centre for the prevention and treatment of urinary stone ...ucgatma/anat3048/lectures...rfh centre...
TRANSCRIPT
-
RFH
Centre for the Prevention and Centre for the Prevention and Treatment of Urinary Stone DiseaseTreatment of Urinary Stone Disease
Department of Physiology Department of Physiology (Centre for Nephrology)(Centre for Nephrology)
Royal Free and University College Royal Free and University College Medical School London Medical School London
Director: Professor RJ UnwinDirector: Professor RJ UnwinCoCo--ordinator: Dr WG Robertsonordinator: Dr WG Robertson
-
Occurrence of Urolithiasis during Last CenturyOccurrence of Urolithiasis during Last Century
0
10
20
30
40
50
60
70
80
1900 1910 1920 1930 1940 1950 1960 1970 1980 1990Year
Norway
UK
3.2
2.4
1.6
0.8
0
Sto
ne C
ases
per
1,0
00 P
atie
nts
(Nor
way
)
Dis
char
ge fo
r Sto
nes
per 1
0,00
0 Po
pula
tion
in U
K
WW I
WW II
Oil crisis
Depression
-
0
20
40
60
80
100
0 5 10 15 20 25 30
Williams (1963)
Blacklock (1968)
Marshall et al (1975) (males)
Marshall et al (1975) (females)
Cum
ulat
ive
Rec
urre
nce
(%)
Years since first stone
Cumulative Recurrence of StoneCumulative Recurrence of Stone--Formation in UKFormation in UK
-
Stone Recurrence Rates 3 Years After Various Stone Recurrence Rates 3 Years After Various Urological Procedures for Stone ManagementUrological Procedures for Stone Management
0
10
20
30
40
50
60
OpenSurgery
PCNL ESWL HM3
ESWL 2 & 3
NewStones
New +ResidualStonesPe
rcen
tage
-
Age at Onset of Stones in Males (1975Age at Onset of Stones in Males (1975--2003)2003)
0
5
10
15
20
25
30
35
0 10 20 30 40 50 60 70 80
London (1975)
Leeds (1985)
London (2003)
Age at Onset (years)
Per
cent
age
(%)
-
Age at Onset of Stones in Females (1975Age at Onset of Stones in Females (1975--2003)2003)
0
5
10
15
20
25
30
35
0 10 20 30 40 50 60 70 80
Age of Onset (years)
London (1975)
Leeds (1985)
London (2003)
Per
cen
tag
e (%
)
-
LifeLife--Time Expectancy of StoneTime Expectancy of Stone--Formation in Men Aged Formation in Men Aged 6060--70 in Various Countries70 in Various Countries
0
5
10
15
20
25Ch
ina
UKFr
ance
Swed
enJa
pan
Germ
any
Cana
daUS
AUA
EKS
A
Perc
enta
ge (%
)
-
URINARY STONES
MINERAL (90%) WATER (7%) ORGANIC MATRIX (3%)
Calcium oxalate (CaOx)Calcium phosphate (CaP)Magnesium ammonium phosphate (MAP)Uric acid/urates (UA)Cystine (Cys)Xanthine2,8-DihydroxyadenineSilicaInsoluble drugs (eg Indinavir, Triamterene etc)
MucoproteinProtein
-
Worldwide Variation in Stone CompositionWorldwide Variation in Stone Composition
Predominant KSA USA UK KSA/UK* Mineral (%) (%) (%) Ratio
Uric acid 14.6 10.1 6.5 5.1
CaOx 71.3 58.8 53.8 2.1
CaP 7.6 20.3 28.9 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
-
The Precipitability of Stone Constituents in Urine at 37The Precipitability of Stone Constituents in Urine at 37°°
0
0 .2
0 .4
0 .6
0 .8
1
1 .2
1 .4
1 .6
1 .8
2
4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0
Urinary pH
Prec
ipita
bilit
y
CaOx
UA
CaP
MAP
Cys
normal range
-
Urine containing
crystals flowing down collecting
tubules
Crystals growing and
agglomerating
Critical particle
trapped in tubule
Particle adheres to damaged site on tubule wall and other crystals
agglomerate with it
Free-Particle Model of
Stone Initiation
Fixed-Particle Model of
Stone Initiation
-
CaOx Crystals and Aggregates Growing in Urine CaOx Crystals and Aggregates Growing in Urine
2020µµm m 2020µµm m 100100µµm m
-
Calcium Oxalate MicrostoneCalcium Oxalate Microstone
100 µm
-
Relative Supersaturation of UrineRelative Supersaturation of Urine
-0.5
0
0.5
1
1 .5
Formation Product
Solubility ProductUNDERSATURATED ZONE: Crystal dissolution
METASTABLE ZONE: Heterogeneous Nucleation
Crystal Growth
UNSTABLE ZONE: Spontaneous Nucleation
Incr
easi
ng S
uper
satu
ratio
nIn
crea
sing
Sup
ersa
tura
tion
-
-7
-6
-5
-4
-3
-2
-1
0
1
2
3
0 0.5 1 1 .5 2 2 .5 3 3 .5 4l l l Homozygotes Heterozygotes Normals
-100
-10
-1
-0.1
-0.01
-0.001
-0.0001
-0.00001
Log
(RS
cyst
ine)
Nor
mal
ised
log
(RS
cyst
ine)
FP
SP
-
Cystine Crystals in UrineCystine Crystals in Urine
-
Risk Factor Model of Cystine StoneRisk Factor Model of Cystine Stone--Formation Formation
↓ Tubularreabsorption
of cystine
↑ Cystinesupersaturation
Abnormalcrystalluria
Cystinestone
↑ Urinarycystine
Possiblemetabolic
factors
-
Risk Factors for Uric Acid Stone DiseaseRisk Factors for Uric Acid Stone Disease
Pre-Urinary Urinary ↓ Renal NH3 production ↓ pH Ileostomy Gout ↑ Uric acid ↑ Purine intake Glycogen storage disease Lesch-Nyhan syndrome Neoplastic disease ↑ Percutaneous loss of fluid ↓ Volume Diarrhoea Ileostomy
-
-2
-1
0
1
2
0 0.5 1 1 .5 2 2 .5 3l l lIdiopathic Ileostomy Normals
Nor
mal
ised
log
(RS
uric
aci
d)
Log
(RS
uric
aci
d)
- 4
- 2
- 1
- 0.5
- 0.25
FP
SP
-
Uric Acid Crystals in Urine
-
Risk Factor Model of Uric Acid StoneRisk Factor Model of Uric Acid Stone--FormationFormation
AgeSex (M > F)Genetic disordersMetabolic disorders↑ Dietary purine
↓ Renal NH3production↑ Dietary acid
↑ Urinaryuric acid
↑ Uric acid supersaturation
Abnormalcrystalluria
Uric acid
stone↓ Urinary
pH
↓ Urinaryvolume
↓ Fluid intake↑ Fluid loss↑ Ambient
temperature
-
Biochemical Effect of Urinary Tract Infection Biochemical Effect of Urinary Tract Infection with a Ureawith a Urea--Splitting OrganismSplitting Organism
NH23H2O + C=O 2NH4+ + HCO3- + OH-
NH2
Urease
-
-2
-1
0
1
2
3
0 0.2 0.4 0.6 0.8 1 1 .2 1 .4 1 .6 -5
-4
-3
-2
-1
0
1
2
3
0 0.2 0.4 0.6 0.8 1 1 .2 1 .4 1 .6l lInfection Normals
Nor
mal
ised
log
(RS
CaP
)- 109
- 106
- 103
- 1
- 10-3
- 10-6
Log
(RS
CaP
)
Nor
mal
ised
log
(RS
MA
P)
-10
- 1
- 0.1
- 0.01
Log
(RS
MA
P)FP
SP
FP
SP
l lInfection Normals
-
Calcium Phosphate Crystals in UrineCalcium Phosphate Crystals in Urine
-
Magnesium Ammonium Phosphate Crystal in UrineMagnesium Ammonium Phosphate Crystal in Urine
-
Risk Factor Model of Infected StoneRisk Factor Model of Infected Stone--FormationFormation
Urinarytract
infectionwith aurea-
splittingorganism
↑ ↑ UrinaryNH4+
↑ CaP and MAPsupersaturation
Abnormalcrystalluria
Infectionstone
↑ Urinarymucoprotein
↓ Urinarycitrate
↓ Inhibitoryactivity
↑ Nucleationand
agglomeration
↑ ↑ UrinarypH
↓ Urinarypyrophosphate
-
Calcium StoneCalcium Stone--FormationFormation
0
20
40
60
80
100
Idiopathic Hyper-Parathyroid
Others
FemaleMale
dRTA
Hyperoxaluria
MSK
Steroids
Hypervitaminosis D
Immobilisation
Milk-Alkali Syndrome
-
-2
-1
0
1
2
0 0.2 0.4 0.6 0.8 1 1 .2 1 .4 1 .6 1 .8 2
Nor
mal
ised
log
(RS
CaP
)
- 106
- 103
- 1
- 10-3
- 10-6
FP
SP
l lRSF Normals
Log
(RS
CaP
)
-1
0
1
2
0 0.2 0.4 0.6 0.8 1 1 .2 1 .4 1 .6 1 .8l lRSF Normals
Nor
mal
ised
log
(RS
CaO
x)
Log
(RS
CaO
x)
FP
SP
- 100
- 10
- 1
- 0.1
-
Inhibitors and Promoters of Crystallisation in UrineInhibitors and Promoters of Crystallisation in Urine
INHIBITORSINHIBITORSCitrate, Pyrophosphate, Magnesium, Citrate, Pyrophosphate, Magnesium, ADP, ATP, Phosphocitrate, ADP, ATP, Phosphocitrate, Glycosaminoglycans, TammGlycosaminoglycans, Tamm--Horsfall Horsfall Mucoprotein, Uromodulin, (Osteopontin), Mucoprotein, Uromodulin, (Osteopontin), αα--11--Microglobulin, Microglobulin, ββ--22--Microglobulin, Microglobulin, Urinary Prothrombin Fragment 1, InterUrinary Prothrombin Fragment 1, Inter--αα--InhibitorInhibitor
PROMOTERSPROMOTERSUromucoid (Polymerised THM), Matrix Uromucoid (Polymerised THM), Matrix Substance ASubstance A
-
RRiisskk FFaaccttoorr MMooddeell ooff CCaallcciiuumm SSttoonnee--FFoorrmmaattiioonn
Abnormal Crystalluria
Stone
↑Supersaturation
↓ Inhibitors
↑ Promoters
-
Urinary Risk Factors for Calcium Stone-Formation
• Low urine volume
• Mild hyperoxaluria
• Increased urinary pH
• Hypercalciuria
• Hypocitraturia
• Hyperuricosuria
• Hypomagnesiuria
-
0
1
2
3
4
5
6
7
8
9
1 0
1 1
0 1 2 3 4 5 6l l l l l l l l lChildren Women Men SSF RSF Hyperparathyroid dRTA Enteric Hereditary
0.9999 -
0.999 -
0.99 -
0.9 -
0.5 -
0.1 -
0.01 -
0.001 -
0.0001 -
Rel
ativ
e Pr
obab
ility
(PSF
)
NORMALS STONE-FORMERS
Calcium Stone-Formation
-
0.9999 -
0.999 -
0.99 -
0.9 -
0.5 -
0.1 -
0.01 -
0.001 -
0.0001 -0
1
2
3
4
5
6
7
8
9
1 0
1 1
0 1 2 3 4 5 6
Rel
ativ
e Pr
obab
ility
(PSF
)
I l l l
Normals Idiopathic UA SF Gout UA SF Ileostomy UA SF
Uric Acid Stone-Formation
-
0
1
2
3
4
5
6
7
8
2 3 4 5 6 7 8
0.001 0.01 0.1 0.5 0.9 0.99 0.999
Relative Probability (PSF)
Severity of Stone-FormationSt
one
Epis
ode
Rat
e (N
o/ye
ar)
-
RRiisskk FFaaccttoorr MMooddeell ooff CCaallcciiuumm SSttoonnee--FFoorrmmaattiioonn
Abnormal Crystalluria
Stone
↑ Calcium
↑ Oxalate
↑ pH
↓ Volume
↓ Citrate
↓ Magnesium
↑ Uric acid
↑Supersaturation
↓ Inhibitors
↑ Promoters
-
Epidemiological Risk Factors for Calcium StoneEpidemiological Risk Factors for Calcium Stone--FormationFormation
AgeGenderSeasonClimate
Fluid IntakeStress
OccupationAffluence
DietMetabolic disordersGenetic disorders
-
SocioSocio--Economic Group and UrolithiasisEconomic Group and Urolithiasis
0
10
20
30
40
50
v iv iii ii i
GB MalePopulation
Male SFLeeds
IdiopathicMale SFLeeds
Socio-Economic Group
Perc
enta
ge
-
0
5
10
15
20
0 10 20 30 40 50
HR
17
16
23
HC8
1819
217
K
R15206
2528
9
273 26
14
1352
11 411210
Ston
e O
ccur
renc
e / 1
04M
ale
Pop'
nStone Occurrence in Men in Leeds Postal DistrictsStone Occurrence in Men in Leeds Postal Districts
% in Socio-Economic Groups i and ii
-
0
2
4
6
8
10
12
2.00 2.50 3.001.5
2.0
2.5
3.0
3.5
2.10 2.20 2.30 2.40 2.50
1.5
2.0
2.5
3.0
3.5
2.10 2.20 2.30 2.40 2.500
5
10
15
20
0 1000 2000 3000 4000 5000
Leeds 1971-73i
ii
iiii
vv
UK Regions 1971-73
Sc
WM
EM
NNW
SW
YHSE
EAWa
InP
T EgIs ItJIrl F
A
UK
N
NZ
NLAus
D S
Can
KSA
USA
UAE
Ann
ual D
isch
arge
s fo
r Sto
nes/
104
Popu
latio
n
Weekly Food Expenditure (£) Gross National Product ($)
UK 1958-73 World
Arg
Stones and Affluence
-
40
45
50
55
2.00 2.50 3.0042
44
46
48
2.10 2.20 2.30 2.40 2.50
42
44
46
48
2.10 2.20 2.30 2.40 2.500
20
40
60
80
100
0 1000 2000 3000 4000 5000
Leeds 1971-73i
iiii
iivv
UK Regions 1971-73
Sc
WM
EMN
NW
SW
YH
SE
EAWa
InP
T Eg
Is ItJ
Irl FA
UK
N
NZ
NL
Aus D
SCan
KSA
USA
UAE
Weekly Food Expenditure (£) Gross National Product ($)
UK 1958-73 World
Arg
Animal Protein Intake and AffluenceAnimal Protein Intake and AffluenceA
nim
al P
rote
in C
onsu
mpt
ion
(g/d
ay)
-
0
2
4
6
8
10
12
42 46 50 541.5
2.0
2.5
3.0
3.5
42 44 46 48
1.5
2.0
2.5
3.0
3.5
42 44 46 480
5
10
15
20
0 20 40 60 80 100
Leeds 1971-73i
ii
iiii
vv
UK Regions 1971-73
Sc
WM
EM
N NW
SW
YH SE
EAWa
InP
T Eg IsIt
J
IrlF
AUK
N
NZ
NLAus
D S
Can
KSA
USA
UAE
Animal Protein Intake (g/day)
UK 1958-73 World
Arg
Stones and Animal Protein IntakeA
nnua
l Dis
char
ges
for S
tone
s/10
4Po
pula
tion
-
0
2
4
6
8
10
12
14
16
18
20
0 20 40 60 80 100
KSA
UAE
USA (1975)
USA (1950)
Can
NZS
It (1978)
ArgAus
D
NL
It (1954)
N J (1990)
J (1960)
UK (1979)UK (1958)
AIrl
F
Is
Eg
PIn
World
Animal Protein Intake (g/day)
Adm
issi
ons
for S
tone
/104
Adu
lt Po
pula
tion
-
20
25
30
0 1 2 3
N RSF 0.5
1.5
2.5
0 1 2 335
45
55
0 1 2 350
100
150
0 1 2 315
20
25
0 1 2 3
N RSF N RSF N RSF N RSF
Ca (mmol)
ns
Ox (mmol)
P (mmol)
Sugars(g)
Fibre (g)
-
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
0 4 8 12
∆
-0.05
0.00
0.05
0.10
0.15
0 4 8 12-1.0
0.0
1.0
2.0
3.0
0 4 8 120.0
0.2
0.4
0.6
0.8
1.0
0 4 8 12Day
Rel
ativ
e Pr
obab
ility
of S
tone
s (P
SF)Calcium Oxalate Uric Acid PSF
Basal +Animal protein Basal +Animal protein Basal +Animal protein Basal +Animal protein
+AP +AP+AP+AP
Effect of High Animal Protein Intake on the Risk of StonesEffect of High Animal Protein Intake on the Risk of StonesU
rinar
y Ex
cret
ion
(mm
ol/d
ay)
-
Adverse Effects on Urinary Composition of Consuming Adverse Effects on Urinary Composition of Consuming a High Animal Protein Dieta High Animal Protein Diet
↓ Urinary pH from ↑ acid ash in diet
↓ Urinary citrate from ↓ urinary pH
↑ Urinary calcium from ↑ urinary acid
↑ Urinary oxalate from ↑ tyrosine, tryptophan,
phenylalanine and
hydroxyproline in diet
↑ Urinary uric acid from ↑ purine in diet
-
0
2
4
6
8
0 1 2 3 4 50.0
0.1
0.2
0.3
0.4
0 1 2 3 4 5 0
2
4
6
0 1 2 3 4 5 0.0
0.2
0.4
0.6
0.8
1.0
0 1 2 3 4 5
Rel
ativ
e Pr
obab
ility
of S
tone
s (P
SF)
Calcium Oxalate Uric Acid PSF
Hi N Lo Veg Hi N Lo Veg Hi N Lo Veg Hi N Lo Veg
Decreasing Animal Protein Consumption
***
******
***
******
***
**
***
**
***
***
Effect of Decreasing Animal Protein Intake on the Risk of StonesEffect of Decreasing Animal Protein Intake on the Risk of StonesU
rinar
y Ex
cret
ion
(mm
ol/d
ay)
-
Prevalence of Urinary Stone Disease in MenPrevalence of Urinary Stone Disease in Men
0
1
2
3
4
5
Leeds Study(1980)
Vegetarians SecondaryStones
Prev
alen
ce (%
)
-
Other Dietary Factors Influencing Urinary StoneOther Dietary Factors Influencing Urinary Stone--FormationFormation
↑ 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
1
2
3
4
5
6
7
8
9
1 0
0 1 2 3 4Urine Volume (litre/day)
0.5
0.01
0.1
0.999
0.9999
0.99
0.9
0.0010.0001
Normal Subjects
Low fluid intake
Normal fluid intake
High fluid intake
Rel
ativ
e Pr
obab
ility
(PSF
)
-
0.99990.999
Stone-Formers
Normal Subjects
I I I I I 0 1 2 3 4
Urine Volume (litre/day)
0.99
Rel
ativ
e Pr
obab
ility
(PSF
)
0.9
0.5
0.1
0.01
0.0010.0001
-
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 20.0 13.0
Oxalate (mmol/day) 1.4 1.6 3.8
Purine (mg/day) 150 257 265
Oxalate/Calcium 0.06 0.08 0.29
-
Epidemiological Risk Factors for Stones in Saudi Arabia
Epidemiological Factors
High intake of animal protein
High intake of purine
Very high intake of oxalate
Low intake of calcium
Mild dehydration
Urinary Risk Factors
↑ uric acid and oxalate
↓ pH and citrate
↑↑ oxalate
↓ urine volume
-
Urinary Risk Factors for Stones in Saudi Arabia
Urinary Risk Factors
↑↑ Uric acid excretion
Consistently acid urine
↓ Urine volume
↑↑ Oxalate excretion
↓ Citrate excretion
Stones
Uric acid
Calcium oxalate
-
IInntteeggrraatteedd MMooddeell ooff CCaallcciiuumm SSttoonnee--FFoorrmmaattiioonn
Age
Gender
Season
Climate
Fluid Intake
Stress
Affluence
Diet
Metabolic disorders
Genetic
disorders
Anatomical factors
AbnormalCrystalluria
Stone
↑ Calcium
↑ Oxalate
↑ pH
↓ Volume
↓ Citrate
↓ Magnesium
↑ Uric acid
↑Supersaturation
↓ Inhibitors
↑ Promoters
Centre for the Prevention and Treatment of Urinary Stone DiseaseOccurrence of Urolithiasis during Last CenturyStone Recurrence Rates 3 Years After Various Urological Procedures for Stone ManagementAge at Onset of Stones in Males (1975-2003)Age at Onset of Stones in Females (1975-2003)Life-Time Expectancy of Stone-Formation in Men Aged 60-70 in Various CountriesThe Precipitability of Stone Constituents in Urine at 37Relative Supersaturation of UrineCalcium Stone-FormationInhibitors and Promoters of Crystallisation in UrineAdverse Effects on Urinary Composition of Consuming a High Animal Protein DietOther Dietary Factors Influencing Urinary Stone-Formation