Down-regulation of inflammatory signaling pathways despite up-regulation of Toll-like receptors; the effects of corticosteroid therapy in brain-dead kidney donors, a double-blind, randomized, controlled trial

Abstract

BACKGROUND: The brain death of a potential organ donor induces a systemic inflammatory response, resulting in inferior organ quality and function. Our study aimed to evaluate the effects of methylprednisolone (MPN) therapy on pattern recognition receptor (PRR) signaling in potential brain-dead (BD) kidney donors. MATERIAL AND METHODS: To evaluate the effects of MPN therapy on PRR signaling in BD kidney donors we performed a prospective randomized treatment-versus-control study. Fifty-one potential kidney donors were randomly divided into three groups: brain-dead donors (BDDs) who received 15mg/kg/d of methylprednisolone (group T1, n=17), BDDs who received 15mg/kg/d of MPN at the time of filling consent for kidney donation and 100mg/2h until kidney harvest (group T2, n=17), and normal donors as controls n=17. Gene expression for Toll-like receptors (TLRs) 1-9 and their signaling pathway molecules including MYD88, TRIF, NF-KB1, IRAK, IRF3, and IRF7, as well as the inflammatory cytokines RANTES, IL-1beta, TNF-alpha, IL-6, CXCL8, IL-18, IFN-alpha, and IFN-beta was determined by PCR array. Due to the crucial role of TLRs 2 and 4 in pattern recognition, surface expression of these molecules was analyzed by flow cytometry. Plasma levels of inflammatory cytokines were measured by immunoassay. Finally, serum creatinine and cystatin C were measured in 100 kidney recipients one week and one, three, and six months after transplant. RESULT: Polymerase chain reaction (PCR) array gene expression revealed greater expression of TLRs and signaling molecules in group T1 than in the controls. Surface expression of TLRs 2 and 4 were significantly greater in group T2 than in group T1 (P<.05). Plasma concentrations of inflammatory cytokines were significantly greater in group T1 than in controls (P<.05). The recipients that received kidneys from group T1 had significantly higher levels of creatinine and cystatin C than the recipients of kidneys from both group T1 and controls (P<0.05). CONCLUSION: Administration of MPN to BDDs at specified periods until kidney harvest resulted in less systemic inflammation in the BDDs and improved renal function in kidney graft recipients compared with common MPN therapy.