Medical Dissolution and Prevention of Canine Struvite Urolithiasis

CANINE UROLITHIASIS

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MEDICAL DISSOLUTION AND PREVENTION OF CANINE STRUVITE UROLITHIASIS Twenty Years of Experience Carl A. Osborne, DVM, Jody P. Lulich, DVM, David J. Polzin, DVM, Timothy A. Allen, DVM, John M. Kruger, DVM, Joseph W. Bartges, DVM, Lori A. Koehler, CVT, LisaK. Ulrich, CVT, Kathleen A. Bird, CVT, and Laura L. Swanson, CVT

The term struvite is an eponym coined by a Swedish geologist in 1845 in honor of H.C.G. Von Struve, a Russian diplomat and naturalist. 32 Struvite uroliths are primarily composed of magnesium ammonium phosphate hexahydrate (MgNH,PO. X 6H20). Struvite uroliths are also referred to by the acronym "MAPs" to emphasize their mineral composition (see Appendix 1). Struvite uroliths have been erroneously termed triple phosphate uroliths. Triple phosphate is of historical interest in that the term was coined on the basis of nonspecific qualitative chemical analyses of uroliths which revealed the cations calcium, magnesium, and ammonium as well as the anion phosphate. The term triple referred to the three cations that were thought to combine with anionic phosphate (POl-). The name is a misnomer, because struvite does not contain calcium; however, canine struvite uroliths are frequently impure and may contain minor quantities of calcium phosphate and calcium carbonate phosphate. Combinations of struvite, calcium phosphate, and calcium carbonate phosphate in the same urolith cannot be differentiated by chemical methods of analysis. Physical methods of analysis with appropriate techniques are required to identify and quantify these mineral types. Names given to emphasize the etiopathogenesis of MAPs include "infection stones," "urease stones," and "urea stones."

From the Minnesota Urolith Center, Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota

VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME 29 • NUMBER 1 • JANUARY 1999

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WHAT IS THE CURRENT PREVALENCE OF CANINE STRUVITE UROLITHS? Prevalence at the Minnesota Urolith Center

Although trends in the prevalence of different types of canine uroliths have been changing, the most common type of mineral encountered in uroliths of dogs remains as magnesium ammonium phosphate hexahydrate. Struvite accounted for 50% (38,285 of 77,191 cases) of all canine uroliths submitted to the Minnesota Urolith Center from 1981 through 1997 and 45% (6,923 of 15,259 cases) of all canine uroliths submitted during 1997. Struvite accounted for 33% (264 of 797 cases) of canine nephroliths analyzed at the Minnesota Urolith Center from 1981 through 1997. Urolithiasis is most commonly recognized in adult dogs; however, 1.2% (950 of 77,196 cases) of the canine uroliths analyzed at the Minnesota Urolith Center were obtained from dogs that were less than 12 months old. In those uroliths retrieved from immature dogs, quantitative analysis revealed that 61% (580 of 950 cases) were struvite uroliths. Thus, infection-induced struvite is the most frequent type of urolith encountered in immature dogs. At the Minnesota Urolith Center, canine urolith submissions outnumber feline urolith submissions by a ratio of 5:1. This observation is of value, because, in general, canine struvite uroliths remain the most common stone type encountered at companion animal veterinary facilities.

Age, Breed, and Gender Prevalence

In our series, the mean age of dogs at the time of MAP retrieval was 6.0 ± 2.9 years (range, 1 month to 19 years). Female dogs (85%) were affected more often than male dogs (15%). One hundred fifty-seven different breeds were affected, including mixed breed (25%), Miniature Schnauzers (12%), Shih Tzus (9%), Bichons Frises (7%), Miniature Poodles (5%), Cocker Spaniels (5%), and Lhasa Apsos (4%).

Location and Architecture

Struvite uroliths were more commonly retrieved from the lower urinary tract (95%) than from the upper urinary tract (5%). As summarized in Appendix 1, canine struvite uroliths form in a variety of sizes and shapes. Spherical and pyramidal shapes are common as is a smooth surface (Fig. 1). Struvite that forms around foreign material may initially take on the shape of that material. Most large radiodense uroliths in dogs are composed primarily of infection-induced struvite (Fig. 2). The overlap in gross appearance between struvite and other stone types as well as the fact that struvite stones may contain more than the mineral precludes a specific diagnosis of mineral type on the basis of gross architecture. On the other hand, isolation of staphylococci or Proteus spp from the urine is presumptive evidence that at least the outer portion of a urolith is composed of struvite. Consult the article on the analysis of 77,000 canine uroliths in this issue for additional information.

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Figure 1. Naturally occurring uroliths formed by eight different dogs illustrating variations in size, shape, and surface characteristics. 1, Struvite nephroliths that have formed a cast of dilated renal pelves. 2, Small pyramidal-shaped struvite urocystoliths. 3, Small sand-like struvite urocystoliths. 4, Huge struvite urocystolith. 5, Larger pyramidal shaped struvite urocystoliths. 6, Spherical struvite urocystolith. 7, Discoid struvite urocystolith. 8, Spherical and pyramidal struvite urocystoliths and urethroliths.

WHAT IS KNOWN ABOUT ETIOPATHOGENIC FACTORS? Overview

In order to develop safe and effective treatment and prevention protocols for struvite urolithiasis, abnormalities in dogs that promote urolith formation must be identified with the goal of eliminating or modifying them. It is therefore necessary to be familiar with the etiology and pathogenesis of the two recognized forms of struvite urolithiasis: those caused by infections and those whose formation is not linked to infections. How Do Infection-Induced Struvite Uroliths Form? Summary

Urine must be oversaturated with MAP for struvite uroliths to form (socalled "nucleation") and supersaturated with MAP for uroliths to grow (consult the article on the effectiveness of treatment of uroliths in this issue for further information about the concepts of nucleation and supersaturation). Supersaturation and oversaturation of urine with MAP are associated with several factors, including (1) urinary tract infections (UTis) with urease-producing microbes, (2)

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Figure 2. Lateral view of the abdomen of a 9-year-old spayed female German Shepherd Dog with hundreds of variable size struvite urocystoliths. This dog also had a Staphylococcus intermedius urinary tract infection.

urea, (3) alkaline urine, and (4) dietary metabolites. In some cases, a genetic predisposition may be a risk factor (Table 1). Depending on dietary factors and the volume of urine produced, the quantity of magnesium and phosphate normally present in urine could be sufficient to form struvite crystals. Nevertheless, they usually do not form, because urine from dogs is usually undersaturated with respect to MAP. Only when sufficient

Table 1. SOME POTENTIAL RISK FACTORS FOR CANINE INFECTION-INDUCED STRUVITE Diet

High protein (source of urea) Urine alkalinizing High phosphorus High magnesium Low moisture Others?

Urine

Metabolic

Drugs

Urease-positive UTI High urea concentration H yperarnrnonuria High ionic phosphorus High magnesium High pH Retention of urine Concentration of urine and thus calculogenic substances

Female gender Breed Miniature Schnauzer Shih Tzu Bichon Frise Miniature Poodle Cocker Spaniel Lhasa Apso Hyperadrenocorticism associated bacterial UTI

Glucocorticoidassociated bacterial UTI

UTI = urinary tract infection.

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ammonia (NH3), bicarbonate (HC03), and sometimes carbonate (C03-) are produced by UTis with urease-producing microbes does urine become oversaturated with the components found in struvite uroliths. Along with struvite, urine may also become oversaturated with calcium phosphate (also called calcium apatite [Ca10 (P04 ) 6 (0H) 2 ]) and, with extreme alkalinity, with calcium carbonate phosphate (also called carbonate apatite [Ca10(P04 X C030.)o(OH)2]). What Are Normal Sources of Urine Ammonia and Ammonium?

Urine ammonium (NH4 +) concentration normally rises when acid catabolites in blood are excreted at a high concentration by the kidneys. The rise in urine concentration of NH4 + in this situation represents a normal compensatory response by the renal tubular cells to secrete NH3 into tubular lumens to reduce acidity by combining with H + (hydrogen ions) in tubular fluid to form NH. +. Whereas NH3 is lipid-soluble and can penetrate tubular cell walls to gain access to tubular lumens, NH. + is lipid-insoluble and cannot penetrate cell walls to return to the body (so-called "ion trapping"). As a result, NH3 buffers H+ to form NH4 + and is excreted in urine. In contrast, excretion of alkaline urine under physiological conditions is associated with reduced renal production of NH3 and thus reduced urine concentration of NH4 +. In general, struvite crystals dissolve if the urine pH is less than 6.3. Once formed, struvite crystals may be maintained at urine pH values that approach 7.0. Struvite crystals form most rapidly at pH values greater than 7.0. Logically, NH3 generated by renal tubular epithelial cells in response to renal excretion of acids is not likely to be a significant component of the infection-induced struvite uroliths that form in alkaline urine. When UTI with urease-producing microbes (e.g., staphylococci) occurs in urine with a sufficient quantity of urea, hydrolysis of urea results in hyperammonuria, even when the pH of glomerular filtrate and renal tubular fluid is alkaline. What Steps Are Involved in the Formation of Struvite Crystals?

Summary. When a UTI with urease-producing staphylococci, ureaplasma, and some fungi occurs in urine with a sufficient quantity of urea, a unique combination of concomitant elevation in the concentrations of NH. +, HC03, and C03- develops in an alkaline environment. Increased concentrations of NH. + are generated regardless of the quantity of acid metabolites excreted by the kidneys. These conditions favor formation of uroliths containing struvite, calcium apatite, and sometimes carbonate apatite. The following mechanisms are involved in the formation of struvite crystals (Figs. 3 and 4) 17• 23· 84 : Urease-Mediated Production of Ammonium. Microbial urease hydrolyzes urea to form two molecules of NH3 and one molecule of carbon dioxide (see Fig. 3). The NH3 molecules react spontaneously with water to form NH. + and OH- (hydroxyl ions) (pK of NH3 = 9.03), which alkalinizes urine by decreasing H+ concentration. Struvite and calcium apatite are less soluble in alkaline urine. 27• 80 In addition to alkalinization of urine, the newly generated NH4 + is available for incorporation into struvite crystals. The quantity of urea and urease present in urine are the rate-limiting factors in this sequence of events. The NH. + ions may also adhere to negatively charged sulfate groups contained in the protective glycosaminoglycan (GAGS) layer coating the mucosal surface comprised of urothelial cells (see Fig. 3). The resulting impairment of the protective hydrophilic activity of GAGS allows struvite crystals to adhere to the mucosa, facilitating their retention and growth within the urinary tract.

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URINARY EXCRETION Excess

~

Mg2+

BACTERIAL UREASE

H20

GAGS Figure 3. Bacterial urease-mediated ureolysis resulting in formation of magnesium ammonium phosphate crystals. The negatively charged glycosaminoglycan (GAGS) layer coating epithelial cells has attracted the positively charged ammonium ion resulting in adherence of the struvite crystal to the mucosal surface (see text).

By generating toxic quantities of NH3 , urease production contributes to the virulence of the uropathogens that produce this enzyme in the following way. 7• 52• 71 • 75 Continued production of NH3 and perhaps other reactants as a consequence of urease-induced ureolysis is toxic to urothelium and adjacent tissues. As a result, a compensatory acute inflammatory response occurs which involves the walls of the urinary tract and urine. 22• 38• 39 The associated increase in urine concentration of proteinaceous inflammatory products contributes to calculogen-

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URINARY EXCRETION

BACTERIAL UREASE

H20 + 2NH3

BACTER.IALlH 2 0 UREASE

Urea Figure 4. Bacterial urease-mediated ureolysis resulting in formation of calcium phosphate and carbonate apatite. Calcium phosphate and carbonate apatite may also be found in infection-induced struvite uroliths.

esis by acting as a component of urolith matrix. If the inflammatory response is substantial, inflammatory reactants may be incorporated into growing uroliths as nonmineralized matrix. This provides a plausible explanation of the variability of radiographic density among different infection-induced struvite uroliths and within different regions of the same urolith. Bacteria are also dispersed throughout the matrix (Figs. 5 and 6)_11· 63 • 69, ?s Urease-Mediated Anionic Phosphate. In the progressively alkaline environment induced by microbial hydrolysis of urea, consumption of H + from dissociation of monobasic hydrogen phosphate (H2P04 -) results in an increased concen-

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Figure 5. Infection-induced struvite urocystolith with a foxtail nidus surrounded by layers of struvite each with different quantities if struvite and matrix.

tration of dibasic hydrogen phosphate (HP04 ~) and then P04 3 - (see Fig. 3). Given a constant concentration of total phosphate, a change in pH from 6.80 to 7.40 increases the P043 - concentration by a factor of approximately 6.2• 5• 59 P043 is then available in increased quantities to combine with Mg2 + and NH4 + to form struvite (Mg2 + NH4 + PO/ - ). What Steps Are Involved in the Concomitant Formation of Calcium Phosphate and Calcium Carbonate Phosphate Crystals?

The following mechanisms are involved in the concomitant formation of calcium phosphate (so-called "calcium apatite") and calcium carbonate phosphate (also called carbonate apatite). • Urease-mediated PO/ - . As is the case with the formation of struvite, in the progressively alkaline environment induced by microbial hydrolysis of urea, dissociation of H 2P04 - results in an increased concentration of HPO. ~ and POl- (see Fig. 4). The POl- is then available in increased quantities to combine with calcium excreted in urine to form calcium apatite. • Urease-mediated carbonate ion . The new ly generated molecule of carbon dioxide combines w ith water to form carbonic acid which, in turn, dissociates to form HC03 (pK = 6.33) and H + (see Fig. 4). In an extremely alkaline environment, HC03 may lose its proton to become Co3 ~ (pK = 10.1). Anions of C03 ~ may displace anions of POl · in calcium apatite crystals to form carbonate apatite crystals. The proportions and locations of calcium apatite and carbonate apatite minerals within struvite uroliths vary depending on the urine concentrations of the components of these minerals, urine pH, and probably other factors. If layers of calcium phosphate precipitate around struvite, they can impede m edical dissolution off struvite (Figs. 7 and 8). 14

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Figure 6. Transmission electron micrograph of a struvite urocystolith removed from an adult female Beagle. The clear paces were occupied by struvite crystals. Note numerous staphylococci in the matrix of the urolith, some of which are exposed at the matrix-crystal interface (original magnification X 5000).

What Is Newberyite?

Following exposure to air or formalin, struvite can lose water and NH 3 and change into magnesium hydrogen phosphate trihydrate (also called "newberyite" in honor of James Cosmos Newbery, an Australian geologist. Although newberyite is apparently not a primary constituent of human uroliths,79 we have occasionally (14 of 77,191 uroliths) encountered it in naturally occurring canine uroliths. The precise events leading to the formation of magnesium hydrogen phosphate trihydrate uroliths in dogs are unknown to u s. From a clinical point of view, we manage newberyite uroliths as we would manage struvite uroliths. How Important Is the Urine Concentration of Microbial Urease in the Formation of Infection-Induced Struvite Uroliths?

Infection-induced struvite uroliths cannot form in the absence of a su fficient urine concentration of urease (or urea). Urease (molecular w eight ± 483,000 d) is essential for (1) production of NH,, HC03 , and C03 from urea (Fig. 3); (2) urine alkalinization; and (3) subsequent precipitation of struvite, calcium apatite, and carbonate apatite crystals. Urease in vertebrates must be derived from microbes (some bacteria, some yeasts, or ureaplasmas).n 24• 37• 43 Urease-producing bacteria hydrolyze urea to NH3 and assimilate the NH3 into glutamate and glutamine to meet their metabolic requirements.80 Because of the importance of urease in the etiopathogenesis of struvite urolithiasis in m an and many animals, the terms urease stones and infection stones

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Figure 7. Laminated urocystolith removed from the urinary bladder of a 2-year-old spayed Bichon Frise. The nidus (n) was composed of 10% calcium apatite, 155 ammonium urate, and 75% struvite. The stone (s) was composed of 15% calcium apatite and 85% struvite. The shell (L) was composed of 75% calcium apatite and 25% struvite. The surface crystals (c) were composed of 75% calcium apatite and 25% struvite.

have been proposed. 23 Because of the importance of urea as the substrate of urease, the term urea stones would also be appropriate. 63 What Types of Microbes Are Associated with Canine Struvite Urolithiasis ?

Clinical and experimental studies of dogss· 9 • 11• 16• 34• 35• 63 have repeatedly demonstrated a close relationship between the formation of struvite uroliths and UTis caused by urease-producing bacteria. Staphylococcus intermedius and Proteus spp are consistent and potent urease producers and have been commonly isolated from dogs with infection-induced struvite uroliths. 22• 23• 4 " · 58 For reasons that are unexplained, staphylococci have been more commonly associated with struvite uroliths in dogs than Proteus spp (see Table 1)/· 11• 16• 59 whereas Proteus spp are more commonly associated with struvite uroliths in human beings.15• 24• 44• 7" In studies of dogs performed at the University of Minnesota, w e had better success in inducing struvite uroliths with clinical isolates of staphylococci than with Proteus spp. Results of studies in rats were interpreted to indicate that different strains of staphylococci have different calculogenic potentiaU9 Although other microbes such as Klebsiella spp and Pseudomonas spp have the potential to produce varying quantities of urease, they have not been as

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Figure 8. Lateral view of the abdomen of a 7-year-old spayed female Pug with a urocystolith composed of a mixture of struvite and calcium phosphate. The central portions of the urolith were 95% struvite and 5% calcium phosphate. The outer layer was composed of 70% struvite and 30% calcium apatite.

commonly associated with initiation of struvite urolith formation in humans or dogs. 23• 48 Likewise, Escherichia coli and other nonurease-producing microbes have not been linked to naturally occurring struvite uroliths, presumably because they infrequently produce urease.23 Nevertheless, it has been reported that urease is plasmid-encoded and that it therefore can be transferred from one microbe to another. 21• 84 Bacteria that become trapped within struvite uroliths may remain viable for weeks (see Fig. 6). Several studies have revealed that calculogenic bacteria harbored within uroliths are protected from the destructive effects of antimicrobial agents in urine. 19 • 56• 74• 81 Therefore, when dissolving struvite uroliths by medical protocols, antimicrobial drugs should be administered as long as the uroliths can be identified by survey radiography.57 Although the urine and surface of uroliths may be sterilized following appropriate antimicrobial therapy, the original and secondary infecting organisms may remain viable 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 UTis. After the formation of struvite uroliths in dogs as a result of staphylococcal UTis, the bacterial flora of urine surrounding the urolith(s) may change. Risk factors that may be associated with a change in bacterial flora (a form of recurrent UTI due to reinfection) include (1) damage to local host defense mechanisms by uroliths, (2) iatrogenic infection induced by urinary catheters, and (3) administration of antimicrobial agents with the suppression of susceptible bacteria and emergence of resistant bacteria. A small percentage of dogs with struvite urolithiasis have sterile urine. In some of these cases, however, bacteria have been isolated from the inside of uroliths. This observation indicates that bacterial infection of the urinary tract may undergo spontaneous remission after initiating urolith formation in some patients. In contrast to struvite uroliths, bacterial UTI is not a consistent finding in

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dogs with nonstruvite uroliths (e.g., ammonium urate, calcium oxalate, cystine, silica). 48 When infection does occur in association with these so-called "metabolic uroliths" it appears to be a sequela rather than a predisposing cause of urolith formation. What Role Does Ureaplasma Play in Infection-Induced Struvite Urolithiasis?

Ureaplasmas differ from all other mycoplasmas by their production of urease and therefore their ability to hydrolyze urea. 18• 78 Urea is required for growth of these organisms. Struvite urocystoliths have been rapidly produced in male rats by intrarenal or intravesical injection of urease-producing ureaplasmas isolated from human beings. 21 • 41 Ureaplasma urealyticum has also been isolated from struvite uroliths removed from the renal pelves of human patients. 27• 68 It could not be isolated from renoliths composed of calcium oxalate, calcium phosphate, or uric acid. We have repeatedly isolated large numbers of ureaplasma from an adult female Basset Hound with uroliths presumed to be composed of struvite and located in the renal pelves and urinary bladder (C.A. Osborne, unpublished data, 1987). 60 Although the urine from this dog contained urease, attempts to culture urease-producing bacteria from her urine were unsuccessful. Efforts at the University of Minnesota to isolate ureaplasma from urine of other dogs with nonbacterial struvite uroliths have been unsuccessful. Further studies are desirable, however, because ureaplasmas are fastidious and cell associated. Factors reported to limit growth of ureaplasmas in broth cultures include pH over 7.5/ 8• 40• 78 osmotic activity more than 600 m0sm/kg30 and high NH3 concentration. 18• 75 What Role Does Diet Play in Infection-Induced Struvite Urolithiasis?

In addition to microbial urease, urea (the substrate of urease) is required for NH3 production, alkalinization, supersaturation, and the subsequent precipitation of struvite crystals. The majority of urea in urine originates from dietary protein. In addition, diets high in protein are also high in phosphorus (see Table 1). The high concentration of urea and phosphorus normally present in the urine of individuals who consume dietary protein in excess of daily requirements for protein anabolism makes urine an environment well suited to support the calculogenic effects of urease-producing microbes. What Role Does Genetics Play in Infection-Induced Struvite Urolithiasis?

The high incidence of struvite urolithiasis in some breeds of dogs such as Miniature Schnauzers suggests a familial tendency (see Table 1). We hypothesize that susceptible Miniature Schnauzers inherit some abnormality of local host defenses of the urinary tract that increases their susceptibility to bacterial UTis. 34• 35 Hereditary factors thought to be associated with inbreeding have been reported to increase the incidence of struvite uroliths in Beagles. 29 The incidence of struvite uroliths was 10.7% in an inbred line of Beagles compared with only 2.0% in an outbred line of Beagles.

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How Do Sterile Struvite Uroliths Form? Overview

Clinical studies indicate that microbial urease is not involved in formation of struvite uroliths in some dogs_<, 6, 69 Several observations suggest that dietary or metabolic factors may be involved in the genesis of sterile struvite uroliths in these species, Pilot studies of clinical cases of struvite uroliths in dogs at the University of Minnesota revealed a population of patients (9 of 20 dogs) whose urine was frequently alkaline but did not contain identifiable bacteria and did not contain detectable quantities of urease, Light and transmission electron microscopic examination of some demineralized struvite uroliths removed from dogs with bacteriologically sterile urine revealed no gram-positive bacteria (Fig, 9) (CA. Osborne, unpublished data, 1987)_11 Whereas infection-induced human struvite uroliths frequently contain calcium apatite or carbonate apatite, a large number of the canine sterile uroliths were 100% struvite, In this regard, they are similar to the sterile struvite uroliths that form in cats, What Role Does Diet Play in Sterile Struvite Urolithiasis?

Although not validated by experimental or clinical studies in dogs, lowmoisture (dry) alkalinizing diets high in magnesium and phosphorus would be expected to predispose to sterile struvite urolith formation in susceptible dogs,

Figure 9. Transmission electron micrograph of a sterile struvite urocystolith removed from an 8-year-old Miniature Schnauzer, Bacteria were not cultured from the urine, bladder wall, or inside the urolith, Bacteria were not detected within the stone matrix by electron microscopy, The clear paces were occupied by struvite crystals (original magnification x 2640).

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What Role Does Urine pH Play in Sterile Struvite Urolithiasis?

Although struvite is less soluble in alkaline than acid urine, the mechanism(s) of sterile struvite urolith formation in dogs is not clear. Under physiological conditions associated with alkaluria, urine contains low concentrations of NH3 (and thus ammonium ion). 63 Therefore, alkaline urine formed in the absence of ureolysis would not be expected to favor the formation of crystals that contain ammonium ion (such as magnesium ammonium phosphate hexahydrate). Clinical studies of naturally occurring urolithiasis in human patients support this generality.Z4 Formation of persistently alkaline urine in the absence of urease-mediated ureolysis may predispose to the formation of uroliths containing calcium apatite but not carbonate apatite. Pathological conditions that may result in this sequence of events include distal renal tubular acidosis/ incomplete distal renal tubular acidosis/ and perhaps primary hyperparathyroidism. 2• 33 Because alkaline urine favors dissociation of H 2P04 - to HPOi- and P04 3 - , formation of calcium phosphate is enhanced. Patients with distal renal tubular acidosis have an impaired ability to acidify urine associated with hypercalciuria and excretion of a reduced concentration of urine citrate. 2 • 12• 53• 82 The question remains as to the source of NH4 + (ammonium ions) in sterile struvite uroliths. In vitro studies consisting of the addition of magnesium, ammonium, or phosphate to sterile human urine ranging in pH from 5.0 to 9.6 revealed that struvite crystals could be induced in an acid or an alkaline environment.' High NH3 concentrations were not necessary for the formation of struvite crystals provided that the concentration of magnesium (Mg2 +) X (NH. +) X (P04=) was of sufficient magnitude at a given pH. Corresponding in vivo studies in dogs have not been performed. What Role Does Genetics Play in Sterile Struvite Urolithiasis? In our series, recurrent urocystoliths composed of sterile struvite occurred in three related English Cocker Spaniels: a sire and two of his male offspring from different dams.• Sterile struvite uroliths in this breed have been recognized by others. 42 Episodes of struvite urocystolithiasis were associated with alkaluria but unassociated with bacterial UTis, urinary urease enzyme activity, or renal tubular acidosis.

WHAT IS THE BIOLOGICAL BEHAVIOR OF CANINE STRUVITE UROLITHIASIS? Infection-Induced Struvite Uroliths

Struvite crystals can form rapidly. For example, struvite crystals were observed as early as 4 hours after adding Proteus spp to artificial urine. 84 During clinical and experimental studies on dogs, we observed that radiographically detectable struvite uroliths formed within 2 to 8 weeks following infection with urease-producing staphylococci-34• 35 Struvite uroliths associated with UTis caused by staphylococci or Proteus spp have been detected in puppies as young as 5 weeks of age. 26• 50 Fueled by a constant supply of urea from dietary protein catabolism and urease from microbes, struvite crystals can grow to form uroliths of a large size. In fact, most large uroliths are composed primarily of struvite. The rapid rates

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at which struvite uroliths form and the potential that 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. Although spontaneous dissolution of uroliths appears to be uncommon, it can occur. We have observed five cases (2 renoliths and 3 cystic uroliths) of struvite urolithiasis in dogs in which uroliths underwent spontaneous dissolution.32 Spontaneous dissolution of canine nephroliths has also been reported by othersY If urease-positive infections persist in urine with sufficient urea, however, existing struvite uroliths are likely to persist and grow. Additional uroliths may also form. Struvite uroliths have a tendency to recur following surgical removal or medical dissolution. 8• 10• 11 • 63 We have evaluated Miniature Schnauzers with more than seven known recurrences following surgery. Most episodes of multiple recurrence have been associated either with lack of removal of all uroliths at the time of surgery (pseudorecurrence) or poor control of recurrent UTis with urease-producing pathogens. With the advent of effective therapeutic and preventive antimicrobial protocols to control recurrent or persistent UTis, the frequency of recurrent infection-induced struvite urolithiasis in dogs has declined. In our experience, the rate of recurrence following medical dissolution of canine struvite uroliths is less frequent than that associated with surgery. In addition, time elapsed between recurrent episodes is longer following medical dissolution. The apparent higher rate of recurrence associated with surgical removal of uroliths may be associated with an inability to remove all of the uroliths, especially those located in inaccessible places or those that are subvisual in size (Fig. 10). Residual stone debris enhances symptomatic urolithiasis by contributing to relapsing UTis and by contributing to heterogeneous nucleation of new uroliths. The tendency for uroliths to recur following surgery may also be associated with the persistence of abnormalities in local host defense mechanisms that favor recurrent UTis. The key to preventing recurrent infectioninduced struvite uroliths is to eradicate or control UTis.

Sterile Struvite Uroliths

We have also observed multiple recurrences of sterile struvite uroliths in dogs." We hypothesize that this is related, at least in part, to the underlying mechanisms that persist following medical dissolution or surgical removal of stones.

Changes in Location, Size, and Number of Struvite Uroliths

The location, size, and shape of infection-induced struvite uroliths may rapidly change. Uroliths located in the urinary bladder pass into or through the urethra, especially when they are associated with dysuria and stranguria. They commonly lodge behind the os penis in male dogs but frequently are voided to the exterior by female dogs. Small renoliths may pass into the ureters or urinary bladder. Therefore, if significant time has elapsed between the time of diagnostic radiography or ultrasonography and the date of initiation of medical or surgical therapy, the number, size, shape, and location of uroliths should be re-evaluated.

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Figure 10. A subvisual struvite urolith located in the lumen of a urachal diverticulum of a 2-year-old Sealyham Terrier. The matrix of the urolith contained countless gram-positive urease-producing staphylococci. The open spaces in the urolith represent the sites of dissolved struvite crystals.

It is not possible to medically dissolve ureteroliths or urethroliths by dietary or antibiotic therapy.

WHAT ARE THE CURRENT RECOMMENDATIONS FOR MEDICAL MANAGEMENT OF STRUVITE UROLITHS? Overall Objectives

The objectives of medical management of struvite uroliths are to arrest further growth and to promote urolith dissolution by correcting or controlling underlying abnormalities (see Appendix 2). For therapy to be effective, it must induce undersaturation of urine with struvitogenic crystalloids by (1) increasing the solubility of these crystalloids in urine, (2) increasing the volume of urine in which these crystalloids are dissolved or suspended, or (3) reducing the quantity of calculogenic crystalloids in urine. 63 For example, attempts to increase the solubility of struvite in urine often include strategies designed to reduce urine pH in order to create a less favorable environment for crystallization. Induction of diuresis is a m ethod commonly used to increase the volume of urine in which struvite crystalloids are dissolved or suspended. Change in diet is an example of a method to reduce the quantity of struvitogenic crystalloids in urine. In general, medical treatment should be formulated in a stepwise fashion, with the initial goal of reducing the urine concentration of calculogenic sub-

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stances. Medications such as urease inhibitors that have the potential to induce a sustained alteration in body composition of metabolites (in addition to urine concentration of metabolites) should be reserved for patients with active or frequently recurrent uroliths. Caution must be used so that the sii:le effects of treatment are not more detrimental than the effects of the uroliths. Our current recommendations for medical dissolution of canine struvite include the following: (1) eradication or control of UTis (if present), (2) use of high-moisture (canned) struvitolytic diets, and (3) administration of urease inhibitors (acetohydroxamic acid [AHA]) to patients if struvite uroliths remain because of persistent infections caused by urease-producing microbes (see Appendix 2). Uroliths cannot be dissolved by following medical protocols while they remain in the ureters or urinary bladder. 60 Medical therapy designed to induce urolith dissolution by changing the composition of urine is ineffective for stones in the urethra and ureters, because these areas are only intermittently exposed to urine that is undersaturated with struvite. Consult the article on canine and feline nephrolithiasis in this issue for recommendations about struvite nephroliths in patients with renal dysfunction. The section in the current article on precautions to be taken in patients with concomitant illness or risk for illness provides additional information about the benefits and risks of medical dissolution protocols. How Should Infection-Induced Struvite Uroliths Be Managed? How Important Is Treatment of Urinary Tract Infections?

The importance of UTis with urease-producing bacteria in the formation of many struvite uroliths in dogs emphasizes the necessity of therapy to eliminate or control them. The goal of antimicrobial therapy is to sterilize urine and thereby recreate an environment that is undersaturated with struvite (consult the article in this issue on the effectiveness of treatment of uroliths for further information about the concept of undersaturation). Of What Value Are Urinary Acidifiers in Treating Urease-Positive Urinary Tract Infections

Because of the quantity of urease produced by struvitogenic bacterial pathogens, it may be impossible to acidify urine with urine acidifiers administered at doses that prevent systemic acidosis. 55 We do not use urine-acidifying drugs in our medical protocols for dissolution of infection-induced uroliths. In general, urine acidifiers should not be used concomitantly with an acidifying diet or when there is evidence of underlying metabolic acidosis. How Should Antibiotics Be Used?

We recommend the use of therapeutic doses of antimicrobial agents selected on the basis of antibiotic dilution susceptibility tests designed to determine minimum inhibitory concentrations of antimicrobial drugs in urine. 46• 58 Preference should be given to bacteriocidal drugs excreted in high concentration in urine, with a wide margin of safety between therapeutic and toxic doses. The fact that diuresis reduces the urine concentration of antimicrobial agents should

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be considered when formulating antimicrobial doses. 48 In this circumstance, flexible dosage strategies are needed, with preference given to the high end of dosage recommendations. Therapeutic doses of antimicrobial agents should be administered as long as uroliths remain in the urinary tract (see Appendix 2). This recommendation is based on the fact that bacterial pathogens harbored inside uroliths may be protected from antimicrobial agents. 57 Although the urine and surface of uroliths may be sterilized following appropriate antimicrobial therapy, the original and secondary infecting organisms may remain viable below the surface of the urolith. Therefore, discontinuation of antimicrobial therapy before the uroliths are completely dissolved may result in relapse of bacteriuria and infection. Do Antimicrobial Drugs Induce Struvite Urolith Dissolution without Dietary Therapy?

Use of antimicrobial agents alone may result in dissolution of struvite uroliths in some patients. Experimental studies in rats54 and dogs64• 76 and clinical studies in human beings 15• 45 indicate that this phenomenon represents the exception rather than the rule, however. In one controlled study performed at the University of Minnesota, dissolution of urocystoliths occurred in only two of six dogs given oral ampicillin (35 mg/lb/d divided into three equal subdoses) and an adult maintenance diet. 61 • 69 Struvite urocystoliths in the remaining four dogs increased in size (C.A. Osborne, unpublished data, 1987). In addition to the unpredictable response to this form of therapy, the time required to induce urolith dissolution with antimicrobial agents is usually measured in multiples of months rather than in multiples of weeks. Of What Value Are Struvitolytic Diets?

Goals of Dietary Therapy. The goal of dietary modification for patients with struvite uroliths is to increase urine volume and to reduce urine concentration of urea (the substrate of urease), phosphorus, and magnesium. A high-moisture (canned) calculolytic diet that contains a reduced quantity of high-quality protein and reduced quantities of phosphorus and magnesium (Prescription Diet Canine s/d; Hill's Pet Nutrition, Topeka, KS) was formulated. 1 The diet was supplemented with sodium chloride to stimulate thirst and induce compensatory polyuria. Reduction of hepatic production of urea from dietary protein reduced renal medullary urea concentration and further contributed to diuresis. As described in detail elsewhere, the canine calculolytic diet designed to promote dissolution of infection-induced struvite (Prescription Diet Canines/ d) is substantially different from the calculolytic diet designed to promote dissolution of feline sterile struvite uroliths (Prescription Diet Feline s I d; Hill's Pet Nutrition). 61 • 68 Effectiveness of Dietary Therapy. The efficacy of the aforementioned diet in inducing dissolution of infected struvite uroliths has been confirmed by controlled experimental studies in dogs.' Calculolytic diet monotherapy (without antimicrobial drugs) was highly effective in dissolving induced struvite urocystoliths in five of six dogs despite persistent infection with urease-producing bacteria. The uroliths dissolved in about 3.5 months (range, 8-20 weeks). The urolith in the remaining dog decreased to less than one half of its pretreatment size at the termination of the study, 6 months following initiation of dietary therapy. UTis persisted in these dogs until the uroliths dissolved, at which time, they spontaneously resolved in three dogs. In the corresponding control group

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fed a maintenance diet, uroliths increased in size by a mean of 5.5 times their pretreatment size (range, 3-8 times). A urolith developed in the renal pelvis of one of these dogs. UTis persisted in control dogs throughout the 6-month study. Safety of Struvitolytic Diets. Consumption of calculolytic diets by young adult female Beagle dogs with experimentally induced staphylococcal UTI 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 6-month experimental studies or during clinical studies. Nevertheless, 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. A reduction in concentrations of serum urea nitrogen may be used as one index of client and patient compliance with dietary recommendations. Effectiveness of a Combination of Dietary and Antimicrobial Drug Therapy. The struvitolytic effects of various combinations of (1) antibiotics (ampicillin given orally at a dosage of 16 mg/kg/ d), (2) AHA (a urease inhibitor given orally at a dosage of 25 mg/kg/ d) and (3) a calculolytic diet were studied in female Beagle dogs with staphylococcally induced struvite uroliths (C.A. Osborne, unpublished data, 1987). 61 • 69 In four of six dogs given ampicillin and a maintenance diet, urocystoliths increased in size during 5 months of therapy. Urocystoliths in two of six dogs dissolved. In four of six dogs given ampicillin and a struvitolytic diet for up to 5 months, urocystoliths dissolved in four dogs, although uroliths in the remaining two dogs decreased in size. In young adult Beagle dogs treated with a combination of a calculolytic diet, ampicillin, and AHA, all uroliths dissolved within 6 weeks of initiation of therapy. When a combination of a calculolytic diet and antimicrobial agents was given to 11 dogs with naturally occurring urease-positive UTis and urocystoliths presumed to be composed of struvite, similar results were obtained (Figs. 11 and 12) (C.A. Osborne, unpublished data, 1987). 61 • 69 The mean time required to induce urocystolith dissolution in these dogs was approximately 3 months (range, 2 weeks to 7 months). Is There Evidence to Support the Use of Urease Inhibitors?

Acetohydroxamic Acid. AHA (Lithostat; Mission Pharmacal, San Antonio, TX) is a competitive and noncompetitive inhibitor of microbial urease. 23• 25 Its inhibition of microbial urease activity decreases urine NH3 and alkalinity caused by the enzymatic hydrolysis of urea. In this way, it impedes the pathophysiological events leading to struvite urolith formation. AHA does not have significant antibacterial activity in vivo and thus cannot be relied on to reduce the number of viable microbes. 80 It is an antiurolithic, and not an antibiotic. Whereas it is indicated as adjunct therapy for infection-induced struvite urolithiasis, in terms of bacterial UTis, it should be regarded as a palliative (rather than specific) treatment for the effects of urease activity. Evaluation of Acetohydroxamic Acid in Dogs. Experimental and clinical studies in dogs have revealed that treatment with AHA at a dose of 25 mg/kg (divided into two daily subdoses), inhibits struvite urolith growth and promotes struvite urolith dissolution. AHA given orally to dogs at this level reduces urease activity, struvite crystalluria, and urolith growth. 38 By reducing the patho-

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Figure 11. Lateral view of the abdomen of a 4-year-old spayed female Beagle with two naturally occurring urocystoliths presumed to be composed of struvite. The urocystolith was associated with a staphylococcal urinary tract infection.

genicity of staphylococci, it may also result in less severe dysuria, bacteriuria, pyuria, hematuria, and proteinuria. Routine Use of Acetohydroxamic Acid to Treat Struvite Uroliths. We have not routinely utilized AHA in promoting dissolution of infection-induced struvite uroliths in dogs because of the efficacy of the calculolytic diet and antimicrobial therapy. We have utilized AHA in combination with calculolytic diets and antimicrobial agents in patients that have recalcitrant urease-producing UTis associated with persistent struvite uroliths, however. If infection-induced struvite uroliths do not dissolve following an appropriate trial of therapy with diet modification and antimicrobial agents, AHA may be added to the therapeutic regime. Contraindications to the Use of Acetohydroxamic Acid. Although higher doses of AHA given to dogs may result in urolith dissolution, we do not recommend this approach, because high doses of AHA may cause a reversible hemolytic anemia and abnormalities in bilirubin metabolism. 36• 38 As AHA is primarily excreted in urine, it should not be given to patients with azotemic renal failure, because the risk of systemic toxicity is increased and the quantity excreted in urine is decreased. 84 Likewise, AHA should not be administered to pregnant dogs because it is teratogenic. 3 How Should Infection-Induced Struvite Nephroliths Be Managed?

Consult the article on canine and feline nephrolithiasis in this issue for recommendations. How Should Infection-Induced Uroliths Be Managed in Immature Dogs?

We have successfully dissolved struvite urocystoliths in several immature dogs (see Appendix 2). One was a 12-week-old female Miniature Dachshund

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Figure 12. Lateral view of the abdomen of the dog described in Figure 11 obtained 80 days after initiating therapy with a calculolytic diet and an antimicrobial drug. There are no uroliths in the urinary tract.

with a sterile struvite urocystolith. 65 The urocystolith was dissolved within a 2week period of feeding a calculolytic diet (Prescription Diet Canine s / d), at which time the diet was discontinued. Another case was a 9-week-old male mixed-breed puppy with a vesicourachal diverticulum, urethral stricture, S. intermedius UTI, and multiple struvite urocystoliths.50 In that dog, the urocystoliths dissolved within 9 days of initiation of the calculolytic diet and antimicrobial (amoxicillin and clavulanic acid) treatment; the diet was discontinued on day 10. In both dogs, slight reductions in serum albumin concentration (from approximately 3.2-2.7 g/ dL) w ere observed during the 2 weeks of dietary treatment. Serum albumin concentrations returned to reference values soon after the pups resumed eating a normal growth diet. We do not recommend feeding the canine calculolytic diet to immature dogs for more than a few weeks. If the diet is used, we recommend serially monitoring body weight, serum albumin concentration, and packed cell volume for evidence of protein/ calorie malnutrition. If substantial reductions in these variables are observed, appropriate adjustments in dietary management should be made. If the urocystoliths have been sufficiently reduced in size so that they could pass through a distended urethra, they may be removed b y voiding urohydropropulsion.51 Combined Surgical and Medical Therapy

There are occasionally situations in w hich a combination of surgical removal of urate uroliths followed by medical dissolution protocols might be beneficial. One involves the inability to remove all uroliths by surgery. Another is unintentional failure to remove all uroliths at the time of surgery. In some patients, immediate surgery may be required to remove uroliths obstructing the renal pelvis(es), ureters or urethra. If such patients have multiple uroliths in several

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locations and if circumstances preclude their surgical removal from multiple sites at the time the obstructing urolith is removed, subsequent initiation of medical dissolution protocols may prove to be advantageous. We have had only limited experience with the use of protein-restricted calculolytic diets immediately following surgery. To date, we have encountered no problem with dehiscence or delayed healing of surgical incisions. Our patients were in good physical condition, however, and meticulous procedure was followed in repairing surgical incisions. How Should Sterile Struvite Uroliths Be Managed? Current Recommendations

Current recommendations include the use of calculolytic diets and utilization of urine acidifiers (see Appendix 2). There is absolutely no indication for the use of urease-inhibiting drugs in dogs with sterile struvite uroliths. Likewise, unless secondary UTI develops, antibiotics are not required. Of What Value Is Dietary Modification?

Controlled experimental and clinical studies have confirmed the efficacy of calculolytic diets (Prescription Diet Canine s/ d) in inducing sterile struvite urolith dissolution. 66• 69 The time required to induce dissolution of sterile struvite is usually shorter than that required for infection-induced struvite (Table 2). In a study of sterile struvite urocystoliths in adult female Beagle dogs, consumption of the calculolytic diet resulted in urolith dissolution in a mean of 3.3 weeks (range, 2--4 weeks). 1 In a corresponding control group of Beagles fed a maintenance diet, uroliths in four dogs dissolved over a mean period of 14 weeks (range, 2-5 months). In the remaining two control dogs, uroliths were one fifth of their initial size at the termination of the study. When the struvitolytic diet was given to 9 dogs with naturally occurring sterile urocystoliths presumed to be composed of struvite, the stones dissolved in a mean time of 6 weeks (range, 1-3 months) (C.A. Osborne, unpublished data, 1987). 61 • 65• 69 Management of six episodes of naturally occurring sterile struvite urocystoliths affecting two related male English Cocker Spaniels with a calculolytic diet resulted in urolith dissolution in a mean of 38.5 ± 12.8 days (see Table 2). 4 Is It Necessary to Reduce Dietary Protein to Dissolve Sterile Struvite Uro/iths?

Protein restriction is not essential for dissolution of canine sterile struvite uroliths. Nevertheless, dietary protein restriction has the advantage of contributing to obligatory polyuria by decreasing renal medullary urea concentration and thus enhancing the rate of sterile struvite urolith dissolution. Protein restriction would also have the advantage of reducing consumption and urinary excretion of phosphorus. Of What Value Is Urine Acidification? If dietary management is not feasible, acidification of urine to a pH of approximately 6.0 has been effective in promoting sterile struvite urolith dissolu-

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Table 2. TIME REQUIRED TO DISSOLVE CANINE STRUVITE UROLITHS

Cause

Site

Induced infection Bid

Number of Dogs

Prescription Prescription Diet* Antibioticst

Prescription Acetohydroxamic Acid

6/6

Yes

No

No

Natural infection

Bid

11/11

Yes

Yes

No

Natural infection

Kid

6/6

Yes

Yes

No

infection Bid infection Bid infection Bld sterile Bid

4/6 2/6 6/6 6/6

Yes No Yes Yes

Yes Yes Yes No

No No Yes No

Natural sterile

Bid

9/9

Yes

No

No

Natural sterile

Bld

Yes

No

No

Natural Natural Natural Natural Natural Natural

Bid Bid Bid Bid Bid Bid

2/2 (6 episodes) 1/1 1/1 1/1 1/1 1/1 7/7

Yes Yes Yes Yes Yes Yes

No No Yes Yes Yes Yes

No No No No No No

Induced Induced Induced Induced

sterile sterile infected infected infected infected

Time

14 wk (8--20) 12 wk (2-28) 26 wk (10-43) 20 wk 20 wk 6wk 3wk (2-4) 6wk (4-12) 5wk (4-9) 4wk 5wk 9d 15wk 5wk 5wk (4-8)

References

65,69 65

65,69 65,69 65,69 1 65, 69 4 42 67 50 64 66 Unpublished data

*Prescription Diet Canine s/d; Hill's Pet Nutrition, Topeka, KS. t Antimicrobial drugs selected on the basis of in vitro susceptibility tests. :j:Lithostat; Mission Pharmacol, San Antonio, TX. Bid = urinary bladder, Kid = kidneys, wk = weeks, d = days.

tion. 67 In this respect, canine sterile struvite uroliths are similar to feline sterile struvite uroliths. In dogs, augmenting urine volume by feeding high-moisture canned (rather than dry) maintenance diets should also be considered. Of What Value Is the Administration of Sodium Chloride to Enhance Diuresis?

Diuresis induced by augmenting water consumption appears to be a logical method to decrease the urine concentration of struvite and other calculogenic substances. Additional salt is not recommended for dogs fed the high-moisture calculolytic diet previously described because that diet has been formulated to contain supplemental sodium chloride. In addition, depletion of renal medullary urea as a consequence of dietary protein restriction is associated with an obligatory diuresis.' Another point to consider is that excess dietary sodium chloride causes increased calcium excretion which would increase the risk for formation of calcium-containing uroliths. 49 How Should Response to Therapy Be Monitored? How Much Time Is Required for Struvite Uroliths to Dissolve?

There is no rigid therapeutic time interval after which response to dissolution therapy is unlikely. The size and number of uroliths as such do not dictate

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the likelihood of response to therapy. We have had success in dissolving uroliths that are small and large as well as those that are single and multiple. The rate of dissolution is related to the size and surface area of the urolith exposed to urine, however. Just as one large ice cube dissolves more slowly than an equal volume of crushed ice, one large urolith dissolves more slowly than an equal volume of many smaller uroliths. The rate of dissolution is influenced by the surface area of the urolith exposed to undersaturated urine. Some of our experiences with the rates of dissolution of infection-induced and sterile struvite uroliths using various types of therapy are summarized in Table 2. We emphasize that several factors influence the rate of struvite urolith dissolution, including: 1. Whether the struvite uroliths are infection induced or sterile 2. Size, number, and location of the uroliths. 3. Location and quantity of calcium phosphate (if any) mixed with infection-induced struvite uroliths 4. Whether or not the nidus of the urolith(s) is composed of a different type of mineral than struvite 5. Proper selection and administration of antimicrobial agents 6. Client and patient compliance with diet recommendations

A summary of expected responses to therapy is presented in Table 3. What Advice and Recommendations Should Be Given to Clients?

Because calculolytic diets stimulate thirst and promote diuresis, clients should be informed that the magnitude of pollakiuria in dogs with urocystoliths may increase for a variable time following initiation of dietary therapy. Pollakiuria and the abnormal odor of urine caused by bacterial degradation of urea usually subside as infection is controlled and uroliths decrease in size (see Table 3). Reduction in ammonia-induced and chemical inflammation as a result of ureolysis is also a factor associated with remission of these clinical signs. 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 urethral 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 (consult the article in this issue on canine retrograde urohydropropulsion for further information). If warranted, tenesmus and dysuria may then be temporarily suppressed by giving drugs that reduce pain or cause muscle relaxation. Consult the section in the current article on precautions to be taken in patients with concomitant illnesses for additional information about benefits and risks of struvite urolith dissolution protocols. What Procedures Are Recommended to Monitor Response to Therapy?

Regardless of the type of management selected, periodic re-evaluation of the patient to determine therapeutic efficacy and safety is recommended. We recommend scheduled re-examinations at 4-week intervals (see Table 3).

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Table 3. CHARACTERISTIC CLINICAL FINDINGS BEFORE AND FOLLOWING INITIATION OF MEDICAL THERAPY* TO DISSOLVE STRUVITE UROLITHS IN NONAZOTEMIC DOGS

Factor

Pretherapy

Polyuria Pollakiuria

Sometimes 1 + to 4+

Gross hematuria Abnormal urine odor Small uroliths voided

0 to 4+ 0 to 4+ Sometimes

Urine specific gravity Urine pH Urine protein Urine red blood cells Urine white blood cells Struvite crystals Other crystals Bacteriuria Quantitative bacterial urine culture Serum urea nitrogen Serum creatinine Serum alkaline phosphatase Serum albumin Serum phosphorus Urolith size (radiographic) Hemogram

During Therapy

Following Successful Therapyt

Negative Negative

Variable ;o,:7.0 1+ to 4+ 1 + to 4+ 1 + to 4+ 0 to 4+ Variable 0 to 4+ 0 to 4+

1+ to 3+ Transient j but subsequent 1 t by 5 to 10 days 1by 5 to 10 days Common in female dogs ± 1.004 to ± 1.014 Decreased (usually acid) Decreased to absent Decreased to absent Decreased to absent Usually absent May persist Decreased to absent Decreased to absent

Normal Variable Negative Negative Negative Variable May persist Negative Negative

>15 mg/dL Normal Normal

5 to 15 mg/dL Normal j by two to five times

Dependent on diet Normal Normal

Normal

1by 0.5 to 1.0 g/dL

Normal

Normal Small to large

from baseline Slight decrease Progressive decrease

Normal Absent

Normal

Normal

Normal

Negative Negative Negative

*For dogs with bacterial urinary tract infection, therapy consists of calculolytic diet and antimicrobial agents; for dogs without bacterial urinary tract infection, therapy consists of calculolytic diet. tAll forms of therapy withdrawn.

In patients with concomitant disease and in those at high risk for adverse events associated with consumption of struvitolytic diets, serum biochemical profiles and other monitoring procedures may be warranted. Because the calculolytic diet is relatively high in fat, precautions should be considered for patients with a predisposition to acute pancreatitis. In this situation, we recommend periodically monitoring serum amylase, lipase, or trypsin-like immunoreactivity activity and comparing the values obtained during therapy with pretreatment baseline values (refer to the section in this chapter on precautions to be taken in patients with concomitant illness or risk for illness for additional information). What Type of Radiography Is Recommended?

The number, size, and location of uroliths should be periodically monitored by survey radiography and, if necessary, by contrast radiography (see Figs. 11 and 12). Although retrograde double-contrast cystography is more sensitive in identifying small urocystoliths, survey radiography is usually preferable, be-

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cause use of catheters during retrograde radiographic studies may result in iatrogenic UTis. Alternatively, ultrasonography or intravenous urography may be considered. Consult the article on imaging canine urocystoliths in this issue for additional information. In patients at high risk for acute pancreatitis, it may be useful to employ radiography and ultrasonography of the pancreas at the time of evaluation of the urinary tract. This provides baseline data with which to compare radiographic and ultrasound studies of the pancreas at a later date should they be necessary. 28 What Type of Urine Examination Should Be Considered?

Monthly evaluation of urine pH, protein, and occult blood with reagent test strips, as well as evaluation of sediment for crystalluria, hematuria, and pyuria is recommended. Struvite crystals should not form in fresh uncontaminated urine if therapy has been effective in promoting the formation of urine that is undersaturated with MAP. What Can Be Expected Regarding the Status of Urinary Tract Infections?

UTis may persist despite antimicrobial therapy in patients having infectioninduced struvite uroliths and consuming the calculolytic diet. In most patients, however, the magnitude of bacteriuria is usually reduced substantially (i.e., > 100,000 bacteria per milliliter of urine to approximately 1000 bacteria per milliliter of urine), and the associated inflammatory response progressively subsides. Difficulty in eradication of infection while uroliths persist may be related to the persistence of viable microbes harbored within the stones that are not exposed to antimicrobial drugs (see Fig. 6). 57 The concentration of antimicrobial drug may also be a factor. Diet-induced diuresis should also be considered when formulating antimicrobial drug doses so that a quantity of drug greater than four times the minimum inhibitory concentration is present in urine. Should Urine Cultures and Antimicrobial Susceptibility Tests Be Monitored?

An important difference exists in the criteria for evaluating the effectiveness of therapy in patients with bacterial UTis and in that for evaluating patients with bacterial UTis and struvite uroliths. When monitoring the response of patients to antimicrobial treatment of bacterial UTis without uroliths, culture of a urine sample collected by cystocentesis 3 to 5 days following the initiation of therapy is recommended. Therapy is considered to be successful only if urine does not contain any pathogenic organisms; the urine should be sterile. Treatment is ineffective and relapse occurs if bacterial counts have only been reduced (e.g., from 105 to 103 ). As described in the section on what can be expected regarding the status of urinary tract infections in this article, reduced numbers of bacteria commonly persist in urine during antimicrobial therapy of patients with infection-induced struvite uroliths that are consuming the calculolytic diet. The presumption is that they are being released from inner portions of dissolving uroliths. Despite persistent urease-positive bacteriuria during antimicrobial and dietary treatment of infected patients with struvite uroliths, we have had excellent success in

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inducing dissolution of uroliths. Even though the urine is not sterile, reduction in bacterial colony counts by logarithmic magnitudes (e.g., from 106 to 104 colony forming units) has a substantial effect in reducing the quantity of microbial urease in urine. 25 If urease-positive bacteria are isolated during antimicrobial therapy, their susceptibility to the antibiotic currently being given should be evaluated. If the microbes become resistant to that drug, appropriate adjustments in therapy should be made. Isolation of different bacteria during therapy as compared to bacteria isolated at the time of diagnosis may be associated with the following events: (1) poor client compliance with drug therapy, (2) transurethral catheterization, or (3) ascending migration of bacteria through the urethra. Rapid recurrence of a UTI caused by the same type of organism (relapse) or a different type of bacterial pathogen (reinfection) following withdrawal of antimicrobial therapy may indicate residual uroliths within the urinary tract or other abnormalities in local host defense mechanisms that predispose to UTis and subsequent urolithiasis. These possibilities should be investigated.

How Long Should Therapy Be Continued?

Because small (<3 mm in diameter) struvite uroliths may escape detection by survey radiography or ultrasonography, we recommend that the calculolytic diet and (if necessary) antimicrobial agents be continued for approximately 1 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 radiographically detectable uroliths and bacterial UTI following cessation of therapy.

What Should Be Considered If Uroliths Persist Despite Therapy?

Difficulty in inducing complete dissolution of uroliths by creating urine that is undersaturated with the suspected calculogenic crystalloid should prompt consideration that (1) the wrong mineral component was identified, (2) the nucleus of the urolith is of a different mineral composition than outer portions of the urolith, or (3) the owner or the patient is not complying with therapeutic recommendations (Table 4, Fig. 13). Consult the article on imaging canine urocystoliths in this issue for information about the radiographic characteristics of different types of uroliths. The protein-, phosphorus-, and magnesium-restricted diets designed to promote dissolution of struvite uroliths do not dissolve calcium oxalate, calcium phosphate, or silica uroliths. Consult appropriate articles in this issue for current recommendations about medical management of these forms of uroliths. Attempts to induce dissolution of struvite uroliths may be hampered if the uroliths are heterogeneous in composition (see Table 4). This has not been a significant problem in dogs with uroliths composed primarily of MAP with lesser quantities of calcium apatite. We have encountered difficulty in dissolving uroliths composed primarily of struvite with an outer shell composed primarily of calcium apatite, however, because calcium phosphate is resistant to dissolution by the struvitolytic protocol. It has been hypothesized that differences

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Table 4. MANAGING MAGNESIUM AMMONIUM PHOSPHATE UROLITHS REFRACTORY TO COMPLETE DISSOLUTION Causes Client and patient factors Inadequate dietary compliance

Inadequate or inappropriate administration of antibiotics Clinician factors Incorrect prediction of mineral type Inappropriate antibiotic choice

Identification

Therapeutic Goal

Question owner Persistent struvite crystalluria Serum urea nitrogen > 10 to 15 mg/dL and urine specific gravity > 1.010 to 1.015 during treatment with Prescription Diet Canine s/d (Hill's Pet Nutrition, Topeka, KS) Question owner Evaluate timeliness of prescription refills Count remaining antibiotic pills

Emphasize need to feed dissolution diet ~xclusively and discuss what treats are acceptable to veterinarian

Analysis of retrieved urolith

Inappropriate antibiotic dose for degree of diuresis

Positive urine culture with poor susceptibility for chosen antibiotic Positive quantitative urine culture with same or different bacterial species

Premature discontinuation of antibiotic

Discontinuing antibiotic prior to complete urolith dissolution

Disease factors Change in bacterial susceptibility New bacterial infections

Compound uroliths

Positive urine culture with susceptibility results different from previous culture Positive urine culture identifying new bacterial species Radiographic density of nucleus and outer layer(s) of urolith are different Analysis of retrieved uroliths

Emphasize need to administer the full dose of antibiotics Determine if owner is capable and willing to administer medication Demonstrate a variety of methods to administer medication Alter therapy based on identification of mineral type Choose antibiotics based on susceptibility testing Administer antibiotic at the highest recommended dose or consider a higher dose than recommended Prescribe full antibiotic dose for the entire period of urolith dissolution Choose antimicrobic drugs based on susceptibility tests Choose antibiotic effective against both bacteria Avoid procedures requiring urinary catheterization Check client compliance Alter therapy based on identification of new mineral type Asymptomatic uroliths may not be removed, but patient should be monitored for potential adverse consequences (e.g., obstruction, urinary tract infection) Clinically active uroliths may require surgical removal Small urocystoliths may be removed by voiding urohydropropulsion

related to the "porosity" of struvite stones may also be a factor affecting the rate of their dissolution. 14 Difficulty is also encountered in attempting to induce complete dissolution of a urolith with a nucleus of calcium oxalate or silica and a shell of struvite, because the solubility characteristics of these two minerals are dissimilar. This

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Figure 13. Lateral view of the abdomen of an adult spayed female Beagle with infectioninduced struvite urocystoliths. The radiodense material in the large intestine indicates a lack of compliance with dietary recommendations.

phenomenon should be considered if medical therapy seems to be ineffective after initially reducing the size of a urolith. If the reduction in size of the urolith has been sufficient to allow it to pass through the urethra, however, it may be removed by voiding urohydropropulsion. Consult the article on voiding urohydropropulsion in this issue for additional information. How Important Is Client and Patient Compliance?

Noncompliance with diet or antimicrobial drug recommendations can be expected to be associated with poorer 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, a special effort should be made to educate clients about the reasons why special diets and drugs are being given as well as the expected outcome if they are unable or unwilling to comply with the dissolution protocol. Consult Table 3 for a summary of expected changes in clinical, laboratory, and radiographic findings during and following successful therapy. In most situations, the expectation of full compliance with diet recommendations may be unrealistic. Clients should be advised as to what types of " treats" have a minimal impact on the success of therapy as well as to what types of treats significantly reduce the likelihood of urolith dissolution. In general, less than full compliance is acceptable as long as the desired therapeutic benefit can be safely achieved in an appropriate time. Clients should be educated about the importance of antimicrobial drug therapy for bacterial UTis. The dose of antibiotic and the frequency with which it is administered should be devised in cooperation with the client's input as to what is realistic.

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What Precautions Should Be Taken If Patients Have Concomitant Illnesses or Are at High Risk For Illnesses?

There are benefits and risks associated with feeding a struvitolytic diet. Not all patients may qualify for dietary medical management. If the following problems coexist in patients with struvite uroliths, before proceeding with their medical management, benefits and risks of the treatment protocol should be considered and discussed with the client. During such discussions with clients, we avoid making "all or none" and "always or never" statements, as risk factor associations are not synonymous with cause and effect relationships. Consult the article on risk and protective factors for urolithiasis in this issue for additional information. Patients with Abnormal Fluid Retention

The diet (Prescription Diet Canine s/ d) 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 (e.g., heart failure, nephrotic syndrome) or hypertension. Azotemic Primary Renal Failure

Complete obstruction to urine outflow caused by uroliths in patients with a concomitant UTI should be regarded as an emergency. In this situation, rapid spread of infection and associated damage to the urinary tract, especially the kidneys, are likely to induce septicemia and acute renal failure by a combination of obstruction and pyelonephritis. The risks and benefits associated with medical therapy to dissolve uroliths should not be considered until adequate urine flow has been restored. Nonobstructing struvite nephroliths have been dissolved in patients with nonazotemic renal failure caused by ascending pyelonephritis.66• 69 Nevertheless, protein-restricted calculolytic diets should be used with caution in patients with azotemic primary renal failure. The diet could induce protein malnutrition if given for prolonged periods to dogs with moderate azotemic primary renal failure.73 To minimize adverse drug reactions/ events, adjustments in doses and maintenance intervals of drugs excreted primarily by the kidneys should be considered in patients with azotemic primary renal failure. Patients at Risk for Pancreatitis

The struvitolytic diet is relatively high in fat, which serves primarily as a source of calories. Because dietary fat is a risk factor for pancreatitis, the serum activity of pancreatic enzymes (amylase, lipase, trypsin-like immunoreactivity) should be monitored before initiating therapy in patients known to be at higher risk for pancreatitis. These tests should be repeated if signs of pancreatitis develop during therapy. Because abnormal increases in these enzymes are not pathognomonic for pancreatitis, other relevant findings should also be considered. Consult the section in this article on what type of radiography is recommended for additional suggestions about evaluation of the pancreas. We emphasize that female Miniature Schnauzers are at increased risk for

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infection-induced struvite uroliths and pancreatitis. Likewise, patients with hyperadrenocorticism are at increased risk for UTis (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 about adverse events that need medical attention and those that need medical attention only if they continue or are bothersome. HOW CAN STRUVITE UROLITH RECURRENCE BE MINIMIZED? Summary

Infection-induced and sterile struvite uroliths tend to recur. Prevention of recurrent uroliths, which reduces the need for medical therapy or surgery, is therefore cost-effective. In general, prevention strategies are designed to eliminate or control the underlying causes of various types of uroliths. When causes cannot be identified, prevention strategies encompass efforts to minimize risk factors associated with calculogenesis. These strategies commonly include dietary modifications. How Can Infection-Induced Struvite Uroliths Be Prevented? Eradication or Control of Infection

Eradication or control of infections of the urinary tract due to ureaseproducing bacteria is the most important factor in preventing recurrence of most infection-induced struvite uroliths. In the absence of infection with ureaseproducing microbes, infection-induced struvite uroliths cannot form. A negative culture of urine for bacteria 10 to 14 days after antimicrobial therapy is withdrawn indicates that the UTI has been eradicated. If the patient has a history of recurrent bacterial UTI due to reinfections, this is the time that long-term prophylactic antimicrobial therapy should be initiated. The protocol is described elsewhere. 46' 58 If reinfections with different microbes occur, use of antimicrobial preventive protocols should be considered. If relapses with the same microbial pathogen occur, long-term full-dose therapy with an antibiotic that reaches sufficient concentration in tissue sites of infection is recommended. Dietary Considerations In light of the effectiveness of diets in inducing dissolution of struvite uroliths, the use of dietary modification to minimize recurrence of uroliths is logical and feasible. Studies are in progress to evaluate the preventive efficacy of mild to moderate restrictions in the protein, magnesium, and phosphorus content of acidifying diets. Caution must be used in deciding whether or not to induce prophylactic diuresis in patients with a history of struvite uroliths induced by recurrent urinary tract infection. Although formation of dilute urine tends to minimize the supersaturation of urine with calculogenic crystalloids, it tends to counteract innate antimicrobial properties of urine. Therefore, polyuric patients are at increased risk for bacterial UTis.

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How Can Sterile Struvite Uroliths Be Prevented?

When compared with infection-induced struvite uroliths in which the UTI has been eradicated or controlled, sterile struvite uroliths have a greater tendency to recur. 4 If the urine pH of patients with sterile struvite urolithiasis remains alkaline despite dietary therapy, administration of urine acidifiers should be considered. The prophylactic value of concomitant restriction of dietary phosphorus and magnesium is logical but has not yet been evaluated in a large series of clinical cases. How Should Preventive Therapy Be Monitored?

Regardless of the type of management selected, periodic re-evaluation of the patient to determine therapeutic efficacy and safety is recommended. We recommend that the safety and effectiveness of therapy be monitored by survey radiography or ultrasonography, urinalysis (including specific gravity, pH, and urine sediment), and urine culture (see Table 3). If risk factors for a type of urolith other than the one being managed are discovered, appropriate adjustments in management should be made. What If Uroliths Recur Despite Management Strategies to Control Risk Factors?

The following suggestions may be helpful (see Table 4): 1. Consider strategies to prevent recurrence of bacterial UTis. 46' 58 2. Strive to increase urine volume (less concentrated urine) by providing moist rather than dry foods. 3, Evaluate patient and owner compliance with recommendations to control risk factors. 4. Be sure that therapeutic agents are not contributing to risk factors for urolithiasis. 5. If patients develop outflow obstruction due to urethroliths, strive to evaluate pretreatment urinalysis, especially urine pH and in vivo urine crystal patterns. Survey and contrast radiography of the urethra and urinary bladder is also of value. 6. Strive to detect urocystoliths when they are small enough to be removed by voiding urohydropropulsion51 or via aspiration with the aid of a urinary catheter. 61 7. If urocystoliths are removed surgically, consider postoperative radiography. We have found that in up to 20% of patients, uroliths remain after surgery. Failure to recognize this phenomenon may lead to misinterpretation when uroliths are detected at a later date (pseudorecurrence). 8. Save and submit all uroliths for quantitative mineral analysis. We continue to provide this service. You may send samples to: Minnesota Urolith Center c/o Dr Carl A. Osborne Department of Small Animal Clinical Sciences College of Veterinary Medicine University of Minnesota St. Paul, MN 55108 Fax: 612-624-0751

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HOW SHOULD PATIENTS WITH RECURRENT STRUVITE AND CALCIUM OXALATE UROLITHIASIS BE MANAGED?

In those situations where dogs have documented occurrences · of either calcium oxalate or calcium phosphate followed by struvite urolithiasis, or vice versa, uncontrollable risk factors (defective inhibitors of crystal formation and defective inhibitors of crystal aggregation) may be present. The paradox in formulating therapy is that control of some risk factors for struvite urolith formation (see Table 1) enhances the risks of calcium oxalate or calcium phosphate urolith formation (consult the articles on calcium oxalate and calcium phosphate urolithiasis in this issue for details about risk factors). In this situation, veterinarians find themselves caught between the proverbial "rock and a hard place." How can we resolve this dilemma? We must be knowledgeable about, look for, and try to eliminate or control different risk factors for various types of urolithiasis as they affect each patient. If a decision to minimize risk factors associated with urolithiasis by dietary modification is made, periodic re-evaluation of the patient to determine the efficacy of dietary management is essential. Special emphasis should be placed on evaluation of urine specific gravity, urine pH, and in vivo crystalluria. Owners should be educated that dietary changes cannot be expected to eliminate or control all risk factors for urolithiasis. If risk factors for the type of urolith other than the one being prevented result in expression of disease (e.g., crystalluria) as a result of dietary modifications, appropriate adjustments in management should be made. Let us return to the question of how patients with recurrent struvite and calcium oxalate urolithiasis should be managed. The strategy we recommend is that if struvite urolithiasis is associated with urease-positive UTis, therapy should be devised to eradicate the UTI and prevent its recurrence. When considering dietary management, we recommend that emphasis be placed on minimizing recurrence of calcium oxalate or calcium phosphate uroliths, because these types of uroliths cannot be dissolved by medical management. Should struvite uroliths recur, they often can be dissolved by dietary management (Prescription Diet Canine s/d) and, if necessary, by antimicrobial agents. This strategy tends to minimize the need for repeated surgical intervention. For uroliths containing a nidus of calcium oxalate surrounded by layers of struvite, it is probable that the calcium oxalate stones predisposed the patient to infection-induced struvite urolithiasis. Therefore, preventive management should be designed to eradicate the bacterial UTI and to recommend changes in diet to minimize calcium oxalate urolith recurrence.

References 1. Abdullahi SU, Osborne CA, Leininger JR, et al: Evaluation of a calculolytic diet

in female dogs with induced struvite urolithiasis. Am J Vet Res 45:1508-1519, 1984 2. Asplin JR, Flavus MJ, Coe FL: Nephrolithiasis. In Brenner BM, Rector FC (eds): The Kidney, vol 2, ed 5. Philadelphia, WB Saunders, 1996, pp 1893-1935 3. Baillie NC, Osborne CA, Leininger JR, et al: Teratogenic effect of acetohydroxamic acid in clinically normal beagles. Am J Vet Res 47:2604-2611, 1986

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4. Bartges JW, Osborne CA, Polzin DJ: Recurrent sterile struvite urocystolithiasis in three related cocker spaniels. JAm Anim Hosp Assoc 28:459-469, 1992 5. Boistelle R, Abbona F, Berland Y, et al: Growth and stability of magnesium phosphate (struvite) in acidic sterile urine. Urol Res 12:79-83, 1984 6. Bovee KC, McGuire T: Qualitative and quantitative analysis of uroliths in dogs: Definitive determination of chemical type. JAVMA 185:983-987, 1984 7. Brande AI, Siemienski J: Role of bacterial urease in experimental pyelonephritis. J Bacteriol 80:171-179, 1960 8. Brodey RS: Canine urolithiasis: A survey and discussion of fifty-two clinical cases. JAVMA 126:1-9, 1955 9. Brown NO, Parks JL, Greene RW: Canine urolithiasis. Retrospective analysis of 438 cases. JAVMA 170:415-418, 1977 10. Brown NO, Parks JL, Greene RW: Recurrence of canine urolithiasis. JAVMA 170:419422, 1977 11. Clark WT: Staphylococcal infection of the urinary tract and its relation to urolithiasis in dogs. Vet Rec 95:204-206, 1974 12. Dedmond RE, Wrong 0: The excretion of organic anion in renal tubular acidosis with particular reference of citrate. Clin Sci (Colch) 22:19-32, 1962 13. Delluva AM, Markley K, Davies RE: The absence of gastric urease in germ-free animals. Biochem Biophys Acta 151:646-650, 1968 14. Domingo-Neumann RA, Ruby AL, Ling GL, et a!: Ultrastructure of selected struvitecontaining urinary calculi from dogs. Am J Vet Res 57:1274-1287, 1996 15. Feit RM, Fair WR: The treatment of infection stones with penicillin. J Urol 122:592594, 1979 16. Finco DR, Rosin E, Johnson KH: Canine urolithiasis: A review of 133 clinical and 23 necropsy cases. JAVMA 157:1225-1228, 1970 17. Fishbein WN: Urease inhibitors in the treatment of infection-induced stones: Some chemical, pharmacologic, and clinical considerations. In Smith LH, Robertson WG,

18. 19. 20. 21. 22. 23. 24. 25.

Finlayson B (eds): Urolithiasis: Clinical and Basic Research. New York, Plenum Press, 1981, pp 209-214 Ford DK, MacDonald J: Influence of urea on the growth ofT-strain mycoplasmas. J Bacteriol 93:1509-1512, 1967 Fowler JE: Bacteriology of branched renal calculi and accompanying urinary tract infection. J Urol 131:213-215, 1984 Friedlander AM, Braude AI: Production of bladder stones by human T-mycoplasmas. Nature 247:67-69, 1974 Grant RB, Penner JL, Hennessy JN, et a!: Transferable urease activity in Providencia stuartii. J Clin Microbiol 13:561-565, 1981 Griffith DP: Infection-induced stones. In Coe FL (ed): Nephrolithiasis: Pathogenesis and Management. Chicago, Year Book Medical, 1978, pp 203-228 Griffith DP: Struvite stones. Kidney Int 13:372-382, 1978 Griffith DP, Klein AS: Infection-induced urinary stones. International Perspectives in Urology 6:210-227, 1983 Griffith DP, Osborne CA: Infection (urease) stones. Miner Electrolyte Metab 13:278-

285, 1987 26. Hardy RM, Osborne CA, Cassidy FC: Urolithiasis in immature dogs. Vet Med Small Anim Clin 67:1205-1211, 1972 27. Hedelin H, Brorson JE, Grenabo L, et a!: Ureaplasma urealyticum and renal stones. Urol Res 12:30, 1984 28. Hess RS, Sanders H, Van Winkle TJ, et a!: Clinical, clinicopathologic, radiographic,

and ultrasonographic abnormalities in dogs with fatal acute pancreatitis. JAVMA 213:665-670, 1998 29. Kasper LV, Poole CM, Norris WP: Incidence of struvite urinary calculi in two ancestral lines of beagles. Lab Anim Sci 28:545-550, 1978 30. Kenney GE, Cartwright FD: Effect of urea concentration on growth on Ureaplasma urealyticum (T-strain mycoplasma). J Bacteriol 132:144-150, 1977 31. Kirby R, Crane S, Schaer M: Dissolution of a nephrolith in a dog. JAVMA 178:827828, 1983

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32. Klausner JS, Osborne CA: Dissolution of a struvite nephrolith in a dog. JAVMA 174:1100-1104, 1979 33. Klausner JK, O'Leary TP, Osborne CA: Calcium urolithiasis in two dogs with parathyroid adenomas. JAVMA 191:1423-1426, 1987 34. Klausner JS, Osborne CA, O'Leary TP, et al: Struvite urolithiasis in a litter of miniature schnauzer dogs. Am J Vet Res 40:712-719, 1980 35. Klausner JS, Osborne CA, O'Leary TP, et al: Experimental induction of struvite uroliths in Miniature Schnauzer and Beagle dogs. Invest Urol 18:127-132, 1980 36. Kobashi K, Kumaki K, Hose J: Effect of acryl residues of hydroxamic acids on urease inhibition. Biochem Biophys Acta 227:429-441, 1971 37. Kornberg HL, Davies RE, Wood DR: The breakdown of urea in cats not secreting gastric juice. Biochem J 56:355-363, 1954 38. Krawiec DR, Osborne CA, Leininger JR, et al: Effect of acetohydroxamic acid on dissolution of canine uroliths. Am J Vet Res 45:1266-1275, 1984 39. Krawiec DR, Osborne CA, Leininger JR, et al: Effect of acetohydroxamic acid on prevention of canine struvite uroliths. Am J Vet Res 45:1276-1282, 1984 40. Krieger JN, Boatman ES, Kenny GE: Ureaplasma urealyticum upper urinary tract infection: Persistence and pathogenicity in a canine model. J Urol141:1437-1443, 1989 41. Lamm DL, Johnson SA, Friedlander AM, et al: Medical therapy of experimental infection stones. Urology 10:418-421, 1977 42. Lees GE, Helman RG, Homco LD, et al: Early diagnosis of familial nephropathy in English cocker spaniels. JAm Anim Hosp Assoc 34:189-195, 1998 43. Levenson SM, Crowley LV, Horowitz RE, et al: The metabolism of carbon-labeled urea in the germ-free rat. J Biol Chern 234:2061-2062, 1959 44. Lewi HJE, White A, Hutchinson AG, et al: The bacteriology of the urinary and renal calculi. Urol Res 12:107-109, 1984 45. Lewis GA, Schuster GA, Cooper RA: Dissolution of renal calculi with dicloxacillin. Urology 22:401-403, 1983 46. Ling GV: Lower Urinary Tract Diseases of Dogs and Cats. St. Louis, Mosby, 1995 47. Ling GV, Hirsch DC: Antimicrobial susceptibility tests for urinary tract pathogens. In Kirk RW (ed): Current Veterinary Therapy VIII. Philadelphia, WB Saunders, 1983, pp 1048-1051 48. Ling GV, Franti CE, Johnson BA, et al: Urolithiasis in dogs. III. Prevalence of urinary tract infection, age, sex, and mineral composition. Am J Vet Res 59:643-D49, 1998 49. Lulich JP: Influence of dietary sodium on urinary calcium excretion in clinically normal dogs [PhD thesis]. University of Minnesota, St. Paul, MN, 1991, pp 123-133 50. Lulich JP, Osborne CA, Johnston GR: Non-surgical correction of infection-induced struvite uroliths and a vesicourachal diverticulum in an immature dog. J Small Anim Pract 30:613-617, 1989 51. Lulich JP, Osborne CA, Unger LK, et al: Nonsurgical removal of urocystoliths by voiding urohydropropulsion. JAVMA 203:660-D63, 1993 52. MacLaren DM: The significance of urease in Proteus pyelonephritis: A bacteriological study. J Pathol Bacteriol 96:45-56, 1968 53. Morrissey JF, Ochoa M, Lotspeich WD, et al: Citrate excretion in renal tubular acidosis. Ann Intern Med 58:159-166, 1963 54. Musher DM, Saenz C, Griffith DP: Interaction between acetohydroxamic acid and 12 antibiotics against 14 gram-negative pathogenic bacteria. Antimicrob Agents Chemother 5:106-110, 1974 55. Musher DM, Griffith DP, Tyler M, et al: Potentiation of the antibacterial effect of methenamine by acetohydroxamic acid. Antimicrob Agents Chemother 5:101-105, 1974 56. Nemoy NJ, Stamey TA: Surgical, bacteriological, and biochemical management of infection stones. JAMA 215:1470-1476, 1971 57. Nickel JC, Emtage J, Costerton JW: Ultrastructural microbial ecology of infectioninduced urinary stones. J Urol 133:622-627, 1985 58. Osborne CA, Lees GE: Bacterial infections of the canine and feline urinary tract. In Osborne CA, Pineo DR (eds): Diseases of the Canine and Feline Urinary System. Baltimore, Williams & Wilkins, 1995, pp 759-797 59. Osborne CA, Klausner JS, Lulich JP: Canine and feline calcium phosphate urolithiasis.

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60. 61.

62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84.

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In Bonagura JD, Kirk RW (eds): Current Veterinary Therapy, vol 12. Philadelphia, WB Saunders, 1995, pp 966-1001 Osborne CA, Unger LK, Lulich JP: Prevalence, diagnosis and management of canine and feline nephroliths. In Bonagura JD, Kirk RW (eds): Current Veterinary Therapy, vol 12. Philadelphia, WB Saunders, 1995, pp 981-985 Osborne CA, Lulich JP, Unger LK, et a!: Canine and feline urolithiasis: Relationship of etiopathogenesis to treatment and prevention. In Osborne CA, Pineo DR (eds): Diseases of the Canine and Feline Urinary System. Baltimore, Williams & Wilkins, 1995, pp 798888 Osborne CA, Abdullahi SU, Polzin DJ, et a!: Current status of medical dissolution of canine and feline uroliths. In Proceedings of the Seventh Kal Kan Symposium, Vernon, CA, 1984, pp 52-79 Osborne CA, Klausner JS, Polzin DJ, et a!: Etiopathogenesis of canine struvite urolithiasis. Vet Clin North Am Small Anim Pract 16:67-86, 1986 Osborne CA, Klausner JS, Abdullahi SU, et a!: Medical dissolution and prevention of canine struvite uroliths. In Kirk RW (ed): Current Veterinary Therapy, ed 8. Philadelphia, WB Saunders, 1983, pp 1066-1072 Osborne CA, Polzin DJ, Kruger JM, et a!: Medical dissolution of canine struvite uroliths. Vet Clin North Am Small Anim Pract 16:349-374, 1986 Osborne CA, Polzin DJ, Kruger JM, et a!: Medical dissolution and prevention of canine struvite uroliths. In Kirk RW (ed): Current Veterinary Therapy, ed 9. Philadelphia, WB Saunders, 1986, pp 1177-1187 Osborne CA, Polzin DJ, Johnston GR, eta!: Medical management of canine uroliths with special emphasis on dietary modifications. Comp Anim Pract 1:72-87, 1987 Osborne CA, Polzin DJ, Lulich JP, eta!: Relationship of nutritional factors to the cause, dissolution, and prevention of canine uroliths. Vet Clin North Am Small Anim Pract 19:583-619, 1989 Osborne CA, Polzin DJ, Abdullahi SU, eta!: Struvite urolithiasis in animals and man: Formation, detection and dissolution. Adv Vet Sci Comp Med 29:1-101, 1985 Pak CYC, Fuller C, Sakhaee K, et a!: Management of cystine nephrolithiasis with alpha mercaptopropionyl glycine. J Urol 136:1003-1008, 1986 Parsons CL, Stauffer C, Mulholland SG, et al: Effect of ammonia on bacterial adherence to bladder transitional epithelium. J Urol 132:365-366, 1984 Pettersson S, Brorson JE, Grenabo L, et al: Ureaplasma urealyticum in infectious urinary tract stones. Lancet 1:526-527, 1983 Polzin DJ, Osborne CA, Hayden DW, et a!: Effects of modified protein diets in dogs with chronic renal failure. JAVMA 183:980-986, 1983 Rocha AH, Santos LCS: Relapse of urinary tract infection in the presence of urinary tract calculi. The role of bacteria within calculi. J Med Microbial 2:372-376, 1969 Rosenstein IJM, Hamilton-Miller JMT: Inhibitors of urease as chemotherapeutic agents. Crit Rev Microbial 11:1-12, 1984 Senior DF, Thomas WC, Gaskin JM, et a!: Relative merit of various strategies of nonsurgical treatment of infection stones in dogs. Urol Res 12:39, 1984 Shepard MC, Lunceford CD: Occurrence of urease in T-strains of mycoplasma. J Bacterial 93:1513-1520, 1967 Stamey TA: Pathogenesis and Treatment of Urinary Tract Infections. Baltimore, Williams & Wilkins, 1980 Sutor DJ: The nature of urinary stones. In Finlayson B (ed): Urolithiasis: Physical Aspects. Washington, National Academy of Science, 1992, pp 43-60 Takeuchi H, Takayama H, Konishi T, et al: Scanning electron microscopy detects bacteria with infection stones. J Urol 132:67-69, 1984 Tannen RL: Ammonia metabolism. Am J Physiol 235(suppl):F265-F277, 1978 Thornhill JA: Renal tubular acidosis. In Kirk RW (ed): Current Veterinary Therapy VII. Philadelphia, WB Saunders, 1977, pp 1087-1097 Vermeulen CW, Goetz R: Experimental urolithiasis. IX. Influence of infection on stone growth in rats. J Urol 72:761-769, 1954 Wong HY, Riedl CR, Griffith DP: Medical management and prevention of struvite

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stones. In Coe FL, Favus MJ, Pak CYC, et a!: Kidney Stones: Medical And Surgical Management. Philadelphia, Lippincott-Raven, 1996, pp 941-950

Address reprint reqeusts to: Carl A. Osborne, DVM Minnesota Urolith Center Department of Small Animal Clinical Sciences College of Veterinary Medicine University of Minnesota St. Paul, MN 55108

APPENDIX 1

Common Characteristics of Canine Struvite Uroliths Chemical name: Magnesium ammonium phosphate hexahydrate Crystal name: Struvite Formula: MgNH.P04 • 6H20 Variations in mineral composition: Struvite only Struvite mixed with lesser amounts of calcium apatite, carbonate apatite, and ammonium urate Nucleus of a different mineral surrounded by variable layers composed primarily of struvite. Small quantities of calcium apatite or ammonium acid urate also may be present. Physical characteristics: Color: Struvite uroliths are usually white, cream, or light brown in color. The surface of uroliths is commonly red because of concomitant hematuria and may be green (caused by bile pigments). Shape: Variable; solitary urocystoliths are commonly round or elliptic, and multiple urocystoliths may be any shape but are often pyramidal. Rapidly growing uroliths with a large quantity of matrix may form a cast of the lumen (renal pelvis, ureter, bladder, urethra) in which they are formed. Nuclei and laminations: Common in infection-induced uroliths Density: Variable; soft if they contain a large quantity of matrix but dense and harder to cut if little matrix is present. A combination of hard and soft internal density may occur within the same urolith. Radiodense compared with nonskeletal tissue on survey radiographs. The degree of radiodensity is related to the quantity of matrix (inversely proportional) and other minerals, especially calcium apatite (more proportional). Number: Single or multiple Location: May be located in the kidney, ureter, urinary bladder, or urethra. Most occur in the urinary bladder. Size: Subvisual to a size limited by the capacity of the structure (kidney and urinary bladder) in which they form. Extremely large uroliths are often composed of struvite. Predisposing factors: Urinary tract infections with urease-producing microbes in urine with a large quantity of urea Alkaline urine pH

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Abnormal retention of urine Unidentified factors Characteristics of affected patients: Mean age: 6 years (range, <1 to >9 years) Breeds: Commonly encountered in Miniature Schnauzers, Shih Tzus, Bichon Frises, Miniature Poodles, Cocker Spaniels, and Lhasa Apsos, but any breed may be affected Gender: More common in female (85%) than male (15%) dogs

APPENDIX 2

Summary of Recommendations for Medical Dissolution of Canine Struvite Uroliths I. Adult dogs with urinary tract infection induced struvite A. Perform appropriate diagnostic studies, including complete urinalyses, quantitative urine culture, and diagnostic radiography. Determine precise location, size, and number of uroliths. The size and number of uroliths are not a reliable index of probable efficacy of therapy. B. If available, determine mineral composition of uroliths. If unavailable, "guesstimate" their composition by evaluation of appropriate clinical data. C. Consider surgical correction if uroliths are (1) obstructing urine outflow and cannot be moved by urohydropropulsion, (2) if surgically correctable abnormalities predisposing to recurrent urinary tract infection are identified by radiography or other means, or (3) if the benefit-to-risk ratio warrants surgery rather than medical dissolution protocols. Small urocystoliths may be removed by voiding urohydropropulsion. D. Eradicate or control urinary tract infections with appropriate antimicrobial agents selected on the basis of appropriate antimicrobial susceptibility tests. Maintain full-dose antimicrobial therapy during and for 3 to 4 weeks following urolith dissolution. E. Initiate therapy with calculolytic diets. Other foods or mineral supplements should not routinely be fed to the patient. Compliance with dietary recommendations is suggested by reduction in the serum urea nitrogen concentration (usually below 10-15 mg/ dL in patients with adequate renal function). F. Devise a protocol to monitor efficacy and safety of therapy. 1. Try to avoid diagnostic follow-up studies that require urinary catheterization. If it is required, give appropriate pericatheterization antimicrobial agents to prevent iatrogenic urinary tract infection. 2. Evaluate serial urinalyses. Urine pH, specific gravity, and microscopic examination of sediment for crystals are especially important. Remember that crystals formed in urine stored at room or refrigeration temperature may represent in vitro artifacts. 3. Perform serial radiography or ultrasonography at monthly intervals to evaluate stone location(s), number, size, density, and shape. 4. If necessary, perform quantitative urine cultures. They are especially

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important in patients that are infected prior to therapy and in patients that are catheterized during therapy. 5. For patients predisposed to pancreatitis, periodically monitor appropriate diagnostic protocols to evaluate the integrity of the pancreas. 6. Feed patients calculolytic diet for 1 month following disappearance of uroliths as detected by survey radiography. 7. If uroliths increase in size during dietary management or do not begin to decrease in size after approximately 4 to 8 weeks of appropriate medical management, alternative methods should be considered. Difficulty in inducing complete dissolution of uroliths by creating urine that is undersaturated with the suspected calculogenic crystalloid should prompt consideration that (1) the wrong mineral component was identified, (2) the nucleus of the uroliths is of different mineral composition than other portions of the urolith, or (3) the owner of the patient is not complying with medical recommendations. 8. Consider administration of acetohydroxamic acid (25 mg/kg/ d divided into two equal doses) to patients with persistent uroliths and persistent urease-producing microburia despite the use of antimicrobial agents and calculolytic diets. II. Adult dogs with persistently sterile urine A. Follow the protocol described above, but do not administer antimicrobial agents or acetohydroxamic acid. B. If warranted on the basis of the results of urinalysis, periodically culture urine specimens obtained by cystocentesis to detect secondary urinary tract infections. If a urinary tract infection develops, initiate antimicrobial therapy. III. Immature dogs A. Use caution in consideration of the use of protein-restricted diets in growing pups. B. Short-term therapy with calculolytic diets has been effective in dissolving struvite urocystoliths. If initiated, monitor the patient for evidence of nutritional deficiencies (especially protein malnutrition). C. Acetohydroxamic acid has not been evaluated in growing pups. D. Small urocystoliths may be removed by voiding urohydropropulsion. Pending further studies, surgery remains the safest means of removing large uroliths from immature dogs.