Acute kidney injury

Acute kidney injury (AKI) – a large unmet medical need

Acute kidney injury (AKI) affects millions of people annually and involves a rapid loss of kidney function because of various types of injuries to the kidneys. Without access to highly specialized medical care, mortality is often high and those who survive are at risk of suffering from chronic loss of kidney function, which in turn is associated with increased morbidity and reduced quality of life.

There are many different causes of AKI, for example major surgical procedures, solid organ transplantation, serious infections (e.g. sepsis) and various cancer treatments such as chemotherapy and radiation. Unfortunately, there are no specific pharmacotherapies available for the prevention of AKI. Current treatment paradigm is mainly focused on symptomatic relief, management of fluid and metabolic abnormalities and, if necessary, provision of life-sustaining dialysis treatment.

Guard Therapeutics aims to develop novel and innovative treatments for AKI, an area with a large unmet medical need and currently without effective therapies. The aim is to prevent both the occurrence of AKI and to reduce its severity when injury is already present.

The company's lead investigational drug RMC-035 is currently being evaluated in clinical studies covering two separate indications: open heart surgery and kidney transplantation. The principal treatment objectives in both indications are similar:

To prevent AKI and acute complications thereof, such as dialysis treatment and prolonged hospitalization time (including intensive care)

To prevent a sustained (chronic) loss of kidney function. This reduces the risk of future need for dialysis treatment or kidney transplantation.

AKI in cardiac surgery

AKI may occur as a direct and undesirable consequence of open heart surgery, i.e. when surgery is performed with open chest and use of a heart-lung machine (cardiopulmonary bypass). This technique is commonly used for patients undergoing coronary artery bypass graft (CABG) surgery and/or valve replacement. It is estimated that up to 30% of all patients undergoing open heart surgery develop AKI, but this figure is significantly higher (>50%) in some patients with additional risk factors, such as diabetes, heart failure or chronic kidney disease.

Several factors contribute to the development of AKI in this setting. A main cause is oxygen deficiency within the kidneys, which lead to so-called ischemia-reperfusion injuries, and another reason is that the kidneys are exposed to a harmful breakdown product of the oxygen-carrying substance hemoglobin (heme) resulting from hemolysis in patients undergoing cardiopulmonary bypass. A secondary inflammatory reaction typically ensues that fuels an expansion of the initial injury and increases the risk that AKI transitions into a chronic loss of kidney function.

AKI in kidney transplantation

In kidney transplantation, oxygen deficiency and ischemic injuries inevitably arise during the organ procurement process when the kidney is stored outside the body without blood supply. This means that normal cell functions within the donated kidney cannot be adequately maintained. In the short term, this leads to a poor graft function in the recipient of the donated kidney immediately following the transplantation, and in the longer term to adverse clinical outcomes such as a lower peak kidney function and shorter graft survival.

Sometimes supportive dialysis treatment is required in the post-operative period, which is commonly referred to as delayed graft function (DGF). This condition is also linked to a worse long-term prognosis including shorter graft survival.

The ischemic injuries causing AKI in kidney transplantation are in many ways similar to those underlying AKI following cardiac surgery and are characterized by elevated levels of reactive oxygen species and impaired function of energy-producing units within the cells (mitochondria). As in cardiac surgery patients, RMC-035 treatment can be given to the kidney transplant recipient during hospitalization in conjunction with the surgical procedure. An important difference, however, is that in kidney transplantation there is also an opportunity to pre-treat the kidney outside the body (i.e., before it has been surgically implanted into the recipient) to maximize the overall treatment effect of RMC-035.