Transcript Urolithiasis - Ohio State University

Urolithiasis
Stephen P. DiBartola, DVM
Department of Veterinary Clinical Sciences
College of Veterinary Medicine
Ohio State University
Columbus, OH 43210
The Nephronauts
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
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
Urolithiasis
• Supersaturation (solubility product
exceeded) of urine with a crystalloid
depends on:
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Amount of solute ingested and excreted
Urine volume
Urine pH
Promoters
Inihibitors
General theories of urolithiasis
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Precipitation-crystallization theory
Matrix-nucleation theory
Crystallization-inhibition theory
Some combination of the above?
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
Inhibitors of crystallization
and aggregation
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Pyrophosphates
Diphosphonates
Citrate
Some cations (e.g. Mg+2)
Glycosaminoglycans
Nephrocalcin
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
Prevalence of stone types
Stone type
Number
Struvite
Oxalate
Dogs
77,190
50%
31%
Cats
20,343
43%
46%
Urate
Cystine
Silicate
Calcium phosphate
8%
1%
1%
< 1%
6%
< 1%
< 0.1%
< 1%
Data from University of Minnesota Stone Laboratory 2000
Struvite urolithiasis
• Most common stone
type in dogs
• Major crystalloid is
MgNH4PO4•H2O
• Calcium phosphate
also present in small
amounts (2-10%)
Struvite urolithiasis
• Bladder is most
common site in
dogs and cats
• High recurrence
rate (> 20%)
• Younger animals
Struvite urolithiasis
• Struvite solubility
decreases in alkaline
urine
• UTI with ureasepositive bacteria
(Staphylococci,
Proteus spp) plays
primary role in
pathogenesis in
dogs but not cats
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
Oxalate urolithiasis
• Composed of
calcium oxalate
monohydrate
(whewellite) or
calcium oxalate
dihydrate (weddelite)
• Frequently not
detected by
qualitative analysis
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%)
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
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
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
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 (?)
Oxalate urolithiasis: Other
associations
• Hyperadrenocorticism
• Increased risk of calciumcontaining stones
• Decreased renal reabsorption of
calcium?
• Idiopathic hypercalcemia of cats
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
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)
Urate urolithiasis
• Males > females
• Bladder, urethra
• UTI is a
complicating rather
than predisposing
factor
• High recurrence
rate (30 to 50%)
Urate urolithiasis
“ Defective” uric
acid metabolism
in Dalmatian is a
predisposing
factor rather
than primary
cause
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
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)
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
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
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)
Silicate urolithiasis
• Uncommon in
dogs; extremely
rare in cats
• Not detected by
qualitative analysis
• Often have “jacklike” appearance
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
Carbonate urolithiasis
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Most common in horses
Rare in older male dogs
Not reported in cats
Calcium carbonate is less soluble
in alkaline urine
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
History in urolithiasis
• Urate
• Dalmatian,
English bulldog
• Male > female
• Middle-aged
• Cystine
• English bulldogs,
Newfoundlands,
Dachshunds, Irish
terriers, Basset hounds,
Bull Mastiffs, Rottweilers
• Male >> female (except
Newfoundland)
• Young to middle-aged
History in urolithiasis
• Silicate
• German
shepherd, Old
English
sheepdog
• Male > female
• Middle-aged
• Carbonate
• Adult horses
• No breed or sex
predilection
History in urolithiasis
• Depends upon:
• Anatomic location of uroliths
• Duration of presence of uroliths
• Physical features of uroliths
• Presence or absence of UTI
History in urolithiasis
• Kidney
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No signs
Flank pain
Painless hematuria
Signs of infection
Signs of renal
failure
History in urolithiasis
• Ureter
• No signs (especially
cats)
• Flank pain (acute
ureteral obstruction)
• Signs of post-renal
azotemia (if bilateral
or ureteral rupture)
History in urolithiasis
• Bladder
• No signs
• Dysuria
• Increased
frequency
• Hematuria
History in urolithiasis
• Urethra
• Signs of obstruction
• Signs of post-renal
azotemia
• Dysuria
• Increased frequency
• Hematuria
• No signs (uncommon)
Physical findings in
urolithiasis depend primarily
on anatomic location of
uroliths
Physical findings in
urolithiasis
• Kidney or ureter
• Renomegaly if
hydronephrosis or
pyonephrosis
present
• Abdominal pain
• No abnormal
findings if kidneys
not enlarged or
palpable
Physical findings in
urolithiasis
• Bladder
• Palpable stones
• Thickened
bladder wall
Physical findings in
urolithiasis
• Urethra
• Large distended
bladder suggestive
of obstruction
• Stone palpable on
rectal or perineal
exam
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
Laboratory findings in
urolithiasis: Urine culture
• Staph or Proteus in dogs with
struvite urolithiasis and ureasepositive UTI
• Usually negative in cats with
urolithiasis
• UTI may complicate metabolic stone
types (oxalate, urate, cystine, silicate)
Laboratory findings in
urolithiasis: Stone analysis
• Qualitative analysis NOT recommended
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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
Laboratory analysis in
urolithiasis: Stone analysis
• Use quantitative analysis (e.g.
optical crystallography)
• University of Minnesota
• University of California, Davis
• Commercial medical laboratories
Radiographic findings in
urolithiasis
Most radiopaque
Calcium phosphate
Calcium oxalate
Silicate
Struvite *
* Radiopacity will depend on
how much calcium
Cystine
phosphate is present
Urate
Most radiolucent
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
Urolithiasis: Management
Relief of obstruction
• Passage of small
diameter, welllubricated catheter
beyond urethral
obstruction
• Urohydropropulsion
• Decompression by
cystocentesis
• Emergency
urethrotomy
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.
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.
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
Urolithiasis: Medical
dissolution of uroliths
• Protocols devised for struvite,
urate, and cystine
• No effect protocol for oxalate yet
Urolithiasis: General principles of management
Induction of polyuria with NaCl
• Aim to decrease USG to < 1.025
(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
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
Struvite urolithiasis
Medical management
• Eliminate UTI
• If urine pH still
alkaline search for
another reason
• Diet
• Metabolic (e.g.
distal RTA)
• Calculolytic diet
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
Struvite urolithiasis
Calculolytic diet (S/d)
• Must eradicate UTI
• Dissolution takes 2 to 3 months; continue for 1
additional month
• Side effects
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PU/PD
Decreased BUN
Increased SAP (hepatic isoenzyme)
Decreased serum phosphorus
Decreased serum albumin
Possible passage of nephrolith into ureter
Struvite urolithiasis
Calculolytic diet (S/d)
• Is is struvite?
• Urease-positive
UTI
• Alkalkine urine
• Struvite
crystalluria
• Radiodense
calculus
?
Struvite urolithiasis
Calculolytic diet (Feline S/d)
• Similar to Canine S/d
but not proteinrestricted
• Average time for
dissolution for sterile
struvite stones: 30 days
• Success rate > 90%
• Don’t add acidifier!
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
Oxalate urolithiasis
Medical management
• Potassium citrate (100-150 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
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
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
Urate urolithiasis
Medical management: Diet
• Diets low in organderived meats may
reduce ingested
purine load
• Low protein, low
purine diet reduces
urinary excretion of
urate in normal dogs
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 7.0-7.5)
• Avoid in young growing dogs due to
low protein (surgery preferred)
• Avoid in English bulldogs (risk of
dilated cardiomyopathy?)
Urate urolithiasis
Medical management: U/d Diet
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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
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
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
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
Cystine urolithiasis: Medical management
2-MPG (tiopronin)
• Dissolution: 20 mg/kg PO q12h
• Prevention: 15 mg/kg PO q12h
• Adverse effects (13% of dogs)
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Aggressiveness
Myopathy
Immune-mediated reaction
Skin lesions
Abnormal liver function tests
• Signs resolve when drug
discontinued
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
Cystine urolithiasis
Prevention protocol
• 2-MPG (tiopronin) 15 mg/kg PO q12h
• Add water (not sodium) to food*
• Alkalinize urine with potassium
citrate (100-150 mg/kg/day)
• Recurrence prevented in 86% of
treated dogs
* Natriuresis may increase urinary excretion of cystine
Cystine urolithiasis
Alkalinization
• Cystine has limited solubility in urine pH
range of 5.5-7.0 (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
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
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 ?
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
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