Specific Nutritional Management

7. Specific Nutritional Management

Struvite Urolithiasis

Medical Dissolution

Infection-induced struvite uroliths require a combination of appropriate antimicrobial and calculolytic dietary therapy. Sterile struvite uroliths do not need antibiotics, and can be dissolved using calculolytic dietary therapy alone or by using urinary acidifiers (Osborne et al., 1999d; Rinkardt & Houston, 2004) (Figure 17).

Figure 17. Formation of struvite crystals in urine.

Eliminate UTI

Antibiotic treatment should be based upon culture and sensitivity determination of urine obtained by cystocentesis. It should be continued until uroliths can no longer be detected radiographically, since viable bacteria may remain inside the urolith (Seaman & Bartges, 2001). Urine should be sterile on repeated cultures, and antibiotics should be changed (according to sensitivity results) if UTI persists.

Struvite molecule. Three molecules are needed to form one struvite molecule. This reaction is reversible in an acid environment.

Calculolytic Diet to Dissolve Uroliths

These diets are aimed to reduce urine concentrations of urea, phosphorus and magnesium (Lulich et al., 2000). Commercial calculolytic diets contain moderate amounts of protein (15 - 20% in a 4000 kcal/kg diet), are highly digestible, low in fiber (to reduce fecal water loss), and contain increased levels of NaCl. Dietary protein restriction reduces the amount of substrate (urea) available in urine for urease-producing bacteria. Dietary efficacy has been shown in clinical studies (Osborne et al., 1999d; Rinkardt & Houston, 2004). Calculolytic diets should be given for at least one month after removal or dissolution of struvite uroliths, because uroliths too small for radiographic detection may still be present. Dogs can then be changed to a normal diet.

Dissolution therapy should be monitored with monthly abdominal radiographs or ultrasound examination and regular urinalyses (pH of morning urine should be 6.5, with no evidence of UTI). The average time for dissolution of infection-induced struvite uroliths is approximately 3 months, although clinical signs usually resolve in the first 2 weeks, probably due to control of the UTI. Sterile struvite stones tend to dissolve more rapidly, typically taking 5 - 6 weeks (Osborne et al., 1999d).

Drug Therapy

Urinary acidifying agents such as ammonium chloride are not necessary provided a calculolytic diet and antimicrobials are given. Persistent alkaline urine pH indicates continued UTI, and pH will not go down until this is controlled (Lulich et al., 2000).

Acetohydroxamic acid (AHA) is a microbial urease inhibitor that blocks the hydrolysis of urea to ammonia, consequently lowering urine pH and ammonium concentration. It may therefore inhibit struvite growth and promote dissolution. AHA (12.5 mg/kg orally every 12 h) may be helpful in dogs with infection-induced struvite urolithiasis that is refractory to antibiotic therapy and dietary dissolution (Krawiec et al., 1984). However, this drug has many side effects, including hemolytic anemia, anorexia and vomiting. It should not be given to dogs with renal failure, since it is excreted via the kidneys, or to pregnant animals, since it is teratogenic (Baillie et al., 1986; Osborne et al., 1995).

Amino acid preparations have been reported effective in the dissolution of sterile struvite nephroliths, although this concerned only 2 dogs; their efficacy is probably due to urine acidification (Mishina et al., 2000). There are no reports of its use in dogs with infection-induced struvite stones.

The most important factor in preventing infection-induced struvite urolithiasis is resolution of the underlying UTI and prevention of recurrence. Preventative dietary therapy is particularly important for the rare dogs with sterile struvite calculi without concomitant infection. Only those diets specifically designed for long term feeding should be fed for prolonged periods.

Calcium Oxalate Urolithiasis

Calcium oxalate uroliths do not respond to medical dissolution. Symptomatic calculi require mechanical removal, after which preventative medical protocols should be implemented to prevent recurrence.

Calcium oxalate molecule. One molecule of oxalate will associate with one molecule of calcium to form a very stable molecule of calcium oxalate.

Dogs predisposed to calcium oxalate urolithiasis may also benefit from a preventative diet (Figure 18).

Figure 18. Comparison of calcium oxalate RSS in healthy dogs and dogs predisposed to calcium oxalate stones based on diet (Stevenson et al., 2004).

Prevention of Recurrence

These uroliths have a high recurrence rate, up to 50% by 2 years after initial removal (Lulich et al., 1995; 1998). Medical protocols are therefore essential to reduce urolith recurrence following removal and dietary modification can greatly reduce the risk of recurrence in affected individuals (Stevenson et al., 2004).

Eliminate Risk Factors

If the dog is hypercalcemic or has other diseases (e.g., hyperadrenocorticism), the underlying cause should be corrected. Usually no further preventative measures will be required (Lulich et al., 1998).

If the dog is normocalcemic, risk factors for urolithiasis should be identified and controlled. Dry acidifying diets that have not been formulated to increase diuresis and drugs that promote excessive urinary calcium excretion (urinary acidifiers, furosemide, glucocorticosteroids) should be avoided.

No treats or dietary supplements containing calcium, vitamin D or excessive amounts of vitamin C should be given, since these can promote increased excretion of calcium and/or oxalate (Lulich and Osborne, 1995).

Calcium oxalate preventative diets should stimulate water consumption, and should not be restricted in protein, calcium or phosphorus. A recent clinical study has proven that dietary modification can reduce the risk factors associated with calcium oxalate formation thereby reducing the risk of recurrence in susceptible individuals (Figure 19) (Stevenson et al., 2004).

Figure 19. Effect of a diet specifically designed to lower the urinary calcium oxalate RSS in dogs with naturally occuring calcium oxalate urolithiasis (Stevenson et al., 2004).

Dietary Modification

Diuresis

Augmenting water intake, either by feeding a canned diet or by adding water and/or sodium chloride to the food, remains the major factor in managing and preventing calcium oxalate urolithiasis (Lulich et al., 1998; Lekcharoensuk et al., 2002b; Stevenson et al., 2003a, 2003b, Lulich et al., 2005).

Sodium

Dry diets have been associated with a greater risk of stone formation (Lekcharoensuk et al., 2002a), particularly if the diet is low in sodium chloride. This may be due to the fact that these diets do not stimulate adequate diuresis, particularly in small-breed dogs that have been shown to eliminate smaller quantities of urine less frequently than large-breed dogs (Stevenson et al., 2001).

Research has shown that urinary calcium oxalate RSS, and therefore the risk of calcium oxalate formation, can be significantly decreased by increasing the dietary sodium content from 0.06 g/100 kcal to 0.30 g/100 kcal (Stevenson et al., 2003a).

Calcium and Phosphorus

Recommendations for dietary calcium and phosphorus levels in calcium oxalate preventative diets are changing. Previously it was advised to restrict dietary calcium and phosphorus, but recent studies suggest that this may actually promote calcium oxalate stone formation (Curhan et al., 1993; Lekcharoensuk et al., 2002a, 2002b). Restriction of dietary calcium without concomitant reduction in oxalate results in augmented intestinal absorption and urinary excretion of oxalate, which increases the risk of urolithiasis (Lulich et al., 2000; Stevenson et al., 2003a). Dietary phosphorus restriction also increases calcium absorption (Lulich & Osborne, 1995). Consequently, calcium oxalate preventative diets should not be calcium or phosphorus restricted (Curhan et al., 1993, 1997).

Protein

Dietary protein content is controversial. Previously it was recommended to lower protein content, since protein could increase calcium excretion and reduce excretion of citrate (citrate chelates calcium to form a soluble salt) (Lulich et al., 1995, 2000). However, studies indicate that higher levels of dietary protein reduced the risk of urolithiasis (Lekcharoensuk et al., 2002a; 2002b). The mechanism is unknown but may well be due to other factors, since high protein diets stimulate diuresis and also contain more phosphorus and potassium.

Urinary pH

Calcium oxalate crystals are generally not sensitive to urine pH, although pH affects the minerals that co-precipitate with calcium oxalate (Robertson, 1993). Marked acidification that induces metabolic acidosis can increase urinary calcium concentration to such extent that it promotes calcium oxalate stone formation (Lekcharoensuk et al., 2002a; 2002b). Marked alkalinization should also be avoided since it promotes calcium phosphate urolithiasis. Diets resulting in mild acidification (pH 5.5 - 6.5) and increased diuresis may reduce the risk of both calcium oxalate and struvite crystal formation, useful in breeds predisposed to both stone types (Stevenson et al., 2002).

Drug Therapy

Adjunct medical therapy is used if there is persistence of calcium oxalate crystalluria or recurrence of urolithiasis.

Potassium citrate has been useful in humans to prevent recurrent calcium oxalate urolithiasis, via its alkalinizing properties and by forming soluble salts with calcium.

Oral potassium citrate increases urine pH, which causes decreased tubular resorption of citrate, thus increasing urinary citrate excretion. However, oral administration of up to 150 mg/kg/day did not cause a consistent increase in urine citrate concentrations in healthy dogs, although it maintained a higher urine pH later in the day (Stevenson et al., 2000). There was no difference between wax matrix and powder supplements.

Hydrochlorothiazide (2 - 4 mg/kg orally BID) reduces urine calcium excretion, possibly by promoting mild volume contraction resulting in increased proximal tubular reabsorption of several solutes, including calcium and sodium (Lulich et al., 2000). Its hypocalciuric effects may be helpful in minimizing recurrence of calcium oxalate urolith formation, especially when combined with a urolith prevention diet (Lulich et al., 2001). However, long-term clinical studies are needed to confirm safety and effectiveness of prolonged administration; it has the potential to cause hypokalemia, hypercalcemia and dehydration.

Monitoring

Efficacy of therapy should initially be monitored with urinalysis (pH, specific gravity) every 2 to 4 weeks. With hydrochlorothiazidetreatment serum electrolytes should also be checked. Imaging every 6 to 12 months may help to detect any new uroliths when they are small enough to be removed non-invasively (e.g., voiding urohydropropulsion) (Lulich et al., 2000).

Urate Urolithiasis

Medical Dissolution in Dogs without Portosystemic Shunts

The chief goal in dietary dissolution of urate uroliths in Dalmatian dogs is to raise urine pH and to lower urine concentrations of uric acid, ammonium and/or hydrogen ions.

Calculolytic Diet

The dietary strategy aims at decreasing the purine content of the diet. This goal is achieved through general protein restriction (18 to 10%). However, it is possible to design a low purine diet without imposing a severe protein restriction if appropriate ingredients are selected. Fish or glandular organs, which are high in purine, should be avoided. Alternative protein sources that are relatively low in purine precursors include: vegetable proteins, eggs and dairy products (Ling & Sorenson, 1995). No other food supplements should be given. Low protein anti-uric acid diets may contain insufficient protein to sustain growth and lactation. Experimental diets have been designed that could meet both requirements (Bijster et al., 2001). As with all urolith types, feeding a canned diet, adding supplemental water to the food, or increasing the sodium content can help to increase urinary volume. In addition, low-protein diets impair urinary concentrating capacity by decreasing the medullary concentration gradient, due to the lower urea concentration in the renal medulla.

Alkalinization of Urine

Alkaline urine contains low concentrations of ammonia and ammonium ions, and thus decreases the risk of ammonium urate urolithiasis. Low-protein diets have an alkalinizing effect, but it may be necessary to administer additional urine alkalinizing agents (Lulich et al., 2000). Sodium bicarbonate (25 - 50 mg/kg every 12 hours) and potassium citrate (50 - 150 mg/kg every 12 hours) are used most commonly. The dose should be individualized to maintain a urine pH of approximately 7.0. Urine pH >7.5 should be avoided since this promotes formation of secondary calcium phosphate deposits, which will hamper stone dissolution (Bartges et al., 1999).

Xanthine Oxidase Inhibitors

Urinary urate excretion is lowered most effectively by using allopurinol, which is an inhibitor of xanthine oxidase, the enzyme responsible for catalyzing the conversion of xanthine and hypoxan-thine to uric acid (Figure 20). As a result of allopurinol therapy, xanthine and hypoxanthine concentrations in the urine increase, but urate decreases.

The medical dissolution of urate calculi includes a combination of:

• Feeding a low purine diet that has been designed to dissolve urate calculi
• Alkalinization of the urine
• Increasing urine volume
• Controlling urinary tract infections
• Administering xanthine oxidase inhibitors (allopurinol)

Allopurinol should be given in conjunction with a low-purine diet, in order to minimize the risk of xanthine stone formation (Ling et al., 1991; Bartges et al., 1999). The recommended dose for dissolution of urate uroliths is 15 mg/kg every 12 hours (Lulich et al., 2000). The dose must be reduced in patients with renal dysfunction, since allopurinol is excreted by the kidneys. A variety of adverse effects, including skin rashes, GI upsets and hemolytic anemia, have been described in humans, but these are rare in the dog. The most common adverse effect of allopurinol therapy in dogs is development of xanthine uroliths, either in pure form or as an outer shell around pre-existing urate stones. Discontinuing allopurinol and instituting a low-purine diet can sometimes dissolve xanthine uroliths (Ling et al., 1991).

Figure 20. Normal canine purine degradation.

Monitoring

During dissolution the size of the urolith(s) must be periodically monitored by survey and/or double contrast radiography, or ultrasonography. Excretory urography or ultrasonography are used to monitor dissolution of renal urate stones (Bartges et al., 1999). Time required for dissolution is highly variable and can take between 4 and 40 weeks although average length of time in one study was 14 weeks (Bartges et al 1999). Following removal or dissolution, urinalysis and ultrasonographic examination (or double contrast cystography) should be performed every 1 to 2 months for 6 months.

Even if uroliths do not reoccur the purine-restricted alkalinizing diet should be continued. Follow-up examinations can then be extended to every 2 to 4 months, and the intervals between examinations can be gradually increased.

In Dalmatian dogs, 82% of stones are urate stones (Bartges et al., 1994). (© F. Haymann).

Medical Dissolution in Dogs with Portosystemic Shunts

Little is known about the biologic behavior of urate calculi following surgical correction of portosystemic shunts. When the urolith cannot be removed at the time of shunt ligation, postsurgical medical dissolution should be considered. However, more studies are needed to compare the relative value of calculolytic diet, alkalinization and/or allopurinol in dissolving ammonium urate uroliths in dogs with portosystemic shunts.

Prevention

Dalmatian Dogs

Preventative treatment following removal or dissolution is important in Dalmatian dogs because of their high risk for urate urolith recurrence. As a first choice, low-purine diets that promote the formation of dilute alkaline urine should be fed. If urine pH is not consistently alkaline and/or crystalluria persists, alkalinizing agents may be added. Preventative treatment with allopurinol is not recommended routinely due to the risk of xanthine urolith formation, but it may be added to the protocol if difficulties persist. Long-term allopurinol therapy is not recommended.

It is not necessary to feed purine-restricted diets to Dalmatian dogs that have not had urate urolithiasis. Acidifying high-protein diets that enhance excretion of ammonium ions should however be avoided as ammonium ions are likely to get linked to urate ions to from ammonium urate crystals.

Non-Dalmatian Dogs

Recurrence of urate urolithiasis has been described in English bulldogs, and preventative measures as discussed for Dalmatian dogs should be implemented (Bartges et al., 1999). Dogs fed protein-restricted diets (10 %) long-term may develop taurine deficiency, which might lead to dilated cardiomyopathy. Commercial protein-restricted diets are therefore now supplemented with taurine (Sanderson et al., 2001a).

Cystine Uroliths

Medical Dissolution

The aim of therapy is to reduce the concentration of cystine in the urine and to increase cystine solubility. This usually requires dietary modification in combination with a thiol-containing drug.

Calculolytic Diet

Reduction of dietary protein can reduce cystine excretion, presumably because these diets contain fewer cystine precursors (Osborne et al., 1999g). However, the optimal degree of protein restriction is controversial, since cystinuric dogs also excrete carnitine and therefore have the potential to develop carnitine deficiency and dilated cardiomyopathy when fed low-protein diets. It is therefore recommended to supplement cystinuric dogs eating a protein-restricted diet with carnitine as well as taurine (Sanderson et al., 2001b).

Alkalinization of Urine

The solubility of cystine is pH dependent. It is markedly more soluble at urine pH of 7.5 - 7.8. Urine alkalinization may be achieved using a commercial moderate to low-protein alkalinizing diet. If urine pH does not become sufficiently alkaline on dietary therapy alone, additional potassium citrate may be given to sustain a urine pH of approximately 7.5 (Osborne et al., 1999g). This has to done cautiously, since alkalinization can be a risk factor for calcium phosphate urolithiasis.

Cystine uroliths can be dissolved medically, using a combination of:

• Protein-restricted alkalinizing diet
• Increasing urine volume
• Alkalinization of urine (pH around 7.5)
• Administration of thiol-containing drugs

Thiol-containing drugs

These drugs react with cystine by a thiol disulfide exchange reaction, resulting in the formation of a complex that is more soluble in urine than cystine. N-(2-mercaptopropionl)-glycine (2-MPG) is most commonly used, at a dose of 20 mg/kg twice daily orally. It has proven effec tive in dissolving cystine uroliths, especially when used in conjunction with a calculolytic diet (Lulich et al., 2000).

Time for dissolution ranges from 1 to 3 months. Side-effects are relatively uncommon; aggression, myopathy, anemia and/or thrombocytopenia have been reported, but signs resolved when the treatment was stopped (Osborne et al., 1999g; Hoppe & Denneberg, 2001). D-penicillamine is an older thiol-containing drug that has been used with some efficacy in the past, but it is no longer used due to an unacceptable number of adverse effects, including frequent hypersensitivity reactions.

Monitoring

Urolith dissolution should be monitored at 30-day intervals by urinalysis (pH, specific gravity, sediment) and serial radiography to evaluate stone location, number, size, density and shape. Contrast radiography may be used for radiolucent stones. The calculolytic diet, 2-MPG and alkalinizing therapy should be continued for at least one month following radiographic disappearance of uroliths.

Prevention

Preventative therapy is important, because cystinuria is an inherited metabolic defect and because cystine uroliths recur in most stone-forming dogs within 12 months following surgical removal. Recurrence is more likely to occur if the dog excretes large amounts of cystine. A moderate to low-protein diet that promotes formation of alkaline urine can be effective in preventing cystine urolith recurrence in dogs with low to moderate cystinuria. If necessary, dietary therapy may be combined with alkalinzation therapy to increase urinary pH and prevent cystine urolithiasis (Hoppe et al., 1993; Hoppe & Denneberg, 2001).

Treatment should be titrated to maintain a negative urine cyanide-nitroprusside test. The severity of cystinuria may decline with advancing age in some dogs; consequently, the dose of 2-MPG may be decreased or even stopped (Hoppe & Denneberg, 2001).

Calcium Phosphate Urolithiasis

Medical Dissolution

Underlying Metabolic Disease

Calcium phosphate uroliths may rarely dissolve spontaneously following parathyroidectomy for treatment of primary hyperparathyroidism. If stones are clinically silent, one might wait for this to occur before contemplating surgical or non-surgical removal. Medical dissolution is not effective in distal renal tubular acidosis.

Idiopathic Uroliths

If a specific underlying disorder is not diagnosed, calcium phosphate uroliths are removed surgically and then managed as for calcium oxalate urolithiasis (Lulich et al., 2000).

Prevention

Recognition and management of underlying contributing conditions is the first and most important step in the prevention of calcium phosphate urolithiasis. The patient should be assessed for evidence of primary hyperparathyroidism, hypercalcemia, excessive urine concentrations of calcium and/or phosphate, and inappropriately alkaline urine pH. There may also be a previous history of dietary therapy and administration of alkalinizing agents to prevent another urolith type.

If a specific underlying disorder is not diagnosed, calcium phosphate uroliths are generally managed similar to strategies used for calcium oxalate urolithiasis (Lulich et al., 2000). One should however be careful to avoid excessive urine alkalinization, which may occur with some diets used for prevention of calcium oxalate uroliths.

Calcium phosphate uroliths cannot be medically dissolved, and surgical removal is usually necessary. Correction of underlying metabolic abnormalities may minimize recurrence. If no underlying cause is found, management is similar to that of calcium oxalate urolithiasis.

Silica Urolithiasis

Prevention

Because the initiating and precipitating causes of silica urolithiasis are not well known, only nonspecific recommendations are available.

Silica uroliths may occur in dogs with pica (i.e., eating soil) or in dogs eating diets high in cereal grains containing silicates. Empiric recommendations are to change the diet to one with high quality protein and if possible reduced quantities of non nutritive plant ingredients (Osborne et al., 1999a).

As with all uroliths, increased water intake should be promoted to decrease the resulting concentration of calculogenic material in urine.

Compound Uroliths

Dissolution of compound uroliths should theoretically be aimed at implementing subsequent protocols for dissolving the various layers of the urolith, starting with the outer layer. In practice, most compound uroliths are removed surgically or by other non-surgical means. The post-removal strategy is generally aimed at preventing the reformation of the mineral that composed the core of the removed urolith, since the outer layer(s) were probably deposited secondarily due to heterogeneous nucleation (Osborne et al., 1999c).

Conclusion

Dietary modification is an important part of the management regimen for struvite urolithiasis. Diet influences the saturation of urine with struvite as it impacts urine pH, volume and solute concentration. Urine pH is the most important factor controlling struvite saturation. Reduction of urine pH through dietary manipulation is thus likely to be the most reliable means of achieving urine which is undersaturated with struvite. Restriction of dietary crystalloid intake may also be beneficial, although changes in urinary magnesium or phosphate concentration individually, have much less impact on struvite saturation than changing urine pH.

Following removal of compound (mixed) uroliths, medical dissolution strategies are usually based on preventing the reformation of the mineral that composed the core of the compound urolith.

The goal of dietary management for calcium oxalate urolithiasis is to create urine that has a low saturation with calcium oxalate. Ideally, urine should be undersaturated as new crystal formation cannot occur under these circumstances; however, this may be difficult to achieve in some patients. Homogeneous crystal formation will not occur, and heterogeneous crystal formation is unlikely to occur, in the lower part of the metastable zone of supersaturation. Therefore this represents a reasonable target that should reduce the risk of recurrence in patients.

Enhancing urine volume for a given solute load will also reduce saturation, as it will decrease the concentrations of crystalloids. In addition, increasing urine volume may influence crystal transit time through the urinary tract, thus reducing the potential for crystal growth.