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, RussiaOctober 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 disease1994 - 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;112:27-36http://www.era-edta-reg.org

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

100%

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

hyperglycemia19%

Cho HY. Pediatr Nephrol 2008; 23:243-249;Claverie-Martin F. Pediatr Nephrol 2011; 26:693-704

Dent’s disease 1: renal biopsy findings

Hodgin JB. Kidney Int 2008; 73:1320-1323

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.

No indications for kidney biopsy in pts with phenotype of Dent’s disease!

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; 53:3-17Ludwig M. et al. Pediatr Nephrol 2006; 21:1241-1250Copelovitch L. et al. Clin J Am Soc Nephrol 2007; 2:914-918

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%

Elevated serum levels of muscle enzymes (LDH, CPK)

frequently rare

Bokenkamp A. J Pediatr 2009; 155:94-99; Bokenhauer D. Pediatr Genetics 2011;

Dent’s disease 2 vs Lowe syndrome

Major features

Dent 2(OCRL1) (n=2)

Lowe syndrome (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

Wu F. et al. Nephron Physiol 2009; 112:53-62 Shrimpton AE. et al. Nephron Physiol 2009;112:27-36Devust O., Thakker RV. Orphanet Journal of Rare Diseases 2010; 5:28

60%

15%

25%Dent disease 1 (CLCN5)

Dent disease 2 (OCRL1)

Dent disease nei-ther 1 nor 2 (?)

(?)

Dent’s disease 1: genetics

• Gene: CLCN5, 17 exons, 170 kb

• Cytogenetic location: Xp11.22

• Protein: CIS-5

• Mutations: >150

• 10% of the mutations de novo

36%

33%

14%

5%

3%3%

2%1%1% 1% 1%

NonsenseMissenseFrameshift deletionsFrameshift insertionsDonor splice siteAcceptor splice siteIntragenic deletionsNovel splice siteComplete deletionsIn-frame insertionsIn-frame deletions

Hoopes RR. et al. Am J Hum Genet 2005; 76: 260-267

• No evidence for major mutational hot spots

• No genotype-phenotype correlation

• No correlations between the presence or absence of mutations and phenotypes

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 familyHichri 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

• 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.

No defects observed

Dent’s disease 1: pathophysiology

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

Dent’s disease 1: pathophysiology

A. Small vesicles in the secondary foot processes of podocytes.B-C. Particles in podocytes

40000x40000x9000x

Dent’s disease 2: pathophysiology

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

Inherited disorders:• Dent’s disease• 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

Differential diagnosis of Dent’s disease: causes of Fanconi syndrome

Cochat P. et al. Pediatr Nephrol 2010; 25:415-424 Igarashi T. In Pediatr Nephrol 2009;1039-1067.

Acquired disorders:• Glomerular proteinuria (nephrotic 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 6-mercaptopurine, toluene, maleate)• Heavy metals (lead, cadmium, chromium, platinum, uranium, mercury)

Dent’s disease: diagnostic algorithm

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

(> 100 mg per day)

Dent’s disease: diagnostic algorithm

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

(> 100 mg per day)

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 -?

• 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

Risk of enhance hypercalciuria & nephrocalcinosis

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

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?

Evidence-based statements: no

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.