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
 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
 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*)
 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

 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
 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
 Dent’s disease 1: characteristics in males
Major features Definitions Affected males
with CLCN5
mutations
LMW proteinuria ≥5-x increasing of urinary RBP, β2- or α1 100%
(M< 30 kDa) 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 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 19%
hyperglycemia

Cho HY. Pediatr Nephrol 2008; 23:243-249;

Claverie-Martin F. Pediatr Nephrol 2011; 26:693-704
 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

 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
 Dent’s disease 2 vs 1: characteristics in males

Major Dent 2 Dent 1

features (OCRL1) (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%
Elevated serum levels of muscle frequently rare
enzymes (LDH, CPK)
Bokenkamp A. J Pediatr 2009; 155:94-99; Bokenhauer D. Pediatr Genetics 2011;
 Dent’s disease 2 vs Lowe syndrome
Major Dent 2 Lowe syndrome
features (OCRL1) (n=2) (OCRL1) (n=7)
Urine β2-MG/Cr (ug/mg) 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%)
Cho HY. Pediatr Nephrol 2008; 23:243-249
 Dent’s disease: genetics

X-linked recessive inheritance Genetic heterogeneity

Dent disease 1
25% (CLCN5)
60%
(?) Dent disease 2
(OCRL1)
15% Dent disease
neither 1 nor 2
(?)

Wu F. et al. Nephron Physiol 2009; 112:53-62

Devust O., Thakker RV. Orphanet Journal of Rare Diseases 2010; 5:28 Shrimpton AE. et al. Nephron Physiol 2009;112:27-36
 Dent’s disease 1: genetics

• Gene: CLCN5, 17 exons, 170 kb

Nonsense
• Cytogenetic location: Xp11.22 1% 1% Missense
3%
2% 1% 1% Frameshift deletions
3%
• Protein: CIS-5 5%
36%
Frameshift insertions
Donor splice site
14%
• Mutations: >150 Acceptor splice site
Intragenic deletions
33%
Novel splice site
• 10% of the mutations de novo 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
 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
 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 No defects

observed
• SLC9A6, located on Xq26.3, encoding Na+/H+ exchanger

• 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.
Dent’s disease 1: pathophysiology

Devust O., Pirson Y. Kidney Int 2007; 72;1065-1072

 Dent’s disease 1: pathophysiology

9000x 40000x 40000x

A. Small vesicles in the secondary foot processes of podocytes.

B-C. Particles in podocytes
Dent’s disease 2: pathophysiology

Claverie-Martin F. Pediatr Nephrol 2011; 26:693-704

 Differential diagnosis of Dent’s disease:
causes of Fanconi syndrome
Inherited disorders: Acquired disorders:
• Dent’s disease • Glomerular proteinuria (nephrotic syndrome)
• Lowe syndrome • Light chain nephropathy (multiple myeloma)
• Cystinosis • Sjogren syndrome
• Galactosemia • Auto-immune interstitial nephritis
• Hereditary fructose intolerance • Acute tubulo-interstitial nephritis with uveitis
• Glycogen storage disease • Renal transplantation
• Fanconi-Bickel syndrome • Anorexia nervosa
• Tyrosinemia type 1
• Wilson disease Exogenous substances:
• Mitochondrial diseases (cytochrome-C oxidase • Drugs: aminoglycosides, outdated tetracycline,
deficiency) valproate salicylate, adefovir, cidofovir,
• Idiopathic Fanconi syndrome tenofovir, ifosfamide, cisplatin, imanitib mesylate
• Sporadic Fanconi syndrome • Chinese herbs
• Chemical compounds (paraquat, diachrome 6-
mercaptopurine, 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.
Dent’s disease: diagnostic algorithm
(> 100 mg per day)

Edvardsson VO. et al. Pediatr Nephrol 2013; 10: 1923-1942

Dent’s disease: diagnostic algorithm
(> 100 mg per day)

Edvardsson VO. et al. Pediatr Nephrol 2013; 10: 1923-1942

 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

 Dent’s disease: supportive treatment

Treatment of rickets:
• Vitamin D: doses -? Risk of enhance hypercalciuria
& nephrocalcinosis
• Phosphate supplementation: doses -?

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

 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.
 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?
 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.