Differences in Acute Kidney Injury Ascertainment for Clinical and Preclinical Studies

Marco Fiorentino; Giuseppe Castellano; John A. Kellum


Nephrol Dial Transplant. 2017;32(11):1789-1805. 

In This Article

Abstract and Introduction


Background Acute kidney injury (AKI) is a common clinical condition directly associated with adverse outcomes. Several AKI biomarkers have been discovered, but their use in clinical and preclinical studies has not been well examined. This study aims to investigate the differences between clinical and preclinical studies on AKI biomarkers.

Methods We performed a systematic review of clinical and preclinical interventional studies that considered AKI biomarkers in enrollment criteria and/or outcome assessment and described the main differences according to their setting, the inclusion of biomarkers in the definition of AKI and the use of biomarkers as primary or secondary end points.

Results In the 151 included studies (76 clinical, 75 preclinical), clinical studies have prevalently focused on cardiac surgery (38.1%) and contrast-associated AKI (17.1%), while the majority of preclinical studies have focused on ether ischemia–reperfusion injury or drug-induced AKI (42.6% each). A total of 57.8% of clinical studies defined AKI using the standard criteria and only 19.7% of these studies used AKI biomarkers in the definition of renal injury. Conversely, the majority of preclinical studies defined AKI according to the increase in serum creatinine and blood urea nitrogen, and 32% included biomarkers in that definition. The percentage of both clinical and preclinical studies with biomarkers as a primary end point has not significantly increased in the last 10 years; however, preclinical studies are more likely to use AKI biomarkers as a primary end point compared with clinical studies [odds ratio 2.31 (95% confidence interval 1.17–4.59); P = 0.016].

Conclusion Differences between clinical and preclinical studies are evident and may affect the translation of preclinical findings in the clinical setting.


Acute kidney injury (AKI) is a common and serious clinical condition with an overall incidence estimated to be ~ 2–3/1000 population, a rate very similar to that for myocardial infarction.[1] Critically ill patients who develop AKI have worse outcomes, such as higher mortality, prolonged hospitalization and increased risk for progression to cardiovascular events and chronic kidney disease (CKD).[2,3] Even small increases in serum creatinine may greatly impact long-term outcomes.[4] Despite intense investigation, therapeutic interventions to limit the development and impact of AKI have not been successful. This may be related, at least in part, to the difficulties in identifying patients who are at high risk for AKI or to detect kidney damage early when it may be more treatable.[5] Current AKI definitions are based on changes in serum creatinine and urine output—the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) criteria[6] for example. However, serum creatinine is a late indicator of AKI and is often influenced by factors such as age, muscle mass, protein intake and gender.[7] Urine output may be more sensitive but is less specific for AKI unless severely decreased. Over the last decade, there has been extensive research for novel biomarkers of kidney injury for timely identification of AKI, to allow appropriate interventions and to improve outcomes.[8] The most promising biomarkers can be separated into different classes: (i) tubular cell enzymes released after renal injury, (ii) inflammatory mediators or cytokines released by kidney-specific cells or by inflammatory cells after damage and (iii) low molecular weight proteins, which either are filtered freely in the glomeruli and not adequately reabsorbed or digested by injured tubular cells or are released by injured tubular cells following acute damage. More recently, cell cycle arrest biomarkers, like tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor–binding protein 7 (IGFBP7) have been validated as indicators of renal damage and their product can predict the onset of severe AKI within 12 h better than other known biomarkers.[9] AKI biomarkers may help explain the molecular mechanisms of AKI and could perhaps be used as phenotyping tools in clinical practice to identify patients with specific AKI etiologies or to predict long-term outcomes.[8,10] The adoption of novel AKI biomarkers into clinical practice may depend in part on whether therapies can be directly linked to biomarker signals. As such, it is vital to understand whether these markers are being incorporated into clinical and preclinical studies. The purpose of this systematic review is to evaluate the use of AKI biomarkers in preclinical and clinical studies, analyzing the differences in how these markers were used in different settings.