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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.

Seasonal influenza epidemics are associated with high morbidity and mortality particularly in high-risk patients. Conventionally administered influenza vaccines show reduced efficacy in populations with weakened immune systems such as solid-organ transplant patients. This study assesses the safety and immunogenicity of an intradermally administered influenza vaccine in renal transplant patients previously identified as non-responders to a licensed trivalent inactivated influenza vaccine (TIV). Renal transplant patients with low or no hemagglutination inhibiting (HI) antibody response to an A influenza (H3N2) vaccine strain were enrolled in a descriptive phase II, open-label, randomized, multicentre trial: 31 received an investigational intradermal TIV, and 31 received a conventionally administered TIV. Both vaccines contained 15 μg hemagglutinin (HA) per strain. The 62 study subjects were selected from 201 renal transplant patients aged 18-60 years who had been vaccinated in the previous year with a conventionally administered TIV. Vaccination was safe and well tolerated by each administration route. The immunogenicity results of this descriptive study showed ID TIV vaccination to induce HI antibody responses that trended higher in renal transplant patients than conventionally administered TIV. Our results suggest that ID influenza vaccination may offer enhanced immunogenicity and protection in persons who do not respond well to conventional TIV. Further studies should be conducted in immunocompromised populations to validate the trends for higher efficacy of ID vs. conventional route of immunization against influenza.