Katy Trébern-Launay

Background: End-stage renal failure occurs in a substantial number of patients having received a nonrenal transplantation (NRT), for whom a kidney transplantation is needed. The medical strategy regarding the use of immunosuppression (IS) for a kidney graft in patients after an NRT is not well established. The prekidney grafts long-term IS advocates for a mild induction, such as using anti-IL-2R antibodies, whereas addition of new incompatibilities and anti-HLA preimmunization may suggest using stronger IS such as induction by polyclonal antithymocyte globulins (ATG). Methods: We performed Cox multivariate and propensity score analysis of our validated transplant database to study the impact of the type of induction therapy on kidney graft survival of recipients of a kidney graft after NRT. Results: We report here that kidney transplantation after NRT treated with an ATG induction has a poorer outcome (kidney and recipient survival) than that with an anti–IL-2R induction. After accounting for potential baseline differences with a multivariate Cox model, or by adjusting on a propensity score, we found that despite patients having received ATG cumulate more risk factors, ATG appears independently involved. As animal-derived biotherapeutics induce antiglycan antibodies and particularly anti–N-glycolylneuraminic acid (Neu5Gc) IgGs which may activate endothelial cells in patients and grafts, we also investigated the magnitude and the nature of the anti-Neu5Gc elicited by the induction and showed that induction was associated with a shift in anti-Neu5Gc IgG repertoire. Possible reasons and mechanisms of a deleterious ATG usage in these patients are discussed. Conclusions: Our study suggests that ATG induction after a kidney transplantation in recipients already under maintenance IS for a NRT should be used cautiously.

When a patient is registered on renal transplant waiting list, she/he expects a clear information on the likelihood of being transplanted. Nevertheless, this event is in competition with death and usual models for competing events are difficult to interpret for non-specialists. We used a horizontal mixture model. Data were extracted from two French dialysis and transplantation registries. The “Ile-de-France” region was used for external validation. The other patients were randomly divided for training and internal validation. Seven variables were associated with decreased long-term probability of transplantation: age over 40 years, comorbidities (diabetes, cardiovascular disease, malignancy), dialysis longer than 1 year before registration and blood groups O or B. We additionally demonstrated longer mean time-to-transplantation for recipients under the age of 50, overweight recipients, recipients with blood group O or B and with pre-transplantation anti-HLA class I or II immunization. Our model can be used to predict the long-term probability of transplantation and the time in dialysis among transplanted patients, two easily interpretable parts. Discriminative capacities were validated on both the internal and external (AUC at 5 years = 0.72, 95% CI from 0.68 to 0.76) validation samples. However, calibration issues were highlighted and illustrated the importance of complete re-estimation of the model for other countries. We illustrated the ease of interpretation of horizontal modelling, which constitutes an alternative to sub-hazard or cause-specific approaches. Nevertheless, it would be useful to test this in practice, for instance by questioning both the physicians and the patients. We believe that this model should also be used in other chronic diseases, for both etiologic and prognostic studies.

We aimed to assess the correlation of anti‐angiotensin II type 1 receptor antibodies (anti‐AT1R‐Abs) before transplantation on a multicentric cohort of kidney transplant recipients (2008–2012), under tacrolimus and mycophenolate mofetil (MMF), screened by Luminex technology for anti‐HLA immunization. Anti‐AT1R antibody levels were measured by ELISA in pretransplantation sera of 940 kidney recipients from three French centers of the DIVAT cohort. Multivariable Cox models estimated the association between pretransplant anti‐angiotensin II type 1 receptor antibodies and time to acute rejection episodes (ARE) or time to graft failure. Within our cohort, 387 patients (41.2%) had pretransplant AT1R‐Abs higher than 10 U/ml and only 8% (72/970) greater than 17 U/ml. The cumulative probability of clinically relevant (cr)‐ARE was 22.5% at 1 year post‐transplantation [95% CI (19.9–25.4%)]. The cumulative probability of graft failure and patient death were 10.6% [95% CI (8.4–13.3%)] and 5.7% [95% CI (4.0–8.1%)] at 3 years post‐transplantation, respectively. Multivariate Cox models indicated that pretransplant anti‐AT1R antibody levels higher than 10 U/ml were not significantly independently associated with higher risks of acute rejection episodes [HR = 1.04, 95% CI (0.80–1.35)] nor with risk of graft failure [HR = 0.86, 95% CI (0.56–1.33)]. Our study did not confirm an association between pretransplant anti‐AT1R antibody levels and kidney transplant outcomes.

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.

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.

Background: Whereas the prognosis of second kidney transplant recipients (STR) compared to the first ones has been frequently analyzed, no study has addressed the issue of comparing the risk factor effects on graft failure between both groups. Methods: Here, we propose two alternative strategies to study the heterogeneity of risk factors between two groups of patients: (i) a multiplicative-regression model for relative survival (MRS) and (ii) a stratified Cox model (SCM) specifying the graft rank as strata and assuming subvectors of the explicatives variables. These developments were motivated by the analysis of factors associated with time to graft failure (return-to-dialysis or patient death) in second kidney transplant recipients (STR) compared to the first ones. Estimation of the parameters was based on partial likelihood maximization. Monte-Carlo simulations associated with bootstrap re-sampling was performed to calculate the standard deviations for the MRS. Results: We demonstrate, for the first time in renal transplantation, that: (i) male donor gender is a specific risk factor for STR, (ii) the adverse effect of recipient age is enhanced for STR and (iii) the graft failure risk related to donor age is attenuated for STR. Conclusion: While the traditional Cox model did not provide original results based on the renal transplantation literature, the proposed relative and stratified models revealed new findings that are useful for clinicians. These methodologies may be of interest in other medical fields when the principal objective is the comparison of risk factors between two populations.