Prevention and Treatment of Urinary Stone Disease

Prevention and Treatment of Urinary Stone Disease

Prevention and Treatment of
Urinary Stone Disease
Stone Cases per 1,000 Patients (Norway)
80
Oil
crisis
70
60
3.2
2.4
50
40
Norway
WW II
1.6
UK
30
Depression
20
10
0
1900
0.8
WW I
0
1910
1920
1930
1940
1950
Year
1960
1970
1980
1990
Discharge for Stones per 10,000 Population in UK
Occurrence of Urolithiasis during Last Century
Cumulative Recurrence of Stone-Formation in UK
Cumulative Recurrence (%)
100
80
Williams (1963)
60
Blacklock (1968)
Marshall et al (1975) (males)
40
Marshall et al (1975) (females)
20
0
0
5
10
15
20
Years since first stone
25
30
Stone Recurrence Rates 3 Years After Various
Urological Procedures for Stone Management
Percentage
60
50
New
Stones
40
New +
Residual
Stones
30
20
10
0
Open
Surgery
PCNL
ESWL
HM3
ESWL
2&3
Age at Onset of Stones in Males
35
London (1975)
Percentage (%)
30
Leeds (1985)
25
London (2001)
20
15
10
5
0
0
10
20
30
40
50
Age at Onset (years)
60
70
80
Age at Onset of Stones in Females
35
Percentage (% )
London (1975)
30
Leeds (1985)
London (2001)
25
20
15
10
5
0
0
10
20
30
40
50
Age of Onset (years)
60
70
80
Life-Time Expectancy of Stone-Formation in Men Aged
60-70 in Various Countries
20
15
10
5
KS
A
UA
E
US
A
UK
Ge
rm
an
y
Sw
ed
en
Ja
pa
n
Ca
na
da
0
Ch
ina
Percentage (%)
25
URINARY STONES
MINERAL (90%)
WATER (7%)
Calcium oxalate
Calcium phosphate
Magnesium ammonium phosphate
Uric acid/urates
Cystine
Xanthine
2,8-Dihydroxyadenine
Silica
Insoluble drugs (eg Indinavir,
Triamterene etc)
ORGANIC MATRIX 3%)
Mucoprotein
Protein
Predominant
Mineral
KSA
(%)
USA
(%)
UK
(%)
KSA/UK*
Ratio
Uric acid
14.6
10.1
4.5
5.1
CaOx
71.3
58.8
53.8
2.1
CaP
7.6
20.3
30.9
0.4
MAP
3.7
9.3
9.6
0.6
Rare
2.8
1.5
1.7
2.6
* Including overall Saudi/UK prevalence ratio in adults of 1.6:1
Mineral Solubilities in Water at 37ºC and pH 6
Mineral
Maximum Solubility (g/litre)
Calcium oxalate
0.0071
Calcium phosphate
0.08
Magnesium ammonium phosphate
0.36
Uric acid
0.08
Cystine
0.17
Calcium sulphate
2.1
Calcium citrate
2.2
Magnesium sulphate
293
Calcium chloride
560
Simplest Model of Urinary Stone-Formation
Free-Particle Model
1. Crystal nucleation
2. Crystal growth and agglomeration
3. Retention of critically-sized particle
4. Growth of trapped particle into stone
CaOx Crystals and Aggregates Growing in Urine
20µm
20µm
100µm
Calcium Oxalate Microstone
100 µm
Diagram of Kidney
Stylised
nephron
Urine
containing
crystals flowing
down collecting
tubules
FreeParticle
Model of
Stone
Initiation
Crystals growing
and
agglomerating
Critical
particle
trapped in
tubule
Particle adheres to
damaged site on
tubule wall and
other crystals
agglomerate with it
FixedParticle
Model of
Stone
Initiation
Supersaturation of Urine
Increasing Supersaturation
1.5
UNSTABLE ZONE:
Formation Product
1
METASTABLE ZONE:
0.5
0
Spontaneous Nucleation
Heterogeneous Nucleation
Crystal Growth
Solubility Product
UNDERSATURATED ZONE: Crystal dissolution
-0.5
Risk Factor Model of Cystine Stone-Formation
↓ Tubular
reabsorption
of cystine
↑ Urinary
cystine
Possible
metabolic
factors
↑ Cystine
supersaturation
Abnormal
crystalluria
Cystine
stone
Cystine Stone-Formation
Stone:
Occurrence:
Age:
Gender:
Abnormal
24-h Urine cystine ↑↑
24-h Urine lysine ↑↑,
arginine ↑↑, ornithine ↑↑
Cystine (+calcium phosphate)
~1%
Child and adult
Male and female
Normal
Calcium metabolism
MSU
Risk Factors for Uric Acid Stone Disease
Pre-Urinary
Urinary
↓ Renal NH3 production
Ileostomy
↓ pH
Gout
↑ Purine intake
Glycogen storage disease
Lesch-Nyhan syndrome
Neoplastic disease
↑ Uric acid
↑ Percutaneous loss of fluid
Diarrhoea
Ileostomy
↓ Volume
Uric Acid Stone-Formation
Stone:
Uric acid (+calcium oxalate)
Occurrence:~5%
Age:
30 - 70
Gender:
Male > female
Abnormal
Plasma uric acid ↑
24-h Urine uric acid ↑,
24-h Urine pH ↓
24-h Urine volume ↓
Normal
Calcium metabolism
MSU
Other Features
Ileostomy
Risk Factor Model of Uric Acid Stone-Formation
Age
Sex (M > F)
Genetic
disorders
Metabolic
disorders
↑ Dietary purine
↓ Renal NH3
production
↑ Dietary acid
↓ Fluid intake
↑ Fluid loss
↑ Ambient
temperature
↑ Urinary
uric acid
↓ Urinary
pH
↓ Urinary
volume
↑ Uric acid
supersaturation
Abnormal
crystalluria
Uric
acid
stone
Additional Features of Infected Stone-Formation
• There is a metabolic abnormality in > 50% of patients
with infection stones
• Any anatomical abnormality may lead to infection
• Ammonia may cause damage to protective GAG layer
• Recurrence in 10% of patients after complete
removal
• Recurrence in 85% of patients if fragments remain
• Antibiotics may suppress bacteriuria and afford
symptomatic relief but rarely totally eliminate
infection in the presence of calculi
Calcium Stone-Formation
100
dRTA
80
Hyperoxaluria
Female
Male
MSK
60
Steroids
Hypervitaminosis D
40
Immobilisation
20
Milk-Alkali
Syndrome
0
Idiopathic
HyperParathyroid
Others
Inhibitors and Promoters of Crystallisation in Urine
INHIBITORS
Citrate, Pyrophosphate, Magnesium,
ADP, ATP, Phosphocitrate,
Glycosaminoglycans, Tamm-Horsfall
Mucoprotein, Uromodulin, (Osteopontin),
α-1-Microglobulin, β-2-Microglobulin,
Urinary Prothrombin Fragment 1, Inter-αInhibitor
PROMOTERS
Uromucoid (Polymerised THM), Matrix
Substance A
Normal Subjects
RSF
RSF
Recurrent CaOx Stone-Former (RSF)
Severity of Calcium Stone Disease and Crystalluria
2.5
Stone episodes/year
Basal
+ Orthophosphate
2
1.5
1
0.5
0
0
10
20
30
Percentage of large crystals (>12 µm in diameter)
40
Risk Factor Model of Calcium Stone-Formation
↑Supersaturation
↓ Inhibitors
↑ Promoters
Abnormal
Crystalluria
Stone
Urinary Risk Factors for Calcium Stone-Formation
• Low urine volume
• Mild hyperoxaluria
• Increased urinary pH
• Hypercalciuria
• Hypocitraturia
• Hyperuricosuria
• Hypomagnesiuria
Urinary Risk Factors in Stone-Formers and Normals
50
Calcium (mmol)
Volume
(litres)
SF
SF
SF
N
pH
Oxalate (mmol)
SF
N
N
N
Frequency (%)
25
1
2
3
5
10
0.2
15
0.6
0.4
5.0
.
50
Citrate (mmol)
SF
SF
7.0
Log RS (Uric Acid)
Magnesium (mmol)
Uric Acid (mmol)
6.0
SF
SF
25
N
N
N
N
l
l
l
l
l
l
l
l
l
l
l
l
l
l
l
0
2
4
0
2
4
6
0
3
6
9 -1
0
1
2
Relative Risk Factor (α = SF/N)
Risk Curves for Urinary Risk Factors for Stone-Formation
20
Volume
15
Oxalate
Citrate
pH
10
Calcium
5
Uric Acid
Magnesium
0
-3
-2
-1
0
1
2
3
SD Units from Mean Value in Normal Population
4
Stone Episode Rate (No/year)
8
Severity of Stone-Formation
7
6
5
4
3
2
1
0
2
3
0.001
4
0.01
5
0.1
6
0.5
7
0.9
Relative Probability (PSF)
0.99
8
0.999
Example of Risk Accumulation in a "Normal-Looking" Urine
from a CaOx/CaP Stone-Former Compared with that of a Normal
Patient (AGW)
Volume (litre/day)
1.50
pH
6.10
Calcium (mmol/day)
5.98
Magnesium (mmol/day) 3.62
Oxalate (mmol/day)
0.40
Uric acid (mmol/day)
3.66
Citrate (mmol/day)
2.11
PSF(CaOx)
PSF(CaOx/CaP)
PSF(CaP)
0.85****
0.90*****
0.67**
Normal (JHT)
1.65
6.00
5.50
4.50
0.35
3.20
2.50
0.35
0.36
0.42
Idiopathic Calcium Stone-Formation
Stone:
Calcium oxalate and/or
calcium phosphate or uric acid
Occurrence: 70%
Age:
15 - 75
Gender:
Male > female (3:1)
Abnormal
24-h Urine volume ↓
24-h Urine pH ↑
24-h Urine calcium ↑
24-h Urine oxalate ↑
24-h Urine uric acid ↑
24-h Urine citrate ↓
24-h Urine magnesium ↓
Normal
Plasma Ca, Pi, PTH
MSU
Risk Factor Model of Calcium Stone-Formation
↑ Calcium
↑ Oxalate
↑Supersaturation
↑ pH
↓ Volume
↓ Inhibitors
↓ Citrate
↓ Magnesium
↑ Uric acid
↑ Promoters
Abnormal
Crystalluria
Stone
Epidemiological Risk Factors for Calcium Stone-Formation
Age
Gender
Season
Climate
Fluid Intake
Stress
Occupation
Affluence
Diet
Metabolic disorders
Genetic disorders
Annual Discharges for Stones/104 Population
Stones and Affluence
3.5
12
Leeds 1971-73
10
UK Regions 1971-73
i
3.0
8
6
2.5
i
i
4
2
0
2.00
v
i
v
2.0
ii
i
S
c
1.5
2.10
3.00
2.50
3.5
YH
N
S
NW
W
W
M
2.20
2.30
2.40
2.50
KSA
UAE
World
3.0
S
E
E
M
20
UK 1958-73
W
a
EA
15
2.5
10
NZ
Arg
2.0
5
1.5
2.10
0
2.20
2.30
2.40
2.50
Weekly Food Expenditure (£)
Ca
n
F A
Irl
N
In T Eg Is
It U
J
P
K
0
1000
D
Au
sNL
2000
USA
S
3000
4000
5000
Gross National Product ($)
Animal Protein Intake and Affluence
Animal Protein Consumption (g/day)
55
48
i
Leeds 1971-73
50
45
v
i
v
ii
i
40
2.00
S
E
UK Regions 1971-73
YH
46
i
i
S
N W
E
W
N M
W
M
44
42
3.00
2.10
2.50
48
EA
W
a
S
c
2.20
2.30
2.40
2.50
100
UK 1958-73
World
80
46
UAE
NZ
60
Arg
A
40
44
20
42
2.10
0
2.20
2.30
2.40
2.50
Weekly Food Expenditure (£)
KSA
Irl F
Is It
T Eg J
In
P
0
1000
N
Au
D
s
NL
S
Ca USA
n
U
K
2000
3000
4000
5000
Gross National Product ($)
Annual Discharges for Stones/104 Population
Stones and Animal Protein Intake
12
Leeds 1971-73
10
3.5
i
3.0
8
i
i
6
4
2
v
i
v
YH
2.5
N
ii
i
2.0
0
S
c
1.5
42
46
50
W
a
UK Regions 1971-73
42
54
3.5
W
M
S
E
S
W
N
WE
M
44
EA
46
48
20
UK 1958-73
World
3.0
UAE
KSA
15
USA
2.5
Ca
n
10
NZ
S
A N NLAu Arg
Irl
It
Us
F
Is
K
D
2.0
5
Eg
InT
1.5
42
44
46
48
J
P
0
0
20
40
Animal Protein Intake (g/day)
60
80
100
Admissions for Stone/104 Adult Population
20
18
KSA
World
UAE
16
USA (1975)
14
12
USA (1950)
Can
10
8
S
NZ
D
6
Aus
Arg
NL
4
It (1954)
2
In
P
Eg
0
0
Is
It (1978)
N
J (1990)
F
A
Irl UK (1979)
UK (1958)
J (1960)
20
40
60
80
Animal Protein Intake (g/day)
100
Stones Received for Analysis (no/year)
20
Uric acid
15
10
Cystine
5
0
1 96 5
19 7 0
19 7 5
1 9 80
1 9 85
250
Calcium
200
150
100
Infection
50
0
1965
1970
1975
Year
1980
1985
Prevalence of Urinary Stone Disease in Men
5
Prevalence (%)
4
3
2
1
0
Leeds Study
(1980)
Vegetarians
Secondary
Stones
Other Dietary Factors Influencing Urinary Stone-Formation
↑ Calcium
-
↑ Urinary calcium
↓ Calcium
-
↑ Urinary oxalate
↑ Oxalate
-
↑ Urinary oxalate
↑ Sodium
-
↑ Urinary calcium
↑ Refined sugars
-
↑ Urinary calcium
↓ Fibre
-
↑ Urinary calcium
↑ Fibre
-
↓ Urinary volume
↓ Magnesium
-
↓ Urinary magnesium
0.9999
Relative Probability (PSF)
0.999
0.99
0.9
1 0
Normal Subjects
9
8
Low fluid intake
7
6
0.5
5
Normal fluid intake
0.1
4
3
0.01
2
0.001
0.0001
1
High fluid intake
0
0
1
2
3
Urine Volume (litre/day)
4
Occupation, Low Urine Volume and Urolithiasis
Occupation
Percent of Male
Stone-Formers
Urine
Volume
(litre/day)
Taxi-Drivers, Chauffeurs
5.6
1.42 ± 0.27
Chefs, Kitchen-Workers
6.3
1.31 ± 0.34
Dietary Risk Factors for Stones in Saudi Arabia
Dietary Constituent
UK
USA
KSA
Animal protein (g/day)
61
85
87
Calcium (mmol/day)
24.5
25.0
13.0
Oxalate (mmol/day)
1.4
-
3.8
Purine (mg/day)
150
257
265
Oxalate/Calcium
0.06
-
0.29
Effect of Small Increase in Urinary Calcium Excretion in the Population
14
25
12
Mean 6.2 mmol/day
10
Mean 6.5 mmol/day
15
8
6
10
Normals
4
Stimulated
5
Risk curve
2
0
0
0
2
4
6
8
10
12
14
Urine Calcium (mmol/day)
16
18
20
Calcium Risk Curve
Frequency (%)
20
Medical Management of Urolithiasis
Objectives:
• To identify the particular risk factors for stoneformation in the patient concerned
• To reduce the supersaturation of urine with
respect to the stone-forming mineral concerned
in order to minimise the risk of forming abnormal
crystals and aggregates in urine
• This may be achieved by means of dietary and/or
medical treatment
Medical Management of Non-Calcium-Containing Stones
Stone
Treatment
2,8-DHA
Xanthine
Very high fluids + allopurinol
Hereditary: High fluid intake + alkali (pH >7.4)
Iatrogenic: Withdraw allopurinol
Cystine
Very high fluids + alkali (pH >7.5) or
D-penicillamine or α-mercaptopropionylglycine
High fluids + alkali (pH >6.2) or reduce purine
intake or allopurinol
Uric acid
Infected
Antibiotics + high fluids + oral acid (pH <6.2)
Iatrogenic Discontinue drug concerned and replace with
alternative treatment + high fluids
Medical Management of Calcium Stones
Patient Type
Idiopathic
Treatment
High fluids + relevant dietary advice or
thiazides or phosphate or magnesium
supplements or potassium citrate (K3Cit)
Hyperparathyroid
Parathyroidectomy or high fluid + acids
High fluids + pyridoxine
1° Hyperoxaluric
High fluids + low Ox + high Ca or K3Cit
2° Hyperoxaluric
Distal RTA
High fluids + thiazides or K3Cit
MSK
Treat as for idiopathic
Corticosteroid
Discontinue steroids; treat as idiopathic
Milk-alkali syndrome Discontinue alkali; reduce Ca + fluids
Vit D intoxication
Discontinue vitamin D supplements
Problems in the Medical Management of Patients with
Urinary Stones
• It is impossible to treat stone patients satisfactorily
without proper biochemical screening and this has
been abandoned by many hospitals world-wide
• Most stone patients feel well most of the time apart
from the occasions when they have renal colic
• It is difficult to motivate them to keep to their dietary
or medical treatment over a long period and their
biochemical risk of forming stones increases (the
Anti-"Stone Clinic Effect")
The Anti-"Stone Clinic Effect"
Urine Calcium (mmol/day)
20
Colic
15
10
5
0
0
4
8
12
16
Time (weeks)
20
24
20
24
Urine Oxalate (mmol/day)
0.8
Colic
0.6
0.4
0.2
0
0
4
8
12
16
Time (weeks)