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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.

SUBMITTER: Skrypnyk NI

PROVIDER: S-EPMC4889323 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Bridging translation for acute kidney injury with better preclinical modeling of human disease.

Skrypnyk Nataliya I NI Siskind Leah J LJ Faubel Sarah S de Caestecker Mark P MP

American journal of physiology. Renal physiology 20160309 10

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 ...[more]

PMID: 26962107

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Project description:BackgroundNeurocognitive impairment is a common finding across the spectrum of kidney disease and carries important consequences for quality of life. We previously demonstrated that robotic technology can identify neurocognitive impairments not readily detectable by traditional testing in patients with acute kidney injury (AKI) and chronic kidney disease (CKD).ObjectiveThe present study aimed to assess whether these quantifiable deficits in neurocognition differ based on a diagnosis of AKI, CKD, or kidney failure.DesignThis was a cross-sectional analysis of participants previously enrolled in an observational study.SettingPatients were enrolled at a tertiary academic hospital, Kingston Health Sciences Centre, Kingston, ON, Canada.PatientsAdults with AKI, CKD, or kidney failure.MeasurementsEach participant underwent robotic neurocognitive assessment using the Kinarm: an interactive robotic device that uses a series of behavioral tasks involving movement of the upper limbs to precisely quantify neurocognitive impairment across a variety of neurocognitive domains.MethodsMultilevel modeling was used to determine the effect of Kinarm task type, kidney diagnostic group (AKI vs CKD vs kidney failure), and the interaction between the two, on neurocognitive performance.ResultsA total of 104 participants within 1 year of an AKI event or with CKD category G3-5 were enrolled. We found that across all of the kidney diagnostic groups, participants performed worst on the Kinarm tasks of Reverse Visually Guided Reaching (b = 0.64 [95% confidence interval = 0.42, 0.85]), Visually Guided Reaching (b = 0.28 [0.07, 0.49]), and Trail Making (b = 0.50 [0.28, 0.72]), relative to all other tasks. There were no significant differences in average performance across tasks based on kidney diagnostic group. However, diagnostic group and neurocognitive task type interacted to determine performance, such that patients with AKI performed worse than those with either CKD or kidney failure on the Reverse Visually Guided Reaching task.LimitationsKinarm assessment was performed at a single time point, and the sample size itself was small, which may lead to the risk of a false-positive association despite the use of multilevel modeling. Our sample size also did not permit inclusion of the underlying etiology of kidney impairment as a covariate in our analyses, which may have also influenced neurocognitive function.ConclusionsIn this study that utilized the Kinarm to assess neurocognitive function, patients with AKI demonstrated significantly worse neurocognitive functioning than patients with CKD or kidney failure on a task measuring executive function and visuomotor control.

Dataset Information

Bridging translation for acute kidney injury with better preclinical modeling of human disease.

Publications

Bridging translation for acute kidney injury with better preclinical modeling of human disease.

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