Drug-Induced Nephrotoxicity: Clinical Impact and Preclinical in Vitro Models

Abstract

The kidney is a major target for drug-induced toxicity. Drug-induced nephrotoxicity remains a major problem in the clinical setting, where the use of nephrotoxic drugs is often unavoidable. This leads frequently to acute kidney injury, and current problems are discussed. One strategy to avoid such problems would be the development of drugs with decreased nephrotoxic potential. However, the prediction of nephrotoxicity during preclinical drug development is difficult and nephrotoxicity is typically detected only late. Also, the nephrotoxic potential of newly approved drugs is often underestimated. Regulatory approved or validated in vitro models for the prediction of nephrotoxicity are currently not available. Here, we will review current approaches on the development of such models. This includes a discussion of three-dimensional and microfluidic models and recently developed stem cell based approaches. Most in vitro models have been tested with a limited number of compounds and are of unclear predictivity. However, some studies have tested larger numbers of compounds and the predictivity of the respective in vitro model had been determined. The results showed that high predictivity can be obtained by using primary or stem cell derived human renal cells in combination with appropriate end points.

Human Urine-Derived Renal Progenitors for Personalized Modeling of Genetic Kidney Disorders

“…35 By contrast, u-RPC technology may provide the means to screen drug efficacy and toxicity, which are strongly influenced by the genetic background and by epigenetic factors, at the earliest stages of drug development in a patient-specific manner. 36 In conclusion, u-RPCs provide an innovative tool for personalized modeling of kidney disorders that has the potential to increase our knowledge of the pathogenesis of renal diseases and of patient-specific biology.…”

Combining Extracellular miRNA Determination with Microfluidic 3D Cell Cultures for the Assessment of Nephrotoxicity: a Proof of Concept Study

“…The use of nephrotoxic drugs has been implicated in up to 25% of all cases of severe acute renal failure, in particular tubular necrosis, in critically ill patients (1). Despite its clinical relevance, detection of DIKI during the drug development process relies mainly on animal experimentation and histopathological examination (2,3). In the last years, advances have been made in qualifying novel biomarkers to detect kidney injury using body fluids and seven biomarkers have been successfully qualified for preclinical animal tests (4,5).…”

“…In addition to the advancements in biomarkers of kidney injury in vivo, there is quite some interest in developing human in vitro test systems and biomarkers that can be used early in the drug screening process. Currently used systems apply either simple twodimensional (2D) cell cultures or more complex, 3D cell cultures combined with microfluidics devices (3,9). Some published results on human proximal tubule epithelial cells (PTEC) grown on filter inserts or on microphysiologic systems (kidney-on-a-chip) used gene expression analysis for the detection of drug-induced cell injury (10,11).…”

Nephrotoxicity of Natural Products

“…Xenobioticinduced acute kidney injury (AKI) accounts for approxi-mately 20% of reported cases of AKI [8] . Given this statistic, it is reasonable to expect that some natural products may impact renal function.…”