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Dent Disease

Dent Disease. David A Hughes Consultant Paediatric Nephrologist . Case 1 - presentation. Presented age 1 ½ years and referred age 2 years Polydipsia and polyuria Glycosuria Generalised aminoaciduria Nephrocalcinosis Ca:Creatinine – ‘normal’ ‘Normal’ acidaemia

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Dent Disease

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  1. Dent Disease David A Hughes Consultant Paediatric Nephrologist

  2. Case 1 - presentation • Presented age 1½ years and referred age 2 years • Polydipsia and polyuria • Glycosuria • Generalised aminoaciduria • Nephrocalcinosis • Ca:Creatinine – ‘normal’ • ‘Normal’ acidaemia • Low phosphate – supplemented • Ix for cystinosis, galactosaemia and Wilson’s -ve

  3. Case 1 - investigation • Investigation at 2 years 3 months • Ht 89cm (50-75th C) Wt 11.1 (3-10th C) • BP 104/61 • Urine: ++ blood, ++ protein, no glycosuria, pH 7 • Creatinine 53; GFR 90mls/min/1.73m2; Alb 48g/L • Ca:Cr 0.01mmol/mmol; TRP 47% • Serum Ca, PO4, 1.25D3 and PTH normal • P:CR 500mg/mmolCreat (normal <20) • Normal acidaemia HCO3 25mmol/L • Nephrocalcinosis; no bony rachitic changes • Urine AAs – sample too dilute

  4. Case 1 - progress • Age 2½ years • phosphate supplement stopped. Serum PO4 maintained. • Age 10½ years • persistent proteinuria – P:CR 150-240mg/mmolCr • Microscopic haematuria trace - 2+ • Ca:Cr 1.0mmol/mmol • Creatinine 120μmol/L; GFR 67mls/min/1.73m2 • β2-microglobulin raised 94.8mg/L (normal <0.3) • Urinary AAs – high normal excretion • Progressive medullary nephrocalcinosis

  5. Case 1 – genetic test • Proband • Nucleotide deletion in exon 3 causing frameshift mutation (c.181delA) in the CLCN5 gene consistent with diagnosis of X-linked Dent Disease • Mother • carrier status confirmed genetically with known mutation • Minor nephrocalcinosis on US noted • Sister • confirmed not carrier • No previous FH suggesting X-linked renal disease

  6. Case 1 - current • CKD 3 • eGFR 50mls/min/1.73m2 • 2ry hyperparathyroidism • controlled on alfacalcidol • Proteinuria 2+ and haematuria 2+ • P:CR 120 - 150mg/mmolCr • on enalapril 5mg daily • BP 96/59 • Growth: Ht 152.5cm (2-9th C) Wt 37.5 (2nd C)

  7. Case 2 - presentation • Age 3 years old • Balanitis and persistent proteinuria • Proteinuria 4+; haematuria 2+ • FH maternal grandfather and great uncle died age 30s from renal disease

  8. Case 2 - investigation • Ht 99.2cm (50-75th C) Wt 15.4kg (50th C) • BP 100/60 • Proteinuria 4+; haematuria 2+ • P:CR 300mg/mmolCr • Cr 42 μmol/L; Albumin 41g/L • Normal acidaemia HCO3 21mmol/L • Normal C3/C4; ANA –ve • Normal renal US - ?cyst

  9. Case 2 - progress • Age 4½ years • Cr 42 μmol/L; GFR 137mls/min/1.73m2 • Persistent proteinuria P:CR 250 -350mg/mmolCr • Normal renal US – no cyst • Renal biopsy – normal LM appearance; -ve IF; ??splitting of BM on EM • Normal audiometry and opthalmology • Age 13 years – 16 years • Persistent proteinuria P:CR 966→150mg/mmolCr; A:CR 63mg/mmolCr • β2-microglobulin >51 and 85 mg/L (normal <0.3) • Ca:Creat 0.22; 0.64 • No aminoaciduria • Cr 57 – 72 μmol/L; Albumin 42 – 48 g/L • Normal renal US (14 years) • On Enalapril 15mg daily (introduced age 7 years)

  10. Case 2 – genetic test • Proband • nucleotide transition (C1834A) in exon 10 in the CLCN5 gene • should be responsible for the phenotype • Mother • microscopic haematuria 3+; no proteinuria • carrier status not tested • Sister • -ve for haematuria and proteinuria • carrier status not yet tested • FH consistent with X-linked renal disease

  11. Case 2 - current • CKD 2 • eGFR 82mls/min/1.73m2 • PTH within normal limits • Proteinuria 2+ and haematuria 2+ • P:CR 102 - 146mg/mmolCr • on Enalapril 15mg daily • Irbersartan 150mg daily • BP 122/47 • Growth: Ht 173.3cm (25-50th C) Wt 80.3 (97th C) • Transfer to adult services

  12. Dent('s) Disease • 1964 – Dent and Friedmann. Arch. Dis. Child. • 2 unrelated English boys. • Rickets and renal tubular abnormalities • Phenotype development on follow up • Familial proximal renal tubular syndrome • Low-molecular-weight proteinuria • Hypercalciuria • Nephrocalcinosis • Metabolic bone disease • Progressive renal failure • Marked male predominance • Wrong et al. QJM. 1994.

  13. Dent Disease • 4 disorders of hereditary hypercalciuric nephrolithiasis • Dent’s Disease • X-linked nephrolithiasis (XLN) • X-linked recessive hypophosphataemic rickets (XLHR) • Idiopathic low molecular weight proteinuria of Japanese children (JILMWP)

  14. Molecular Genetics of Dent Disease • Dent Disease 1 • 11 kindreds • Mutations in the CLCN5 gene on chromosome Xp11.22 • Gene codes for chloride channel CLC-5 • Lloyd et al. Nature, 1996. • 19 of 32 families (60%) with CLCN5 mutations • Total of 70 mutations in 90 families recorded • Hoopes et al. Kidney International. 2004

  15. Schematic representation of a predicted topology of CLC-5 Figure 1 . Schematic representation of a predicted topology of CLC-5, based on the reported DNA sequence, to illustrate the mutations associated with X-linked hypercalciuric nephrolithiasis. The mutations found in 11 families with X-linked hypercalciuric nephrolithiasis A common molecular basis for three inherited kidney stone diseases. Lloyd, Sarah; Pearce, Simon; Fisher, Simon; Steinmeyer, Klaus; Schwappach, Blanche; Scheinman, Steven; Harding, Brian; Bolino, Alessandra; Devoto, Marcella; Goodyer, Paul; Rigden, Susan; Wrong, Oliver; Jentsch, Thomas; Craig, Ian; Thakker, Rajesh Nature. 379(6564):445-449, February 1, 1996. © 1996 Macmillan Magazines Ltd. Published by Nature Publishing Group. 3

  16. CLCN5 molecular function • Sited in epithelial cells • proximal renal tubule • medullary Thick Ascending Limb of Henle’s loops • collecting duct intercalated cells • Codes the renal chloride channel CLC-5 • Acidification of endosomes • Solute reabsorption function • Membrane recycling in proximal tubule • Megalin-cubilin endocytic pathway

  17. Regulation and maintenance of organelle pH CLC-5 chloride-proton exchanger adapted from Weisz in Ludwig et al. NDT 2006.

  18. CLCN5 knock out mice • Reduces expression of CLC-5 in KO mice • Phenotype exhibited • LMWP, glycosuria, aminoaciduria, polyuria, renal phosphate wasting • Hypercalciuria, nephrocalcinosis, progressive renal failure • Reduced amount of cell surface receptors • megalin and cubilin • Proximal tubular cell protein uptake function

  19. Megalin and cubilin handling in the proximal tubular cells. Ligands bind to megalin/cubilin Megalin/cubilin receptors recycle to membrane Ligands released from receptor by low pH in endosome Ludwig et al. NDT 2006.

  20. Megalin binds a variety of filtered molecules • >50 ligands identified • Cubilin - multiple binding domains • 15 ligands identified • peripheral membrane protein • Amnionless • probably assists cubilin in endocytosis

  21. Biochemical consequences • Proximal tubule • Proteinuria – LMWP and albuminuria • Urinary peptides unfiltered • Prolactin, insulin, angiotensin II. • Higher urinary PTH down-regulates Na-Phosphate co transporter • AA and glucose loss related to poor membrane transporter recycling • TAL of loop of Henle • Role in hypercalciuria here? • Impaired concentrating capacity? • Collecting duct intercalated cells • A nucleus for crystal agglomeration?

  22. 19/32 families (60%) with CLCN5 mutations 13 (40%) without CLCN5 mutation No clinical correlations

  23. Dent Diseases • Dent Disease 2 • 5 of 13 families with Dent Disease and no CLCN5 mutation • Mutation in the OCRL1 gene on chromosome Xq26 • Features of (OculoCerebroRenal) Lowe’s syndrome absent • Cataract • Renal tubular Acidosis • Mental retardation

  24. OCRL1 molecular function • OCRL1 on chromosome Xq25-27 • Codes PIP2 5-phosphatase of OCRL1 protein • Impaired function increases cellular PIP2 involved in vesicle trafficking at the Golgi apparatus • PIP2 has wide distribution • Functional disturbance in Lowe’s may require additional gene defect

  25. Clinical diagnosis of Dent disease • Affected male • LMWP (> x5 ULN) • Hypercalciuria • At least one of: • Nephrocalcinosis • Nephrolithiasis • Haematuria • Hypophosphatemia • Renal insufficiency

  26. Treatment strategies • Hypercalciuria • Dietary sodium restriction • Thiazide diuretics • Bone disease – hypophosphataemia • Phosphate supplements • Vitamin D supplements • Renal protection – anti-proteinuric agents • ACEi and/or ARBs • Dialysis and transplantation • Genetic counselling in families

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