Prevention and Treatment of Urinary Stone Disease Biomaterials... · Urine containing crystals flowing ... Risk Curves for Urinary Risk Factors for Stone-Formation. 0 1 2 3 4 5 6

Prevention and Treatment of Prevention and Treatment of Urinary Stone DiseaseUrinary Stone Disease

Occurrence 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

Ston

e 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

Recu

rren

ce (%

)

Years since first stone

Cumulative Recurrence of Stone-Formation in UK

Stone Recurrence Rates 3 Years After Various Urological 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

0

5

10

15

20

25

30

35

0 10 20 30 40 50 60 70 80

London (1975)

Leeds (1985)

London (2001)

Age at Onset (years)

Perc

enta

ge (%

)

Age at Onset of Stones in Females

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 (2001)

Perc

enta

ge (%

)

Life-Time Expectancy of Stone-Formation in Men Aged 60-70 in Various Countries

0

5

10

15

20

25Ch

ina

UKGer

man

ySw

eden

Japa

nCa

nada

USA

UAE

KSA

Perc

enta

ge (%

)

URINARY STONES

MINERAL (90%) WATER (7%) ORGANIC MATRIX 3%)

Calcium oxalateCalcium phosphateMagnesium ammonium phosphateUric acid/uratesCystineXanthine2,8-DihydroxyadenineSilicaInsoluble drugs (eg Indinavir, Triamterene etc)

MucoproteinProtein

Predominant KSA USA UK KSA/UK* Mineral (%) (%) (%) 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

Free-Particle Model of

Stone Initiation

Fixed-Particle 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

Supersaturation of Urine

-0.5

0

0.5

1

1.5

Incr

easi

ng S

uper

satu

ratio

n

Formation Product

Solubility Product

UNDERSATURATED ZONE: Crystal dissolution

METASTABLE ZONE: Heterogeneous Nucleation

Crystal Growth

UNSTABLE ZONE: Spontaneous Nucleation

↓ Tubularreabsorption

of cystine

Possiblemetabolic

factors

↑ Urinarycystine

↑ Cystinesupersaturation

Abnormalcrystalluria

Cystinestone

Risk Factor Model of Cystine Stone-Formation

Cystine Stone-Formation

Stone: Cystine (+calcium phosphate)Occurrence: ~1%Age: Child and adultGender: Male and female

Abnormal Normal

24-h Urine cystine ↑↑ Calcium metabolism24-h Urine lysine ↑↑, MSUarginine ↑↑, ornithine ↑↑

Risk 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

Uric Acid Stone-Formation

Stone: Uric acid (+calcium oxalate)Occurrence:~5%Age: 30 - 70Gender: Male > female

Abnormal NormalPlasma uric acid ↑ Calcium metabolism24-h Urine uric acid ↑, MSU24-h Urine pH ↓24-h Urine volume ↓

Other FeaturesIleostomy

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

Risk Factor Model of Uric Acid Stone-Formation

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

0

20

40

60

80

100

Idiopathic Hyper-Parathyroid

Others

FemaleMale

dRTA

Hyperoxaluria

MSK

Steroids

Hypervitaminosis D

Immobilisation

Milk-Alkali Syndrome

Inhibitors and Promoters of Crystallisation in Urine

INHIBITORSCitrate, Pyrophosphate, Magnesium, ADP, ATP, Phosphocitrate, Glycosaminoglycans, Tamm-Horsfall Mucoprotein, Uromodulin, (Osteopontin), α-1-Microglobulin, β-2-Microglobulin, Urinary Prothrombin Fragment 1, Inter-α-Inhibitor

PROMOTERSUromucoid (Polymerised THM), Matrix Substance A

Normal Subjects RSF RSF

Recurrent CaOx Stone-Former (RSF)

0

0.5

1

1.5

2

2.5

0 10 20 30 40

Basal

+ Orthophosphate

Percentage of large crystals (>12 µm in diameter)

Ston

e ep

isod

es/y

ear

Severity of Calcium Stone Disease and Crystalluria

Risk Factor Model of Calcium Stone-Formation

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

Urinary Risk Factors in Stone-Formers and Normals

Volume (litres)

Calcium (mmol) Oxalate (mmol) pH

Citrate (mmol) Uric Acid (mmol) Magnesium (mmol)

SF SF SF SF

SF SF SF

N N N N

N N N

1 2 3 5 10 15 0.2 0.4 0.6 . 5.0 6.0 7.0

25

50

25

50

Freq

uenc

y (%

)

Log RS (Uric Acid)

SF

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

0

5

10

15

20

-3 -2 -1 0 1 2 3 4

Oxalate

pH

Calcium

Uric Acid

Volume

Citrate

Magnesium

SD Units from Mean Value in Normal Population

Rel

ativ

e R

isk

Fact

or (α

= SF

/N)

Risk Curves for Urinary Risk Factors for 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)

Ston

e Ep

isod

e R

ate

(No/

year

) Severity of Stone-Formation

Example of Risk Accumulation in a "Normal-Looking" Urine from a CaOx/CaP Stone-Former Compared with that of a Normal

Patient (AGW) Normal (JHT)Volume (litre/day) 1.50 1.65pH 6.10 6.00Calcium (mmol/day) 5.98 5.50Magnesium (mmol/day) 3.62 4.50Oxalate (mmol/day) 0.40 0.35Uric acid (mmol/day) 3.66 3.20Citrate (mmol/day) 2.11 2.50

PSF(CaOx) 0.85**** 0.35PSF(CaOx/CaP) 0.90***** 0.36PSF(CaP) 0.67** 0.42

Idiopathic Calcium Stone-Formation

Stone: Calcium oxalate and/or calcium phosphate or uric acid

Occurrence: 70%Age: 15 - 75Gender: Male > female (3:1)

Abnormal Normal24-h Urine volume ↓ Plasma Ca, Pi, PTH24-h Urine pH ↑ MSU24-h Urine calcium ↑24-h Urine oxalate ↑24-h Urine uric acid ↑24-h Urine citrate ↓24-h Urine magnesium ↓

Risk Factor Model of Calcium Stone-Formation

Abnormal Crystalluria

Stone

↑ Calcium

↑ Oxalate

↑ pH

↓ Volume

↓ Citrate

↓ Magnesium

↑ Uric acid

↑Supersaturation

↓ Inhibitors

↑ Promoters

AgeGenderSeasonClimate

Fluid IntakeStress

OccupationAffluence

DietMetabolic disordersGenetic disorders

Epidemiological Risk Factors for Calcium Stone-Formation

0

2

4

6

8

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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 S

Can

KSA

USA

UAE

Ani

mal

Pro

tein

Con

sum

ptio

n (g

/day

)

Weekly Food Expenditure (£) Gross National Product ($)

UK 1958-73 World

Arg

Animal Protein Intake and Affluence

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 EgIsIt

J

IrlF

AUK

N

NZ

NLAus

D S

Can

KSA

USA

UAE

Ann

ual D

isch

arge

s fo

r Sto

nes/

104

Popu

latio

n

Animal Protein Intake (g/day)

UK 1958-73 World

Arg

Stones and Animal Protein Intake

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

050

100150200250

1965 1970 1975 1980 1985

0

5

10

15

20

1 9 6 5 1 9 7 0 1 9 7 5 1 9 8 0 1 9 8 5

Year

Uric acid

Cystine

Calcium

Infection

Ston

es R

ecei

ved

for A

naly

sis

(no/

year

)

0

1

2

3

4

5

Leeds Study(1980)

Vegetarians SecondaryStones

Prev

alen

ce (%

)Prevalence of Urinary Stone Disease in Men

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

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

Rel

ativ

e Pr

obab

ility

(PSF

)Normal Subjects

Low fluid intake

Normal fluid intake

High fluid intake

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

0

5

10

15

20

25

0 2 4 6 8 10 12 14 16 18 20Urine Calcium (mmol/day)

Freq

uenc

y (%

)

0

2

4

6

8

10

12

14

Cal

cium

Ris

k C

urve

Normals

Stimulated

Risk curve

Effect of Small Increase in Urinary Calcium Excretion in the Population

Mean 6.2 mmol/day

Mean 6.5 mmol/day

Medical Management of Urolithiasis

• To identify the particular risk factors for stone-formation 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

Objectives:

Medical Management of Non-Calcium-Containing Stones

Stone Treatment

2,8-DHA Very high fluids + allopurinolXanthine Hereditary: High fluid intake + alkali (pH >7.4)

Iatrogenic: Withdraw allopurinolCystine Very high fluids + alkali (pH >7.5) or

D-penicillamine or α-mercaptopropionylglycineUric acid High fluids + alkali (pH >6.2) or reduce purine

intake or allopurinolInfected Antibiotics + high fluids + oral acid (pH <6.2)

Iatrogenic Discontinue drug concerned and replace withalternative treatment + high fluids

Medical Management of Calcium Stones

Patient Type TreatmentIdiopathic High fluids + relevant dietary advice or

thiazides or phosphate or magnesiumsupplements or potassium citrate (K3Cit)

Hyperparathyroid Parathyroidectomy or high fluid + acids1° Hyperoxaluric High fluids + pyridoxine2° Hyperoxaluric High fluids + low Ox + high Ca or K3CitDistal RTA High fluids + thiazides or K3CitMSK Treat as for idiopathicCorticosteroid Discontinue steroids; treat as idiopathicMilk-alkali syndrome Discontinue alkali; reduce Ca + fluidsVit 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")

0

5

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0 4 8 12 16 20 24Time (weeks)

Urin

e C

alci

um (m

mol

/day

)

0

0.2

0.4

0.6

0.8

0 4 8 12 16 20 24Time (weeks)

Urin

e O

xala

te (m

mol

/day

)

The Anti-"Stone Clinic Effect"

Colic

Colic