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THE HYPERKALEMIC SYNDROMES - Budapest Nephrology … · cardiac standstill rare skeletal muscle...
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THE HYPERKALEMIC SYNDROMES THE HYPERKALEMIC SYNDROMES
Transcript of THE HYPERKALEMIC SYNDROMES - Budapest Nephrology … · cardiac standstill rare skeletal muscle...
THE HYPERKALEMIC SYNDROMES THE HYPERKALEMIC SYNDROMES
KK++ BALANCEBALANCE
intakeintake
renalrenaloutputoutput
distaldistal NaNa++
deliverydeliveryaldosteronealdosteronelumen voltagelumen voltage
{{
ECF (60ECF (60 mEqmEq )) ExternalExternalCellsCells (3400(3400 mEqmEq ))
PumpPump
LeakLeak
KK
NaNainsulininsulin
catecholscatechols
KK
pH;pH; osmolalityosmolalitymembrane integritymembrane integrity
DisorderDisorder
periodic paralysisperiodic paralysisheart generally unaffectedheart generally unaffected
cardiac standstillcardiac standstillrare skeletal musclerare skeletal muscle
paralysisparalysis
TWO KINDS OF HYPERKALEMIC TWO KINDS OF HYPERKALEMIC SYNDROMESSYNDROMES
FiberFiber
Skeletal muscleSkeletal muscleTTX TTX -- sensitivesensitive
MyocardiumMyocardiumTTX TTX -- insensitiveinsensitive
ActivationActivationThresholdThreshold
-- 6060
-- 7575
{{
{{
RENAL HANDLING OF KRENAL HANDLING OF K ++
I.I. Complete proximalComplete proximal reabsorptionreabsorption
II.II. AldoAldo --mediated principal cell secretionmediated principal cell secretion
THE CCD PRINCIPAL CELLTHE CCD PRINCIPAL CELL
ATPaseATPase
NaNa
2K2K
KK
ClCl
-- 20 mV20 mV -- 80 mV80 mV 0 mV0 mV
ClCl
amilorideamiloride
KK
•• Predominant inPredominant inlate DCT and late DCT and CCTCCT
•• AldosteroneAldosterone --responsiveresponsive
•• Sensitive to:Sensitive to:amilorideamiloridetriamterenetriamterenespironolactonespironolactone
3Na3Na
ENaCEpithelial Na Channel
News in Physiol. Sci.12:55, 1997
• Each αααα subunit :amiloride-sensitiveNa channel
• ββββ and γγγγ subunits:↑↑↑↑surface delivery of ENaC
• Liddle's syndrome:ββββ subunit mutation
• pseudohypoaldo I:αααα or ββββ subunit mutation
• ARDS :αααα subunit mutation
MAJOR CAUSES OF HYPERKALEMIAMAJOR CAUSES OF HYPERKALEMIA
I. Diminished Renal ExcretionI. Diminished Renal ExcretionReduced GFRReduced GFR
ATNATNESRDESRD
Reduced Tubular SecretionReduced Tubular SecretionAddisonAddison ’’ss diseasediseaseDCT diseaseDCT diseasePrincipal cell diseasePrincipal cell diseasePotassium Potassium -- sparing diureticssparing diuretics
II.II. TranscellularTranscellular ShiftsShiftsAcidosisAcidosisCell destructionCell destructionHPPHPPDiabetic hyperglycemiaDiabetic hyperglycemiaInsulin Insulin -- dependencedependence
plusplus aldosteronealdosterone lacklackDepolarizing muscleDepolarizing muscle
paralysisparalysis
WNK 1, 4 mutations activateWNK 1, 4 mutations activatethiazidethiazide --sensitive NaCl transportersensitive NaCl transporter
•• ↑↑↑↑↑↑↑↑ shunt Cl permeability;shunt Cl permeability;paracellinparacellin --mediatedmediated
•• NaNa avidavid•• ↓↓↓↓↓↓↓↓ VVMM
•• ↓↓↓↓↓↓↓↓ K, H K, H secretion: CCTsecretion: CCT•• lowlow reninrenin hypertensionhypertension•• responsive to diuretics,responsive to diuretics,
NaNa restrictionrestriction
DISTAL CONVOLUTED TUBULEDISTAL CONVOLUTED TUBULE DISEASEDISEASEGORDONGORDON’’S SYNDROME (PSEUDOHYPOALDOSTERONISM II)S SYNDROME (PSEUDOHYPOALDOSTERONISM II)
2K2K
3Na3Na
aldoaldo
ClCl
KK
ClCl
NaNa
ClCl
GORDON'S SYNDROMEA DCT DISEASE
WNK: with no lysineWNK I: ↑↑↑↑ NCC activityWNK IV: function unknown Yang et al.
JCI 111:1039, 2003
HYPERKALEMIC RTA SYNDROMESHYPERKALEMIC RTA SYNDROMESPRINCIPAL CELL DISORDERSPRINCIPAL CELL DISORDERS
DISORDERDISORDER PRINCIPAL DEFECTPRINCIPAL DEFECT PRINCIPAL FEATURESPRINCIPAL FEATURES
PseudohypoaldosteronismPseudohypoaldosteronism II
Interstitial Interstitial diseasedisease
↑↑↑↑↑↑↑↑ KK++;; NaNa+ + wasting;wasting;RTARTA
↑↑↑↑↑↑↑↑ KK++; Na; Na++ wasting;wasting;RTARTA
ClosedClosed NaNa++ channelchannel
HyporeninemicHyporeninemichypoaldosteronismhypoaldosteronism
NaNa Channel BlockadeChannel Blockade ::•• Prototype:Prototype: amilorideamiloride RxRx•• NaNa wastingwasting•• ↓↓↓↓↓↓↓↓ VVMM•• ↓↓↓↓↓↓↓↓ K, H secretionK, H secretion•• AldosteroneAldosterone
unresponsiveunresponsive•• αααααααα or or ββββββββ subunitsubunit
mutations inmutations in ENaCENaC
KK
ClCl
2K2K
3Na3Na
NaNa
KK
aldoaldo
ClCl
PRINCIPAL CELL DISEASESPRINCIPAL CELL DISEASESNaNa++ CHANNEL BLOCKADE (PSEUDOHYPOALDOSTERONISM I)CHANNEL BLOCKADE (PSEUDOHYPOALDOSTERONISM I)
PRINCIPAL CELL DISEASESPRINCIPAL CELL DISEASESHYPORENINEMIC HYPOALDOSTERONISMHYPORENINEMIC HYPOALDOSTERONISM
(GENERALIZED DISTAL NEPHRON DISEASE)(GENERALIZED DISTAL NEPHRON DISEASE)
2K2K
3Na3Na
NaNa
KKaldoaldo
ClCl
•• Interstitial renal diseaseInterstitial renal disease•• ↓↓↓↓↓↓↓↓ reninrenin ,, aldosteronealdosterone•• NaNa wastingwasting•• ↓↓↓↓↓↓↓↓ VVMM
•• ↓↓↓↓↓↓↓↓ K, H secretionK, H secretion•• lowlow reninrenin hypertensionhypertension•• furosemidefurosemide benefitsbenefits
KK
ClCl
TREATMENT REGIMENS FOR TREATMENT REGIMENS FOR HYPERKALEMIAHYPERKALEMIA
KK+ + REMOVALREMOVAL
KAYEXALATE: APPROXIMATE LY 1KAYEXALATE: APPROXIMATE LY 1 mEqmEq K / Gm RESINK / Gm RESIN
(30 (30 -- 5050 mEqmEq / 30 / 30 -- 60 MINUTES)60 MINUTES)
HEMODIALYSIS:HEMODIALYSIS: KK++ CLEARANCE: 200 ml / MINUTECLEARANCE: 200 ml / MINUTE
(85(85 mEqmEq / HR)/ HR)
PERITONEAL DIALYSIS: KPERITONEAL DIALYSIS: K ++ CLEARANCE: 20 CLEARANCE: 20 -- 25 ml / MINUTE25 ml / MINUTE
(8.5 (8.5 -- 1010 mEqmEq / HR)/ HR)
KK++ ENTRY INTO CELLSENTRY INTO CELLS
ALKALINIZATION: 0.6ALKALINIZATION: 0.6 mEqmEq KK++ / 0.1 pH UNIT/ 0.1 pH UNIT
GLUCOSE AND INSULIN: 0.5GLUCOSE AND INSULIN: 0.5 mEqmEq KK++ / 25 Gm GLUCOSE/ 25 Gm GLUCOSE
CARDIAC PROTECTION IN HYPERKALEMIACa++ SCREENING OF SURFACE POTENTIAL
DisorderDisorder
periodic paralysisperiodic paralysisheart generally unaffectedheart generally unaffected
cardiac standstillcardiac standstillrare skeletal musclerare skeletal muscle
paralysisparalysis
TWO KINDS OF HYPERKALEMIC TWO KINDS OF HYPERKALEMIC SYNDROMESSYNDROMES
FiberFiber
Skeletal muscleSkeletal muscleTTX TTX -- sensitivesensitive
MyocardiumMyocardiumTTX TTX -- insensitiveinsensitive
ActivationActivationThresholdThreshold
-- 6060
-- 7575
{{
{{
HYPERKALEMIC PERIODIC HYPERKALEMIC PERIODIC PARALYSISPARALYSISA SKELETAL MEMBRANE DISORDERA SKELETAL MEMBRANE DISORDER
•• TTX TTX -- sensitivesensitive NaNa++ channel mutationschannel mutations
•• Chromosome 17 mutationChromosome 17 mutationHPPHPPparamyotoniaparamyotonia
•• Human formHuman form : often with familial inbreeding: often with familial inbreedingEquine form: Equine form: inbred quarterinbred quarter --horseshorses
•• HPP: episodic; may occur with normal KHPP: episodic; may occur with normal K ++ levelslevelsparamyotoniaparamyotonia : cold: cold --sensitivesensitive
•• KK--sensitive;sensitive; acetazolamideacetazolamide --responsiveresponsive
allelic variantsallelic variants}}
PROPERTIES OF SOMEPROPERTIES OF SOME NaNa++ CHANNELSCHANNELS
TTX TTX -- SENSITIVESENSITIVE TTX TTX -- INSENSITIVEINSENSITIVE
Primary locationPrimary location Brain , Muscle HeartBrain , Muscle Heart
Activation voltages Activation voltages -- 60 60 -- 7575(mV)(mV)
THE GREAT HODGKINTHE GREAT HODGKIN --HUXLEY HUXLEY CONTRIBUTIONCONTRIBUTION
CLASSICAL CYCLE OF ELECTRICAL EXCITATIONCLASSICAL CYCLE OF ELECTRICAL EXCITATION
∆∆∆∆ Membranepotential
Ionic fluxes
Other transportmechanisms
Otherstimuli
Gating ofchannels
CATION CHANNEL KINETICS
NaNa++ CHANNEL INACTIVATION: KEY FEATURESCHANNEL INACTIVATION: KEY FEATURES
1. INACTIVATION IS NOT, STRICTLY, VOLTAGE 1. INACTIVATION IS NOT, STRICTLY, VOLTAGE --DEPENDENTDEPENDENT
2. ACTIVATION GATES MUST OPEN BEFORE2. ACTIVATION GATES MUST OPEN BEFOREINACTIVATION GATES CLOSEINACTIVATION GATES CLOSE
3. THE 3. THE SEEMINGSEEMING VOLTAGEVOLTAGE --DEPENDENCE OFDEPENDENCE OFINACTIVATION RELATES TO THE VOLTAGEINACTIVATION RELATES TO THE VOLTAGE --DEPENDENCE OF ACTIVATION GATEDEPENDENCE OF ACTIVATION GATEOPENINGOPENING
VOLTAGE-GATED CATION CHANNELS
PtáčekAm. J. Med. 104:58, 1998
+ 20 + 20
-- 50 50 -- 70 70
SODIUM CHANNEL ACTIVITY: NORMALSODIUM CHANNEL ACTIVITY: NORMALRESTINGRESTING ACTIVATIONACTIVATION
REPOLARIZATIONREPOLARIZATION
OUT INOUT IN
VVM M
VVMM
VVM M = = -- 9090
LOWLOW PPNaNa
LOWLOW PPNaNa
INACTIVATIONINACTIVATION
HIGHHIGH PPNaNa
VVM M
LOWLOW PPNaNa
~~~~~~~~
~~~~
HYPERKALEMIC PERIODIC HYPERKALEMIC PERIODIC PARALYSISPARALYSISA SKELETAL MEMBRANE DISORDERA SKELETAL MEMBRANE DISORDER
•• TTX TTX -- sensitivesensitive NaNa++ channel mutationschannel mutations
•• Chromosome 17 mutationChromosome 17 mutationHPPHPPparamyotoniaparamyotonia
•• Human formHuman form : often with familial inbreeding: often with familial inbreedingEquine form: Equine form: inbred quarterinbred quarter --horseshorses
•• HPP: episodic; may occur with normal KHPP: episodic; may occur with normal K ++ levelslevelsparamyotoniaparamyotonia : cold: cold --sensitivesensitive
•• KK--sensitive;sensitive; acetazolamideacetazolamide --responsiveresponsive
allelic variantsallelic variants}}
Scientific American May, 1991
THE MAGNIFICENT FLAWED THOROUGHBRED
Pillars of the STUD BOOKJames Weatherby, 1791
Godolphin Arabian1725
Darley Arabian1688
Byerley Turk1690
THE GREAT RACES
Scientific American May, 1991
QUARTER HORSESQUARTER HORSES
1. Sprint races ~ 0.25 miles1. Sprint races ~ 0.25 miles
2. Primarily aerobic2. Primarily aerobic
3. Selective in3. Selective in --breeding: very muscularbreeding: very muscular
4. Continued in4. Continued in --breeding:breeding:
HPPHPP
Laryngeal neuropathyLaryngeal neuropathy
YearlingYearling osteoarthritisosteoarthritis
THE HYPP INDEX HORSE
SODIUM CHANNEL ACTIVITY: SODIUM CHANNEL ACTIVITY: HPPHPPRESTINGRESTING ACTIVATIONACTIVATION
OUT INOUT IN
VVMM ≅≅≅≅≅≅≅≅ + 20+ 20VVM M = = -- 9090
LOWLOW PPNaNaHIGHHIGH PPNaNa
HPP : TTX HPP : TTX -- SENSITIVE MUSCLE FIBERSSENSITIVE MUSCLE FIBERS
1 . FAILURE OF INACTIVATION GATES TO CLOSE1 . FAILURE OF INACTIVATION GATES TO CLOSE
2 . PERSISTENT TTX 2 . PERSISTENT TTX -- SENSITIVE iSENSITIVE i NaNa
Na+ CHANNEL DEFECT IN HPP
DisorderDisorder
periodic paralysisperiodic paralysisheart generally unaffectedheart generally unaffected
cardiac standstillcardiac standstillrare skeletal musclerare skeletal muscle
paralysisparalysis
TWO KINDS OF HYPERKALEMIC TWO KINDS OF HYPERKALEMIC SYNDROMESSYNDROMES
FiberFiber
Skeletal muscleSkeletal muscleTTX TTX -- sensitivesensitive
MyocardiumMyocardiumTTX TTX -- insensitiveinsensitive
ActivationActivationThresholdThreshold
-- 6060
-- 7575
{{
{{
PARTIAL DEPOLARIZATION INACTIVATES CARDIAC ACTION POTENTIAL
TSIEN & HESS, 1986
THE CARDIAC ACTION POTENTIALS
GATING CaCa++++ NaNa++ NaNa++ CaCa++++ NaNa++ NaNa++
TSIEN & HESS, 1986
SODIUM CHANNEL ACTIVITY: SODIUM CHANNEL ACTIVITY: HYPERKALEMIAHYPERKALEMIARESTINGRESTING ACTIVATIONACTIVATION
OUT INOUT IN
VVM M VVMM = = -- 7070
LOWLOW PPNaNa
≅≅≅≅≅≅≅≅ -- 20 20
LOWLOW PPNaNa
CARDIOTOXICITYCARDIOTOXICITY
1 . 1 . ↑↑↑↑↑↑↑↑ KK++ DEPOLARIZES VDEPOLARIZES V MM
2 . ACTIVATION GATES PARTIALLY OPEN2 . ACTIVATION GATES PARTIALLY OPEN
3 . INACTIVATION GATES CLOSED3 . INACTIVATION GATES CLOSED
4 .4 . iiNaNa BLOCKEDBLOCKED
NaNa++ CHANNELSCHANNELS
SKELTALSKELTAL CARDIACCARDIACMUSCLEMUSCLE
TTX SENSITIVETTX SENSITIVE INSENSITIVEINSENSITIVE
CHANNEL LOWCHANNEL LOW HIGHHIGHACTIVATION VOLTAGEACTIVATION VOLTAGE VOLTAGEVOLTAGE
+ 20
- 50 - 70
SODIUM CHANNEL ACTIVITY: NORMALSODIUM CHANNEL ACTIVITY: NORMALRESTINGRESTING ACTIVATIONACTIVATION
REPOLARIZATIONREPOLARIZATION
OUT IN
VM
VM
VM = - 90
LOW PNa
LOW PNa
INACTIVATIONINACTIVATION
HIGH PNa
VM
LOW PNa
~~~~
~~
SODIUM CHANNEL ACTIVITY: SODIUM CHANNEL ACTIVITY: HPPHPPRESTINGRESTING ACTIVATIONACTIVATION
OUT INOUT IN
VVMM ≅≅≅≅≅≅≅≅ + 20+ 20VVM M = = -- 9090
LOWLOW PPNaNaHIGHHIGH PPNaNa
HPP : TTX HPP : TTX -- SENSITIVE MUSCLE FIBERSSENSITIVE MUSCLE FIBERS
1 . FAILURE OF INACTIVATION GATES TO CLOSE1 . FAILURE OF INACTIVATION GATES TO CLOSE
2 . PERSISTENT TTX 2 . PERSISTENT TTX -- SENSITIVE iSENSITIVE i NaNa
SODIUM CHANNEL ACTIVITY: SODIUM CHANNEL ACTIVITY: HYPERKALEMIAHYPERKALEMIARESTINGRESTING ACTIVATIONACTIVATION
OUT INOUT IN
VVM M VVMM = = -- 7070
LOWLOW PPNaNa
≅≅≅≅≅≅≅≅ -- 20 20
LOWLOW PPNaNa
CARDIOTOXICITYCARDIOTOXICITY
1 . 1 . ↑↑↑↑↑↑↑↑ KK++ DEPOLARIZES VDEPOLARIZES V MM
2 . ACTIVATION GATES PARTIALLY OPEN2 . ACTIVATION GATES PARTIALLY OPEN
3 . INACTIVATION GATES CLOSED3 . INACTIVATION GATES CLOSED
4 .4 . iiNaNa BLOCKEDBLOCKED
