Preventing acute kidney injury during transplantation: the application of novel oxygen carriers

ABSTRACT

Introduction: Delayed graft function (DGF) has a significant impact on kidney transplantation outcome. One of the underlying pivotal mechanisms is organ preservation and associated hypothermia and biochemical alteration.

Area covered: This paper focuses on organ preservation and its clinical consequences and describes 1. A comprehensive presentation of the pathophysiological mechanism involved in delayed graft function development; 2. The impact on endothelial cells and microvasculature integrity and the consequences on transplanted organ outcome; 3. The reassessment of dynamic organ preservation motivated by the growing use of extended criteria donors and the interest in the potential of normothermia; 4. The role of oxygenation during dynamic preservation; and 5. Novel oxygen carriers and their proof of concept in transplantation, among which M101 (HEMO₂life®) is currently the most extensively investigated.

Expert opinion: Metabolic disturbances and imbalance of oxygen supply during preservation highlight the importance of providing oxygen. Normothermia, permitted by recent advances in machine perfusion technology, appears to be the leading edge of preservation technology. Several oxygen transporters are compatible with normothermia; however, only M101 also demonstrates compatibility with standard hypothermic preservation.

KEYWORDS:

• Oxygen carrier
• transplantation
• organ preservation
• machine perfusion
• ischemia reperfusion

Article Highlights

• Recent studies have demonstrated that cold storage is not an innocuous period for the organ, with specific lesions associated with hypothermia and hypoxia that need to be further understood for fragile organs to be better preserved.

• The vascular bed is one of the primary targets of ischemia-reperfusion, particularly its smallest sections (<30 µm diameter).

• While HIF-1α appears to present an interesting target for therapy, ischemia appears to dysregulate this pathway downstream of HIF-1α, and it would thus appear that therapeutics should be aimed at the source of HIF-1α activation: the lack of oxygen.

• The development of machine preservation introduces the possibility of active oxygenation, through the design of the machine. While promising, equipment costs as well as logistical issues (transport of pressurized oxygen can be problematic) may dissuade from pursuing this solution to the benefit of a simpler approach: the use of oxygen transporters.

• Three oxygen transporters have so far been tested in organ preservation: HBOC-201, HbV, and M101. While all are compatible with subnormothermic preservation, with varying benefits, only M101 showed a range of temperatures reaching 4°C.

• M101 was demonstrated to improve organ preservation quality, and thus outcome, in preclinical models of transplantation for kidney, lung, heart, liver, and pancreas; both in static and dynamic preservation. It recently went through a clinical safety trial and is now entering an effectiveness clinical trial.

This box summarizes key points contained in the article.

Declaration of interest

F Zal is Hemarina founder and holds stock in the company that produces HEMO2life®. E Delpy is an employee of Hemarina. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.