External Potassium Balance

  • External Potassium Balance refers to the regulation of renal potassium excretion and is responsible for long-term control of total body potassium stores. Potassium excretion is ultimately determined by the balance between its rate of glomerular filtration, resorption, and secretion. Because the rate of glomerular filtration is maintained at a fairly constant level, specific regulation of potassium excretion is achieved by modulation of its tubular resorption and secretion rates. Below we detail where along the nephron potassium resorption and secretion occur and then discuss how these processes are regulated to maintain relatively constant total body potassium stores.
Potassium Transport
  • Overview
    • Nearly 65% of filtered potassium is resorbed in the proximal tubule, likely by a paracellular route, while 25% is resorbed in the thick ascending Henle using the Na2ClK Symporter. The proportion of filtered potassium resorbed in these segments is relatively constant and is not subject to regulation. Regulated potassium transport appears to occur in the late distal tubule and collecting duct which can either resorb nearly all of the remaining tubular potassium or can secrete large amounts of potassium depending on the physiological requirements of the body. Resorption and secretion of potassium by the late distal tubule and collecting ducts appear to occur in distinct cell types as described below.
  • Intercalated Cells
    • Intercalated Cells of the late distal tubule and collecting duct are responsible for regulated tubular resorption of potassium. When ECF potassium concentrations are low, the intercalated cells can resorb nearly all of the remaining tubular potassium; however, as ECF potassium concentrations increase toward normal, resorption by intercalated cells progressively declines to zero. The precise molecular mechanism by which intercalated cells resorb potassium is not well-understood but may involve a luminal HK ATPase that actively resorbs K+ in exchange for H+ secretion. Basolateral transport may occur via a potassium channel.
  • Principal Cells
    • Principal Cells of the late distal tubule and collecting duct are responsible for regulated tubular secretion of potassium. As ECF potassium concentrations progressively increase above normal, the secretion rate of potassium by principal cells increases proportionally and can achieve significant rates. The molecular mechanism by which principal cells secrete potassium begins with basolateral primary active transport of potassium into the cell by the basolateral NaK ATPase. Potassium is then secreted passively through the luminal membrane via K+ channels and is dictated by the electrochemical gradient for potassium. As a result, high intracellular concentrations of potassium compared to that of the tubular fluid, typically yield potassium secretion.
  • Overview
    • Because modern diets contain significant amounts of potassium, regulation of tubular secretion is the principal mechanism by which external potassium balance is achieved in most individuals today. A variety of mechanisms appear to modulate secretion of potassium by principal cells and these are discussed below.
  • Direct Action on Na-K ATPase Activity
    • Physiological studies have shown that increases in the extracellular fluid concentration directly stimulate principal cells to secrete potassium. While a variety of molecular mechanisms may be responsible for this phenomenon, increased extracellular potassium concentrations may directly enhance the activity of the basolateral NaK ATPase, thus increasing intracellular potassium concentrations and in turn boosting the electrochemical gradient for luminal potassium secretion.
  • Aldosterone
    • As described in aldosterone physiology, increased ECF potassium concentrations also appear to directly stimulate the adrenal cortices to synthesize and secrete aldosterone. Aldosterone in turn modulates multiple biochemical features of the principal cell to enhance potassium secretion. First, the presence of aldosterone appears to directly stimulate the basolateral NaK ATPase which enhances potassium secretion as described above. Secondly, aldosterone promotes the placement of additional potassium channels into the luminal principal cell membrane, thus boosting its permeability for potassium secretion. The effect of aldosterone on principal cell potassium secretion is extremely powerful and likely represents the dominant mechanism for proper maintenance of ECF potassium levels.
  • Distal Tubular Flow Rate
    • The rate of potassium secretion by principal cells is affected by the adjacent rate of tubular fluid flow through the distal tubule and collecting duct. High rates of distal tubular flow enhance potassium secretion whereas lower rates of distal tubular flow reduce potassium secretion. The mechanism of this phenomenon appears to be based on changes in the electrochemical gradient for potassium between the tubular fluid and the intracellular space of the secreting principal cells. When distal tubular flow rates are slow, potassium concentrations build up relatively earlier in the tubule, thus progressively decreasing the electrochemical gradient for outward diffusion from the principal cells and thus decreasing the rate of potassium secretion. When distal tubular flow rates are high, potassium concentrations build up relatively late in the tubule as any secreted potassium is rapidly washed away; consequently, the electrochemical gradient for outward diffusion of potassium remains high throughout the tubule, thus enhancing potassium secretion by the principal cells.
    • The relationship between distal tubular flow rate and potassium secretion is an important mechanism for preventing a physiological conflict between the role for aldosterone in the regulation of potassium and sodium excretion. Recall that the the presence of aldosterone not only promotes tubular potassium secretion but also sodium resorption via the Renin-Angiotensin-Aldosterone System (RAAS). Interestingly, aldosterone-mediated stimulation of the principal cell basolateral NaK ATPase is the common mechanism for both of these phenomenon. Given this dual role of aldosterone, it might be imagined that aldosterone secreted by the RAAS for correcting hypotension may cause an inappropriate secretion of tubular potassium.
    • However, in an individual with deficient ECF volume, distal fluid flow rates are reduced thus blunting any aldosterone-mediated enhancements of potassium excretion. Equally, any reductions in aldosterone secretion mediated by the RAAS in an individual with an expanded ECF volume (Say who just ate a large sodium load) would not interfere with potassium homeostasis as increased distal tubular flow rates in this context would enhance potassium secretion. However, it should be pointed that the use of certain diuretics can cause high distal tubular flow rates that can lead to profound hypokalemia if not corrected.
  • Acute Acid-Base Changes
    • Acute changes in the extracellular fluid pH can result in modulation of principal cell potassium secretion. In contexts of acute metabolic acidosis, potassium secretion is blunted whereas in contexts of acute metabolic alkalosis, potassium secretion is enhanced. The precise mechanism of this phenomenon is not well-understood although it is possible that acute acidosis does inhibit the basolateral principal cell NaK ATPase. Additionally, acute acidosis may result in a transient decline of intracellular potassium concentration in the principal cell, thus reducing the electrochemical gradient for luminal potassium secretion. This may occur because a basolateral principal cell HK Antiporter may exchange increased concentrations of extracellular H+ for intracellular K+, thus partially reducing the intracellular potassium concentration.