Emerging therapeutic strategies for transplantation-induced acute kidney injury: protecting the organelles and the vascular bed

ABSTRACT

Introduction: Renal ischemia-reperfusion injury (IRI) is a significant clinical challenge faced by clinicians in a broad variety of clinical settings such as perioperative and intensive care. Renal IRI induced acute kidney injury (AKI) is a global public health concern associated with high morbidity, mortality, and health-care costs.

Areas covered: This paper focuses on the pathophysiology of transplantation-related AKI and recent findings on cellular stress responses at the intersection of 1. The Unfolded protein response; 2. Mitochondrial dysfunction; 3. The benefits of mineralocorticoid receptor antagonists. Lastly, perspectives are offered to the readers.

Expert opinion: Renal IRI is caused by a sudden and temporary impairment of blood flow to the organ.

Defining the underlying cellular cascades involved in IRI will assist us in the identification of novel interventional targets to attenuate IRI with the potential to improve transplantation outcomes. Targeting mitochondrial function and cellular bioenergetics upstream of cellular damage may offer several advantages compared to targeting downstream inflammatory and fibrosis processes.

An improved understanding of the cellular pathophysiological mechanisms leading to kidney injury will hopefully offer improved targeted therapies to prevent and treat the injury in the future.

KEYWORDS:

• Transplantation-induced acute kidney injury
• delayed graft function
• ischemia reperfusion
• unfolded protein response
• mitochondrial energetic modulation
• mineralocorticoid receptor
• stem cells
• gene therapy

Article Highlights

• The endoplasmic reticulum response to stress is finely regulated during organ preservation, and its pharmacological modulation can protect from transplantation-induced AKI.

• The microcirculation is the principal site of ischemia-reperfusion impact, with long-term impact on organ irrigation and chronic loss of function.

• Mitochondrial protection using specific molecules, such as GC7 which potentially induces mitochondrial dormance, improves organ quality and decreases the onset of transplantation-induced AKI.

• The mineralocorticoid pathway is a promising target to protect the vascular bed and indeed compounds such as soludactone has shown benefits against ischemia-reperfusion.

• Advances in stem cell therapy are discussed, in particular, the potential for organ repair before and after ischemia-reperfusion, a critical area in the current donor demographic evolution.

• Reprogramming the organ through gene therapy is compatible with preservation for several organ types, opening new avenues for non-pharmaceutical therapies and preconditioning strategies.

This box summarizes the key points contained in the article.

Declaration of interest

The authors have no 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. The work of the authors is funded by Inserm, CNRS, Université de Poitiers, CHU de Poitiers