You need only look at an old air conditioner filter to gain an enormous appreciation for our kidneys. Every day, our kidneys filter just under 200L of fluid, filled with all kinds of gnarly toxins that we’d rather not know about. Most of the time, they operate glitch free. But sometimes, the toxins they are supposed to filter don’t go quietly, and kidney damage ensues.
Nephrotoxicity – i.e. “kidney damage” is actually an extremely important issue when it comes to drug development. As many of you know, a new drug must go through several phases of trials to demonstrate efficacy, dosing, and most of all – safety. These trials cost millions of dollars and are one reason (but certainly not the only reason) for the sometimes astronomical cost of drugs that finally become approved. Often times, these drugs are shown to be nephrotoxic in the later phase trials, after millions of dollars and significant time has been invested. Even when drugs make it to market, kidney damage may still be a limiting factor to the use of otherwise extremely efficacious drugs (e.g. cyclosporine).
From a stem cell scientist’s perspective one may ask: “Well, if the kidneys are damaged, can’t they just regenerate?”
While the kidney is able to repair itself to some extent upon damage, all nephrons (the functional units – the individual “mini-filters” of the kidney) are formed before birth. Thus, to our knowledge, stem cells do not regenerate nephrons once we’re born.
Just because they don’t do this physiologically, however, doesn’t mean that scientists can’t try their hand at it.
In a recent article published in Nature Cell Biology, an Australian group of scientists has demonstrated directed differentiation of human embryonic stem cells into various kidney precursor cells. These cells were able to interact with each other to self-organize into early nephrons.
I think this study is exciting because it helps advance our understanding of the developmental program of the kidney, and it may serve as a basis for future attempts towards kidney tissue engineering for replacement or repair of partially functional kidneys. With the high prevalence of end-stage renal disease, this latter application is not insignificant. The most immediate and salient application of this study, however, is that the development of nephron-like-units in vitro may give us a tool for preventative medicine and more efficient resource utilization – by serving as a screening tool for potential toxicity from new drugs and/or their metabolites.
Given the kidney’s central role in clearing a wide variety of drugs from our bodies, these findings are relevant to everyone, and it is rather fitting that a nephron may serve as a “biological filter” for drug development.
Bobadilla N.A. & Gamba G. (2007). New insights into the pathophysiology of cyclosporine nephrotoxicity: a role of aldosterone, AJP: Renal Physiology, 293 (1) F2-F9. DOI: 10.1152/ajprenal.00072.2007
Takasato M., Er P.X., Becroft M., Vanslambrouck J.M., Stanley E.G., Elefanty A.G. & Little M.H. (2013). Directing human embryonic stem cell differentiation towards a renal lineage generates a self-organizing kidney, Nature Cell Biology, 16 (1) 118-126. DOI: 10.1038/ncb2894
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