Identification of a substrate of the renal tubular transporters for detecting drug-induced early acute kidney injury

Abstract Early identification of drug-induced acute kidney injury (AKI) is essential to prevent renal damage. The renal tubules are typically the first to exhibit damage, frequently accompanied by changes in renal tubular transporters. With this in mind, we have identified an endogenous substrate of the renal tubular transporters that may serve as a biomarker for early detection of drug-induced AKI. Using gentamicin- and vancomycin-induced AKI models, we found that traumatic acid (TA), an end metabolite, was rapidly increased in both AKI models. TA, a highly albumin-bound compound (96% to 100%), could not be filtered by the glomerulus and was predominantly eliminated by renal tubules via the OAT1, OAT3, OATP4C1, and P-gp transporters. Importantly, there is a correlation between elevated serum TA levels and reduced OAT1 and OAT3 levels. A clinical study showed that serum TA levels rose before an increase in serum creatinine in 13 out of 20 AKI patients in an intensive care unit setting. In addition, there was a notable rise in TA levels in the serum of individuals suffering from nephrotic syndrome, chronic renal failure, and acute renal failure. These results indicate that the decrease in renal tubular transporter expression during drug-induced AKI leads to an increase in the serum TA level, and the change in TA may serve as a monitor for renal tubular injury. Acute kidney injury (AKI) has a high clinical incidence, and if patients do not receive timely treatment and intervention, it can lead to severe consequences. During AKI, tubular damage is often the primary issue. Endogenous biomarkers of tubular damage are critical for the early diagnosis and treatment of AKI. However, there is currently a lack of reliable endogenous biomarkers for diagnosing tubular damage in clinical practice. Tubular secretion is primarily mediated by renal tubular transporters (channels), which are also impaired during tubular damage. Therefore, we aim to identify endogenous biomarkers of tubular damage from the perspective of renal tubular transporters, providing support for the early detection and intervention of AKI. TA is a substrate of multiple channels, including OAT1, OAT3, OATP4C1, and P-gp, and is primarily secreted by the renal tubules. In the early stages of rat AKI induced by GEN and VCA, serum TA levels are significantly elevated, occurring earlier than the rise in serum creatinine (SCr). Thus, TA is expected to become a potential endogenous biomarker for the early diagnosis of tubular damage.