1. Hypercalciuria William vant Hoff Great Ormond Street Hospital London

2. 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)

3. Hypercalciuria: presentation Haematuria Dysuria Polyuria / polydipsia / enuresis Abdominal pain (stones) Features of an underlying cause (e.g. Fanconi syndrome) Asymptomatic

5. Hypercalciuria: definitions Second morning urine calcium/creatinine ratio < 0.74 mmol / mmol Variation in reported normal ranges (population sampled, timing of sampling, age) 95 th 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)

6. Metabolic evaluation of children with urolithiasis (GOSH, 1997-2007) n=250 Any metabolic abnormality 48% Hypercalciuria27% Cystinuria10% Primary hyperoxaluria 3% Other oxaluria6% Other2%

7. Idiopathic hypercalciuria Most children with hypercalciuria have no currently definable renal, skeletal or gastrointestinal defect - Idiopathic

8. 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)

9. Hypercalciuria: Tubulopathies (rare) Proximal –Fanconi syndromes (some) –Dents disease –Lowes syndrome –HHRH TAL: –Bartters syndrome (some) –Hypomagnesaemia / hypercalciuria –CaSR activating mutation Distal –dRTA –PHAII

10. 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

11. Hypercalciuria: Hypercalcaemia (rare) Vitamin D toxicity Primary hyperparathyroidism Hypophosphatasia Alactasia Williams syndrome Thyrotoxicosis Sarcoidosis

12. 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

13. 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

14. Hypercalciuria: management Many do not need treatment Consider intervention if: –recurrent / severe stone disease –nephrocalcinosis –tubulopathies ( with caution) –impaired GFR –history of fractures / osteoporosis

15. 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)

16. 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

17. Bisphosphonates in hypercalciuria (Freundlich & Alon Ped Neph epub 2008)

18. 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