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Causes of uroliths

There are 3 primary factors which contribute to urolith formation:

• supersaturation of urine with minerals leading to crystalluria. Urine may be supersaturated with crystals due to increased dietary intake of those crystals, reduced solubility of crystals due to pH, concentrated urine enhancing crystal concentration or congenital abnormalities resulting in the presence of abnormal crystals in the urine
• delayed passage of crystals through the urinary tract. Crystal elimination may be delayed due to adherence of crystals to damaged mucosa, stationary foreign bodies (i.e., suture), sludging in an atonic bladder, or in a urachal diverticulum. A calculus of one mineral type may act as a stationary foreign body upon which minerals of a different type may deposit .
• reduction of normally present inhibitors of crystal growth and aggregation (i.e. citrate, pyrophosphates).

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Clinical presentations

The clinical presentation of an animal with urolithiasis depends upon the location of the uroliths. Uroliths can lodge in the urethra of the male dog, but rarely lodge in the urethra of bitches as the female urethra is shorter and more distensible. Uroliths usually lodge at the two narrowest regions of the male urethra; the caudal aspect of os penis and the point at which the urethra curves around the ischium of the pelvis (called the ischial arch). The urethra is less distensible in these two locations and uroliths will result in partial or total obstruction. Clinical signs associated with urethral obstruction may include:

• frequent attempts to urinate producing small amounts of urine
• straining to urinate (stranguria or dysuria)
• inability to urinate (anuria) if the obstruction is complete
• incontinence. The animal may unconsciously dribble urine past a partial obstruction
• hematuria
• cver-distended urinary bladder
• rupture of the urinary bladder resulting in ascites
• signs of postrenal uremia

Cystic calculi (bladder location) result in signs including:

• dysuria/stranguria
• hematuria
• pollakiuria
• the bladder is small due to the frequent voiding but lack of obstruction
• systemic signs are usually absent

Renal or ureteral calculi may result in the following signs:

• abdominal pain
• hematuria
• hydronephrosis causing renal enlargement may occur if the calculus obstructs urine flow
• systemic signs of anorexia, depression and fever may occur if a UTI accompanies the calculus

Animals with bladder or renal calculi may be asymptomatic.

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Clinical evaluation

Laboratory

The laboratory evaluation of many patients with non-obstructive urolithiasis is normal. Leukocytosis may be observed if there is an acute infection of the kidneys or prostate. Anemia may be present due to blood loss or due to the anemia of chronic inflammatory disease . If the animal has an obstruction, serum biochemical abnormalities are those of post renal obstruction. Patients with calcium oxalate calculi may be hypercalcemic.

Urinalysis often discloses

• hematuria
• pyuria due to inflammation or infection
• proteinuria from blood or inflammation or infection (secretory/post glomerular proteinuria)
• crystalluria
• bacteria if UTI is present
• isosthenuria may be present if concurrent pyelonephritis led to renal dysfunction. Isosthenuria may also reflect an under lying disease that led to stone formation such as liver disease which may result in urate uroliths and dilute urine.

The urine pH is variable and may provide a clue as to the type of urolith present

• struvite uroliths form in alkaline urine
• calcium oxalate uroliths form in acid urine

Crystals in the urine represent a risk factor for urolithiasis but are not proof positive that uroliths are present. Animals can have crystals without having uroliths and some animals with uroliths do not have crystals in the urine. The significance of crystals is as follows:

• magnesium, ammonium phosphate (struvite) crystals may indicate the presence of struvite uroliths but can be seen in the urine of normal animals
• ammonium urate crystals can be seen in the urine of animals with portal vascular anomalies, severe hepatic disease, or normal Dalmatians
• calcium oxalate crystals can be seen in the urine of normal animals, ethylene glycol intoxicated animals, animals with calcium oxalate calculi or hypercalcemic animals
• cystine crystals are always abnormal and indicate an impaired ability of the renal tubules to reabsorb the amino acid cystine

In vitro variables may affect the formation or dissolution of crystals in vitro. Evaporation, pH changes, and temperature all may all affect the appearance or disappearance of crystals. Analysis of fresh urine will provide a better indicator of the degree of crystal saturation in vivo. Drugs including sulfonamides, contrast agents, ampicillin, and primidone may precipitate as crystals in the urine. Urine crystals that form while patients are consuming diets fed in the hospital may be different than the urine crystals formed by patients fed in the home environment.

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Radiology

The radiographic appearance of calculi depends on the size and mineral composition of the urolith(s). Based on mineral content, calcium oxalate, struvite, and silica are almost always radio opaque. Very small uroliths of radio dense minerals may be over-looked on radiographic examination. Cystine and ammonium urate are less radio opaque and may require contrast studies to be seen. If they are moderate to large in size then they may be seen without contrast.

If uroliths are found in one portion of the urinary tract, other parts of the urinary system should also be evaluated radiographically for calculi. Radiographic evaluation may also disclose predisposing or complicating abnormalities. Ultrasound can also be used to detect calculi in both the bladder and kidneys.

The qualitative and quantitative mineral composition of calculi should be determined to help formulate prophylactic measures to prevent recurrence after surgical removal of the calculi or to institute medical dissolution. A urolith should be broken and the center of the calculus should be evaluated separately from the outer layers as the nidus (center) may differ in mineral composition from the outer layers. A commercial kit is available--the Oxford stone analysis kit--but the kit will not detect xanthine or silica, and has been reported unreliable in consistently detecting calcium.

Commercial laboratories will perform stone analysis by crystallographic methods which provide the percentages of all mineral types which comprise the stone.

Urolithiasis Laboratory

PO Box 25375

Houston, TX 77005

Urinary Stone Analysis Laboratory

Dept of Medicine

School of Veterinary Medicine

University of California

Davis, CA 95616

Urolithiasis Laboratory
College of Veterinary Medicine
University of Minnesota
St. Paul, Minnesota

Cultures should be obtained from both the center and outer layer of the urolith. If the animal has recently received antibiotics, the urine and the external surface of the uroliths may be sterile but the center may still harbor bacteria, indicating that bacterial infection was present at the onset of stone formation and may have contributed to stone formation

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Struvite urolithiasis

Struvite is composed primarily of magnesium ammonium phosphate but may be impure, containing minor quantities of calcium phosphate. Other names for struvite uroliths include phosphate calculi, triple phosphate stones, and infection stones. Struvite uroliths are the most common type of calculi occurring in dogs. They can affect any age animal and are more common in female dogs. The breeds most commonly affected are the miniature schnauzer and the poodle, Shih Tzu, Bichon Frise, Lhasa Apso, and Cockers

There are several factors which promote development of struvite uroliths including:

• alkaline urine
• increased mineral concentration
• concentrated urine
• genetic predisposition

UTI with urease producing bacteria (urease catalyzes the conversion of urea to ammonia) results in alkaline urine and increases the concentration of ammonium ion in urine. Staphylococcus, proteus, and ureaplasma are urease producing bacteria. Most, but not all dogs with struvite uroliths have a UTI. Experimentally produced urinary tract infections have resulted in struvite calculi formation in 2-8 weeks (average = 4.5 weeks).

Struvite crystals are less soluble in alkaline urine and are more likely to precipitate on an organic matrix as uroliths. Other causes of alkaline urine include drugs such as sodium bicarbonate, renal tubular acidosis in which bicarbonate is lost in the urine resulting in systemic acidosis, and diets high in cereal proteins.

Concentrated urine and increased amounts of crystals in the urine increases the probably of crystals aggregating to form uroliths.

There is a high frequency of occurrence of struvite uroliths in Miniature Schnauzers suggesting a genetic predisposition.

The gross appearance of struvite uroliths may be smooth or spiked like a jack.

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Treatment of patients with struvite uroliths

If urethral obstruction is present, the obstruction should be removed by hydropropulsion of the urolith(s) into the bladder. If the urethral stone cannot be dislodged, a urethrotomy must be performed to alleviate the obstruction.

Struvite uroliths in the bladder can be treated by surgical removal or medical dissolution. Small uroliths may be missed during surgery so medical dissolution measures are advised for 3-4 weeks post surgical to dissolve any remaining small uroliths. Postoperatively a urolith should be analyzed for chemical composition and a bacterial culture performed. Surgical candidates include patients with obstruction that cannot be corrected by nonsurgical means, patients with anatomic defects of the urogenital tract that predispose to urolithiasis and are amenable to surgical correction, poor client compliance with therapeutic recommendation and patients with stones that are not decreasing in size in response to medical measures.

In order to initiate medical dissolution of uroliths, you need to have some information regarding the mineral type of the urolith. "Guess-timate" of mineral type is made upon

• radiographic density
• alkaline urine pH
• struvite crystals,
• urinary tract infection especially with staphylococcus or proteus
• analysis of any stones voided. You may catch small stones in a screen fish net as they are voided, or may aspirate small stones with a catheter.
• frequency of occurrence in the breed
• history of uroliths in related animals

The goal of medical management is to promote dissolution by inducing undersaturation of urine with minerals causing the minerals in the uroliths to go into solution. The components of medical management are:

• Administer antibiotics based on urine culture for as long as uroliths are visible radiographically and for one additional month.
• Feed a calculolytic diet (SD- Hills) until uroliths are no longer radiographically visible and for one additional month. SD diet has the following attributes:

  1. reduced protein (7.6%-9.4%). Less protein in the diet results in less urea in the urine and less ammonia production by urease producing bacteria. There is less ammonia to contribute as a substrate of struvite uroliths as well as less effect on increasing urine pH.

  2. reduced magnesium and reduced phosphorus which are the mineral substrates of struvite uroliths

  3. high salt to promote diuresis and dilute crystals

  4. production of acid urine which makes struvite crystals more soluble

It is important to feed ONLY the calculolytic diet. Owner and animal compliance can be evaluated. If the protocol was followed properly the BUN will be <10 mg/dl, urine pH < 6.5, and urine SG < 1.015.

If UTI persists despite appropriate antibiotic therapy, acetohydroxamic acid can be added to the treatment regime. Acetohydroxamic acid is a urease inhibitor. It is dosed at 25 mg/kg/day divided in 2 doses. Potential side effects include:

• teratogenesis
• hemolytic anemia
• abnormal bilirubin metabolism.

During medical treatment, monitor the patient monthly including BUN, albumin, urinalysis, and abdominal radiographs. Stones dissolve in 8-20 weeks (mean = 3.5 months). If there is no change in the size of uroliths in 8 weeks, the stone is probably not struvite or is refractory to dissolution and surgery should be performed. For those patients who show regression in size of the stone, continue medical therapy for 1 month after the stone can no longer be visualized on radiographs.

If the urine is sterile, then feed only the calculolytic diet without antibiotics. Use this protein restricted diet in growing pups with caution. Severely protein restricted diets such as SD should not be fed long term as hypoproteinemia may develop.

The recurrence rate of struvite uroliths is 21 - 25% if a prophylactic measure is not implemented.

Methods to prevent reoccurrence include:

• Early identification and treatment of UTI. Have the owner monitor urine pH on the first urine voided in the morning, once a week. If the urine is alkaline then it should be cultured to identify UTI early, before stones reoccur.
• If urine remains alkaline despite antimicrobial therapy, the diet can be changed to promote formation of acid urine or an acidifier can be administered without a change in diet. Hills CD (22.2-22.8% protein dry matter) is mildly protein restricted, mineral restricted, and promotes acid urine. SD is too low in protein for long term use and will result in protein depletion if used long term.
• The diet can be salted to encourage increased water intake and formation of dilute urine to dilute crystals but chronic salt administration can predispose to development of hypertension and therefore is NOT recommended.

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Urate uroliths

Urate calculi form from uric acid which is the end product of purine metabolism. Purines are components from the nuclei of cells.

Purines are converted to xanthines which are converted to uric acid which is converted to allantoin. Allantoin is the substance which is excreted in the urine in most dogs and cats.

The prevalence of urate calculi is less than for struvite uroliths. Urate uroliths can be comprised of 100% uric acid or a sodium or ammonium salt of uric acid. In dogs, 90% of urate uroliths are ammonium urate. Urate uroliths may be mixed with calculi of other mineral types.

Predisposing factors for development of urate uroliths include:

• enhanced uric acid excretion in urine
• acid urine pH
• absence of inhibitors of urolith formation
• elevated blood ammonia

Dalmatian dogs are homozygous for a recessive trait which predisposes them to development of urate calculi. The defect results in impaired ability of hepatocytes to take up uric acid. The hepatocytes are responsible for the conversion of uric acid to allantoin. If the hepatocytes cannot take up uric acid, the concentration of uric acid is increased in the blood. Additionally, Dalmatians have impaired renal proximal tubular reabsorption of uric acid leading to increased levels of uric acid in urine. It is possible that non Dalmatian dogs which form urate uroliths are also homozygous for this trait.

Patients with hepatic disease or portosystemic shunts have a reduced ability to produce allantoin from uric acid with a resultant increase in blood and urine uric acid concentration. Additionally patients with hepatic disease have an impaired ability to convert ammonia to urea with resultant hyperammonia.

Approximately 70% of dogs which develop urate uroliths are male. Breeds which are particularly susceptible include the Dalmatian (60% of urate stones occur in Dalmatians), bulldogs, and Yorkshire terriers. Urate calculi are generally not associated with UTI. They appear as multiple small, round, green-brown calculi.

If urethral calculi are present they should be hydropropulsed into the bladder. Urate calculi can be surgically removed or dissolved. Medical management includes:

• feeding a low protein/low purine diet which avoids lean meats and glandular organs which are high in purines. UD diet by Hills is 9.5%-10.4% protein dry matter
• allopurinol which is a xanthine oxidase inhibitor is administered at 30 mg/kg/day divided BID or TID
• sodium bicarbonate or potassium citrate will reduce the renal production of ammonia and should be dosed to a urine pH of 7.0 with 1/4 tsp/5 kg TID (sodium bicarbonate) as a starting dose. UD may maintain alkaline urine without addition of an alkalinizing agent.
• Salt diuresis (1/4 tsp/5 kg daily) or mixing water with food will dilute crystals

Medical therapy is continued therapy for at least 1 month following radiographic disappearance of uroliths.

Recurrence is common with 33-50% recurrence within 1 year. UD may be fed indefinitely to reduce recurrence. Other measures (alkalinizing agents, allopurinol) may need to be introduced in a stepwise fashion if diet change alone is insufficient to control recurrence.

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Cystine calculi are caused by an inherited sex linked metabolic abnormality resulting in tubular inability to reabsorb the amino acid, cystine and occasionally other amino acids. The prevalence is low compared to other mineral types. Cystinuria may occur in both sexes but cystine calculi occur more often in males. Not all dogs with cystinuria develop urolithiasis. The calculi usually occur in younger animals, with a mean age of 4.8 years.  Dachshunds are the most common breed to develop cystine uroliths. 

Cystine uroliths are usually small, smooth, yellow brown to yellow green. They can be radiopaque or radiolucent depending upon their size.

Cystinuria can be detected by identification of hexagonal cystine crystals in acid urine or by performing a nitroprusside test on urine.

Cystine uroliths can be surgically removed or medically dissolved. Medical management includes:

• feeding a protein restricted diet low in methionine such as UD
• increasing water intake will dilute the crystals but salt should not be administered as increased sodium may increase urine cystine excretion
• increasing urine pH > 7.5 will increase solubility of crystals. Potassium citrate is preferred over sodium bicarbonate due to sodium's effect on increasing urine cystine.
• D-penicillamine changes cystine to more soluble form. It is dosed at 10-30 mg/Kg divided BID. One author suggests this dose to be intolerable by many patients and advocates a dose of 10 mg/Kg. D-penicillamine delays wound healing, so avoid use immediately postoperative if calculi are surgically removed. Alpha-mercaptopropionylglycine (MPG) -  has fewer side effects which appears to be more effective than D-penicillamine but is not approved yet for use in dogs. Dr. Osborne at the University of Minnesota has had success in dissolving cystine calculi using Hills UD and 2 MPG.

Avoid breeding affected animals due to the inherited nature of the defect.

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Calcium oxalate urolithiasis

Calcium oxalate urolithiasis occurs most commonly in older male dogs although they may occur in females as well. They are the second most common stone type occurring in dogs. A contribution to development may be the reduction of estrogens and increase in testosterone which occurs with advancing age. Estrogens increase the concentration of citrate in the urine and decrease the excretion of calcium. As estrogens decrease, the opposite situation exists which is a reduction in urine citrates and an increase in urine calcium. Testosterone may increase hepatic oxalate production. A crystal inhibiting agent, nephrocalcin is abnormal in humans with calcium oxalate uroliths. Nephrocalcin has been measured in some dogs and appears as though it may also be abnormal in dogs with calcium oxalate uroliths. 

Oxalate calculi usually occur in the bladder and urethra in dogs compared to humans which develop renal oxalate uroliths. 

Breeds most commonly developing calcium oxalate uroliths:

Schnauzers
Lhasa Apso
Yorkshire terriers
Bichon Frise
Shih Tzu
Miniature poodles

Factors predisposing an animal to oxalate uroliths include:

• hypercalcemia from primary hyperparathyroidism, vitamin D intoxication, osteolytic neoplasia, or pseudohyperparathyroidism
• hypercalciuria with normocalemia (most animals with calcium oxalate calculi are normocalcemic) due to increased intestinal absorption of calcium and decreased renal tubular reabsorption of calcium
• hyperuricosuria which may serve as nidus for oxalate stone formation
• hyperoxaluria
• Dogs with hyperadrenocorticism have a predisposition to developing calcium oxalate uroliths. Glucocorticoids increase the urinary excretion of calcium.

Diagnostic information includes:

dihydrate	monhydrate

Calcium oxalate crystals may be observed in urine. They may be octahedral shaped (dihydrate) or spindle shaped (monohydrate). Normal animals can have a few oxalate crystals and not all animals with calcium oxalate uroliths will have crystals in their urine.

Calculi are radiodense and can be observed on survey radiographs or with ultrasound unless they are very small.

Calcium oxalate uroliths must be surgically removed since attempts to dissolve calcium oxalate uroliths in dogs have been unsuccessful.   After removal preventative measures against reoccurrence include:

• avoidance of oxalates from foods such as spinach, rhubarb and  parsley
• avoid vitamin C, which increases oxalate production
• avoid high calcium or sodium content in water or diet. Avoid milk products  Boiling water will precipitate calcium as calcium carbonate.
• avoid additional salt which increases calcium in urine
• avoid excessive dietary protein that may increase urine calcium and oxalate excretion in urine. Hills UD, KD or WD are recommended.
• thiazide diuretics (hydrochlorothiazide) decrease urine calcium excretion. They should be avoided in hypercalcemic states.
• do not restrict P which contributes to the pyrophosphate, a crystal inhibiting agent. Low P in the diet may increased Ca uptake.
• avoid acidifiers which increase urine calcium excretion and decrease urine citrate. 
• citrate inhibits calcium oxalate crystal formation and promotes alkaline urine which enhances the tubular reabsorption of calcium. Potassium citrate may be administered. UD contains potassium citrate so additional citrate is not needed if feeding UD unless crystalluria and acid urine persist.
• High fiber diets seem to decrease the degree of hypercalcemia in those patients with elevated serum calcium.
• Vitamin B6

Although a diet specifically designed to prevent calcium oxalate stone formation has not yet been developed, most (but NOT ALL) of the criteria for prevention are met by UD, KD or WD.

Monitor UA. Effective control should result in neutral to slightly alkaline pH and absence of CaOx crystals.

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Silica uroliths are composed of amorphous silica. The prevalence is low and German Shepherds may be over represented. Silica uroliths occur frequently in dogs in Kenya as dog food is predominantly corn. Dogs drinking from water sources containing sand may also develop silica uroliths. Silica uroliths are shaped like a jack and are radiodense. There are no characteristic crystals in the urine. Silica will not be detected by calculi analysis using commercial kits (Oxford stone analysis set - Oxford labs).

They must be surgically removed.

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Feline urolithiasis:

20,343 Calculi, Published 2000, Ettinger Textbook of Veterinary Internal Medicine, p 1719

Calculi occur less frequently in cats compared to dogs. Widespread use of diets designed to reduce struvite crystals in the urine have resulted in calcium oxalate and ammonium urate becoming more prevalent than in the past when struvite stones were the most common type occurring in cats.  Amorphous urethral plugs of struvite and large amounts of matrix which obstruct the urethra of some male cats are not truly uroliths.   Struvite uroliths in the cat are usually sterile. Struvite uroliths are usually wafer or disc shaped and may be difficult to palpate but are usually radiodense.

Treatment can be surgical removal or medical dissolution with a calculolytic diet such as feline SD (Hills). The feline struvite diet contains a normal protein content for cats, (not like the reduced protein content of canine SD) reduced magnesium and phosphorus, high salt to promote diuresis, and it promotes acid urine (pH - 6.0). The diet is not protein restricted as infection is not a component of feline uroliths and the purpose of protein restriction in dogs is to reduce urea in the urine which is a substrate for ammonia production. Monitor dissolution as for dogs.

Prevention of recurrence should be accomplished by feeding a low phosphorus and magnesium diet (e.g., Hills CD).

Metabolic uroliths have a low rate of occurrence in cats and surgical removal is the treatment of choice.

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Nephroliths

Most nephroliths in dogs and cats are calcium oxalate or struvite, with calcium oxalate being the most common.

Clinical signs are determined by:

• the size and rate of growth of nephroliths
• unilateral or bilateral involvement
• location (do the stones obstruct the ureters?)
• concomitant infection
• renal function prior to stone formation

Clinical signs may include:

• a symptomatic
• hematuria (microscopic or gross)
• signs of uremia and/or sepsis if pyelonephritis is present
• death from bilateral obstruction of renal pelves/ ureters
• unilateral obstruction causes unilateral hydronephrosis that may be silent. if not associated with infection 

Treatment

Not all animals with clinically silent nephroliths need to be treated. Symptomatic and young animals should be considered candidates for treatment. Treatment may be medical or surgical. Surgical removal of uroliths is usually staged into 2 procedures, 4 to 6 weeks apart in animals with bilateral stones. Nephrotomy was shown to cause a 20 to 40% reduction in GFR in previously healthy dogs. The study only lasted 6 weeks so it is unknown how much function may be regained. You might consider removing stones(s) from one kidney and if the mineral analysis is struvite, attempting medical dissolution of the stone(s) in the opposite kidney.

An alternative to surgery is the use of shock wave lithotripsy to break stones into smaller pieces that can be passed. Although the technique is not widely available for animal patients, it has been shown to be effective in dogs with nephroliths. The use of lithotripsy requires the stone be in a fixed position. Therefore lithotripsy is not very effective for bladder stones although some veterinarians have used lithotripsy to break up large stones in the bladder to hasten their dissolution by dietary means.

There is a fair amount of information on the use of lithotripsy for fragmenting renal calculi in dogs and some recent information on the use of lithotripsy in cats. Lithotripsy does cause some degree of renal trauma resulting in renal swelling or hemorrhage and has been associated with worsening of renal function in cats so the risks versus benefits need to be weighed in this species.

Lithotripsy: an update on urologic applications in small animals.
 

Struvite nephroliths can be dissolved using an acidifying diet restricted in protein, magnesium, phosphorus and high in salt, monitoring as for dissolution of bladder stones.

Method to prevent reoccurrence are the same as for struvite calculi in the bladder. 

Calcium oxalate calculi can not be dissolved. Management to prevent reoccurrence of calcium oxalate nephroliths after surgical removal is the same as for preventing bladder stones of the same mineral type. 

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Dietary Manipulation

Given that several parameters that constitute risk factors for calcium oxalate urolithiasis predispose to struvite urolithiasis and vice versa, pet food companies have adopted one of 2 strategies:

1. separate diets designed to reduce the occurrence of each mineral type

2. a combined diet that results in a pH low enough to reduce struvite urolith formation yet high enough to reduce calcium oxalate urolith formation. These diets have varied degrees of mineral restriction and some have potassium citrate added to increase the solubility of oxalate crystals. 

Also see Nutrition Support Service at Ohio State