PAEDIATRIC UROLITHIASIS PAEDIATRIC UROLITHIASIS

Epidemiology Epidemiology
Uncommon presentation of renal or urinary tract Countries have variable
pathology, but increased by a third 1980 to1995 with
1. Incidence
lifetime risk of 12% for Amales and 5% Afemales
Males predominate in most studies 2. Composition
M:F = 1.5 to 4:1, & 3. Clinical characteristics
except in children who have had bladder Dependent upon
reconstruction 1. Population genetic factors
Average age between 5 to 9 years 2. Socio-economic factors
Family history in 22% 3. Diet
4. Climate

PAEDIATRIC UROLITHIASIS PAEDIATRIC UROLITHIASIS

Epidemiology Epidemiology
1. Endemic Calculi 2. Infective Calculi
Pakistan Turkey Thailand
Incidence 1:100,000 children/y*
Pattern in 19th C England
g
C
Comp. Struvite
St it Mg
M NH4 PO4
eg: Cameroon*- Arid
triple phosphate
Bladder 90%
organic matrix
Male 75%
Upper tract 90%
Cereal diet (rice)
Proteus UTI
Comp: = calcium oxalate 80%
ammonium urate 57% *Ghazali et al, Arch. Dis. Child 1973
calcium phosphate 42%
*Angwafo et al Eur Urol 2000

PAEDIATRIC UROLITHIASIS PAEDIATRIC UROLITHIASIS

Epidemiological Patterns
Epidemiological Patterns
3. Metabolic Calculi
Hypercalciuria 4. Bladder abnormalities
“Stone Belt” Southeastern USA
Most common metabolic cause
Hyperoxaluria Cause of majority of lower urinary tract stones in
1: 60-120 thousand children developed countries
Tunisia – 13% ESRF
Cystinuria
1: 7-15 thousand children
Disorders of Purine Metabolism
Uric acid
dihydroxyadenine
xanthinuria

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PAEDIATRIC UROLITHIASIS Categorisation and Size

Presentation* Chance of spontaneous passage:

Abdominal pain 50%
<5mm high
Haematuria microscopic p 90%
macroscopic 10%
5-7mm 50%
Investigation of UTI
Renal failure >7 urological treatment
Adult “classic acute flank colic” 7% usually

* Tekin et al J Urol 2000

PAEDIATRIC UROLITHIASIS PAEDIATRIC UROLITHIASIS

Investigation 1. Confirmation of Urinary Calculi

(a) Renal ultrasound*
cf AXR equally sensitive ~ 60%
z Confirmation of urinary calculi more specific
ifi
detects radio lucent calculi
z Complications (uric acid)
z Cause may miss small calculi
cannot identify ureteric calculi
standard for follow-up
(b) AXR
*Smith et al Clin Rdiol 2000

PAEDIATRIC UROLITHIASIS

1. Confirmation of Urinary Calculi (continued)

(c) CT/Spiral CT –
unenhanced
imaging of choice in adults
less experience in children
young require anaesthetic
Onen* 59 children investigated
20 ureteric calculus
13 calyceal calculus
12 non urologic cause
14 no diagnosis
2 US +ve were –ve
* Onen et al BJU Int 2000

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PAEDIATRIC UROLITHIASIS PAEDIATRIC UROLITHIASIS
3. Cause
(i) Store analysis*
2. Complications
Ingredient Crystal structure Implication
Ca PO4 Apatite(Ca5(PO4)3(OH) ?hypercalciuria
brushite(CaHPO
( 4) post SWL & citrate
p
UTI urine
i culture
lt hard & poor response to SWL
whitlockite
Obstruction Renal ultrasound DTAP/MAG III
Mg NH4 PO4(H2O)6 struvite infection (proteus- urease)
Function DTPA/MAG III/DMSA
Ca O whewellite ?hypercalciuria
Renal injury DMSA/US weddellite ?hyperoxaluria

Purine urate hyperuricosuria

uric acid hyperuricosuria
2,8 dihydroxyadenine APRTase deficiency
xanthine xanthine oxidase def
Cystine cystinuria
*Leusmann, BJU Int, 2000

Three Pathways for Kidney Stone

PAEDIATRIC UROLITHIASIS Formation and Growth

William Whewell A crystal of apatite

(1) ‘free particle’ formation, either in
the collection system of the
kidney or along the nephron
( t i k) with
(asterisk), ith supersaturation
t ti

(2) crystal nuclei form in the lumen

of a nephron at sites of cell
injury (eg high [oxalate]) such as
at the opening of a duct of
Bellini

(3) crystalline deposits of interstitial

calcium phosphate followed by
loss of the normal urothelial
James Weddell covering allowing crystals in the
urine to become attached
Leusmann, BJU Int, 2000

PAEDIATRIC UROLITHIASIS PAEDIATRIC UROLITHIASIS

3. Cause 3. Cause
(ii) Urine microscopy (iii) Urine cystine
(a) cyanide – nitroprusside test
Cystine crystals
(b) urine aa chromatography
urine aa HVE
(iv) Urine excretion of
calcium
oxalate
uric acid
citrate
(v) Identified abnormality leads to further definitive tests

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 PAEDIATRIC UROLITHIASIS
INFECTION STONES

Clinical
age median 2y
75% < 5yy
sex 80% male
infection 90% at time of diagnosis
resistant to therapy
associated FTT common
proteus – urease
site left 66%
upper tract 85%
bilateral 15%
*Hulton, Arch Dis Child, 2001

INFECTION STONES INFECTION STONES

Composition
Treatment
1. struvite and apatite hence, triple phosphate
2. Organic matrix removal essential
if nott:
Urologic Abnormalities z xanthogranulomatous pyelonephritis
33% VUR (later 11%) z pyonephrosis
33% other abnormality z renal scarring
lumbar ureter dilation z nephrectomy

Calcium Excretion
Often transiently raised acutely

URINE CALCIUM EXCRETION HYPERCALCIURIA

99% filtered calcium is reabsorbed

proximal tubule Causes
thick ascending limit of loop of Henle
Hypercalciuria: with calculus defined as:
( ) 24hr
(a) 24h urine
i CaC excretion
ti >0.1
0 1 mmol/kg/d
l/k /d 1
1. Nephrocalcinosis
(b) 2 fasting Uca/Ucr ratios > 0.7 in children over 2y look for (i) hypercalcaemia
Uca increased by dietary sodium
(ii) RTA
calcium (iii) hyperoxaluria
vitamin C 2. Urinary Calculi
vitamin D
immobilization
relative oliguria
Uca decreased by dietary K+

4
HYPERCALCIURIA HYPERCALCIURIA

Exclude hypercalcaemia
Causes: hyperparathyroidism Normocalcaemia hypercalciuria (continued)
Idiopathic hypercalciuria
vitamin D excess
Immobilization
immobolisation M d ll
Medullary S
Sponge Kid
Kidney
hyperphosphatasia Drugs topirimate
Ketogenic diet
Normocalcaemia hypercalciuria CLCN5 chloride channel defects
TALLH (Barrter’s syndrome)
1. Acid base disorders
Dent’s disease
(a) Distal RTA ↑ Uca
hypercalciuria, calculi, nephrocalcinosis, LMW prot, CRI rickets
↓ Ucitrate
High urine pH
Associated nephrocalcinosis, osteoporosis,
poor growth, deafness

Stone Development in Idiopathic Calcium

IDIOPATHIC HYPERCALCIURIA Oxalate Stone Formers

Polygenic 1 apatite deposits develop in the BM of the

thin loops of Henle;
Some families autosomal dominant 2 extension into the interstitial space and are
Classified in past as embedded in matrix, forming islands of
interstitial plaque termed Randall’s
renal: thiazide plaque;
p
absorptive: diet Ca restriction 3 loss of urothelial covering;
Problems 4 urine proteins and ions coat the exposed
interstitial plaque;
difficulty in classification 5 a layer of amorphous apatite forms on top
dietary Ca restriction of the interstitial plaque, and this new
↑ oxalate absorption mineral layer is coated with urine matrix
molecules;
reduced bone mineralisation 6 a layer of biological apatite with matrix
Clinical coating forms on the amorphous apatite;
haematuria 7 a layer of both apatite and CaOx forms,
and, at the outer margin of this small
leucocyturia stone, only CaOx is found
decreased bone mineral
nephrocalcinosis, calculi

Stone Development in Idiopathic Calcium

Oxalate Stone Formers IDIOPATHIC HYPERCALCIURIA

a Endoscopic image of CaOx stone (arrow) on a papilla from an idiopathic calcium oxalate
stone former. Treatment
Diet 1. Fluid increase
2
2. Dietary Na decrease
3. Dietary K+ increase: ↓Uca, Up,
↓1,25(OH)2vit D3
4. Citrate chelates urine Ca
Thiazides

b The stone had been attached and attached to a site of Randall’s plaque
(arrowhead) : interstitial calcium phosphate plaque forming in the BM’s of thin
loops.

5
DISORDERS OF PURINE METABOLISM DISORDERS OF PURINE METABOLISM

Uric acid over production

1. Dihydroxyadeninuria
1. Leukaemia/lymphoma tumor lysis
APRTase deficiency
2. Lesch-Nyhan syndrome HXG PRTase
hypoxanthine
yp guanyl
g y phosphoribosyl
p p y transferase deficiency
y May cause renal failure
3. 10 Gout Alkalinisation makes worse
4. Type 1 GSD Allopurinol blocks production of dihydroxyadenine
5. Ketogenic or high protein diet
6. Drugs - salicylates 2. Xanthinuria
Treatment: Failure of XO to convert xanthine to uric acid
Alkalinize urine Plasma uric acid low
Allopurinol
Uricase

CYSTINURIA CYSTINURIA

z Defective re-absorption of cystine in renal Genetics

tubule
1992 SLC3A1 ((rBAT)
BAT) 22p21
21
z Cystine precipitates i.e. parents cystine excretion normal
1997 SLC7A9 199
z Hexagonal crystals
encodes for light subunit of aa
transporter

CYSTINURIA CYSTINE SOLUBILITY

pH Solubility Product* Metastablezone+ Uric Acid

Molecular basis mmol/L (mg/L) mmol/L (mg/L) (mmol/L)
5 - 3.0 (720) 1
6 1 3 (312)
1.3 3 2 ((768)
3.2 68) 4
Transport channel 6.5 - - 10
cystine 7 1.4 (336) 3.5 (8.40)
SLC 7A9
8 2.5 (600) 6 (1440)
Transporter subunit
R BAT 8.5 6 (1440)
“key to unlock”
* Solubility product: above level aggregates of crystals, growth about nidus
+ Metastable zone: to this concentration spontaneous precipitates without nidus
do not occur

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CYSTINURIA CYSTINURIA

Diagnosis
Epidemiology
1. Flat hexagonal crystals
Microscopy
IIncidence:
id 1 7000 tto 1
1:7000 1:15,000
15 000 morning urine
+/- acidification
1-3% nephrolithiasis 2. Cyanide – nitropresside test:
+ve at 35-60 µm/MM Cr (75-125mg/g/Cr)
6-8% of all nephrolithiasis in children
(heterozygote 120 µm/mM Cr (250mg/g/Cr))
Age of presentation: 50% < 10y not specific – acetone, homocystine +ve
3. Urinary concentration
90% < 20y HVE and/or urine aa chromatography
Stone free interval: 3-6 months Raised concentration of L, O, A & C

Endoscopic and Histologic Images from a

Cystinuric Stone Former CYSTINURIA

Treatment
a to d Papillary morphology varies from
normal to flattened and deformed

d A lloop off Henle,

H l filled
fill d with
i h apatite
i deposits,
d i Principle: raise solubility of cystine
and a grossly dilated inner medullary
collecting duct (asterisk). 1. Increase urine volume
2. Alkalize urine
e Cystine plugs are seen protruding from the
dilated mouths of ducts of Bellini 3. Reduce diet sodium content
f Medullary tubules of cystinuric patients may 4. Form mixed disulphides more soluble than
be filled with either cystine at the ducts of cystine using penicillamine
Bellini or apatite along inner medullary
collecting ducts or loops of Henle

PRIMARY HYPEROXALURIA OXALATE METABOLISM

Endogenous overproduction of oxalic acid

PH1
PH2
Others?
20
Enteric disease
Dietary PH1 AGT alanine glyoxylate aminotransferase –
transaminates glyoxylate
PH2 D-glycerate dehydrogenase
HRP hydroxypyruvate reductase
GR glyoxalate reductase
GO glycolate oxidase
DAO D-amino oxidase

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GENETICS OF PH1 CLINICAL

AGXT 2q37.3
Consanguinity – homozygotes 1. Infantile nephrocalcinosis & ESRF rare
Many – compound heterozygotes
2 Recurrent nephrolithiasis
2.
50% no activity
50% residual activity 2-48% Nephrocalcinosis
60% 630G→A Progressive loss of renal function
Gly170 - Arg aa sub most common child or adol
enzyme directed to mitochondria
3. Elderly occ stone
some pyridoxine responsive

EPIDEMIOLOGY CLINICAL

Incidence Systemic Oxalosis

1:60,000-120,000 (Tunisia 13% ESRF), Occurs when saturation point reached
ESRF 20% 15 y 50% 25yy = plasma oxalate >30µM
p µ in earlyy renal
infantile 80% at 3 y insufficiency -40ml/min/1.73m2
50% 1st symptom <5y Deposition in all tissues except liver
1m to 60y Bones – radio dense metaphyseal bands
diagnosis usually >5y later diffuse demineralization
M=F replaces marrow
Complete clinical heterogeneity even with identical pain, fracture
mutation EPO resistant anaemia

CLINICAL CLINICAL

System oxalosis
Deposition (cont.)
R ti l
Retinal
Media of vessels
Peripheral nervous system
Myocardium – AV block
Thyroid
Skin-livido reticularis

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TREATMENT Calculi In Dysfunctional Bladders

Conservative Common
Aim: ↓ oxalate production Incidence of calculi
↑ urinary solubility Barroso* 400 children
1. Urethral CIC 5%
Means: 1. Pyridoxine
2. Mitrofanoff CIC 11%
2. Solubility
3. Aug. bladder + Urethral CIC 8%
3. Diet
4. Aug. bladder + Mitrofanoff CIC 10%
ESRF Treatment:
1. Dialysis
2. Kidney Transplant Mathoera+ 89 children augmented bladders
3. Liver/Kidney 16% developed bladder calculi
4. Pre-emptive liver
+Mathoera et al Urology 2000
*Barroso et al BJU Int 2000

Calculi In Dysfunctional Bladders Calculi In Dysfunctional Bladders

Risk factors
70% asymptomatic – female sex
– Urinaryy tract infection
70% solitary
lit – Bowel mucosa used in bladder
33% recur after removal augmentation
– Vaginal reconstruction
– Bladder neck surgery

Routine radiological or endoscopic evaluation

Citrate Deficiency MANAGEMENT

Primary: In General
? Distinct entity
1. Fluids
Secondary: 2. Pain
Hypokalaemia 3. Exclude infection
metabolic acidosis 4. Assess likelyhood of spont passage
ketogenic diet <7mm wait and repeat US 6-12 weekly
UTI >7mm surgical referral
5. Investigations

9
SURGICAL MANAGEMENT ESWL

Multiple approaches often used: Indications:

renal pelvic or calyceal calculi up to 2cm diameter
1. Extracorporeal shock wave lithotripsy Relative Contraindications:
- method of choice cystine stores
2. Ureteroscopy dilated obstructed kidneys
- difficult in smaller children large stone burden
3. Percutaneous nephrolithotomy radiolucent stones
- larger stones Technique:
4. Open / laparoscopic surgery
lung protection – not with newer machines
- anatomical abnormalities
General anaesthetic – young children
Pre-operative ureteric stenting used with obstructed
upper tract

ESWL ESWL

Results: Complications
Stone-free rates variable from study to study: often
need more than one treatment
C
Common: skin
ki h
haemorrhage
h
immediate: 50% haematuria
3 months: 60-90% obstruction
2y: 60-90% Rare: lung contusion
4y: 70% with 56*
perirenal haematoma
more stone regrowth and stone recurrence
renal injury
* Schultz Lampel Urol A 1997

PCNL

Relative indications
larger calculi >2cm
l
lower pole
l calculi
l li >1
>1.5cm
5
impaired urinary drainage
softer stones (cystine or struvite)

10