Urine protein markers distinguish stone-forming from non-stone-forming relatives of calcium stone formers

Bergsland, Kristin J.; Kelly, Jennifer K.; Coe, Brian J.; Coe, Fredric L.

doi:10.1152/ajprenal.00370.2005

Cited by 30 publications

(20 citation statements)

References 49 publications

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“…Such a functional redundancy is highly desirable for the kidneys to remain in a crystal-free environment to perform vital functions, and could therefore be a result of evolutionary pressure. Given that urine contains other putative macromolecule inhibitors, such as bikunin, prothromin fragment 1, inter-alpha trypsin (3,7,22,24), this type of redundancy may not be limited to OPN and THP, but may be applicable to other macromolecules. It will be of considerable interest to determine how other molecules respond to the loss of OPN and/or THP under normal and hyperoxaluric conditions, and whether loss of additional molecules could lead to more frequent and severe renal calcinosis and stones.…”

Section: Discussionmentioning

confidence: 99%

Renal calcinosis and stone formation in mice lacking osteopontin, Tamm-Horsfall protein, or both

Liaw

Evan³

et al. 2007

American Journal of Physiology-Renal Physiology

109

103

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Although often supersaturated with mineral salts such as calcium phosphate and calcium oxalate, normal urine possesses an innate ability to keep them from forming harmful crystals. This inhibitory activity has been attributed to the presence of urinary macromolecules, although controversies abound regarding their role, or lack thereof, in preventing renal mineralization. Here, we show that 10% of the mice lacking osteopontin (OPN) and 14.3% of the mice lacking Tamm-Horsfall protein (THP) spontaneously form interstitial deposits of calcium phosphate within the renal papillae, events never seen in wild-type mice. Lack of both proteins causes renal crystallization in 39.3% of the double-null mice. Urinalysis revealed elevated concentrations of urine phosphorus and brushite (calcium phosphate) supersaturation in THP-null and OPN/ THP-double null mice, suggesting that impaired phosphorus handling may be linked to interstitial papillary calcinosis in THP-but not in OPN-null mice. In contrast, experimentally induced hyperoxaluria provokes widespread intratubular calcium oxalate crystallization and stone formation in OPN/THP-double null mice, while completely sparing the wild-type controls. Whole urine from OPN-, THP-, or double-null mice all possessed a dramatically reduced ability to inhibit the adhesion of calcium oxalate monohydrate crystals to renal epithelial cells. These data establish OPN and THP as powerful and functionally synergistic inhibitors of calcium phosphate and calcium oxalate crystallization in vivo and suggest that defects in either molecule may contribute to renal calcinosis and stone formation, an exceedingly common condition that afflicts up to 12% males and 5% females. kidney stone; urolithiasis; uromodulin CLINICAL KIDNEY STONE DISEASE is classified into a number of forms, each requiring a specific plan for medical treatment. It has only been recently demonstrated through a series of biopsy studies of renal papillae from human stone formers that the different stones can develop through different pathways (7,13). Whether the pathogenetic process leading to stone formation involves interstitial plaque or intratubular crystal deposits, a range of host factors appears to be involved, some acting as facilitators and others as inhibitors. Under normal conditions, there is a fine equilibrium between pro-and anticrystallization forces, which helps keep the kidneys stone-free so that they can carry out important physiological functions. However, when the equilibrium breaks down, urine constituents can precipitate out, allowing insoluble crystals to form. Although the mechanisms that mediate retention of urinary crystals into stones remain poorly defined, it is clear that the degree of urinary supersaturation predicts stone risk and type (24,28,38). Furthermore, the urine of most individuals is frequently supersaturated with calcium oxalate and calcium phosphate. These observations suggest a critical role for urinary supersaturation and inhibitors of crystallization. This paradigm of nephrolithiasis has ...

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Section: Discussionmentioning

confidence: 99%

Renal calcinosis and stone formation in mice lacking osteopontin, Tamm-Horsfall protein, or both

Liaw

Evan³

et al. 2007

American Journal of Physiology-Renal Physiology

109

103

View full text Add to dashboard Cite

show abstract

“…This protein can bind with calcium and is a tumor marker for endometrial cancer (25). Moreover, Bergsland et al (26) used Western blotting to investigate urine inhibitors from patients with stones and patients without stones and found that calgranulin B was different between these two groups. They concluded that changes in form or amount of calgranulin B may be associated with stone formation.…”

Section: Discussionmentioning

confidence: 99%

Mass spectroscopic characteristics of low molecular weight proteins extracted from calcium oxalate stones: preliminary study

Chen

Lai

Tsai

et al. 2008

Clinical Laboratory Analysis

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It is believed that boundary compositions of matrix proteins might play a role in stone formation; however, few proteomic studies concerning matrix proteins in urinary stones have been conducted. In this study, we extracted low molecular weight proteins from calcium oxalate stones and measured their characteristic patterns by mass spectroscopy. A total of 10 stones were surgically removed from patients with urolithiasis. Proteins were extracted from the stones and identified by one‐dimensional electrophoresis (sodium dodecyl sulfate buffer [SDS]–polyacrylamide gel electrophoresis [SDS‐PAGE]). After in‐gel digest, samples were analyzed by the surface‐enhanced laser desorption ionization‐time of flight (SELDI‐TOF) technique. The peptide sequences were analyzed from the data of mass spectroscopy. Proteins were identified from Database Search (SwissProt Protein Database; Swiss Institute of Bioinformatics; http://www.expasy.org/sprot) on a MASCOT server (Matrix Science Ltd.; http://www.matrixscience.com). A total of three bands of proteins (27, 18, and 14 kDa) were identified from SDS‐PAGE in each stone sample. A database search (SwissProt) on a MASCOT server revealed that the most frequently seen proteins from band 1 (27 kDa) were leukocyte elastase precursor, cathepsin G precursor, azurocidin precursor, and myeloblastin precursor (EC 3.4.21.76) (leukocyte proteinase 3); band 2 (18 kDa) comprised calgranulin B, eosinophil cationic protein precursor, and lysozyme C precursor; band 3 (14 kDa) showed neutrophil defensin 3 precursor, calgranulin A, calgranulin C, and histone H4. The modifications and deamidations found from the mass pattern of these proteins may provide information for the study of matrix proteins. Various lower molecular weight proteins can be extracted from calcium oxalate stones. The characteristic patterns and their functions of those proteins should be further tested to investigate their roles in stone formation. J. Clin. Lab. Anal. 22:77–85, 2008. © 2008 Wiley‐Liss, Inc.

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“…Differences in the isoforms and abundance of several urine proteins, including calgranulin B, inter-␣-trypsin inhibitor, prothrombin fragment 1, and CD59, were known to be associated with stone formation (26). There have been no previous reports on their association with diabetes or other renal diseases.…”

Section: Downregulated Urinary Proteins In Diabetic Nephropathymentioning

confidence: 99%

Proteomic Identification of Urinary Biomarkers of Diabetic Nephropathy

et al. 2007

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OBJECTIVE -Diabetic nephropathy is a serious complication of both type 1 and type 2 diabetes, and, unless arrested, leads to end-stage renal disease. Current diagnosis consists of urine assays of microalbuminuria, which have inadequate specificity and sensitivity.RESEARCH DESIGN AND METHODS -We used proteomic analyses to identify novel biomarkers of nephropathy in urine from type 2 diabetic patients with demonstrated normo-, micro-, or macroalbuminuria. Samples were analyzed by fluorescence two-dimensional (2-D) differential in-gel electrophoresis (DIGE), and protein identification was performed by liquid chromatography-tandem mass spectrometry.RESULTS -2-D DIGE analysis of the urinary proteome in diabetes with nephropathy identified 195 protein spots representing 62 unique proteins. These proteins belonged to several functional groups, i.e., cell development, cell organization, defense response, metabolism, and signal transduction. Comparisons between control and diabetic subjects with different stages of renal dysfunction revealed the differential expression of several proteins. Spot volume quantification identified 7 proteins that were progressively upregulated with increasing albuminuria and 4 proteins that exhibited progressive downregulation. The majority of these potential candidate biomarkers were glycoproteins.CONCLUSIONS -These data demonstrate the ability of proteomic analyses to reveal potential biomarkers for diabetic nephropathy in urine, an important step forward in advancing accurate diagnosis and our understanding of disease mechanisms. Diabetes Care 30:629 -637, 2007

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Urine protein markers distinguish stone-forming from non-stone-forming relatives of calcium stone formers

Cited by 30 publications

References 49 publications

Renal calcinosis and stone formation in mice lacking osteopontin, Tamm-Horsfall protein, or both

Renal calcinosis and stone formation in mice lacking osteopontin, Tamm-Horsfall protein, or both

Mass spectroscopic characteristics of low molecular weight proteins extracted from calcium oxalate stones: preliminary study

Proteomic Identification of Urinary Biomarkers of Diabetic Nephropathy

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