Hyperkalemia

Question 1

Hyperkalemia:

Clinical Manifestations

Answer 1

Muscle weakness, cardiac arrhythmias

ECG changes:

Peaked T waves: tall peak (sharp tented) T waves; T wave taller than R wave in ≥2 leads

Question 2

Hyperkalemia:

Clinical Manifestations

Answer 2

Flattened P waves; Prolonged PR interval

Changes associated with high risk of cardiac arrest: widened QRS complex; merging of S and T waves; bradycardia, idioventricular rhythm; sine wave formation; ventricular fibrillation

Question 3

Causes and Mechanisms of Hyperkalemia

Pseudohyperkalemia

Answer 3

Pseudohyperkalemia

In vitro (test tube) hyperkalemia, not in vivo hyperkalemia

Correction (treatment) of hyperkalemia is not necessary.

Common conditions associated with pseudohyperkalemia

Question 4

Causes and Mechanisms of Hyperkalemia

Answer 4

Question 5

Causes and Mechanisms of Hyperkalemia

Pseudohyperkalemia

Answer 5

Excessive fist clinching with blood draw: exercising (of hand) reduces local ATP and opens up ATP-dependent K+ channels, and allows extracellular K+ shift.

Mechanical trauma, hemolysis with blood draw: release of intracellular K+

Question 6

Causes and Mechanisms of Hyperkalemia

Pseudohyperkalemia

Answer 6

Thrombocytosis, e.g., for every 100,000 platelets/μL, serum K+ can increase by ~0.15 mEq/L because K+ moves out of platelets after clotting has occurred in test tube. Diagnosis: obtain plasma [K+] (i.e., [K+] measured from blood sample collected in heparin-containing tube to avoid clotting process).

Question 7

Causes and Mechanisms of Hyperkalemia

Pseudohyperkalemia

Answer 7

If serum [K+] (i.e., [K+] measured in usual manner in nonanticoagulated blood) is greater than P[K+] (i.e., S[K+] − P[K+] > 0.3 mEq/L), pseudohyperkalemia is likely present.

Question 8

Causes and Mechanisms of Hyperkalemia

Pseudohyperkalemia

Pseudohyperkalemia may also be seen with erythrocytosis and leukocytosis, with the following exception:

Answer 8

“Reverse” pseudohyperkalemia:

Condition where P[K+] > S[K+] (not the usual S[K+] > P[K+] with “regular” pseudohyperkalemia)

Due to cell fragility and lysis with centrifugation, traumatic blood handling (shuttling pneumatic tube system) − heparin-induced K+ leakage from white blood cells

Reported with chronic lymphocytic leukemia

To minimize cell lysis, hand-carry specimen to lab immediately following blood draw and avoid heparin-containing tubes

Question 9

Causes and Mechanisms of Hyperkalemia

Pseudohyperkalemia

Answer 9

Benign familial (autosomal dominant) pseudohyperkalemia ± associated stomatocytosis: Passive K+ leaks from red blood cells into serum when the blood sample is left at room temperature. This K+ leakage does not occur in vivo. Diagnosis: serial S[K+] measurements while blood is allowed to cool down to normal temperature leads to increasing S[K+] levels.

Question 10

Increased K+ Input

Answer 10

Dietary: High K+-containing foods, salt substitutes (typical salt-substitute contains 10 to 13 mEq KCl/g or 283 mEq of KCl/tablespoon), mixed fruit juice

K+-containing medications: KCl, high-dose penicillin K, K-citrate, polycitrate

Question 11

Increased K+ Input

Answer 11

Supplements: fruit/herbal extracts

Red blood cell transfusion due to K+ leakage, particularly problematic with massive transfusions or transfusions of prolonged stored blood

Question 12

NOTE

Answer 12

Hyperkalemia from intake is not common except in cases of accidental large quantity ingestion, or moderate ingestion in those with poor kidney function and/or reduced mineralocorticoid activity.

Question 13

Reduced Bodily K+ Loss/Output

Answer 13

Gastrointestinal: severe, chronic constipation with concurrent poor kidney function

Question 14

Extracellular K+ Shift

Answer 14

Extracellular pH:

Metabolic acidosis:

Inorganic acids (e.g., HCl or sulfuric acid), but not organic acids, cause K+ shift.

Organic acidosis seen with kidney failure or administration of arginine hydrochloride or aminocaproic acid may cause K+ shift.

Question 15

Extracellular pH:

Metabolic Acidosis:

Answer 15

Lactic acidosis or ketoacidosis has smaller effect on hyperkalemia, partially due to concurrent entry of both anion and hydrogen ion into cells via a sodium-organic anion cotransporter, thus eliminating the need for K+ shifting out of cells to maintain electroneutrality.

Question 16

Extracellular pH:

Respiratory acidosis:

Answer 16

No significant effect on extracellular K+ shift unless severe and prolonged

Mechanisms for difference on K+ shift compared with metabolic acidosis are not well understood.

Question 17

Extracellular pH:

Extracellular osmolality:

Answer 17

Increased osmolality (e.g., hyperglycemia, sucrose containing intravenous immune globulin, radiocontrast media, hypertonic mannitol) leads to extracellular K+ shift due to:

Extracellular H2O shift with hyperosmolality increases intracellular K+ concentration, hence greater concentration gradient favoring extracellular shift.

Extracellular H2O shift drags K+ along: “solvent drag” effect.

Question 18

NOTE

Answer 18

Hyperkalemia is often observed in fasting (e.g., immediate preoperative) blood draws in type 2 diabetic patients. This is thought to be due to the lack of endogenous insulin secretion with fasting, hence reduced insulin-stimulated cellular K+ uptake as well as hyperglycemia/hyperosmolality-inducedhyperkalemia, as described above.

Question 19

NOTE

Answer 19

To correct this hyperkalemia, administer 5% dextrose (D5) saline solutions ± insulin depending on degree of hyperglycemia. The administration of D5 alone can induce sufficient endogenous insulin secretion and ameliorate hyperkalemia.

Question 20

Extracellular K+ Shift

Answer 20

Therapy with somatostatin or somatostatin agonist (octreotide) can lead to a fall in insulin and hyperkalemia in susceptible individuals.

Cell death/increased tissue catabolism: e.g., tumor lysis (cytotoxic or radiation therapy), hemolysis, rhabdomyolysis, bowel infarction, soft tissue trauma, severe accidental hypothermia, etc.

Question 21

Extracellular K+ Shift

Altered Na+-K+-ATPase activity:

Answer 21

Reduced insulin

Reduced β2-adrenergic activity reduces cellular K+ uptake:

1. Digitalis overdose (digoxin, ingestion of common oleander or yellow oleander): inhibition of Na+-K+-ATPase
2. β-Antagonists and hyperkalemia: (1) inhibits catecholamine-stimulated renin release, hence aldosterone; (2) most important: inhibits Na+-K+-ATPase activity via β2-inhibition. Nonselective agents, therefore, cause more hyperkalemia compared with β1-selective antagonists.

Question 22

Extracellular K+ Shift

Altered Na+-K+-ATPase activity:

Answer 22

Nonselective β-antagonists: alprenolol, bucindolol, carteolol, carvedilol (+ α-antagonism), labetalol (+ α-antagonism), nadolol, penbutolol, pindolol, propranolol, timolol

Selective β1-antagonists: acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, esmolol, metoprolol, nebivolol

Question 23

Extracellular K+ Shift

Exercise-induced hyperkalemia:

Answer 23

Delay between K+ exit from cells during depolarization and subsequent cellular reuptake via Na+-K+-ATPase

Exercise-induced reduction in ATP reduces ATP-dependent inhibition of K+-channels, hence more open K+ channels, and increases K+ leak extracellularly.

Question 24

Extracellular K+ Shift

Exercise-induced hyperkalemia:

Answer 24

Extracellular K+ shift is thought to be adaptive since higher K+ concentration has a vasodilatory effect, hence improved blood flow and energy supply to exercising muscles.

Exercise-induced hyperkalemia is reversed within a few minutes of rest.

Question 25

Extracellular K+ Shift ATP-dependent K+ Channels: Opening of K+ channels leads to K+ efflux:

Answer 25

Lack of ATP as seen with exercise. Medications: Calcineurin Inhibitors (cyclosporine and tacrolimus), diazoxide, minoxidil, and isoflurane.

Question 26

Hyperkalemic periodic paralysis:

Answer 26

Autosomal dominant, varying penetrance Rare channelopathy involving α1-subunit of skeletal muscle Na+ (SCN4A) channels

Question 27

Hyperkalemic periodic paralysis:

Answer 27

Age of onset: infancy to second decade of life May be associated with prolonged QT interval (Anderson syndrome), malignant hyperthermia, or paramyotonia congenital von Eulenburg (paradoxical myotonia may be prominent feature, which is worsened with activity or aggressive lowering of S[K+]).

Question 28

Hyperkalemic periodic paralysis:

Answer 28

Episodic weakness or paralysis may be precipitated by rest after activity, changes in daily level of activity especially in cool temperature, K+ administration Attacks last 10 to 60 minutes, rarely 1 to 2 days; abrupt paralysis onset may result in falls

Question 29

Hyperkalemic periodic paralysis:

Answer 29

Stiffness may be aborted with walking, high carbohydrates (candy) intake S[K+] most often normal, may be high (minimally high), or even low during recovery

Question 30

Hyperkalemic periodic paralysis:

Answer 30

Diagnosis: Compound muscle amplitude test Genetic testing for a small number of mutations available

Question 31

Hyperkalemic periodic paralysis:

Answer 31

Treatment: Diet—high carbohydrates, candy; avoid high K+-containing foods; consider diuretics (thiazides, loop diuretics), β-agonists such as albuterol.

Question 32

Hyperkalemic periodic paralysis:

Answer 32

Administration of succinylcholine to susceptible patients with conditions where there is upregulation of acetylcholine receptors (e.g., neuromuscular disease, severe trauma, burns, chronic immobilization, or infections). Succinylcholine activation of acetylcholine receptors causes cell depolarization and large K+ efflux.

Question 33

Hyperkalemic periodic paralysis: Heparin may cause hyperkalemia by several mechanisms:

Answer 33

Inhibition of aldosterone production via reduction in the number and affinity of angiotensin II receptors in zona glomerulosa Inhibition of the final enzymatic steps of aldosterone formation (18- hydroxylation) Adrenal hemorrhage

Question 34

Reduced Renal K+ Loss

Answer 34

Recall renal K+ secretion depends on: (1) distal Na+ delivery, (2) generation of transepithelial potential difference (negative lumen) via Na+ entry into ENaC in principal cells at aldosterone-sensitive distal nephron segment, (3) distal urine flow, (4) presence of aldosterone, (5) sensitivity to aldosterone, and (6) kidney mass.

Question 35

Reduced Renal K+ Loss

Answer 35

Reduced renal K+ secretion occurs when: Distal Na+ delivery to cortical and corticomedullary collecting tubules is reduced: Reduced effective circulating volume (heart failure, cirrhosis, volume depletion, etc.), dietary sodium restriction

Question 36

Reduced Renal K+ Loss

Answer 36

Diagnosis: clinical history, U[Na+] \< 20 mEq/L, improved urinary K+ (U[K+]) excretion with saline infusion Increased proximal Na+ uptake at distal convoluted tubules, hence reduced Na+ delivery to the more distal collecting tubules (pseudohypoaldosteronism type 2/Gordon syndrome).

Question 37

Reduced Renal K+ Loss

Answer 37

Reduced generation of transepithelial potential difference (negative lumen) generated by Na+entry into ENaC in principal cells at aldosterone-sensitive distal nephron segment: inhibitors of ENaC—triamterene, amiloride, trimethoprim, pentamidine Compromised urine flow: obstructive uropathy.

Question 38

Reduced Renal K+ Loss

Answer 38

Lack of aldosterone: Hypoaldosteronism: diabetes mellitus → type 4 RTA, primary adrenal insufficiency Medications: renin angiotensin aldosterone system inhibitors, nonsteroidal anti-inflammatory drugs, COX-2 inhibitors, calcineurin inhibitors, heparin (low molecular weight as well), ketoconazole, drospirenone-containing oral contraceptives (e.g., Yaz, Yasmin): drospirenone has mineralocorticoid antagonist activity

Question 39

Reduced Renal K+ Loss Resistance to aldosterone:

Answer 39

Medications: aldosterone antagonists (spironolactone, eplerenone) a. Pseudohypoaldosteronism type 1 (PHA 1) 1. Hyperkalemia associated with metabolic acidosis and salt-wasting 2. Autosomal dominant form (AD PHA1): Aldosterone receptor mutation Treatment: high-dose fludrocortisone, salt supportA

Question 40

Reduced Renal K+ Loss Resistance to aldosterone:

Answer 40

3. Autosomal recessive form (AR PHA1): Inactivating mutations in α, β, or γ subunits of ENaC; associated with pulmonary infections More severe than AD PHA1

Question 41

Reduced Renal K+ Loss Resistance to aldosterone:

Answer 41

Salt-wasting in organs requiring ENaC for salt transport (lungs, kidneys, colon, sweat, salivary glands) High sodium chloride content in sweat and salivary testing 4. Treatment: high salt support; NSAIDS have been reported to be beneficial in AR PHA1

Question 42

Resistance to aldosterone: Pseudohypoaldosteronism type 2 (Gordon syndrome, a.k.a. familial hyperkalemic hypertension [FHH])

Answer 42

Enhanced paracellular Cl− reabsorption Enhanced Na+ reabsorption via NaCl cotransporter (NCC) in distal convoluted tubules (DCT), leading to reduced Na+ availability for delivery to cortical collecting tubules (CCT). Reduced Na+ availability at CCT reduces CCT ability to secrete K+ and H+ →hyperkalemia and metabolic acidosis.

Question 43

Resistance to aldosterone: Pseudohypoaldosteronism type 2 (Gordon syndrome, a.k.a. familial hyperkalemic hypertension [FHH])

Answer 43

The increased Na+ and Cl− reabsorption leads to volume-expanded state, which suppresses renin angiotensin aldosterone system. Reduced aldosterone also contributes to hyperkalemia and metabolic acidosis.

Question 44

Resistance to aldosterone: Pseudohypoaldosteronism type 2 (Gordon syndrome, a.k.a. familial hyperkalemic hypertension [FHH])

Answer 44

Clinical manifestations: hypertension in early adulthood, non-AG metabolic acidosis and hyperkalemia, hypercalciuria, osteoporosis, nephrolithiasis

Question 45

Resistance to aldosterone: Pseudohypoaldosteronism type 2 (Gordon syndrome, a.k.a. familial hyperkalemic hypertension [FHH])

Answer 45

Reported NCC regulatory molecules with mutations leading to FHH: with-no-lysine (WNK) 1-4 (inactivating mutations of WNK4 or activating mutations of WNK1), Kelch-Like 3 (KLHL3), and Cullin 3 (CUL3). Mutations in WNK4 also downregulate the transient receptor potential V5 channel (TRPV5, calcium channel) and decrease Ca2+reabsorption in DCT, thus hypercalciuria and osteoporosis. (See Hypertension) Treatment: thiazide diuretics

Question 46

Reduced renal K+ secretion occurs when: Kidney mass/function is reduced:

Answer 46

Reduced overall capacity for renal K+ secretion Reduced Na+-K+-ATPase activity with uremia, thus reduced cellular uptake

Answer 47

Ureterojejunostomy: increased absorption of urinary K+ by jejunum Selective impairment of K+ secretion of unclear mechanisms: interstitial disease—lupus nephritis, sickle cell disease

Question 48

NOTE

Answer 48

Common clinical scenarios with multiple reasons for hyperkalemia: Diabetic patient: (1) neurogenic bladder leading to urinary stasis; (2) low aldosterone state due to reduced sympathetic stimulation for renin release, adrenal atrophy, and use of renin angiotensin aldosterone inhibitors; and (3) insulin deficiency leading to reduced cellular K+ uptake via Na+-K+-ATPase, hyperosmolality from hyperglycemia leading to cellular K+ efflux, metabolic acidosis with diabetic ketoacidosis leading to K+efflux, and hypovolemia leading to reduced Na+ delivery to collecting tubules

Answer 49

Patient with cirrhosis or heart failure: (1) use of spironolactone, (2) low effective circulating volume leading to poor Na+ delivery to collecting tubules, and (3) recurrent kidney injuries

Question 50

Management of Hyperkalemia: Temporizing Measures

Answer 50

For patients with relatively good kidney function and nonthreatening ECG changes, consider volume resuscitation with normal saline and administration of loop diuretics.

Question 51

Management of Hyperkalemia: Temporizing Measures

Answer 51

For severe hyperkalemia with high-risk ECG changes and kidney failure, emergent hemodialysis is indicated. Consider nutritional consult for low-K+ diet if applicable. Good bowel regimen and other emergent

Question 52

Treatment of Hyperkalemia

Answer 52