title: Bridging translation for acute kidney injury with better preclinical modeling of human disease.
abstract: The current lack of effective therapeutics for patients with acute kidney injury (AKI) represents an important and unmet medical need. Given the importance of the clinical problem, it is time for us to take a few steps back and reexamine current practices. The focus of this review is to explore the extent to which failure of therapeutic translation from animal studies to human studies stems from deficiencies in the preclinical models of AKI. We will evaluate whether the preclinical models of AKI that are commonly used recapitulate the known pathophysiologies of AKI that are being modeled in humans, focusing on four common scenarios that are studied in clinical therapeutic intervention trials: cardiac surgery-induced AKI; contrast-induced AKI; cisplatin-induced AKI; and sepsis associated AKI. Based on our observations, we have identified a number of common limitations in current preclinical modeling of AKI that could be addressed. In the long term, we suggest that progress in developing better preclinical models of AKI will depend on developing a better understanding of human AKI. To this this end, we suggest that there is a need to develop greater in-depth molecular analyses of kidney biopsy tissues coupled with improved clinical and molecular classification of patients with AKI.
authors.affiliation: Division of Nephology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee;
authors.forename: Nataliya I
authors.initials: NI
authors.lastname: Skrypnyk
authors.affiliation: Department of Pharmacology and Toxicology, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky; and.
authors.forename: Leah J
authors.initials: LJ
authors.lastname: Siskind
authors.affiliation: Renal Division, University of Colorado Denver and Denver Veterans Affairs Medical Center, Aurora, Colorado.
authors.forename: Sarah
authors.initials: S
authors.lastname: Faubel
authors.affiliation: Division of Nephology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee; mark.de.caestecker@vanderbilt.edu.
authors.forename: Mark P
authors.initials: MP
authors.lastname: de Caestecker
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D006348:Cardiac Surgical Procedures / Q000009:adverse effects; D002945:Cisplatin / Q000009:adverse effects; D003287:Contrast Media / Q000009:adverse effects; D004195:Disease Models, Animal; D006801:Humans; D018805:Sepsis / Q000150:complications; D057170:Translational Research, Biomedical
chemical_list: D000970:Antineoplastic Agents; D003287:Contrast Media; D002945:Cisplatin
keywords: acute kidney injury; animal models; drug discovery; human disease; preclinical research