Health Questions and Answers

POTASSIUM BALANCE

How is potassium (K+) distributed between the intracellular fluid (ICF) and ECF compartments?
A 70-kg man contains approximately 3500 mEq of K+ (approximately 50 mEq/kg body weight). The vast majority of this (98%) is in the ICF space. Therefore, the amount in the ECF compartment (the portion that we routinely measure) represents only a small percentage of the total body K+.

How is the large chemical gradient between intracellular and extracellular K+ concentration maintained?
The Na+-K+ adenosine triphosphate (ATPase) pump actively extrudes Na+ from the cell and pumps K+ into the cell. This pump is present in all cells of the body. In addition, the cell is electrically negative compared to the exterior, which serves to keep K+ inside the cell.

Given the relatively small extracellular compared to intracellular concentration of K+, why are some electrical processes (cardiac conduction, skeletal and smooth muscle contraction) sensitive to changes in the ECF K+ concentration?
It is the ratio of the ECF to ICF K+ concentration more than the absolute level of either that determines the sensitivity of these electrical processes. Because the ECF concentration of K+ is small compared to the ICF concentration, a small absolute change in ECF K+ concentration results in a large change in the ECF to ICF K+ ratio.

What factors commonly influence the movement of K+ between the intracellular and extracellular compartments?
Acid-base changes: Acidemia (increased concentration of H+ in serum) leads to intracellular buffering of H+, with subsequent extrusion of K+ into the ECF, increasing the concentration of K+ in this compartment. Similarly, alkalemia leads to hypokalemia.Hormones: Insulin, epinephrine, growth hormone, and androgens all promote net movement of K+ into cells.Cellular metabolism: Synthesis of protein and glycogen is associated with intracellular K+ binding.Extracellular concentration: All other things being equal, K+ tends to enter the cell when its extracellular concentration is high and vice versa.

How is K+ handled by the kidney?
Most of the filtered K+ is reabsorbed in the proximal tubule, and there is net secretion or net resorption in the distal nephron, depending on the body’s K+ needs. Under most conditions, we are in K+ excess, and the kidney must excrete K+ to maintain whole-body K+ balance. K+ restriction leads to renal K+ conservation, but this process is neither as rapid nor as efficient as the process for Na+.

How does aldosterone influence K+ metabolism?
Aldosterone is the main regulatory hormone for K+ metabolism. It promotes Na+ resorption and K+ secretion in the distal nephron, gut, and sweat glands. Quantitatively, its greatest effect is in the kidney. Its secretion is increased by an increasing K+ concentration in the ECF and is decreased by low K+ concentrations.

How does hypoaldosteronism affect K+ and Na+ levels?
Asymptomatic hyperkalemia is a common presentation of patients with mineralocorticoid deficiency. Na+ deficiency and volume depletion are not seen unless there is concomitant glucocorticoid deficiency. Na+ balance is maintained by other factors, such as angiotensin II and catecholamines, although the ability to conserve Na+ maximally is generally lost. Thus, urine Na+ < 10 mEq/L is unusual in primary hypoaldosteronism.

How is hypoaldoteronism diagnosed?
To diagnose hypoaldosteronism, the first step is to exclude drug-induced hyperkalemia (such as angiotensin-converting enzyme (ACE) inhibitors, beta blockers, NSAIDs, heparin, or K+-sparing diuretics). The next step is to obtain morning samples of plasma for renin, aldosterone, and cortisol measurements. Administration of furosemide (20-40 mg) at 6 pm and 6 am before samples are drawn enhances the utility of the test by stimulating plasma renin activity in normal persons but not in those with hypoaldosteronism.

List conditions that can lead to increased renal K+ excretion.

  • Increased dietary K+ intake
  • Increased aldosterone secretion (as in volume depletion)
  • Alkalosis
  • Increased flow rate in the distal tubule
  • Increased Na+ delivery to the distal nephron
  • Decreased chloride concentration in tubular fluid in the distal nephron
  • Natriuretic agents

How does increased sodium delivery promote renal excretion of K+?
Increased Na+ delivery to the distal nephron promotes Na+ resorption in exchange for K+ secretion. The process is accelerated in the presence of aldosterone.

Explain how decreased chloride concentration leads to an increase renal excretion of K+.
Decreased chloride concentration in tubular fluid in the distal nephron allows Na+ to be resorbed with a less permeable ion (e.g., bicarbonate or sulfate) that increases the negativity of the tubular lumen in the distal nephron. The increased negativity of the tubular lumen promotes K+ secretion.

How do natriuretic agents increase renal excretion of K+?
Natriuretic agents, such as loop diuretics, thiazides, and acetazolamide, lead to increased Na+ delivery to the distal nephron, volume depletion with increased aldosterone secretion, and subsequent increased renal K+ excretion.

In addition to the kidney, what is the other major route of K+ loss?
The GI tract. Fluids in the lower GI tract, particularly those of the small bowel, are high in K+. Therefore, diarrhea can result in significant losses of K+. However, upper GI losses, such as vomiting or nasogastric suction, cause renal K+ loss. This renal K+ loss is multifactorial and includes the following:

  • Alkalosis
  • Volume depletion, which leads to increased aldosterone secretion
  • Chloride depletion from the loss of HCl in gastric fluid, which leads to a high tubular concentration of HCO3-, a relatively nonresorbable anion

What causes a spuriously elevated serum K+ determination?

  • Hemolysis, with the release of intraerythrocytic K+.
  • Pseudohyperkalemia, seen in marked thrombocytosis or leukocytosis. It is due to the disproportionately increased amounts of the normally released K+ that occurs with clotting. This condition can be corrected by inhibiting clotting and measuring the plasma K+ concentration.

List the four common mechanisms by which hyperkalemia develops.

  • Inadequate excretion
  • Excessive intake
  • Shift of potassium from tissues
  • Pseudohyperkalemia (due to thrombocytosis, leukocytosis, poor venipuncture technique, in vitro hemolysis) Singer GG, Brenner BM: Fluids and electrolytes. In Fauci A, et al (eds): Harrison’s Principles of Internal Medicine, 14th ed. New York, McGraw-Hill, 1998.

What factors lead to inadequate potassium excretion?

  • Renal disorders (acute renal failure, severe chronic renal failure, tubular disorders)
  • Hypoaldosteronism .Adrenal disorders
  • Hyporeninemia (as with tubulointerstitial diseases, drugs such as NSAIDs, ACE inhibitosr, and beta blockers
  • Diuretics that inhibit potassium secretion (spironoloactone, triamterene, amiloride) What factors lead to a shift of potassium from tissues? .Tissue damage (muscle crush, hemolysis, internal bleeding)
  • Drugs (succinylcholine, arginine, digitalis poisoning, beta blockers)
  • Acidosis
  • Hyperosmolality
  • Insulin deficiency
  • Hyperkalemic periodic paralysis

What is the first step in the diagnostic approach to patients with disturbances in serum K+ concentration?
Determine whether the disturbance results from:

  • Abnormal K+ intake or metabolism (excessive catabolism or anabolism)
  • Intra-and extracellular compartmental shifts
  • Disturbances in renal excretion or extrarenal loss

What should you do next?
After the patient is placed in one of these three categories, it is possible to narrow the differential diagnosis, order appropriate diagnostic tests, and decide on the appropriate management. Disturbances of intake can be investigated by history and physical examination. The possibility of cellular shifts can be investigated by looking for any of the disturbances that result in compartmental movement of this cation. Determination of the urinary K+ concentration can help in distinguishing renal from nonrenal causes. High urinary K+ excretion in the setting of hypokalemia is compatible with a renal cause for K+ deficiency. In contrast, an appropriately low urinary K+ excretion in the setting of hypokalemia suggests extrarenal (possibly GI) losses.

How does hypokalemia present clinically?
The major manifestations are seen in the neuromuscular system. When K+ falls to 2.0-2.5 mEq/L, muscular weakness and lethargy are seen. With further decreases, the patient manifests paralysis with eventual respiratory muscle involvement and death. Hypokalemia also can cause rhabdomyolysis, myoglobinuria, and paralytic ileus. Prolonged hypokalemia can lead to renal tubular damage (called hypokalemic nephropathy).

How do you manage a patient with hypokalemia?
Management must be directed at the disturbance causing the abnormal K+ concentration. If hypokalemia is associated with alkalosis, then the alkalosis should be corrected in addition to providing K+ supplements. In general, patients with K+ depletion should be given supplements slowly to replace the deficit. The oral route is preferred because of its safety as well as efficacy. Some instances require more rapid repletion with IV supplements, but this should not exceed 20 mEq/h. Cardiac monitoring should accompany infusions of > 10 mEq/h.

What are the manifestations of hyperkalemia besides ECG changes?
The most important manifestation is the increased excitability of cardiac muscle. With severe elevations in K+, a patient can suffer diastolic cardiac arrest. Skeletal muscle paralysis also can be seen. Again, the symptoms produced by hyperkalemia are dependent on the rapidity of the change. Patients with chronically elevated serum K+ levels can tolerate higher levels with fewer symptoms than patients with acute hyperkalemia.

How is hyperkalemia generally managed?
Treatment depends on the extent of the hyperkalemia and the clinical setting. Mild levels of hyperkalemia (5.0-5.5 mEq/L) associated with the hyporenin-hypoaldosterone syndrome are tolerated well and usually require no treatment. Higher levels not associated with ECG changes may require treatment with a synthetic mineralocorticoid.

Describe the management of hyperkalemia as a medical emergency.
Hyperkalemia occasionally presents as a medical emergency with very high levels (> 7.0 mEq/L) and cardiac conduction system abnormalities as determined by the ECG changes. In this emergent setting, management includes:

  • IV calcium must be administered to immediately counteract the effect of hyperkalemia on the conduction system.
  • Calcium administration must be followed by maneuvers to shift K+ into cells, thereby decreasing the ratio of extra-to intracellular K+. This goal can be accomplished by administering glucose with insulin and/or bicarbonate to increase serum pH.
  • Finally, a maneuver to remove K+ from the body must be instituted, such as a cation-exchange resin (Kayexalate) and/or hemodialysis or peritoneal dialysis.

A 61-year-old woman with end-stage renal disease missed her dialysis twice and presents to the emergency department with a serum K+ of 6.4 mEq/L. How should you manage this patient?
The severity of hyperkalemia is assessed by both the serum K+ level and ECG changes. If the ECG shows only tall T waves and the serum K+ is < 6.5 mEq/L, the hyperkalemia is mild, whereas K+ levels of 6.5-8.0 mEq/L are associated with more severe ECG changes, including absent P waves and wide QRS complexes. At higher K+ levels, ventricular arrhythmias tend to appear, and the prognosis is grave unless proper treatment is given.

If the ECG shows only tall T waves, which agents should you administer? Why?

  • Hypertonic glucose infusion, along with 10 units of insulin (e.g., 10 units of insulin with 200-500 mL of 10% glucose in 30 min followed by 1 L of the same in the next 4-6 hours).
  • Sodium bicarbonate, 50-150 mEq given by IV (if the patient is not in fluid overload).

Both of these agents shift K+ into cells and start acting within an hour. Total body K+ can be decreased by using cation-exchange resins, such as sodium polysterone sulfonate; usually, 20 gm with 20 mL of 70% sorbitol solution is started every 4-6 h.

If the ECG shows the more severe changes, what should you do?
The patient should first receive 10% calcium gluconate (10-30 mL IV) while being monitored. Arrangements must be made to dialyze the patient as soon as possible to correct the hyperkalemia.

A 71-year-old diabetic with a nonhealing foot ulcer is on tobramycin and piperacillin. This patient has a resistant hypokalemia. How do you approach this problem?
Aminoglycosides and penicillins are both known to deplete serum K+. The former do this by defective proximal tubular K+ resorption and the latter by increased renal K+ excretion induced by the poorly resorbable anion (penicillin). With aminoglycosides, magnesium-wasting is another complication. Hence, in addition to K+ repletion, correction of hypomagnesemia is important, since hypokalemia is often resistant to correction unless the magnesium deficit is also corrected.

A 67-year-old man with congestive heart failure treated with furosemide has a serum K+ of 2.4 mEq/L. How would you correct his K+ deficit?
Hypokalemia is an important complication of diuretic therapy (except with K+-sparing diuretics). It is important to monitor serum K+ periodically in these patients, especially those with cardiac illnesses who are likely to be on digoxin because hypokalemia can exacerbate digitalis toxicity. The K+ deficit requires replacement (except in patients who are on minimal doses of diuretics), particularly if serum K+ is < 3 mEq/L. The serum K+ level is not an exact indicator of the total body deficit, but severe hypokalemia with serum K+ of < 3 mEq/L is usually associated with a deficit of approximately 300 mEq. KCl elixir or tablets are the treatment of choice. Enteric-coated K+ supplements are known to cause gastric ulceration.

What is the primary defect in Bartter’s syndrome?
The primary defect in Bartter’s syndrome seems to be impaired NaCl reabsorption in the thick ascending loop of Henle or distal tubule. Recent genetic studies indicate the defect involves a mutation of Na+-K+-2Cl cotransporter or K+ channel in the thick ascending limb of Henle. The diagnosis is often made by exclusion. Surreptitious use of diuretics and vomiting (urine Cl- is often low!) can mimic most of the findings of this syndrome.

Describe the treatment of Bartter’s syndrome.
Treatment consists of a K+-sparing diuretic (such as amiloride in doses of 10-40 mg) and NSAIDs to raise the plasma K+ by reversing the physiologic abnormalities.
Wingo C: Disorders of potassium balance. In Brenner B, Rector CR (eds): The Kidney, 6th ed. Philadelphia, W.B. Saunders, 2000.

A 55-year-old man with a history of congestive heart failure and chronic obstructive pulmonary disease (COPD) presents with extreme weakness and fatigue. His medications include digoxin 0.25 mg/day, hydrochlorothiazide 50 mg/day, and albuterol inhalations for his asthma. The patient reports a few days of exacerbation of COPD symptoms, forcing him to use the inhaler more frequently. What is the likely cause of his weakness?
The most likely cause of weakness in this patient is severe hypokalemia resulting from overuse of beta agonists such as albuterol especially in the presence of potassium losing diuretics, since both effects could be additive. The hypokalemic effects of inhaled beta agonists are often so potent that they are used to treat patients with hyperkalemia acutely.

References
BIBLIOGRAPHY

  1. Brenner RM (ed): Brenner & Rector’s The Kidney, 7th ed. Philadelphia, W.B. Saunders, 2004.
  2. Goldman L, Ausiello D (eds): Cecil Textbook of Medicine, 22nd ed. Philadelphia, W.B. Saunders, 2004.
  3. Rose BD, Post T (eds): Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed. New York, McGraw-Hill, 2001.
  4. Schrier RW (ed): Renal and Electrolyte Disorders, 6th ed. Philadelphia, Lippincott Williams & Wilkins, 2003.
  5. Wingo C: Disorders of potassium balance. In Brenner B, Rector CR (eds): The Kidney, 6th ed. Philadelphia, W.B. Saunders, 2000.
  6. Singer GG, Brenner BM: Fluids and electrolytes. In Fauci A, et al (eds): Harrison’s Principles of Internal Medicine, 14th ed. New York, McGraw-Hill, 1998.

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