Disorders of Potassium Metabolism

Introduction

Dyskalemias (i.e., hypo- and hyperkalemia) are common abnormalities that occur frequently in patients with chronic kidney disease and are associated with increased morbidity and mortality. Due to their acute effects on cardiac arrhythmias, severe hypo- and hyperkalemia are medical emergencies that require immediate intervention. Because of their potential for recurrence, dyskalemias require long-term interventions to minimize their recurrence. The recent development of newer potassium binders has resulted in a re-evaluation of the optimal strategies for the chronic management of hyperkalemia.

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 distribution between the extracellular and intracellular fluid compartments.

External Potassium Balance

The average American diet contains about 100 mmol (4 g) of potassium per day, with higher average potassium intake in women compared to men, older individuals compared to younger, and Caucasians compared to African-Americans. 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, requiring 6 to 12 hours to eliminate an acute load.

Kidney Handling of Potassium

To understand the physiologic factors that determine kidney 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. The majority of filtered potassium is subsequently 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 Kidney 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 cells, 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 and distal sodium delivery (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 rather than hypokalemia because of decreased delivery of sodium to the distal nephron. Many diuretics increase kidney 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 enhanced distal delivery of sodium.

Table 10.1

Physiologic Factors Increasing Kidney Potassium Excretion

Factor	Mechanism	Medical Conditions Affecting It	Drugs Affecting It
Aldosterone	Increase Na ⁺ /K ⁺ -ATPase activity in collecting duct	Diabetic nephropathyInterstitial nephritisPrimary hyperaldosteronismSecondary hyperaldosteronism	NSAIDsACE inhibitorsARBsHeparinSpironolactone
Distal Na ⁺ delivery	Create electrochemical gradient	Uncontrolled diabetes	Loop diureticsThiazide diuretics
Urine flow	Increase concentration gradient	Uncontrolled diabetes	Loop diureticsThiazide diuretics
Tubular [K ⁺ ]	Increase concentration gradient	Hyperkalemia	—
Metabolic alkalosis	Decreased proximal Na ⁺ reabsorption	Primary hyperaldosteronism	Loop diureticsThiazide diuretics

ACE , angiotensin converting enzyme; ARB , angiotensin receptor blocker; NSAIDs , nonsteroidal antiinflammatory drugs.

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.

An increase in dietary potassium causes an inhibition of the thiazide-sensitive NaCl cotransporter in the distal convoluted tubule through an enteric sensing mechanism, prior to a detectable rise in plasma potassium concentration. This leads to increased flow and delivery of sodium to the downstream distal nephron and increased potassium secretion.

Adaptation in Chronic Kidney Disease

In patients with chronic kidney disease (CKD), three major mechanisms protect against hyperkalemia: (1) increased kidney 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. A normal plasma potassium concentration is typically maintained under steady state circumstances (i.e., stable dietary potassium intake), but the kidneys’ ability to acutely dispose of increased potassium loads diminishes significantly in patients with advanced stages of CKD, who experience increasing frequencies of hyperkalemic episodes. 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, and severe hyperkalemia occurs more frequently in patients with AKI as compared with those with CKD. Moreover, patients with AKI are often hypotensive, resulting in hypoperfusion and release of potassium from ischemic tissues.

A subset of patients with CKD fails 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 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 providing a significant contribution to potassium homeostasis. This adaptation is limited and is inadequate to compensate for the loss of urinary excretion in patients with advanced kidney disease but is a significant contributor to the potassium balance in patients with kidney failure on dialysis.

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 kidney 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.

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 plasma 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 plasma potassium by 2.5 mmol/L (35 mmol/14 L). In the absence of extrarenal potassium disposal, the patient’s plasma potassium would rise acutely to 7.0 mmol/L, a level frequently associated with serious ventricular arrhythmias. In practice, the increase in plasma potassium is much smaller because of efficient physiologic mechanisms that promote potassium shifts into the intracellular fluid compartment.

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