Improving management of urolithiasis: canine struvite uroliths

Magnesium ammonium phosphate (MAP, also called struvite) comprised 41 percent of 28,629 canine uroliths submitted to the Minnesota Urolith Center during the year 2003 (Table 1).

Table 1: Quantitative mineral composition of 28,629 canine uroliths -- 2003

Calcium oxalate comprised 40 percent of the canine uroliths submitted. Almost all struvite uroliths encountered in dogs occur as a consequence of infection of the urinary tract with urease producing microbes (especially staphylococci). Unlike cats, where >95 percent of the struvite uroliths are linked to urinary excretion of excessive quantities of dietary minerals (so-called sterile struvite), we estimate that <2 percent of the canine struvite uroliths form under sterile conditions.

The objective of this continuing series is to provide insight into the risks and benefits associated with therapeutic strategies designed to dissolve and prevent recurrence of canine infection-induced MAP uroliths. Therapeutic caveats associated with other types of uroliths will be the subject of future Diagnotes.

Carl A. OsborneDVM, Ph.D., Dipl. ACVIM

Prevalance

1. Infection-induced struvite uroliths may form in any breed of dog. Struvite uroliths formed by more than 160 breeds have been evaluated at the Minnesota Urolith Center including mixed breeds (25 percent), Miniature Schnauzers (12 percent), Shih Tzus (9 percent), Bichon Frises (7 percent), Cocker Spaniels (5 percent) and Lhasa Apsos (4 percent).

2. Struvite uroliths are more common in females (85 percent) than males (15 percent). Mean age of affected dogs is 6 years (range <1 to >19 years).

3. Struvite uroliths are more commonly retrieved from the lower urinary tract (95 percent) than from the upper urinary tract (5 percent).

4. Approximately two-thirds of uroliths detected in immature (<12 months of age) dogs are composed of infection-induced struvite.

Etiology

5. Urine must be oversaturated with MAP for struvite uroliths to form and supersaturated with MAP for struvite uroliths to grow. Although oversaturation of urine with MAP may be associated with several factors, the most important are 1) urinary tract infections (UTI) with urease producing bacteria, and 2) formation of urine with large quantities of urea (Table 2). Increased excretion of magnesium, ammonium, and phosphorus may increase the risk of stone formation; however, this is not required for initiation or growth of infection-induced struvite.

6. Urease in vertebrates must be derived from microbes (some bacteria, some yeasts or urea plasmas). Urease produced by microbes hydrolyzes urea to ammonia. Subsequent formation of ammonium ion reduces hydrogen concentration and results in increased urine pH.

7. The majority of urea in urine originates from dietary protein. In addition, diets high in protein are high in phosphorus (Table 2).

Table 2: Some Potential Risk factors for Canine Infection Induced Struvite

8. UTIs caused by urease producing microbes (frequently staphylococci; infrequently Proteus spp. and ureaplasma) in dogs that are excreting urine with sufficient quantities of urea results in significant alkalinity associated with increased quantities of ammonia and ammonium ion, phosphate ion and carbonate ion. These changes increase the risk of rapid formation of uroliths containing primarily struvite, with smaller quantities of calcium phosphate (so-called calcium apatite) and calcium carbonate phosphate (so-called) carbonate apatite.

9. The proportions and locations of calcium apatite and carbonate apatite minerals within struvite uroliths vary depending on the urine concentrations of these minerals, urine pH, and probably other factors. If layers of calcium phosphate precipitate to form a layer around struvite, they can impede medical dissolution of struvite.

10. The solubility of struvite, calcium apatite and carbonate apatite decreases in alkaline urine. In contrast, struvite crystals typically dissolve if the urine pH is less than 6.3.

11. In addition to contributing to the formation of MAP, high concentrations of ammonium cations bind to negatively charged sulfate groups contained in the protective glycosaminoglycan (GAGS) layer coating the mucosal surface of the urinary tract. As a consequence, struvite crystals may adhere to the mucosa, facilitating their retention and growth within the urinary tract. Damage to the protective GAGS layer by high concentrations of ammonia may also result in increased adherence of bacteria to the mucosal surface of the urinary tract.

12. Bacteria that become trapped within the matrix of struvite uroliths may remain viable for long periods. In this location, they are often protected from the effects of antimicrobial drugs. Therefore, when dissolving struvite uroliths by medical protocols, antimicrobial drugs should be administered as long as the uroliths can be identified by survey radiography. Although the urine and surface of uroliths may be sterilized following appropriate antimicrobial therapy, viable microbes may remain below the surface of the urolith. This observation is of clinical importance because premature discontinuation of antimicrobial therapy may result in relapse of bacteriuria and reduced efficacy of dietary therapy.

Biological behavior

13. Infection-induced uroliths can form within a few days to a few weeks following infection of the urinary tract with urease- producing microbes. Struvite uroliths associated with UTIs caused by staphylococci or Proteus spp have been detected in puppies as young as 5 weeks of age.

14. Fueled by a constant supply of urea from dietary protein and urease from microbes, struvite crystals can rapidly grow to form uroliths that fill the lumen of the urinary bladder or renal pelvis. The rapid rate at which uroliths form and the potential they have to migrate to lower portions of the urinary tract are of clinical importance. If several days have elapsed between the date of diagnostic radiography and the date of surgery scheduled to remove uroliths, the number and location of stones should be reevaluated by radiography or ultrasonography.

15. Struvite uroliths have a tendency to recur following surgical removal or medical dissolution. Most episodes of recurrence are associated with lack of removal of all uroliths at the time of surgery (pseudorecurrence) or poor control of recurrent UTIs with urease producing microbes. The key to preventing recurrent infection-induced struvite uroliths is to eradicate or control UTIs.

Dissolution therapy

16. Prior to attempting dissolution, perform diagnostic studies (urinalysis, urine culture, radiography, analysis of voided stones, etc.) to evaluate urolith size and location, as well as confirmation of urolith composition.

17. Urethroliths and ureteroliths cannot be dissolved by the medical protocols. Medical therapy designed to induce urolith dissolution by changing the composition of urine will be ineffective for stones in the urethra and ureters because they are only intermittently exposed to urine that is undersaturated with struvite.

18. The importance of UTIs with urease-producing bacteria in formation of struvite uroliths emphasizes the necessity of therapy to eliminate or control them. By eliminating the infection, the urine typically becomes less alkaline with a concomitant increase in solubility of MAP.

19. We recommend antimicrobial drugs selected on the basis of antibiotic dilution susceptibility tests designed to determine minimum inhibitory concentrations (MIC) of antimicrobial drugs in urine. Preference is given to bacteriocidal drugs excreted in high concentration in urine, and with a wide margin of safety between therapeutic and toxic doses. The fact that diuresis reduces the urine concentration of antimicrobic agents should be considered when formulating drug doses. The goal is to establish a dose so that the quantity of drug present in urine is greater than four times the MIC.

20. Therapeutic doses of antimicrobics should be administered until there is radiographic evidence of complete dissolution of uroliths. This recommendation is based on the fact that bacterial pathogens harbored inside uroliths may be protected from antimicrobial agents.

21. Because of the large quantity of urease produced by struvitogenic microbes, it may be impossible to acidify urine with urine acidifiers administered as doses do not result in systemic acidosis. We do not use urine-acidifying drugs in our medical protocols for dissolution of infection-induced uroliths.

22. Antimicrobial therapy alone is usually ineffective in dissolving infection-induced struvite uroliths. However, a combination of antibiotics and dietary modification has been very effective. We evaluated a high moisture (canned) struvitolytic diet formulated to contain a reduced quantity of high-quality protein and reduced quantities of phosphorus and magnesium (Prescription Diet Canine s/d; Hill's Pet Nutrition).

The diet was supplemented with sodium chloride to stimulate thirst and induce compensatory polyuria. In addition, reduction of dietary protein reduces renal medullary urea concentration and further contributes to diuresis. The efficacy of this diet in inducing dissolution of infected struvite uroliths was been confirmed by controlled experimental and clinical studies.

In our studies, the mean time for dissolution of naturally occurring infection induced urocystoliths in dogs fed the struvitolytic diet and appropriate antimicrobics was approximately three months (range equals two weeks to seven months).

23. Consumption of the struvitolytic diet by young adult dogs with staphylococcal urinary tract infection and struvite uroliths was associated with a marked reduction in the serum concentration of urea nitrogen and mild reductions in the serum concentrations of magnesium, phosphorus and albumin. A mild increase in the serum activity of hepatic alkaline phosphatase isoenzyme also was observed.

These alterations in serum chemistry values were of no detectable clinical consequence during six-month experimental studies or during clinical studies. However, they underscore the fact that the diet is designed for short-term (weeks to months) dissolution therapy rather than long-term (months to years) prophylactic therapy. Reduction in concentrations of serum urea nitrogen may be used as one index of client and patient compliance with dietary recommendations.

Monitoring response

24. Efficacy of therapy should be periodically monitored (every two to four weeks) by evaluating appropriate indices of therapeutic response. These typically include timely urinalyses, urine cultures, serum biochemical profiles, and radiography or ultrasonography (Table 3, p. 8S). Therapy should be adjusted to meet each individual patient's needs.

Table 3: Characteristic clinical findings before and following initiation of medical therapy to dissolve struvite uroliths in nonazotemic dogs

25. The number, size and location of uroliths should be monitored by survey radiography, and if necessary by contrast radiography. Although retrograde double contrast cystography is more sensitive in identifying small urocystoliths, survey radiography is usually preferable because use of catheters during retrograde radiographic studies may result in iatrogenic UTI. Alternatively, ultrasonography or intravenous urography may be considered.

26. Because stuvitolytic diets promote diuresis, clients should be informed that the magnitude of pollakiuria in dogs with urocystoliths may increase for a short time following initiation of dietary therapy. However, pollakiuria and abnormal odor of urine caused by bacterial degradation of urea usually subside as the infection is controlled and uroliths decrease in size.

27. Large urocystoliths that decrease in size as a result of dissolution have the potential to pass into the urethra where they may cause partial or total outflow obstruction. This has been an uncommon problem in our experience because proper treatment results in decreased dysuria, pollakiuria and tenesmus. Movement of urocystoliths into the urethra is most likely to occur in patients with substantial dysuria and tenesmus, or in patients with uethral strictures. Clients should be given a written summary of clinical manifestations of impaired urine flow through the urethra so that if this problem occurs, it can be quickly recognized and corrected. Urethroliths may be readily returned to the urinary bladder lumen by urohydropropulsion. If warranted, tenesmus and dysuria may then be temporarily suppressed by giving drugs that reduce pain and/or cause muscle relaxation.

28. Since small (<3 mm in diameter) struvite uroliths may escape detection by survey radiography or ultrasonography, we recommend that calculolytic diet and (if necessary) antimicrobial agents be continued for approximately one month following radiographic documentation of urolith dissolution.

If urinalysis results are normal, dissolution therapy may be discontinued. This maneuver is likely to prevent rapid recurrence of bacterial UTI and radiographically detectable uroliths following cessation of therapy.

Poor response to therapy

29. Difficulty in inducing complete dissolution of uroliths by creating urine that is undersaturated with MAP should prompt consideration that:

1) the wrong mineral component was identified;

2) the nucleus of the uroliths of different mineral composition than outer portions of the urolith; and/or,

3) the owner or the patient is not complying with therapeutic recommendations.

30. Noncompliance with diet and/or antimicrobial drug recommendations can be expected to be associated with poor treatment outcomes. In our experience, veterinarians and their staff typically overestimate rates of compliance among their clients, and are also unable to identify noncompliant individuals. Therefore, special effort should be made to educate clients about the reasons why special diets and drugs are being given, and the expected outcome if they are unable or unwilling to comply with the dissolution protocol. Consult Table 3, p. 8S for a summary of expected changes in clinical, laboratory and radiographic findings during and following successful therapy.

31. In most situations, the expectation of full compliance with diet recommendations may be unrealistic. Clients should be advised of what types of "treats" will have minimal impact on the success of therapy, and the types of treats that will significantly reduce the likelihood of urolith dissolution. In general, less than full compliance is acceptable to us, as long as the desired therapeutic benefit can safely be achieved in an appropriate time.

32. Clients should be educated about the importance of antimicrobial drug therapy for bacterial UTI. The dosage of antimicrobic and the frequency with which it is administered should be devised in cooperation with the client's input of what is realistic for them.

Precautions

33. In patients with concomitant disease and those at high risk for adverse events associated with consumption of struvitolytic diets, serum biochemical profiles and other monitoring procedures may be warranted.

34. The struvitolyic diets are relatively high in fat, which serves primarily as a source of calories. Because dietary fat is a risk factor for pancreatitis, patients known to be at higher risk for pancreatitis should be carefully evaluated prior to dissolution therapy, and closely monitored during dissolution therapy. We emphasize that Miniature Schnauzers are at increased risk for infection-induced struvite uroliths, lipid abnormalities and pancreatitis.

Likewise, patients with hyperadrenocorticism are at increased risk for UTI (which could include staphylococci) and pancreatitis. Although risk factors are not to be considered as synonymous with cause and effect, clients should be informed of these associations and advised of how to respond to adverse events if they occur. They should be informed of adverse events that need medical attention and those that need medical attention only if they continue or are bothersome.

35. The diet (Prescription Diet Canine s/d, Hill's) designed to dissolve canine struvite uroliths is restricted in protein and supplemented with sodium chloride. Both could affect fluid balance. Therefore, it should not be routinely given to patients with concomitant diseases associated with positive fluid balance (heart failure, nephrotic syndrome, etc.) or hypertension.

Prevention

36. Infection-induced struvite uroliths will not form in the absence of urease-positive microbial infections. Therefore, perform appropriate diagnostic studies with the goal of detecting and eradicating or controlling bacterial UTI. We emphasize that eradication or control of UTI by urease-producing bacteria is the most important factor in preventing recurrence of most infection-induced struvite uroliths.

36. In context of the effectiveness of diets in inducing dissolution of struvite uroliths, use of dietary modification to minimize recurrence of uroliths is logical and feasible. Studies are in progress to evaluate the preventative efficacy of mild to moderate restrictions in protein, magnesium and phosphorus of acidifying diets.