bartter's / gitelman's / hhs · pdf filebartter's / gitelman's / hhs...

BARTTER'S / GITELMAN'S / HHS SYNDROMESBARTTER'S / GITELMAN'S / HHS SYNDROMES

•• August Krogh:August Krogh: Active transport should existActive transport should exist

•• Hans Ussing's short circuit current experiment (1947)Hans Ussing's short circuit current experiment (1947)::the Rosetta Stone for epithelial ion transportthe Rosetta Stone for epithelial ion transport

•• How epithelia workHow epithelia work

•• The Bartter syndrome:The Bartter syndrome: LasixLasix --likelike

•• The Gitelman syndrome:The Gitelman syndrome: ThiazideThiazide --likelike

•• Hypomagnesemic hypercalciuria: HHSHypomagnesemic hypercalciuria: HHS

•• Current enigmasCurrent enigmas

THE ROSETTA STONE: USSING'S SHORT CIRCUIT EXPERIMENT ON FROG SKIN

22Na 24Na

Outside Inside

shunt closed- 100 mV

THE ROSETTA STONE: USSING'S SHORT CIRCUIT EXPERIMENT ON FROG SKIN

22Na 24Na

Outside Inside

The S.C.C. at zero mV equals net inward Na + flux ( 22Na - 24Na)

shunt closed- 100 mV

0 mV shunt open

USSING'S FULL ROSETTA STONEUSSING'S FULL ROSETTA STONE

UssingUssing ::

•• Apical and basalApical and basalmembranes membranes differdiffer

•• NaNa++, K, K++ and Cland Cl --

permeabilities differpermeabilities differ•• Paracellular shuntParacellular shunt•• "Exchange diffusion""Exchange diffusion"NaNa

OutsideOutside InsideInside

USSING, USSING, SKOU AND CRANESKOU AND CRANEHow Epithelia WorkHow Epithelia Work

2 K2 K

3 Na3 Na

((--))

UssingUssing ::

•• ApicalApical and basaland basalmembranesmembranes differdiffer

•• Paracellular shuntParacellular shunt•• "Exchange diffusion""Exchange diffusion"

SkouSkou ::

•• ( Na + K ) ( Na + K ) -- ATPaseATPase•• Asymmetrical pumpAsymmetrical pump

CraneCrane ::

•• CoCo--transporttransport

FOUR RELATED SYNDROMESFOUR RELATED SYNDROMES

BartterBartter

MTALMTAL

��

+ / + / --

Affected segmentAffected segment

NaClNaCl wastingwasting

CaCa++++ excretionexcretion

MgMg++++ excretionexcretion

GitelmanGitelman

DCTDCT

��

Antenatal BartterAntenatal Bartter(Hyper(Hyper --PGEPGE22))

MTALMTAL

��

+ / + / --

Hypo MgHypo Mghypercalciurichypercalciuric

(HHS)(HHS)

MTAL / DCTMTAL / DCT

��

CLINICAL FEATURES OF BARTTER, HHSCLINICAL FEATURES OF BARTTER, HHSAND GITELMAN SYNDROMESAND GITELMAN SYNDROMES

AgeAge

�� GrowthGrowth

Plasma MgPlasma Mg

Urine CaUrine Ca

Urine MgUrine Mg

NephrocalcinosisNephrocalcinosis

Urinary PGEUrinary PGE 22

IndocinIndocin responseresponse

BartterBartter

infancy / adultinfancy / adult

+ / + / --

��

+ / + / --

highhigh

GitelmanGitelman

childhood / adultchildhood / adult

+ / + / --

��

Antenatal BartterAntenatal Bartter

antenatalantenatal

++++++

+ / + / --

��

+ / + / --

very highvery high

HHSHHS

childhoodchildhood

+ / + / --

��

BartterBartter

MTALMTAL

��

+ / + / --

GitelmanGitelman

DCTDCT

��

MTALMTAL

��

+ / + / --

(HHS)(HHS)

��

MTALMTAL SALT ABSORPTIONSALT ABSORPTION

•• locus for Bartter syndromes I locus for Bartter syndromes I -- VV

•• ~~ 25% of GFR25% of GFR

•• HH22O impermeableO impermeable

•• site of action for highsite of action for high --ceiling diuretics ceiling diuretics

•• heterogeneity between MTAL and CTALheterogeneity between MTAL and CTAL

•• MTAL: concentrating segment; regulatesMTAL: concentrating segment; regulates intrarenalintrarenal

salt balancesalt balance

•• CTALCTAL : diluting segment; regulates free water for mation: diluting segment; regulates free water for mation

•• principal modulators of principal modulators of MTALMTAL NaClNaCl absorption:absorption:

ADH; PGEADH; PGE22 ; interstitial ; interstitial osmolalityosmolality; Ca; Ca++++

THE MTALTHE MTAL

2ClClCl

+ 10 mV+ 10 mV -- 40 mV40 mV 00

ADHADHcAMPcAMP

CaSRCaSR

[[Cl]Cl] ii

gClgCl

PGEPGE22EPEP33

BarttinBarttin

ParacellinParacellin(Ca(Ca++++, Mg, Mg++++))

THE VARIOUS BARTTER SYNDROMESTHE VARIOUS BARTTER SYNDROMES

Bartter SyndromeBartter Syndrome

Type 1Type 1 Type 2 Type 3 Type 4 Type 5Type 2 Type 3 Type 4 Type 5

Gene nameGene name SLC12A1SLC12A1 KCNJ1 CLCNKB BSNDKCNJ1 CLCNKB BSND CASRCASR

Protein nameProtein name NKCC2 NKCC2 ROMK CICNROMK CICN--Kb Kb BarttinBarttin CaRCaR

Major symptomsMajor symptoms PolyuriaPolyuria / / As for type 1 Variable As for type 1 As for type 1 Variable As for type 1 HypocalcemiaHypocalcemiaDehydration/ Dehydration/ (from mild + deafness Seiz(from mild + deafness Seiz uresuresGrowth retardationGrowth retardation to severe)to severe)

"Antenatal" phenotype "Antenatal" phenotype +++ +++ +++ +++ ++ +++ +++ ----

NephrocalcinosisNephrocalcinosis ++++++ +++ +++ ++ ---- ++++++

TYPE I BARTTER SYNDROMETYPE I BARTTER SYNDROME

2Cl2Cl

Am. J. Am. J. PhysiolPhysiol..271:F961, 1996271:F961, 1996

• Type I: Loss of function NKCC2Type I: Loss of function NKCC2

mutation; chromosome 15mutation; chromosome 15

• Na+, KK++ wasting:wasting:22o o hyperaldosteronismhyperaldosteronism↑↑↑↑↑↑↑↑ distal deliverydistal delivery

• ↓↓↓↓ VVMM : : ↓↓↓↓ CaCa++ ++ absorption;absorption;hypercalciuriahypercalciuria

•• Despite Despite ↓↓↓↓ VVM M , minimal , minimal ↑↑↑↑↑↑↑↑ urinary Mgurinary Mg ++++

KKClCl

CaSRCaSR

ParacellinParacellin

BarttinBarttin

0 mV0 mV -- 50 mV50 mV 0 mV0 mV

Na/K/2Cl CO-TRANSPORTER MUTATIONSIN TYPE I BARTTER'S

Type 1 Type 1 Type 2Type 2 Type 3 Type 4 Type 5Type 3 Type 4 Type 5

Gene nameGene name SLC12A1SLC12A1 KCNJ1 KCNJ1 CLCNKB BSNDCLCNKB BSND CASRCASR

Protein nameProtein name NKCC2 NKCC2 ROMKROMK CICNCICN--Kb Kb BarttinBarttin CaRCaR

Major symptomsMajor symptoms PolyuriaPolyuria / / As for type 1As for type 1 Variable As for type 1 Variable As for type 1 HypocalcemiaHypocalcemiaDehydration/ (from mild Dehydration/ (from mild + deafness Seizures+ deafness SeizuresGrowth retardationGrowth retardation to severe)to severe)

"Antenatal" phenotype +++ "Antenatal" phenotype +++ +++ +++ ++ +++ +++ ----

NephrocalcinosisNephrocalcinosis +++ +++ +++ +++ ++ ---- ++++++

TYPE II BARTTER SYNDROMETYPE II BARTTER SYNDROME

2Cl2Cl

• Type II: Loss of function ROMType II: Loss of function ROM --KK

mutation; chromosome 11mutation; chromosome 11

• Na+ KK++ wasting:wasting:22o o hyperaldosteronismhyperaldosteronism↑↑↑↑↑↑↑↑ distal deliverydistal delivery

KKClCl

CaSRCaSR

BarttinBarttin

0 mV0 mV -- 50 mV50 mV 0 mV0 mV

ROM ROM -- KK

From: S.C. HebertAm. J. Physiol. Renal275:F325, 1998

ROM ROM -- K GENE MUTATIONS IN BARTTER SYNDROME IIK GENE MUTATIONS IN BARTTER SYNDROME II

Type 1 Type 2 Type 1 Type 2 Type 3 Type 3 Type 4 Type 5Type 4 Type 5

Gene nameGene name SLC12A1SLC12A1 KCNJ1 KCNJ1 CLCNKB CLCNKB BSNDBSND CASRCASR

Protein nameProtein name NKCC2 ROMK NKCC2 ROMK CICNCICN--KbKb BarttinBarttin CaRCaR

Major symptomsMajor symptoms PolyuriaPolyuria / As for type 1 / As for type 1 Variable Variable As for type 1 As for type 1 HypocalcemiaHypocalcemiaDehydration/ Dehydration/ (from mild (from mild + deafness Seizures+ deafness SeizuresGrowth retardationGrowth retardation to severe)to severe)

"Antenatal" phenotype +++ +++ "Antenatal" phenotype +++ +++ ++ ++++++ ----

TYPE III BARTTER SYNDROMETYPE III BARTTER SYNDROME

2Cl2Cl

• Type III: Loss of function Type III: Loss of function ClCClC--KbKb

mutation; chromosome Ip31mutation; chromosome Ip31

KKClCl

IIIIII

CaSRCaSR

BarttinBarttin

0 mV0 mV -- 50 mV50 mV 0 mV0 mV

TOPOLOGY OF BASOLATERAL mTALCl- CHANNELS

o phosphorylation by cAMP-dependent protein ki nase (PKA)

+ arginine and lysine residues MikhailovaMikhailova , , et al.et al.Kidney InternationalKidney International61:1003, 200261:1003, 2002

BASOLATERAL Cl - CHANNEL MUTATIONS IN BARTTER TYPE III

Simon, et al.Nature Genetics17:171, 1997

Type 1 Type 2 Type 3 Type 1 Type 2 Type 3 Type 4Type 4 Type 5Type 5

Gene nameGene name SLC12A1SLC12A1 KCNJ1 CLCNKB KCNJ1 CLCNKB BSNDBSND CASRCASR

Protein nameProtein name NKCC2 ROMK CICNNKCC2 ROMK CICN --Kb Kb BarttinBarttin CaRCaR

Major symptomsMajor symptoms PolyuriaPolyuria / As for type 1 Variable / As for type 1 Variable As for type 1As for type 1 HypocalcemiaHypocalcemiaDehydration/ (from mild Dehydration/ (from mild + deafness+ deafness SeizuresSeizuresGrowth retardationGrowth retardation to severe)to severe)

"Antenatal" phenotype +++ +++ "Antenatal" phenotype +++ +++ ++ +++ +++ ----

TYPE IV BARTTER SYNDROMETYPE IV BARTTER SYNDROME

2Cl2Cl

• Type IV: Loss of function Type IV: Loss of function barttinbarttin

mutation; chromosome Ip31mutation; chromosome Ip31

KKClCl

CaSRCaSR

BarttinBarttin

0 mV0 mV -- 50 mV50 mV 0 mV0 mV

Type 1 Type 2 Type 3Type 1 Type 2 Type 3 Type 4 Type 4 Type 5Type 5

Gene nameGene name SLC12A1SLC12A1 KCNJ1 CLCNKBKCNJ1 CLCNKB BSNDBSND CASRCASR

Protein nameProtein name NKCC2 ROMK CICNNKCC2 ROMK CICN --Kb Kb BarttinBarttin CaRCaR

Major symptomsMajor symptoms PolyuriaPolyuria / As for type 1 Variable As for t ype 1 / As for type 1 Variable As for t ype 1 HypocalcemiaHypocalcemiaDehydration/ Dehydration/ (from mild + deafness (from mild + deafness SeizuresSeizuresGrowth retardationGrowth retardation to severe)to severe)

"Antenatal" phenotype +++ +++ "Antenatal" phenotype +++ +++ ++ ++++++ ----

TYPE V BARTTER SYNDROMETYPE V BARTTER SYNDROME

2Cl2Cl

• Gain of function mutation Gain of function mutation CaSRCaSR

chromosome 39chromosome 39

• ↓↓↓↓ VVMM : : ↓↓↓↓↓↓↓↓ CaCa++ ++ absorption;absorption;hypercalciuriahypercalciuria

•• Despite Despite ↓↓↓↓↓↓↓↓ VVM M , minimal , minimal ↑↑↑↑↑↑↑↑ urinary Mgurinary Mg ++++

•• HypocalcemiaHypocalcemia due to PTHdue to PTHsuppressionsuppression

KKClCl

CaSRCaSR

BarttinBarttin

0 mV0 mV -- 50 mV50 mV 0 mV0 mV

THE Ca - SENSING RECEPTOR

From Brown, et al.Metabolic Bone DiseaseKrane & Avioli, 1998

BartterBartter

MTALMTAL

��

+ / + / --

GitelmanGitelman

DCTDCT

��

MTALMTAL

��

+ / + / --

(HHS)(HHS)

��

GITELMAN'S SYNDROMEGITELMAN'S SYNDROME

•• Mimics thiazide therapyMimics thiazide therapy

•• NaCl wastingNaCl wasting

•• MgMg++++ wastingwasting

•• HypocalciuriaHypocalciuria

THE LATE DCTTHE LATE DCT

paracellinparacellin

-- 25 mV25 mV -- 60 mV60 mV 0 mV0 mV

thiazidethiazidesensitivesensitiveNCCTNCCT

ECaCECaC

THE LATE DCT THE LATE DCT -- 2 IN GITELMAN SYNDROME2 IN GITELMAN SYNDROME

-- 0 mV0 mV -- 80 mV80 mV 0 mV0 mV

NCCTNCCT

ECaCECaC

KNOWN PATHOPHYSIOLOGY OF GITELMAN KNOWN PATHOPHYSIOLOGY OF GITELMAN SYNDROMESYNDROME

•• Loss of function mutation: NCCTLoss of function mutation: NCCTNaClNaCl wastingwasting

•• Secondary Secondary hyperaldosteronismhyperaldosteronism : K wasting: K wasting

•• Cellular Cellular hyperpolarizationhyperpolarization 22oo decreased decreased ClCl -- entryentry↑↑↑↑↑↑↑↑ apical apical ECaCECaC entryentry↑↑↑↑↑↑↑↑ basolateralbasolateral Na/Ca exchangeNa/Ca exchange

net effect: net effect: hypocalciuriahypocalciuria

•• Mg wasting: uncertain mechanismMg wasting: uncertain mechanism

BartterBartter

MTALMTAL

��

+ / + / --

GitelmanGitelman

DCTDCT

��

MTALMTAL

��

+ / + / --

(HHS)(HHS)

��

KEY TRANSPORT PROTEINS IN LATE DCT(DCT-2)

D.H. EllisonAm. J. Physiol.: Renal279:F616, 2000

PARACELLIN - 1Deduced Structure

Simon, et al.Science285:103, 1999

PARACELLIN GENE MUTATIONSPARACELLIN GENE MUTATIONSParacellin Paracellin -- 1: 1: ClaudinClaudin Family of Tight Junction Proteinsof Tight Junction Proteins

Simon, et al.Science285:103, 1999

BartterBartter

MTALMTAL

��

+ / + / --

GitelmanGitelman

DCTDCT

��

MTALMTAL

��

+ / + / --

(HHS)(HHS)

��

THE MTALTHE MTAL

2ClClCl

+ 10 mV+ 10 mV -- 40 mV40 mV 00

ADHADHcAMPcAMP

CaSRCaSR

[[Cl]Cl] ii

gClgCl

PGEPGE22EPEP33

BarttinBarttin

ParacellinParacellin(Ca(Ca++++, Mg, Mg++++))

THE LATE DCTTHE LATE DCT

-- 25 mV25 mV -- 60 mV60 mV 0 mV0 mV

thiazidethiazidesensitivesensitiveNCCTNCCT

ECaCECaC

KEY TRANSPORT PROTEINS IN LATE DCT(DCT-2)

FEATURES OF HPPFEATURES OF HPP

•• MgMg++++ wastingwasting

•• CaCa++++ wastingwasting

•• No No NaClNaCl or K wastingor K wasting

BartterBartter

TALTAL

��

+ / + / --

Metabolic alkalosisMetabolic alkalosis

�� reninrenin axisaxis

GitelmanGitelman

DCTDCT

��

TALTAL

��

+ / + / --

(HHS)(HHS)

TALTAL

��

THE Na/K/2Cl CO-TRANSPORTER

From: B. ForbushJ. Biol. Chem.270:17977, 1995

USSING'S ROSETTA STONEUSSING'S ROSETTA STONE

KEY TRANSPORT PROTEINS IN mTAL AND DCT(DCT-2)

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