k homeos
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Potassium Homeostasis & Disorders
Kevin Ho, M.D.Assistant Professor of Medicine
Renal-Electrolyte Division
University of Pittsburgh School of Medicine
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Potassium Distribution in the Body
Potassium distribution in body fluidcompartments
Total body K+ stores: 50-55 meq/kgbody weight (3500-4000 meq K+
total)
Extracellular fluid compartment: 2%
[K+] = 3.5-5.0 meq/L (50-100 meq K+)
Intracellular fluid compartment: 98%
[K
+
] = 120-150 meq/L
Large cellular K+ (and Na+)concentration gradients aremaintained by the Na,K-ATPase
Intracellular [K+
]120-150 meq/L
Extracellular [K+]3.5-5.0 meq/L
Em = -90mV
Na+
K+3 Na+
2 K+
Resting membrane potential
Nernst equation
EK = RT ln [K]ozF [K]i
Steady-state equationVm = RT ln r[K]o + b[Na]o
zF r[K]i + b[Na]I
r = 3:2 Na/K active transportb = 0.01 relative permeability of Na+ to K+
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Potassium Gradient and Cellular Functions
Cellular functions Primary determinant of cell resting
membrane potential
Substrate for membrane transportprocesses
Determinant of cell volume
Changes in transmembranepotassium gradient
Alter cell membrane resting potential
Alter neuromuscular excitability
Cardiac conduction & cardiacpacemaker rhythmicity
Neuronal function
Vascular smooth muscle tone
Skeletal muscle function
Impair cell membrane transport
processes
Intracellular [K+]120-150 meq/L
Extracellular [K+]3.5-5.0 meq/L
Em = -90mV
Na+
K+3 Na+
2 K+ K+K+
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Extracellular Potassium Concentration andCell Membrane Potential
-120
-90
-60
-30
0
+30
mV
Resting
Threshold
Normal HyperkalemiaHypokalemia
Hyperpolarization
Depolarization
Hypokalemia hyperpolarizes excitable tissuesHyperkalemia depolarizes excitable tissues
Membrane potential ln [K]o[K]i
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Potassium Homeostasis
The regulation of potassium homeostasis can be divided into two
main processes:External Balance: The regulation of total body potassium contentthrough alterations in potassium intake (e.g. dietary) and excretion(e.g. renal, GI)
Internal Balance: The regulation of the distribution of potassiumbetween intracellular fluid (ICF) and extracellular fluid (ECF)
compartments
Intracellular Fluid (ICF)
Extracellular Fluid (ECF)
Internal
BalanceK+
K+
ExternalBalance
Intake
Excretion
3.5-5.0 meq/L
120-150 meq/L
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External Potassium Balance:Intake & Renal K+ Reabsorption
Potassium intake
Dietary intake = 50-150 meq/day(3-9 grams KCl/day)
IV KCl, hyperalimentation, drugs
Blood products
K+ Intake
RenalK+ Reabsorption
Proximal Tubule
Thick Ascending Limb
Collecting Duct
Renal potassium reabsorption
Proximal tubuleMajority of solute and H2O
transport Passive processes 65% filtered K+ load
Thick ascending limb
25% filtered K+ load Active + passive processes Na-K-2Cl cotransporter
Cortical and medullary collecting ducts Intercalated cells (Type A + Type B) Active process H-K-ATPase
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Renal Potassium Handling
Outer Stripe
Inner Stripe
O
uter
M
edulla
Inner
Medulla
Cortex CCDPCT
TALS3
OMCD
IMCD
DCT
tiDL
tiAL
K+
H2O
10-15%
65%25%
35%
35%
K+
K+
K+
K+
K+
K+
K+
K+
K+
H2OK+
K+
K+
K+
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External Potassium Balance:Excretion & Renal K+ Secretion
Potassium excretion
Renal K+ handling
Excretion of 90-95% dietary K+ intake
Only renal K+ excretion is tightlyregulated
Regulation of final urinary K+ contentoccurs in the collecting duct
Variable urinary K+ loss: 5-25 meq/dayto >400 meq/day
Renal K+ Secretion
K+ secretion in the collecting duct
Principal cells
Apical K+ channels
K+ Intake
Renal
K+ Secretion
Collecting Duct
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Renal Potassium Handling
Outer Stripe
Inner Stripe
O
uter
M
edulla
Inner
Medulla
Cortex CCDPCT
TALS3
OMCD
IMCD
DCT
tiDL
tiAL
K+
H2O
10-15%
65%25%
35%
35%
K+
K+
K+
K+
K+
K+
K+
K+
K+
H2OK+
K+
K+
K+
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Distal Renal K+ Secretion:The Principal Cell in the Collecting Duct
Major determinants of K+ secretion in the collecting duct
Potassium-secreting cell in the collecting duct is the principal cell
K+ gradient across the membrane is generated by the Na+-K+-ATPase
K+ permeability of the apical membrane is determined by K+ channels
Na+ reabsorption by Na+ channels results in a lumen-negative potentialdifferenceacross the apical membrane
These K
+
and Na
+
transport processes are stimulated by aldosterone
Apical Basolateral
Principal Cell
TubuleLumen
2 K+
3 Na+
Na+K+
ENaC Channel
ROMK Channel
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Distal Renal K+ Reabsorption:The Intercalated Cell in the Collecting Duct
2 K+
3 Na+
Apical Basolateral
K+
H+
H+
K+
Cl-
HCO3-
Cl-Intercalated Cell
Major determinants of K+
reabsorption in the collecting duct The potassium-absorbing cell in the collecting duct is the intercalated cell
The intercalated cell is also responsible for H+ secretion
Potassium reabsorption by the intercalated cell is an active process whichis mediated by the apical membrane H+,K+-ATPase
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Regulation of Renal Potassium Secretion
Peritubular Factors
Plasma potassium concentration
Aldosterone Extracellular pH
Luminal Factors
Distal tubular flow rate
Sodium delivery Anion composition
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Regulation of Potassium Secretion:Plasma K+ Concentration
Potassium intake potassium adaptation Urinary K+ secretion increases with a high K+ diet
Adaptive changes K+ secretion in the collecting duct principal cell Na+,K+-ATPase activity + Na+ and K+ channel transport area of basolateral membrane in principal cells K+ reabsorption by intercalated cells
Both increased plasma K+ and aldosterone are required for maximal
adaptation(Stanton BA, Giebisch G: Am J Physiol 243:F487-F493 (1982))
Plasma [K+] (meq/L)3 4 5 6 7 8
Urin
aryK+Secretion
High K Diet
Normal Diet
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Morphological Alterations in Potassium Adaptation
(Stanton BA: Am J Physiol 257:R989-R997 (1989))
Normal Diet
High-K+ Diet
Low-K+ Diet
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Aldosterone Effects on the Principal Cell
Regulation of K+
secretionbyprincipal cells in the collecting ductis the primary basis for K+homeostasis
Na+ reabsorption via Na+ channels(ENaC) results in a lumen-negative
transcellular potential difference Lumen-negative potential difference
favors K+ secretion via K+ channels(ROMK)
Aldosterone
Aldosterone stimulates K+ secretionby principal cells in the collectingduct
Aldosterone binds to an intracellularreceptor, which when activatedfunctions as a transcriptionalregulator synthesis ofaldosterone-induced proteins
K+
ROMK
3 Na+
2 K+(-)
Principal Cell
Na+
ENaC
AldoMR
Aldo
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Distal Renal K+ Secretion:Effects of Aldosterone on the Principal Cell
basolateral Na+,K+-ATPase activity K+ entry and Na+ gradient for apical Na+ reabsorption
apical membrane Na+ and K+ channels Na+ reabsorption via apical Na+ channels generates a lumen-negative
electrical potential difference across the apical membrane favoring K+secretion into the lumen of the collecting duct via K+ channels
Basal
Apical Basolateral
K+
Na+
Lumen
Na+K+
(-)
+ Aldosterone
Apical Basolateral
AldoR
R-Aldo
AIPs
(+)
Lumen
Na+Na+
(-)
K+K+
K+
K+
Na+
Na+
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Regulation of Potassium Secretion: Plasma pH
Extracellular pH
Changes in extracellular pHproduce reciprocal shiftsin H+ and
K+
between the extracellular fluidand intracellular fluid compartments
Acidemia decreasesintracellular[K+] in principal cells and decreasesK+ secretion
Alkalemia increasesintracellular
[K+] in principal cells and increasesK+ secretion
(Stanton BA, Giebisch G: Am J Physiol 242:F544-F551 (1982))
2
4
6
3 5 7
K
+excretionmeq/
Lfiltrate
Plasma [K+] meq/L
pH 7.41
pH 7.17
pH 7.57
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Regulation of Renal Potassium Secretion
Peritubular Factors
Plasma potassium concentration
Aldosterone Extracellular pH
Luminal Factors
Distal tubular flow rate
Sodium delivery Anion composition
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Regulation of Potassium Secretion:Distal Tubular Flow Rate
Distal flow rate
Increase in distal flow rate favors
K+ secretion
Enhances luminal K+ gradient
Increases distal Na+ delivery Na+ reabsorption lumen-negative potential difference
Response dependent on highK+ diet
( plasma [K+] + aldosterone) Flow-dependent K+ secretion
mediated by maxi-K Ca2+-activated) K+ channel
0.1
0.3
0.5
10 20 30
DistalK+secretio
n
Distal flow rate
High K
+
diet
Control K+ diet
Low K+ diet
Brenner BM. Brenner & Rectors The Kidney.Philadelphia: W.B. Saunders Co., 1996:391
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Regulation of Potassium Secretion:Na+ Delivery to the Distal Nephron
Increasing distal tubular Na+ delivery stimulates distal tubular Na+reabsorption resulting in the generation of a lumen-negative potentialdifference which stimulates K+ secretion
Increased distal flow is usually associated with increased distal Na+
delivery (e.g. intravascular volume expansion, diuretic administration)
Distal Flow Distal [Na+]
K+Secretion
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Effect of Luminal Anions on Potassium Secretion
Distal luminal anioncomposition
Substitution of another anion
for Cl-
(poorly reabsorbableanion) lumen-negativepotential difference favoring K+secretion
HCO3-
Acetoacetate
b-hydroxybutyrate Carbenicillin Hippurate
Na+
K+
Na+K+
HCO3-
HCO3-
HCO3-
(-)
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Transtubular Potassium Gradient
Transtubular potassiumgradient
Clinical index of K+ secretion inthe cortical collecting duct
TTKG = ratio of the
estimated urinary K+
concentration in the corticalcollecting duct to theplasma K+ concentration
CCDK is estimatedbycorrecting the UK for waterreabsorption in themedullary collecting duct
Potassium depletion:
TTKG < 2.5
Potassium loading:
TTKG > 10
TTKG = CCDK / PK
CCDK = UK x
CCDOsm= POsm
CCDK = UK x
CCDOsm
UOsm
POsm
UOsm
TTKG =UK / PK
UOsm/ POsm
CCDK
UKU
Osm
PK
CCDOsm
POsm
H2O
H2O
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Potassium Homeostasis
The regulation of potassium homeostasis can be divided into two
main processes:External Balance: The regulation of total body potassium contentthrough alterations in potassium intake (e.g. dietary) and excretion(e.g. renal, GI)
Internal Balance: The regulation of the distribution of potassiumbetween intracellular fluid (ICF) and extracellular fluid (ECF)compartments
Intracellular Fluid (ICF)
Extracellular Fluid (ECF)
InternalBalance
K+
K+
ExternalBalance
Intake
Excretion
3.5-5.0 meq/L
120-150 meq/L
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Potassium Homeostasis: Internal Balance
Internal Balance
Regulation of K+ distribution between the intracellular and extracellularcompartments is responsible for the moment-to-momentcontrol of theextracellular potassium concentration
Internal balance is the net result of two cellular processes:
(1) Cellular potassium uptake
Mediated by the Na+,K+-ATPase
(2) Cellular potassium secretionMediated by K+ channels which determine the K+ permeability of
the cell membrane
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Internal Balance: Physiologic Factors
Internal Balance
Insulin
Catecholamines
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Potassium Homeostasis: Insulin
Insulin stimulates the cellular uptake of potassium via an increase
in Na+,K+-ATPase activity
Insulin and potassium are components of a regulatory loop
splanchnic K+ concentration stimulates pancreatic insulin secretion Insulin stimulates K+ uptake by the liver and muscle returning serum
[K+] to normal
Pancreas
Liver
Muscle
[K+]
[K+]
Insulin
K+
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Potassium Homeostasis: Catecholamines
Catecholamines stimulate the cellular uptake of potassium viab2-adrenergic receptors by increasing Na+,K+-ATPase activity(Williams et al: N Engl J Med 312:823-827 (1985))
Exercise Recovery
10 20 30 40
Minutes
0
2.5
2.0
1.5
1.0
0.5
ChangeinPla
smaPotassium
(mmol/L)
Control
Propranolol
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Internal Balance: Pathophysiologic Factors
Internal Balance
Acid-Base Disturbances
Plasma Tonicity
Cell Lysis & Cell Proliferation
P i H i
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Potassium HomeostasisInternal Balance: Pathophysiologic Factors I
Acid-Base Disturbances
Changes in extracellular pH produce reciprocal shifts in H+ and K+between extracellular and intracellular fluid compartments
Metabolic acid-base disturbances have a greater effect thanrespiratory disturbances
Metabolic acidoses due to organic acids (ketoacidosis, lacticacidosis) have smallereffects than do acidoses due to mineralacids
K+
H+H+
K+ K+
H+H+
K+
Acidemia Alkalemia
P t i H t i
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Potassium HomeostasisInternal Balance: Pathophysiologic Factors II
Plasma Tonicity
Increases in plasma tonicity fluid shifts from the intracellular to theextracellular compartments and K+ exits the intracellular compartmentalong with water via solvent drag
H2OK+
Increased Plasma Tonicity
P t i H t i
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Potassium HomeostasisInternal Balance: Pathophysiologic Factors III
Cell Lysis & Cell Proliferation
With cell lysis intracellular K+ is released into the extracellular space
yielding an increase in extracellular [K+]
With rapid cellular proliferation, K+ is rapidly taken up by proliferatingcells causing extracellular potassium to fall
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HyperkalemiaPlasma [K+] > 5.0
Hyperkalemia may be the result of disturbancesin external balance (total body K+ excess) or ininternal balance (shift of K+ from intracellular to
extracellular compartments)
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Hyperkalemia: Disorders of External Balance
ExcessiveK+ intake
Distal tubularflow
Mineralocorticoid
deficiency
Acute & chronicrenal failure
Distal tubulardysfunction
Renal K+ excretion
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Hyperkalemia: Disorders of External Balance
Excessive Potassium IntakeOral or Parenteral Intake
Decreased Renal Excretion
Acute and Chronic Renal Failure
Decreased Distal Tubular Flow Volume depletion Decreased effective arterial blood volume (CHF, cirrhosis) Drugs altering glomerular hemodynamics with a decrease in GFR
(NSAIDs, ACE inhibitors, ARBs)
Mineralocorticoid Deficiency Combined glucocorticoid and mineralocorticoid (adrenal insufficiency) Hyporeninemic hypoaldosteronism (diabetes mellitus)
Drug-induced (ACE inhibitors, ARBs)
Distal Tubular Dysfunction Disorders causing impaired renal tubular function with
hyporesponsiveness to aldosterone (interstitial nephritis) Potassium-sparing diuretics (amiloride, triamterene, spironolactone)
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Hyperkalemia: Disorders of Internal Balance
Insulin deficiency
b2-Adrenergic blockade Hypertonicity
Acidemia
Cell lysis
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Clinical Manifestations of Hyperkalemia
Clinical manifestations result primarily from the depolarization ofresting cell membrane potential in myocytes and neurons
Prolonged depolarization decreases membrane Na+ permeability throughthe inactivation of voltage-sensitive Na+ channels producing a reduction
in membrane excitability
Cardiac toxicity
EKG changes
Cardiac conduction defects
Arrhythmias
Neuromuscular changes
Ascending weakness, ileus
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EKG Manifestations of Hyperkalemia
Wide QRS ComplexShortened QT IntervalProlonged PR Interval
Further Widening of QRS ComplexAbsent P-Wave
Sine-Wave Morphology(e.g. Ventricular Tachycardia)
Peaked T
-
wave
Normal
IncreasingSe
rumK
+
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Medical Treatment of Hyperkalemia
Membrane Stabilization
IV calcium
Internal Redistribution IV insulin (+ glucose) b-adrenergic agonist (albuterol inhaled)
Enhanced Elimination
Kayexalate (sodium polystyrene sulfonate) ion exchange resin Loop diuretic Hemodialysis
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HypokalemiaPlasma [K+] < 3.5
Hypokalemia may also result from disturbancesin external balance (total body K+ deficiency) orinternal balance (transmembrane K+ shifts)
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Hypokalemia: Disorders of External Balance
Inadequate
dietary intake
Increased
extrarenalK+ losses
Increasedrenal K+ losses+ Hypertension
Increased
renal K+ losses- Hypertension
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Hypokalemia: Disorders of External Balance
Inadequate K+ Intake
Malnutrition
Extrarenal Losses
Gastrointestinal losses Diarrhea
Enteric fistulas
Cutaneous losses Burns
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Hypokalemia: Disorders of External Balance
Disorders Associated with Renal Potassium Losses
Hypertensive Disorders
Hyperreninemia
Renin excess (renal artery stenosis, renin-secreting tumor)
Primary hyperaldosteronism (Conns Syndrome)
Mineralocorticoid excess (adrenal hyperplasia, tumor)
Cushings syndrome
Glucocorticoid excess (exogenous, pituitary, adrenal)
Congenital adrenal hyperplasia
Enzymatic defects in cortisol biosynthesis (excessaldosterone precursors)
Hypokalemia:
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Hypokalemia:Disorders of External Balance
Disorders Associated with Renal Potassium Losses
Normotensive Disorders
Diuretics
Osmotic diuresis
Glucosuria
Renal tubular acidoses
Prolonged vomiting, nasogastric drainage
Ureteral diversion
Ureteroileostomy, ureterosigmoidostomy
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Hypokalemia: Disorders of Internal Balance
Insulin excess
Catecholamine excess
Myocardial ischemia/infarction Delirium tremens Pharmacologic agents
Alkalemia
Cell proliferation
Rapidly proliferating leukemia or lymphoma
Cli i l M if i f H k l i
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Clinical Manifestations of Hypokalemia
Cardiac
EKG changes
Arrhythmias
Smooth muscle
Hypertension
Ileus
Skeletal muscle
Weakness
Rhabdomyolysis
Metabolic
Glucose intolerance
Growth retardation
Renal
Increased renal ammoniagenesis
Nephrogenic diabetes insipidus
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EKG Manifestations of Hypokalemia
Prominent U-wave
Flat T-wave
Depressed ST-segment
Normal
DecreasingSerumK
+
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Treatment of Hypokalemia
Potassium Replacement
Oral or IV
Potassium-sparing diuretics
ENaC sodium channel inhibitors
Amiloride, triamterene
Mineralocorticoid antagonists
Spironolactone