Dr. Joshua Kausman

Paediatric

Nephrologist, RCH

Paediatric calculi: medical aspects

PAEDIATRIC UROLITHIASIS

Epidemiology 5-20% for adults (Europe↓; Mid–East↑)

Paed: ~0.5% (↑ 5x last 10-20 yr)

Main RFs: Geography, diet, race.– ↑ SES: ↑ Ca oxalate/ Phos

– ↓ SES: ↑ Urate/ infection stones

M > F

FHx +ve 20-40%

60% have a metabolic RF

“Stone belts”

PAEDIATRIC UROLITHIASIS

Epidemiology- Diet Dev’d: ↑ protein upper tract; Ca Ox/P stone

Dev’g: ↑cereal bladder; NH4/UA/ infection stone

Na (↓ Ca reabsorption)

Citrate, Potassium, Mg

Ca (↑ risk with low intake!)

? Low GI CHO and obesity

Metabolic syndrome!

PAEDIATRIC UROLITHIASIS

Stone composition

Ca oxalate 60-90%

Ca Phos 10%

Struvite 1-14%

Uric acid 5-10%

Cystine 1-5%

Mixed/ other 4%

Three Pathways for Kidney Stone Formation and Growth

(1) ‘free particle’ formation, either in

the collection system of the

kidney or along the nephron

(asterisk), with supersaturation

(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

covering allowing crystals in the

urine to become attached

Ped Nephrol 2010 Evan

PAEDIATRIC UROLITHIASIS

Presentation

Abdominal/ flank pain 50%

Haematuria

– microscopic 90%

– macroscopic 10%

Ix of UTI or CKD

Classic renal colic 7%

Passage of stone/ ‘gravel’

Hx of immobilisation/ chronic bowel disease

Opportunistic: appendicitis/ LRD work-up

Location and Size

Chance of spontaneous passage:

<5mm high

5-7mm 50%

>7 urological treatment usually

PAEDIATRIC UROLITHIASIS

Investigation

Confirmation of urinary calculi

Complications

Cause

– Genetics!

Nat Rev Nephrol 2012 Monico

PAEDIATRIC UROLITHIASIS

1. Confirmation of Urinary Calculi(a)Renal ultrasound

– specific >1.5mm

– detects radio lucent calculi (uric acid)

– associated obstruction

– may miss small/ ureteric calculi

(b)AXR- especially if US negative

(c)CT/ Spiral CT (unenhanced)– most sensitive; all stones

– stones in any location

Normal echogenic (NN) THP Kidney

Mild Med NCMod Med NC

Severe Med NCSevere diffuse NC

KI 2011

Habbig et al

PAEDIATRIC UROLITHIASIS

2. Complications

UTI - Urine culture

Obstruction- Renal US or DTPA/ MAG3

Function- DTPA/ MAG3/ DMSA

Renal injury- DMSA/ US

↓ BMD (~1/3 hyperCa’uria)- DXA

Severe damage

Poor adherence with fluids.

Resistant to repeat ESWL and

stenting:

Persist or nephrectomy?

Cause and Px are integral.

PAEDIATRIC UROLITHIASIS

3. Cause

(i)Stone analysis

(ii) Urine pH, microscopy and culture

(iii) Urine metabolite excretion (24hr or Cr ratios)

Cystine

Calcium

Oxalate

Uric acid

Citrate

Mg

(iv) Serum Ca, Mg, uric acid, acid-base

(v) Identified abnormality definitive tests

PAEDIATRIC UROLITHIASIS

3. Cause- 24 hr urine collection

Painless, inexpensive, most useful diagnostic test

~Hardest test in medicine!– You try and catch every wee in same bottle

For 24 hr

3 times

– Collection 1: Oxalate & Ca, acidified container

– Collection 2: Citrate, different acidified container

– Collection 3: Cystine & uric acid, non-acidified container

If referring for stone work-up, please request urine tests first...at least the spot Cr ratios.

PAEDIATRIC UROLITHIASIS

3. CauseIngredient Crystal structure Implication

Ca PO4 Apatite ?hypercalciuria

brushite

whitlockite

Mg NH4 PO4 struvite infection (proteus)

Ca O whewellite ?hypercalciuria

weddellite ?hyperoxaluria

Purine urate hyperuricosuria

uric acid hyperuricosuria

2,8 dihydroxyadenine APRTase deficiency

xanthine xanthine oxidase def

Cystine cystinuria

*Leusmann, BJU Int, 2000

James WeddellWilliam Whewell

*Hulton, Arch Dis Child, 2001

PAEDIATRIC UROLITHIASIS

Clinical Age: median 2y; 75% < 5y

Sex: 80% male

Infection: – 90% at Dx

– resistant to therapy

– Proteus – urease alkaline urine

FTT common

Site: – left 66%

– upper tract 85% staghorn

– bilateral 15%

INFECTION STONES

Composition1. Struvite: MgNH4PO4-6H2O triple phosphate

2. Carbonate apatite: Ca10[PO4]6CO3

Urologic Abnormalities– 33% VUR (later 11%)

– 33% other abnormality

– Ureteric dilation

Calcium Excretion– Often transiently raised acutely

INFECTION STONES

Treatment

Removal essential

? acidify the urine (acid phosphate)

If not treated:

– xanthogranulomatous pyelonephritis

– pyonephrosis

– renal scarring

– nephrectomy

INFECTION STONES

99% filtered calcium is reabsorbed– proximal tubule

– thick ascending limb of loop of Henle

Hypercalciuria:– 24hr urine Ca excretion >0.1 mmol/kg/d

– 2 fasting Uca/Ucr ratios > 0.7 in children over 2y

Uca increased by – dietary Na, Ca (NHE3)

– vitamins C & D

– immobilization

– relative oliguria

Uca decreased by dietary K+ & citrate

URINE CALCIUM EXCRETION

Stone Development in Idiopathic Calcium Oxalate Stone Formers

1 apatite into BM of thin LOH

2 extension into interstitial space Randall’s plaque;

3 loss of urothelial covering;

4 urine proteins and ions coating

5 apatite forms on plaque,

6 biological apatite with matrix coating

7 apatite and CaOx at outer margin, only CaOx (stone)

Stone Development in Idiopathic Calcium Oxalate Stone Formers

Crystal stalactitesPapilla with Randall’s plaque and overlying CaOx calculus

HYPERCALCIURIA

Exclude hypercalcaemia

Hyperparathyroidism

Vitamin D excess

Immobilisation

Hypophosphatasia

Hypophosphataemia

HYPERCALCIURIA

Normocalcaemia hypercalciuria

Idiopathic hypercalciuria

Immobilization

Medullary Sponge Kidney

Drugs: frusemide, topiramate, steroids

Ketogenic diet

Genetic:

– FHNCC, Barrter’s syndrome, Dent’s

– Distal RTA: Uca; U citrate; urine pH

IDIOPATHIC HYPERCALCIURIA

Polygenic (some autosomal dominant)

In past: 1. renal thiazide vs 2. absorptive diet Ca restriction

BUT, dietary Ca= oxalate absorption & BMD

Clinical– haematuria/ leucocyturia– nephrocalcinosis, calculi– BMD

IDIOPATHIC HYPERCALCIURIA

Treatment

1. Fluid

2. * Dietary Na (not Ca)

3. Dietary K+

4. Citrate Ca chelation and alkalinisation (CaP)

5. Thiazides

6. *BMD- ? Bisphosphonates

* dietary Ca= oxalate absorption & BMD

DISORDERS OF PURINE METABOLISM( Radio-lucent stones)

Uric acid over production1. Leukaemia/lymphoma tumor lysis

2. Lesch-Nyhan syndrome HGPRTase 3. 10 Gout

4. Type 1 GSD

5. Ketogenic or high protein diet

6. Drugs - salicylates

Treatment:

Alkalinize urine

Allopurinol (Xanthine stones in L-N S.)

Uricase

DISORDERS OF PURINE METABOLISM

Dihydroxyadeninuria

– APRT deficiency

– May cause CKD

– Alkalinisation worse!

– Allopurinol blocks production DHA

– N Se & U Uric acid

Xanthinuria

– Failure of XO to convert xanthine to uric acid

– Low Se & U Uric acid!

– Orange nappies

DHA

XO

CYSTINURIA

Defective re-absorption of of dibasic AAs

– renal tubule and intestinal (COAL)

Genetics– 1992 SLC3A1 (rBAT) 2p21 Type A

Heterozygote: cystine excretion normal

– 1997 SLC7A9 Type B and AB

Light subunit of AA transporter

Heterozygote: cystine excretion abnormal

CYSTINURIA

Epidemiology

Incidence: 1:7000 to 1:15,000

1-3% nephrolithiasis

6-8% of all nephrolithiasis in children

Age of presentation:

– 50% < 10y

– 90% < 20y

Stone free interval: 3-6 months

Cystinuric Stones: free particle formation

c Flattened, damaged papilla

d A loop of Henle, filled with apatite deposits,

and a grossly dilated inner medullary

collecting duct (asterisk).

e Cystine plugs are seen protruding from the

dilated mouths of ducts of Bellini

f Medullary tubules of cystinuric patients may

be filled with either cystine at the ducts of

Bellini or apatite along inner medullary

collecting ducts or loops of Henle

CYSTINURIA

Diagnosis

1. Flat hexagonal crystalsMicroscopy

morning urine

+/- acidification

2. Cyanide – nitropresside test:+ve at 35-60 µm/MM Cr (75-125mg/g/Cr)

(heterozygote 120 µm/mM Cr (250mg/g/Cr))

not specific – acetone, homocystine +ve

3. Urinary conc’n: 400-3000mg/ day ( 1.7-13mmol)Raised concentration C,O,A, L

CYSTINE SOLUBILITY

pH Solubility Product* Metastablezone+ Uric Acidmmol/L (mg/L) mmol/L (mg/L) (mmol/L)

5 - 3.0 (720) 1

6 1.3 (312) 3.2 (768) 4

6.5 - - 10

7 1.4 (336) 3.5 (8.40)

8 2.5 (600) 6 (1440)

8.5 6 (1440)

* Solubility product: threshold for crystal aggregation/ growth about nidus

+ Metastable zone: threshold for spontaneous precipitation

CYSTINURIA

Treatment

solubility of cystine (<1mmol/l; <100 µmol/mol Cr)

Increase urine volume (Fluid 1.5-2 l/ m2/ d)

Eg. pass 750mg (3mmol)/d need 3l UO/day

Alkalinize urine ( K citrate)

diet Na

Solubilise cystine (~50x ): penicillamine/ tiopronin, ?captopril

Monitoring:

– U. Cystine< 100 µm/mmol Cr

– SG<1.010; U. pH >7

– Renal US

10 Endogenous overproduction of oxalic acid

PH1

PH2

PH3

20

– Enteric disease– Distal ileal disease and loss of GI flora

– Dietary

PRIMARY HYPEROXALURIA

PH1 AGT alanine glyoxylate aminotransferase –

transaminates glyoxylate

PH2 D-glycerate dehydrogenase

HRP hydroxypyruvate reductase

GR glyoxalate reductase

GO glycolate oxidase

DAO D-amino oxidase

OXALATE METABOLISM

AGXT 2q37.3

Consanguinity – homozygotes

Many – compound heterozygotes– 50% no activity

– 50% residual activity 2-48%

– 60% 630GA

– Gly170 - Arg aa sub

Enzyme directed to mitochondria– Diagnostic issues with molec techniques

10-30% pyridoxine responsive

GENETICS OF PH1

EPIDEMIOLOGY

Incidence 1:60,000-120,000 (Tunisia 13% ESRF)

M=F

ESKD– 20% 15yr; 50% 25y; infantile 80% at 3 y

50% develop 1st symptom <5yr (1m to 60yr)– Dx usually >5y later

Clinical heterogeneity even with identical mutation

CLINICAL

Infantile nephrocalcinosis & ESKD rare

Recurrent nephrolithiasis

– Nephrocalcinosis

– Progressive loss of renal function

– Mostly as child or adol

Elderly occ stone

CLINICAL

Systemic Oxalosis Occurs when saturation point reached

= plasma oxalate >30µM in early renal insufficiency -40ml/min/1.73m2

Deposition in all tissues except liver

Bones – radio dense metaphyseal bands– diffuse demineralization

– replaces marrow

– pain, fracture

EPO resistant anaemia

CLINICAL

System oxalosis

Deposition (cont.)

– Retinal

– Media of vessels

– Peripheral nervous system

– Myocardium – AV block

– Thyroid

– Skin- livedo reticularis

ConservativeAim: oxalate production & urinary solubility

Future- gene Rx/ chemical chaperones

1. Pyridoxine (AGT cofactor)

2. Solubility: Fluid 2-3 l/ m2/ d; citrate/Pi/Mg

3. Diet, ?oxalobacter formigenes

4. ESKD Treatment:– Dialysis

– Kidney Transplant

– Liver/Kidney

– Pre-emptive liver

TREATMENT

Miscellaneous

Calculi In Dysfunctional Bladders (5-16%)

Drugs: ceftriaxone, indinavir

Melamine (~uric acid)

Cysts

Premature NNs & NC (7-41% GA<32/40; BW< 1500g)

Fungal balls

SURGICAL MANAGEMENT

Multiple approaches often used:

1. Extracorporeal shock wave lithotripsy

- method of choice

2. Ureteroscopy

- difficult in smaller children

3. Percutaneous nephrolithotomy

- larger stones

4. Open / laparoscopic surgery

- anatomical abnormalities

ESWL

Indications:Pelvic or calyceal calculi up to 2cm diameter

Relative Contraindications:– cystine stones

– dilated obstructed kidneys

– large stone burden

– radiolucent stones

Technique:– lung protection – not with newer machines

– General anaesthetic – young children

– Pre-op ureteric stenting with obstructed upper tract

ESWL

Results:Stone-free rates variable:

often need >1 treatment

Immed: 50%

3 mth: 60-90%

2y: 60-90%

4y: 70% Schultz Lampel Urol A 1997

Recent RCTs comparing ESWL vs PCNL:

– stone-free 37-63% vs 95-100%

NEJM 2012 Pearle

Complications

Common:

– skin haemorrhage

– haematuria

– obstruction (‘steinstrasse’)

Rare:

– lung contusion

– perirenal haematoma

– renal injury

E S W L

Relative indications

– larger calculi >2cm

– lower pole calculi >1.5cm

– poor Ur drainage: soft stones (cystine/ struvite)

PCNL

SUMMARY MANAGEMENT- Initial

1. Fluids!!!

2. Diet- Na!

3. Pain

4. Exclude infection

5. Assess likelyhood of spont passage

<7mm wait and repeat US 3mthly

>7mm surgical referral

6. Investigations cause specific Rx

7. Don’t forget the family

Specific Rx

At the end of the day…. make them drink!

SUMMARY MANAGEMENT- LTm

1. All: High fluid, low salt diet forever

2. Idiopathic: once educated and 2 U/S neg, D/C

3. Metabolic defects esp. Cystinuria/ Oxalosis

Surveillance U/S, urine 3-6 monthly

Monitor bloods on penicillamine- 3 monthly

4. BMD- ?DXA

5. Rec calculi tailored Med/ Surg plan

Take home messages…

Diagnosis:

Expect a metabolic defect to be present

Good FHx

Stone work-up in every child

Bare minimum: MSU- M/C/S

Spot urine Cr with Ca, Ox, Urate, Cystine

Management:

Clear pathway for large stones and tiny stones

For medium (most) and recurrent stones:

Combined med/ surg Mx

Role of stone clinic