fereshtehsaddadi

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K

• Hyper Hypokalemia

F.Saddadi MD Nephrologist Associate Professor
IUMS 2019
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BRIEF REVIEW OF POTASSIUM PHYSIOLOGY

• Total body potassium stores
• 3000 meq or more (50 to 75 meq/kg body weight)
• intracellular 98 percent of body potassium \140
  meq/L
• extracellular fluid 4 to 5 meq/L

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BRIEF REVIEW OF POTASSIUM PHYSIOLOGY

• HyperkalemiaK level gt 5.5 mEq/L
• 10 of hospitalized patients
• severe hyperkalemia 1
• increased risk of mortality

• Hypokalemia
• K level lt 3.5 mEq/L
• Mild 3.0 3.5 mEq/L asymptomatic
• lt 3.0 mEq/L symptomatic
• Clinical manifestations of hypokalemia vary
  greatly between individual patients

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Internal Balance of K

• The Regulation of K Distribution between the
  Intracellular and Extracellular space
• changes in extracellular K concentration are
  initially buffered by movement of K into or out
  of skeletal muscle. (Na-K ATPase pump)
• The kidney is primarily responsible for
  maintaining total body K content by matching K
  intake with K excretion.
• Adjustments in renal K excretion occur over
  several hours

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Ingestion of a potassium load

• leads
• initially to the uptake of most of the excess
  potassium by cells in muscle and the liver,
• a process that is facilitated by
• Insulin
• the beta-2-adrenergic receptors
• Increase the Activity of Na-K-ATPase Pumps in the
  cell membrane .

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 Hyperkalemia
Hypokalemia

• decreased intake
• increased translocation into the cells
• increased losses in
• urine
• gastrointestinal tract
• sweat

1. increased potassium release from the cells
2. reduced urinary potassium excretion

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Main Factors modifying transcellular K
distribution

• Insulin
• Plasma Osmolality
• Catecholamines
• Acid- base status

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Main Factors modifying transcellular K
distribution

• Insulin stimulates cellular uptake of K by
  activating NaKATPase
• Beta 2 adrenergic activity
• Alpha adrenergic antagonists
• (decreasing plasma K )

• Hyperosmolality
• ( Mannitol infusion / hyperglycemia in DM )
• increase plasma K

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Insulin deficiency, hyperglycemia, hyperosmolality
Hyperkalemia

• in uncontrolled Diabetes Mellitus.
• combination of
• insulin deficiency (either impaired secretion or
  insulin resistance)
• and hyperosmolality induced by hyperglycemia
• frequently leads to hyperkalemia

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The increase in plasma Osmolality
Hyperkalemia

• results in osmotic water movement from the cells
  into the extracellular fluid.
• This is accompanied by K movement out of the
  cells by two proposed mechanisms

1?The loss of cell water Raises the cell
potassium concentration, thereby creating a
favorable gradient for passive potassium exit
through potassium channels in the cell membrane.
2?The friction forces between solvent (water) and
solute can result in potassium being carried
along with water through the water pores in the
cell membrane. This phenomenon of solvent drag is
independent of the electrochemical gradient for
potassium diffusion.
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Hyperkalemia
Insulin deficiency
Hyperosmolality

• Fasting
• an appropriate Reduction in Insulin levels that
  can lead to an increase in plasma potassium.
• This may be a particular problem in
• dialysis patients.
• preoperative fasting

• hypernatremia
• sucrose contained in intravenous immune globulin
• radiocontrast media
• and the administration of hypertonic mannitol
• Most of the reported patients had renal failure

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Increased availability of Insulin
Hypokalemia

• Endogenous insulin released in response to a
• Carbohydrate load in patients with
• refeeding syndrome
• intravenous k in a dextrose in water solution.

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Main Factors modifying transcellular K
distribution

• Insulin
• Plasma Osmolality
• Catecholamines
• Acid- base status

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Elevated beta-adrenergic activity
Hypokalemia

•  Endogenous catecholamines, acting via beta-2
  adrenergic receptors can promote K entry into
  cells by Increasing the activities of the
• Na-K-ATPase pump
• Release of insulin

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Beta blockers
Hyperkalemia

• nonselective beta blockers (such as propranolol
  and labetalol).
• beta-1-selective blockers such as atenolol have
  little effect on serum potassium since beta-2
  receptor activity remains intact .

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Hypokalemic Periodic Paralysis
Hypokalemia

• a rare neuromuscular disorder
• characterized by
• potentially fatal episodes of muscle weakness
• paralysis
• that can affect the respiratory muscles.
• hereditary, with an autosomal dominant
  inheritance
• acquired in hyperthyroidism.

• sudden movement of potassium into the cells
• can reduce the serum potassium to as low as 1.5
  to 2.5 mEq/L,
• are often precipitated by Rest
• after
• exercise
• stress
• a carbohydrate meal.

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Hyperkalemic Periodic Paralysis
Hyperkalemia
a point mutation in the gene for the alpha
subunit of the skeletal muscle cell sodium
channel.

•   an autosomal dominant disorder
• episodes of weakness or paralysis are usually
  precipitated by
• cold exposure
• rest after exercise
• fasting
• the ingestion of small amounts of potassium.

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translocation of potassium from the cells into
the extracellular fluid
Hyperkalemia

• Digitalis overdose, due to dose-dependent
  inhibition of the Na-K-ATPase pump.
• Red cell transfusion leakage of potassium out of
  the red cells during storage. (in infants and
  with massive transfusion).
• drugs that Activate ATP-dependent Potassium
  Channels in cell membranes, such as
• calcineurin inhibitors (eg, cyclosporine and
  tacrolimus),
• diazoxide
• minoxidil
• anesthetics (eg, isoflurane)

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Administration of succinylcholine
Hyperkalemia

• to patients with
• burns,
• extensive trauma,
• prolonged immobilization,
• chronic infection,
• or neuromuscular disease .
• Acetylcholine receptors are normally concentrated
  within the neuromuscular junction, and the efflux
  of intracellular potassium caused by
  depolarization of these receptors is confined to
  this space.
• Succinylcholine cause upregulation and
  widespread distribution of acetylcholine
  receptors throughout the entire muscle membrane
  .

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arginine hydrochloride
Hyperkalemia

• ?is metabolized in part to hydrochloric acid and
  has been used to treat refractory metabolic
  alkalosis.
• The entry of cationic arginine into the cells
  presumably obligates potassium exit to maintain
  electroneutrality.
• The drug, aminocaproic acid, can cause
  hyperkalemia by the same mechanism since it is
  structurally similar to arginine .

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Main Factors modifying transcellular K
distribution

• Insulin
• Plasma Osmolality
• Catecholamines
• Acid- base status

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Acid- base statustranscellular K distribution
Hyperkalemia
Hypokalemia

• Metabolic acidosis diminishes K uptake by cells.
  

Metabolic Alkalosis promotes K uptake by cells

•   buffering of excess hydrogen ions in the cells
• leads to potassium movement into the
  extracellular fluid,
• a transcellular shift

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Absent effect in lactic acidosis or ketoacidosis
Hyperkalemia

• the development of hyperkalemia in patients with
  diabetic ketoacidosis is primarily due to
• insulin deficiency
• hyperosmolality,
• not acidemia

• hyperkalemia due to an acidosis-induced shift of
  potassium from the cells into the extracellular
  fluid
• does Not occur in the organic acidosis lactic
  acidosis and ketoacidosis
• ability of the organic anion and the hydrogen ion
  to enter into the cell via a sodium-organic anion
  cotransporter.

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transcellular shift Increased Tissue Catabolism
Hyperkalemia

• particularly if renal failure is also present.
• include
• trauma (including non crush trauma),
• the tumor lysis syndrome the administration of
  cytotoxic or radiation therapy to patients with
  lymphoma or leukemia
• severe accidental hypothermia

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Homeostatic mechanisms

• The kidney
• plays a dominant role in potassium homeostasis

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Increase in plasma K

• stimulates
• the secretion of Aldosterone
• Directly enhances sodium reabsorption
• Indirectly enhances potassium secretion
• in the Principal cells.

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Aldosterone

• The increase in sodium reabsorption is mediated
  primarily by an increase in the number of open
  sodium channels
• in the luminal membrane of the principal cells.
• makes the lumen more electronegative,
• enhancing the electrical gradient that
• promotes the secretion of potassium from the
  cells into the tubular fluid via potassium
  channels in the luminal membrane .

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Aldosterone

• Increases the number and activity of
• basolateral Na-K-ATPase pumps in Principal
  cells,
• sodium reabsorption and potassium secretion.
• The net effect is that most of the potassium load
  is excreted within six to eight hours.

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Potassium adaptation?

• potassium excretion is enhanced if potassium
  intake is increased
• a fatal potassium load to be tolerated.
• called potassium adaptation, is mostly due to
  the ability to More Rapidly Excrete Potassium in
  the Urine .

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Potassium adaptation? mediated by three changes

• An aldosterone-independent Increase in the
  Density and Activity of apical secretory
  Potassium Channels.?Increased Na-K-ATPase
  Activity, which enhances potassium uptake into
  the cell across the basolateral (peritubular)
  membrane, ?Increased Activity of apical
  epithelial sodium channels (ENaC), through both
  aldosterone-independent and aldosterone-dependent
  mechanisms.
• increases the electrogenic driving force for
  apical potassium excretion.

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• alpha-intercalated cells
• of the outer medullary CD Reabsorption of
  filtered K
• in K-deficient states.
• HK-ATPase( luminal )

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Hyperkalemia
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Hyperkalemia

• due to Reduced Urinary Potassium secretion

Urine K lt40 meq/d
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REDUCED URINARY POTASSIUM EXCRETION
Hyperkalemia
Urine K lt40 meq/d

• The four major causes?Reduced aldosterone
  secretion?Reduced response to aldosterone
  (aldosterone resistance)?Reduced distal sodium
  and water delivery (Unalt25mmol/l)?Acute and
  chronic kidney disease in which one or more of
  the above factors are present

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Reduced Aldosterone Secretion
Hyperkalemia

•  Hyporeninemic Hypoaldosteronism type 4 RTA
• Drugs
• - Angiotensin inhibitors
• -Nonsteroidal anti-inflammatory drugs
• -Calcineurin inhibitors
• -Heparin

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Potassium-sparing diuretics
Hyperkalemia

• Directly Block the Sodium channels
• in the apical (luminal) membrane of the
  principal cells in the collecting tubule
• (Amiloride and Triamterene)

•  Aldosterone Antagonists that compete with
  aldosterone for receptor sites (Spironolactone
  and Eplerenone),

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Hyperkalemia

• trimethoprim (TMP)
• Pentamidine
• block ENaC
• risk factors for TMP-associated hyperkalemia
  include
• the administered dose
• renal insufficiency,
• hyporeninemic hypoaldosteronism.

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Voltage-dependent renal tubular acidosis
Hyperkalemia

• with distal RTA,
• in the principal cells an impairment in sodium
  reabsorption
• Reduce both Hydrogen and Potassium secretion,
• the development of metabolic acidosis and
  hyperkalemia.
• has been associated with
• urinary tract obstruction
• lupus nephritis
• sickle cell disease
• renal amyloidosis

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Pseudohypoaldosteronism type 1
Hyperkalemia

• Aldosterone Resistance.
• The Autosomal Recessive form affects the
  collecting tubule sodium channel (ENaC)
• the Autosomal Dominant form in most patients
  affects the Mineralocorticoid Receptor

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Acute kidney disease
Hyperkalemia
chronic kidney disease

1. oliguric
2. high-potassium diet
3. increased tissue breakdown
4. reduced aldosterone secretion or responsiveness
5. fasting in dialysis patients which may both
   lower insulin levels and cause resistance to
   beta-adrenergic stimulation of potassium uptake

•   in oliguric patients
• Rhabdomyolysis
• tumor lysis syndrome

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chronic kidney disease
Hyperkalemia

• the ability to excrete potassium at near-normal
  levels without the development of hyperkalemia
  generally persists as long as both
• the secretion of and responsiveness to
  aldosterone are intact and
• distal delivery of sodium and water are
  maintained

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chronic kidney disease
Hyperkalemia

1. oliguric
2. high-potassium diet
3. increased tissue breakdown,
4. reduced aldosterone secretion or responsiveness,
5. fasting in dialysis patients which may both
   lower insulin levels and cause resistance to
   beta-adrenergic stimulation of potassium uptake

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chronic kidney disease
Hyperkalemia

• Impaired cell uptake of potassium.
• Diminished Na-K-ATPase activity
• retained uremic toxins

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Hyperkalemia

• Reduced distal sodium and water delivery

Urine K lt40 meq/d
U Nalt25mmol/l)
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Effective arterial blood volume depletion
Hyperkalemia

•  The effective arterial blood volume
• true volume depletion
• (eg, gastrointestinal or renal losses)
• heart failure
• cirrhosis

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Hyperkalemia
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Hyperkalemia
Inadequate excretion
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Hyperkalemia
Inadequate excretion
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Clinical Features

• Medical Emergency
• Cardiac arrhythmias
• sinus bradycardia
• sinus arrest
• ventricular tachycardia
• ventricular fibrillation
• asystole

• tall peaked T waves (5.56.5 mM)
• loss of P waves (6.57.5 mM)
• widened QRS complex (78 mM)

• Ascending paralysis
• Diaphragmatic paralysis
• Respiratory failure.

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Diagnostic Approach

• Initial laboratory tests
• BUN
• creatinine
• complete blood count
• urinary pH

• History
• physical examination
• medications
• diet and dietary supplement,
• risk factors for kidney failure
• reduction in urine output
• blood pressure
• volume status.
• (urine Na lt20 mM )

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INCREASED POTASSIUM RELEASE FROM CELLS

• Pseudohyperkalemia 
• Mechanical trauma during venipuncture
• fist clenching
• prolonged length of storage
• thrombocytosis
• acute myeloid leukemia
• white blood cell counts (gt120,000/microL)
  chronic lymphocytic leukemia -falsely elevated
  potassium concentrations due to cell fragility.
• asymptomatic patient who has no
  electrocardiographic manifestations of
  hyperkalemia.

Ascending paralysis Diaphragmatic paralysis and
respiratory failure.
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• calculation of the TTKG
• gt8 hyperkalemia. lt5
• Trans Tubular K Gradiant

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TTKG
gt8 hyperkalemia. lt5
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Treatment of Hyper-K

• 1- antagonise the cardiac effects of increased K
• 2- promote intracellular transfer of K
• 3- remove K from the body
• 4- reduce K intake

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Antagonise the cardiac effects Calcium

• The effect of calcium
  begins within
• minutes
• short-lived
• (30 to 60 minutes)
• 1000 mg
• (10 mL of a 10
• infused over
• 2-3minutes
• with constant cardiac monitoring.

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TreatmentDrive Extracellular Potassium Into the
Cells

• Insulin and Glucose
• 1 amp D50 with 5-10 units of regular insulin IV
• Effects seen in 30 min with peak in 60 min
• Duration several hours

• Sodium Bicarbonate (NaHCO3)
• Only works if ongoing severe metabolic acidosis
• HCO3 lt 20 mEq/L
• Onset few minutes but effects are not long lasting

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?-adrenergic agonists

• ? directly stimulate the Na/K ATPase
• ? IV / nebuliser
• ? onset, efficacy, duration of action are
  similar additive to those of insulin dextrose
• ? potential to induce tachyarrhythmias
  cardiac instability
• ? their use is not
  recommended

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Potassium Removal

• ?Diuretics
• ?Cation exchange resin
• ?Dialysis

• Diuretics
• Loop
• Thiazide
• increase potassium loss in the urine

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Cation Exchange resin

• Removing K from the body
• 1- Cation exchange resins
• ? Ca Na polystyrene sulphonate
• ?Oral 15 gr x3 to x4 /day
• ?Rectal suspension of 30 gr resin / 100 mL
  methylcellulose 100 mL water / retained for 9
  hrs.
• ?Almost co-prescribe osmotic laxatives
  lactulose 10-20 mL x3/day
• ?1 mEq of K is excreted for each gr of resin
• ?onset of action 30-60 min rectally, 2-4 hr
  orally
• ?duration of action 4-6 hr
• ?danger of ttt
• a- constipation
• b- hyperCa
• c- salt/water retention
• d- hypo-Mg

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Novel intestinal k binder

• Lack intestinal toxicities
• Patiromer non absorbed polymer
• Zs-9 inorganic no absorbable crystalline
  compound

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Hypokalemia
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Hypokalemia

• due to increased urinary potassium secretion
• Urine K gt15 mmol/day

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Aldosterone-producing Adrenal Adenoma
Hypokalemia

• Hypertensive
• Hypokalemia
• differential diagnosis
• Diuretic therapy in a patient with underlying
  hypertension.
• Renovascular disease, increased secretion of
  Renin leads to enhanced Aldosterone release.

• Screening in
• hypokalemic and/or hypertensive patients,
• testing of
• plasma renin activity (PRA)
• Aldosterone
• AldosteronePRA ratio gt50 primary
  hyperaldosteronism.

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Hypokalemia
Mineralocorticoid-Like Activity Apparent
Mineralocorticoid Excess

• The cortisol has affinity for the
  mineralocorticoid receptor (MLR) equal to that of
  aldosterone,
• with resultant Mineralocorticoid-Like Activity.
• cells in the aldosterone-sensitive distal nephron
  are protected from this illicit activation by the
• enzyme 11 -HydroxySteroid Dehydrogenase-2 (11
  HSD-2),
• which converts cortisol to cortisone

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Increased mineralocorticoid activity
Hypokalemia

• Apparent Mineralocorticoid Excess
• autosomal recessive,
• Loss-of-Function Mutations in the
• 11ß-HydroxySteroid Dehydrogenase-2 gene
• inhibition of 11 HSD-2 by
• glycyrrhetinic/glycyrrhizinic acid
• carbenoxolone
• Glycyrrhizinic acid is a natural sweetener in
  licorice root,
• licorice and as a flavoring agent in tobacco and
  food products

• (SAME),
• hypertension
• Hypokalemia
• Hypercalciuria
• Metabolic alkalosis
• Suppressed PRA
• Suppressed aldosterone.

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Primary hyperaldosteronism
Hypokalemia
familial hyperaldosteronism type I
FH-I glucocorticoid-remediable
hyperaldosteronism (GRA)

• genetic or acquired.
• due to Increases in circulating
• 11-deoxycorticosterone occur in patients with
  congenital adrenal hyperplasia caused by Defects
  in
• either steroid 11 -hydroxylase
• or steroid 17 -hydroxylase

familial hyperaldosteronism type II (FH-II), in
which aldosterone production is not supressible
by exogenous glucocorticoids.
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Hypokalemia

• Increased distal sodium and water delivery
• Urine K gt15 mmol/day

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Diuretics
Hypokalemia

• proximal to the potassium secretory site
• carbonic anhydrase inhibitors (eg,
  acetazolamide)
• loop diuretics
• Thiazide
• increase distal delivery sodium and water
• volume depletion
• activate the renin-angiotensin-aldosterone
  system.

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Hypokalemia

• Loop Diureticslt thiazide
• Loop diuretics lead to a significant Increase in
  Calcium Excretion.

• The Higher luminal calcium concentration in the
  distal nephron produced by Loop diuretics
• Reduces the lumen-negative driving force for
  potassium excretion
• thereby blunting their kaliuretic effect of loop
  diuretics

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Renal tubular acidosis
Hypokalemia

1.   distal (type 1)
2. proximal (type 2)

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Other renal causes potassium and magnesium
losses
Hypokalemia

•  Hypomagnesemia in up to 40 percent of patients
  with hypokalemia
• diuretic therapy
• vomiting
• diarrhea
• Gentamicin
• increased urinary potassium losses via an
  uncertain mechanism,
• an Increase in the number of Open Potassium
  Channels

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Hypokalemia
Tubular injury

• Bartter or Gitelman syndrome,
• reflux nephropathy
• nephritis due to Sjögren's syndrome
• hypercalcemia
• cisplatin
• amphotericin B

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Liddle's syndromehypokalemia hypertension
autosomal dominant gain-of-function mutation in
ENaCmimicking the syndrome of mineralocorticoid
excess
Hypokalemia

•  Bartter and Gitelman syndromes
• Hypokalemia
• Metabolic alkalosis
•  mimic the effects of
• loop diuretics (Bartter syndrome)
• thiazide diuretics (Gitelman syndrome)

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HypokalemiaExtra renal causesUrine K
lt15mmol/day

1. Decreased Intake
2. Increased loss(GI tract Sweat)
3. Transcellular Shift

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DECREASED POTASSIUM INTAKE
Hypokalemia

•  Potassium intake is normally 40 to 120 mEq per
  day,
• Low Intake
• The kidney is able to lower potassium excretion
  to a minimum of
• 5 to 15 mEq per day

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GI tract Upper gastrointestinal losses
Hypokalemia

•   The concentration of potassium in gastric
  secretions is only
• 5 to 10 mEq/L
• potassium depletion in this setting is primarily
  due to increased urinary losses .

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Upper gastrointestinal losses
Hypokalemia

• Rise in plasma bicarbonate concentration
• Metabolic Alkalosis
• increases the filtered Bicarbonate Load above its
  reabsorptive threshold.
• sodium bicarbonate and water are delivered to the
  distal potassium secretory site.
• a hypovolemia-induced increase in aldosterone
  release,
• increased potassium secretion
• Because of inappropriate Na wasting with HCO3,
• a Low urine Chloride concentration is used to
  detect the presence of volume depletion

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Upper gastrointestinal losses
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Lower gastrointestinal losses
Hypokalemia

• villous adenoma
• vasoactive intestinal peptide secreting tumor
  (VIPoma)
• persistent infectious diarrhea

•  Diarrhea
• bicarbonate wasting
• hyperchloremic metabolic acidosis
• hypokalemia

• Bowel cleansing for colonoscopy with both
• sodium phosphate
• polyethylene-glycol (PEG)-based preparations,
  ?Acute colonic pseudo-obstruction (Ogilvie's
  syndrome),
• ?Ingestion of clay ("geophagia"),

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Increased blood cell production
Hypokalemia

•  An acute increase in hematopoietic cell
  production
• with potassium uptake by the new cells
• vitamin B12 or folic acid to treat a
  megaloblastic anemia
• granulocyte-macrophage colony-stimulating factor
  (GM-CSF) to treat neutropenia.

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Symptoms of Hypokalemia

• Palpitations
• Skeletal muscle weakness or cramping
• Paralysis, paresthesias
• Constipation
• Nausea or vomiting
• Abdominal cramping
• Polyuria, nocturia, or polydipsia
• Psychosis, delirium, or hallucinations
• Depression

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INCREASED cellular POTASSIUM uptake

• pseudohypokalemia
• in vitro cellular uptake of K after
  venipuncture,
• leukocytosis in acute leukemia

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lt 15 mEq/L
gt 15 mEq/L
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Renal Vs Extra renal loss

• Urinary K gt 15 mEq/L Renal loss TTKG gt
  4
• Urinary K lt 15 mEq/L Extrarenal loss
  TTKG lt 4

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Renal Loss Kgt 20 mEq/L
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Renal Loss Metabolic Alkalosis
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Renal loss Urine Cl gt 20 mEq/L
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Extra Renal Loss Urinelt 15 mEq/L
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RENIN HIGH ALD HIGH RENIN LOW ALD HIGH LOW RENIN LOW ALD
RAS Primary Hyperaldosteronism NORMAL CORTISOL
Malignant HTN Glucorticoid remediable HTN Exogenous mineralocorticoid
Renin Secreting Tumor Liddles syndrome

LOW CORTISOL
Adrenogenital syndrome

HIGH CORTISOL
Familial Glucocorticoid Resistance
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