Profiling sirolimus-induced inflammatory syndrome: a prospective tricentric observational study

• Published in: PloS one Vol. 8; no. 1; p. e53078
• Main Authors: Buron, Fanny, Malvezzi, Paolo, Villar, Emmanuel, Chauvet, Cécile, Janbon, Bénédicte, Denis, Laure, Brunet, Maria, Daoud, Sameh, Cahen, Rémi, Pouteil-Noble, Claire, Gagnieu, Marie-Claude, Bienvenu, Jacques, Bayle, François, Morelon, Emmanuel, Thaunat, Olivier
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07.01.2013; Public Library of Science (PLoS)
• Subjects: Acute phase proteins; Acute phase substances; Adult; Aged; Analysis; Anemia; Biology; Calcineurin; Calcineurin Inhibitors; Cell cycle; Cytochrome P-450 CYP3A - genetics; Cytokines; Destabilization; Drug dosages; Feedback loops; Female; Genotype; Hemoglobin; Humans; Immunology; Immunosuppression; Immunosuppressive agents; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - immunology; Immunotherapy; Impact analysis; Inflammation; Inflammation - chemically induced; Inflammatory response; Interleukin 1; Interleukin 10; Interleukin 6; Interleukin-10 - blood; Interleukin-10 - immunology; Interleukin-6 - blood; Interleukin-6 - immunology; Iron; Kidney transplantation; Kidney Transplantation - adverse effects; Kidneys; Lability; Male; Medical research; Medicine; Medicine, Experimental; Middle Aged; Mucosa; Negative feedback; Observational studies; Organ transplant recipients; Patients; Prospective Studies; Proteins; Rapamycin; Receptors; Regression analysis; Regression models; Side effects; Sirolimus - adverse effects; Sirolimus - immunology; Stochasticity; Transplantation; Transplants & implants; Tumor necrosis factor receptors; Tumor Necrosis Factor-alpha - blood; Tumor Necrosis Factor-alpha - immunology; Tumor necrosis factor-α; France
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0053078

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. 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. 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. 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.