1 / 34

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

britain
Download Presentation

Dent Disease

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  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

More Related