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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
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THE ROSETTA STONE: USSING'S SHORT CIRCUIT EXPERIMENT ON FROG SKIN
22Na 24Na
Outside Inside
shunt closed- 100 mV
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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
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USSING'S FULL ROSETTA STONEUSSING'S FULL ROSETTA STONE
NaNa
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
NaNa
XX
HH
ClCl
KK
OutsideOutside InsideInside
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USSING, USSING, SKOU AND CRANESKOU AND CRANEHow Epithelia WorkHow Epithelia Work
NaNa
NaNa
XX
HH
KK
2 K2 K
3 Na3 Na
ClCl
NaNa
((--))
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
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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
00
������������������������
������������������������
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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
+ / + / --
������������������������
��������
������������������������
--
NLNL
00
Antenatal BartterAntenatal Bartter
antenatalantenatal
++++++
+ / + / --
������������������������
+ / + / --
++++
very highvery high
++
HHSHHS
childhoodchildhood
+ / + / --
������������������������
������������������������
������������������������
++++
NLNL
00
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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
00
������������������������
������������������������
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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++++
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THE MTALTHE MTAL
KK
KK
K
KNa
2ClClCl
Na
+ 10 mV+ 10 mV -- 40 mV40 mV 00
ADHADHcAMPcAMP
CaSRCaSR
[[Cl]Cl] ii
gClgCl
PGEPGE22EPEP33
vv22
BarttinBarttin
ParacellinParacellin(Ca(Ca++++, Mg, Mg++++))
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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 ++++++ +++ +++ ++ ---- ++++++
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TYPE I BARTTER SYNDROMETYPE I BARTTER SYNDROME
KK
KK
NaNa
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
II
CaSRCaSR
ParacellinParacellin
BarttinBarttin
0 mV0 mV -- 50 mV50 mV 0 mV0 mV
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Na/K/2Cl CO-TRANSPORTER MUTATIONSIN TYPE I BARTTER'S
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THE VARIOUS BARTTER SYNDROMESTHE VARIOUS BARTTER SYNDROMES
Bartter SyndromeBartter Syndrome
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 +++ +++ +++ +++ ++ ---- ++++++
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TYPE II BARTTER SYNDROMETYPE II BARTTER SYNDROME
KK
KK
NaNa
2Cl2Cl
Am. J. Am. J. PhysiolPhysiol..271:F961, 1996271:F961, 1996
• 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
• ↓↓↓↓ VVMM : : ↓↓↓↓ CaCa++ ++ absorption;absorption;hypercalciuriahypercalciuria
•• Despite Despite ↓↓↓↓ VVM M , minimal , minimal ↑↑↑↑↑↑↑↑ urinary Mgurinary Mg ++++
KKClCl
IIII
CaSRCaSR
ParacellinParacellin
BarttinBarttin
0 mV0 mV -- 50 mV50 mV 0 mV0 mV
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ROM ROM -- KK
From: S.C. HebertAm. J. Physiol. Renal275:F325, 1998
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ROM ROM -- K GENE MUTATIONS IN BARTTER SYNDROME IIK GENE MUTATIONS IN BARTTER SYNDROME II
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THE VARIOUS BARTTER SYNDROMESTHE VARIOUS BARTTER SYNDROMES
Bartter SyndromeBartter Syndrome
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 +++ +++ ++ ++++++ ----
NephrocalcinosisNephrocalcinosis +++ +++ +++ +++ ++ ---- ++++++
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TYPE III BARTTER SYNDROMETYPE III BARTTER SYNDROME
KK
KK
NaNa
2Cl2Cl
Am. J. Am. J. PhysiolPhysiol..271:F961, 1996271:F961, 1996
• Type III: Loss of function Type III: Loss of function ClCClC--KbKb
mutation; chromosome Ip31mutation; chromosome Ip31
• 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
IIIIII
CaSRCaSR
ParacellinParacellin
BarttinBarttin
0 mV0 mV -- 50 mV50 mV 0 mV0 mV
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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
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BASOLATERAL Cl - CHANNEL MUTATIONS IN BARTTER TYPE III
Simon, et al.Nature Genetics17:171, 1997
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THE VARIOUS BARTTER SYNDROMESTHE VARIOUS BARTTER SYNDROMES
Bartter SyndromeBartter Syndrome
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 +++ +++ ++ +++ +++ ----
NephrocalcinosisNephrocalcinosis +++ +++ +++ +++ ++ ---- ++++++
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TYPE IV BARTTER SYNDROMETYPE IV BARTTER SYNDROME
KK
KK
NaNa
2Cl2Cl
• Type IV: Loss of function Type IV: Loss of function barttinbarttin
mutation; chromosome Ip31mutation; chromosome Ip31
• 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
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THE VARIOUS BARTTER SYNDROMESTHE VARIOUS BARTTER SYNDROMES
Bartter SyndromeBartter Syndrome
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 +++ +++ ++ ++++++ ----
NephrocalcinosisNephrocalcinosis +++ +++ +++ +++ ++ ---- ++++++
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TYPE V BARTTER SYNDROMETYPE V BARTTER SYNDROME
KK
KK
NaNa
2Cl2Cl
• Gain of function mutation Gain of function mutation CaSRCaSR
chromosome 39chromosome 39
• Na+ KK++ wasting:wasting:22o o hyperaldosteronismhyperaldosteronism↑↑↑↑↑↑↑↑ distal deliverydistal delivery
• ↓↓↓↓ VVMM : : ↓↓↓↓↓↓↓↓ CaCa++ ++ absorption;absorption;hypercalciuriahypercalciuria
•• Despite Despite ↓↓↓↓↓↓↓↓ VVM M , minimal , minimal ↑↑↑↑↑↑↑↑ urinary Mgurinary Mg ++++
•• HypocalcemiaHypocalcemia due to PTHdue to PTHsuppressionsuppression
KKClCl
CaSRCaSR
ParacellinParacellin
BarttinBarttin
0 mV0 mV -- 50 mV50 mV 0 mV0 mV
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THE Ca - SENSING RECEPTOR
From Brown, et al.Metabolic Bone DiseaseKrane & Avioli, 1998
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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
00
������������������������
������������������������
![Page 29: BARTTER'S / GITELMAN'S / HHS · PDF fileBARTTER'S / GITELMAN'S / HHS SYNDROMES • August Krogh: Active transport should exist • Hans Ussing's short circuit current experiment (1947)](https://reader031.vdocuments.us/reader031/viewer/2022030412/5a9e41e57f8b9a2e688ca2df/html5/thumbnails/29.jpg)
GITELMAN'S SYNDROMEGITELMAN'S SYNDROME
•• Mimics thiazide therapyMimics thiazide therapy
•• NaCl wastingNaCl wasting
•• MgMg++++ wastingwasting
•• HypocalciuriaHypocalciuria
![Page 30: BARTTER'S / GITELMAN'S / HHS · PDF fileBARTTER'S / GITELMAN'S / HHS SYNDROMES • August Krogh: Active transport should exist • Hans Ussing's short circuit current experiment (1947)](https://reader031.vdocuments.us/reader031/viewer/2022030412/5a9e41e57f8b9a2e688ca2df/html5/thumbnails/30.jpg)
THE LATE DCTTHE LATE DCT
NaNa
ClCl
paracellinparacellin
-- 25 mV25 mV -- 60 mV60 mV 0 mV0 mV
thiazidethiazidesensitivesensitiveNCCTNCCT
ECaCECaC
CaCa
NaNa
NaNa
KK
ClCl
![Page 31: BARTTER'S / GITELMAN'S / HHS · PDF fileBARTTER'S / GITELMAN'S / HHS SYNDROMES • August Krogh: Active transport should exist • Hans Ussing's short circuit current experiment (1947)](https://reader031.vdocuments.us/reader031/viewer/2022030412/5a9e41e57f8b9a2e688ca2df/html5/thumbnails/31.jpg)
THE LATE DCT THE LATE DCT -- 2 IN GITELMAN SYNDROME2 IN GITELMAN SYNDROME
NaNa
ClCl
paracellinparacellin
-- 0 mV0 mV -- 80 mV80 mV 0 mV0 mV
NCCTNCCT
ECaCECaC
CaCa
NaNa
NaNa
KK
ClCl
![Page 32: BARTTER'S / GITELMAN'S / HHS · PDF fileBARTTER'S / GITELMAN'S / HHS SYNDROMES • August Krogh: Active transport should exist • Hans Ussing's short circuit current experiment (1947)](https://reader031.vdocuments.us/reader031/viewer/2022030412/5a9e41e57f8b9a2e688ca2df/html5/thumbnails/32.jpg)
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
![Page 33: BARTTER'S / GITELMAN'S / HHS · PDF fileBARTTER'S / GITELMAN'S / HHS SYNDROMES • August Krogh: Active transport should exist • Hans Ussing's short circuit current experiment (1947)](https://reader031.vdocuments.us/reader031/viewer/2022030412/5a9e41e57f8b9a2e688ca2df/html5/thumbnails/33.jpg)
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
00
������������������������
������������������������
![Page 34: BARTTER'S / GITELMAN'S / HHS · PDF fileBARTTER'S / GITELMAN'S / HHS SYNDROMES • August Krogh: Active transport should exist • Hans Ussing's short circuit current experiment (1947)](https://reader031.vdocuments.us/reader031/viewer/2022030412/5a9e41e57f8b9a2e688ca2df/html5/thumbnails/34.jpg)
KEY TRANSPORT PROTEINS IN LATE DCT(DCT-2)
D.H. EllisonAm. J. Physiol.: Renal279:F616, 2000
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PARACELLIN - 1Deduced Structure
Simon, et al.Science285:103, 1999
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PARACELLIN GENE MUTATIONSPARACELLIN GENE MUTATIONSParacellin Paracellin -- 1: 1: ClaudinClaudin Family of Tight Junction Proteinsof Tight Junction Proteins
Simon, et al.Science285:103, 1999
![Page 37: BARTTER'S / GITELMAN'S / HHS · PDF fileBARTTER'S / GITELMAN'S / HHS SYNDROMES • August Krogh: Active transport should exist • Hans Ussing's short circuit current experiment (1947)](https://reader031.vdocuments.us/reader031/viewer/2022030412/5a9e41e57f8b9a2e688ca2df/html5/thumbnails/37.jpg)
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
00
������������������������
������������������������
![Page 38: BARTTER'S / GITELMAN'S / HHS · PDF fileBARTTER'S / GITELMAN'S / HHS SYNDROMES • August Krogh: Active transport should exist • Hans Ussing's short circuit current experiment (1947)](https://reader031.vdocuments.us/reader031/viewer/2022030412/5a9e41e57f8b9a2e688ca2df/html5/thumbnails/38.jpg)
THE MTALTHE MTAL
KK
KK
K
KNa
2ClClCl
Na
+ 10 mV+ 10 mV -- 40 mV40 mV 00
ADHADHcAMPcAMP
CaSRCaSR
[[Cl]Cl] ii
gClgCl
PGEPGE22EPEP33
vv22
BarttinBarttin
ParacellinParacellin(Ca(Ca++++, Mg, Mg++++))
![Page 39: BARTTER'S / GITELMAN'S / HHS · PDF fileBARTTER'S / GITELMAN'S / HHS SYNDROMES • August Krogh: Active transport should exist • Hans Ussing's short circuit current experiment (1947)](https://reader031.vdocuments.us/reader031/viewer/2022030412/5a9e41e57f8b9a2e688ca2df/html5/thumbnails/39.jpg)
THE LATE DCTTHE LATE DCT
NaNa
ClCl
paracellinparacellin
-- 25 mV25 mV -- 60 mV60 mV 0 mV0 mV
thiazidethiazidesensitivesensitiveNCCTNCCT
ECaCECaC
CaCa
NaNa
NaNa
KK
ClCl
![Page 40: BARTTER'S / GITELMAN'S / HHS · PDF fileBARTTER'S / GITELMAN'S / HHS SYNDROMES • August Krogh: Active transport should exist • Hans Ussing's short circuit current experiment (1947)](https://reader031.vdocuments.us/reader031/viewer/2022030412/5a9e41e57f8b9a2e688ca2df/html5/thumbnails/40.jpg)
KEY TRANSPORT PROTEINS IN LATE DCT(DCT-2)
D.H. EllisonAm. J. Physiol.: Renal279:F616, 2000
![Page 41: BARTTER'S / GITELMAN'S / HHS · PDF fileBARTTER'S / GITELMAN'S / HHS SYNDROMES • August Krogh: Active transport should exist • Hans Ussing's short circuit current experiment (1947)](https://reader031.vdocuments.us/reader031/viewer/2022030412/5a9e41e57f8b9a2e688ca2df/html5/thumbnails/41.jpg)
FEATURES OF HPPFEATURES OF HPP
•• MgMg++++ wastingwasting
•• CaCa++++ wastingwasting
•• No No NaClNaCl or K wastingor K wasting
![Page 42: BARTTER'S / GITELMAN'S / HHS · PDF fileBARTTER'S / GITELMAN'S / HHS SYNDROMES • August Krogh: Active transport should exist • Hans Ussing's short circuit current experiment (1947)](https://reader031.vdocuments.us/reader031/viewer/2022030412/5a9e41e57f8b9a2e688ca2df/html5/thumbnails/42.jpg)
FOUR RELATED SYNDROMESFOUR RELATED SYNDROMES
BartterBartter
TALTAL
++
++
����������������
+ / + / --
Affected segmentAffected segment
NaClNaCl wastingwasting
Metabolic alkalosisMetabolic alkalosis
�������� reninrenin axisaxis
CaCa++++ excretionexcretion
MgMg++++ excretionexcretion
GitelmanGitelman
DCTDCT
++
++
����������������
������������������������
Antenatal BartterAntenatal Bartter(Hyper(Hyper --PGEPGE22))
TALTAL
++
++
������������������������
+ / + / --
Hypo MgHypo Mghypercalciurichypercalciuric
(HHS)(HHS)
TALTAL
00
00
������������������������
������������������������
![Page 43: BARTTER'S / GITELMAN'S / HHS · PDF fileBARTTER'S / GITELMAN'S / HHS SYNDROMES • August Krogh: Active transport should exist • Hans Ussing's short circuit current experiment (1947)](https://reader031.vdocuments.us/reader031/viewer/2022030412/5a9e41e57f8b9a2e688ca2df/html5/thumbnails/43.jpg)
THE Na/K/2Cl CO-TRANSPORTER
From: B. ForbushJ. Biol. Chem.270:17977, 1995
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USSING'S ROSETTA STONEUSSING'S ROSETTA STONE
NaNa
![Page 45: BARTTER'S / GITELMAN'S / HHS · PDF fileBARTTER'S / GITELMAN'S / HHS SYNDROMES • August Krogh: Active transport should exist • Hans Ussing's short circuit current experiment (1947)](https://reader031.vdocuments.us/reader031/viewer/2022030412/5a9e41e57f8b9a2e688ca2df/html5/thumbnails/45.jpg)
KEY TRANSPORT PROTEINS IN mTAL AND DCT(DCT-2)
D.H. EllisonAm. J. Physiol.: Renal279:F616, 2000