Our histopathologic studies performed during the previous grant period have characterized the histopathological and mineral composition in three groups of stone formers: common idiopathic calcium oxalate stone formers, patients with stones due to intestinal bypass surgery for obesity and brushite stone formers (as well as non-stone formers) to test the hypothesis that Randall's plaque, calcium phosphate deposits in kidneys of patients with calcium renal stones, arise in unique anatomical regions of the kidney, their formation conditioned by specific stone-forming pathophysiologies. We were amazed at the finding, in that, each group of stone formers had a different and unique histopathologic pattern of crystal desposition while all intraparenchymal and interstitial sites of crystalline material were hydroxyapatite, yet another surprise. Because we were so highly successful in the last funding period in identifying a clear set of surgical/ morphological/metabolic characteristics in these three different groups of human stone formers (CaOx, intestinal bypass for obesity and brushite) and will extend these analyses to new groups of stone formers: apatite (including RTAs) stone formers, primary hyperparathyroidism with kidney stones, ileostomy with kidney stones, cystine stone formers, uric acid stones, bariatric patients with stones and CaOx stone formers with high urine pH (> pH 6.3) using histopathology,mu CT, and mu FTIR. In addition, we will seek to test a new set of hypotheses concerning the mechanisms of stone formation. First, we will test the hypothesis that the progression of HA accumulation occurs along a specific segment of the loops of Henle, the thin descending limb. Second, the mechanism of crystal particle formation and coalescence in the common CaOx patients will be determined by quantitative TEM and tetracycline studies. Third, test the hypothesis that there are candidate proteins that either promote or inhibit crystal nucleation and growth within the papillary interstitium or tubular lumens. This will be done using TEM immunohistochemical analysis to define the interaction of osteopontin, prothrombin fragment 1,fetuin-A and bikunin on interstitial and the plaque-stone interface. Fourth, we will use RT-PCR techniques to detect transcripts for the presence of osteoblast-like activity. Lastly, we will examine the idea that a loss of fluid pH control in the inner medullary collecting ducts due to SWL injury may result in an alkalization of the bulk urine and, therefore, give insights into the mechanisms of stone formation in brushite stone disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
2P01DK056788-06
Application #
6898583
Study Section
Special Emphasis Panel (ZDK1-GRB-3 (J2))
Project Start
2005-06-01
Project End
2010-05-31
Budget Start
2005-06-01
Budget End
2006-08-31
Support Year
6
Fiscal Year
2005
Total Cost
$49,409
Indirect Cost
Name
University of Chicago
Department
Type
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Williams Jr, James C; Borofsky, Michael S; Bledsoe, Sharon B et al. (2018) Papillary Ductal Plugging is a Mechanism for Early Stone Retention in Brushite Stone Disease. J Urol 199:186-192
Worcester, Elaine M; Bergsland, Kristin J; Gillen, Daniel L et al. (2018) Mechanism for higher urine pH in normal women compared with men. Am J Physiol Renal Physiol 314:F623-F629
Bergsland, Kristin J; Coe, Fredric L; Parks, Joan H et al. (2018) Evidence for a role of PDZ domain-containing proteins to mediate hypophosphatemia in calcium stone formers. Nephrol Dial Transplant 33:759-770
Borofsky, Michael S; Dauw, Casey A; York, Nadya et al. (2017) Accuracy of daily fluid intake measurements using a ""smart"" water bottle. Urolithiasis :
Winfree, Seth; Ferkowicz, Michael J; Dagher, Pierre C et al. (2017) Large-scale 3-dimensional quantitative imaging of tissues: state-of-the-art and translational implications. Transl Res 189:1-12
Cohen, Andrew J; Borofsky, Michael S; Anderson, Blake B et al. (2017) Endoscopic Evidence That Randall's Plaque is Associated with Surface Erosion of the Renal Papilla. J Endourol 31:85-90
Gilad, Ron; Williams Jr, James C; Usman, Kalba D et al. (2017) Interpreting the results of chemical stone analysis in the era of modern stone analysis techniques. J Nephrol 30:135-140
Williams Jr, James C; Worcester, Elaine; Lingeman, James E (2017) What can the microstructure of stones tell us? Urolithiasis 45:19-25
Kleinguetl, Colin; Williams Jr, James C; Ibrahim, Samar A et al. (2017) Calcium Tartrate Tetrahydrate, Case Report of a Novel Human Kidney Stone. J Endourol Case Rep 3:192-195
Mulay, Shrikant R; Eberhard, Jonathan N; Desai, Jyaysi et al. (2017) Hyperoxaluria Requires TNF Receptors to Initiate Crystal Adhesion and Kidney Stone Disease. J Am Soc Nephrol 28:761-768

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