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Hypercalciuria
William van’t Hoff
Great Ormond Street Hospital
London
Hypercalciuria: relevance
• Commonest metabolic abnormality in paediatric urolithiasis & nephrocalcinosis
• Found in 30% paediatric stone formers• Strongly related to dietary intake (e.g. of
sodium)• Associated with negative calcium balance
(e.g. reduced bone mineral density in ~ 30% at diagnosis)
Hypercalciuria: presentation
• Haematuria• Dysuria• Polyuria / polydipsia / enuresis• Abdominal pain (stones)• Features of an underlying cause
(e.g. Fanconi syndrome)• Asymptomatic
Hypercalciuria: definitions
• Second morning urine calcium/creatinine ratio < 0.74 mmol / mmol
• Variation in reported normal ranges (population sampled, timing of sampling, age)
• 95th centile changes from 2.2 to 0.7 mmol/mmol between 1 month and 14 years
• 24 hour urine > 0.1 mmol (4mg) /kg/day
• Urine Ca/Osm if muscle mass reduced (Richmond et al. Clin Nephrol. 2005. 64:264-70)
0
10
20
30
40
50
60
% p
atie
nts
Metabolic evaluation of children with urolithiasis (GOSH, 1997-2007) n=250
Any metabolic abnormality
48%
Hypercalciuria 27%
Cystinuria 10%
Primary hyperoxaluria
3%
Other oxaluria 6%
Other 2%
Idiopathic hypercalciuria
Most children with hypercalciuria have
no currently definable renal, skeletal or
gastrointestinal defect - Idiopathic
Idiopathic hypercalciuria: candidates
• Vitamin D receptor (VDR)• Calcium sensing receptor (CaSR)• Epithelial calcium channel (ECaC)• Adenylate cyclase• Crystallisation inhibitors:
– Osteopontin
– Tamm-Horsfall protein (uromodulin)
– Ostoecalcin related gene (ORG)
• No positive results to date
• Polygenic trait (50% first degree relative)
Hypercalciuria: Tubulopathies (rare)
• Proximal– Fanconi syndromes (some)– Dent’s disease– Lowe’s syndrome– HHRH
• TAL:– Bartter’s syndrome (some)– Hypomagnesaemia / hypercalciuria– CaSR activating mutation
• Distal– dRTA– PHAII
• Ex-premature infants (multifactorial)• Ketogenic diet (40% at start, 75% after 6 months,
1 in 20 develop stones, hypocitraturia ± immobility)
• Drugs (furosemide, topiramate, acetozolamide)
• Glycogen storage disease type 1 (+ hypocitraturia) • Beckwith Wiedemann syndrome• Vesico-Ureteric reflux / PUJ obstruction
Hypercalciuria: Normocalcaemia
Hypercalciuria: Hypercalcaemia (rare)
• Vitamin D toxicity• Primary hyperparathyroidism• Hypophosphatasia• Alactasia• Williams syndrome • Thyrotoxicosis• Sarcoidosis
Idiopathic hypercalciuria: risk of stone formation / recurrence
• Risks of stone formation in long term follow up studies varies between 3 and 33%
• Variation in part due to different study groups• May be other confounding variables:
e.g.hypocitraturia and hyperoxaluria more frequent in calcium stone formers
Hypercalciuria: assessment
• Confirm if possible with 24 hour urine or repeated spot samples (age-matched reference range)
• Exclude secondary causes:– check renal tubular function– check plasma Ca, Mg, Vit D, PTH– check for nephrocalcinosis
• Bone mineral density if history of fractures or osteoporosis
Hypercalciuria: management
• Many do not need treatment
• Consider intervention if:– recurrent / severe stone disease– nephrocalcinosis– tubulopathies ( with caution) – impaired GFR– history of fractures / osteoporosis
Hypercalciuria: diet
• Children with persistent HC have higher Na excretion than those in whom HC resolves (Polito Nephron, 2002)
• Low sodium/high potassium can reduce calcium excretion by 50% in trial conditions (Alon,Berenbom Ped
Nephrol 2000) • In adult females, increased dietary calcium intake
associated with reduced stone formation but calcium supplements with increased stone risk (Curhan Ann Int Med 1997)
• Reduced protein and salt / normal calcium intake, reduced stone risk in adult males compared to low calcium diet (Borghi NEJM 2002)
Hypercalciuria: medication
• Potassium citrate:
– increases urine pH, citrate and reduces urine calcium & oxalate supersaturation
– reduces stone recurrence
• Thiazides:
– reduce urine calcium– restore bone mineral density
• Combination (with low calcium and oxalate diet) reduced stone recurrence by 98%, improve BMD (Pak et al. J Urol 2003)
• Bisphosphonate therapy improves BMD and reduces hypercalciuria
Bisphosphonates in hypercalciuria(Freundlich & Alon Ped Neph epub 2008)
Hypercalciuria: summary
• Common metabolic abnormality with or without urolithiasis / nephrocalcinosis
• Often associated with reduced bone mineral density
• Requires careful evaluation• Usually has good prognosis for the kidney• If necessary, treatment combines dietary and
pharmacological interventions
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