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Urolithiasis: pathophysiology, diagnosis and clinical

management

Core Curriculum Course Nephrology

Christian Tielemans

Supersaturation = equilibrium rupture

Promotors calcium

oxalate

phosphate

uric acid

ammonium

cystine

dihydroxyadenine

xanthine

drugs

Inhibitors citrate

pyrophosphate

magnesium

zinc

glycoproteins

glycosaminoglycans

ARN

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Present in

ormal persons

Crystals en stone formation

Crystal formation

Crystal growth

Crystals agregates

Kidney or

bladder stone

Nephron obstruction:

e.g: tumoral lysis syndrome

phagocytosis adhesion ?

nephrocalcinosis,

inflammation,

CKD

dissolution in

lysosomes or

interstitium

+

-

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voided

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• 2nd most frequent disease (after dental decay)

• 10% of the population : at least one symptomatic episode

• recurrent episodes:

- man: 60%

- women: 40%

+ 0.5 106 patients with recurrent urolithiasis

in Belgium

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%

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C2 AU0 PAM Cys

C1= CaOxalate monohydrated= whewellite

C2= CaOxalate dihydrated= weddellite

CA= carbapatite (Ca phosphate)

AU0= water free uric acid

Thus in men: C1 > C2 > AU0 > CA

in women: C1 > CA > C2 > AU0

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Men

< 30 y C2

30-80 C1

> 80 AU

Women

< 30 y CA ~ C1 > 30-80 C1

AU with age

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• children and people < 20 years

• recurrent or « active » stoneformers (> 0.6 events / year)

• nephrocalcinosis

• lithiasis associated with CKD

• primary prevention (1ary hyperoxaluria , cystinuria, Dent, etc…)

• everybody ?

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Which investigations ?

• stone analysis

• evaluation of crystalluria

• blood and urinalysis

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Stone available: analysis

No stone available: speculation over the nature of the stone:

• density of the stone ( Rx, CT scan)

• crystalluria

• metabolic abnormalities (blood en urine)

• often is only a part of the stone available (ESWL)

• a patient may have more than one urolithiasis (heterogenous stone))

• the story of the stone can be complex: e.g core # periphery

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Morphologic analysis:

• organo-leptic characteristics of the stone: appearance, colour,

organization, crystallization… of surface and section

• classification in 6 classes en 22 sub-classes

• very good correlation with chemical composition ( > 95%)

• tells a lot over underlying physiopathology

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Type Ia: bumpy, smooth surface, homogenous brown

Whewellite

umbilication (25%)

(kidney papilla)

Common hyperoxaluria (24h output or concentration)

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Whewellite

Type Ia: sectionk: concentric organization, with radial crystallization,

homogeneously dark brown ch tielemans

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Type Ic: rough, cauliflower aspect, bright colour

Whewellite

Primary hyperoxaluria

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Just the same composition !!

Whewellite

Type Ic: the center is not organized, periphery: beginning of

concentric organization, with radial crystallization, beige colour

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section

Type I sub-class composition

Ia whewellite: Ca-oxalate monohydrated Ib whewellite Ic whewellite Id whewellite I active whewellite

Morfologic classification

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Type I sub-class composition

Ia whewellite Ib whewellite Ic whewellite Id whewellite I active whewellite

Morphologic classification

Microcristallisation

pulvérulente de

whewellite de

couleur claire

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Type II sub-classes composition

IIa weddellite [Ca-oxalaat(H20)2] IIb weddellite ± whewellite IIc weddellite

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Morphologic classification

Type III sub-class composition

IIIa dehydrated uric acid (AU0) IIIb di-hydrated uric acid 2H20 ± AU0 IIIc various urates IIId ammonium urate

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acidic pH alkaline pH

Morphologic classification

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Type IV sub-class composition (calcium-phosphate)

IVa carbapatite IVa2 carbapatite IVb carbapatite + struvite IVc struvite IVd brushite

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Morphologic classification

Type V sub-class composition

Va cystine Vb cystine

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Morphologic classification

Type sub-class composition

VIa proteins VIb proteins + drugs VIc proteins + whewellite

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Morphologic classification

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Hyperoxaluria (common) Ia, Ib, Id

1ary hyperoxaluria Ic

Enteric-hyperoxaluria I active

Hypercalciuria (common) IIa, IIc

Hypercalciuria + hyperoxaluria IIb

Hypercalciuria + phosphaturia IVb struvite -, brushite

Cacchi et Ricci Ia, IVa2, brushite

Infection (urease +) IIIc, IIId, IVa1of IVb

struvite+, struvite

Urease - infection IVa1 struvite-, IVa2, IVb

struvite-,

DTA IVa1 struvite-, IVa2, brushite

1aire HPTH IVa1of IVa2 struvite-, brushite

Insuline resistance IIIb

Hyperuricuria (acidic urine) IIIa, IIIb

Hyperuricuria (alkaline urine) IIIc, IIId

Chemical analysis: reliability 40%

Low precision

The only reimbursed !

X rays diffraction

expensive !

Not all stones can be identified

Infra-red spectroscopy: de « golden standard »

cheap

All species can be identified (specific spectroscopic spectrum)

Quantitative determination of each component

Core and periphery can be analyzed separately so needed

Physico-chemical analysis

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Identification of crystals in the urine (approximately one hundredspecies)

Some crystalurias are very suggestive for given medical situations

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Ethylene glycol intoxication

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Urine sampling Morning fasting urine (or 2nd morning urine)

Analysis must take place within two hours

Ambiant temperature (or 37°C)

Never at 4°C !!! (artifactual crystalluria)

Technique pH (pH meter)

microscope with polarized light (10x, 40x)

Crystal numeration (cell Malassez 1mm³, checkerboard of 50 mm)

qualitative analysis: identification

quantitative analysis

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• contribution to diagnosis (for e.g. no stone available for analysis)

• detection of hereditary urolithiasis (e.g. cystinuria, 2,8-dihydroxy-

adenine)

• identification of medicamentous crystaluria

• contribution to follow-up: positive crystalurias are associated

with a higher rate of recurrence

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Ur am

Struviet

Brushiet

WHE

WED

UAC

5,0

AU2

6,0 7,0 8,0

PACC/CA

7,95 7,45 6,65 6,35 5,90 5,55

5,20

• pH helps for crystal

identification

• AU2 crystals at pH 5.7 indicate

an hyperuricuria

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AU2

Polychromatic tiles

2 obtuse, 2 acute angles

aggregates

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AU0

Aggregation with weddelite

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Big crystals 50-100 mm

polygonal, mostly hexagonal

Irregular thick sides

monochromatic, polarizing

urine pH + 5.4 (5 to 6)

BRUSHITE

Brushite = acid dihydrated calcium phosphate

pH 6.35 (6 to 7)

thick sticks, with irregular width

aggregation by

extremities

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STRUVITE: ammonium-Mg-phosphate

Big crystals ( > 100 mm),monochromatic, very coloured

Trapezoidal sides, « coffin cover »

pH > 7 (7 to 9)

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Ammonium urate

Monochromatic spheres

Struvite

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Alkaline pH

WHEWELLITE (C1)

Fairly pH independent (5 - 8)

Small oval crystals

Depressed centre

Polychromatic

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WEDDELLITE (C2)

2 pyramids attached by

their base

pH 6 (5 - 8)

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Fairly pH independent

CYSTINE

Hexagonal crystal

Equal angles and sides

+ 70 mm

pH 5 - 7.5

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Very polarized concentric spheres

Central black cross

About 10-15 mm

dihydroxyadénine

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urea, creatinine

Na, K, Cl, CO2

Ca, P, PTH, 25-OH vit D3

Mg

uric acid, glucose

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Microscopic examination and culture

24hrs urine collection

• urine outpout (min 1.5L), density: target < 1010

• urea*, creatinine (collection validity)

• Na*

• uric acid ( < 750 mg/24 h)

• calcium ( < 4 mg/kg IW/d), phosphate (< 1500 mg/d)

• citrate ( > 1500 mmol/d), (Mg)

• oxalate ( < 40 mg/d)

* Proteins and sodium intake are associated with lithiasic risk

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Increase urine output is ALWAYS USEFUL

(not during renal colic !!)

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• proteins and oxalate limited diet (particularly important in case of

enteric hyperoxaluria)

• normal Ca diet (Ca supplements with meals)

• K citrate (if associated hypocitraturia)

• future: oxalobacter formigenes enzyme ?

• intestinal oxalate binders ?

• specific inhibitors of oxalate transporters ?

Hyperoxaluria

Hypercalciuria:

• normal Ca diet (800-900 mg/d, 3 units a day)

• drinking water with low calcium concentration

• thiazides (??)

• K citrate

Uric acid:

• most often due to low urine pH (90%)

• sometimes hyperuricuria (10%)

Stones not seen on plain films ( + 400 HU)

! urates also not !

• lower proteins and purines intake, if needed

• allopurinol, febuxostat (in case of high uric acid excretion)

• urine pH (K citrate)

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• complete elimination of stones

• complete eradication of infection (prolonged therapy

according to antibiogram)

• correction of anatomic abnormalities (30%)

• acidification of urine (Suby’s solution, NH4Cl, Cola ?)

Infections with urease + bacteria and stones (struvite,

carbapatite, ammonium urate):

Cystinuria:

• methionine poor diet: 1 g/day (cystine precursor) (eggs,

gruyère en parmesan cheese, horse meat, many fishes,…)

• urine output > 3L (to be calculated according to daily

excretion)

• NaCl poor diet ! (linear relationship between Na and cystine

excretion: unexplained)

• K citrate 6 to 10 g/d, according to pH (solubility very pH

dependent)

• Cola !

Nuttige maatregelen

Cacchi en Ricci

• K citraat