Potassium Homeostasis & Disorders

Kevin Ho, M.D. Assistant Professor of Medicine Renal-Electrolyte Division University of Pittsburgh School of Medicine

Potassium Distribution in the Body

Intracellular [K+] 120-150 meq/L 2 K+ K+ Em = -90mV Extracellular [K+] 3.5-5.0 meq/L

Na+

Potassium distribution in body fluid compartments

Total body K+ stores: 50-55 meq/kg body 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

3 Na+

Resting membrane potential

Nernst equation EK = RT ln [K]o zF [K]i Steady-state equation Vm = RT ln r[K]o + b[Na]o zF r[K]i + b[Na]I r = 3:2 Na/K active transport b = 0.01 relative permeability of Na+ to K+

Large cellular K+ (and Na+) concentration gradients are maintained by the Na,K-ATPase

Potassium Gradient and Cellular Functions

Cellular functions
Primary determinant of cell resting membrane potential Substrate for membrane transport processes Determinant of cell volume

Na+

Intracellular [K+] 120-150 meq/L

Changes in transmembrane potassium gradient

Alter cell membrane resting potential Alter neuromuscular excitability Cardiac conduction & cardiac pacemaker rhythmicity Neuronal function Vascular smooth muscle tone Skeletal muscle function Impair cell membrane transport processes
K+

+ K
Em = -90mV

2 K+

3 Na+

K+

Extracellular [K+] 3.5-5.0 meq/L

Extracellular Potassium Concentration and Cell Membrane Potential

+30 0 -30 mV -60 -90 -120 Normal

Membrane potential ln [K]o [K]i

Depolarization Hyperpolarization
Threshold Resting

Hypokalemia

Hyperkalemia

Hypokalemia hyperpolarizes excitable tissues Hyperkalemia depolarizes excitable tissues

Potassium Homeostasis
The regulation of potassium homeostasis can be divided into two main processes:
External Balance: The regulation of total body potassium content through alterations in potassium intake (e.g. dietary) and excretion (e.g. renal, GI) Internal Balance: The regulation of the distribution of potassium between intracellular fluid (ICF) and extracellular fluid (ECF) compartments

Intake External Balance K+

3.5-5.0 meq/L Extracellular Fluid (ECF) 120-150 meq/L

Internal Balance

+ K
Intracellular Fluid (ICF)

Excretion

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

Renal potassium reabsorption

Proximal tubule Majority 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

K+ Intake

Renal K+ Reabsorption Proximal Tubule

Thick Ascending Limb

Collecting Duct

Renal Potassium Handling

Cortex PCT
K+ H2O

DCT 10-15%

CCD

65% Outer Medulla

K+ H2O

K+

K+

S3 35% tiDL

TAL
K+ K+

25%
K+ K+ K+ K+ K+

Outer Stripe OMCD Inner Stripe

35%
K+

tiAL
K+

IMCD

Inner Medulla

K+

External Potassium Balance: Excretion & Renal K+ Secretion

Potassium excretion
Renal K+ handling Excretion of 90-95% dietary K+ intake Only renal K+ excretion is tightly regulated Regulation of final urinary K+ content occurs in the collecting duct Variable urinary K+ loss: 5-25 meq/day to >400 meq/day

K+ Intake

Renal K+ Secretion
K+ secretion in the collecting duct Principal cells Apical K+ channels

Renal K+ Secretion

Collecting Duct

Renal Potassium Handling

Cortex PCT
K+ H2O

DCT 10-15%

CCD

65% Outer Medulla

K+ H2O

K+

K+

S3 35% tiDL

TAL
K+ K+

25%
K+ K+ K+ K+ K+

Outer Stripe OMCD Inner Stripe

35%
K+

tiAL
K+

IMCD

Inner Medulla

K+

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 potential difference across the apical membrane These K+ and Na+ transport processes are stimulated by aldosterone

ENaC Channel

Na+

2 K+

Tubule Lumen
ROMK Channel
Apical

3 Na+

K+

Principal Cell
Basolateral

Distal Renal K+ Reabsorption: The Intercalated Cell in the Collecting Duct

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 which is mediated by the apical membrane H+,K+-ATPase

Apical

Basolateral

H+

K+

K+

3 Na+

H+

K+ HCO3Cl-

Intercalated Cell

Cl-

Regulation of Renal Potassium Secretion

Peritubular Factors
Plasma potassium concentration Aldosterone Extracellular pH

Luminal Factors
Distal tubular flow rate Sodium delivery Anion composition

Regulation of Potassium Secretion: Plasma K+ Concentration

Urinary K+ Secretion

High K Diet

Normal Diet

5 6 7 +] (meq/L) Plasma [K

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))

Morphological Alterations in Potassium Adaptation

Low-K+ Diet

Normal Diet
High-K+ Diet

(Stanton BA: Am J Physiol 257:R989-R997 (1989))

Aldosterone Effects on the Principal Cell

Regulation of K+ secretion by principal cells in the collecting duct is 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)

(-)
Na+ ENaC K+ ROMK

3 Na+
Aldo MR

2 K+
Aldo

Aldosterone
Aldosterone stimulates K+ secretion by principal cells in the collecting duct Aldosterone binds to an intracellular receptor, which when activated functions as a transcriptional regulator synthesis of aldosterone-induced proteins

Principal Cell

Distal Renal K+ Secretion: Effects of Aldosterone on the Principal Cell

Apical Basolateral Apical Basolateral

(-)
Na+ K+
Na+

(-)
Na+ Na+ K+ K+
Lumen

R- Aldo

R Aldo

K+

(+)
Na+

K+

K+
Lumen

Na+
AIPs

Basal
basolateral Na+,K+-ATPase activity

+ Aldosterone

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

Regulation of Potassium Secretion: Plasma pH

Extracellular pH
Changes in extracellular pH produce reciprocal shifts in H+ and K+ between the extracellular fluid and intracellular fluid compartments
Acidemia decreases intracellular [K+] in principal cells and decreases K+ secretion
Alkalemia increases intracellular [K+] in principal cells and increases K+ secretion K+ excretion meq/L filtrate
6

pH 7.57

pH 7.41
4

pH 7.17

Plasma

[K+]

meq/L

(Stanton BA, Giebisch G: Am J Physiol 242:F544-F551 (1982))

Regulation of Renal Potassium Secretion

Peritubular Factors
Plasma potassium concentration Aldosterone Extracellular pH

Luminal Factors
Distal tubular flow rate Sodium delivery Anion composition

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 lumennegative potential difference Response dependent on high K+ diet ( plasma [K+] + aldosterone) Flow-dependent K+ secretion mediated by maxi-K Ca2+activated) K+ channel

Distal K+ secretion

0.5 0.3

High K+ diet

Control K+ diet
0.1 10 20

Low K+ diet
30

Distal flow rate

Brenner BM. Brenner & Rectors The Kidney. Philadelphia: W.B. Saunders Co., 1996:391

Regulation of Potassium Secretion: Na+ Delivery to the Distal Nephron

K+ Secretion

Distal Flow

Distal [Na+]

Increasing distal tubular Na+ delivery stimulates distal tubular Na+ reabsorption resulting in the generation of a lumen-negative potential difference which stimulates K+ secretion Increased distal flow is usually associated with increased distal Na+ delivery (e.g. intravascular volume expansion, diuretic administration)

Effect of Luminal Anions on Potassium Secretion

Distal luminal anion composition

Substitution of another anion for Cl- (poorly reabsorbable anion) lumen-negative potential difference favoring K+ secretion HCO3 Acetoacetate b-hydroxybutyrate Carbenicillin Hippurate

HCO3-

Na+ HCO3K+

Na+

(-)

K+

HCO3-

Transtubular Potassium Gradient

Transtubular potassium gradient
TTKG = CCDK / PK CCDK = UK x CCDOsm = POsm CCDK = UK x POsm UOsm UOsm UK H2O CCDOsm UOsm

CCDK CCDOsm
PK POsm

Clinical index of K+ secretion in the cortical collecting duct TTKG = ratio of the estimated urinary K+ concentration in the cortical collecting duct to the plasma K+ concentration CCDK is estimated by correcting the UK for water reabsorption in the medullary collecting duct Potassium depletion: TTKG < 2.5 Potassium loading: TTKG > 10

H2O

TTKG =

UK / PK
UOsm / POsm

Potassium Homeostasis
The regulation of potassium homeostasis can be divided into two main processes:
External Balance: The regulation of total body potassium content through alterations in potassium intake (e.g. dietary) and excretion (e.g. renal, GI) Internal Balance: The regulation of the distribution of potassium between intracellular fluid (ICF) and extracellular fluid (ECF) compartments

Intake External Balance K+

3.5-5.0 meq/L Extracellular Fluid (ECF) 120-150 meq/L

Internal Balance

+ K
Intracellular Fluid (ICF)

Excretion

Potassium Homeostasis: Internal Balance

Internal Balance
Regulation of K+ distribution between the intracellular and extracellular compartments is responsible for the moment-to-moment control of the extracellular 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 secretion Mediated by K+ channels which determine the K+ permeability of the cell membrane

Internal Balance: Physiologic Factors

Internal Balance
Insulin Catecholamines

Potassium Homeostasis: Insulin

[K+]

Pancreas

Insulin
Liver

[K+]
Muscle

K+

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

Potassium Homeostasis: Catecholamines

2.5

Exercise

Recovery

Change in Plasma Potassium (mmol/L)

2.0 1.5 1.0 0.5 0

Propranolol Control

10

20

30

40

Minutes

Catecholamines stimulate the cellular uptake of potassium via b2-adrenergic receptors by increasing Na+,K+-ATPase activity
(Williams et al: N Engl J Med 312:823-827 (1985))

Internal Balance: Pathophysiologic Factors

Internal Balance
Acid-Base Disturbances

Plasma Tonicity
Cell Lysis & Cell Proliferation

Potassium Homeostasis Internal 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 than respiratory disturbances Metabolic acidoses due to organic acids (ketoacidosis, lactic acidosis) have smaller effects than do acidoses due to mineral acids

H+
K+

H+ K+

H+

H+

K+

K+

Acidemia

Alkalemia

Potassium Homeostasis Internal Balance: Pathophysiologic Factors II

Plasma Tonicity
Increases in plasma tonicity fluid shifts from the intracellular to the extracellular compartments and K+ exits the intracellular compartment along with water via solvent drag

Increased Plasma Tonicity

H2O K+

Potassium Homeostasis Internal 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 proliferating cells causing extracellular potassium to fall

Hyperkalemia
Plasma [K+] > 5.0
Hyperkalemia may be the result of disturbances in external balance (total body K+ excess) or in internal balance (shift of K+ from intracellular to extracellular compartments)

Hyperkalemia: Disorders of External Balance

Renal K+ excretion
Excessive K+ intake
Acute & chronic renal failure

Distal tubular flow

Distal tubular dysfunction

Mineralocorticoid deficiency

Hyperkalemia: Disorders of External Balance

Excessive Potassium Intake
Oral 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)

Hyperkalemia: Disorders of Internal Balance

Insulin deficiency b2-Adrenergic blockade Hypertonicity Acidemia Cell lysis

Clinical Manifestations of Hyperkalemia

Clinical manifestations result primarily from the depolarization of resting cell membrane potential in myocytes and neurons
Prolonged depolarization decreases membrane Na+ permeability through the 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

EKG Manifestations of Hyperkalemia

Normal
+ Increasing Serum K

Peaked T-wave Wide QRS Complex Shortened QT Interval Prolonged PR Interval Further Widening of QRS Complex Absent P-Wave Sine-Wave Morphology (e.g. Ventricular Tachycardia)

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

Hypokalemia
Plasma [K+] < 3.5
Hypokalemia may also result from disturbances in external balance (total body K+ deficiency) or internal balance (transmembrane K+ shifts)

Hypokalemia: Disorders of External Balance

Inadequate dietary intake

Increased extrarenal K+ losses

Increased renal K+ losses + Hypertension

Increased renal K+ losses - Hypertension

Hypokalemia: Disorders of External Balance

Inadequate K+ Intake
Malnutrition

Extrarenal Losses
Gastrointestinal losses
Diarrhea Enteric fistulas

Cutaneous losses
Burns

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 (excess aldosterone precursors)

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

Hypokalemia: Disorders of Internal Balance

Insulin excess
Catecholamine excess
Myocardial ischemia/infarction Delirium tremens Pharmacologic agents

Alkalemia Cell proliferation

Rapidly proliferating leukemia or lymphoma

Clinical Manifestations of Hypokalemia

Cardiac
EKG changes Arrhythmias

Metabolic
Glucose intolerance Growth retardation

Smooth muscle
Hypertension Ileus

Renal
Increased renal ammoniagenesis Nephrogenic diabetes insipidus

Skeletal muscle
Weakness Rhabdomyolysis

EKG Manifestations of Hypokalemia

Normal Decreasing Serum K+

Flat T-wave Prominent U-wave

Depressed ST-segment

Treatment of Hypokalemia

Potassium Replacement
Oral or IV

Potassium-sparing diuretics
ENaC sodium channel inhibitors Amiloride, triamterene Mineralocorticoid antagonists Spironolactone