Improving Translation from Preclinical Studies to Clinical Trials in Acute Kidney Injury

Abstract

Background: Several cellular and molecular targets and mechanisms have been investigated in preclinical studies of acute kidney injury (AKI), but translation in successful clinical studies has failed to date. This article reviews many issues that have limited this and the potential future perspectives in AKI prevention and treatment. Summary: Preclinical models of AKI should closely mimic the complexity of human AKI, considering the importance of several comorbidities in determining the clinical course and outcomes in the human disease. Moreover, studies should test novel interventions in models where AKI is already established, instead of focusing only at primary prevention. AKI definitions and endpoints in animal studies should be similar to those applied in clinical studies; in particular, AKI biomarkers should be implemented to guide patient selection for clinical trials and monitor intervention efficacy. In this scenario, cell-cycle arrest biomarkers have been widely investigated as AKI predictors in both preclinical and clinical studies and they serve as useful tools for future interventional studies. A better understanding of human AKI through a large collection of biological samples and kidney biopsies and omics applications, and an iterative relationship between preclinical and clinical studies are critical steps to improve future preclinical models and clinical trials. Finally, given the great variability in clinical manifestation of AKI, a strong collaboration between research centers and industry is recommended. Key messages: Several methodological issues have hampered the translation of basic research findings in clinical studies, and overcoming these obstacles is necessary to achieve success.

Protective effects of D-005, a lipid extract from Acrocomia crispa fruits, against ischemia/reperfusion-induced acute kidney injury in rats

“…Additionally, they are not effective to avoid progression of AKI to chronic kidney disease [9]. In this context, new drugs have been evaluated to prevent or treat AKI, but new treatments that can be translated to clinical practice have not yet been established [10]. Therefore, it is necessary to search for new therapeutic strategies to prevent and/or treat AKI.…”

Roadblocks and Opportunities to the Implementation of Novel Therapies for Acute Kidney Injury: A Narrative Review

“…18-21 In contrast, preclinical studies are typically performed on pure disease processes with minimal consideration given to the genetic background of the model or cell line chosen. 22 The context of treatment must also be considered—many preclinical studies attempt to prevent renal injury in response to a specific insult, whereas, in clinical practice, AKI is usually established at the time therapy is being considered. 22 These factors are likely at play when promising preclinical therapies have disappointing outcomes in human studies.…”

“…22 The context of treatment must also be considered—many preclinical studies attempt to prevent renal injury in response to a specific insult, whereas, in clinical practice, AKI is usually established at the time therapy is being considered. 22 These factors are likely at play when promising preclinical therapies have disappointing outcomes in human studies. Meanwhile, careful attention to disease contexts in promising preclinical studies may also improve clinical translation by informing the design of subsequent human studies.…”

Current Concepts on the Reno-Protective Effects of Phosphodiesterase 5 Inhibitors in Acute Kidney Injury: Systematic Search and Review

“…Nevertheless, a recent systematic review evaluating the methods used to investigate AKI biomarkers showed that results are difficult to interpret, not comparable, and not consistently reproducible due to the impact of the variable AKI definitions still used to determine the outcome of interest in human studies (38.0% of the studies used the AKIN; 21.4% used the RIFLE; 20.3% used the KDIGO; and 20.3% used another definition) [2]. Similarly, variable definitions of AKI have been used in animal studies, a fact that has been recognized as an important limitation in translating preclinical findings in clinical studies [7,8] among others [9]. Several reviews of available animal models, including their advantages and disadvantages, have been discussed [10]; however, the types of models are often incomplete and many details, such as model techniques and modeling time, are not mentioned.…”