Metabolic aspects of stone disease
and metabolic management
16/07/2015
M Smolski
Mr A Parnham
Mr T Gunendran
Source
• EAU guidelines, Update March 2015
• Metabolic Evaluation and Recurrence Prevention
for Urinary Stone Patients: EAU Guidelines. E
Urol. 2015
• Calcium Kidney Stones. NEJM 2010
• Pearle at al. Medical management of stones. 2nd
edition.
• AUA guidelines
• General metabolic tests for stone formers
• Low risk and high risk patients
• Evaluation of recurrent stone formers and
patients at risk
• Evaluation of patient based on stone composition
• Non-medical and medical treatment in stone
patients
Case 1
• 50 female
• Right colicky pain
Case 1
• Hx
– Mother had stones
• Examination – mild tenderness R renal angle
• Urinanalysis – pH 6.5, bld++, leuc++
Case 1
Management ?
Basic metabolic testing
Emergency and non-emergency setting:
– Urinary dipstick + MSU
– U+E, FBC, CRP, coagulation screen
– Calcium
– Uric acid
– Stone for analysis
UROLITHIASIS - LIMITED UPDATE MARCH 2015
Stone analysis
•
•
•
•
IRS (infrared spectroscopy)
XRD (x-ray diffraction)
Polaristaion microscopy
Wet chemistry – obsolete?
Repeat stone analysis
• Recurrence under pharmacological prevention
• Early recurrence after interventional therapy
with complete stone clearance
• Late recurrence after a prolonged stone-free
period
Mandel et al. J. Urol. 2003
Patients with stones of unknown
composition
Medical history
Stone history (former stone events, family history)
Dietary habits
Medication chart
Diagnostic
imaging
Ultrasound
Unenhanced helical CT in cases of a suspected stone
Blood analysis
Calcium (ionized calcium or total calcium + albumin)
Uric acid
Creatinine
Urinalysis
Dipstick test: leukocytes, erythrocytes, nitrite,
protein, urine pH, specific weight
Urine culture
Urine pH profile
Microscopy of urinary sediment (morning urine)
Cyanide nitroprusside test (exclusion of cystinuria)
Case 1
•
•
•
•
•
URS
U+E NAD
Ca, Uric acid NAD
Stone analysis - CaC2O4 or Ca (COO)2
FU?
Case
FU 1
Evaluation of patient’s risk
• Low risk stone formers – general fluid and
nutritional intake guidelines, lifestyle
modification advice
• High risk stone formers – extended metabolic
evaluation
Evaluation of patient’s risk
•
•
•
•
•
General factors
Diseases associated with stone formation
Genetically determined stone formation
Drugs associated with stone formation
Anatomical abnormalities associated with stone
formation
Skolarikos et al. E. Urol 2015
Extended metabolic evaluation
• Basic metabolic evaluation
• Plus stone type individualised specific
metabolic evaluation:
– 2 x 24-h urine collection
– Spot urine sample where urine collection difficult
i.e. children
Timing
• First timer - when the patient stone-free, 20
days after stone passage, on normal diet
• For follow ups:
– 8-12/52 after commencing prophylaxis/treatment
– Then 12 monthly
24-H urine collection test
•
Liaise with local laboratory regarding the day of urine collection, as collection finished
on the weekend may be difficult for lab analysis
•
Liaise with local laboratory re: number of bottles used and preservatives in bottle
•
In UK – usually use 2 bottles
– Bottle 1- Hydrochloric Acid to maintain pH 2-2.5 to prevent precipitation of calcium
oxalate or calcium phosphate, to test calcium, oxalate, phosphate, citrate and
magnesium
– Bottle 2 – plain, to test for uric acid and pH
•
Variation such as –
Bottle 1 – Hydrochloric acid (reason as above),
Bottle 2 – Alkali preservative to achieve pH=9 to prevent or reduce risk
of uric acid precipitation and same specimen can be use for cystine analysis
5% Thymol in isopropanol
stored at  8o C
24-H urine collection test
•
First 24-hr Urine Collection (Container with preservatives)
•
•
Get up at normal time in the morning
First urine sample in the morning flush down the toilet. Note the exact time (This
will be the start time of the urine collection). Do not collect this sample.
Write down the start date and time on bottle
Collect every drop of urine passed during the day and night into the bottle provided.
At exactly the same time the following morning, empty bladder again (i.e. 1st urine
in the morning) and add this sample to the collection container. Write down
collection finish date and time
•
•
•
•
Second 24-hr Urine Collection (Container without preservatives)
•
Repeat the same procedure as above
•
The urine bottles should be brought into the lab on the same morning when the
second urine collection is finished.
Recommendations for general
preventative measures
•
•
•
•
•
•
•
Diuresis 2.0-2.5L/day
Limit NaCl – 4-5 g/day
Limit animal protein 0.8-1.g/kg/day
Normal Ca content 1-1.2g/day
Diet rich in fibre
Retain normal BMI level
Adequate physical activity
Case 2
• 16 female
• f/h of stones
• Lt renal colic
•
•
•
•
USS NAD
CT KUB
URS
Stone analysis
Case 2
• Carbonate apatite phosphate/ Calcium oxalate
monohydrate
• 80/20%
• Further tests?
Stone specific metabolic evaluation
Calcium oxalate stone disease
Calcium oxalate stone
• Calcium oxalate monohydrate/ dihydrate
• 90% idiopathic
• 10% metabolic abnormality
Tests
• Plasma Creatinine, Na, K, Cl, Ca, uric acid, PTH
(if Ca high)
• Urinanalysis – volume, pH, specific weight, Na,
Ca, Oxalate, uric acid, citrate, magnesium
Hypercalcaemia
-HPT
-Sarcoidosis (Calcitriol)
-Malignancy
Urine pH
• “Acidic arrest” (urine pH constantly < 6) may
promote co-crystallisation of uric acid and
calcium oxalate. Similarly, increased uric acid
excretion (> 4 mmol/day in adults or > 12
mg/kg/day in children) can act as a promoter
• Urine pH levels constantly > 5.8 in the day profile
indicate renal tubular acidosis (RTA), provided
urinary tract infection (UTI) has been excluded.
UROLITHIASIS - LIMITED UPDATE MARCH 2015
Results
EUROPEANUROLOGY67(2015)750–763
Hypercalcuria
– 4mg/kg/24hrs
– >7mmol (men) or >6mmol (women)
– 250mg/day
• with normocalcemia (idiopathic hypercalciuria,
or granulomatous diseases)
• with hypercalcaemia (hyperparathyroidism,
granulomatous diseases, vitamin D excess, or
malignancy
Hypercalcuria-classification
• Absorptive
– Type1
– Type2
– Type3
• Renal leak
• Resorptive
• Idiopathic
Hypercalcuria
Absorptive
Renal leak
Resorptive
Fasting Ca/Cr
<0.11
>0.11
>0.11
Calcium load Ca/Cr
>0.22
>0.22
>0.22
Serum calcium
normal
normal
increased
Serum PTH
normal
marginal
increased
Hypercalcuria-treatment
EUROPEANUROLOGY67(2015)750–763
Hypercalcuria-management
• Thiazides (chlortalidone, indapamide,
hydrochlorothiazide)
– Prevent exchange Na and Ca in distal tubules
– Proven 50% reduction of Ca stone recurrence rate
during a 3 year period in placebo controlled trials
• Potassium citrate
– inhibits growth and aggregation of
calcium oxalate
Ettinger et al. J. Urol. 1988
Hypocitrituria
•
•
•
•
Urinary citrate < 320mg/day
Implicated in up to 50% stone formers
Reflects acid/base balance
Common in RTA
Hypocitrituria - treatment
• Potassium Citrate
EUROPEANUROLOGY67(2015)750–763
Hyperoxaluria
• Dietary, Enteric, Primary
• >40mg/day oxalate in the urine
• <80mg/day – dietary hyperoxaluria
• >80mg/day enteric or primary hyperoxaluria
Causes
• Dietary hyperoxaluria
Reduce intake of rhubarb, tea, chocolate, nuts, spinach and strawberries
Eliminate megadoses of vitamin C
• Enteric hyperoxaluria (most common)
Malabsorption syndromes (Crohn’s etc.)
Bile salts increase permeability of intestinal mucosa to oxalate and
calcium soap formation results in increased free gut oxalate
• Primary hyperoxaluria
Rare autosomal recessive disease
Mutated alanine-glycoxylate aminotransferase (AGT) leads to very high
levels of urinary oxalate (>100mg/day), causing CaOx stone disease,
nephrocalcinosis and renal impairment (liver and kidney transplant required)
Hyperoxaluria-treatment
• Lifestyle modification - fluids, low oxalate diet
• Pharmacological - K Citrate, Calcium supplements
• Piridoxine at specialist
centres?
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0–763
Hyperuricosuria
• Uric acid >700mg/day
• Associated with excessive dietary intake of
animal protein
• Decrease the solubility of calcium oxalate and
thus can increase the incidence of calcium
oxalate stones
Hyperuricosuria-treatment
• Allopurinol
• Alkaline Citrate or
sodium bicarbonate
EUROPEANUROLOGY67(2015)750–763
Ettinger at al NEJM 1986
Other recommendation
• High sodium excretion
• Restricted intake of salt
• Small urine volume - Increased fluid intake
• Urea level indicating a high intake of animal
protein - Avoid excessive intake of animal protein
• No abnormality identified - High fluid intake
Stone specific metabolic evaluation
Calcium Phosphate stone disease
Calcium Phosphate stone disease
• Calcium hydroxyl phosphate - Carbonite
apatite - Ca5(PO3)3(OH)
• b-tricalcium phosphate - Whitlockite Ca3(PO4)2
• Carbonate apatite phosphate - Dahllite
Ca5(PO4)3OH
• Calcium hydrogen phosphate - Brushite
PO4.2H2O
Calcium Phosphate stone disease
• Apatite – may be associated with infection
• Brushite – crystallises at high urinary
concentration of calcium and phosphate. Not
related to UTI. Very hard hence difficult to
treat
• Possible causes include HPT, RTA, UTI
Tests
• Plasma Creatinine, Na, K, Cl, Ca, PTH
• Urinanalysis – volume, pH, specific weight, Ca,
P, Citrate
Carbonate apatite stones
EUROPEANUROLOGY67(2015)750–763
RTA
• Renal tubular acidosis is caused by severe
impairment of proton or bicarbonate handling
along the nephron
• Kidney stone formation most probably occurs
in patients with distal RTA type I.
EUROPEANUROLOGY67(2015)750–763
RTA
RTA - Management
• The main therapeutic aim is restoring a
normal acid-bas equilibrium
• Alkaline citrates or sodium bicarbonate is key
to normalising the metabolic changes
(intracellular acidosis) responsible for stone
formation
Brushite stones
Stone AUA guidelines in a snapshot
Uric acid stones
Overview
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•
•
•
•
•
15% of urinary stones
Elderly i.e >60 or young chubsters
Uric acid stones form in acidic conditions
Diet rich in proteins and purines and alcohol
20-40% of gout patients will form uric acid stones
Uric acid dihydrate forms in really acidic urine
<5.5
• Only stones that can be dissolved medically
• Different from Urate stones
Uric acid vs Urate stones
Low urine
pH
High urine pH
High conc
of uric acid
High conc. Of
urate and cation
Uric acid
stone
Urate stone
Notes
• Medical history
– Disturbances in metabolism of uric acid
• Cell death
– Anaemia, neoplastic conditions, intoxication, cardiac infarct,
irradiation, cytotoxics
• Enzyme defects
– Primary gout, Lesch-Nyhan
• Alterations in the excretion
– Renal insufficiency, metabolic acidosis
– Medications
• Uricosurics, diuretics, analgesics, vitamin C
Programme for testing
• Urine analysis
– pH <5.8
– Crystals with whetstone appearance or right
angles. Fine crystalline ‘brick-meal’ in sediment
• Serum analysis
– Uric acid >380υmol/l (6.4mg/100ml)
• Establishing diagnosis
– Stone analysis
Biochemical investigations
• Serum uric acid
– Man 155-404 υmol/l
– Women 119-375 υmol/l
• Blood pH is slightly alkaline and the risk of precipitation
is determined by the solubility of sodium urate
• The solubility limit at pH 7.4 @ 37oC is 380υmol/l
• Therefore values above 380 are considered as
hyperuricaemia and require therapeutic measures
• If uric acid is persistently between 300 and 380
suspicion of latent hyperuricaemia in dietetic purine
loading
Urine analysis
• The lower the pH and the higher the uric acid,
the greater the risk of uric acid precipitation
• The reason for an extremely low pH should be
investigated
Urine analysis
• Spot urine
– pH <5.8 suspect constantly acidic urine
• pH day profile
– Patient records urine pH every time voids for 24
hrs (check vision)
– pH constantly <6.0 establishes diagnosis of acid
urine
• 24 hr urine
– Uric acid ≥4.0mmol/24hrs (672mg)
Treatment
• Chemolysis
• Metaphylactic
Treatment- Chemolysis
• Stone dissolution (Chemolysis)
– Stone free rates ~90%
– Clearance rate depends on size, purity and
diuresis
– Remember uric acid stones form in low pH and
high concentrations of uric acid so…
1. Increase urinary pH
2. Decrease uric acid excretion
3. Increase urine dilution
1. Chemolysis Urine alkalinisation
– Aim for pH 7.0-7.2
• Medicinal agents
– Alkaline citrate(potassium citrate, Uralyt U, Lithurex)
• Dose depends on pH
– Sodium Bicarbonate
• Drinks
– Mineral water with high concentration of bicarbonate
(>1500mg HCO3-/L)
– Citrus juices (beware energy load)
2. Chemolysis- Reduction of uric acid
excretion
Inhibiting endogenous production
of uric acid
– Aim for <4.0mmol uric
acid/24hrs
– Allopurinol
• Dose 300mg OD if serum uric
acid >380 and urine uric acid
>4.0mmol/24 hrs
• Dose 100mg OD if urine only
>4.0mmol/24hrs
• CI: reduce dose in renal
insufficiency. Pregnancy and
liver disease
• SE: Increased xanthine excretion
(xanthine stones in pts with
Lesch-Nyhan. Altered blood cell
formation, hypersensitivity,
interactions with anticoag and
antihistamine
Adenine
Hypoxanthine
Allopurinol
Xanthine oxidase
Guanine
Xanthine
Xanthine oxidase
Uric acid
Oxypurinol
2. Chemolysis- Reduction of uric acid
excretion
Reduce purine intake
• Restrict meat, fish, sausage, bean and
mushrooms
• Avoid innards, sardines, anchovies, sprats,
herring, shellfish, skin from poultry and fish
• Prefer eggs, dairy, fruits, veg, cereals
– Plants have a lower purine content and can have
an alkalising effect
3. Chemolysis- Increased diuresis
• Aim for 2.5l of urine in 24 hr period
• Mineral water rich in bicarbonate (>1500mg
HCO3-/L
• Citrus juice
Metaphylaxis
General measures
• Weight loss
– Avoid extreme fasting as increases uric acid excretion
• Avoid large losses of fluid
– Sweating, laxative abuse, sauna
Urine dilution
• Alkalising beverages- as previous
• Urine neutral- kidney tea, bladder tea and fruit tea, dilute apple juice,
mineral water with low mineral content
• Suitable in limited amounts- coffee (max 2/day), black tea (max 2/day)
– Stimulate metabolism and therefore can increase uric acid excretion
• Unsuitable- all alcohol but beer worst, cola, lemonade and soft drinks with
sugar
– Increase uric acid excretion and acidify urine
Metaphylaxis
Diet
• As previous
Medical
• Alkaline citrate or sodium bicarbonate
– Increase urinary pH
– CI: recurrent UTI, hypertension (control!), Phosphate stones, renal insufficiency, metabolic
alkalosis, hyperkalaemia
– SE: GI disturbances
– Long term admin of Na-K-Citrate to patients with reduced renal function can lead to
potassium intoxication. Replace with calcium citrate
– Try to reduce dose with generous intake of alkalinsation beverages
Long term Goals
• Increased pH (6.5-6.8),
• Reduced excretion of uric acid (<4mmol/24hrs),
• Sufficient urine dilution ≥2.5L/24 hrs
Struvite
Overview
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•
•
•
4-6%
Always caused by UTI with urease producing bacteria
2x more common in females than males
Stones in infants are mostly struvite, whereby boys are
afflicted
• UTI high ammoniapH>7.0 reduced solubility of
phosphatesstruvite ad carboonate apatite
crystallisation
• High urine volume and acidification mainstays of
treatment
Notes
Medical history
– Fertile women and during pregnancy, <15 yrs old
at first presentation
– Recurrent UTIs (commonly found in association
with anatomical and functional abnormalities)
Programme for testing
• Urine analysis
– pH >7.0
– Leucocytes and nitrites
– Sediment with coffin lid like crystals
• Serum analysis
– Creatinine possibly increased
• Establishing diagnosis
– Stone analysis
Biochemical investigations
pH day-profile
• pH constant >7.0 (keep in mind RTA)
24 hr urine collection
• Ammonium ≥50mmol/24hrs
• Phosphate ≥35 mmol/24hrs
Diagnosis of UTI
• Test strips
• Number of bacteria
• Bacterial strain, resistance pattern and urease activity
– Proteus, klebsiella, pseudomonas, providencia, serratia,
staph
Metaphylaxis
• Complete removal of stone
– Residual concrements not only hinder recovery
but inevitably result in relapse
– General measures
• UTI prevention measures
• Avoid excessive fluid losses (see before)
• Avoid immobilisation
– Increased calcium and phosphate excretion as a result of
osteolysis, reduced urine flow
Metaphylaxis
• Urine dilution
– 2.5-3L/day
– Preferably acidifiying and neutral beverages
• HCO3- poor mineral water
• Dilute cranberry juice? (1L cranberry juice contains
480Kcal)
– Unsuitable
• Citrus juices (alkalising)
• HCO3-rich mineral water (>500mg HCO3-/l)
• Cola, lemonades, soft drinks with sugar, alcohol
Metaphylaxis
Diet
• Balanced diet
• Avoid pure vegetarian diet as can cause
alkalization
• Animal foodstuffs cause acidification
Metaphylaxis
Medical
• Long term infection therapy
• Acidification of urine (beware complete RTA)
– Monitor pH daily
– L-methionine (Acimethin)
• Dose: pH dependent 200-500mg TDS (to pH 5.8-6.2)
• Metabolism of sulforous amino acids produces sulfate and protons pH decreases
– Ammonium chloride
• Dose: pH dependent 200-500mg TDS (to pH 5.8-6.2)
• Modulation of acid base metabolism
• Reduction of phosphate excretion
– If proven hyperphosphateamia >35 mmol/24hrs
– Aluminium hydroxide
• Dose 2.2-3.5g/day
• Inhibits intestinal phosphate absorption by formatinoof insoluble aluminium phosphate
salts
• SE: GI upset
Cysteine
Overview
• Frequency 1-2 %
• Autosomal recessive hereditary transport
defect of the amino acids cystine, lysine,
arginine and ornithine (COLA)
• Cystine is poorly soluble
• Although can present in infancy usually seen
in 2nd decade
• High urine volume, alkalinisation and educing
excretion are mainstays of treatment
Notes
Medical history
• <15 yrs old, 15-20 yrs old at first manifestation
• Family history
Programme for testing
• Urine analysis
– pH normal
– Sediment with hexagonal, plain crystals
• Serum analysis
– Normal values
• Establishing diagnosis
– Cystine test positive
– Stone analysis
Biochemical investigations
24 hr urine collection
• Quantative cystine analysis
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–
–
–
–
Normal 0.17-0.33mmol/24hrs (40-80mg/24hrs)
Homozygous often >4.16 mmol/24hrs (1000mg/24hrs)
Start treatment ≥0.8 mmol/24hrs (192mg/24hrs)
Limit of solubility 1.33 mmol/l (320mg/L) @ pH 6.0
If diagnosed should arrange family screening
• Analysis according to quality standard
– Accompanying metabolic disorders can occur. Therefore
calcium, oxalate and urate should be checked
• Bacteriology
– As urine alkalinisation is required a urinary tract infection should
be excluded
Chemolysis
• The solubility of cystine rapidly increase with
pH greater than 7.0
• Although possible it is difficult to achieve and
may require support of ESWL and visa versa
– ESWL + THAM solution (tris-hydroxymethylaminomethane) and acetylcysteine
Metaphylaxis
1. Reduction of cystine concentration by
extensive urine dilution
2. Reduction of cystine excretion by reducing
protein and sodium in the diet
3. Increasing the solubility of cystine by urine
alkalinisation
4. Medicinal reduction of urine concentration
with sulphide containing compounds
General measures
• Patient monitored control of pH and close control
of relevant serum and urinary parameters
– Serum
• Creatinine, uric acid
– Urine
• Volume, density, cystine, pH, nitrite, calcium and phosphate
(risk of phosphate stone formation with high pH), oxalate
(important with ascorbic acid therapy), uric acid
(accompanying metabolic disease possible)
• Prevention of infections
• Avoid excessive fluid loss
Metaphylaxis
Urine dilution
• To remain below the critical 1.3mmol cystine/L
(300mg/l) with excretion of >4.2 mmol/24 hr
(1000mg/24hrs) the mean urine volume should
be at least 3.5L/day. This needs to be evenly
distributed throughout the 24 hr period.
• Preferable drinks
– HCO3- rich mineral water (Na as low as possible),
Citrus juice
• Avoid
– cola, lemonade, soft drinks with sugar, alcohol
Metaphylaxis
Diet
• Cystine is formed from the metabolism of methionine.
However to remove methionine from the diet
completely is awful.
• Should have a low protein diet <0.8g protein/kg/ day
• Vegetarian diet has low protein content and causes
urinary alkalinisation and therefore should be the
mainstay.
– Note in children need iron and iodine so can have 1-2 meat
meal and 1 fish meal weekly
• Cystine excretion increase with a high sodium intake
and therefore NaCl should be limited
Metaphylaxis
Medical treatment
• Alkalinisation (aim for pH >7.5)
– Alkaline citrate or sodium bicarbonate
• Increase urinary pH
• CI: recurrent UTI, hypertension (control!), Phosphate
stones, renal insufficiency, metabolic alkalosis,
hyperkalaemia
• SE: GI disturbances
• Long term admin of Na-K-Citrate to patients with
reduced renal function can lead to potassium
intoxication. Replace with calcium citrate
Metaphylaxis
• Reduction of cystine excretion
– α-Mercaptopropionylglycine (tiopronin, Thiola)
•
•
•
•
•
•
Use when cystine excretion >3.0-3.5 mmol/24hrs (720-840mg/24hrs)
Start slowly with 250mg/day and increase dependent on cystine excretion to 2g/day
Transforms cystine to one molecule cysteine and one molecule cysteine+drug
SE:dysgeusia, gastritis, dermatosis, nephrotic syndrome
Need to check serum and urine values regularly
Tachyphylaxis- loses efficacy during long-term therapy
– Ascorbic acid
• Changes the redox balance between cystine and cysteine in favour of the latter whichis
more soluble
• Dose 3-5g/day
• SE: Increased excretion of oxalate
• Use effervescent tablets as they support alkalinisation, unlike pure ascorbic acid which
might result in acidification
• Note cystine monitoring and directed therapy not possible by routine analysis a cystine
and cysteine are assessed together as total cystine (oxygen oxidises back to cystine) Need
to ask for separate measurement
2,8-Dihydroxyadenine stones
Overview
• Normally 2,8-dihydroxyadenine does not occur as
a metabolic product
• Autosomal recessive hereditary defect of adenine
phosphoribosyltransferase adenine cannot be
converted to AMP.
• Alternatively adenine is oxidised to 2,8dihydroxyadenine by xanthine oxidase
• Usually found in infancy
• Ca be confused with uric acid stones
• Treatment is with allopurinol
Notes
• First manifests in infancy
• Possible history of stones in the family
• Progressive renal insufficiency
Programme for testing
• Urine analysis
– pH normal
– Sediment with circular brown crystals
• Serum analysis
– Normal uric acid
• Establishing diagnosis
– Stone analysis
Biochemical investigations
24 hr urine collection
• Quantative 2,8-dihydroxyadenine
analysis
– If diagnosed should arrange family
screening
•
Analysis according to quality standard
– Accompanying metabolic disorders can
occur. Therefore calcium, oxalate and
urate should be checked
Serum
• Measurement of APRT activity in the
erythrocyte lysate.
– Normal 24.7±4.8nmol adenine/mg
Hb/H
– Homozygous grave or complete loss
– Heterozygous moderate loss
APRT defect
adenine
AMP
Xanthine oxidase
8-hydroxyadenine
Xanthine oxidase
2,8-hydroxyadenine
Metaphylaxis
Urine dilution
• 2.5-3l/day
• Can check urine density (>1.010g/cm3 should increase
fluid intake)
Diet
• Reduce purine intake
• Ovo-lacto-vegetarian diet
Medical
• Dose 5-10mg/kg/day in paeds, 200-600mg/day adults
• Titrate by measuring the excretion of unmetabolised
allopurinol
Xanthine stones
Overview
• Vanishingly rare
• Autosomal recessive hereditary defect of
xanthine oxidase
• Xanthine can not be oxidised to uric acid so
excretion of hypoxanthine and xanthine
increases
• Treatment: hydration, ovo-lacto-vegetarian
diet
Notes
Medical history
• Stones in family
• Treatment with high dosed of allopurinol
• Lesch-Nyhan
• Chemo
• Mostly presents in infancy
Programme for testing
• Serum analysis
– Markedly decreased serum uric acid <119μmol/l
(2mg/100ml)
• Establishing diagnosis
– Stone analysis
Biochemical investigations
24 hr urine collection
• Quantative
GMP
– Xanthine- significantly
higher than normal
(<40μmol/24hrs)
– Hypoxanthine- normal or
increased (normal
<70μmol/24hrs)
– If diagnosed should
arrange family screening
Serum
• Significantly low uric acid
Guanosine
Guanine
Inosine
Adenosine AMP
Hypoxanthine
Xanthine oxidase
xanthine
Xanthine oxidase
Uric acid
Metaphylaxis
Urine dilution
• 2.5-3l/day
• Can check urine density (>1.010g/cm3 should
increase fluid intake)
Diet
• Reduce purine intake
• Ovo-lacto-vegetarian diet
Ammonium Urate
Overview
• 0.5%
• Rare in industrial nations and are normally
caused by infections
• Unbalanced diet, reduced phosphate intake (from
milk and meat) results in a low urinary phosphate
buffer increased transformation of glutamine
to ammonium.
• Low pyrophosphate and a high urinary pH and
uric acid excretion results in ammonium urate
stone formation
Notes
Medical history
• Unbalanced diet
• Phosphate malnutrition
• Laxative abuse
• Anorexia
Programme for testing
• Urine Analysis
– pH >6.5
– Possible nitrite positive
• Serum analysis
– Uric acid possibly increased
– Hypokalaemia
• Establishing diagnosis
– Stone analysis
Biochemical investigations
pH day profile
• pH>7.0 infection + increased uric acid excretion
• pH6.5-7.0 reduced phosphate excretion
24 hr urine collection
• Quantative
–
–
–
–
–
Uric acid >4mmol/24hrs
Ammonium >50mmol/24hrs
Phosphate very much decreased
Sodium decreased
Potassium decreased
Bacteriology
Metaphylaxis
General
• Treatment of UTI
Urine dilution
• 2.5-3l/day
• Can check urine density (>1.010g/cm3 should
increase fluid intake)
Diet
• Reduce purine intake
• Ovo-lacto-vegetarian diet
Metaphylaxis
Medical
• Acidification
– Keep pH >6.2
– L-methionine
– Ammonium Chloride
• Reduction of uric acid excretion
– Allopurinol (see uric acid)