Self-organized kidney rudiments: prospects for better in vitro nephrotoxicity assays.

Kidneys are essential to life but vulnerable to a range of toxicants, including therapeutic drugs and their metabolites: indeed, nephrotoxicity is often a limiting factor in both drug use and drug development. Most toxicants damage kidneys by one of four mechanisms: damage to the membrane and its junctions, oxidative stress and free radical generation, activation of inflammatory processes, and interference with vascular regulation. Traditionally, pre-clinical screening for nephrotoxicity has used animal models but these can be poorly predictive of human reactions. Animal screens have been joined by simple single-cell-type in vitro assays using primary or immortalized human cells, particularly proximal tubule cells as these are especially vulnerable to toxicants. Recent research, aimed mainly at engineering new kidneys for transplant purposes, has resulted in a method for constructing anatomically realistic mini-kidneys from renogenic stem cells. So far, this has been done only using renogenic stem cells obtained directly from mouse embryos but, in principle, it should be possible to make them from renogenically directed human induced pluripotent (hiPS) cells. If this can be done, the resulting human-based mini-kidneys would be a promising system for detecting some types of nephrotoxicity and for developing nephroprotective drugs.