Bénédicte Janbon

Post-Transplantation Lymphoproliferative Disorder After Kidney Transplantation: Report of a Nationwide French Registry and the Development of a New Prognostic Score

PURPOSE Post-transplantation lymphoproliferative disorder (PTLD) is associated with significant mortality in kidney transplant recipients. We conducted a prospective survey of the occurrence of PTLD in a French nationwide population of adult kidney recipients over 10 years. PATIENTS AND METHODS A French registry was established to cover a nationwide population of transplant recipients and prospectively enroll all adult kidney recipients who developed PTLD between January 1, 1998, and December 31, 2007. Five hundred patient cases of PTLD were referred to the French registry. The prognostic factors for PTLD were investigated using Kaplan-Meier and Cox analyses. RESULTS Patients with PTLD had a 5-year survival rate of 53% and 10-year survival rate of 45%. Multivariable analyses revealed that age > 55 years, serum creatinine level > 133 μmol/L, elevated lactate dehydrogenase levels, disseminated lymphoma, brain localization, invasion of serous membranes, monomorphic PTLD, and T-cell PTLD were independent prognostic indicators of poor survival. Considering five variables at diagnosis (age, serum creatinine, lactate dehydrogenase, PTLD localization, and histology), we constructed a prognostic score that classified patients with PTLD as being at low, moderate, high, or very high risk for death. The 10-year survival rate was 85% for low-, 80% for moderate-, 56% for high-, and 0% for very high-risk recipients. CONCLUSION This nationwide study highlights the prognostic factors for PTLD and enables the development of a new prognostic score. After validation in an independent cohort, the use of this score should allow treatment strategies to be better tailored to individual patients in the future.

Conversion to mammalian target of rapamycin inhibitors increases risk of de novo donor-specific antibodies

In kidney transplantation, conversion to mammalian target of rapamycin (mTOR) inhibitors may avoid calcineurin inhibitor (CNI) nephrotoxicity, but its impact on post‐transplant allo‐immunization remains largely unexplored. This retrospective cohort study analyzed the emergence of donor‐specific antibodies (DSA) in kidney transplant recipients relative to their immunosuppressive therapy. Among 270 recipients without pretransplant immunization who were screened regularly for de novo DSA, 56 were converted to mTOR inhibitors after CNI withdrawal. DSA emergence was increased in patients who were converted to mTOR inhibitors (HR 2.4; 95% CI 1.06–5.41, P = 0.036). DSA were mainly directed against donor HLA‐DQB1 antigens. The presence of one or two DQ mismatches was a major risk factor for DQ DSA (HR 5.32; 95% CI 1.58–17.89 and HR 10.43; 95% CI 2.29–47.56, respectively; P < 0.01). Rejection episodes were more likely in patients converted to mTOR inhibitors, but this difference did not reach significance (16% vs. 7.9%, P = 0.185). Concerning graft function, no significant change was observed one year after conversion (P = 0.31). In conclusion, conversion to mTOR inhibitors may increase the risk of developing class II DSA, especially in the presence of DQ mismatches: this strategy may favor chronic antibody‐mediated rejection and thus reduce graft survival.

Profiling Sirolimus-Induced Inflammatory Syndrome: A Prospective Tricentric Observational Study

Background The use of the immunosuppressant sirolimus in kidney transplantation has been made problematic by the frequent occurrence of various side effects, including paradoxical inflammatory manifestations, the pathophysiology of which has remained elusive. Methods 30 kidney transplant recipients that required a switch from calcineurin inhibitor to sirolimus-based immunosuppression, were prospectively followed for 3 months. Inflammatory symptoms were quantified by the patients using visual analogue scales and serum samples were collected before, 15, 30, and 90 days after the switch. Results 66% of patients reported at least 1 inflammatory symptom, cutaneo-mucosal manifestations being the most frequent. Inflammatory symptoms were characterized by their lability and stochastic nature, each patient exhibiting a unique clinical presentation. The biochemical profile was more uniform with a drop of hemoglobin and a concomitant rise of inflammatory acute phase proteins, which peaked in the serum 1 month after the switch. Analyzing the impact of sirolimus introduction on cytokine microenvironment, we observed an increase of IL6 and TNFα without compensation of the negative feedback loops dependent on IL10 and soluble TNF receptors. IL6 and TNFα changes correlated with the intensity of biochemical and clinical inflammatory manifestations in a linear regression model. Conclusions Sirolimus triggers a destabilization of the inflammatory cytokine balance in transplanted patients that promotes a paradoxical inflammatory response with mild stochastic clinical symptoms in the weeks following drug introduction. This pathophysiologic mechanism unifies the various individual inflammatory side effects recurrently reported with sirolimus suggesting that they should be considered as a single syndromic entity.

A French Cohort Study of Kidney Retransplantation after Post-Transplant Lymphoproliferative Disorders

BACKGROUND AND OBJECTIVES Post-transplant lymphoproliferative disorders arising after kidney transplantation portend an increased risk of morbidity and mortality. Retransplantation of patients who had developed post-transplant lymphoproliferative disorder remains questionable owing to the potential risks of recurrence when immunosuppression is reintroduced. Here, we investigated the feasibility of kidney retransplantation after the development of post-transplant lymphoproliferative disorder. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We reviewed the data from all patients who underwent kidney retransplantation after post-transplant lymphoproliferative disorder in all adult kidney transplantation centers in France between 1998 and 2015. RESULTS We identified a total of 52 patients with kidney transplants who underwent 55 retransplantations after post-transplant lymphoproliferative disorder. The delay from post-transplant lymphoproliferative disorder to retransplantation was 100±44 months (28-224); 98% of patients were Epstein-Barr virus seropositive at the time of retransplantation. Induction therapy for retransplantation was used in 48 patients (i.e., 17 [31%] patients received thymoglobulin, and 31 [57%] patients received IL-2 receptor antagonists). Six patients were also treated with rituximab, and 53% of the patients received an antiviral drug. The association of calcineurin inhibitors, mycophenolate mofetil, and steroids was the most common maintenance immunosuppression regimen. Nine patients were switched from a calcineurin inhibitor to a mammalian target of rapamycin inhibitor. One patient developed post-transplant lymphoproliferative disorder recurrence at 24 months after retransplantation, whereas post-transplant lymphoproliferative disorder did not recur in 51 patients. CONCLUSIONS The recurrence of post-transplant lymphoproliferative disorder among patients who underwent retransplantation in France is a rare event.

The age-calibrated measured glomerular filtration rate improves living kidney donation selection process

Recommendations on the glomerular filtration rate (GFR) threshold compatible with living kidney donation are not agreed upon. The recent KDIGO guidelines suggested a reset of the conventional cutoff value of 80 to 90 mL/min/1.73 m2. While GFR physiologically declines with age, it is unclear whether and how age should be taken into account for selecting acceptable pre-donation GFR. In this multicenter retrospective study encompassing 2007 kidney donors in France, we evaluated the impact of age using two threshold measured GFR (mGFR)s (80 and 90 mL/min/1.73 m2). Three groups of donors were defined according to baseline mGFR: below 80, 80-89.9 and 90 mL/min/1.73 m2 or more. Thirty-two percent of donors were selected despite an mGFR below 90 mL/min/1.73 m2. Donors with the lowest mGFR were significantly older (60 ± 9 vs. 47 ± 11 years) and this applied to both male and female donors. The lifetime-standardized renal reserve, defined as the pre-donation mGFR value divided by the expected number of remaining years of life, was similar irrespective of baseline mGFR groups. Similar results were obtained when eGFR was used instead of mGFR. Finally, in a subgroup of 132 donors with repeated mGFR five years after donation, the magnitude of mGFR decrease was similar in all groups (-34.3%, -33.9%, and -34.9% respectively). Thus, the decision to accept individuals with mGFR lower than 90 mL/min/1.73 m2 for kidney donation is highly dependent on the age of the candidate. Hence, threshold values lower than 90 mL/min/1.73 m2 are reasonable for older donors. Age-calibrated mGFR may improve efficiency of the selection process.

Aortic bypass surgery for asymptomatic patients awaiting a kidney transplant: A word of caution

In the presence of severe aorto‐iliac calcification, aortic bypass surgery can be mandatory to allow kidney transplantation. The aim of our study was to evaluate the safety and outcomes of this strategy among asymptomatic patients.