renal fanconi syndromes -...
TRANSCRIPT
Renal Fanconi syndromes
Elena Levtchenko, MD, PhD
University Hospitals Leuven
Renal Fanconi syndrome
Guido Fanconi (1892 - 1979)
Independently
described by deToni,
Debré and Fanconi in
1930s:
Combination of
• Renal rickets
• Glucosuria
• Hypophosphatemia
lumen
Na-dependent transporters Receptor-mediated endocytosis
Na+/K+-ATP-ase interstitium
Renal Fanconi syndrome = generalized
dysfunction of renal proximal tubules
Aa, glucose, phosphate,
bicarbonate
ATP ADP
De Matteis MA NEJM 2011
Christensen et al. 2009
Receptor mediated endocytosis
Christensen et al. Physiol Rev 2012
Age-dependent protein excretion (1)
Age-dependent protein excretion (2)
Lehrnbecher et al. Pediatr Nephrol 1998
Clinical features of renal Fanconi
syndrome
• Growth retardation & failure to thrive
• Hypotonia
• Dehydration
• Rickets
• Vomiting
• Constipation
• Specific symptoms related to
individual diseases & syndromes
Biochemical features of renal
Fanconi syndrome: blood
• Hypokalemia
• Hypophosphatemia
• Proximal tubular metabolic acidosis
• Low uric acid
• Hyponatremia: rare
• Normal serum glucose, amino acids,
albumin
Biochemical features of renal
Fanconi syndrome: urine
• Polyuria
• Aminoaciduria
• Glucosuria
• Phosphaturia
• Na+, K+ , HCO3- losses
• Hypercalciuria
• Hyperuricosuria
• Low molecular weight proteinuria
• Albuminuria
Account GFR –
related changes
in excretions!
Causes of renal Fanconi syndrome
Cystinosis AR (CTNS) Amynoglycosides
Dent’s disease X-linked (CLCN5; OCRL1) Cispaltin, ifosfamide
Lowe syndrome X-linked (OCRL1) Autosomal dominant Fanconi syndrome (EHHADH)
Azathiaprine
Mitochondrial cytopathies (divers) Valproate
Glycogenosis AR (SLC2A2) Glue sniffing
Wilson disease AR (ATP7B) Post-ischemic tubulopathy
Tyrosinemia AR (FAH)
Hereditary fructose intolerance AR (ALDOB)
Multiple myeloma
Galactosemia AR (GALT)
Inherited Acquired
Bockenhauer et al. Nephrol Dial Transpl 2015
Treatment of renal Fanconi syndrome
• Symptomatic: replacement of renal losses:
– Fluid!!
– Potassium chloride
– Sodium or potassium bicarbonate
– Sodium chloride (rarely required)
– Sodium and potassium phosphate salts
– Calcium
– Vitamin D
• Specific: related to the cause of Fanconi
syndrome
Cystinosis
• An autosomal recessive disease caused by lysosomal
accumulation of cystine due to defective exodus of
cystine out of the lysosomes
• Orphan disease: incidence ~1:100,000-200,000
(clustering in some populations)
• Most common cause of inherited generalized
proximal tubular dysfunction (renal Fanconi syndrome)
nucleus
H+
H+
protein
degradation
cystine
cystine
cysteine
lysosome
cytoplasma
cystinosin
Town et al. 1998, Kalatzis et al. 2001
Cystinosis is caused by mutations in the
CTNS gene (17p13)
100 mutations described Levtchenko et al. Eur J Hum Genet 2014
Cystine accumulation in cystinosis
Kidney: 200 - 400 x normal
Liver: 80 - 1000 x normal
Muscle: 40 - 70 x normal
Brain: 5 - 20 x normal
Gahl et al. 2001
Clinical forms of cystinosis
• Infantile form: • Fanconi syndrome ~ 3-6 months
• End stage renal disease (ESRD) ~ 10 years
• “Late-onset” form: • Later onset (often during puberty)
• Mild tubulopathy, proteinuria,
sometimes nephrotic syndrome
• Later progression to ESRD
• Ocular form
Less severe
mutations of
the CTNS
18
Diagnosis of cystinosis
• Suspected clinical presentation
– Cystinosis - most common cause of Fanconi syndrome
– Unexplained eye complaints, photophobia
– Glucosuria, proteinuria (check for low molecular weight proteins)
• Measurement of elevated cystine content in granulocytes:
– Controls < 0.3 nmol ½ cystine/mg protein
– Heterozygotes < 1 nmol ½ cystine/mg protein
– Patients at diagnosis > 2 nmol ½ cystine/mg protein
– Patients on cysteamine therapy < 1 nmol ½ cystine/mg protein
– Values of your own laboratory!
• Cystine crystals in cornea (>1 year)
• Molecular analysis of cystinosis gene
19
Fair skin and hear Rickets at presentation
Corneal cystine crystals
20
Extra-renal involvement in cystinosis
Eye
– Photophobia 50% 8-12 years
– Retinal blindness 10-15% 13-40 years
Endocrine organs
– Hypothyroidism 50% 5-10 years
– Diabetes mellitus 5% 18-40 years
– Male hypogonadism 70% 18-40 years
Neuromuscular disease
– Myopathy 20% 12-40 years
Neurological complaints 2-10% 21-40 years
– Epilepsy mental deterioration
– Cerebella and pyramidal signs
– Stroke-like episodes
Gahl et al. 2002
Treatment of cystinosis
• Symptomatic:
– Free access to water and toilet
– Replacement of urinary losses due to renal
Fanconi syndrome
– Indomethacin
– Hormone replacement when required (thyroxin,
insulin, testosterone)
– Growth hormone in children with poor growth
• Specific treatment with cysteamine
22
Cysteamine depletes lysosomal cystine
accumulation in cystinosis
PQLC2 transporter
Jézégou et al. 2013
Adapted from Besouw et al. 2014
Markello et al. 1993
n= 67
n = 32
n = 17
Cysteamine therapy prevents or postpones extra-renal
complications (Nesterova et al. 2008)
2 males with a combination of renal
rickets, defective tubular reabsorption
of phosphate, calcium, amino acids
and protein and severe growth
retardation
1925-2012
Follow-up of the first two patients over 30 years
Detailed description of 25 affected patients
(15 males and 10 females, 22 members of 5
families (up to three generations)
Dent’s disease
= X-linked recessive hypophosphatemic rickets
(XLRH) = X-linked recessive nephrolithiasis (XRN) =
familial idiopathic low molecular weight proteinuria in
Japanese patients (JILMWP)
Loyd et al. Nature 1996
“A common molecular basis for three inherited kidney stone diseases”
• Exact prevalence is unknown
~250 families reported
Dent’s disease 1: pathophysiology
Devust & Pirson. Kidney Int 2007 Christensen et al. PNAS 2003
• Majority of mutants: loss of Cl- conductivity altering function of early endosomes and
receptor recycling
• Inconsistent results on endosomal acidification in CLCN5 mutants
(Loyd et al. 1996; Piwon et al. 2000; Smith et al. 2009, 2010; Novarino et al. 2010)
: megalin
cubilin
Pathogenesis of proximal tubular
dysfunction in Lowe syndrome
Vicinanza et al. EMBO J 2011
PIP5K
inhibition
PtdIns[4,5]P2
Improvement
of membrane
trafficking in
OCRL
deficient cells
Dent’s disease: genetics
Inheritance: X-linked
recessive Dent 1: 60% CLCN5 (Xp11.22)
Lloyd et al. 1996
Dent 2: 15%
OCRL1 (Xq25)
Hoopes et al. 2005
?
CLCN5 gene:
150 mutations
• Missense 44%
• Nonsense 26%
• Small insertions &
deletions 15%
• Splice defects 11%
• Large insertions &
deletions 4%
• De novo 10% • 50% chance to have affected son
• 50% chance to have carrier daughter
Ludwig et al. Eur J Hum Genet 2014
Dent 1 disease (MIM #300008)
caused by CLCN5 mutations encoding CLC5 (746 aa)
A R
• CLC5 expression in the kidney:
- Proximal tubules (highest)
- -type intercalated cells of collecting duct
- Medullary thick Henle’s loop
Endosomal
lumen
Cytosole Cl-
Cl-
ADP +
Pi
ADP +
Pi
H+
H+
H+ ATP
V-
ATPase
2Cl-
TRPML3
ATP
Na +, K + ATPase
NHE6
Ca 2+
ClC-5
Ca 2+
TPC
Adapted from Levtchenko et al. In-Tech 2012
Picollo, Pusch. Nature 2005
Scheel et al. Nature 2005
Dent’s disease 1: clinical features
Cho HY. Pediatr Nephrol 2008
Affected
females
60-90%
30%
rare
rare
rare
Mostly: PTH and 1,25(OH)2 vit D levels
Clinical features of Dent 2 (MIM #300555)
Bokenkamp A. J Pediatr 2009; 155:94-99; Bokenhauer D. Pediatr Nephrol 2011
Extrarenal features in Dent 2: peripheral cataract, mild retardation,
elevation of CK, LDH, AST
Oculo-cerebro-renal syndrome
(Lowe syndrome, MIM #309000)
• Congenital cataract
• Mental retardation, behavioral
disturbance
• (Incomplete) Renal Fanconi syndrome
• Slowly progressive renal failure
• Destructive arthropathy
• Growth failure
• Mild CK and LDH elevations (x 1.5 - 2)
Billcliff & Lowe Biochem J 2014
Genetic basis of Lowe syndrome and Dent 2
• Mutations in OCRL1 gene (Xq25), encoding phosphatidyl-inositol 4,5-biphosphate
5-phosphatase (PtdIns[4,5]P2 5-phosphatase) (exons 9-22 encoding three
functional domains
• OCRL is expressed in all nucleated cells: plasma membrane, clathrin-coated
vesicles, multiple endosomal compartments, TGN
In OCRL deficient cells:
accumulation of PtdIns[4,5]P2 in
early endosomes (EE) “traffic
jam” of EE
OCRL1 mutations in Lowe and Dent 2
Shrimpton et al. Nephron Physiol 2009
Treatment of Dent’s disease and
Lowe syndrome
Prevention of renal stone formation
• High fluid intake: ≥3 L/m2 per 24
• No special dietary interventions
• Thiazides (Raja et al. JASN 2002)
– risk of hypovolemia & hypokalemia
• Oral citrate ? (Cebotary et al. Am J Kid Dis 2005)
Decrease proteinuria
• RAAS inhibition?
Treatment of rickets
• Phosphate and vitamin D
- risk to enhance hypercalciuria and nephrocalcinosis
Chaperon therapy for missense mutants?
Smith et al. AJP Renal 2009
Autosomal dominant renal FS
EHHADH gene is mutated in AD
renal FS
Klootwijk et al. NEJM 2014
Drug-induced renal FS
Hall et al. Q J Med 2014
Take home message
• Renal Fanconi syndromes are a heterogenous
group of disorders causing generalized
proximal tubular (PT) dysfunction
• Evaluation of PT function requires use of age-
related and GFR-related reference values
• Acquired causes of renal Fanconi syndrome
are more common than genetic causes
• Cystinosis is the most common genetic cause
Acknowledgements
Bert Van den Heuvel
Martine Besouw Katja Ivanova Mohamed
Elmonem Koenraad Veys
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