Acute kidney injury (AKI) is a serious condition with high morbidity and mortality and AKI patients are at high risk of developing chronic kidney disease (CKD) and end-stage renal disease. The poor outcome is mainly attributable to: (1) Lack of efficacious interventions to prevent or mitigate kidney damage after exposure to renal insults; and (2) Limited strategies to slow or stop progression to CKD after an episode of AKI. We are in dire need of novel diagnostic and therapeutic strategies for patients with AKI or at high risk of AKI. Klotho protein is highly expressed in the kidney. We have demonstrated that Klotho is drastically reduced in rodents with AKI induced by ischemia-reperfusion injury and nephrotoxic drug and Klotho is not a mere biomarker but Klotho deficiency is pathogenetically important. The rodent data supports three therapeutic windows with different objectives. 1. When given before or immediately after renal insult, recombinant Klotho prevents AKI. 2. When given immediately after exposure to IRI, Klotho promoted renal recovery. 3. When given one day after AKI continued for ~10 days, Klotho retarded AKI progression to CKD and improved cardiac remodeling. Hence, Klotho is a potential therapeutic agent post-AKI that can be of enormous clinical significance. To launch the clinical trial, the first step is to explore whether humans with AKI have Klotho deficiency which has been repeatedly confirmed in rodent AKI models. We hypothesize that humans with incident AKI post cardiac surgery have Klotho deficiency. To prove our hypothesis, we will examine serum Klotho levels prior and post cardiac surgery and define whether Klotho levels in serum decrease and the decline precedes an increase in serum creatinine in adults at risk of AKI who undergo cardiac surgery. We will further explore the association of lower serum Klotho levels with the episode and severity of AKI. This is the first translational step to investigate whether Klotho deficiency in rodents is reproduciblein humans with AKI. We will conduct a nested case-control study in two well-established cohorts: Translational Research Investigating Biomarker End-Points cohort, a completed multicenter prospective cohort and. Coronary Artery Bypass Graft Surgery Genomic Cohort, an ongoing multicenter prospective cohort. We will have banked sera of AKI patients and controls from the completed subjects from these two cohorts. Confirmation of our hypothesis will constitute a foundation for future early clinical trials in humans to validate Klotho as novel target of AKI wit diagnostic, prognostic, and therapeutic applications, which is one mission of PAR-14-006, i.e., target validation.

Public Health Relevance

Acute kidney injury patients have high morbidity and mortality and also have high risk of developing chronic kidney disease and end-stage renal disease. We will measure serum Klotho in patients undergoing cardiac surgery to confirm Klotho deficiency in patients developing AKI. Anticipated data will set the stage for Klotho treatment for AKI patients.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-EMNR-R (56))
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Rys-Sikora, Krystyna E
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University of Texas Sw Medical Center Dallas
Internal Medicine/Medicine
Schools of Medicine
United States
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