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.

Modulators of urinary stone formation.

Urinary stone disease is an ailment afflicting human kind for many centuries. It can affect up to a quarter the population in certain geographic areas and hence poses a significant health problem. Various aetiological factors have been attributed to stone formation – hereditary, dietary, geographical, infective etc. Approximately 85% of the stones in human are calcium stones comprising oxalate and phosphate, either alone or combined. Though supersaturation of stone forming salts in urine is essential, abundance of these salts by itself will not always result in stone formation. The pathogenesis of calcium oxalate stone formation is a multi-step process and in essence includes – nucleation, crystal growth, crystal aggregation and crystal retention. Various substances in the body have an effect on one or more of the above stone forming processes, thereby influencing a person's ability to promote or prevent stone formation. Promoters of stone formation facilitate stone formation whilst inhibitors prevent it. Low urine volume, low urine pH, calcium, sodium, oxalate, and urate are known to promote stone formation. Many inorganic (eg. Citrate, magnesium) and organic (eg. Urinary prothrombin fragment 1, glycosaminoglycans, osteopontin) substances are known to inhibit stone formation. Organic inhibitory compounds adsorb to the surface of the crystal, thereby inhibiting crystal growth and nucleation. This review presents a comprehensive account of the basic principles of stone formation and role of urinary inhibitors/promoters in calcium oxalate crystallisation.

The Role of Urinary Kidney Stone Inhibitors and Promoters in the Pathogenesis of Calcium Containing Renal Stones

Calcium oxalate (CaOx) kidney stones are formed attached to Randall's plaques (RPs) or Randall's plugs. Mechanisms involved in the formation and growth are poorly understood. It is our hypothesis that stone formation is a form of pathological biomineralization or ectopic calcification. Pathological calcification and plaque formation in the body is triggered by reactive oxygen species (ROS) and the development of oxidative stress (OS). This review explores clinical and experimental data in support of ROS involvement in the formation of CaOx kidney stones. Under normal conditions the production of ROS is tightly controlled, increasing when and where needed. Results of clinical and experimental studies show that renal epithelial exposure to high oxalate and crystals of CaOx/calcium phosphate (CaP) generates excess ROS, causing injury and inflammation. Major markers of OS and inflammation are detectable in urine of stone patients as well as rats with experimentally induced CaOx nephrolithiasis. Antioxidant treatments reduce crystal and oxalate induced injury in tissue culture and animal models. Significantly lower serum levels of antioxidants, alpha-carotene, beta-carotene and beta-cryptoxanthine have been found in individuals with a history of kidney stones. A diet rich in antioxidants has been shown to reduce stone episodes. ROS regulate crystal formation, growth and retention through the timely production of crystallization modulators. In the presence of abnormal calcium, citrate, oxalate, and/or phosphate, however, there is an overproduction of ROS and a decrease in the antioxidant capacity resulting in OS, renal injury and inflammation. Cellular degradation products in the urine promote crystallization in the tubular lumen at a faster rate thus blocking the tubule and plugging the tubular openings at the papillary tips forming Randall's plugs. Renal epithelial cells lining the loops of Henle/collecting ducts may become osteogenic, producing membrane vesicles at the basal side. In addition endothelial cells lining the blood vessels may also become osteogenic producing membrane vesicles. Calcification of the vesicles gives rise to RPs. The growth of the RP's is sustained by mineralization of collagen laid down as result of inflammation and fibrosis.

Reactive oxygen species, inflammation and calcium oxalate nephrolithiasis

Urease activity is a physiological function of many bacteria that enables these organisms to utilize urea as a source of nitrogen. The association of ureolytic bacteria with human or animal hosts varies widely from a commensal relationship as demonstrated with skin microflora, a symbiotic relationship in the gastrointestinal tract, to a pathogenic relationship in the urinary tract. Since similar or identical species of bacteria such as Staphylococcus aureus are found in all three environments, the effect of urease activity on the host must be solely a function of the environment of these organisms. In this review, the importance of urease to bacteria is discussed, identifying the gastrointestinal tract as a major reservoir of ureolytic bacteria and investigating the urinary tract environment and the infectious struvite stone production that often accompanies urease-producing bacteria there. Finally, an infection model is presented which explains the development and growth of these urinary calculi and their remarkable persistence in spite of modern urological treatments.

The Ecology and Pathogenicity of Urease-Producing Bacteria in the Urinary Tract

Urinary stone disease , Urinary stone disease , کتابخانه دیجیتالی دانشگاه علوم پزشکی و خدمات درمانی شهید بهشتی

Sheldon D. Roberts

Papers

Glycosaminoglycans content of stone matrix.

Metastatic Transitional Cell Carcinoma in an Ileal Conduit Following Cystectomy