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.