1. Urolithiasis Stephen P. DiBartola, DVM
Department of Veterinary Clinical Sciences
College of Veterinary Medicine
Ohio State University
Columbus, OH 43210
The Nephronauts

2. 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

3. 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

4. Urolithiasis
Supersaturation (solubility product exceeded) of urine with a crystalloid depends on:
Amount of solute ingested and excreted
Urine volume
Urine pH
Promoters
Inihibitors

5. General theories of urolithiasis
Precipitation-crystallization theory
Matrix-nucleation theory
Crystallization-inhibition theory
Some combination of the above?

6. 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

7. Inhibitors of crystallization and aggregation
Pyrophosphates
Diphosphonates
Citrate
Some cations (e.g. Mg+2)
Glycosaminoglycans
Nephrocalcin

8. 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

9. 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

10. Struvite urolithiasis
Most common stone type in dogs
Major crystalloid is MgNH4PO4•H2O
Calcium phosphate also present in small amounts (2-10%)

11. Struvite urolithiasis
Bladder is most common site in dogs and cats
High recurrence rate (> 20%)
Younger animals

12. 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

13. 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

14. Oxalate urolithiasis
Composed of calcium oxalate monohydrate (whewellite) or calcium oxalate dihydrate (weddelite)
Frequently not detected by qualitative analysis

15. 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%)

16. 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

17. 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

18. 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

19. 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 (?)

20. Oxalate urolithiasis: Other associations
Hyperadrenocorticism
Increased risk of calcium-containing stones
Decreased renal reabsorption of calcium?
Idiopathic hypercalcemia of cats

21. 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

22. 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)

23. Urate urolithiasis Males > females Bladder, urethra
UTI is a complicating rather than predisposing factor
High recurrence rate (30 to 50%)

24. Urate urolithiasis
“ Defective” uric acid metabolism in Dalmatian is a predisposing factor rather than primary cause

25. 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

26. 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)

27. 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

28. 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

29. 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)

30. Silicate urolithiasis
Uncommon in dogs; extremely rare in cats
Not detected by qualitative analysis
Often have “jack-like” appearance

31. 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

32. Carbonate urolithiasis
Most common in horses
Rare in older male dogs
Not reported in cats
Calcium carbonate is less soluble in alkaline urine

33. 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

34. 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

35. History in urolithiasis
Silicate
German shepherd, Old English sheepdog
Male > female
Middle-aged
Carbonate
Adult horses
No breed or sex predilection

36. History in urolithiasis
Depends upon:
Anatomic location of uroliths
Duration of presence of uroliths
Physical features of uroliths
Presence or absence of UTI

37. History in urolithiasis
Kidney
No signs
Flank pain
Painless hematuria
Signs of infection
Signs of renal failure

38. History in urolithiasis
Ureter
No signs (especially cats)
Flank pain (acute ureteral obstruction)
Signs of post-renal azotemia (if bilateral or ureteral rupture)

39. History in urolithiasis
Bladder
No signs
Dysuria
Increased frequency
Hematuria

40. History in urolithiasis
Urethra
Signs of obstruction
Signs of post-renal azotemia
Dysuria
Increased frequency
Hematuria
No signs (uncommon)

41. Physical findings in urolithiasis depend primarily on anatomic location of uroliths

42. Physical findings in urolithiasis
Kidney or ureter
Renomegaly if hydronephrosis or pyonephrosis present
Abdominal pain
No abnormal findings if kidneys not enlarged or palpable

43. Physical findings in urolithiasis
Bladder
Palpable stones
Thickened bladder wall

44. Physical findings in urolithiasis
Urethra
Large distended bladder suggestive of obstruction
Stone palpable on rectal or perineal exam

45. 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

46. 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)

47. 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

48. Laboratory analysis in urolithiasis: Stone analysis
Use quantitative analysis (e.g. optical crystallography)
University of Minnesota
University of California, Davis
Commercial medical laboratories

49. 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

50. 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

51. Urolithiasis: Management Relief of obstruction
Passage of small diameter, well-lubricated catheter beyond urethral obstruction
Urohydropropulsion
Decompression by cystocentesis
Emergency urethrotomy

52. 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.

53. 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.

54. 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

55. Urolithiasis: Medical dissolution of uroliths
Protocols devised for struvite, urate, and cystine
No effect protocol for oxalate yet

56. 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

57. 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

58. Struvite urolithiasis Medical management
Eliminate UTI
If urine pH still alkaline search for another reason
Diet
Metabolic (e.g. distal RTA)
Calculolytic diet

59. 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

60. 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

61. Struvite urolithiasis Calculolytic diet (S/d)
Is is struvite?
Urease-positive UTI
Alkalkine urine
Struvite crystalluria
Radiodense calculus ?

62. 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!

63. 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

64. 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

65. 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

66. 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

67. 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

68. 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?)

69. 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

70. 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

71. 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

72. 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

73. 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

74. 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

75. 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

76. 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

77. 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

78. 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 ?

79. 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

80. 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