Pathophysiology

4. Pathophysiology

Urolith Formation

Relative Supersaturation (Figure 14)

Urine supersaturation is the driving force for the formation of crystals within the urinary tract. Determination of the relative supersaturation (RSS) of urine with specific minerals has been used to identify dogs at risk for urolith formation. RSS is considered a more accurate predictor of urine crystallization potential than the formerly used activity product ratio (APR). The main limitation of the APR technique is the assumption that a steady state with respect to the solid phase will be reached by the end of the 48-hour incubation period, whereas it may take urine up to nine days to reach the equilibrium, particularly when coming from oversaturation (Robertson et al., 2002; Stevenson et al., 2003c). In a simple solution, an RSS less than one corresponds to the undersaturated zone, and an RSS greater than one indicates the supersaturated zone. However, as urine is a complex solution, even if the urine is supersaturated, significant urine flow, inhibitors of crystallization or aggregation, and ionic forces can prevent stone formation. This is the metastable zone (Figure 14). If the urine becomes even more concentrated, crystals will form spontaneously, which is called supersaturation. The RSS at which the urine will become supersatured depends upon the mineral(s) involved; it is around 2.5 for struvite and 10 to 14 for calcium oxalate in human urine (Robertson, personal communication).

Figure 14. Urine relative super saturation.

Nucleation

The first step in the urolith development process is the formation of a crystal nidus (embryo). This phase, called nucleation, is dependent on supersaturation of urine with calculogenic substances, so that precipitation of salts and crystallization can occur (Robertson, 1993). The degree of urine supersaturation may be influenced by factors such as the magnitude of renal excretion of crystalloids, favorable urine pH for crystallization (Figure 15), urinary retention, and a decreased concentration of crystallization inhibitors in the urine (Robertson et al., 2002).

Figure 15. Solubility and pH (personal communication with Dr WG Robertson). Urinary pH can have a marked influence on the solubility of certain crystals and calculi. Struvite crystals are the most sensitive to changes in urine pH. Acidification of urine increases the solubility of struvite crystals, reducing the risk of struvite urolithiasis. Other crystals, particularly calcium oxalate, are less sensitive to urine pH.

There are many documented urinary inhibitors of calcium oxalate formation including magnesium, citrate, and macromolecular inhibitors such as nephrocalcin and glycosaminoglycans (Robertson et al., 2002). The role of inhibitors within canine calcium oxalate formation has yet to be fully explored.

Urinary ion composition can affect nucleation and precipitation when there is interaction between elements in the urine. For example, magnesium binds to oxalate and citrate can bind to calcium; magnesium and citrate are therefore considered inhibitors of calcium oxalate urolithiasis.

Growth of Crystals

Once nucleation has occurred, crystal growth may occur at lesser degrees of supersaturation. Further growth of the crystal nidus then depends on the duration of its passage through the urinary tract, degree and duration of urine supersaturation for similar or other crystalloids, and crystal properties. The mechanisms leading to crystal growth are still uncertain and may include growth around a nidus or a matrix lattice, which might be facilitated by a lack of crystal aggregation inhibitors (Osborne et al., 1995).

Fate of Uroliths

Uroliths may pass through various parts of the urinary tract and/or be voided, undergo spontaneous dissolution, become inactive or continue to grow. Not all persistent uroliths result in clinical signs.