Figure provided by Dr. Richard Zager
Acute kidney injury (AKI) is serious health problem that has limited public awareness. One to five percent of all hospital patients are at risk of AKI, largely as a result of ischemic injury during or immediately following surgery. The reduced blood flow and thereby oxygenation of kidney tissue is particularly common in patients undergoing cardiopulmonary bypass 15% of these patients incur kidney injury, which is lethal in a third of cases. Surgery induced injury poses a unique problem because doctors know exactly when a patient is at risk. This means with the right therapy patients could be prepared or protected. With this approach in mind, the Zager Lab (Clinical Research Division) is working to stimulate the kidney’s natural, protective pathways and prevent AKI. In a recent publication in Kidney International the group observed promising kidney protection in multiple murine models of AKI using a single injection IV therapy.
In previous work Dr. Richard Zager and colleagues found that administering nitrited myoglobin and tin (Sn) protoporphyrin (SnPP) to mice, upregulated protective genes in the kidney and protected against kidney injury. This preclinical study found the approach to be safe and efficacious; however, alternatives are worth considering because high levels myoglobin are nephrotoxic. Myoglobin was hypothesized to prevent kidney injury because its heme group stimulated protective genes. Thus in this study researchers replaced nitrited myoglobin with an FDA approved iron-containing molecule, iron sucrose (FeS). Similarly, there is no source for clinical grade SnPP so an alternative protoporphyrin, cyanocobalamin (CCB) was also tested.
Renal injury can be induced in mice using either a nephrotoxin like maleate or by causing ischemia using microclamps to transiently stop kidney blood flow. As kidney function is lost serum levels of creatinine rise exponentially, serving as a simple and reliable measure of AKI severity. Excitingly, FeS paired with either SnPP or CCB protected against kidney damage in both models. To further this therapy it is also important to understand the molecular mechanisms driving cellular protection. Iron containing compounds are believed to induce these pathways by causing mild oxidative stress and altering the transcriptome. Consistent with this idea, researchers observed elevated mRNA and protein levels of genes involved in oxidative stress response, including, HO-1, haptoglobin, IL-10, and alpha-1-antitrypsin. This work has led to further exploration of the cellular mechanisms through which kidney protection is achieved, "We are currently performing microarray analysis after SnPP treatment to understand the mechanism responsible for protection. One of the most upregulated genes we are particularly interested to study is cytochrome p4502A5." said Dr. Zager.
While this combination therapy provided protection from kidney injury caused either by toxins or ischemia, damage is often more widespread. With ischemia, injury happens to multiple tissues as Dr. Zager explained, "When patients experience ischemic injury to the kidney it’s often accompanied by hepatic and cardiac damage as well." Moreover, any AKI may cause system damage through the release of inflammatory cytokines. Knowing this, researchers also tested if this therapy also mitigated cardiac damage AKI. The therapy also reduced cardiac damage as assessed by measuring serum levels of cardiac specific troponin I.
While the Zager Lab is pursuing a scientific understanding of cytoprotective mechanisms these compounds stimulate, a newly developed company, Renibus Therapeutics, is moving this treatment closer to the clinic. In collaboration with Fred Hutch and Dr. Zager, Renibus Therapeutics will begin human trials soon, "The goal is to initiate phase I trials by the end of this year or early next year." said Dr. Zager. This is another example of the many ways Fred Hutch researchers are translating scientific questions into real therapies.
Zager RA, Johnson AC, Frostad KB. (2016). Combined iron sucrose and protoporphyrin treatment protects against ischemic and toxin-mediated acute renal failure. Kidney International; 90(1):67-76.
Funding for this research was provided by the National Institutes of Health.