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Urolithiasis Stephen P. DiBartola, DVM
Department of Veterinary Clinical Sciences College of Veterinary Medicine Ohio State University Columbus, OH 43210 The Nephronauts
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Urolithiasis Urine: a complex aqueous solution of organic and inorganic solutes More of a given solute can remain in solution in urine than in water due to the complex interactions among the various constituents of urine
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Urolithiasis Urine is commonly supersaturated with crystalloids
Observation of individual crystal types in urine does not necessarily mean the patient is at risk for developing urolithiasis
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Urolithiasis Supersaturation (solubility product exceeded) of urine with a crystalloid depends on: Amount of solute ingested and excreted Urine volume Urine pH Promoters Inihibitors
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General theories of urolithiasis
Precipitation-crystallization theory Matrix-nucleation theory Crystallization-inhibition theory Some combination of the above?
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Urolithiasis: Crystal growth
Homogenous nucleation: crystals precipitate spontaneously (unlikely in urine) Heterogenous nucleation: another substance acts as a nidus for crystal precipitation (likely in urine) Epitaxy: Precipitation of one crystal on the surface of another
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Inhibitors of crystallization and aggregation
Pyrophosphates Diphosphonates Citrate Some cations (e.g. Mg+2) Glycosaminoglycans Nephrocalcin
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Urolithiasis: Naming of stones
When 70% of the urolith is composed of one type of crystal it is named for the crystal Mixed urolith < 70% one crystal; no identifiable nidus or shell Compound urolith Identifiable nidus of one crystal with surrounding layers of another crystal Matrix urolith Matrix without appreciable crystalloid
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Prevalence of stone types
Dogs Cats Number 77,190 20,343 Struvite 50% 43% Oxalate 31% 46% Urate 8% 6% Cystine 1% < 1% Silicate < 0.1% Calcium phosphate Data from University of Minnesota Stone Laboratory 2000
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Struvite urolithiasis
Most common stone type in dogs Major crystalloid is MgNH4PO4•H2O Calcium phosphate also present in small amounts (2-10%)
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Struvite urolithiasis
Bladder is most common site in dogs and cats High recurrence rate (> 20%) Younger animals
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Struvite urolithiasis
Struvite solubility decreases in alkaline urine UTI with urease-positive bacteria (Staphylococci, Proteus spp) plays primary role in pathogenesis in dogs but not cats
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Oxalate urolithiasis Most common stone type in humans
Incidence in cats and (to a lesser extent) dogs has been increasing in the past 20 years
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Oxalate urolithiasis Composed of calcium oxalate monohydrate (whewellite) or calcium oxalate dihydrate (weddelite) Frequently not detected by qualitative analysis
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Oxalate urolithiasis Most often in bladder in dogs
Kidneys, ureters, bladder in cats May have jagged edges UTI is a complication rather than predisposing factor High recurrence rate (25 to 48%)
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Risk factors for oxalate urolithiasis in dogs
Age > 4 years (highest risk between 8 and 12 years of age) Neutered male Breeds: miniature Schnauzer, Lhasa apso, Yorkshire terrier, Bichon frise, Shih tzu, miniature Poodle Overweight Pet dog vs working dog
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Risk factors for oxalate urolithiasis in cats
Exclusive feeding of an acidifying diet Middle-aged to older Males (usually neutered) more commonly than females Breeds: Persian, Himalayan Exclusive indoor environment Increased incidence over past 20 years NOT related to changes in age, breed, gender, or reproductive status of cat population during this time
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Oxalate urolithiasis: Pathogenesis
Derived from diet and endogenously from metabolism of ascorbic acid and glycine In humans, increased dietary calcium or oxalate, increased GI absorption of calcium or oxalate, or inherited defects of oxalate metabolism may predispose to oxalate urolithiasis
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Oxalate urolithiasis: Pathogenesis
Altered calcium metabolism can result in increased urinary excretion of calcium (hypercalciuria) Absorptive (GI) hypercalciuria Some miniature Schnauzers (?) Renal leak hypercalciuria Resorptive (bone) hypercalciuria Primary hyperparathyroidism Chronic acidosis and acidifying diets (?)
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Oxalate urolithiasis: Other associations
Hyperadrenocorticism Increased risk of calcium-containing stones Decreased renal reabsorption of calcium? Idiopathic hypercalcemia of cats
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Idiopathic hypercalcemia of cats
33% of cats with oxalate stones have hypercalcemia Idiopathic hypercalcemia has become more common in cats in past 10 years and many have oxalate stones Frequent history of acidifying diet Hypercalcemia responds to high fiber diet or prednisone
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Urate urolithiasis Usually composed of ammonium acid urate in dogs (vs uric acid in humans) Dalmatians and English bulldogs Dogs with portosystemic shunts (often also contain struvite)
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Urate urolithiasis Males > females Bladder, urethra
UTI is a complicating rather than predisposing factor High recurrence rate (30 to 50%)
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Urate urolithiasis “ Defective” uric acid metabolism in Dalmatian is a predisposing factor rather than primary cause
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Urate urolithiasis Urate derived from metabolism of purines
Converted to allantoin by dogs other than Dalmatians Impaired transport of urate into hepatocytes; not lack of uricase Urate reabsorption decreased and secretion increased in Dalmatian kidney
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Cystine urolithiasis Uncommon in dogs; rare in cats
Many breeds: English bulldogs, Newfoundlands, Dachshunds, Irish terriers, Basset hounds Almost exclusively males (except Newfoundlands) Middle aged (4 to 6 years)
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Cystine urolithiasis Usually in bladder and urethra
UTI is a complicating rather than predisposing factor High recurrence rate (47 to 75%) Cystinuria decreases in severity with age (> 5 years) in some affected dogs
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Cystine urolithiasis Cystinuria is an inherited defect in renal tubular transport of cystine or cystine and other amino acids (e.g. COLA group) Cystine crystals are not normally found in urine
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Cystinuria in Newfoundlands
Males and females - Autosomal recessive Mutation in SLC3A1 gene (associated with type I cystinuria in humans) Where tested in other breeds SLC3A1 gene not involved (“non-type I” cystinuria)
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Silicate urolithiasis
Uncommon in dogs; extremely rare in cats Not detected by qualitative analysis Often have “jack-like” appearance
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Silicate urolithiasis
Diets high in corn gluten or soybean hulls may be contributory Bladder and urethra German shepherds, Old English sheepdogs, other breeds Occasionally recur after surgery
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Carbonate urolithiasis
Most common in horses Rare in older male dogs Not reported in cats Calcium carbonate is less soluble in alkaline urine
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History in urolithiasis
Struvite Miniature Schnauzer, Bichon frise, Lhasa apso, Shih tzu, miniature Poodle Female > male Generally younger Oxalate Miniature Schnauzer, Bichon frise, Lhasa apso, Shih tzu, Yorkshire terrier, miniature Poodle Male > female Generally older
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History in urolithiasis
Cystine English bulldogs, Newfoundlands, Dachshunds, Irish terriers, Basset hounds, Bull Mastiffs, Rottweilers Male >> female (except Newfoundland) Young to middle-aged Urate Dalmatian, English bulldog Male > female Middle-aged
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History in urolithiasis
Silicate German shepherd, Old English sheepdog Male > female Middle-aged Carbonate Adult horses No breed or sex predilection
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History in urolithiasis
Depends upon: Anatomic location of uroliths Duration of presence of uroliths Physical features of uroliths Presence or absence of UTI
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History in urolithiasis
Kidney No signs Flank pain Painless hematuria Signs of infection Signs of renal failure
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History in urolithiasis
Ureter No signs (especially cats) Flank pain (acute ureteral obstruction) Signs of post-renal azotemia (if bilateral or ureteral rupture)
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History in urolithiasis
Bladder No signs Dysuria Increased frequency Hematuria
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History in urolithiasis
Urethra Signs of obstruction Signs of post-renal azotemia Dysuria Increased frequency Hematuria No signs (uncommon)
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Physical findings in urolithiasis depend primarily on anatomic location of uroliths
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Physical findings in urolithiasis
Kidney or ureter Renomegaly if hydronephrosis or pyonephrosis present Abdominal pain No abnormal findings if kidneys not enlarged or palpable
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Physical findings in urolithiasis
Bladder Palpable stones Thickened bladder wall
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Physical findings in urolithiasis
Urethra Large distended bladder suggestive of obstruction Stone palpable on rectal or perineal exam
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Laboratory findings in urolithiasis: Urinalysis
Inflammatory sediment (pyuria, hematuria, proteinuria, bacteriuria) Urine pH variable Struvite: Alkaline if urease-positive UTI Cystine: Acidic Oxalate, urate, silicate: Variable Cystine crystals are abnormal – other crystals are not diagnostic
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Laboratory findings in urolithiasis: Urine culture
Staph or Proteus in dogs with struvite urolithiasis and urease-positive UTI Usually negative in cats with urolithiasis UTI may complicate metabolic stone types (oxalate, urate, cystine, silicate)
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Laboratory findings in urolithiasis: Stone analysis
Qualitative analysis NOT recommended Xanthine and silicate not detected Oxalate frequently not detected False positive results for urate and cystine Cannot tell which crystalloids are primary and which are secondary
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Laboratory analysis in urolithiasis: Stone analysis
Use quantitative analysis (e.g. optical crystallography) University of Minnesota University of California, Davis Commercial medical laboratories
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Radiographic findings in urolithiasis
Most radiopaque Calcium phosphate Calcium oxalate Silicate Struvite * Cystine Urate Most radiolucent * Radiopacity will depend on how much calcium phosphate is present
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Urolithiasis: General principles of management
Relief of urinary tract obstruction Correction of fluid, electrolyte, and acid-base disturbances Non-surgical retrieval of uroliths Surgical removal of urolithis (if necessary) Medical dissolution of uroliths Preventive therapy
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Urolithiasis: Management Relief of obstruction
Passage of small diameter, well-lubricated catheter beyond urethral obstruction Urohydropropulsion Decompression by cystocentesis Emergency urethrotomy
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From Lulich JP et al. JAVMA 203:660, 1993.
Urolithiasis: Nonsurgical removal of uroliths Voiding urohydropropulsion Stones must be small < 7 mm in female dog < 5 mm in male dog or female cat General anesthesia Distend bladder with saline via cystoscope Radiograph afterward From Lulich JP et al. JAVMA 203:660, 1993.
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From Lulich JP et al. JAVMA 201:111, 1992.
Urolithiasis: Nonsurgical removal of uroliths Catheter-assisted retrieval of uroliths Small stones can be collected from male dog for quantitative analysis From Lulich JP et al. JAVMA 201:111, 1992.
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Urolithiasis: Nonsurgical removal of uroliths Lithotripsy
Electrohydraulic shock wave lithotripsy Shock wave generated in close proximity to urolith in bladder under cystoscopic visualization Extracorporeal shock wave lithotripsy Shock wave generated outside of body and transmitted to patient through water (used for nephroliths and ureteroliths) Requires special equipment and expertise
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Urolithiasis: Medical dissolution of uroliths
Protocols devised for struvite, urate, and cystine No effect protocol for oxalate yet
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Urolithiasis: General principles of management Induction of polyuria with NaCl
Aim to decrease USG to < (decreased concentration of crystalloids) Allow animal to void frequently Only recommended for struvite stones 0.5 to 10 grams salt per day (1 tsp NaCl = 6 g NaCl) No controlled studies for this recommendation
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Urolithiasis: General principles of management Eradication of UTI
UTI may predispose to (struvite in dogs) or complicate (oxalate, urate, cystine) urolithiasis Culture urine to identify UTI Treat with appropriate antibiotic therapy Follow up diligently to document eradication of infection
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Struvite urolithiasis Medical management
Eliminate UTI If urine pH still alkaline search for another reason Diet Metabolic (e.g. distal RTA) Calculolytic diet
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Struvite urolithiasis Calculolytic diet (S/d)
Low in phosphorus and magnesium High in NaCl Canine product low in protein to reduce urea availability to urease-positive bacteria
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Struvite urolithiasis Calculolytic diet (S/d)
Must eradicate UTI Dissolution takes 2 to 3 months; continue for 1 additional month Side effects PU/PD Decreased BUN Increased SAP (hepatic isoenzyme) Decreased serum phosphorus Decreased serum albumin Possible passage of nephrolith into ureter
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Struvite urolithiasis Calculolytic diet (S/d)
Is is struvite? Urease-positive UTI Alkalkine urine Struvite crystalluria Radiodense calculus ?
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Struvite urolithiasis Calculolytic diet (Feline S/d)
Similar to Canine S/d but not protein-restricted Average time for dissolution for sterile struvite stones: 30 days Success rate > 90% Don’t add acidifier!
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Oxalate urolithiasis Medical management
Attempts at dissolution have been unsuccessful Dietary modifications to prevent recurrence Low calcium, low oxalate Do not restrict phosphorus (decreased phosphorus may enhance GI calcium absorption; pyrophosphate is a crystallization inhibitor) Do not restrict magnesium (CaOx crystallization inhibitor) Do not add NaCl (may increase hypercalciuria) Less animal protein (less acidifying) Citrate (CaOx crystallization inhibitor) Avoid vitamin C
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Oxalate urolithiasis Medical management
Potassium citrate ( mg/kg/day) ? CaOx crystallization inhibitor Alkalinizing effect may reduce bone release of calcium Hydrochlorothiazide 2-4 mg/kg q12h ? Reduces urinary calcium excretion in dogs Diuretic effect Vitamin B6 ? (promotes transamination of oxalate precursor glyoxylate to glycine
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Urate urolithiasis Medical management: Allopurinol
Competitive inhibitor of xanthine oxidase Dissolution: 15 mg/kg PO q12h Prevention: 5-10 mg/kg PO q12h Dogs on allopurinol should be fed low purine diet to reduce risk of xanthine stone formation
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Urate urolithiasis Medical management: Alkalinization
Uric acid becomes more soluble in acid urine; urate becomes less soluble* Alkalinization decreases urinary NH4+ and H+ concentrations Potassium citrate may be preferable to NaHCO3 because natriuresis will enhance calciuresis * Urate calculi in dogs usually are ammonium acid urate vs uric acid in humans
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Urate urolithiasis Medical management: Diet
Diets low in organ-derived meats may reduce ingested purine load Low protein, low purine diet reduces urinary excretion of urate in normal dogs
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Urate urolithiasis Medical management: U/d Diet for dissolution and prevention
Decreases urinary excretion of uric acid, ammonia, titratable acid Increases urinary excretion of bicarbonate (urine pH ) Avoid in young growing dogs due to low protein (surgery preferred) Avoid in English bulldogs (risk of dilated cardiomyopathy?)
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Urate urolithiasis Medical management: U/d Diet
10-11% casein-based protein Low in purines Added potassium citrate No supplemental sodium (reduction of USG probably due to reduced renal medullary urea content) Used in both dissolution and prevention protocols
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Urate urolithiasis Medical management: U/d Diet
Client compliance indicated by: Disappearance of urate crystals from sediment BUN < 10 mg/dl USG < 1.020 Urine pH > 7.0 Results Complete dissolution 33% Partial dissolution 33% No dissolution 33% Time to dissolution 1 to 10 mos Average 3 to 4 mos
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Urate urolithiasis Prevention
Feed low protein, low purine diet (e.g. U/d) Monitor response (e.g. urate crystals in sediment) Add allopurinol 5-10 mg/kg PO q12h if crystalluria persists Continue low protein, low purine diet while using allopurinol to reduce risk of xanthine stones
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Cystine urolithiasis Medical management: d-penicillamine
Mixed disulfide 50 X more soluble than cystine in urine 30 mg/kg/day divided BID Most effective at neutral to alkaline urine pH May cause vomiting
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Cystine urolithiasis: Medical management 2-MPG (tiopronin)
Dissolution: 20 mg/kg PO q12h Prevention: 15 mg/kg PO q12h Adverse effects (13% of dogs) Aggressiveness Myopathy Immune-mediated reaction Skin lesions Abnormal liver function tests Signs resolve when drug discontinued
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Cystine urolithiasis Dissolution protocol
2-MPG (tiopronin) 20 mg/kg PO q12h 60% success rate Time for dissolution: 1 to 3 mos Consider surgery if no dissolution by 3 mos
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Cystine urolithiasis Prevention protocol
2-MPG (tiopronin) 15 mg/kg PO q12h Add water (not sodium) to food* Alkalinize urine with potassium citrate ( mg/kg/day) Recurrence prevented in 86% of treated dogs * Natriuresis may increase urinary excretion of cystine
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Cystine urolithiasis Alkalinization
Cystine has limited solubility in urine pH range of (twice as soluble in urine of pH 7.8 as compared to pH 6.5) NaHCO3 can be used at dosage of 1 g per 5 kg but effectiveness may be limited Potassium citrate may be preferable (natriuresis may increase urinary cystine excretion) Potential risk of struvite urolithiasis with urine pH in alkaline range
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Cystine urolithiasis Dietary modification
Low protein diet may result in lower USG (less urea for medullary interstitial hypertonicity) and increased urine pH Prescription Diet U/d has been recommended
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Silicate urolithiasis Medical management
Effect of urine pH on silicate solubility not established Avoid diets high in plant proteins (e.g. soybean hulls, corn gluten) Induction of polyuria ? Change water source ?
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Carbonate urolithiasis Medical management
Specific preventive measures after surgical removal in horses not reported but recurrence of solid stones is uncommon High grain diet may reduce urine pH and increase carbonate solubility
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Urolithiasis Complications
In dogs, recurrence rate is highest for metabolic stones (e.g. oxalate, urate, cystine) and lowest for struvite Post-renal azotemia and associated fluid, electrolyte, acid-base imbalances Drug and special diet side effects Urinary tract infection
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