Increased Urinary Excretion of Renal Enzymes in Idiopathic Calcium Oxalate Nephrolithiasis

Baggio, Bruno; Gambaro, Giovanni; Ossi, Elena; Favaro, S.; Borsatti, A.

doi:10.1016/s0022-5347(17)52619-1

Cited by 88 publications

(50 citation statements)

References 5 publications

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“…Human urine contains type IV collagenase (42), NAG, cathepsins L and B (22,52), cathepsin H (52), alkaline phosphatase, leucine aminopeptidase, and ␥-glutamyl transpeptidase (22). The activities of NAG and ␤-galactosidase (3,21) and also those of ␣-glucosidase and ␥-glutamyl transpeptidase (3) are elevated in urine from stone patients, as is the level of an unidentified serine protease that cleaves OPN (4). Similar changes accompany nephrocalcinosis induced in hyperoxaluric rats (24,25,56), in which COM crystal formation is associated with significant, proportional increases in urinary oxalate and activity of NAG and the brush-border enzymes alkaline phosphatase, leucine aminopeptidase, and ␥-glutamyl transpeptidase (24,25,56).…”

Section: Discussionmentioning

confidence: 99%

Intracrystalline urinary proteins facilitate degradation and dissolution of calcium oxalate crystals in cultured renal cells

Grover¹,

Thurgood²,

Fleming³

et al. 2008

American Journal of Physiology-Renal Physiology

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134: 5-14, 2001. The aim of this investigation was to determine the effect of increasing concentrations of intracrystalline protein on the rate of CaOx crystal dissolution in Madin-Darby canine kidney (MDCKII) cells. Crystal matrix extract (CME) was isolated from urinary CaOx monohydrate (COM) crystals. Cold and [ 14 C]oxalate-labeled COM crystals were precipitated from ultrafiltered urine containing 0 -5 mg/l CME. Crystal surface area was estimated from scanning electron micrographs, and synchrotron X-ray diffraction was used to determine nonuniform strain and crystallite size. Radiolabeled crystals were added to MDCKII cells and crystal dissolution, expressed as radioactive label released into the medium, was measured. Increasing CME content did not significantly alter crystal surface area. However, nonuniform strain increased and crystallite size decreased in a dose-response manner, both reaching saturation at a CME concentration of 3 mg/ and demonstrating unequivocally the inclusion of increasing quantities of proteins in the crystals. This was confirmed by Western blotting. Crystal dissolution also followed saturation kinetics, increasing proportionally with final CME concentration and reaching a plateau at a concentration of ϳ2 mg/l. These findings were complemented by field emission scanning electron microscopy, which showed that crystal degradation also increased relative to CME concentration. Intracrystalline proteins enhance degradation and dissolution of CaOx crystals and thus may constitute a natural defense against urolithiasis. The findings have significant ramifications in biomineral metabolism and pathogenesis of renal stones. nephrocalcinosis; urolithiasis THE PATHOGENESIS OF RENAL calculi requires the sequential combination of two processes, namely, the nucleation of crystals and their retention within the kidney. While crystal nucleation requires supersaturation of urine with calcium oxalate (CaOx), renal crystal trapping has been explained by either the "free particle" or "fixed particle" theory. Although both these theories appear equally plausible (26), current consensus favors a fixed particle mechanism. This view is supported by the results of studies performed in the early 1990s, which demonstrated for the first time that CaOx crystals irreversibly adhere to and are phagocytosed by cultured renal epithelial cells (35,39). These findings introduced a new paradigm to urolithiasis research because they validated the credibility of using this experimental approach to examine and manipulate factors affecting the regulation of crystal retention, which had not previously been possible. Consequently, there followed a series of reports investigating factors affecting interactions between CaOx monohydrate (COM) crystals and renal cells (reviewed in Refs. 30 and 38). Those studies showed that COM crystals, which are the predominant form of CaOx occurring in human kidney stones (41), are highly membranolytic (55), and also that their adherence to renal epithelial cells is very rapid, concentration ...

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Section: Discussionmentioning

confidence: 99%

Intracrystalline urinary proteins facilitate degradation and dissolution of calcium oxalate crystals in cultured renal cells

Grover¹,

Thurgood²,

Fleming³

et al. 2008

American Journal of Physiology-Renal Physiology

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“…Increased excretion of cellular enzymes has been observed in the urine of stoneforming humans (18,19) and of oxalate-loaded rats (20), and it has been postulated that cellular damage could result from crystal deposition. However, when the nephrotoxin gentamycin was administered to rats together with oxalate, crystal deposition was enhanced (31), suggesting that cellular damage might precede and promote crystal retention, rather than be a consequence of the crystals.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, studies in stoneforming humans (18,19) and oxalate-loaded rats (20) have demonstrated that renal cellular injury occurs. In the current study, we defined the effect of diverse injuries to renal cells on crystal adhesion and how the PGE system might modulate this response.…”

mentioning

confidence: 99%

Modulation of Proliferating Renal Epithelial Cell Affinity for Calcium Oxalate Monohydrate Crystals

Farell¹,

Huang

Kim

et al. 2004

Journal of the American Society of Nephrology

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Abstract. Adhesion of urinary crystals to distal tubular cells could be a critical event that triggers a cascade of responses ending in kidney stone formation. Monolayer cultures of distal nephronderived MDCKI cells were used as a model to study crystal-cell interactions. COM crystal adhesion reached a peak 2 d after plating and progressively fell thereafter. The decline in crystal binding was accelerated by prostaglandin E 2 (PGE 2 ) supplementation and delayed by blockade of PG production. Crystals avidly adhered to cells that migrated in to repair a scrape wound made in the monolayer and after a transient hypoglycemic insult. Exposure of MDCKI cells to uric acid crystals and soluble uric acid was also associated with increased crystal adhesion. Treatment of physically or hypoglycemically injured cells with trypsin or neuraminidase reduced crystal binding to baseline levels, suggesting that increased exposure of cell surface glycoproteins mediated the effect, whereas PGE 2 treatment blunted crystal binding to regenerating cells. Furthermore, when cells were grown in the presence of synthetic D-mannosamine analogues that can modify the conformation of cell surface sialoglycoconjugates, crystal binding to proliferating cells was decreased, whereas blockade of N-

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“…Crystal retention could be caused by adherence of crystals to the epithelial cells lining the renal tubules (2). Although many investigators recognized a role for renal tubular injury in the pathophysiology of nephrolithiasis, definite proof for this concept and the mechanisms involved are not yet available (3)(4)(5)(6)(7).…”

mentioning

confidence: 99%

Calcium Oxalate Crystal Adherence to Hyaluronan-, Osteopontin-, and CD44-Expressing Injured/Regenerating Tubular Epithelial Cells in Rat Kidneys

Asselman¹,

Verhulst²,

Broe³

et al. 2003

Journal of the American Society of Nephrology

186

154

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Abstract. Retention of crystals in the kidney is an essential early step in renal stone formation. Studies with renal tubular cells in culture indicate that hyaluronan (HA) and osteopontin (OPN) and their mutual cell surface receptor CD44 play an important role in calcium oxalate (CaOx) crystal binding during wound healing. This concept was investigated in vivo by treating rats for 1, 4, and 8 d with ethylene glycol (0.5 and 0.75%) in their drinking water to induce renal tubular cell damage and CaOx crystalluria. Tubular injury was morphologically scored on periodic acid-Schiff-stained renal tissue sections and tissue repair assessed by immunohistochemical staining for proliferating cell nuclear antigen. CaOx crystals were visualized in periodic acid-Schiff-stained sections by polarized light microscopy, and renal calcium deposits were quantified with von Kossa staining. HA was visualized with HA-binding protein and OPN and CD44 immunohistochemically with specific antibodies and quantified with an image analyzer system. Already after 1 d of treatment, both concentrations of ethylene glycol induced hyperoxaluria and CaOx crystalluria. At this point, there was neither tubular injury nor crystal retention in the kidney, and expression of HA, OPN, and CD44 was comparable to untreated controls. After 4 and 8 d of ethylene glycol, however, intratubular crystals were found adhered to injured/regenerating (proliferating cell nuclear antigen positive) tubular epithelial cells, expressing HA, OPN, and CD44 at their luminal membrane. In conclusion, the expression of HA, OPN, and CD44 by injured/regenerating tubular cells seems to play a role in retention of crystals in the rat kidney.

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Increased Urinary Excretion of Renal Enzymes in Idiopathic Calcium Oxalate Nephrolithiasis

Cited by 88 publications

References 5 publications

Intracrystalline urinary proteins facilitate degradation and dissolution of calcium oxalate crystals in cultured renal cells

Intracrystalline urinary proteins facilitate degradation and dissolution of calcium oxalate crystals in cultured renal cells

Modulation of Proliferating Renal Epithelial Cell Affinity for Calcium Oxalate Monohydrate Crystals

Calcium Oxalate Crystal Adherence to Hyaluronan-, Osteopontin-, and CD44-Expressing Injured/Regenerating Tubular Epithelial Cells in Rat Kidneys

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