Supplementation With a New Therapeutic Oxygen Carrier Reduces Chronic Fibrosis and Organ Dysfunction in Kidney Static Preservation

Abstract

† Both the authors have equally contributed to this work.Static preservation is currently the most widely used organ preservation strategy; however, decreased donor organ quality is impacting outcome negatively. M101 is an O 2 carrier with high-oxygen affinity and the capacity to function at low temperatures. We tested the benefits of M101 both in vitro, on cold preserved LLC-PK1, as well as in vivo, in a large white pig kidney autotransplantation model. In vitro, M101 supplementation reduced cold storage-induced cell death. In vivo, early follow-up demonstrated superiority of M101-supplemented solutions, lowering the peak of serum creatinine and increasing the speed of function recovery. On the longer term, supplementation with M101 reduced kidney inflammation levels and maintained structural integrity, particularly with University of Wisconsin (UW). At the end of the 3-month followup, M101 supplementation proved beneficial in terms of survival and function, as well as slowing the advance of interstitial fibrosis. We show that addition of M101 to classic organ preservation protocols with UW and Histidine-Tryptophane-Ketoglutarate, the two most widely used solutions worldwide in kidney preservation, provides significant benefits to grafts, both on early function recovery and outcome. Simple supplementation of the solution with M101 is easily translatable to the clinic and shows promises in terms of outcome.Key words: Graft preservation, ischemia reperfusion injury, kidney transplantation, oxygen, oxygen transporters Abbreviations: ATP, adenosine 5 -triphosphate; CS, cold storage; HBL-Hb, hexagonal-bilayer hemoglobin; HBOC, hemoglobin-based oxygen carrier; HTK, histidine tryptophane ketoglutarate; IFTA, interstitial fibrosis and tubular atrophy; IRI, ischemia reperfusion injury; LDH, lactate dehydrogenase; M101, hemarina-M101; NBT, nitroblue tetrazolium; PFCs, perfluorocarbons; SOD, superoxide dismutase; UW, University of Wisconsin.

Cerebral Vasoactivity and Oxygenation with Oxygen Carrier M101 in Rats

“…The M101 product also has high oxygen affinity (P 50 ~ 7 mm Hg) and high oxygen carrying capacity; carrying up to 156 oxygen molecules per hemoglobin. It is active over a wide range of temperatures 12 and has a half-life, determined using M101 tagged with fluorescent dye, of age 3 of 39 4 ~24 h in rats. 13 M101 has been shown to improve organ preservation 12,14 and a recent study, measuring arterioles and venules in the hamster dorsal skin fold, reports that M101 does not have vasoconstrictive properties.…”

“…It is active over a wide range of temperatures 12 and has a half-life, determined using M101 tagged with fluorescent dye, of age 3 of 39 4 ~24 h in rats. 13 M101 has been shown to improve organ preservation 12,14 and a recent study, measuring arterioles and venules in the hamster dorsal skin fold, reports that M101 does not have vasoconstrictive properties. 10 These product characteristics and pharmacodynamic data make M101 a candidate for further development for pre-hospital treatment for TBI if the product 1) does not cause cerebral arteriolar vasoconstriction (safety) and 2) shows evidence of reducing brain injury (efficacy) in TBI models.…”

Strategies to optimize kidney recovery and preservation in transplantation: specific aspects in pediatric transplantation

“…SCOT15, which belongs to these fourth-generation solutions, combines an extracellular-like composition with a 20-kDa PEG and is known for its cell-protection capacity and immunocamouflage properties [13,31,32]. Although insufficient data are currently available to provide guidelines on preservation solutions for pediatric kidney transplantation, numerous preclinical studies have shown the potential of modifying preservation solutions to improve graft survival [33][34][35].…”

L’ischémie reperfusion

“…Cette approche a montré des bénéfices en clinique, notamment sur les greffons « à critères élargis » (provenant de donneurs ayant des comorbidités) [27]. Des études expérimentales sont en cours pour évaluer de nouveaux concepts et adopter des conditions plus propices au maintien physiologique des tissus par l'oxygénation du milieu de perfusion [28] ou par l'ajout de transporteurs d'oxygène ou de nutriments [29].…”