Modulators of urinary stone formation

Abstract

Urine contains compounds that modulate the nucleation, growth and aggregation of crystals as well as their attachment to renal epithelial cells. These compounds may function to protect the kidneys against: 1, the possibility of crystallization in tubular fluid and urine, which are generally metastable with respect to calcium salts, 2, crystal retention within the kidneys thereby preventing stone formation and 3, possibly against plaque formation at the nephron basement membrane. Since oxalate is the most common stone type, the effect of various modulators on calcium oxalate (CaOx) crystallization has been examined in greater details. Most of the inhibitory activity resides in macromolecules such as glycoproteins and glycosaminoglycans while nucleation promotion activity is most likely sustained by membrane lipids. Nephrocalcin, Tamm-Horsfall protein, osteopontin, urinary prothrombin fragment 1, and bikunin are the most studied inhibitory proteins while chondroitin sulfate (CS), heparan sulfate (HS) and hyaluronic acid (HA) are the best studied glycosaminoglycans. Crystallization modulating macromolecules discussed here are also prominent in cell injury, inflammation and recovery. Renal epithelial cells on exposure to oxalate and CaOx crystals produce some of the inflammatory molecules such as monocyte chemoattractant protein-1 (MCP-1) with no apparent role in crystal formation. In addition, macrophages surround the CaOx crystals present in the renal interstitium. These observations indicate a close relationship between inflammation and nephrolithiasis.

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

“…urolithiasis, such as inter-a-trypsin inhibitor, prothrombin families, osteopontin, albumin, Tamm-Horsfall protein, nephrocalcin, and a1-microglobulin (3)(4)(5). However, it is unclear which of the matrix proteins found in the stones are promoters or inhibitors of urolithiasis.…”

From crystalluria to kidney stones, some physicochemical aspects of calcium nephrolithiasis

“…These modulators comprise citrate, pyrophosphate, some glycosaminoglycans and a large group of proteins [23] . The most intensively studied and probably most important proteins are albumin, inter alpha inhibitor, nephrocalcin, osteopontin, prothrombin fragment 1 and Tamm Horsfall glycoprotein.…”

“…Since urine often is only metastability supersaturated with respect to CaOx and storage and cooling have a minimal influence on CaOx formation [26] , heterogenous nucleation seems to play an important role in crystalluria. Acid phospholipids accumulate Ca on cell membranes which thus become ideal nucleators for CaOx [23] . This heterogenous nucleation can occur by tubular cells in the kidney as well as by cellular debris in urine.…”

“…The composition of these proteins showed no difference whether they were precipitated from urine of stone patients or of controls. Inhibition of crystal AGN by urinary macromolecules (UM's) was demonstrated in various studies [23] . But a deficient urinary inhibitory activity in urine of stone patients could only be demonstrated in some studies [35][36][37] but not in all [38,39] .…”

Nephrocalcinosis in preterm neonates

“…Stone-inhibiting macromolecules Urine contains macromolecules, such as osteopontin, nephrocalcin and TammHorsfall protein, which can inhibit the processes of nucleation, agglomeration and growth in vitro [66]. Osteopontin, a glycoprotein originally identified as a component of bone, has been associated with a variety of functions, including mineralization, signalling and cell adhesion.…”