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.
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.
|Winfree, Seth; Khan, Shehnaz; Micanovic, Radmila et al. (2017) Quantitative Three-Dimensional Tissue Cytometry to Study Kidney Tissue and Resident Immune Cells. J Am Soc Nephrol 28:2108-2118|
|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|
|Williams Jr, James C; Worcester, Elaine; Lingeman, James E (2017) What can the microstructure of stones tell us? Urolithiasis 45:19-25|
|Borofsky, Michael S; Paonessa, Jessica E; Evan, Andrew P et al. (2016) A Proposed Grading System to Standardize the Description of Renal Papillary Appearance at the Time of Endoscopy in Patients with Nephrolithiasis. J Endourol 30:122-7|
|Coe, Fredric L; Worcester, Elaine M; Evan, Andrew P (2016) Idiopathic hypercalciuria and formation of calcium renal stones. Nat Rev Nephrol 12:519-33|
|Borofsky, Michael S; Wollin, Daniel A; Reddy, Thanmaya et al. (2016) Salvage Percutaneous Nephrolithotomy: Analysis of Outcomes following Initial Treatment Failure. J Urol 195:977-81|
|Handa, Rajash K; Lingeman, James E; Bledsoe, Sharon B et al. (2016) Intraluminal measurement of papillary duct urine pH, in vivo: a pilot study in the swine kidney. Urolithiasis 44:211-7|
|Hoover, Robert S; Tomilin, Viktor; Hanson, Lauren et al. (2016) PTH modulation of NCC activity regulates TRPV5 Ca2+ reabsorption. Am J Physiol Renal Physiol 310:F144-51|
|Witzmann, Frank A; Evan, Andrew P; Coe, Fredric L et al. (2016) Label-free proteomic methodology for the analysis of human kidney stone matrix composition. Proteome Sci 14:4|
|Ko, Benjamin; Bergsland, Kristin; Gillen, Daniel L et al. (2015) Sex differences in proximal and distal nephron function contribute to the mechanism of idiopathic hypercalcuria in calcium stone formers. Am J Physiol Regul Integr Comp Physiol 309:R85-92|
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