• State the normal balance and distribution of potassium between cells and extracellular fluid.
  
• Describe how potassium moves between cells and the extracellular fluid, and how, on a short-term basis, the movement protects the extracellular fluid from large changes in potassium concentration.
  
• State why plasma levels of potassium do not always reflect the status of total-body potassium.
  
• State how insulin and epinephrine influence the cellular uptake of potassium and identify the situations in which these hormonal influences are most important.
  
• State the relative amounts of potassium reabsorbed by the proximal tubule and thick ascending limb of Henle’s loop regardless of the state of potassium intake.
  
• Describe how nephron segments beyond the thick ascending limb can manifest net secretion or reabsorption; describe the role of principal cells and intercalated cells in these processes.
  
• List inputs that control the rate of potassium secretion by the distal nephron.
  
• Describe the actions of ROMK and BK potassium channels in conditions of low, normal, and high potassium excretion.
  
• Describe how changes in plasma potassium influence aldosterone secretion.
  
• State the effects of most diuretic drugs on potassium excretion.

The vast majority of body potassium is freely dissolved in the cytosol of tissue cells and constitutes the major osmotic component of the intracellular fluid (ICF). Only about 2% of total-body potassium is in the extracellular fluid (ECF). This small fraction, however, is absolutely crucial for body function, and the concentration of potassium in the ECF is a closely regulated quantity. Major increases and decreases (called hyperkalemia and hypokalemia) in plasma values are cause for medical intervention. The importance of maintaining this concentration stems primarily from the role of potassium in the excitability of nerve and muscle, especially the heart. The ratio of the intracellular to extracellular concentration of potassium is the major determinant of the resting membrane potential in these cells. A significant rise in the extracellular potassium concentration causes a sustained depolarization. Low extracellular potassium may hyperpolarize or depolarize depending on how changes in extracellular potassium affect membrane permeability. Both conditions lead to muscle and cardiac disturbances.

Given that the vast majority of body potassium is contained within cells, the extracellular potassium concentration is crucially dependent on (1) the total amount of potassium in the body and (2) the distribution of this potassium between the extracellular and intracellular fluid compartments. Total-body potassium is determined by the balance between potassium intake and excretion. Healthy individuals remain in potassium balance, as they do in sodium balance, by excreting potassium in response to dietary loads and withholding excretion when body potassium is depleted. The urine is the major route of potassium excretion, although some is lost in the feces and sweat. Normally the losses via sweat and the gastrointestinal tract are small, but large quantities can be lost from the digestive tract during vomiting or diarrhea. The control of renal potassium transport is the major mechanism by which total-body potassium is maintained in balance.

The fact that most body potassium is in the ICF follows strictly from the size and properties of the intracellular and extracellular compartments. About two thirds of the body fluids are in the ICF, and typical cytosolic potassium concentrations are about 140 to 150 mEq/L. One third of the body fluids are in the ECF, with a potassium concentration of about 4 mEq/L. In a clinical setting, only the extracellular concentration can be measured (the intracellular potassium is, in a sense, hidden behind the wall of the cell membrane). Furthermore, the extracellular value does not necessarily reflect total-body potassium. A patient may, for example, be hyperkalemic (high plasma potassium concentration) and yet at the same time be depleted of total-body potassium.

The high level of potassium within cells is maintained by the collective operation of the Na-K-ATPase plasma membrane pumps, which actively transport potassium into cells. Because the total amount of potassium in the extracellular compartment is so small (40–60 mEq total), even very slight shifts of potassium into or out of cells produce large changes in extracellular potassium concentration. Similarly, a meal rich in potassium (eg, steak, potato, and spinach) could easily double the extracellular concentration of potassium if most of that potassium were not transferred from the blood to the intracellular compartment. It is crucial, therefore, that dietary loads be taken up into the intracellular compartment rapidly to prevent major changes in plasma potassium concentration.

The tissue contributing most to the sequestration of potassium is skeletal muscle, simply because muscle cells collectively contain the largest intracellular volume. Muscle effectively buffers extracellular potassium by taking up or releasing it to keep the plasma potassium concentration close to normal. On a moment-to-moment basis, this is what protects the ECF from large swings in potassium concentration. Major factors involved in these homeostatic processes include insulin and epinephrine, both of which cause increased potassium uptake by muscle and certain other cells through stimulation of plasma membrane Na-K-ATPases. Another influence is the gastrointestinal (GI) tract, which contains an elaborate neural network (the “gut brain”) that sends signals to the central nervous system. It also contains a complement of enteroendocrine cells that release an array of peptide hormones. Together these neural and hormonal signals affect many target organs, including the kidneys (see later discussion) in response to dietary input.

The increase in plasma insulin concentration after a meal is a crucial factor in moving potassium absorbed from the GI tract into cells rather than allowing it to accumulate in the ECF. This newly ingested potassium then slowly comes out of cells between meals to be excreted in the urine. Moreover, a large increase in plasma potassium concentration facilitates insulin secretion at any time, and the additional insulin induces greater potassium uptake by the cells, a negative feedback system for opposing acute elevations in plasma potassium concentration. In the natural order of things, insulin also stimulates glucose uptake and metabolism by cells: a necessary source of energy to drive the insulin-activated Na-K-ATPase responsible for moving potassium into cells.

The effect of epinephrine on cellular potassium uptake is probably of greatest physiological importance during exercise when potassium moves out of muscle cells that are rapidly firing action potentials. In fact, very intense intermittent exercises such as wind sprints can actually double plasma potassium for a brief period. However, at the same time, exercise increases adrenal secretion of epinephrine, which stimulates potassium uptake by the Na-K-ATPase in muscle and other cells and the transiently high potassium levels are restored to normal with a few minutes of rest.1 Similarly, trauma causes loss of potassium from damaged cells and epinephrine released due to stress stimulates other cells to take up plasma potassium.

Still another influence on the distribution of potassium between the ICF and ECF is the ECF hydrogen ion concentration: An increase in ECF hydrogen ion concentration (acidemia; see Chapter 9) is often associated with net potassium movement out of cells, whereas a decrease in ECF hydrogen ion concentration (alkalemia) causes net potassium movement into them. It is as though potassium and hydrogen ions were exchanging across plasma membranes (ie, hydrogen ions moving into the cell during acidemia and out during alkalemia and potassium doing just the opposite), but the precise mechanism underlying these “exchanges” has not yet been clarified. However, like the effect of insulin, it probably involves an inhibition (acidemia) or activation (alkalemia) of the Na-K-ATPase.

1Intense activity of the Na-K-ATPase hyperpolarizes the cells and prevents what otherwise would be a dangerous depolarization due to the high extracellular potassium.

Overview

Although skeletal muscle and other tissues play an important role in the moment-to-moment control of plasma potassium concentration, in the final analysis, the kidney determines total-body potassium content. Therefore, understanding potassium handling by the kidneys is the key to understanding whole body potassium balance. It is helpful to keep in mind several major differences between the renal handling of sodium and potassium. First, the filtered load of sodium is 30 to 40 times greater than the filtered load of potassium and the tubules always have to recover the majority of filtered sodium. This is not the case for potassium. Second, sodium is only reabsorbed, never secreted. In contrast, potassium is both reabsorbed and secreted, and its regulation is primarily focused on secretion. Third, the renal handling of sodium has a much greater effect on potassium than vice versa, which, as explained later, is a major feature of control.

Potassium is freely filtered into Bowman’s space. Under all conditions, almost all the filtered load (~90%) is reabsorbed by the proximal tubule and thick ascending limb of the loop of Henle. Then, if the body is conserving potassium, most of the rest is reabsorbed in the distal nephron and medullary collecting ducts, leaving almost none in the urine. In contrast, if the body is ridding itself of potassium, a large amount is secreted in the distal nephron, resulting in a substantial excretion. When secretion occurs at high rates, the amount excreted may exceed the filtered load. The chief means of regulation lies in control of secretion in parts of the nephron beyond the loop of Henle. Let us look at potassium handling by various nephron segments and then address the issue of control.

At a normal plasma level of 4 mEq/L and GFR of 150 L/day or more, and given that potassium is freely filtered, this results in a daily filtered load of about 600 mEq/day. The subsequent events in various tubule segments are summarized in Table 8–1. In the proximal tubule about 65% of the filtered load is reabsorbed, mostly via the paracellular route. The flux is driven by the concentration gradient set up when water is reabsorbed, which concentrates potassium and other solutes remaining in the tubular lumen. This flux is essentially unregulated and varies mostly with how much sodium, and therefore water, is reabsorbed.