Hypokalemia and Hyperkalemia Flashcards
4 Mechanisms of Potassium Balance
- K+ intake through the diet
- GI losses
– GI tract secretes 5-10% of absorbed K+ daily
• Renal losses
– 90-95% is regulated by the kidney
• Transcellular K+ shift
– Overall K+ stores remain the same but redistribute between the ICF and ECF
Renal Handling of Potassium
- K+ is freely filtered at the glomerulus
- ~65-70% of filtered K+ reabsorbed in proximal tubule
- Passive transport
– Paracellular route by solvent drag and diffusion
Renal Handling of Potassium - Ascending Loop of Henle
- Reabsorbs 10-25% K+
- Driven by luminal Na+-K+-2Cl- (NKCC2) multiporter
- Active transport driven by Na+-K+ ATPase
- Transporter affinity for Na+, K+ high • Max activity when TF [Na+, K+] are <5-10 meq
- K+ recycling across luminal membrane allows for continued activation of NKCC2
- Activity of K+ channel is inhibited by ATP allowing a link to level of Na+ reabsorption
- As more Na+ enters cell, Na+ will be transported out of the cell into the peritubular capillary by Na+-K+ ATPase –> lowering cellular ATP level and stimulates activity of luminal K+ channel
- Permits return of reabsorbed K+ into lumen and further Na+ absorption
Renal Handling of Potassium Primary Regulatory Site Of K+ Excretion: Principal Cell
- K+ actively transported into cell by Na+-K+ ATPase at basolateral membrane
- Secreted into tubular fluid (TF) down a favorable electrochemical gradient via luminal K+ channels (ROMK)
- Governed by factors that affect passive transport
- Concentration gradient across luminal membrane
– High intracellular [K+] and low TF [K+]
- Electrical gradient generated by reabsorption of Na+ via luminal Na+ channels (ENaC)
- K+ permeability of luminal membrane
– # of open K+ channels
K+ Regulation in the Principal Cell 4 main factors that affect K+ secretion into the tubular fluid
- Aldosterone
- Plasma K+ concentration
- Distal Flow Rate
- Distal Na+ delivery
K+ Regulation in the Principal Cell 4 main factors that affect K+ secretion into the tubular fluid: Aldosterone
– augments K+ secretion in principal cells
– Increase # open Na+ and K+ channels in luminal membrane
– Enhances activity of Na+-K+ ATPase pump
K+ Regulation in the Principal Cell 4 main factors that affect K+ secretion into the tubular fluid: Plasma K+ concentration
– Increase # open Na+ and K+ channels in luminal membrane
– Enhances activity of Na+-K+ ATPase pump
K+ Regulation in the Principal Cell 4 main factors that affect K+ secretion into the tubular fluid: Distal Flow Rate
– Increase in distal flow rate washes secreted K+ away and replaces with relatively K+ free fluid–> favorable [K+] gradient for secretion into TF
– When distal flow rate reduced, high luminal [K+] (due to less washout of secreted K+) and low urine flow –> reduction in absolute rate of K+ secretion (additionally voltage gated channels – Maxi K – stimulated by flow)
K+ Regulation in the Principal Cell 4 main factors that affect K+ secretion into the tubular fluid: Distal Na+ delivery
– Entry of Na+ via Na+ channel (ENaC) makes lumen electronegative
– Transport of Na+ into peritubular capillary by ATPase pumps more K+ into cell
– More K+ secreted into electronegative lumen
Renal Handling of Potassium Intercalated cell in the collecting duct is a site of K+ reabsorption
- α-Intercalated cells reabsorb K+ via apical H+-K+ ATPase – Active process
- Actively secretes H+ into luminal fluid in exchange for K+ reabsorption
- Active reabsorption by H+- K+ATPase enables urinary K+ excretion to decrease to <15 mmol/d in severe K+ deficiency
Hypokalemia
- Transcellular
- GI Losses
- Renal Losses
- poor intake
Hypokalemia - Transcellular Shift
• Insulin
– Promotes K+ entry into cell by stimulating Na+-K+ ATPase
• Β2 adrenergic agonist
– Catecholamines or drugs acting via β2 adrenergic receptors increases K+ entry into cell by increasing activity of Na+-K+ ATPase
• Alkalosis
– H+ will leave cell in order to lower extracellular pH
– K+ enters cell in order to maintain electroneutrality
• Hypokalemic periodic paralysis
– Acute attacks precipitated by sudden movement of K+ into cells
– Lowers plasma K+ to 1.5-2.5 mEq/L
– Precipitated by:
- Rest after exercise
- Stress
- High carbohydrate meal
– Familial
• Autosomal dominant
– mutations in dihydropyridine calcium channel in skeletal muscle
– Acquired
• Thyrotoxicosis
– Predominantly young Asian males
Hypokalemia - GI Losses
• Vomiting and nasogastric tube output
– Associated with metabolic alkalosis due to HCl loss
– K+ loss from emesis ~ 5-10 mEq/L
– Concurrent urinary losses
- Activation of aldosterone
- Increase in plasma bicarbonate –> increases filtered bicarbonate above its reabsorptive threshold
- Because Na+ must pair with bicarbonate in TF
– the increase in distal delivery of Na+ further promotes K+ loss
- Diarrhea
- Laxatives
– Associated with metabolic acidosis due to bicarbonate losses
– K+ loss from the stool ~ 20- 50 mEq/L
Hypokalemia - Renal Losses
•Metabolic Alkalosis
- normohypotension
- hypertension
•Metabolic Acidosis
- renal tubular
- nonreabsorbable anion
•magnesium
Hypokalemia Renal losses associated with metabolic alkalosis - normohypotension
• Conditions associated with metabolic alkalosis and normohypotension
– Diuretics
- Loops and thiazides
- Activate aldosterone by volume depletion
- Increase distal delivery of Na+
– Salt wasting nephropathies
- Bartter’s syndrome
- Gitelman’s syndrome
Hypokalemia Alkalosis: Salt wasting nephropathies - Bartter’s Syndrome
• Bartter’s syndrome (think loop diuretic)
– Autosomal recessive presents early in life
– Defect in NaCl reabsorption in thick ascending limb of Henle
– 3 main transporters can be involved by mutations
- Na+ 2Cl- K+ (NKCC2)
- Luminal K+ channel
- Basolateral Cl- channel
– Clinical presentation
- Hypotension
- Impaired concentrating capacity
- Hypokalemic metabolic alkalosis
Hypokalemia Alkalosis: Salt wasting nephropathies - Gitelman’s Syndrome
• Gitelman’s syndrome (think thiazide diuretic)
– Autosomal recessive can present in later childhood or early adulthood
– Defect in gene encoding the thiazidesensitive NaCl cotransporter in the distal convoluted tubule
– Clinical presentation
- Normo-hypotension
- Impaired concentrating capacity
- Hypokalemic metabolic alkalosis
– Low urinary calcium distinguishes Gitelman’s from Bartter’s syndrome Hyp
Hypokalemia Alkalosis associated with metabolic alkalosis hypertension
• Mineralocorticoid excess
– Primary hyperaldosteronism
- Adrenal tumor
- Bilateral adrenal hyperplasia
– Glucocorticoid remedial aldosteronism
• Autosomal dominant
– ACTH dependent production of aldosterone
– Renovascular disease
• Renal artery stenosis
– Defects in 11-β-hydroxysteroid dehydrogenase type 2
- Converts cortisol to corticosterone
- Black licorice root
- Syndrome of apparent mineralocorticoid excess (SAME)
– Congenital adrenal hyperplasia
-Liddle’s syndrome
- Autosomal dominant
- Presents during adolescence and early adulthood
- Gain of function mutation in the epithelial Na+ channel (ENaC)
- Excessive Na+ reabsorption
- Triad
*Hypertension
*Metabolic alkalosis
*Hypokalemia
Hypokalemia Associated with metabolic acidosis
• Renal tubular acidosis (RTA)
– Hyperchloremic, nonanion gap metabolic acidosis
• Distal hypokalemic RTA (type I)
– Impaired distal acidification
– Familial
– Autoimmune disease
– Drugs (Ifosfamide)
• Proximal RTA (type II)
– Reduction in proximal bicarbonate reabsorptive capacity
– Bicarbonate wasting in urine until plasma bicarbonate has fallen to level low enough to allow filtered bicarbonate to be reabsorbed
– Familial
– Multiple myeloma
– Drugs (tenofavir)
• Nonreabsorbable anions
– Toluene
- Paint thinner
- Metabolite
– hippurate
– Nonreabsorable anion
– Pairs with Na+
– Leads to increased distal Na+ delivery
– Diabetic ketoacidosis
• β-hydroxybuterate
– Nonreabsorbable anion
– Pairs with Na+
– Leads to increased distal Na+ delivery
Hypokalemia Magnesium
• Magnesium
– Hypokalemia occurs in 40-60% of cases
– Often due to underlying disorders that waste both Mg and K+
- Diarrhea, diuretics
- Renal K+ wasting occurs independently due to increased secretion into the loop of Henle and collecting duct
– Mechanism is not well understood
• Must correct Mg deficit in order to restore K+
Hypokalemia Clinical Manifestations: Cardiovascular
• Cardiac arrhythmias and ECG abnormalities
– Premature atrial and ventricular beats
– Sinus bradycardia
– AV block
– Ventricular tachycardia/fibrillation
• Decrease in amplitude of T wave and increase in amplitude of U wave
– Occurs at the end of T wave
– Seen in lateral precordial leads
Hypokalemia Clinical Manifestations: Muscular
• Weakness and muscle cramps
– Low K+ (<2.5 mEq/L) can hyperpolarize skeletal muscle cell impairing contraction
– Can reduce skeletal muscle blood flow by impairing local nitric oxide release
• Predisposes to rhabdomyolysis (muscle breakdown) during vigorous exercise
– Severe K+ depletion (<2.0 mEq/L) can cause respiratory muscle weakness leading to respiratory failure and death
– GI muscle weakness can result in ileus (bowel obstruction due to decreased muscular activity)
Hypokalemia Hormonal and Renal Manifestations
• Hormonal
– Impairs insulin release and end-organ sensitivity to insulin
- Worsened glucose control in diabetic patients
- Renal
– Tubulointerstitial and cystic changes in the parenchyma of the kidney (prolonged hypokalemia)
– Polyuria
- Severe hypokalemia impairs concentrating ability causing mild polyuria (2-3L/d)
- Due to both increase thirst and mild nephrogenic diabetes insipidus
– Hypertension
- Increase in renal vascular resistance
- Sensitizes vessels to endogenous vasoconstrictors
Hypokalemia Diagnosis
• Clinical history
– Help determine source of K+ loss
* Shift, GI, renal
• Urinary K+ determination
– Distinguish urinary losses from shift or GI losses
*Urinary K+ to creatinine ratio
– assumes a 24h value of urinary K+ based on a spot sample
– most patients will excrete 1000 mg of urinary creatinine in 24h
*< 15 mEq/g of creatinine suggests appropriate conservation of K+ and extrarenal loss
* > 15 mEq/g of creatinine suggests urinary losses
Hypokalemia Diagnosis - Acid Base Status
• Determination of acid base status
– Metabolic acidosis
• Low urinary K+ to creatinine ratio (< 15 mEq/g)
– Stool losses
• High urinary K+ to creatinine ratio (> 15 mEq/g)
– RTA
– Nonreabsorbable anion
– Metabolic alkalosis
• Low urinary K+ to creatinine ratio (< 15 mEq/g)
– Vomiting
• High urinary K+ to creatinine ratio (> 15 mEq/g)
– Check blood pressure and volume status
» Low to normal BP/volume depleted (diuretics, salt wasting nephropathies, ongoing vomiting with sustained metabolic alkalosis)
» High BP/volume overload (mineralocorticoid excess, Liddle’s)
– Always check Magnesium
• Hypokalemia due to low Mg cannot be corrected until Mg is corrected
Hypokalemia Treatment
- Underlying disorder needs to be corrected
- K+ < 2.5 mEq/L carries risk of dangerous cardiac arrhythmias and needs replacement – Oral replacement
- Mild hypokalemia
– Parenteral replacement
- Severe hypokalemia or patients who cannot tolerate oral intake
- Maximum KCl concentration is 20 mEq/100ml
– Administered at a maximum rate of 10 mEq/h
Hyperkalemia
- Transcellular Shift
- Pseudohyperkalemia
- Renal: decreased urinary secretion
Hyperkalemia Pseudohyperkalemia
– Elevation in measured serum K+ is due to K+ movement out of cells during or after a blood specimen has been drawn
- Hemolysis (destruction of red blood cells) due to technique during blood draw – Clenching, prolonged tourniquet, venipuncture trauma
- Thrombocytosis (increased platelets)
- Leukocytosis (acute leukemia)
Hyperkalemia: Transcellular Shift
• Metabolic acidosis
– H+ will enter cell in order to buffer the extracellular pH
– K+ will leave the cell in order to maintain electroneutrality
- Applies to inorganic acids (not organic acidosis –i.e. diabetic ketoacids)
- Overall small effect
- Hyperglycemia and hyperosmolarity
– Elevation in serum osmolality results in H20 movement from the ICF to ECF
- Results in increased [K+] in the cell
- K+ will move out of cell down concentration gradient
- Solvent drag from water movement out of cell
Hyperkalemia: Transcellular Shift
• Nonselective β-antagonists
– Interfere with K+ uptake into cell by β-adrenergic receptors
• Exercise
– K+ released by muscle cells
- Causes local vasodilation for increased blood flow
- Tissue breakdown
– Rhabdomyolysis (muscle breakdown)
– Lysis of large tumor burden after chemotherapy
– Burns
• Digitalis (Digoxin®) toxicity
– Inhibits Na+-K+ ATPase pump
• Hyperkalemic familial periodic paralysis
– Autosomal dominant
– point mutation in skeletal muscle Na+ channel
– Precipitated by cold, rest after fasting, K+ ingestion
Hyperkalemia: Renal: Decreased urinary excretion
• Renal failure
– Able to maintain near normal levels of K+ as long as distal flow rate and aldosterone secretion is maintained
– Hyperkalemia occurs in patients who are oliguric (decreased distal flow rate) who have an additional problem
- Excess K+ load
- Aldosterone blockade (ACE inhibitors, angiotensin receptor blockers, and aldosterone blockers)
- Volume depletion with decreased distal Na+ delivery
– Hypovolemia
– Effective arterial volume depletion with extracellular volume excess
- Heart failure
- Cirrhosis of the liver
Hyperkalemia: Renal: Decreased urinary excretion
• Functional hypoaldosteronism (either low aldosteronism state or resistance to the effect of aldosterone)
– Mineralocorticoid deficiency
- Primary adrenal insufficiency (adrenal gland does not generate aldosterone in response to renin)
- Hyporeninemic hypoaldosteronism
– Diabetic
– type IV RTA
– Low plasma renin levels and aldosterone levels
– Tubulointerstitial disease
• Sickle cell disease and urinary tract obstruction
– Distal hyperkalemic RTA
– Impaired Na+ reabsorption in the principal cell reducing K+ and H+ secretion
Hyperkalemia: Renal: Decreased urinary excretion- Drugs
• Drugs
– Block conversion to aldosterone or binding to aldosterone receptor
• ACE inhibitors, angiotensin receptor blockers, aldosterone antagonists (spironolactone, eplerenone)
– Decreased renin release
• Nonsteroidal anti-inflammatory drugs (NSAIDS), betablockers, renin inhibitors (Tekturna®)
– Binds to luminal Na+ channel (ENaC) in the principal cell
• Amiloride, triamterene, trimethoprim (Bactrim®), pentamidine
– Multiple effects
• Calcineurin inhibitors (used for organ transplant to prevent rejection)
Hyperkalemia Clinical Manifestations
• Severe muscle weakness or paralysis
– Ascending weakness begins with lower extremities and progresses to trunk, upper extremities –> flaccid paralysis
• Cardiac arrhythmias and ECG abnormalities
– Bundle branch block, advanced AV block, sinus bradycardia, sinus arrest, slow idioventricular rhythm, ventricular tachycardia, fibrillation, asystole
– ECG findings
- Early – tall peaked T waves and shortening of the QT interval
- Late – prolongation of PR and QRS interval – May lose P wave altogether with widened QRS –> sine wave
Hyperkalemia Diagnosis
- Clinical history and physical exam
- Measurement of plasma K+ in suspected pseudohyperkalemia
- Plasma renin activity and aldosterone concentration
– High renin, low aldosterone
• Adrenal insufficiency
– Low renin, low aldosterone
• Type IV RTA
– diabetic nephropathy
– Normal renin, high aldosterone (aldosterone resistance)
• Tubulointerstitial disease – Sickle cell disease, urinary obstruction
Hyperkalemia Diagnosis - Transtubular Gradient
• Transtubular K+ gradient (TTKG) may help distinguish functional hypoaldosteronism from other disorders (i.e. transcellular shift)
– Gradient between the tubular fluid and plasma K+ - estimates aldosterone activity by measuring the K+ concentration in the tubular fluid at the end of the cortical collecting tubule (site of K+ secretion)
– [Urine K (Urine osmolality/Plasma osmolality)] Plasma K+
– Value < 5 is suggestive of hypoaldosteronism
Hyperkalemia Treatment
- Antagonizing membrane effects of K+ with calcium
- Driving extracellular K+ into cells
- Removing excess K+ from the body
Hyperkalemia treatment - Antagonizing membrane effects of K+ with calcium
– Reserved for patient’s with ECG changes or acute rise in serum K+
– Calcium chloride
• Mechanism
– Hyperkalemia induces depolarization of the resting membrane potential leading to inactivation of the Na+ channels and decreased membrane excitability
– Calcium antagonizes this membrane effect (mechanism is not well understood)
Hyperkalemia Treatment - • Driving extracellular K+ into cells
– Insulin administered with glucose
- Insulin will cause uptake of K+ into the cell by stimulating activity of the Na+-K+ ATPase
- Administer with glucose to avoid hypoglycemia
– Β-2 agonist (albuterol)
• Stimulates Na+-K+ ATPase via different mechanism then insulin (cAMP) and provides synergism when used with insulin
– Can lower K+ by 1.2-1.5 mEq/L when used together
Hyperkalemia Treatment - K+ removal
– Diuretics
• Loops and thiazides
–Can be used long-term in patients with chronic kidney disease
–Loops are effective in short-term when combined with saline to maintain distal delivery of Na+ and distal tubular flow
• K+ Removal
– Cation Exchange Resins
• Sodium polystyrene sulfonate (Kayexalate®)
– Takes up K+ in the gut and releases Na+
– Most preparations are prepared in sorbitol (osmotic laxative)
» Sorbitol component can lead to intestinal necrosis
» Surgical patients are highest risk
• Patiromer (Veltassa®)
– Takes up K+ in exchange for calcium in the colon
– Will likely replace sodium polystyrene sulfonate
– Dialysis
- Warranted when the prior measures are insufficient to correct hyperkalemia
- Or when K+ expected to increase rapidly (tissue breakdown)
- Hemodialysis is preferred modality – can remove 25-50 mEq of K+ per hour
- Treatment of choice in end-stage-renal-disease (ESRD) patients
-Treatment of reversible causes
- Discontinuation of drugs that cause hyperkalemia
- Volume expansion with saline in patients with volume depletion
