title: Profiling sirolimus-induced inflammatory syndrome: a prospective tricentric observational study.
abstract: 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.
authors: Service de Transplantation, néphrologie et Immunologie Clinique de l'Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France ; Université de Lyon, Lyon, France.
authors: Fanny
authors: F
authors: Buron
authors: Paolo
authors: P
authors: Malvezzi
authors: Emmanuel
authors: E
authors: Villar
authors: Cécile
authors: C
authors: Chauvet
authors: Bénédicte
authors: B
authors: Janbon
authors: Laure
authors: L
authors: Denis
authors: Maria
authors: M
authors: Brunet
authors: Sameh
authors: S
authors: Daoud
authors: Rémi
authors: R
authors: Cahen
authors: Claire
authors: C
authors: Pouteil-Noble
authors: Marie-Claude
authors: MC
authors: Gagnieu
authors: Jacques
authors: J
authors: Bienvenu
authors: François
authors: F
authors: Bayle
authors: Emmanuel
authors: E
authors: Morelon
authors: Olivier
authors: O
authors: Thaunat
mesh_terms: D000328:Adult; D000368:Aged; D065095:Calcineurin Inhibitors; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000276:immunology; D007249:Inflammation / Q000139:chemically induced; D016753:Interleukin-10 / Q000097:blood / Q000276:immunology; D015850:Interleukin-6 / Q000097:blood / Q000276:immunology; D016030:Kidney Transplantation / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D020123:Sirolimus / Q000009:adverse effects* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000276:immunology
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D020123:Sirolimus