hypercalciuria genetic and environmental basis pascal houillier paris-descartes university
TRANSCRIPT
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Hypercalciuria
Genetic and environmental basis
Pascal HouillierParis-Descartes University
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Hypercalciuria is a risk factor for calcium nephrolithiasis
N Lerolle et al, Am J Med, 2002
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Thiazide diuretics decreases the
recurrence of stone
FL Coe et al, Kidney Int, 1988
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SHOK syndrome
• Stroke• Hypertension• Osteoporosis• Kidney
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Primary mechanisms resulting in hypercalciuria
ECFCa
ECFCa
ECFCa
Hypercalciuria Hypercalciuria Hypercalciuria
Primary disorderRenal leak
Primary disorderBone resorption
Primary disorderIntestine hyperabsorption
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Idiopathic (genetic) hypercalciuria
• Familial inheritance
• Heavy influence of environmental (dietary) factors
• Complex pathophysiology
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Low Ca excretion
High Ca excretion
Gene1Gene2 Gene3 Gene4 Gene5Gene1
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Influence of environmental factors
Low Ca excretion
High Ca excretion
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High Na intake increases urinary Ca excretion
High Na intake
Increased ECF volume
Decreased proximalNa and Ca
absorptions
J Lemann, Jr, 1992
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Thiazides reduce urinary calcium excretion through a decrease in ECF volume
T Nijenhuis et al, JCI, 2005
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7 male patients with Dent syndrome (CLNC5 defect)
A. Blanchard, unpublished results.
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Ncc inactivation is associated with an increased bone mineral density
Humans Mice
L. Nicolet-Barousse et al, JBMR, 2005
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High dietary protein intake increases
urinary Ca excretion
ECFCa
Hypercalciuria
Increased bone resorption
Decreased tubular Ca reabsorption
Increased animal protein intake :Increased acid load
J Lemann, Jr, 1992
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Metabolic acidosis induces an increase in urinary calcium excretion
Acute Chronic
P. Houillier et al, Kidney Int, 1996 J. Lemann Jr et al, N Engl J Med, 1979
UC
aV
,µ
mol/m
in
Filt
ere
d load
of
Ca,
µm
ol/m
in
Acid load
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Metabolic acidosis induces a negative calcium balance
Sebastian et al, N Eng J Med, 1994J Lemann et al, J Clin Invest, 1966
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Carbohydrates induce an increase in urinary calcium excretion
J. Lemann Jr et al, N Engl J Med, 1969
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Pathophysiology of human idiopathic hypercalciuria
ECFCa
Hypercalciuria
Increased intestinal Ca absorption
Increased Ca release(especially on a low Ca diet)
Decreased renal tubular Ca reabsorption
Primary or secondary disorders ?
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Pathophysiology of rat idiopathic hypercalciuria
ECFCa
Hypercalciuria
D. Bushinsky et al, Semin Nephrol, 1996S. Tsuruoka et al, Kidney Int, 1997
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Role of vitamin D receptor in intestinal epithelial cells
In vitro rat duodenal calcium transportFlux N males IH males N females IH femalesJms 51 ± 12 264 ± 27 29 ± 9 258 ± 40Jsm 11 ± 12 19 ± 2 14 ± 2 23 ± 2Jnet 40 ± 11 245 ± 28 14 ± 8 235 ± 40
From Li, 1993
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VDR-binding sites in intestine and kidney from normal and IHrats
Group N max KdIntestine
Normal Males 243 ± 42 0.33 ± 0.01IH males 536 ± 74 0.49 ± 0.01Kidney
Normal males 34 ± 4 0.27 ± 0.16IH males 87 ± 4 0.45 ± 0.28
From Li, 1993
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0
5
10
15
Uri
nar
y ca
lciu
m e
xcre
tio
n (
mm
ol/d
)
0 5 10 15
Net intestinal calcium absorption (mmol/d)From Coe, 1991
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Role of kidney in idiopathic hypercalciuria
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0
50
100
150
0
1
2
3
4
Filt
ere
d lo
ad
of
ca
lciu
m
(µm
ol/m
in)
Uri
ne
ca
lciu
m e
xc
reti
on
(µ
mo
l/min
)
Controls (n=9)
Hypercalciuric patients (n=34)
Controls (n=9)
Hypercalciuric patients (n=34)
P < 0.02
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Factors decreasing renal tubular calcium reabsorption
• Reduced PTH
• NaCl intake (volume expansion)
• Protein intake (metabolic acidosis)
• Glucose, sucrose, ethanol
• Phosphate restriction
• Loop diuretics
• Calcium, magnesium
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Acute response to hydrochlorothiazide
0
0.05
0.1
0.15
0
0.005
0.01
0.015
0.02
0.025
Incr
ease
in u
rin
ary
calc
ium
exc
reti
on
(m
mo
l/mm
ol c
reat
inin
e)
Incr
ease
in u
rin
ary
calc
ium
ex
cret
ion
(m
mo
l/l G
F)
Controls (n=20)
Fasting hypercalciuria
(n= 20)
Controls (n=9)
Renal hypercalciuria
(n= 20)
AB
From Sutton, 1980 and Sakhaee, 1985
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Calciuric response to an acute acid load
-2
0
2
4
6
8
Mea
n in
crea
se in
cal
ciu
m e
xcre
tio
n
(µm
ol/m
in)
0 1 2 3 4 5 6 7
Baseline Calcium excretion (µmol/min)
From Houillier, 1996
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Calciuric response to furosemide
0
2
4
6
8U
rin
ary
calc
ium
ex
cret
ion
(µ
g/m
in)
Furo 0 + 0 +
Control rats Hypercalciuric ratsFrom Tsuruoka, 1997
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CLC-5OCRLATP7BFAHG6PCNPT2NHERF-1AKr1b1CAII
TRPV5VDRCalbindin-D28k
WNK1-4T Kallikrein
NKCC2ROMKCLC-KbBarttinCaSRPCLN-1
ATP6V1B1ATP6V0V4SLC4A1 (AE1)SCNN1B and G(ENaC ß and subunits)
Kidney as the primary defect : monogenic disease in humans and/or mice
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TRPV5 (ECaC 1)
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Copyright ©2000 American Physiological Society
Hoenderop, J. G. J. et al. Am J Physiol Renal Physiol 278: F352-F360 2000
Fig. 1.TRPV5 (ECaC) is the gatekeeper for Ca absorption in the distal tubule
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Phenotype of Trpv5 -/- mice
J. Hoenderop et al, J Clin Invest, 2003
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Phenotype of Trpv5 -/- mice
Decreased distal tubular Ca reabsorption
Adaptive increase in intestinalCa absorption
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CaSR
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CaSR and model of ion transport in the TAL
Na
2Cl
K
K
Ca, Mg
-
-+
Ca
CaSR
Lumen Cell Interstitium
Cl
PCLN-1
-
PTH
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CaSR +/+
CaSR +/-
CaSR -/-
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Croisement de souris mutées pour CaSR et de souris hypoparathyroïdiennes (Gcm2-/-)
I : normales ; II : CaSR -/-, Gcm2+/+; III : CaSR+/+, Gcm2-/- ; IV : CaSR-/-, Gcm2 -/- ; V: CaSR+/-, Gcm2 +/+ ; VI : CaSR +/-,Gcm2-/-
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Copyright ©2003 American Society for Clinical Investigation
Tu, Q. et al. J. Clin. Invest. 2003;111:1029-1037
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Copyright ©2003 American Society for Clinical Investigation
Tu, Q. et al. J. Clin. Invest. 2003;111:1029-1037
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Copyright ©2003 American Society for Clinical Investigation
Tu, Q. et al. J. Clin. Invest. 2003;111:1029-1037
CaSR +/+Gcm2+/+
CaSR -/-Gcm2+/+
CaSR +/+Gcm2-/-
CaSR -/-Gcm2-/-
CaSR +/-Gcm2+/+
CaSR +/-Gcm2-/-
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Copyright ©2003 American Society for Clinical Investigation
Tu, Q. et al. J. Clin. Invest. 2003;111:1029-1037
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Gain-of-function mutations in CASR gene induce a renal leak of calcium
Yamamoto et al, JCEM, 2000
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Table 1. Clinical laboratory data of patient 1
7 yr 9 yr Normal Values--------------------------------------- --------------- ----------- ---
Plasma
potassium 2.5 to 3.4 2.9 to 3.0 3.5 to 4.7 mmol/L
calcium 1.5 to 1.8 1.7 to 2.16 2.25 to 2.65 mmol/L
magnesium 0.5 to 0.63 0.59 to 0.67 0.75 to 0.96 mmol/L
bicarbonate 27 to 32 30.2 to 30.4 23 to 28 mmol/L
creatinine 50 60 30 to 90 µmol/L
renin 158 113 6.5 to 80 pg/ml
aldosterone ND 56 4 to 40 ng/dl
PTH 6 Undetectable 10 to 65 pg /ml
Urine
calcium 2.4 to 2.6c 1.44 to 1.7 <0.3 mmol/mmol of creatininemagnesium 0.8 1.8 to 2 <0.4 mmol/mmol of creatininesodium 53 10.7 <1.6 mmol/mmol of creatininefractional excretion of16.5 to 26.7e 17.5 to 21.6e2.15 to 15.9 %K (FEK)osmolality after nasalND 460 >800 mOsm/kgdDAVP
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7 yr 9 yr Normal Values
Plasmapotassium 2.5 to 3.4 2.9 to 3.0 3.5 to 4.7 mmol/L
calcium 1.5 to 1.8 1.7 to 2.16 2.25 to 2.65 mmol/L
magnesium 0.5 to 0.63 0.59 to 0.67 0.75 to 0.96 mmol/L
bicarbonate 27 to 32 30.2 to 30.4 23 to 28 mmol/L
creatinine 50 60 30 to 90 µmol/L
renin 158 113 6.5 to 80 pg/ml
aldosterone ND 56 4 to 40 ng/dl
PTH 6 Undetectable 10 to 65 pg /ml
Urine
calcium 2.4 to 2.6c 1.44 to 1.7 <0.3 mmol/mmol of creatinine
magnesium 0,8 1.8 to 2 <0.4 mmol/mmol of creatinine
sodium 53 10,7 <1.6 mmol/mmol of creatinine
fractional excretion of 16.5 to 26.7e 17.5 to 21.6e2.15 to 15.9 %
K (FEK)
osmolality after nasal ND 460 >800 mOsm/kgdDAVP
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Expression hétérologue du CaSR
Vargas-Poussou, JASN, 2002
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CaSR in idiopathic hypercalciuria
• Petrucci et al, 2000:No significant linkage between CaSR variants and idiopathic hypercalciuria
• Lerolle et al, 2002: No point mutation in CASR gene in families with idiopathic hypercalciuria
• Vezzoli et al, 2002: higher urinary Ca excretion in patients bearing the R990G polymorphism (ARQ/AGQ or AGQ/AGQ)
• Yao et al, 2005: GHS rats have a higher renal content in CaSR protein and mRNA
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Paracellin-1 (Claudin 16) and hypercalciuria
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Tubular phenotype of patients with loss-of-function in PCLN-1 gene
HHFControls
0
5
10
15
20
UV/GFRmmol/l GF
Na +
0
0,1
Ca ++
baseline furo0
0,1
0,2
Mg ++
0
10
Cl -
20
baseline furo baseline furo
baseline furo
Na+K+2 Cl-
3 Na+
2 K+
Cl-K+
Ca++
Mg++
Na+K+2 Cl-
3 Na+
2 K+
Cl-K+
?
+ -
Paracellin-1
A. Blanchard et al, Kidney Int, 2002
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CLC5 and hypercalciuria
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Canaux chlore : 3 familles distinctes
• "Cystic fibrosis transmembrane conductance regulator (CFTR)" Cl- channel
• Extracellular-ligand gated (ELG), post synaptic Cl- channels
• CLC family : voltage-gated Cl- channels– CLC-1 à CLC-7, CLC-Ka, CLC-Kb
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Néphrolithiase hypercalciurique liée à l'X
• Maladie de Dent (Grande-Bretagne)
• Protéinurie de bas poids moléculaire avec hypercalciurie et néphrocalcinose (Japon)
• Néphrolithiase récessive liée à l'X (Etats-Unis, Canada)
• Rachitisme hypophosphatémique récessif lié à l'X (Italie, France)
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Syndrome Maladie deDent
Protéinurie deBPM avecnéphrocalcinose
Néphrolithiaserécessive liée àl'X
Rachitismehypophosphatémique récessif lié à l'X
Rachitisme + +Protéinurie + + + +Perte rénale dephosphate
+ + +
Hypercalciurie + + + +Lithiase + +Néphrocalcinose + + + +Insuffisancerénale
+ +
Prédominancemasculine
+ + + +
Mutation du gèneCLCN-5
+ + + +
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Xp11.22Xp22.1 Xq22 Xq28
Rachitisme hypophosphatémique
Maladie de Dent
Diabète insipide
néphrogénique
Syndrome d'Alport
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Mutations du gène CLCN5 : perte de fonction du canal
• Faux-sens• Non sens• Mutation d'un site d'épissage• Insertion • Délétion
Absence de parallélisme entre le phénotype et le génotype
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CLC-5
CLC-5CLC-5
Colocalisation avec Rab4 et H+-ATPase
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A-ClC-5B-H+ATPaseC=A+B
D-CLC-5E-2microglob.F=D+E
G-CLC-5H- 2microglobI=G+H 13min.
ME CLC-5
Localisation de CLC-5 dans le tubule proximal
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ß2 microglobLactoglobuline
lactoglobuline
FITC-dextran
CLC-5
horseradish peroxydase CLC-5
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Expression de la mégaline à la surface des cellules du tubule proximal en l’absence ou en présence de CLC-5
CLC-5Mégaline CLC-5+mégaline
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mégaline mégaline + CLC-5ClC-5
NaPi 2+/+ -/- -/-
+/- +/-
Physiopathologie diabète phosphaté
Diminution de l’expression apicale de NaPi-2 chez la souris CLC-5-/-
Pas de modification de l’expression de NaPi-2 à la surface des cellules CLC-5- chez la souris CLC-5+/-.
S1
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Apex
H+ Cl-
Fonction de CLC-5
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PHYSIOPATHOLOGIERôle de ClC5 dans le diabète phosphaté
Piwon Nils, Nature, 2000, vol 408, 369-373.
Hypothèse : la diminution de l ’expression basale de NaPi-2 est liée à une augmentation de PTH. Elévation luminale et non basolatérale ([PTH] systémique Nle).
Diminution de l’endocytose
PTH filtrée
[PTH] nle
[PTH]>
Nle« hyperparathyroidisme »
luminal (S3)
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Tissue kallikrein and hypercalciuria
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Tissue kallikrein and TRPV5 are coexpressed in the renal tubule
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Copyright ©2001 by the National Academy of Sciences
Meneton, Pierre et al. (2001) Proc. Natl. Acad. Sci. USA 98, 2634-2639
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FemellesC57Bl6/J
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MalesC57Bl6/J
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Femelles129Sv
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Tissue kallikrein gene expression is controlled by calcium intake
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Expression des transcrits des transporteurs
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Mécanisme d’action de la TK
D. Gkika et al, EMBO J, 2006
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L’effet de la TK est dépendant de la PKC
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Effet des mutations des sites consensus de la PKC
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La TK stabilise TRPV5 à la membrane
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Monogenic hypercalciuria : clues to the genetics of idiopathic hypercalciuria ?
• Intestine as the primary defect : – > 5 genes, no gene encoding a Ca transporter
Bone as the primary defect : – > 5 genes, no gene encoding a Ca transporter
• Kidney as the primary defect : – > 18 genes, only one gene encoding a Ca
transporter (PCLN-1)
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Genetics of idiopathic hypercalciuria : lessons from genetic hypercalciuric rats
• Selective genotyping of F2 (GHS female x normocalciuric male WKY rats)
• Linkage between hypercalciuria and chromosomal regions– Significant at D1Rat169– Suggestive to regions of Chr. 4, 7, 10, 14– No linkage with CaSR or VDR gene
regionsR. Hoopes et al, J.A.S.N., 2003
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Conclusion• Hypercalciuria is a complex trait, and its expression
depends on both– Environmental factors– Genetic factors
Modification of dietary factors is efficient but not specificContinuing efforts are warranted
- detailed proximal phenotype definition- study of monogenic causes of hypercalciuria- identification of loci linked to idiopathic hypercalciuria
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• Georges Pompidou Hospital– Pascal Houillier– Anne Blanchard– Marie Briet– Marc Froissart– Gérard Maruani– Laurence Nicolet
• Tenon Hospital– Eric Rondeau– Pierre Ronco– Brigitte Lantz– Françoise Paillard
• INSERM Unit– Nicolas Picard
• Nijmegen University– Joost Hoenderop– Rene Bindels
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Pathophysiology of human idiopathic hypercalciuria
0
50
100
150
0
1
2
3
4
Filt
ere
d lo
ad
of
ca
lciu
m
(µm
ol/m
in)
Uri
ne
ca
lciu
m e
xc
reti
on
(µ
mo
l/min
)
Controls (n=9)
Hypercalciuric patients (n=34)
Controls (n=9)
Hypercalciuric patients (n=34)
P < 0.02
0
2.5
5
7.5
10
Ne
t in
tes
tin
al
ca
lciu
m
ab
so
rpti
on
,mm
ol/
da
y
ControlsIdiopathic
hypercalciuria
Diet Ca25.4 mmol/d
Diet Ca23.6 mmol/d
Adapted from Lemann, 1992
ECFCa
HypercalciuriaAdapted from Houillier, 1996
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Monogenic renal hypercalciuria : clues to the genetics of idiopathic
hypercalciuria ?
• Trpv5 (ECaC1)• CaSR• Paracellin-1 (Claudin 16)