The Progress Report of Projects 1, 2 and 3 of this application illustrate the highly successful surgical, histologic and metablic analyses that were performed and published during this last funding peroid on seven different groups of stone formers, common CaOx stone formers (SF), intestinal bypass patients for obesity with kidney stones, brushite SF, cystine SF, ilesotomy patients, primary hyperparathyroidism with phosphate stones, distal renal tubular acidosis with phosphate stones (as well as non-SF). This core will conduct all the morphological/pathology analyses for Projects 1, 2, and 3. Human tissue collected by Project 2 from a highly selected and metabocally characterized patient pool will be studied using the following techniques: 1) specialized stains of biopsy material for light microscopy (LM), 2) transmission electron microscopy (TEM) of stone-plaque interface, 3) LM and TEM immunohistochemistry to detect the presence of a select group of known inhibitor proteins of crystal formation (osteopontin, prothrombin fragment 1) in stone-plaque interface, 4) LM and TEM immunohistochemistry to determine abundance and location of VDR, CaSR (Aim 3.5), markers of inflammation and fibrosis (Aim 3.3), and membrane transports (Aim 3.6), 5) micro-CT analysis to quantitate, localize and characterize mineral type of new sites of crystal deposition in biopsies samples, 6) micro-FTIR and Raman analysis to indentify specific sites of crystal deposition in human biopsy samples. Project 2 will supply Core B with all of the cortical and papillary biopsy samples required for the studies outlined in Projects 2 and 3, 7) Western blot analysis of VDR and CaSR on cortical and outer medullary biopsies (Aim 3.5), and 8) prepare video loops and micrographs to preform plaque mapping studies (Aims 3.1 and 3.4b) with Project 2. Core B will supply Project 1 and Core A with quantitative evaluation of glomerular and interstitial fibrosis values for all cortical samples, mineral analysis of all interstitial and tubular depsoits, quantitation of human VDR and CaSR, plaque area determinations, histopathogic scoring of papillary deformities, number of plugged IMCD and BD tubules, number of attached stones and their mineral analysis, presences of yellow plaque, and degree of papillary fibrosis.

Public Health Relevance

Our enduring objective has been to learn how kidney stones form, so that treatments can be improved by a greater understanding. Along the way we have realized that stone formers are not homogeneous, even when they seem to be so. Calcium oxalate stone formers grow their stones over papillary deposits of interstitial apatite called Randall's plaque, we will determine how hyprcalciuria, or other factors create plaque so that new treatments can be developed to prevent plague formation and thus, stone formation.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
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Special Emphasis Panel (ZDK1-GRB-R)
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University of Chicago
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Williams Jr, James C; Lingeman, James E; Coe, Fredric L et al. (2015) Micro-CT imaging of Randall's plaques. Urolithiasis 43 Suppl 1:13-7
Connors, Bret A; Evan, Andrew P; Blomgren, Philip M et al. (2014) Comparison of tissue injury from focused ultrasonic propulsion of kidney stones versus extracorporeal shock wave lithotripsy. J Urol 191:235-41
Evan, Andrew P; Lingeman, James E; Worcester, Elaine M et al. (2014) Contrasting histopathology and crystal deposits in kidneys of idiopathic stone formers who produce hydroxy apatite, brushite, or calcium oxalate stones. Anat Rec (Hoboken) 297:731-48
Handa, Rajash K; Evan, Andrew P; Connors, Bret A et al. (2014) Shock wave lithotripsy targeting of the kidney and pancreas does not increase the severity of metabolic syndrome in a porcine model. J Urol 192:1257-65
Williams Jr, James C; McAteer, James A (2013) Retention and growth of urinary stones: insights from imaging. J Nephrol 26:25-31
Bergsland, Kristin J; Worcester, Elaine M; Coe, Fredric L (2013) Role of proximal tubule in the hypocalciuric response to thiazide of patients with idiopathic hypercalciuria. Am J Physiol Renal Physiol 305:F592-9
Childs, M Adam; Mynderse, Lance A; Rangel, Laureano J et al. (2013) Pathogenesis of bladder calculi in the presence of urinary stasis. J Urol 189:1347-51
Xu, Hongshi; Zisman, Anna L; Coe, Fredric L et al. (2013) Kidney stones: an update on current pharmacological management and future directions. Expert Opin Pharmacother 14:435-47
Worcester, Elaine M; Bergsland, Kristin J; Gillen, Daniel L et al. (2013) Evidence for increased renal tubule and parathyroid gland sensitivity to serum calcium in human idiopathic hypercalciuria. Am J Physiol Renal Physiol 305:F853-60
Lingeman, James E (2013) Pathogenesis of nephrolithiasis. J Urol 189:417-8

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