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