Biomarkers for drug-induced renal damage and nephrotoxicity-an overview for applied toxicology

Abstract

The detection of acute kidney injury (AKI) and the monitoring of chronic kidney disease (CKD) is becoming more important in industrialized countries. Because of the direct relation of kidney damage to the increasing age of the population, as well as the connection to other diseases like diabetes mellitus and congestive heart failure, renal diseases/failure has increased in the last decades. In addition, drug-induced kidney injury, especially of patients in intensive care units, is very often a cause of AKI. The need for diagnostic tools to identify drug-induced nephrotoxicity has been emphasized by the ICH-regulated agencies. This has lead to multiple national and international projects focusing on the identification of novel biomarkers to enhance drug development. Several parameters related to AKI or CKD are known and have been used for several decades. Most of these markers deliver information only when renal damage is well established, as is the case for serum creatinine. The field of molecular toxicology has spawned new options of the detection of nephrotoxicity. These new developments lead to the identification of urinary protein biomarkers, including Kim-1, clusterin, osteopontin or RPA-1, and other transcriptional biomarkers which enable the earlier detection of AKI and deliver further information about the area of nephron damage or the underlying mechanism. These biomarkers were mainly identified and qualified in rat but also for humans, several biomarkers have been described and now have to be validated. This review will give an overview of traditional and novel tools for the detection of renal damage.

Fig. 1

Only substantial loss of renal biomass leads to a lack of renal functionality. Traditional clinical–chemical parameters like serum creatinine or BUN only detected this decrease in kidney function. The novel urinary biomarkers are accepted to detect renal damage earlier because not the function but the damage of tissue was predicted

Fig. 2

Shown is an integrated approach for the inclusion of novel Omics data in the toxicological routine safety assessment and the identification and implementation of novel biomarkers into the standard battery or else for the submission to the FDA/EMA qualification process. Figure adapted by (45)

Fig. 3

Shown are several urinary biomarkers with their predictive area within the nephron. These biomarkers include qualified as well as exploratory once