This presentation was given at the Educational Seminar at Dr. Jack McAninch’s honoring and celebration, San Francisco, CA 2014
See video here: http://vimeo.com/90597909
A growing and significant urologic disorder--Nephrolithiasis
Nephrolithiasis accounted for more than $2.1billion in medical expenditures annually in the United States in 2000, encompassing costs in both the out patient and in patient settings. Symptomatic kidney stones are a source of severe pain, infection, and morbidity. Consequently, new insights that would lead to effective medical treatment of stone formation would reduce the morbidity and costs associated with this significant disease. Current animal models have not led to tangible progress in understanding the genetics and mechanisms behind stone formation or development of new medical treatments for nephrolithiasis. Though several models have been developed, none are without significant limitations.
A new model that could help
Though several models have been developed, none are without significant limitations. For example, mice fed with glyoxylic acid and pigs fed with hydroxyl proline are used to generating calcium oxalate stones. However, neither glyoxylic acid nor hydroxy proline are normal dietary components for animals or humans in excess and, as such, these models have questionable translational significance. While much progress has been made in surgical therapy for kidney stones, no FDA-approved drug for prevention of nephrolithiasis has been developed in more than 20 years. We observe that the concretions in the fly Malpighian tubule, like human stones, bind bisphosphonates (molecules with a high affinity for hydroxyapatite) and look remarkably similar to local calcifications in human kidneys. Moreover, Randall’s plaques, structures occurring in the human renal papilla believed to be the precursor to human kidney stones, also contain hydroxyapatite. Thus, accumulation of concretions in the fruit fly could represent a process very similar to early events in human stone formation. The use of a new animal model demonstrating early stone formation with genetic and dietary manipulation alone without the use of toxins will open new avenues of discovery in the study of nephrolithiasis and the potential identification of novel therapeutics.
This new model could help improve the understanding of other significant disorders
Additionally, we and others have shown that patients with urinary stone disease have an increased likelihood of developing cardiovascular disease, including hypertension, myocardial infarction, congestive heart failure, and coronary artery calcification. The mineralization process underlying early stone formation may be a common linkage between these systemic disorders. Understanding the genetic and environmental modulators of early stone formation in the fruit fly could contribute to an improved understanding of the mechanisms underlying other systemic disease processes as well as stone formation in humans. Non-calcium metals as new therapeutic targets could therefore potentially be applied to multiple disease processes involving mineralization, not limited to urinary stone disease. We anticipate that this model will improve our understanding of the pathophysiology of stone formation and help develop novel therapeutic and prevention strategies for nephrolithiasis