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Browsing by Author "Bledsoe, Sharon"
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Item 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 MedicineObjectives: 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.Item 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 MedicineIntroduction: 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.Item 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 MedicineIntroduction: 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.Item A Precision Medicine Approach Uncovers a Unique Signature of Neutrophils in Patients With Brushite Kidney Stones(Elsevier, 2020-05) Makki, Mohammad Shahidul; Winfree, Seth; Lingeman, James E.; Witzmann, Frank A.; Worcester, Elaine M.; Krambeck, Amy E.; Coe, Fredric L.; Evan, Andrew P.; Bledsoe, Sharon; Bergsland, Kristin J.; Khochare, Suraj; Barwinska, Daria; Williams, James C.; El-Achkar, Tarek M.; Medicine, School of MedicineIntroduction: We have previously found that papillary histopathology differs greatly between calcium oxalate and brushite stone formers (SF); the latter have much more papillary mineral deposition, tubular cell injury, and tissue fibrosis. Methods: In this study, we applied unbiased orthogonal omics approaches on biopsied renal papillae and extracted stones from patients with brushite or calcium oxalate (CaOx) stones. Our goal was to discover stone type-specific molecular signatures to advance our understanding of the underlying pathogenesis. Results: Brushite SF did not differ from CaOx SF with respect to metabolic risk factors for stones but did exhibit increased tubule plugging in their papillae. Brushite SF had upregulation of inflammatory pathways in papillary tissue and increased neutrophil markers in stone matrix compared with those with CaOx stones. Large-scale 3-dimensional tissue cytometry on renal papillary biopsies showed an increase in the number and density of neutrophils in the papillae of patients with brushite versus CaOx, thereby linking the observed inflammatory signatures to the neutrophils in the tissue. To explain how neutrophil proteins appear in the stone matrix, we measured neutrophil extracellular trap (NET) formation-NETosis-and found it significantly increased in the papillae of patients with brushite stones compared with CaOx stones. Conclusion: We show that increased neutrophil infiltration and NETosis is an unrecognized factor that differentiates brushite and CaOx SF and may explain the markedly increased scarring and inflammation seen in the papillae of patients with brushite stones. Given the increasing prevalence of brushite stones, the role of neutrophil activation in brushite stone formation requires further study.Item Randall's plaque in stone formers originates in ascending thin limbs(American Physiological Society, 2018-11) Evan, Andrew P.; Coe, Fredric L.; Lingeman, James; Bledsoe, Sharon; Worcester, Elaine M.; Anatomy and Cell Biology, School of MedicineRandall's plaque, an attachment site over which calcium oxalate stones form, begins in the basement membranes of thin limbs of the loop of Henle. The mechanism of its formation is unknown. Possibly, enhanced delivery of calcium out of the proximal tubule, found in many stone formers, increases reabsorption of calcium from the thick ascending limb into the interstitium around descending vasa recta, which convey that calcium into the deep medulla, and raises supersaturations near thin limbs ("vas washdown"). According to this hypothesis, plaque should form preferentially on ascending thin limbs, which do not reabsorb water. We stained serial sections of papillary biopsies from stone-forming patients for aquaporin 1 (which is found in the descending thin limb) and the kidney-specific chloride channel ClC-Ka (which is found in the ascending thin limb). Plaque (which is detected using Yasue stain) colocalized with ClC-Ka, but not with aquaporin 1 (χ2 = 464, P < 0.001). We conclude that plaque forms preferentially in the basement membranes of ascending thin limbs, fulfilling a critical prediction of the vas washdown theory of plaque pathogenesis. The clinical implication is that treatments such as a low-sodium diet or thiazide diuretics that raise proximal tubule calcium reabsorption may reduce formation of plaque as well as calcium kidney stones.