title: Cyclodextrin curcumin formulation improves outcome in a preclinical pig model of marginal kidney transplantation.
abstract: Decreasing organ quality is prompting research toward new methods to alleviate ischemia reperfusion injury (IRI). Oxidative stress and nuclear factor kappa beta (NF-κB) activation are well-described elements of IRI. We added cyclodextrin-complexed curcumin (CDC), a potent antioxidant and NF-κB inhibitor, to University of Wisconsin (UW) solution (Belzer's Solution, Viaspan), one of the most effective clinically approved preservative solutions. The effects of CDC were evaluated on pig endothelial cells and in an autologous donation after circulatory death (DCD) kidney transplantation model in large white pigs. CDC allowed rapid and lasting uptake of curcumin into cells. In vitro, CDC decreased mitochondrial loss of function, improved viability and lowered endothelial activation. In vivo, CDC improved function recovery, lowered histological injury and doubled animal survival (83.3% vs. 41.7%). At 3 months, immunohistochemical staining for epithelial-to-mesenchymal transition (EMT) and fibrosis markers was intense in UW grafts while it remained limited in the UW + CDC group. Transcriptional analysis showed that CDC treatment protected against up-regulation of several pathophysiological pathways leading to inflammation, EMT and fibrosis. Thus, use of CDC in a preclinical transplantation model with stringent IRI rescued kidney grafts from an unfavorable prognosis. As curcumin has proved well tolerated and nontoxic, this strategy shows promise for translation to the clinic.
authors.affiliation: Inserm U1082, Faculté de Medecine et Pharmacie, Université de Poitiers, Poitiers, France; Département de Biochimie, CHU de Poitiers, Poitiers, France; FLIRT: Fédération pour L'étude de l'Ischémie Reperfusion en Transplantation, Poitiers, France; COPE: Consortium for Organ Preservation in Europe.
authors.forename: R
authors.initials: R
authors.lastname: Thuillier
authors.forename: G
authors.initials: G
authors.lastname: Allain
authors.forename: S
authors.initials: S
authors.lastname: Giraud
authors.forename: T
authors.initials: T
authors.lastname: Saintyves
authors.forename: P O
authors.initials: PO
authors.lastname: Delpech
authors.forename: P
authors.initials: P
authors.lastname: Couturier
authors.forename: C
authors.initials: C
authors.lastname: Billault
authors.forename: E
authors.initials: E
authors.lastname: Marchand
authors.forename: L
authors.initials: L
authors.lastname: Vaahtera
authors.forename: J
authors.initials: J
authors.lastname: Parkkinen
authors.forename: T
authors.initials: T
authors.lastname: Hauet
mesh_terms: D000241:Adenosine; D000493:Allopurinol; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D015153:Blotting, Western; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical; D003474:Curcumin / Q000008:administration & dosage*; D003505:Cyclodextrins / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005355:Fibrosis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D005434:Flow Cytometry; D005978:Glutathione; D006084:Graft Rejection / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D007328:Insulin; D016030:Kidney Transplantation; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D019188:Organ Preservation Solutions; D018384:Oxidative Stress; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D011887:Raffinose; D060888:Real-Time Polymerase Chain Reaction; D015427:Reperfusion Injury / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013552:Swine
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D003505:Cyclodextrins; D007328:Insulin; D019188:Organ Preservation Solutions; D012333:RNA, Messenger; C055206:University of Wisconsin-lactobionate solution; D000493:Allopurinol; D005978:Glutathione; D003474:Curcumin; D000241:Adenosine; D011887:Raffinose
keywords: Antioxidants; graft outcome; ischemia reperfusion injury; kidney transplantation; preservation