Diagnosis

2. Diagnosis

History and Clinical Signs

Symptoms of urolithiasis are mainly due to irritation of the mucosa of the lower urinary tract, resulting in signs of cystitis and/or urethritis. The most common signs are hematuria, dysuria and pollakiuria. Occasionally, urolithiasis may lead to urethral obstruction, which is a medical and surgical emergency. Renal calculi may furthermore cause pyelonephritis, outflow obstruction, reduction of renal mass, azotemia and renal failure. Conversely some patients are clinically asymptomatic.

Differential Diagnosis

Other common causes of hematuria, dysuria and frequent urination, with or without urethral obstruction, are UTI, polyps and neoplasia. These can be distinguished by urine culture and imaging studies.

Laboratory Testing and Imaging

Urinalysis, quantitative urine culture and imaging (plain and double contrast radiography and/or ultrasonography) are required to confirm urolithiasis and to look for predisposing factors.

Evaluation of serum biochemistries is useful for the recognition of underlying abnormalities and assessment of renal function in dogs with nephrolithiasis. Urine chemistries can furthermore reveal excessive quantities of one or more minerals contained in the urolith.

Urinalysis

Urinalysis typically shows inflammation: proteinuria, hematuria and pyuria. Urine pH varies, depending upon stone type, presence or absence of infection, and diet. In general, struvite uroliths are associated with alkaline urine, particularly if urease-producing bacteria are present. Urate and cystine formation tends to be associated with acid to neutral pH (Osborne et al., 1995). In contrast urine pH is a less important factor in calcium oxalate formation.

Crystalluria may be present without urolithiasis, and urolithiasis may occur without crystalluria. In addition, crystals are not necessarily representative of the urolith type, since they may be influenced by a urease-producing bacterial infection that could generate struvite crystals. However, ammonium urate crystals (Figure 4) may indicate portosystemic shunting, and cystine crystals are pathognomonic of cystinuria (Figure 5). The presence of crystals depends on urine pH, temperature and concentration. Urine samples should be examined within 30 minutes of collection and should not be refrigerated.

Figure 4. Ammonium urate urinary crystals. (© Waltham Centre for Pet Nutrition).

Figure 5. Cystine urinary crystals. (© Waltham Centre for Pet Nutrition).

Urine Culture

Urine bacterial culture and sensitivity should be performed in all dogs to assess for primary or secondary UTI. Bacterial culture of the inner parts of possible infection-induced stones may also be beneficial, since bacteria in the urine may not be the same as those harbored in the urolith (Osborne et al., 1995). If a cystotomy is performed for stone removal, it is recommended to submit a piece of bladder mucosa for culture and sensitivity as this is more sensitive than culturing the urine (Hamaide et al., 1998).

Imaging Techniques

Radiography and/or ultrasonography are indicated to verify the presence of uroliths, as well as their location, number, size, radiodensity and shape (Figure 6). Uroliths have to be greater than 3 mm to be detected by survey abdominal radiography or ultrasonography. Urate uroliths are the most radiolucent and usually require double contrast cystography for visualization. Retrograde contrast studies are required to assess urethral stones, and excretory urography if renal calculi are suspected.

Figure 6. Radiographic appearance of cystic calculi in a dog. (© CR Lamb)

Cystoscopy requires specialized equipment and general anesthesia, but it can be very helpful to confirm urolithiasis and to remove small uroliths from the bladder or urethra (Cannizzo et al., 2001).

Analysis of Urolith Composition

Uroliths may be collected by spontaneous voiding, voiding urohydropropulsion (Osborne et al., 1999e), aspiration into a urethral catheter, cystoscopy, or surgical removal. Urolith composition should be determined by quantitative physical analyses, which are far more accurate than qualitative chemical techniques. Uroliths can contain more than one mineral type, and layer-by-layer mineral analysis may be required in compound stones. It is, therefore, important not to crush the uroliths before analysis. The initiating cause of the uroliths can be determined by the mineral composition of the nucleus, which may be different from the surrounding layers (Osborne et al., 1999c).

Determination of the mineral composition of uroliths is vital for specific therapy and to prevent recurrence. Quantitative analysis performed by specialized laboratories is the most reliable method.

Predicting Urolith Type

Effective dissolution of uroliths depends on knowledge of their mineral composition. Ideally a urolith should be retrieved and analyzed, and a number of factors can help in predicting urolith composition (Table 2 and Table 3).

Specific Urolith Types

Struvite

Struvite (Mg NH4 PO4 6 HO2) is one of the most common minerals found in canine uroliths (Figure 7). Oversaturation of urine with magnesium ammonium phosphate ions is a requirement, but several other factors - including UTI, alkaline urine, diet and genetic predisposition - may influence formation. In dogs, most struvite uroliths are associated with a bacterial UTI (Figure 8) with urease producing bacteria such as Staphylococcus spp (often S. intermedius) or, less commonly, Proteus spp. Urease is an enzyme that hydrolyzes urea, leading to elevations of ammonium, phosphate and carbonate, resulting in alkaline urine. Many struvite uroliths also contain a small quantity of other minerals, such as calcium phosphate and, less commonly, ammonium urate.

Figure 7. Struvite stones. (© Waltham Centre for Pet Nutrition).

Figure 8. The role of UTI in struvite urolithiasis (from P. Markwell). Bacterial infection with urease producing organisms results in the cleavage of urea to generate ammonia and carbon dioxide. The carbon dioxide can dissociate with water to alkalinize the urine. The alkaline pH enables phosphate and ammonium ions to bind with magnesium to form a molecule of magnesium ammonium phosphate (struvite).

Sterile struvite uroliths are rare in dogs; their etiopathogenesis may include dietary, metabolic or familial factors, but does not involve bacterial urease (Osborne et al., 1995).

Calcium Oxalate

The main risk factor is supersaturation of urine with calcium and oxalate, with calcium relatively more important (Stevenson, 2002, Stevenson et al 2003a). A major factor is intestinal hyperabsorption of calcium, which is recognized as a cause of calcium oxalate urolithiasis in both humans and dogs susceptible to calcium oxalate urolithiasis (Lulich et al., 2000; Stevenson, 2002). Indirectly, this leads to hyperoxaluria, since it increases the availability of oxalate for absorption. The relationship between intestinal absorption of calcium and oxalic acid is clinically important, since reducing the concentration of calcium increases oxalate absorption, thus maintaining or increasing the risk of stone formation. Diet may have a significant role in the development of these uroliths (see risk factors) (Lekcharoensuk et al., 2002a; 2002b).

Diseases that increase urinary excretion of calcium and oxalic acid play a smaller role. Calcium oxalate (Figure 9) and phosphate uroliths have been reported in dogs with primary hyperparathyroidism, but not in dogs with paraneoplastic hypercalcemia (Klausner et al., 1987; Lulich et al., 2000).

Figure 9. Calcium oxalate stones. (© Waltham Centre for Pet Nutrition).

Urate

Uric acid is one of several biodegradation products of purine nucleotide metabolism. In non-Dalmatian dogs, almost all urate formed from degradation of purine nucleotides is metabolized by hepatic uricase to allantoin, which is very soluble and excreted by the kidneys. In Dalmatian dogs, only 30 - 40% of uric acid is converted to allantoin, resulting in increased serum levels and urinary excretion of urate (Bartges et al., 1999). Ensuing uroliths are most commonly composed of ammonium urate (Figure 10). The defective uric acid mechanism in Dalmatian dogs probably involves both alterations in the hepatic and renal pathways, but the exact mechanism is incompletely understood. Reduced urinary excretion of crystallization inhibitors may contribute to stone formation in Dalmatians (Carvalho et al., 2003). Urolithiasis in the Dalmatian is probably autosomal recessive inherited (Sorenson & Ling, 1993), although this does not explain the increased risk of stone formation for male dogs.

Figure 10. Urate stones. (© Waltham Centre for Pet Nutrition).

Any form of severe hepatic dysfunction may predispose dogs to urate urolithiasis, but there is a specific predisposition in dogs with congenital or acquired portosystemic shunts (Kruger et al., 1986, Bartges et al., 1999). These dogs frequently develop intermittent crystalluria, urate calculi, or both. Hepatic dysfunction in these dogs may be associated with reduced hepatic conversion of uric acid to allantoin and of ammonia to urea, resulting in hyperuricemia and hyperammonemia, but the precise mechanism is uncertain.

Relatively little is known about urate urolithiasis in non-Dalmatian dogs that do not have portosystemic shunts, although a familial tendency has been suggested for English Bulldogs (Kruger et al., 1986; Bartges et al., 1994). Dietary risk factors for urate urolithiasis include high purine diets (e.g., diets rich in offal) and low water consumption. Urine acidity promotes urate lithogenesis, because purines are less soluble at acid pH. Consumption of diets that promote aciduria such as high protein diets are therefore also a risk factor for predisposed dogs (Bartges et al., 1999).

Cystine

These uroliths (Figure 11) occur in dogs with cystinuria, an inborn error of metabolism characterized by a defective proximal tubular reabsorption of cystine and other amino acids. Cystinuric dogs reabsorb a much smaller proportion of cystine that is filtered by the glomerulus and some may even have net cystine secretion (Casal et al., 1995). Cystinuria is usually the only detectable sign of their amino acid loss unless protein intake is severely restricted. Cystine urolithiasis develops because cystine is only sparingly available at the usual urine pH of 5.5 to 7.0. Not all cystinuric dogs form uroliths, and calculi are often not recognized until maturity. They occur predominantly in male dogs, and other undetermined factors may therefore also play a role in the pathogenesis. Canine cystinuria is genetically heterogeneous and has been recognized in more than 60 breeds of dogs with variable patterns of aminoaciduria (Case et al., 1992, 1993; Osborne et al., 1999g, Hen-thorn et al., 2000).

Figure 11. Cystine stones. (© Waltham Centre for Pet Nutrition).

Other Uroliths

Calcium phosphate uroliths (Figure 12) are commonly called apatite uroliths, with hydroxyapatite and carbonate apatite the most common forms. They occur commonly as a minor component of struvite and calcium oxalate stones. Pure calcium phosphate uroliths are infrequently found, and they are usually associated with metabolic disorders (primary hyperparathyroidism, other hypercalcemic disorders, renal tubular acidosis, idiopathic hypercalciuria) and/or excessive dietary calcium and phosphorus (Kruger et al., 1999). Calcium phosphate crystals can trigger calcium oxalate crystallization by allowing heterogeneous crystallization to occur at a lower urinary supersaturation than homogeneous crystallization. The risks associated with calcium phosphate formation therefore should be taken in account when treating other urolith types.

Figure 12. Calcium phosphate stones. (© Waltham Centre for Pet Nutrition).

Silica urolithiasis is a recently discovered disease (Aldrich et al., 1997). The pathogenesis may involve consumption of an absorbable form of silica in various foods, resulting in urinary silica hyperexcretion. The recent emergence of these uroliths may have some relationship to the increased use of plant-derived ingredients such as fibers and bran in dog foods (Osborne et al., 1995).

Compound uroliths consist of a nucleus of one mineral type and a shell of another mineral type. They form because factors promoting precipitation formation of one type of urolith supersede earlier factors promoting precipitation of another mineral type. Some minerals types may also function as a nidus for deposition of another mineral; for instance, all uroliths predispose to UTI, which may result in secondary struvite precipitation.