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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