Abstract
Potassium homeostasis is regulated both by potassium excretion (primarily by the kidneys and to a smaller extent by the gut) and by potassium distribution regulated primarily by insulin and catecholamines). Hypokalemia and hyperkalemia may be caused by disease states or drugs that interfere with these regulatory processes. Hypokalemia is treated acutely by potassium supplementation and chronically by efforts to remedy the underlying mechanism. Severe hyperkalemia is treated acutely with intravenous calcium, insulin with dextrose, nebulized albuterol, and, in patients with kidney failure, with dialysis. Chronic hyperkalemia can be treated by dietary potassium restriction, discontinuation of contributory drugs, diuretics, and, in refractory cases, by colonic potassium binders.
Keywords
hyperkalemia, hypokalemia, aldosterone, insulin, albuterol, diuretic, patiromer, zirconium
Mechanisms of Potassium Homeostasis
Total body potassium is about 3500 mmol. Approximately 98% of this total is intracellular, primarily in skeletal muscle, and to a lesser extent in the liver. The remaining 2% (about 70 mmol) is in the extracellular fluid. Two homeostatic systems help maintain potassium homeostasis. The first system regulates potassium excretion from the kidney and gut. The second regulates potassium shifts between the extracellular and intracellular fluid compartments.
External Potassium Balance
The average American diet contains about 100 mmol (4 g) of potassium per day. Dietary potassium intake may vary widely from day to day. To stay in potassium balance, it is necessary to increase potassium excretion when dietary potassium increases and decrease potassium excretion when dietary potassium decreases. Normally the kidneys excrete 90% to 95% of dietary potassium, with the remaining 5% to 10% excreted by the gut. Potassium excretion by the kidney is a relatively slow process, taking 6 to 12 hours to eliminate an acute load.
Renal Handling of Potassium
To understand the physiologic factors that determine renal excretion of potassium, it is critical to review the main features of tubular potassium handling. Plasma potassium is freely filtered across the glomerular capillary into the proximal tubule. It is subsequently completely reabsorbed by the proximal tubule and loop of Henle. In the distal tubule and the collecting duct, potassium is secreted into the tubular lumen. For practical purposes, urinary excretion of potassium reflects potassium secretion into the lumen of the distal tubule and collecting duct. Thus any factor that stimulates potassium secretion increases urinary potassium excretion; conversely, any factor that inhibits potassium secretion decreases urinary potassium excretion.
Physiologic Regulation of Renal Potassium Excretion
Five major physiologic factors stimulate distal potassium secretion (i.e., increase excretion): aldosterone, high distal sodium delivery, high urine flow rate, high [K + ] in tubular cell, and metabolic alkalosis ( Table 10.1 ). Aldosterone directly increases the activity of Na + /K + -adenosine triphosphatase (ATPase) in the collecting duct cells, thereby stimulating secretion of potassium into the tubular lumen. Medical conditions that impair aldosterone production or secretion (e.g., diabetic nephropathy, chronic interstitial nephritis) or drugs that inhibit aldosterone production or action (e.g., nonsteroidal antiinflammatory drugs [NSAIDs], angiotensin converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs], heparin, spironolactone) decrease potassium secretion by the kidney. Conversely, medical conditions associated with increased aldosterone levels (primary hyperaldosteronism, secondary hyperaldosteronism due to diuretics or vomiting) increase potassium loss in the urine. Although there is profound secondary hyperaldosteronism in congestive heart failure and cirrhosis, each of these conditions may be associated with hyperkalemia because of decreased delivery of sodium to the distal nephron. Many diuretics increase renal potassium excretion by a number of mechanisms, including high distal sodium delivery, high urine flow rate, metabolic alkalosis, and hyperaldosteronism due to volume depletion. Poorly controlled diabetes commonly increases urinary potassium excretion due to osmotic diuresis with high urinary flow rate and high distal delivery of sodium.
| Factor | Mechanism | Medical Conditions Affecting It | Drugs Affecting It |
|---|---|---|---|
| Aldosterone | Increase Na + /K + -ATPase activity in collecting duct | Diabetic nephropathy Interstitial nephritis Primary hyperaldosteronism Secondary hyperaldosteronism | NSAIDs ACE inhibitors ARB Heparin Spironolactone |
| Distal Na + delivery | Create electrochemical gradient | Uncontrolled diabetes | Loop diuretics Thiazide diuretics |
| Urine flow | Increase concentration gradient | Uncontrolled diabetes | Loop diuretics Thiazide diuretics |
| Tubular [K + ] | Increase concentration gradient | Hyperkalemia | — |
| Metabolic alkalosis | Decreased proximal Na + reabsorption | Primary hyperaldosteronism | Loop diuretics Thiazide diuretics |
Reabsorption of sodium in the collecting duct occurs through selective sodium channels. This creates an electronegative charge within the tubular lumen relative to the tubular epithelial cell. This in turn promotes secretion of cations (K + and H + ) into the lumen. Therefore drugs that block the sodium channel in the collecting duct decrease potassium secretion. Conversely, in Liddle syndrome, a rare genetic disorder in which the sodium channel is constitutively open, avid sodium reabsorption results in excessive potassium secretion.
Adaptation in Chronic Kidney Disease
In patients with chronic kidney disease (CKD), three major mechanisms protect against hyperkalemia: (1) increased renal potassium excretion mediated by aldosterone, (2) increased intestinal potassium excretion, and (3) increased potassium excretion per nephron. The kidney compensates for reduced nephron number in CKD by increasing the efficiency of potassium excretion. Clearly there is a limit to kidney compensation, and a significant loss of kidney function impairs the ability to excrete potassium, thereby predisposing to a positive potassium balance and a tendency toward hyperkalemia. In most patients with CKD, overt hyperkalemia does not occur until the glomerular filtration rate (GFR) falls below 10 mL/min. Serum aldosterone levels are elevated in many patients with CKD. Aldosterone stimulates the activity of both Na + /K + -ATPase and H + /K + -ATPase, thereby promoting secretion of potassium in the collecting duct and defending against hyperkalemia. These adaptive mechanisms are less effective in patients with acute kidney injury (AKI) as compared with CKD. Moreover, patients with AKI are often hypotensive, resulting in hypoperfusion and release of potassium from ischemic tissues. For these reasons, severe hyperkalemia occurs more frequently in patients with AKI as compared with those with CKD.
A subset of patients with CKD fail to increase aldosterone levels appreciably; as a result, they develop hyperkalemia at moderate levels of GFR loss (<50 mL/min), typically in association with nonanion gap metabolic acidosis (type IV renal tubular acidosis). This condition is most commonly encountered with diabetic nephropathy and chronic interstitial nephritis. Moreover, administration of drugs that inhibit aldosterone production or secretion (e.g., ACE inhibitors, ARBs, NSAIDs, heparin) may provoke hyperkalemia in patients with mild to moderate CKD.
Intestinal Potassium Excretion
Like the renal collecting duct, the small intestine and colon secrete potassium in response to aldosterone. In normal individuals, intestinal potassium excretion plays a minor role in potassium homeostasis, accounting for about 10% of total potassium excretion. However, in patients with significant GFR loss, intestinal potassium secretion is increased three- to fourfold with a significant contribution to potassium homeostasis. This adaptation is limited and is inadequate to compensate for the loss of excretory function in patients with advanced kidney failure.
Internal Potassium Balance
Extracellular fluid [K + ] is approximately 4 mEq/L, whereas the intracellular [K + ] is approximately 150 mEq/L. Because of the uneven distribution of potassium between the fluid compartments, a relatively small net shift of potassium from the intracellular to the extracellular fluid compartment produces marked increases in plasma potassium. Conversely, a relatively small net shift from the extracellular to the intracellular fluid compartment produces a marked decrease in plasma potassium. Unlike renal excretion of potassium that requires several hours, potassium shift between the extracellular and intracellular fluid compartment (also referred to as extrarenal potassium disposal) is extremely rapid, occurring within minutes.
Clearly, in patients with advanced kidney failure whose capacity to excrete potassium is marginal, extrarenal potassium disposal plays a critical role in the prevention of life-threatening hyperkalemia following potassium-rich meals. The following example will illustrate this important principle. Suppose that a 70-kg anephric patient with a serum potassium of 4.5 mmol/L eats 1 cup of pinto beans, which contains 35 mmol of potassium. Initially, the dietary potassium is absorbed into the extracellular fluid compartment (20% × 70 kg = 14 L). This amount of dietary potassium will increase the serum potassium by 2.5 mmol/L (35 mmol/14 L). In the absence of extrarenal potassium disposal, the patient’s serum potassium would rise acutely to 7.0 mmol/L, a level frequently associated with serious ventricular arrhythmias. In practice, the increase in serum potassium is much smaller because of efficient physiologic mechanisms that promote potassium shifts into the intracellular fluid compartment.
Effects of Insulin and Catecholamines on Extrarenal Potassium Disposal
The two major physiologic factors that stimulate transfer of potassium from the extracellular to the intracellular fluid compartments are insulin and epinephrine. The stimulation of extrarenal potassium disposal by insulin and beta-2 adrenergic agonists is mediated by stimulation of the Na + /K + -ATPase activity, primarily in skeletal muscle cells. Interference with these two physiologic mechanisms (insulin deficiency or beta-2 adrenergic blockade, respectively) predisposes to hyperkalemia. On the other hand, excessive insulin or epinephrine levels predispose to hypokalemia.
The potassium-lowering effect of insulin is dose-related within the physiologic range of plasma insulin, and is independent of its effect on plasma glucose. Even the low physiologic levels of insulin present during fasting promote extrarenal potassium disposal. In nondiabetic individuals, hyperglycemia stimulates endogenous insulin secretion, thereby decreasing the serum potassium. In insulin-dependent diabetics, endogenous insulin production is limited, and significant hyperglycemia may occur. Hyperglycemia results in plasma hypertonicity, which promotes potassium shifts out of the cells and produces paradoxic hyperkalemia.
The potassium-lowering action of epinephrine is mediated by beta-2 adrenergic stimulation and is blocked by nonselective beta-blockers but not by selective beta-1 adrenergic blockers. Alpha-adrenergic stimulation promotes shifts of potassium out of cells into the extracellular fluid compartment, leading to an increase in serum potassium. Epinephrine is a mixed alpha-adrenergic and beta-adrenergic agonist, such that its net effect on serum potassium reflects the balance between its beta-adrenergic (potassium-lowering) and alpha-adrenergic (potassium-raising) effects. In normal individuals, the beta-adrenergic effect of epinephrine predominates over the alpha-adrenergic effect, such that the serum potassium decreases. In contrast, the alpha-adrenergic effect of epinephrine on potassium shifts is much more prominent in patients with severe kidney failure; as a result, patients undergoing dialysis are refractory to the potassium-lowering effect of epinephrine.
Effect of Acid-Base Disorders on Extrarenal Potassium Disposal
Acid-base disorders produce internal potassium shifts in a less predictable manner. As a general rule, metabolic alkalosis shifts potassium into cells, whereas metabolic acidosis shifts potassium out of cells. However, the nature of the metabolic acidosis determines its effect on serum potassium. Cells are relatively impermeable to chloride. With mineral acidoses, the entry of protons (but not chloride) into cells results in a reciprocal release of potassium from cells to maintain electro-neutrality. In contrast, cells are highly permeable to organic anions. The addition of an organic acid to the extracellular fluid results in parallel shifts of protons and organic anions into the cells, with no net change in the electric balance; as a result, potassium is not released from cells. Thus mineral acidoses (i.e., hyperchloremic, normal anion gap metabolic acidosis) typically result in hyperkalemia, whereas organic metabolic acidoses (e.g., lactic acidosis) do not affect the serum potassium. Bicarbonate administration to individuals with normal kidney function decreases serum potassium, but this effect is largely due to enhanced urinary excretion of potassium. In contrast, bicarbonate administration to patients undergoing dialysis (in whom the capacity for urinary potassium excretion is negligible) does not lower plasma potassium acutely. Moreover, bicarbonate administration does not potentiate the potassium-lowering effects of insulin or albuterol in patients undergoing dialysis.
Laboratory Tests to Evaluate Potassium Disorders
Differential Diagnosis of Hypokalemia and Hyperkalemia
The clinical history, medication review, family history, and physical examination are sufficient to create a rapid differential diagnosis of most potassium disorders. In selected patients, the etiology of hypokalemia or hyperkalemia is not apparent, and additional specialized laboratory tests may be useful. Measurement of the fractional excretion of potassium (FE K ) may help distinguish between renal and nonrenal etiologies of hyperkalemia and hypokalemia. The general principle underlying this test is that the kidney compensates for hyperkalemia by increasing potassium excretion and compensates for hypokalemia by decreasing potassium excretion. In contrast, when potassium excretion is inappropriate for the serum potassium, this suggests a renal etiology. The optimal use of FE K to inform the differential diagnosis requires that this value be obtained before the potassium abnormality (hyperkalemia or hypokalemia) is corrected.
Fractional Excretion of Potassium
FE K is the percent of potassium filtered into the proximal tubule that appears in the urine. It represents potassium clearance corrected for GFR, or Cl K /Cl Cr . Since the clearance of any substance can be calculated from UV/P, this ratio can be algebraically transformed to:
[ ( U K V / P K ) / ( U Cr V / P Cr ) ] × 100 %
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