Percentage of fitered load transported at different locations depending on diet
The Importance of Potassium Balance
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 quantitiy. 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.
Potassium Movement Between the ICF and ECF
Given that the vast majority of body potassium is contained within cells, the extracellular potassium concentration is cruically 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 withholdin g 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 the lost from 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 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 (e.g., 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 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 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 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.
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 bu the Na-K-ATPase in muscle and other cells and transiently high potassium levels are restored to normal with a few minutes of rest. Similarly, trauma causes of loss of potassium from damaged cells and epinephrine released due to stress stimulates other cells to take up plasma potassium.
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 is often associated with net potassium movement out of cells, whereas a decrease in ECF hydrogen ion concentration causes net potassium movement into them. It is as though potassium and hydrogen ions were exchanging across plasma membranes.
Renal Potassium Handling
Althgouh skeletal msucle 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. It is helpful to keep in mind several major differences between teh renal handling of sodium and potassium.
- 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.
- Sodium is only reabsorbed, never sereted. In contrast, potassium is both reabsorbed and secreted, ant its regulation is primarily focused on secretion.
- The renal handling of sodium has a much greater effect on potassium than vice versa, which 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, of which the amount excreted may exceed the filtered load when secretion occurs at high rates.
PS: Proximal tubule reabsorption percentage: 65%; thick ascending limb of the loop of Henle reabsorption percentage: 25%
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.
The active transport of potassium is always coupled to the active transport of another solute, either sodium or hydrogen. In the proximal tubule the efflux of sodium by the Na-K-ATPase is very vigorous, requiring a high rate of potassium uptake from the interstitium. Since we know that there is net potassium transport into the interstitium, this pumped potassium must therefore recycle right back by passive flux through channels in the basolateral membrane. In some regions influx of potassium across apical membranes occurs via H-K antiporters that are simultaneously secreting protons.
The loop of Henle
The loop of Henle continues the reabsorption of potassium. The major events take place in the thick ascending limb, where the Na-K-2Cl multiporter in the apical membrane of the tubular cells takes up potassium. The interaction with sodium in these cells is even more complicated than in the proximal tubule because potassium is transported into the bubular cells both from the lumen with sodium via Na-K-2Cl symporters and from the interstitium via the Na-K-ATPase. The tubule contains far less potassium than sodium, but the Na-K-2Cl transporter moves equal amounts of each one. Therefore to supply enough potassium to accompany the large amount of sodium being reabsorbed by the symporter, potassium must recycle back to the lumen by passive channel flux. If this did not happen then sodium reabsorption would be limited only to the amount of potassium present in the tubular fluid.
Some potassium entering from the lumen does move through the cells and exit across the basolateral membrane along with the potassium entering via the Na-K-ATPase. It exits by a combination of passive flux through channels and through K-Cl symporters with chloride, thus yielding net transcellular reabsorption. Some potassium is also reabsorbed by the paracellular route in this segment, driven by a lumen-positive voltage.
The distal nephron
The distal convoluted tubule and connecting tubule stand out as being particularly imporant in potassium handling because of their rich complement of transport elements and their location prior to segments where most of water is absorbed. These regions play a major role in potassium secretion when total body potassium is high (high potassium diet). The distal nephron expresses both reabsorptive and secretory mechanisms, and it is the quantitative amount of each that determines net potassium excretion. There are several cell types in the epithelium of the connecting tubule and cortical collecting duct. Principal cells (approximately 70% of the cells) and intercalated cells. The intercalcated cells are further subdivided into type A (more numerous), type B (sparse) and a third type called non-A non-B cells. Potassium secretion occurs in principal cells, whereas the type A intercalated cells reabsorb potassium. The mechanisms of both secretion and reabsorption are straightforward. Secretion of potassium by principal cells involves the uptake of potassium from the interstitium via the Na-K-ATPase and secretion into the tubular lumen through channels. Type A intercalated cells reabsorb potassium via the H-K-ATPase in the apical membrane, which actively takes up potassium from the lumen. They then allow potassium to enter the interstitium across the basolateral membrane via potassium channels.
Finally, the medullary collecting ducts reabsorb small amounts of potassium under all conditions. When the sum of upstream processes has already reabsorbed almost all the potassium, the medullary collecting ducts bring the final urine excretion down to a few percent of the filtered load, for an excretion of about 10 to 15 mEq/day. On the other hand, if upstream segments are secreting avidly, the modest reabsorption in the medullary collecting ducts does little to prevent an excretion that can reach 1000 mEq/day.
Regulation of Potassium Excretion
The mechanisms regulating potassium excretion are as complex, and perhaps more so, than those regulating sodium excretion. And as pointed out earlier, active potassium trasnport is intertwined with sodium and hydrogen transport. But within the complexity one thing is abundantly clear – the healthy kidneys do a remarkable job of integrating signals to increase potassium excretion in response to high dietary loads and reduce excretion in the face of restricted diets.
The key regulated variable is potassium secretion by principal cells in the distal nephron. There are 3 transport processes in these cells that determine the amount of secretion: potassium influx by the Na-K-ATPase, potassium efflux into the lumen, and potassium efflux back into the interstitium (recycling). Much of the control is exerted on the activity of potassium channels. The kidneys and other body organs express numerous potassium channel species; for simplicity we do not usually differentiate between types. However in the apical membrane of principal cells in the distal nephrone, 2 types of channels stand out as being those that secrete potassium in a regulated manner: ROMK and BK. Although ROMK and BK channels are both permeable to potassium, they play different mechanisms. At very low dietary loads of potassium, there is virtually no secretion by either kind of channel. ROMK channels are sequestered in intracellular vesicles and BK channels are closed. At normal potassium loads, ROMK channels are moved to the apical membrane and secrete potassium at a modest rate. BK channels are still closed, held in reserve and ready to respond to appropriate signals when needed. At high excretion rates, both types of channel are present in the luminal membrane and avidly secreting potassium being pumped in by the Na-K-ATPase.
First, the filtered load is directly proportional to plasma concentration. Second, the environment of the principal cells that secrete potassium, that is, the cortical interstitium, has a potassium concentration that is nearly the same as in plasma. The Na-K-ATPase that takes up potassium is highly sensitive to the potassium concentration in this space, and varies its pump rate up and down when potassium levels in the plasma vary up and down. Thus plasma potassium concentration exerts an influence on potassium excretion, but is not the dominant factor under normal conditions.
Dietary potassium must be matched by renal excretion. The healthy kidneys do this very well by increasing and decreasing potassium excretion in parallel with dietary load. Just how the kidneys "know" about dietary input is still somewhat mysterious. Although very large potassium loads can increase plasma potassium somewhat, the changes in excretion assocaited wtih ordinary fluctuations in dietary input do not seem to be accounted for on the basis of either changes in plasma potassium or the other identified factors. One factor known to exert an influence, but not the major one, is the previously mentioned gastrointestinal peptide hormones released in response to ingested potassium. They influence not only the cellular uptake of potassium absorbed from the GI tract, but also the renal handling ot potassium, and seem to be one of the links between dietary load and excretion.
A manifestation of changing dietary loads over time is to regulate the distribution of ROMK channels between the apical membrane and intracellular storage, that is, high-potassium diets lead to insertion of apical channels and therefore highest potassium secretion. In contrast, during periods of prolonged low potassium ingestion, there are few ROMK channels in the apical membrane. Yet another adaptation to prolonged periods of low potassium ingestion is an increase in H-K-ATPase activity in intercalated cells, resulting in even more efficient reabsortpion of filtered potassium.
A stimulator of aldosterone secretion by the adrenal cortex, in addition to AII, is an increase in plasma potassium concentration. This is a direct action of potassium and does not involve the renin-angiotensin system. If anything, high levels of potassium decrease the formation of AII. Aldosterone, as well as increasing expression of the Na-K-ATPase and ENaC sodium channels, also stimulates the activity of ROMK channels in principal cells of the distal nephron. Both actions have the effect of increasing potassium secretion. Greater pumping by the Na-K-ATPase supplies more potassium from the interstitium to the cytosol of the principal cells, and more functioning ROMK channels provide more pathways for secretion. Conversely, low levels of aldosterone deter potassium secretion.
AII is an inhibitor of potassium secretion. Its mechanism of action is to decrease the activity of ROMK channels in principal cells and distal convoluted cells, thereby limiting the potassium flux from cell to lumen. Thus AII and aldosterone exert influences on potassium excretion in opposite directions.
Delivery of sodium to principal cells
Sodium delivery to principal cells in the connecting tubule and cortical collecting duct is a major regulator. High sodium delivery stimulates potassium secretion. It does so in 2 ways. First, sodium entry via sodium channels (ENaC?) in principal cells depolarizes the apical membrane and thereby increases the electrochemical gradient driving the outward flow of potassium through channels. Second, more sodium delivered means more sodium taken up, and therefore more sodium pumped out by the Na-K-ATPase, in turn causing more potassium to be pumped in. Sodium delivery to principal cells, and hence potassium secretion, is strongly affected by the amount of sodium reabsorption in prior segments.