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6-3. Dent's disease. Larisa Prikhodina (eng)
- 1. Dent’s disease: genetics, diagnosis, treatment Larisa Prikhodina Department of Inherited & Acquired Kidney Diseases, Research Institute of Pediatrics & Children’ Surgery, Moscow, Russia The IPNA/ESPN Teaching Course “Pediatric Nephrology: evidence-based statements and open questions“ Moscow, Russia October 22-24, 2013
- 2. Clinical case History: • Since age of 10 mo: proteinuria isolated without NS: 0.5-1.4-3.5 g/L • 1 and 4 y. (locally): steroids 2 mg/kg/d – no effect; Dx: SRNS • 8 y.: CsA 5 mg/kg/d + steroids 1 mg/kg/d for 10 mo – no effect, serum Cr +50% Age on admission: 9 y.o. • Short stature: height: <5‰, weight: 25‰ • Proteinuria isolated: 0.5 g/24h • Hypercalciuria: Ca/Cr 0.7-1.5 • eGFR: 83.6 ml/min/1.73m2 • Renal biopsy: FSGS • Steroids & CsA withdrawal • ACE inhibitors 0.1 mg/kg per day • Hypothiazide 1-1.5 mg/kg per day
- 3. Clinical case Follow up: 10 y.o. • Nephrocalcinosis medullar, 1 grade • Proteinuria: 0.3-0.5 g/24h • Ca/Cr: 0.5-0.9 (N<0.7) • eGFR: 81.1 ml/min/1.73m2 Follow up: 14 y.o. • TRP: 67% • Urine β2-microglobulin: 2.7 µg/mL (N<0.3) • CLCN5 gene: c.1909C>T (p.Arg637*)
- 4. Clinical case Follow up: 10 y.o. • Nephrocalcinosis medullar, 1 grade • Proteinuria: 0.3-0.5 g/24h • Ca/Cr: 0.5-0.9 (N<0.7) • eGFR: 81.1 ml/min/1.73m2 Follow up: 14 y.o. • TRP: 67% • Urine β2-microglobulin: 2.7 µg/mL (N<0.3) • CLCN5 gene: c.1909C>T (p.Arg637*) Dx. Dent disease, 1 type
- 5. Dent’s disease: definition 1964 - Dent C.E. & Friedman M. first report of the disease 1994 - Wrong O.M. coined the term “Dent’s disease” for the combination of X-linked LMW proteinuria, hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressive CRF Dent disease 1 (MIM: #300009): CLCN5 gene • X-linked nephrolithiasis with renal failure (MIM: #310468) • X-linked recessive hypercalciuric hypophosphataemic rickets (MIM: #300554) • LMW proteinuria with hypercalciuria and nephrocalcinosis (MIM: #308990) Dent disease 2 (MIM: #300555): OCRL gene • Clinical phenotype oculo-cerebrorenal syndrome of Lowe Dent C.E, Friedman M. Arch.Dis.Childh. 39:240-249, 1964; Wrong O.M. et al. Q.J.Med. 87:473-493, 1994
- 6. Dent’s disease: epidemiology • Exact prevalence is unknown (rare CKD) • 250 affected families reported to date ICD-10: N39.8 - Other specified disorders of urinary system Old ERA-EDTA PRD code: 99 - Other identified renal disorders New ERA-EDTA PRD code: 2929 SNOMED CT concept identifier and fully specified name: 444645005 Familial / hereditary nephropathies: 10201 Wu F. et al. Nephron Physiol 2009; 112:53-62 Shrimpton AE. et al. Nephron Physiol 2009;112:27-36 http://www.era-edta-reg.org
- 7. Dent’s disease 1: characteristics in males Major features Definitions Affected males with CLCN5 mutations LMW proteinuria (M< 30 kDa) ≥5-x increasing of urinary RBP, β2- or α1 microglobulins Hematuria Presence of ≥5 RBC phpf 94% Hypercalciuria Urinary Ca excretion >4mg/kg/24h or >age-matched N 89% Nephrocalcinosis Renal US 76% Aminoaciduria urinary levels of amino acids 100% 44% Nephrolithiasis Renal US 42% Chronic renal failure ESRD by age 30-50 y.o. 42% Hypophosphatemia Serum P <N level and tubular reapbsorption <85% 32% Rickets Rachitic changes in bone X-ray 32% Glycosuria ≥2 episodes of ≥(+) glycosuria without hyperglycemia 19% Cho HY. Pediatr Nephrol 2008; 23:243-249; Claverie-Martin F. Pediatr Nephrol 2011; 26:693-704
- 8. Dent’s disease 1: renal biopsy findings No indications for kidney biopsy in pts with phenotype of Dent’s disease! a. Two glomeruli are globally sclerotic. b. Normocellular glomeruli without segmental sclerosis or podocyte hypertrophy. c. Many collecting ducts are distended by casts composed of Tamm-Horsfall protein admixed with calcifications. d. Von Kossa stain is positive in the distribution of the calcifications, composed of calcium phosphate. Hodgin JB. Kidney Int 2008; 73:1320-1323
- 9. Dent’s disease 1: characteristics in females Females - obligate carriers with milder phenotype: • Low-molecular-weight proteinuria: 60-90% • Hypercalciuria: 30% • Nephrocalcinosis - rare • ESRD - rare Sсheinman SJ. Kiney Int 1998; 53:3-17 Ludwig M. et al. Pediatr Nephrol 2006; 21:1241-1250 Copelovitch L. et al. Clin J Am Soc Nephrol 2007; 2:914-918
- 10. Dent’s disease 2 vs 1: characteristics in males Major features Dent 2 (OCRL1) Dent 1 (CLCN5) LMW proteinuria 100% 100% Hypercalciuria 86% 90% Nephrocalcinosis 39% 75% Aminoaciduria 52% 41% Chronic renal failure 32% 30% Phosphate wasting 24% 22% Glycosuria 11% 17% frequently rare Elevated serum levels of muscle enzymes (LDH, CPK) Bokenkamp A. J Pediatr 2009; 155:94-99; Bokenhauer D. Pediatr Genetics 2011;
- 11. Dent’s disease 2 vs Lowe syndrome Major features Dent 2 (OCRL1) (n=2) Lowe syndrome (OCRL1) (n=7) 0.1; 6.9 0.7 (0.2 - 6) Urine Ca/Cr (mg/mg) 0.43 ± 0.15 1.16 ± 1.21 Nephrocalcinosis/lithiasis 1/2 (50%) 3/7 (43%) Renal tubular acidosis 0/2 7/7 (100%) Hypophosphatemia 0/2 6/7 (86%) Rickets 0/2 3/7 (43%) Chronic renal failure 0/2 1/7 (11%) Glycosuria 0/2 2/7 (29%) Elevated serum SK/LDH 1/2 3/4 (75%) Urine β2-MG/Cr (ug/mg) Cho HY. Pediatr Nephrol 2008; 23:243-249
- 12. Dent’s disease: genetics X-linked recessive inheritance Genetic heterogeneity 25% (?) 15% Devust O., Thakker RV. Orphanet Journal of Rare Diseases 2010; 5:28 Dent disease 1 (CLCN5) 60% Dent disease 2 (OCRL1) Dent disease neither 1 nor 2 (?) Wu F. et al. Nephron Physiol 2009; 112:53-62 Shrimpton AE. et al. Nephron Physiol 2009;112:27-36
- 13. Dent’s disease 1: genetics • Gene: CLCN5, 17 exons, 170 kb Nonsense • Cytogenetic location: Xp11.22 3% • Protein: CIS-5 • Mutations: >150 5% 3% 1% 1% 2% 1% Missense 1% Frameshift deletions Frameshift insertions 36% 14% • 10% of the mutations de novo Donor splice site Acceptor splice site Intragenic deletions 33% Novel splice site Complete deletions In-frame insertions In-frame deletions • No evidence for major mutational hot spots • No genotype-phenotype correlation • No correlations between the presence or absence of mutations and phenotypes Hoopes RR. et al. Am J Hum Genet 2005; 76: 260-267
- 14. Dent’s disease 2: genetics • Gene: OCRL1 (Oculocerebrorenal syndrome of Lowe), 24 exons, 52 kb • Cytogenetic location: Xq25 • Enzyme: phosphatidylinositol 4,5-biphosphate 5-phosphatase (Golgi apparatus) • Mutations: >20 (n=44) All frame shift & splice OCRL1 mutations: • Dent’s disease 2: cluster in exons 1-7 • Lowe syndrome: affect exons 8-23 OCRL1 mutations: • in Dent disease 2 not overlap with those causing Lowe syndrome • p.Ile274Thr, p.Arg318Cys each causing both phenotypes in the same family Hichri H. et al. Hum Mut 2011; 32: 379-388
- 15. Dent’s disease neither 1 nor 2: genetics Candidate genes: • CLCN4, located on Xp22.3, encoding CIS-4 • CFL1, located on 11q13.1, encoding cofilin • SLC9A6, located on Xq26.3, encoding Na+/H+ exchanger No defects observed • TMEM27, located on Xp22.2, encoding collectrin A further candidate gene awaits identification... Ludwig M. Am J Med Genet 2004; 128:434-435; Hoopes R.R. Am J Hum Genet 2005; 76: 260-267; Tosseto E. Pediatr Nephrol 2009; 24:1967-1973; Wu F. Nephron Physiol 2009; 112:53-62.
- 16. Dent’s disease 1: pathophysiology Devust O., Pirson Y. Kidney Int 2007; 72;1065-1072
- 17. Dent’s disease 1: pathophysiology 9000x 40000x A. Small vesicles in the secondary foot processes of podocytes. B-C. Particles in podocytes 40000x
- 18. Dent’s disease 2: pathophysiology Claverie-Martin F. Pediatr Nephrol 2011; 26:693-704
- 19. Differential diagnosis of Dent’s disease: causes of Fanconi syndrome Inherited disorders: • Dent’s disease Acquired disorders: • Glomerular proteinuria (nephrotic syndrome) • • • • • • • • • • • • • • • Lowe syndrome Cystinosis Galactosemia Hereditary fructose intolerance Glycogen storage disease Fanconi-Bickel syndrome Tyrosinemia type 1 Wilson disease Mitochondrial diseases (cytochrome-C oxidase deficiency) • Idiopathic Fanconi syndrome • Sporadic Fanconi syndrome Light chain nephropathy (multiple myeloma) Sjogren syndrome Auto-immune interstitial nephritis Acute tubulo-interstitial nephritis with uveitis Renal transplantation Anorexia nervosa Exogenous substances: • Drugs: aminoglycosides, outdated tetracycline, valproate salicylate, adefovir, cidofovir, tenofovir, ifosfamide, cisplatin, imanitib mesylate • Chinese herbs • Chemical compounds (paraquat, diachrome 6mercaptopurine, toluene, maleate) • Heavy metals (lead, cadmium, chromium, platinum, uranium, mercury) Cochat P. et al. Pediatr Nephrol 2010; 25:415-424 Igarashi T. In Pediatr Nephrol 2009;1039-1067.
- 20. Dent’s disease: diagnostic algorithm (> 100 mg per day) Edvardsson VO. et al. Pediatr Nephrol 2013; 10: 1923-1942
- 21. Dent’s disease: diagnostic algorithm (> 100 mg per day) Edvardsson VO. et al. Pediatr Nephrol 2013; 10: 1923-1942
- 22. Dent’s disease: supportive treatment Prevention of renal stone formation: • No special dietary interventions • High fluid intake • Oral citrate • Thiazides: risk of hypovolemia & hypokalemia Cebotary V. Am J Kidney 2005; 68:642-652
- 23. Dent’s disease: supportive treatment Treatment of rickets: • Vitamin D: doses -? • Phosphate supplementation: doses -? Risk of enhance hypercalciuria & nephrocalcinosis Slowing down the deterioration of renal function: • High citrate diet delayed loss of kidney function in a mouse model, no data in patients • ACE inhibitors might be potential benefit by reducing proteinuria, unknown effect on disease progression Blanchard A. et al. Am J Kidney Dis 2008; 52:1084-1095
- 24. Dent’s disease: prognosis Kidney function: • Normal during childhood • ESRD in affected males : 30-80% in the 3rd to 5th decade • ESRD in carrier females: 1 of 10 Renal transplantation: • Most of patients with ESRD have kidney Tx with good success. Wrong O.M. et al. Q.J.Med. 87:473-493, 1994; Bokenkamp A. J Pediatr 2009; 155:94-99.
- 25. Dent’s disease: conclusion Evidence-based statements: no Open questions: • How the mutations in Dent 1 (CLCN5) and Dent 2 (OCRL) produce a similar renal phenotype? • Gene (s): Dent disease neither 1 nor 2? • Genotype-phenotype correlations? • Mechanism of hypercalciuria? • What percentage of FSGS pts might have unrecognized Dent disease? • What role of glomerular disfunction might play in the loss of renal function?
- 26. Dent’s disease: conclusion • Keeping balance between potential benefit and harm to avoid withheld effective treatments or administering unnecessary treatments. • Using of ‘expert groups’ with methodologists to balance personal experience and available evidence. Further joint long-term clinical and genetic studies are needed.