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