Genetics & presentation
Genetics
- X-linked recessive
- Type 1: CLCN5 (chloride/proton exchanger ClC-5; ~60% of cases)
- Type 2: OCRL (also Lowe syndrome gene) — may include cataracts, mild cognitive issues, raised CK
- Up to 25% of clinically diagnosed patients have no identified mutation
- Female carriers usually mild; rare severe female phenotypes from X-inactivation skew
- NHS National Genomic Test Directory R190
Presentation
- Childhood / adolescence in most males
- LMW proteinuria — usually asymptomatic, found incidentally
- Stones, renal colic
- Nephrocalcinosis on USS (medullary, bilateral)
- Hypercalciuria with normal or low calcium
- Hypophosphataemia and rickets in some boys
- Polyuria, polydipsia (mild concentrating defect)
- Glycosuria, aminoaciduria in some — partial Fanconi pattern
- Slow CKD progression — accelerates after age 30 in many
Diagnosis
Bloods
- Mild hypophosphataemia possible
- Bicarbonate usually normal (only mild proximal acidosis in some)
- Calcium usually normal — distinguishes from primary hyperparathyroidism
- Urate normal or low
- PTH normal
- Creatinine — variable; rises in adulthood
URINE (key tests):
- 24-h urine calcium > 4 mg/kg/day (> 0.1 mmol/kg/day) — pathognomonic combination with LMW proteinuria
- 24-h urine total protein 1–2 g typical (much higher in some)
- LMW PROTEINURIA: beta-2-microglobulin or retinol-binding protein very high (often 100–1000× normal)
- Glycosuria, generalised aminoaciduria in many
- Stone composition: calcium oxalate / calcium phosphate
Imaging
- USS — bilateral medullary nephrocalcinosis, stones
- Low-dose CT KUB if symptomatic stones
Genetics
- CLCN5 / OCRL sequencing + deletion/duplication
- OCRL: also check eyes (cataracts may be subtle), creatine kinase
Differential
- Other X-linked tubulopathies (Bartter, Gitelman are autosomal recessive — different electrolyte pattern)
- Idiopathic hypercalciuria
- Distal RTA
- Cystinuria (large stones, but no LMW proteinuria)
- Lowe syndrome (full syndrome — congenital cataracts, intellectual disability)
- Primary hyperoxaluria
Management
General Principles
- No disease-modifying therapy; aim is to slow stone disease and CKD
- Lifelong joint nephrology + urology + clinical genetics
- Educate patient and family early — avoid loop diuretics, vitamin D excess, dehydration
Hypercalciuria And Stone Prevention
- High fluid intake — > 2.5–3 L/day; overnight fluids if recurrent stones
- Low-sodium diet (Na < 100 mmol/day) — reduces calcium excretion
- THIAZIDE DIURETIC: bendroflumethiazide 2.5–5 mg or chlortalidone 12.5–25 mg — reduces urinary calcium by 30–50%; monitor K, Na, glucose, urate
- Potassium citrate — alkalinises urine (target pH 6.5–7); also corrects mild acidosis
- Maintain dietary calcium at recommended intake — do NOT restrict (low intake causes oxalate hyperabsorption and worsens stones)
- Avoid loop diuretics — they worsen hypercalciuria
- Avoid high-dose vitamin C, excess vitamin D
Vitamin D And Bone
- 25-OH vitamin D replacement when low, but cautious dosing
- Monitor for worsening hypercalciuria
- Phosphate supplementation if hypophosphataemic rickets in childhood
- Bone densitometry; lifestyle measures
Proteinuria And CKD
- ACE inhibitor or ARB at standard doses — slows progression
- BP target < 130/80
- Avoid NSAIDs
- Standard CKD care: lipid management, smoking cessation, healthy weight
- Annual eGFR, ACR, U&E, calcium, phosphate, urinalysis
Stone Interventions
- Standard urology — ureteroscopy + laser for symptomatic stones; SWL effective for small stones
- Minimise PCNL where possible to protect nephrons
- Always send stone for composition analysis (usually calcium oxalate ± phosphate)
Advanced CKD / Transplant
- Standard pre-transplant work-up
- Living donation must screen donors (male relatives most at risk; female relatives may be carriers — test for LMW proteinuria and CLCN5 status before donation)
- Transplant outcomes excellent — no recurrence
- Bilateral native nephrectomy rarely needed (large stone burden, recurrent infection)
Family
- Pedigree analysis (often pseudo-recessive due to X-linked inheritance)
- Carrier testing for mothers and sisters
- Predictive testing for at-risk sons
- Antenatal / pre-implantation genetic diagnosis available for severe families
UK CARE PATHWAY: regional renal genetics clinic + adult nephrology + urology; paediatric Dent disease managed in tertiary paediatric nephrology centres with metabolic input.
