IU Indianapolis ScholarWorks :: Browsing by Author "Worcester, Elaine M."

Browsing by Author "Worcester, Elaine M."

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Biopsy proven medullary sponge kidney: clinical findings, histopathology, and role of osteogenesis in stone and plaque formation
(John Wiley & Sons, Inc., 2015-05) Evan, Andrew P.; Worcester, Elaine M.; Williams, James C., Jr.; Sommer, Andre J.; Lingeman, James E.; Phillips, Carrie L.; Coe, Fredric L.; Department of Anatomy & Cell Biology, IU School of Medicine
Medullary sponge kidney (MSK) is associated with recurrent stone formation, but the clinical phenotype is unclear because patients with other disorders may be incorrectly labeled MSK. We studied 12 patients with histologic findings pathognomonic of MSK. All patients had an endoscopically recognizable pattern of papillary malformation, which may be segmental or diffuse. Affected papillae are enlarged and billowy, due to markedly enlarged inner medullary collecting ducts (IMCD), which contain small, mobile ductal stones. Patients had frequent dilation of Bellini ducts, with occasional mineral plugs. Stones may form over white (Randall's) plaque, but most renal pelvic stones are not attached, and have a similar morphology as ductal stones, which are a mixture of calcium oxalate and apatite. Patients had no abnormalities of urinary acidification or acid excretion; the most frequent metabolic abnormality was idiopathic hypercalciuria. Although both Runx2 and Osterix are expressed in papillae of MSK patients, no mineral deposition was seen at the sites of gene expression, arguing against a role of these genes in this process. Similar studies in idiopathic calcium stone formers showed no expression of these genes at sites of Randall's plaque. The most likely mechanism for stone formation in MSK appears to be crystallization due to urinary stasis in dilated IMCD with subsequent passage of ductal stones into the renal pelvis where they may serve as nuclei for stone formation.
Collagen fibrils and cell nuclei are entrapped within Randall's plaques but not in CaOx matrix overgrowth: A microscopic inquiry into Randall's plaque stone pathogenesis
(Wiley, 2022) Canela, Victor Hugo; Bledsoe, Sharon B.; Worcester, Elaine M.; Lingeman, James E.; El-Achkar, Tarek M.; Williams, James C., Jr.; Anatomy, Cell Biology and Physiology, School of Medicine
Calcium oxalate (CaOx) stones can grow attached to the renal papillary calcification known as Randall's plaque. Although stone growth on Randall's plaque is a common phenomenon, this mechanism of stone formation is still poorly understood. The objective of this study was to investigate the microenvironment of mature Randall's plaque, explore its molecular composition and differentiate plaque from CaOx overgrowth using multimodal imaging on demineralized stone sections. Fluorescence imaging showed consistent differences in autofluorescence patterns between Randall's plaque and calcium oxalate overgrowth regions. Second harmonic generation imaging established the presence of collagen only in regions of decalcified Randall's plaque but not in regions of CaOx overgrowth matrix. Surprisingly, in these stone sections we observed cell nuclei with preserved morphology within regions of mature Randall's plaque. These conserved cells had variable expression of vimentin and CD45. The presence of nuclei in mature plaque indicates that mineralization is not necessarily associated with cell death. The markers identified suggest that some of the entrapped cells may be undergoing dedifferentiation or could emanate from a mesenchymal or immune origin. We propose that entrapped cells may play an important role in the growth and maintenance of Randall's plaque. Further characterization of these cells and thorough analyses of the mineralized stone forming renal papilla will be fundamental in understanding the pathogenesis of Randall's plaque and CaOx stone formation.
Contrasting histopathology and crystal deposits in kidneys of idiopathic stone formers who produce hydroxy apatite, brushite, or calcium oxalate stones
(Wiley, 2014-04) Evan, Andrew P.; Lingeman, James E.; Worcester, Elaine M.; Sommer, Andre J.; Phillips, Carrie L.; Williams, James C.; Coe, Fredric L.; Department of Anatomy & Cell Biology, School of Medicine
Our previous work has shown that stone formers who form calcium phosphate (CaP) stones that contain any brushite (BRSF) have a distinctive renal histopathology and surgical anatomy when compared with idiopathic calcium oxalate stone formers (ICSF). Here we report on another group of idiopathic CaP stone formers, those forming stone containing primarily hydroxyapatite, in order to clarify in what ways their pathology differs from BRSF and ICSF. Eleven hydroxyapatite stone formers (HASF) (2 males, 9 females) were studied using intra-operative digital photography and biopsy of papillary and cortical regions to measure tissue changes associated with stone formation. Our main finding is that HASF and BRSF differ significantly from each other and that both differ greatly from ICSF. Both BRSF and ICSF patients have significant levels of Randall's plaque compared with HASF. Intra-tubular deposit number is greater in HASF than BRSF and nonexistent in ICSF while deposit size is smaller in HASF than BRSF. Cortical pathology is distinctly greater in BRSF than HASF. Four attached stones were observed in HASF, three in 25 BRSF and 5-10 per ICSF patient. HASF and BRSF differ clinically in that both have higher average urine pH, supersaturation of CaP, and calcium excretion than ICSF. Our work suggests that HASF and BRSF are two distinct and separate diseases and both differ greatly from ICSF.
Demineralization and sectioning of human kidney stones: A molecular investigation revealing the spatial heterogeneity of the stone matrix
(Wiley, 2021-01) Canela, Victor Hugo; Bledsoe, Sharon B.; Lingeman, James E.; Gerber, Glenn; Worcester, Elaine M.; El-Achkar, Tarek M.; Williams, James C., Jr.; Anatomy and Cell Biology, School of Medicine
The molecular mechanisms by which kidney stones grow are largely unknown. Organic molecules from the urine combine with mineral crystals to form stones, but analysis of the stone matrix has revealed over a thousand different proteins, with no clues as to which are important for stone growth. Molecules that are present in every layer of a stone would be candidates for having an essential function, and thus the analysis of the stone matrix at a microscopic level is necessary. For this purpose, kidney stones were demineralized, sectioned, stained, and imaged by microscopy, using micro CT for precise orientation. Histological staining demonstrated heterogeneity in the density of adjacent layers within stones. Additional results also showed brilliant and unique autofluorescence patterns in decalcified nephroliths, indicating heterogeneous organic composition in adjacent layers. Regions of calcium oxalate (CaOx) stones were dissected using laser microdissection (LMD) for protein analysis. LMD of broad regions of demineralized CaOx stone sections yielded the same proteins as those found in different specimens of pulverized CaOx stones. These innovative methodologies will allow spatial mapping of protein composition within the heterogeneous stone matrix. Proteins that consistently coincide spatially with mineral deposition would be candidates for molecules essential for stone growth. This kind of analysis will be required to assess which of the thousand proteins in the stone matrix may be fundamental for stone growth.
Discrepancy Between Stone and Tissue Mineral Type in Patients with Idiopathic Uric Acid Stones
(Liebert, 2020-03) Evan, Andrew P.; Coe, Fredric L.; Worcester, Elaine M.; Williams, James C., Jr.; Heiman, Joshua; Bledsoe, Sharon; Philips, Carrie L.; Lingeman, James E.; Anatomy and Cell Biology, School of Medicine
Objectives: To describe the papillary pathology found in uric acid (UA) stone formers, and to investigate the mineral form of tissue deposits. Materials and Methods: We studied eight UA stone formers treated with percutaneous nephrolithotomy. Papillae were imaged intraoperatively using digital endoscopy, and cortical and papillary biopsies were taken. Biopsies were analyzed by light microscopy, micro-CT, and microinfrared spectroscopy. Results: As expected, urine pH was generally low. UA supersaturation exceeded one in all but one case, compatible with the stone material. By intraoperative imaging, the renal papillae displayed a heterogeneous mixture of plaque and plugging, ranging from normal to severe. All patients had mineral in ducts of Bellini and inner medullary collecting ducts, mainly apatite with lesser amounts of urate and/or calcium oxalate in some specimens. Papillary and cortical interstitial tissue injury was modest despite the tubule plugging. No instance was found of a stone growing attached to either plaque or plugs. Conclusions: UA stone formers resemble those with ileostomy in having rather low urine pH while forming tubule plugs that contain crystals that can only form at pH values above those of their bulk urine. This discrepancy between tissue mineral deposits and stone type suggests that local tubular pH exceeds that of the bulk urine, perhaps because of localized tubule injury. The manner in which UA stones form and the discordance between tubule crystals and stone type remain open research questions.
Endoscopic Evidence That Randall's Plaque is Associated with Surface Erosion of the Renal Papilla
(Mary Ann Liebert, Inc., 2017-01) Cohen, Andrew J.; Borofsky, Michael S.; Anderson, Blake B.; Dauw, Casey A.; Gillen, Daniel L.; Gerber, Glenn S.; Worcester, Elaine M.; Coe, Fredric L.; Lingeman, James E.; Urology, School of Medicine
OBJECTIVE: This study was conducted to assess the reliability and precision of an endoscopic grading scale to identify renal papillary abnormalities across a spectrum of equipment, locations, graders, and patients. MATERIALS AND METHODS: Intra- and interobserver reliability of the papillary grading system was assessed using weighted kappa scoring among 4 graders reviewing a single renal papilla from 50 separate patients on 2 occasions. Grading was then applied to a cohort of patients undergoing endoscopic stone removal procedures at two centers. Patient factors were compared with papillary scores on the level of the papilla, kidney, and patient. RESULTS: Graders achieved substantial (kappa >0.6) intra- and inter-rater reliability in scored domains of ductal plugging, surface pitting, and loss of contour. Agreement for Randall's Plaque (RP) was moderate. Papillary scoring was then performed for 76 patients (89 kidneys, 533 papillae). A significant association was discovered between pitting and RP that held both within and across institutions. A general linear model was then created to further assess this association and it was found that RP score was a highly significant independent correlate of pitting score (F = 7.1; p < 0.001). Mean pitting scores increased smoothly and progressively with increasing RP scores. Sums of the scored domains were then calculated as a reflection of gross papillary abnormality. When analyzed in this way, a history of stone recurrence and shockwave lithotripsy were strongly predictive of higher sums. CONCLUSIONS: Renal papillary pathology can be reliably assessed between different providers using a newly described endoscopic grading scale. Application of this scale to stone-forming patients suggests that the degree of RP appreciated in the papilla is strongly associated with the presence of pitting. It also suggests that patients with a history of recurrent stones and lithotripsy have greater burdens of gross papillary disease.
Idiopathic hypercalciuria and formation of calcium renal stones
(Nature Publishing group, 2016-09) Coe, Fredric L.; Worcester, Elaine M.; Evan, Andrew P.; Anatomy and Cell Biology, School of Medicine
The most common presentation of nephrolithiasis is idiopathic calcium stones in patients without systemic disease. Most stones are primarily composed of calcium oxalate and form on a base of interstitial apatite deposits, known as Randall’s plaque. By contrast some stones are composed largely of calcium phosphate, as either hydroxyapatite or brushite (calcium monohydrogen phosphate), and are usually accompanied by deposits of calcium phosphate in the Bellini ducts. These deposits result in local tissue damage and might serve as a site of mineral overgrowth. Stone formation is driven by supersaturation of urine with calcium oxalate and brushite. The level of supersaturation is related to fluid intake as well as to the levels of urinary citrate and calcium. Risk of stone formation is increased when urine citrate excretion is <400 mg per day, and treatment with potassium citrate has been used to prevent stones. Urine calcium levels >200 mg per day also increase stone risk and often result in negative calcium balance. Reduced renal calcium reabsorption has a role in idiopathic hypercalciuria. Low sodium diets and thiazide-type diuretics lower urine calcium levels and potentially reduce the risk of stone recurrence and bone diseas
In Vivo Renal Tubule pH in Stone Forming Human Kidneys
(Liebert, 2019) Borofsky, Michael S.; Handa, Rajash K.; Evan, Andrew P.; Williams, James C., Jr.; Bledsoe, Sharon; Coe, Fredric L.; Worcester, Elaine M.; Lingeman, James E.; Anatomy and Cell Biology, School of Medicine
Introduction: There is evidence that patients with a history of ileostomies who make acidic urine and form uric acid or calcium oxalate stones may plug some collecting ducts with calcium phosphate (CaP) and urate crystals. This is a paradoxical finding as such minerals should not form at an acid pH. One possible explanation is the presence of acidification defects due to focal damage to inner medullary collecting duct and duct of Bellini (BD) cells. We sought to further investigate this hypothesis through direct measurement of ductal pH in dilated Bellini ducts in patients with ileostomies undergoing percutaneous nephrolithotomy for stone removal. Methods: After obtaining IRB approval, we used a fiber-optic pH microsensor with a 140 µm diameter tip to measure intraluminal pH from the bladder, saline irrigant and dilated BD’s of patients undergoing PCNL. Results: Measurements were taken from three patients meeting inclusion criteria. Measured pH of bladder urine ranged from 4.97 – 5.58 and pH of saline irrigant used during surgery ranged from 5.17 – 5.75. BD measurements were achieved in 11 different BDs. Mean intraductal BD pH was more than 1 unit higher than bulk urine (6.43 ± 0.22 vs. 5.31 ± 0.22, p<0.01). Conclusions: This is the first evidence for focal acidification defects within injured/dilated BD of human kidneys producing a highly acidic bulk phase urine. These results may help explain the paradoxical finding of CaP and urate plugs in dilated ducts of patients with stone forming diseases characterized by highly acidic urine.
In Vivo Renal Tubule pH in Stone-Forming Human Kidneys
(Mary Ann Liebert, Inc., 2020-02) Borofsky, Michael S.; Handa, Rajash K.; Evan, Andrew P.; Williams, James C., Jr.; Bledsoe, Sharon; Coe, Fredric L.; Worcester, Elaine M.; Lingeman, James E.; Urology, School of Medicine
Introduction: There is evidence that patients with a history of ileostomies, who produce acidic urine and form uric acid or calcium oxalate stones, may plug some collecting ducts with calcium phosphate (CaP) and urate crystals. This is a paradoxical finding as such minerals should not form at an acid pH. One possible explanation is the presence of acidification defects due to focal damage to inner medullary collecting duct and Bellini duct (BD) cells. We sought to further investigate this hypothesis through direct measurement of ductal pH in dilated BDs in patients with ileostomies undergoing percutaneous nephrolithotomy (PCNL) for stone removal. Methods: After obtaining institutional review board approval, we used a fiber-optic pH microsensor with a 140-μm-diameter tip to measure intraluminal pH from the bladder, saline irrigant, and dilated BDs of patients undergoing PCNL. Results: Measurements were taken from three patients meeting inclusion criteria. Measured pH of bladder urine ranged from 4.97 to 5.58 and pH of saline irrigant used during surgery ranged from 5.17 to 5.75. BD measurements were achieved in 11 different BDs. Mean intraductal BD pH was more than 1 unit higher than bulk urine (6.43 ± 0.22 vs 5.31 ± 0.22, p < 0.01). Conclusions: This is the first evidence for focal acidification defects within injured/dilated BDs of human kidneys producing highly acidic bulk phase urine. These results may help explain the paradoxical finding of CaP and urate plugs in dilated ducts of patients with stone-forming diseases characterized by highly acidic urine.
Increased Urinary Leukocyte Esterase Distinguishes Patients With Brushite Kidney Stones
(Elsevier, 2021-03-27) Bergsland, Kristin J.; Coe, Fredric L.; El-Achkar, Tarek M.; Worcester, Elaine M.; Medicine, School of Medicine

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