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Hypercalciuria Genetic and environmental basis Pascal Houillier Paris-Descartes University.

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Presentation on theme: "Hypercalciuria Genetic and environmental basis Pascal Houillier Paris-Descartes University."— Presentation transcript:

1 Hypercalciuria Genetic and environmental basis Pascal Houillier Paris-Descartes University

2 Hypercalciuria is a risk factor for calcium nephrolithiasis N Lerolle et al, Am J Med, 2002

3 Thiazide diuretics decreases the recurrence of stone FL Coe et al, Kidney Int, 1988

4 SHOK syndrome Stroke Hypertension Osteoporosis Kidney

5 Primary mechanisms resulting in hypercalciuria ECF Ca ECF Ca ECF Ca Hypercalciuria Primary disorder Renal leak Primary disorder Bone resorption Primary disorder Intestine hyperabsorption

6 Idiopathic (genetic) hypercalciuria Familial inheritance Heavy influence of environmental (dietary) factors Complex pathophysiology

7 Low Ca excretion High Ca excretion Gene1Gene2Gene3Gene4Gene5 Gene1

8 Influence of environmental factors Low Ca excretion High Ca excretion

9 High Na intake increases urinary Ca excretion High Na intake Increased ECF volume Decreased proximal Na and Ca absorptions J Lemann, Jr, 1992

10 Thiazides reduce urinary calcium excretion through a decrease in ECF volume T Nijenhuis et al, JCI, 2005

11 7 male patients with Dent syndrome (CLNC5 defect) A. Blanchard, unpublished results.

12 Ncc inactivation is associated with an increased bone mineral density HumansMice L. Nicolet-Barousse et al, JBMR, 2005

13 High dietary protein intake increases urinary Ca excretion ECF Ca Hypercalciuria Increased bone resorption Decreased tubular Ca reabsorption Increased animal protein intake : Increased acid load J Lemann, Jr, 1992

14 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 UCaV, µmol/min Filtered load of Ca, µmol/min Acid load

15 Metabolic acidosis induces a negative calcium balance Sebastian et al, N Eng J Med, 1994 J Lemann et al, J Clin Invest, 1966

16 Carbohydrates induce an increase in urinary calcium excretion J. Lemann Jr et al, N Engl J Med, 1969

17 Pathophysiology of human idiopathic hypercalciuria ECF Ca Hypercalciuria Increased intestinal Ca absorption Increased Ca release (especially on a low Ca diet) Decreased renal tubular Ca reabsorption Primary or secondary disorders ?

18 Pathophysiology of rat idiopathic hypercalciuria ECF Ca Hypercalciuria D. Bushinsky et al, Semin Nephrol, 1996 S. Tsuruoka et al, Kidney Int, 1997

19 Role of vitamin D receptor in intestinal epithelial cells From Li, 1993

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21 From Coe, 1991

22 Role of kidney in idiopathic hypercalciuria

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24 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

25 Acute response to hydrochlorothiazide From Sutton, 1980 and Sakhaee, 1985

26 Calciuric response to an acute acid load From Houillier, 1996

27 Calciuric response to furosemide From Tsuruoka, 1997

28 CLC-5 OCRL ATP7B FAH G6PC NPT2 NHERF-1 AKr1b1 CAII TRPV5 VDR Calbindin- D28k WNK1-4 T Kallikrein NKCC2 ROMK CLC-Kb Barttin CaSR PCLN-1 ATP6V1B1 ATP6V0V4 SLC4A1 (AE1) SCNN1B and G (ENaC ß and subunits) Kidney as the primary defect : monogenic disease in humans and/or mice

29 TRPV5 (ECaC 1)

30 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

31 Phenotype of Trpv5 -/- mice J. Hoenderop et al, J Clin Invest, 2003

32 Phenotype of Trpv5 -/- mice Decreased distal tubular Ca reabsorption Adaptive increase in intestinal Ca absorption

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34 CaSR

35 CaSR and model of ion transport in the TAL Na 2Cl K K Ca, Mg - -+ Ca CaSR LumenCell Interstitium Cl PCLN-1 - PTH

36 CaSR +/+ CaSR +/- CaSR -/-

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38 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-/-

39 Copyright ©2003 American Society for Clinical Investigation Tu, Q. et al. J. Clin. Invest. 2003;111:1029-1037

40 Copyright ©2003 American Society for Clinical Investigation Tu, Q. et al. J. Clin. Invest. 2003;111:1029-1037

41 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-/-

42 Copyright ©2003 American Society for Clinical Investigation Tu, Q. et al. J. Clin. Invest. 2003;111:1029-1037

43 Gain-of-function mutations in CASR gene induce a renal leak of calcium Yamamoto et al, JCEM, 2000

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46 Expression hétérologue du CaSR Vargas-Poussou, JASN, 2002

47 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

48 Paracellin-1 (Claudin 16) and hypercalciuria

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52 Tubular phenotype of patients with loss- of-function in PCLN-1 gene A. Blanchard et al, Kidney Int, 2002

53 CLC5 and hypercalciuria

54 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

55 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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58 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

59 Colocalisation avec Rab4 et H + -ATPase

60 A-ClC-5 B-H + ATPase C=A+B D-CLC-5 E- 2microglob. F=D+E G-CLC-5 H- 2microglob I=G+H 13min. ME CLC-5 Localisation de CLC-5 dans le tubule proximal

61 ß2 microglob Lactoglobuline lactoglobuline FITC-dextran CLC-5 horseradish peroxydase CLC-5

62 Expression de la mégaline à la surface des cellules du tubule proximal en labsence ou en présence de CLC-5 CLC-5MégalineCLC-5+mégaline

63 mégalinemégaline + CLC-5ClC-5 NaPi 2 +/+ -/- +/- Physiopathologie diabète phosphaté Diminution de lexpression apicale de NaPi-2 chez la souris CLC-5 - /- Pas de modification de lexpression de NaPi-2 à la surface des cellules CLC-5 - chez la souris CLC-5 +/-. S1

64 Fonction de CLC-5

65 PHYSIOPATHOLOGIE Rôle 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 lendocytose PTH filtrée [PTH] nle [PTH] > Nle « hyperparathyroidisme » luminal (S3)

66 Tissue kallikrein and hypercalciuria

67 Tissue kallikrein and TRPV5 are coexpressed in the renal tubule

68 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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71 Femelles C57Bl6/J

72 Males C57Bl6/J

73 Femelles 129Sv

74 Tissue kallikrein gene expression is controlled by calcium intake

75 Expression des transcrits des transporteurs

76 Mécanisme daction de la TK D. Gkika et al, EMBO J, 2006

77 Leffet de la TK est dépendant de la PKC

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79 Effet des mutations des sites consensus de la PKC

80 La TK stabilise TRPV5 à la membrane

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82 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)

83 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 regions R. Hoopes et al, J.A.S.N., 2003

84 Conclusion Hypercalciuria is a complex trait, and its expression depends on both –Environmental factors –Genetic factors Modification of dietary factors is efficient but not specific Continuing efforts are warranted - detailed proximal phenotype definition - study of monogenic causes of hypercalciuria - identification of loci linked to idiopathic hypercalciuria

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87 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

88 Pathophysiology of human idiopathic hypercalciuria Adapted from Lemann, 1992 ECF Ca Hypercalciuria Adapted from Houillier, 1996

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90 Monogenic renal hypercalciuria : clues to the genetics of idiopathic hypercalciuria ? Trpv5 (ECaC1) CaSR Paracellin-1 (Claudin 16)


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