Urinary solids formation

TABLE 19.1. Substances Leading to the Formation of Urinary Solids... 

In many of the rodent models involving formation of urinary solids, there is associated cytotoxicity, regenerative proliferation, and ultimately the induction of tumors of the urothelium, usually of the urinary bladder but occasionally of the kidney pelvis or ureters (Shirai et al. 1989). Cytotoxicity and regenerative... 

URINARY FACTORS INFLUENCING THE FORMATION OF URINARY SOLIDS... 

The critical factor leading to the formation of urinary solids is the solubUity of the substance in the urine. However, this can be influenced by several factors normally present in the urine which can vary considerably, not only between species but also within a given animal or human based on variations in food and water consumption, type of diet, hydration, and alterations in metabolism (Cohen 1995,1998 McPherson et al. 2006 Pearle and Lotan 2007). 

The method used for the collection of luine to detect urinary solids is particularly sensitive to a variety of artifacts and variations in treatment (Cohen et al. 2007). Most of all, it is essential that the animals not be fasted or go without water during the period of collection of urine. Since the excretion of the substances that are included in formation of the urinary solids is dependent on their consmnption, fasting the animals changes the urine composition considerably and can lead to a condition in which the solids are no longer formed. Fiulhermore, urinary solids can be rapidly excreted in the mine and are not retained so if they are not being constantly formed anew, they will not be detected. This includes urinary tract calculi. Some calculi will be small enough that they will be excreted in the urine, or dissolve with the lowering of the concentration of the solute itself. Furthermore, many of these calculi are actually quite soluble in urine, such as uracil, and rapidly solubilize in the urine. 

Numerous substances admiiustered to rats and/or mice lead to formation of urinary solids with consequent cytotoxicity, regenerative proliferation, and ultimately the formation of tmnors. A variety of specific mechanisms have been demonstrated for the formation of these solids (Clayson et al. 1995 Cohen 1998 lARC 1999 RBCWG 1995). 

Numerous substances such as calcium, magnesium, and phosphate, administered to rats and/or mice, have been demonstrated to lead to formation of urinary solids and are listed in Table 19.1. This table includes not only a large number of natural, essential ingredients in om diet, but also a number of substances that are formed from normal intermediary metabolism, such as carbonate, oxalate, cystine, urate, and uracil, which are present in normal urine. Numerous synthetic chemicals also produce urinary solids when administered at very high doses, including agrichemicals (such as sulfosulfuron and Fosetyl-Al), industrial chemicals (such as melamine), and pharmaceuticals (such as sulfonamides, carbonic anhydrase inhibitors, and HIV protease inhibitors). 

The potential for formation of urinary tract crystalluria and calculi in humans can be readily assessed in the clinical setting (McPherson et al. 2006 Pearle and Lotan 2007). This can be accomplished by routine collection of urine for urinalysis, including sediment analysis for crystals, cells, and casts. As indicated above, the presence of abnormal crystals or an increase in crystals is not sufficient to indicate urothelial toxicity in humans. It is only the presence of calculi that poses any potential for urinary toxicity. Since calculi will frequently be associated with obstruction and consequent pain, this will be a cUnical observation that is readily made by the patient with corroboration by the clinician. Many substances that can lead to the production of calculi in rodents do not appear to do so in humans. Thus, sulfonamides can produce crystallmia and calculi frequently in rodents, whereas sulfonamide crystalluria is common in humans but calculi are rare (McPherson et al. 2006 Pearle and Lotan 2007). Another example is muraglitazar (Dominick et al. 2006), which leads to formation of a variety of urinary solids in rats, including calculi, but it is not associated with the formation of urinary crystalluria or calculi in humans. 

Figure 19.1. Alternative processes for formation of urinary tract solids. (A) Direct formation of solids composed of chronically administered parent chemical or metabolite(s). (B) Indirect formation of urinary tract solids composed of chemicals normally present in the urine. Formation occurs because of significant alterations in urine composition secondary to altered urinary physiology, alteration of normal intermediary metabohsm, or secondary to an inherited metabolic disorder (e.g., gout, oxalosis) or surgical procedure (e.g., porta caval shunt).

The high urinary concentrations of NTA required to Inhibit solid phase formation at the alkaline pH associated with the clinical circumstances for this type of stone formation renders the potential applicability of NTA of uncertain value. 

Kidney stones are solid materials that form in the urinary tract. Most kidney stones are composed of calcium phosphate and calcium oxalate, although they can be solid uric acid. The excessive ingestion of minerals and insufficient water intake can cause the concentration of mineral salts to exceed their solubility and lead to the formation of kidney stones. When a kidney stone passes through the urinary tract, it causes considerable pain and discomfort, necessitating the use of painkillers and surgery. Sometimes ultrasound is used to break up kidney stones. Persons prone to kidney stones are advised to drink six to eight glasses of water every day to prevent saturation levels of minerals in the urine. 

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