(584ay) Role of Urinary Proteins in Moderating Calcium Oxalate Kidney Stone Formation

Proteomic studies of organic constituents occluded within the matrix of human kidney stones reveal the presence of more than 60 different proteins, glycosaminoglycans, and other molecular species. Past studies have identified a small fraction of these constituents as putative inhibitors of calcium oxalate monohydrate (COM) crystallization. COM is the most prevalent crystalline component of human stones, accounting for more than 80% of nephrolithiasis incidence. Here we will discuss in vitro studies of COM crystallization in the presence of urinary proteins and biomolecules ranging from anion-rich species (e.g. serum albumin and transferrin) to cation-rich species (e.g. lactoferrin and lysozyme). These studies reveal that urinary proteins function as either inhibitors or promoters of COM crystallization with variable efficacy and specificity for binding to different COM crystal surfaces. We used a combination of experimental techniques to quantify the effects of these urinary constituents on COM crystal size, habit, surface architecture, and growth kinetics. Results of these studies reveal that certain binary combinations of urinary components exhibit a synergetic enhancement of their efficacy, while other combinations yielded antagonistic effects. This work explores the physicochemical properties of effective protein inhibitors of COM crystallization towards an improved understanding of disease pathogenesis; and a generalized framework for the rational design of biomimetic analogues (i.e.peptide and organic growth inhibitors) as potential drug candidates for preventative therapies of kidney stone disease [1,2].

[1] Farmanesh, S., Chung, J., Chandra, D., Sosa, R.D., Karande, P., Rimer, J.D., J. Cryst. Growth (2013) In Press.

[2] Rimer, J.D., An, Z., Zhu, Z., Lee, M.H., Goldfarb, D.S., Wesson, J.A., Ward, M.D., Science

330 (2010) 337-341.