Overcoming Translational Barriers in Acute Kidney Injury

AKI is a complex clinical condition associated with high mortality, morbidity, and health care costs. Despite improvements in methodology and design of clinical trials, and advances in understanding the underlying pathophysiology of rodent AKI, no pharmacologic agent exists for the prevention or treatment of AKI in humans. To address the barriers that affect successful clinical translation of drug targets identified and validated in preclinical animal models of AKI in this patient population, the National Institute of Diabetes and Digestive and Kidney Diseases convened the“AKIOutcomes:OvercomingBarriers inAKI”workshoponFebruary10–12,2015.Theworkshopuseda reverse translational medicine approach to identify steps necessary to achieve clinical success. During the workshop, breakoutgroupswerechargedfirsttodesignfeasible,phase2,proof-of-conceptclinical trials fordelayedtransplantgraft function, prevention of AKI (primary prevention), and treatment of AKI (secondary prevention and recovery). Breakout groups then were responsible for identification of preclinical animal models that would replicate the pathophysiology of the phase 2 proof-of-concept patient population, including primary and secondary end points. Breakout groups identified considerable gaps in knowledge regarding human AKI, our understanding of the pathophysiology of AKI in preclinical animal models, and the fidelity of cellular and molecular targets that have been evaluated preclinically to provide information regarding human AKI of various etiologies. The workshop concluded with attendees defining a new path forward to a better understanding of the etiology, pathology, and pathophysiology of human AKI. Clin J Am Soc Nephrol 13: 1113–1123, 2018. doi: https://doi.org/10.2215/CJN.06820617 Introduction The lack of effective therapeutic interventions for prevention or treatment of AKI remains a major unmet medical need. AKI has a high mortality rate, and longterm outcomes in those who survive include development of CKD and ESRD. In individuals with preexisting CKD, AKI may accelerate progression to ESRD (1). Thus AKI, once thought to have a benign course in patients who recover, can lead to long-term morbidity, mortality, poor quality of life, and burgeoning health care costs (1). In February of 2015, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) convened the “AKI Outcomes: Overcoming Barriers in AKI” workshop at the National Institutes of Health (NIH). The workshop aimed to integrate and advance collective efforts of the AKI community (2–5) by developing an overarching research strategy to facilitate development and testing of therapies that may meaningfully improve clinical outcomes of AKI. This multidisciplinary meeting brought together clinicians, basic scientists, clinical trialists, and representatives from the US Food and Drug Administration (FDA) and industry. Presenters reviewed current AKI research and participants recommended needed changes regarding pathophysiologic targets, animal models, and clinical trial designs for AKI (6). Importantly, a reverse translational medicine approach laid the foundation for the meeting. In contrast to the linear sequence of preclinical activities historically performed for drug discovery and specifically for AKI (i.e., identifying biologic targets, evaluating target modulators in animal models, and if successful, evaluating a drug in human phase 1 safety and phase 2 proof-of-concept clinical studies), workshop participants proceeded backward, first defining needed clinical trial designs by considering the specific patient population, and then the resulting primary and secondary end points. Subsequently, participants identified the animal model to replicate this patient population. By working backward, participants uncovered considerable gaps in our understanding of human AKI, and of the relevance of AKI animal models and common biologic targets, thereby paving the way for improvements in clinical translation (Figure 1). The workshop included speakers from clinical areas unrelated to AKI, where researchers had successfully addressed challenges similar to those faced by the AKI research community. Breakout sessions followed, including (1) Delayed Transplant Graft Function, (2) Primary AKI Prevention, (3) Secondary AKI Prevention, and (4) Hastening Recovery. Breakout group topics were selected Due to the number of contributing authors, the affiliations are listed at the end of