and noon was associated with a lower incidence of delayed graft function, whereas declamping time was not associated with kidney graft outcomes.

Time-dependent lymphocyte count after transplantation is associated with higher risk of graft failure and death.

The transplantation field requires the identification of specific risk factors associated with the level of immunosuppression. Here, our aim was to analyze the association between the number of circulating lymphocytes, monitored routinely by complete blood cell counts during outpatient visits, and patient and graft survival. In total, 2,999 kidney or combined kidney-pancreas recipients transplanted between 2000 and 2016, from two University hospitals, were enrolled. We investigated the etiological relationship between time-dependent lymphocyte count beyond one year after transplantation and patient and graft survival, viral infection and cancer risk using time-dependent multivariate Cox models. Model 1 considered kidney function at one year and model 2 as time-dependent variable. At the time of inclusion (one year after transplantation), 584 patients (19.4%) had deep lymphopenia (under 750 /mm3) and 1,072 (35.7%) had a normal count (over 1,500 /mm3). A patient with deep lymphopenia at a given follow-up time had significantly higher risks of graft failure, death and viral infection than comparable patients with a normal lymphocyte count at the same time point. Thus, after the first year of transplantation, the occurrence of deep lymphopenia within a patient's follow-up is a risk factor for long-term graft failure, death and viral infection.

Meta-analysis of predictive models to assess the clinical validity and utility for patient-centered medical decision making: application to the CAncer of the Prostate Risk Assessment (CAPRA).

BACKGROUND: The Cancer of the Prostate Risk Assessment (CAPRA) score was designed and validated several times to predict the biochemical recurrence-free survival after a radical prostatectomy. Our objectives were, first, to study the clinical validity of the CAPRA score, and, second, to assess its clinical utility for stratified medicine from an original patient-centered approach. METHODS: We proposed a meta-analysis based on a literature search using MEDLINE. Observed and predicted biochemical-recurrence-free survivals were compared to assess the calibration of the CAPRA score. Discriminative capacities were evaluated by estimating the summary time-dependent ROC curve. The clinical utility of the CAPRA score was evaluated according to the following stratified decisions: active monitoring for low-risk patients, prostatectomy for intermediate-risk patients, or radio-hormonal therapy for high risk patients. For this purpose, we assessed CAPRA's clinical utility in terms of its ability to maximize time-dependent utility functions (i.e. Quality-Adjusted Life-Years - QALYs). RESULTS: We identified 683 manuscripts and finally retained 9 studies. We reported good discriminative capacities with an area under the SROCt curve at 0.73 [95%CI from 0.67 to 0.79], while graphical calibration seemed acceptable. Nevertheless, we also described that the CAPRA score was unable to discriminate between the three medical alternatives, i.e. it did not allow an increase in the number of life years in perfect health (QALYs) of patients with prostate cancer. CONCLUSIONS: We confirmed the prognostic capacities of the CAPRA score. In contrast, we were not able to demonstrate its clinical usefulness for stratified medicine from a patient-centered perspective. Our results also highlighted the confusion between clinical validity and utility. This distinction should be better considered in order to develop predictive tools useful in practice.

A mini-review of quality of life as an outcome in prostate cancer trials: patient-centered approaches are needed to propose appropriate treatments on behalf of patients.

BACKGROUND: Patients with prostate cancer (PC) may be ready to make trade-offs between their quantity and their quality of life. For instance, elderly patients may prefer the absence of treatment if it is associated with a low-risk of disease progression, compared to treatments aiming at preventing disease progression but with a substantial deterioration of their Health-Related Quality of Life (HRQoL). Therefore, it seems relevant to compare the treatments by considering both survival and HRQoL. In this mini-review, the aim was to question whether the potential trade-offs between survival and HRQoL are considered in high impact factor journals. METHODS: The study was conducted from the PubMed database for recent papers published between May 01, 2013, and May 01, 2015. We also restricted our search to nine medical journals with 2013 impact factor > 15. RESULTS: Among the 30 selected studies, only six collected individual HRQoL as a secondary endpoint by using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. In four studies, the time to HRQoL change was analyzed, but its definitions varied. In two studies, the mean changes in HRQoL between the baseline and the 12- or 16-week follow-up were analyzed. None of the six studies reported in a single endpoint both the quantity and the quality of life. CONCLUSIONS: Our mini-review, which only focused on recent publications in journals with high-impact, suggests moving PC clinical research towards patient-centered outcomes-based studies. This may help physicians to propose the most appropriate treatment on behalf of patients. We recommend the use of indicators such as Quality-Adjusted Life-Years (QALYs) as principal endpoint in future clinical trials.

Optimal threshold estimator of a prognostic marker by maximizing a time-dependent expected utility function for a patient-centered stratified medicine.

Defining thresholds of prognostic markers is essential for stratified medicine. Such thresholds are mostly estimated from purely statistical measures regardless of patient preferences potentially leading to unacceptable medical decisions. Quality-Adjusted Life-Years are a widely used preferences-based measure of health outcomes. We develop a time-dependent Quality-Adjusted Life-Years-based expected utility function for censored data that should be maximized to estimate an optimal threshold. We performed a simulation study to compare estimated thresholds when using the proposed expected utility approach and purely statistical estimators. Two applications illustrate the usefulness of the proposed methodology which was implemented in the R package ROCt ( www.divat.fr ). First, by reanalysing data of a randomized clinical trial comparing the efficacy of prednisone vs. placebo in patients with chronic liver cirrhosis, we demonstrate the utility of treating patients with a prothrombin level higher than 89%. Second, we reanalyze the data of an observational cohort of kidney transplant recipients: we conclude to the uselessness of the Kidney Transplant Failure Score to adapt the frequency of clinical visits. Applying such a patient-centered methodology may improve future transfer of novel prognostic scoring systems or markers in clinical practice.

Mortality Prediction after the First Year of Kidney Transplantation: An Observational Study on Two European Cohorts.

After the first year post transplantation, prognostic mortality scores in kidney transplant recipients can be useful for personalizing medical management. We developed a new prognostic score based on 5 parameters and computable at 1-year post transplantation. The outcome was the time between the first anniversary of the transplantation and the patient's death with a functioning graft. Afterwards, we appraised the prognostic capacities of this score by estimating time-dependent Receiver Operating Characteristic (ROC) curves from two prospective and multicentric European cohorts: the DIVAT (Données Informatisées et VAlidées en Transplantation) cohort composed of patients transplanted between 2000 and 2012 in 6 French centers; and the STCS (Swiss Transplant Cohort Study) cohort composed of patients transplanted between 2008 and 2012 in 6 Swiss centers. We also compared the results with those of two existing scoring systems: one from Spain (Hernandez et al.) and one from the United States (the Recipient Risk Score, RRS, Baskin-Bey et al.). From the DIVAT validation cohort and for a prognostic time at 10 years, the new prognostic score (AUC = 0.78, 95%CI = [0.69, 0.85]) seemed to present significantly higher prognostic capacities than the scoring system proposed by Hernandez et al. (p = 0.04) and tended to perform better than the initial RRS (p = 0.10). By using the Swiss cohort, the RRS and the the new prognostic score had comparable prognostic capacities at 4 years (AUC = 0.77 and 0.76 respectively, p = 0.31). In addition to the current available scores related to the risk to return in dialysis, we recommend to further study the use of the score we propose or the RRS for a more efficient personalized follow-up of kidney transplant recipients.

Comparison of survival outcomes between Expanded Criteria Donor and Standard Criteria Donor kidney transplant recipients: a systematic review and meta-analysis.

In 2002, the United Network for Organ Sharing proposed increasing the pool of donor kidneys to include Expanded Criteria Donor (ECD). Outside the USA, the ECD definition remains the one used without questioning whether such a graft allocation criterion is valid worldwide. We performed a meta-analysis to quantify the differences between ECD and Standard Criteria Donor (SCD) transplants. We paid particular attention to select studies in which the methodology was appropriate and we took into consideration the geographical area. Thirty-two publications were included. Only five studies, all from the USA, reported confounder-adjusted hazard ratios comparing the survival outcomes between ECD and SCD kidney transplant recipients. These five studies confirmed that ECD recipients seemed to have poorer prognosis. From 29 studies reporting appropriate survival curves, we estimated the 5-year pooled nonadjusted survivals for ECD and SCD recipients. The relative differences between the two groups were lower in Europe than in North America, particularly for death-censored graft failure. It is of primary importance to propose appropriate studies for external validation of the ECD criteria in non-US kidney transplant recipients.

Rabbit antithymocyte globulin-induced serum sickness disease and human kidney graft survival.

BACKGROUND: Rabbit-generated antithymocyte globulins (ATGs), which target human T cells, are widely used as immunosuppressive agents during treatment of kidney allograft recipients. However, ATGs can induce immune complex diseases, including serum sickness disease (SSD). Rabbit and human IgGs have various antigenic differences, including expression of the sialic acid Neu5Gc and α-1-3-Gal (Gal), which are not synthesized by human beings. Moreover, anti-Neu5Gc antibodies have been shown to preexist and be elicited by immunization in human subjects. This study aimed to assess the effect of SSD on long-term kidney allograft outcome and to compare the immunization status of grafted patients presenting with SSD following ATG induction treatment. METHODS: We analyzed data from a cohort of 889 first kidney graft recipients with ATG induction (86 with SSD [SSD(+)] and 803 without SSD [SSD(-)]) from the Données Informatisées et Validées en Transplantation data bank. Two subgroups of SSD(+) and SSD(-) patients that had received ATG induction treatment were then assessed for total anti-ATG, anti-Neu5Gc, and anti-Gal antibodies using ELISA assays on sera before and after transplantation. RESULTS: SSD was significantly associated with long-term graft loss (>10 years, P = 0.02). Moreover, SSD(+) patients exhibited significantly elevated titers of anti-ATG (P = 0.043) and anti-Neu5Gc (P = 0.007) IgGs in late post-graft samples compared with SSD(-) recipients. CONCLUSION: In conclusion, our data indicate that SSD is a major contributing factor of late graft loss following ATG induction and that anti-Neu5Gc antibodies increase over time in SSD(+) patients. FUNDING: This study was funded by Société d'Accélération du Transfert de Technologies Ouest Valorisation, the European FP7 "Translink" research program, the French National Agency of Research, Labex Transplantex, the Natural Science and Engineering Research Council of Canada, and the Canadian Foundation for Innovation.

An original approach was used to better evaluate the capacity of a prognostic marker using published survival curves.

OBJECTIVES: Predicting chronic disease evolution from a prognostic marker is a key field of research in clinical epidemiology. However, the prognostic capacity of a marker is not systematically evaluated using the appropriate methodology. We proposed the use of simple equations to calculate time-dependent sensitivity and specificity based on published survival curves and other time-dependent indicators as predictive values, likelihood ratios, and posttest probability ratios to reappraise prognostic marker accuracy. STUDY DESIGN AND SETTING: The methodology is illustrated by back calculating time-dependent indicators from published articles presenting a marker as highly correlated with the time to event, concluding on the high prognostic capacity of the marker, and presenting the Kaplan-Meier survival curves. The tools necessary to run these direct and simple computations are available online at http://www.divat.fr/en/online-calculators/evalbiom. RESULTS: Our examples illustrate that published conclusions about prognostic marker accuracy may be overoptimistic, thus giving potential for major mistakes in therapeutic decisions. CONCLUSION: Our approach should help readers better evaluate clinical articles reporting on prognostic markers. Time-dependent sensitivity and specificity inform on the inherent prognostic capacity of a marker for a defined prognostic time. Time-dependent predictive values, likelihood ratios, and posttest probability ratios may additionally contribute to interpret the marker's prognostic capacity.

Net time-dependent ROC curves: a solution for evaluating the accuracy of a marker to predict disease-related mortality.

Developing prognostic markers of mortality for patients with chronic disease is important for identifying subjects at high risk of death and optimizing medical management. The usual approach in this regard is the use of time-dependent ROC curves, which are well adapted for censored data. Nevertheless, an important part of the mortality may not be due to the chronic disease, and it is often impossible to individually determine whether or not the deaths are related to the disease itself. In survival regression, one solution is to distinguish between the expected mortality of one general population (from life tables) and the excess mortality related to the disease, by using an additive relative survival model. In this paper, we propose a new estimator of time-dependent ROC curves, which includes this concept of net survival, in order to evaluate the capacity of a marker to predict disease-specific mortality. We performed simulations in order to validate this estimator. We also illustrate this method using two different applications: (i) predicting mortality related to primary biliary cirrhosis of the liver and (ii) predicting mortality related to kidney transplantation in end-stage renal disease patients. For each application, we evaluated a scoring system already established. The results demonstrate the utility of the proposed estimator of net time-dependent ROC curves.

An alternative approach to estimate age-related mortality of kidney transplant recipients compared to the general population: results in favor of old-to-old transplantations.

Compared to dialysis, kidney transplantation appears to be the best treatment for chronic kidney failure, even for older aged patients. Nevertheless, the individual benefit of transplanting elderly patients has to be balanced against the corresponding increase in the number of patients awaiting grafts. We analyzed the excess mortality related to kidney transplant recipients by taking into account the expected mortality of the general population (additive regression model for relative survival). We applied this method to a cohort of patients who received a first deceased-donor kidney transplant between 1998 and 2009 in France (DIVAT, n = 3641). Overall 10-year mortality was 13%. As expected, recipient age was the main risk factor associated with overall mortality. In contrast, recipient age was no longer significantly associated with the excess of mortality related to kidney transplant status by subtracting the expected mortality of the general population. Delayed graft function (DGF), pretransplantation immunization, and past history of diabetes appeared as the main risk factors of this higher mortality rate. Our results constitute a strong argument in favor of kidney transplantation, regardless of the patient's age. Preventing DGF may be more effective for decreasing the risk of death specifically attributable to the disease.