Dent Disease

Dent disease is an X-linked recessive proximal tubulopathy caused by variants in CLCN5 (type 1, 60%) or OCRL (type 2, overlapping with Lowe syndrome), characterised by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis and progressive CKD.

• Affects males primarily; carrier females may have mild features.
• Pathophysiology: defective endosomal acidification and receptor-mediated endocytosis in proximal tubule cells.
• Typically presents in childhood with proteinuria or kidney stones; CKD progresses to ESKD between ages 30 and 50 in many.
• Complications: rickets or osteomalacia, growth retardation, hypophosphataemia, hypokalaemia, renal tubular acidosis, CKD.

• Asymptomatic low molecular weight proteinuria found incidentally; nephrotic range total protein (mostly tubular) can mislead.
• Renal colic and nephrolithiasis, haematuria, polyuria, nephrocalcinosis.
• Rickets, bone pain, short stature, hypophosphataemia (variable).
• Family history of male relatives with kidney disease, stones, rickets.
• Type 2: cataracts, mild intellectual disability, hypotonia (partial OCRL phenotype).

• Low molecular weight proteinuria (beta-2 microglobulin, retinol-binding protein, alpha-1 microglobulin) with normal albumin excretion initially, hypercalciuria (urine calcium over 4 mg/kg/day or over 0.2 mg/mg creatinine), nephrocalcinosis on ultrasound.
• Variable features of Fanconi syndrome: glycosuria, aminoaciduria, phosphaturia, hypokalaemia.
• Serum: normal calcium, low phosphate (some), raised creatinine in progression, high 1,25-dihydroxyvitamin D with hypercalciuria.
• Genetic testing: CLCN5 and OCRL (hemizygous males, heterozygous females).
• Renal biopsy: nonspecific; FSGS and interstitial fibrosis may be seen.
• Exclude cystinosis, Lowe syndrome, Fanconi from other causes, familial hypercalciuria.

• No specific therapy; aim to reduce stones and slow CKD progression.
• High fluid intake (urine volume over 2.5 L/day), low sodium diet (under 2 g/day), normal calcium intake (avoid calcium restriction), moderate protein.
• Thiazide diuretics: hydrochlorothiazide 1 to 2 mg/kg/day (adults 25 to 50 mg) or chlorthalidone to reduce hypercalciuria (reduces calcium excretion by about 30%, with monitoring of potassium and volume; some evidence of improved stone burden); may increase CKD risk through volume depletion, so use cautiously.
• Potassium citrate 1 to 2 mEq/kg/day if acidosis, hypocitraturia and stones.
• Avoid vitamin D and calcium supplementation unless clearly deficient (may worsen hypercalciuria and nephrocalcinosis); phosphate replacement for rickets with caution and calcitriol only when needed.
• ACE inhibitors or ARBs may reduce proteinuria and CKD progression (limited data).
• Stone management: shockwave lithotripsy, ureteroscopy, percutaneous nephrolithotomy.
• Growth hormone for severe growth failure.
• Monitor eGFR, urine calcium, proteinuria and bone health annually; genetic counselling and carrier testing; kidney transplantation without recurrence.