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
