Renal Potassium Reabsorption and Secretion

July 24, 2016 Cardiology, Critical Care, Nephrology, Physiology and Pathophysiology No comments , , , , , , , , , , ,

Percentage of fitered load transported at different locations depending on diet

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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%

Proximal tubule

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.

Plasma potassium

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

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.

Angiotensin II

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.

Regulation of Sodium Excretion

June 25, 2016 Cardiology, Critical Care, Nephrology, Physiology and Pathophysiology No comments , , , , , , , , , , , , , , , , , , , , , , , , ,

Percentage of Sodium Reabsorbed

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The Goals of Regulation

The overriding goals of regulating sodium and water excretion are to support the requirements of the cardiovascular system. This is manifested in 3 ways: 1.the kidneys maintain a sufficient ECF volume to fill the vascular space (mean circulatory filling pressure); 2.keep the osmolality of the ECF at a level consistent with cellular health; and 3.limit the changes in renal blood flow (RBF) and GFR that might otherwise reach deleterious levels. The kidneys and the CV system work cooperatively to ensure that peripheral tissue is sufficiently perfused. An adequate circulating volume is one of the essential requirements for tissue perfusion and it is the kidneys that control this volume. Osmolality is the ratio of solute content to water content. Sodium and chloride together account for 80% of the normal extracellular solute; thus the excretion of sodium and water by the kidneys regulates osmolality in the tight range that is needed for the health of tissue cells. There is a separate goal of regulation that differs from those stated above. Variations in RBF and GFR are major means of regulating sodium excretion. However, the kidney cannot change blood flow and filtration to such extreme values that they compromise the metabolic health of the kidneys or interfere with the excretion of substances other than sodium, particularly organic waste.

Formulas for ECF Volume

There are some formulas showing the relationship between ECF solute content, ECF osmolality, and ECF volume. Since almost all of the ECF solute is accounted for by sodium and an equivalent number of anions (mostly chloride and bicarbonate), the amount of ECF solute is approximately twice the sodium content.

ECF osmolality = ECF solute content / ECF volume (Equation 7-1)

ECF volume = ECF solute content / ECF osmolality (Equation 7-2)

ECF volume ≈ 2 x Na content / ECF osmolality (Equation 7-3)

Therefore, in the face of tightly controlled ECF osmolality, ECF volume varies directly with sodium content. But how do the kidneys know how much sodium there is in the ECF? The detection of sodium content is indirect, based on a combination of assessing sodium concentration and vascular pressures. Glial cells in regions of the brain called the circumventricular organs have sensory Na+ channels that respond to and act as detectors of extracellular sodium concentration. The glial cells modulate the activity of nearby neurons involved  in the control of body sodium. There are also neurons in the hypothalamus contain the sensory Na+ channels that respond to the sodium concentration in the cerebrospinal fluid. Thus cells in or near the hypothalamus monitor extracellular sodium concentration.

The volume affects pressure in different regions of the vasculature. It is the presssure baroreceptors in these regions of the vasculature detect the vascular pressures.

Major Controllers of Sodium Excretion

Sympathetic Stimulation 

Vascular pressures are so important in regard to sodium excretion and because volume affect pressure in different regions of the vasculature, so the changes in ECF affects pressures (arterial and/or venous) and changes in pressure affect sodium excretion (Thread "Regulation of Arterial Pressure" at and thread "Mean Circulatory Filling Pressure and CVP" at

The vasculature and tubules of the kidney are innervated by postganglionic sympathetic neurons that release norepinephrine. In most regions of the kidney, norepinephrine is recognized by alpha-adrenergic receptors. In the renal vasculature activation of alpha1-adrenergic recpetors causes vasoconstriction of afferent and efferent arterioles. This reduces RBF and GFR.

GFR is a crucial determinant of sodium excretion. However, except in body emergencies such as hypovolemic shock, GFR is kept within rather narrow limits due to autoregulatory processes (detail for vascular autoregulatory regulation Thus although neural control does affect GFR, this component of sympathetic control is probably less important in normal circumstances than its effect on sodium reabsorption. Neural control of the renal vasculature is exerted primarily on blood flow in the cortex, allowing preservation of medullary perfusion even when cortical blood flow is reduced.

The proximal tubule epithelial cells are innervated by alpha1- and alpha2-adrenergic receptors. Stimulation of these receptors in the proximal tubule by norepinephrine activates both components of the main transcellular sodium reabsorptive pathway, that is, the sodium-hydrogen antiporter NHE3 in the apical membrane and the Na-K-ATPase in the basolateral membrane. The effects of sympathetic stimulation on cells in the distal nephron are less straightforward. However, the overall outcome of sympathetic stimulation of the kidney is clearly reduced sodium excretion.

The Renin-Angiotensin System

AII's function

  • Reduces the RBF and GFR
  • Stimulation of sodium tubular reabsorption
  • Stimulation of the CNS: salt appetite, thirst, and sympathetic drive
  • Stimulation of aldosterone secretion

The major determinant of circulating AII is the amount of renin available to form angiotensin I.

PS: "Control of the Circulating RAAS" is ready at

AII is a potent vasoconstrictor, acting on the vasculature of many peripheral tissues, the effect of which is to raise arterial pressure. It also vasoconstricts both cortical and medullary vessels in the kidney. This reduces total RBF and reduces GFR, thus decreasing the filtered load of sodium.

AII stimulates sodium reabsorption in both the proximal tubule and distal nephron. In the proximal tubule it stimulates the same transcellular transport pathway as does norepinephrine, namely NHE3 sodium/hydrogen antiporter in the apical membrane and the Na-K-ATPase in the basolateral membrane. In the distal tubule and connecting tubule, it stimulates the activity of sodium/chloride symporters and sodium channels (ENaC) that reabsorb sodium.

AII stimulates behavioral actions in response to fluid loss that increase salt appetite and thirst. AII acts on the circumventricular organs in the brain. These function as detectors of many substances in the blood and convey information to various areas of the brain. In situations of volume depletion and low blood pressure, when circulating levels of AII are high, a key effect, in addition to vascular and tubular actions is increased thirst and salt appetite. These pathways also increase sympathetic drive.

Aldosterone is a major stimulator of sodium reabsorption in the distal nephron, that is, regions of the tubule beyond the proximal tubule and loop of Henle. We focus here on the role of aldosterone in sodium reabsorption, but aldosterone has many other important actions, including stimulation of potassium excretion and acid excretion. The most important physiological factor controlling secretion of aldosterone is the circulating level of AII, which stimulates the adrenal cortex to produce aldosterone. But keep in mind that elevated plasma potassium concentration, atrial natriuretic factors are other stimulators of aldosterone secretion. The aldosterone has enough lipid character to freely cross principal cell membrane in the collecting ducts, after which it combines with mineralocorticoid receptors (aldosterone receptors) in the cytoplasm. After being transported to the nucleus, the receptor acts as a transcription factor that promotes gene expression of specific proteins. The effect of these proteins is to increase the activity or number of luminal membrane sodium channels (ENaCs) and basolateral membrane Na-K-ATPase pumps.


Dopaimine inhibits sodium reabsorption in the kidney. The dopamine that acts in the kidney is not released from neurons; rather it is synthesized in proximal tubule cells from the precursor l-DOPA. l-DOPA is taken up from the renal circulation and glomerular filtrate and converted to dopamine in the proximal tubule epithelium, and then released to act in a paracrine manner on nearby cells. Although the signaling path is not clear, it is known that increases in sodium intake lead to increased production of intrarenal dopamine. Dopamine has 2 actions, both of which reduce sodium reabsorption. First, it causes retraction of NHE antiporters and Na-K-ATPase pumps into intracellular vesicles, thereby reducing transcellular sodium reabsorption. Second, it reduces the expression of AII receptors, thereby decreasing the ability of AII to stimulate sodium reabsorption.

Other Controllers of Sodium Excretion


When ADH binds to V2 reecptors in tubular cells, it increases the production of c-AMP. This results in increased activity of the NKCC multiporter in the thick ascending limb and increased sodium channel (ENaC) presence in principal cells of the distal nephron, thereby increasing the uptake of sodium that, in both regions, is actively transported into the interstitium by the Na-K-ATPase. Interestingly, in the distal nephron the mechanism proceeds, not by moving ENaCs into the membrane, but rather by decreasing their removal and degradation.

Glomerulotubular Balance

Glomerulotubular balance (not to be confused with TG feedback described previously) refers to the phenomenon whereby sodium reabsorption in the proximal tubule varies in parallel with the filtered load, such that approximately two thirds of the filtered sodium is reabsorbed even when GFR varies. The mechanism by which reabsorption varies with filtered load appears to be via mechanotransduction by the microvilli on the apical surface of the proximal tubule cells, similar in principle to mechanotransduction by primary cilia in the macula densa. As flow changes, the amount of bending of the microvilli changes, and this is converted by cellular mechanisms into changes in transport.

Pressure Natriuresis and Diuresis

Because the kidneys are responsive to arterial pressure, there are situations in which elevated blood pressure can lead directly to increased excretion of sodium. This phenomenon is called pressure natriuresis, and because natriuresis is usually accompanied by water, it is often called pressure diuresis. This is an intrarenal phenomenon, not requiring external signaling. However, external signals normally override pressure natriuresis.

Natriuretic Peptides

Several tissues in the body synthesize members of a hormone family called natriuretic peptides. Key among these are atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). The main source of both natriuretic peptides is the heart. The natriuretic peptides have both vascular and tubular actions. The relax the afferent arteriole, thereby promoting increased filtration, and act at several sites in the tubule. They inhibit release of renin, inhibit the actions of AII that normally promote reabsorption of sodium, and act in the medullary collecting duct to inhibit sodium absorption. The major stimulus for increased secretion of the natriuretic peptides is distention of the atria, which occurs during plasma volume expansion. This is probably the stimulus for the increased natriuretic peptides that occurs in persons on a high salt diet.