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.

Retreatment by antithymocyte globulin for second kidney transplantation: efficacy, tolerance and safety.

BACKGROUND: It is unknown whether kidney transplant patients who receive rabbit antithymocyte globulin (rATG) become immunized against rabbit antibodies, leading to reduced efficacy, or are at higher risk of cytomegalovirus infection or post-transplant lymphoproliferative disorder (PTLD) on retreatment. The efficacy and tolerance of rATG when used as induction for the second time in patients undergoing retransplantation have not been evaluated. METHODS: In a retrospective case-control study, 54 retransplanted patients who received rATG (Thymoglobulin) induction for the second time during 2004-2010 were compared to a matched cohort of 108 patients receiving rATG induction for a first kidney transplantation during the same period. Maintenance treatment was similar in both groups. RESULTS: Median follow-up was 45.8 months and 47.3 months in the second and first treatment groups, respectively. No differences were observed between the two groups in terms of leukocyte, lymphocyte or platelet depletion. Dose and duration of rATG treatment were similar in both groups, suggesting a similar tolerance profile. Cytomegalovirus infection (including primoinfection and reactivation) occurred in 4/54 retreated patients versus 22/108 controls (p=0.108). Use of cytomegalovirus prophylaxis was similar between groups. PTLD occurred in one control patient and no retreated patients. CONCLUSION: A second course of rATG induction results in similar lymphocyte depletion and is as well tolerated as a first course. The incidence of cytomegalovirus infection and post-transplant lymphoproliferative disease was not increased during retreatment. Further studies are required to evaluate specific T cell subpopulation depletion and compare long-term outcome in patients receiving a second induction with rATG.