What is the normal plasma K+ range?
Why is deviation of K+ levels outside of the normal range a cause for alarm?
What does hyperkalemia do to resting membrane potential? Hypokalemia?
Where is most of the body's K+ stored? (intracellular or extracellular). What is the result of this as it pertains to maintaing plasma K+ levels?
The normal plasma K+ concentration ranges from ~3.6 to ~5.2 mEq/L. A person is hyperkalemic if their plasma K+ level is higher than this or hypokalemic if it is less. Large deviations in plasma K+ level (<3 or >6 mEq/L) are cause for alarm. The reason is that the resting membrane potential of excitability cells critically depends on the extracellular K+ concentration. Elevated extracellular K+ depolarizes cells while low K+ levels will hyperpolarize cells. The consequences of this can be serious. Remember (from your cardiovascular lectures), shifts in the resting membrane potential of cardiac muscle cells can substantially influence their function. Only ~2% of the body’s K+ is extracellular. Most K+ is inside cells and is kept (or put) there by the collective operation of the Na-K-ATPase in cells around the body. Because the amount of K+ in the extracellular compartment is so low, even small shifts of K+ into or out of cells can produce substantial changes in the extracellular K+ concentration. In fact, shifting K+ into or out of cells (particularly in or out of skeletal muscle cells) is an important means by which the body controls extracellular K+ levels. For example, vigorous exercise may acutely damage some muscle cells and this may dump extra K+ into the extracelullular compartment. A quick shift of K+ into skeletal muscle (body wide) can and does “buffer” this type of K+ disturbance.
What 2 hormones modulate K+ shifts into and out of tissues? By what mechansim do they do this? Under what circumstances is each hormone predominant in its effects on K+ levels?
Two hormones that modulate this kind of K+ shift are epinephrine and insulin. Both of these hormones promote K+ uptake in muscle by stimulating the Na-K-ATPase activity. The action of epinephrine in this regard is probably more important during exercise (or trauma). For example, a crush wound (trauma) may dump excess K+ into the extracelullular compartment and a surge of epinephrine can help maintain extracellular K+ levels within the normal range. The action of insulin is important after a meal. An increase in circulating insulin can help move ingested K+ (i.e. absorbed by the G.I. tract) out of the extracelullular compartment. Interestingly, an elevated extracellular K+ anytime will stimulate insulin production to help correct the K+ disturbance. Of course, insulin also promotes glucose uptake by cells providing a necessary source of energy for the insulin up-regulated Na-K-ATPase.
What hormone is responsible for modulating renal handling of K+?
How is true K+ balance achieved?
How is K+ excreted from the body?
What organ is ultimately responsible for maintaining total K+ balance?
Aldosterone modulates renal handling of K+. It's action is slower than epinephrine and insulin.
To achieve true K+ balance, the amount of K+ that enters the body (ingested) must be excreted from the body. Normally, a person stays in overall K+ balance by excreting K+ in the urine. A relatively small amount of K+ is eliminated in sweat and feces but it is the kidney (via its production of urine) that is ultimately responsible for maintaining total body K+ balance.
What percentage of K+ is reabsorbed from the proximal tubule?
From the loop of Henle? What portion?
How much K+ reaches the distal nephron where K+ handling occurs?
How much K+ is reabsorbed from meduallry collecting ducts?
How much K+ is excreted in urine?
What perecentage of K+ is reabsorbed from the proximal tubule?
Is this reabsoprtion passive or active? Via what route is K+ absorbed?
What is K+ reabsorption coupled to?
The K+ reabsorption process in the proximal tubule is paracellular passive diffusion through tight junctions. Briefly, the large H20 reabsoption from the proximal tubule increases the concentration of certain solutes in the tubular fluid as the fluid moves along. Examples of these solutes that become more concentrated in the proximal tubule are urea, Cl- and K+ . As the K+ concentration in the proximal tubule increases, it provides a driving force for passive K+ diffusion through the tight junctions (that are obviously not so tight). Since the H20 reabsorption that generates this driving force is Na-dependent (as described previously…..recall “H20 follows Na+ ”), the K+ reabsorption in the proximal tubule is indirectly Na+ dependent as well. Remember a substantial portion of filtered K+ (~80%) is reabsorbed in the proximal tubule.
What perecentage of K+ is reabsorbed from the thick ascending loop of Henle?
Is this reabsoprtion passive or active? Via what route is K+ absorbed?
What is K+ reabsorption in the thick ascending LOH coupled to?
The apical membrane of the thick ascending limb contains the Na-K-2Cl symporter (described previously). Briefly, this symporter uses the energy stored in the Na+ gradient that exists across the apical membrane to carry K+ into the cells up its electrochemical gradient. Again, this K+ reabsorption process in the thick ascending limb is Na dependent. About 10% of the filtered K+ load is reabsorbed from the loop of Henle. Combined, the K+ reabsorption that occurs in the proximal tubule and ascending limb means only about 10% of the filtered K+ load will be delivered to the distal segments of the nephron.
What part(s) of the nephron are involved in the "distal nephron K+ handling process"?
What does the influence of this portion of the nephron on K+ excretion depend on?
1. distal tubule and cortical collecting duct. note that the medullary collecting duct always reabsorbs K+
2. The influence of the collective “distal nephron potassium handling process” on the tubular fluid depends on dietary K+ intake. It other words, it depends on whether the body needs to excrete excess K+ or not.
When there is low K+ in the diet, what role does the distal nephron play in K+ excretion?
When there are normal or high levels of K+ in the diet, what role does the distal nephron play in K+ excretion? Which portion of the distal nephron plays a larger role in this circumstance?
1. During periods of low K+ intake (low K+ diet), the distal nephron mediates a relatively small net K+ reabsoption as illustrated in Figure 6.4 (attached). In this low K+ intake example, 2% of the filtered K+ load is reabsorbed. This combined with the 6% reabsorbed from the medullary collecting duct means that 2% of the filtered K+ load is excreted. This means that 98% of the filtered K+ load is reabsorbed and retained by the body. An important conceptual point here is that the distal nephron is relatively inert (i.e. having only a small influence) when there is a need for the body to conserve K+ intake. This is not the case when there is a need to rid the body of K+ .
2. For an individual on a normal or high K+ diet, the distal nephron secretes K+ into the tubular fluid as illustrated in Figure 6.5. This K+ secretion may be relatively minor or quite substantial. In this normal or high K+ intake example (Figure 6.5), 20 to 160% of the filtered K+ load is secreted. The medullary collecting duct still reabsorbs K+ but, when a large amount of K+ secretion is occurring upstream, it can not recapture it all. Note that robust K+ secretion can replace all the K+ reabsorbed earlier in the nephron and more. Consequently, 10 to 150% of the filtered K+ load can be excreted in the urine. Thus, the distal nephron (not including the medullary collecting duct) becomes a robust K+ secretion “machine” when the body needs to rid itself of K+ . Because the contribution of the cortical collecting duct in this robust K+ secretion is huge compared to that of the distal convoluted tubule, it is common to only consider the cortical collecting duct when describing the process.
How can the collecting duct both reabsorb K+ and secrete it? (hint: cell types)
Which process by the distal nephron (reabsorption or secretion) is dominant in modulating urinary
A Logical Question is…. How can one region of the nephron secrete and reabsorb K+ ?
The Answer is…. Different cells do the different things
K+ is reabsorbed by type-A intercalated cells. Small in magnitude (~2% of filtered K+).
K+ is secreted by principal cells. Large in magnitude (20-160% of filtered K+)
The magnitude of K+ reabsorption by the intercalated cells is relatively small (~2% of the filtered K+ load). In constrast, the magnitude of K+ secretion by the principal cells can be huge (160% of the filtered load). Indeed, renal regulation of K+ excretion (in most cases) is due primarily to changes in the magnitude of K+ secretion by cortical principle cells. Stated again but in different words, principle cell K+ secretion is the key variable that modulates urinary K+ excretion.
Explain the mechanism of K+ secretion by principal cells of the cortical collecting duct.
The pathway for K+ secretion across the principle cell is summarized in Figure 6.6. The K+ secretion involves 1) primary active transport by the Na-K-ATPase at the basolateral membrane and 2) passive diffusion through K+ channels in the apical membrane. The active transport by the Na-K-ATPase continuously brings K+ into the cell. This K+ then diffuses passively through apical K+ channels into the tubular fluid. Since there are some K+ channels in the basolateral membrane, some K+ can leak back into the interstitium.
Why is there a basolateral K+ channel in principal cells of the cortical collecting duct? How can there be net secretion of K+ with this channel present?
When apical K+ channel is closed, basolateral K+ channel permits K+ to recycle to keep Na-K pump going.
Since there are some K+ channels in the basolateral membrane, some K+ can leak back into the interstitium. Little does, however, because there is an electrical gradient across the epithelium cell layer. This favors K+ movement across the apical membrane. When apical K+ channels are open, most of the K+ transported into the cell by the Na-K-ATPase will cross the apical membrane.
What effect does the number of open apical K+ channels have on K+ secretion? (in principal cells of cortical collecting duct)
Closing some apical K+ channels would force K+ entering via the Na-K-ATPase to leave through the basolateral K+ channels. This would decrease net K+ secretion. Conversely, opening more apical K+ channels would increase net K+ secretion.
What effect does the number of open apical Na+ channels have on K+ secretion? (in principal cells of cortical collecting duct). Be specific.
Closing some apical Na+ channels (or very low lumen Na+ levels) may limit how much Na+ is available inside the cell for the Na-K-ATPase to pump. Less Na-K-ATPase activity means less basolateral K+ entry and thus less K+ available to move across the apical membrane (regardless of whether apical K+ channels are open or not). The result would decrease K+ secretion. Conversely, there would be increased K+ secretion when more apical Na+ channels open.
Note : Simply lowering or raising tubular Na+ level would do the same :
decreased apical Na+ entry = decreased K+ secretion increased apical Na+ entry= increased K+ secretion
What effect does plasma K+ levels have on K+ secretion from principal cells of the cortical collecting duct?
Abnormally low plasma K+ levels may limit how much K+ is available in the interstitium for the Na-K-ATPase to pump. Less Na-K-ATPase activity means less basolateral K+ entry and thus decreased K+ secretion. Conversely, high plasma K+ levels would have the opposite action (increased K+ secretion).
What effect does tubular K+ concentration have on K+ secretion?
Higher than normal K+ levels in the tubular fluid would reduce the electrochemical gradient that promotes passive K+ diffusion through the apical K+ channels. This result would be decreased K+ secretion. This would be more likely to happen when tubular flow rates are low because local K+ can accumulate before being washed away. Conversely, net K+ secretion would increase at lower than normal tubular K+ levels or when tubular flow rate is high.
Changes in local K+ concentration. ( flow dependence ) - fast flow….keeps washing away tubular K+, keeping local K+ level low steeper K+ gradient = increased secretion
- slow flow….allows local K+ in tubule accumulate near mouth of K+ channel shallower K+ gradient = decreased secretion
What hormone acts on principal cells of the cortical collecting duct to regulate K+ secretion?
How does K+ stimulate or inhibit aldosterone release?
What is the mechanism by which aldosterone regulates K+ handling by the principal cells of the cortical collecting duct? What is the overall effect of its activity?
The role of aldosterone in activating apical Na+ channels in principal cells was described in an earlier lecture in the context of renal Na+ handling. There, we described the stimuli that trigger aldosterone release from the adrenal cortex (elevated plasma K+ concentration and elevated angiotensin II). Here, the focus is renal K+ handling so we will explore further the action of plasma K+ concentration on aldosterone release. Plasma K+ concentration triggers aldosterone release by a direct action on adrenal cells (it changes the surface membrane potential of adrenal cells to modulate aldosterone release). High plasma K+ levels stimulate alsosterone release while low plasma K+ levels reduce aldosterone release. In the principle cell of the collecting duct, aldosterone promotes the opening of apical K+ channels and stimulates basolateral Na-K-ATPase activity. The net result is increased K+ secretion. The magnitude of K+ secretion will vary proportionally with plasma aldosterone level.
Note that changes in plasma K+ level may alter Na-K-ATPase operation (and consequently K+ secretion) independent of aldosterone (explained on notecard 14)
Aldosterone regulates both Na+ reabsorption and K+ secretion. Explain why even when there are low aldosterone levels why K+ levels do not increase.
Which input (Na+ or K+) dominates aldosterone release?
An important point here is that one hormone (aldosterone) is involved in the maintenance of both Na+ and K+ balance. In general, changes in Na+ balance (and blood pressure) have greater effect on aldosterone release than do changes in K+ balance. You might ask; “Does this pose a potential problem for K+ balance?”. The answer is usually no. Imagine a person on a high NaCl diet with an elevated plasma Na+ level, elevated blood volume and high blood pressure. These things will lead to a reduction in circulating aldosterone level (recall here what regulates the renin-angiotensin-aldosterone system). We know that aldosterone promotes Na+ reabsorption and K+ secretion. Thus, the absence (or reduced levels) of alsosterone will increase Na+ excretion and K+ retention. However, the increased GFR and tubular flow rate (associated with increased blood volume and BP) will promote K+ secretion. The net result is that K+ remains relatively unchanged while the excess Na+ is excreted. The bottom line is that changes in aldosterone release (in either direction) induced by an alteration in Na+ balance do not usually upset the body’s K+ balance. The reason is because Na+ balance changes are usually associated with changes in tubular flow that counteract the aldosterone action on K+ secretion.
What are K+ wasting diuretics?
What are K+ sparing diuretics?
Why aren't K+ sparing diuretics always used?
Diuretics Increase Tubular Flow …. and consequently most diuretics K+ secretion
K+ Wasting Diuretics:
- are diuretics that act upstream of collecting duct
- they increase flow through the collecting duct
- these are very effective at reducing blood volume
K+ Sparing Diuretics:
- these have their actions on the collecting duct
- block Na+ entry or inhibit aldosterone action
- these actions also tend to reduce K+ secretion
- caveat is that these are relatively weak diuretics
Imagine a congestive heart failure patient with an elevated aldosterone level being treated with a loop diuretic (not unusual). The high alsosterone level means that K+ secretion from collecting duct principle cells is up-regulated. The diuretic increases tubular flow and this also promotes K+ secretion. Combined, the result is a huge increase in K+ secretion and thus K+ excretion. To prevent this, a potassium-sparing diuretics could be given (instead of the loop diuretic). As mentioned above, the potassium-sparing diuretics work at the level of the principle cell and (one way or another) reduces aldosterone-driven Na+ reabsorption there (i.e. promoting Na+ and H2O excretion). At the same time, these agents decrease aldosterone-driven K+ secretion from the principle cell and this is one reason why these diuretics are referred to as potassiumsparing (they reduce K+ loss in urine). So…Why not just always use a potassium-sparing diuretic? The potassium-sparing diuretics are simply not as effective as the other diuretics at inducing diuresis. Thus, they may spare potassium but they may not be sufficient to get the rest of the job done (e.g. reduce extracellular fluid volume). In some cases, a combination of diuretics may be given to get “the best of both worlds”.
What 2 things determine plasma Ca2+ levels? Which process is relatively fast? Which is relatively slow?
What is the standing reservoir of Ca2+?
What are the 2 key regulators of plasma Ca2+
Renal Ca excretion …. balances dietary Ca intake
Body has standing Ca reservoir …. bones
Calcium is important …. regulates many phenomena Plasma Ca2+ is determined by:
1. Balance between GI Ca2+ uptake and renal Ca2+ excretion (slow)
2. Relative Ca2+ distribution between bone and ECF (relatively fast)
Key regulators are Vitamin D and Parathyroid Hormone
Renal excretion of Ca2+ and phosphate in a normal adult balances the reabsorption of these solutes from the GI tract (i.e. from ingested food). If the plasma levels of Ca2+ and phosphate drop, then more is reabsorbed from the GI tract, bone or the renal tubular fluid to maintain overall Ca2+ and phosphate balance. During growth or pregnancy, GI/bone reabsorption of these solutes exceeds their renal excretion. The Ca2+ and phosphate accumulates in the developing tissues and bones. In osteoporosis patients, urinary loss of Ca2+ and phosphate can exceed their gain. The result is a net loss of Ca2+ and phosphate from the body. The point here is that the kidneys work in conjunction with the GI tract and bones to maintain overall Ca2+ and phosphate balance.
What is the normal plasma Ca2+ concentration?
What is the effect of hypocalcemia on resting membrane potential?
What is the effect of hypercalcemia on resting membrane potential?
It is difficult to overstate the importance of Ca2+ in the body. It is central to contraction, synaptic transmission, bone formation, hormone-response coupling, etc. Most of the Ca2+ in the body (99%) is in the bones. The normal plasma Ca2+ concentration is ~5 mM and is maintained within narrow limits. Hypocalcemia increases the excitability of nerves and muscles which may lead to muscle spasms and/or hypocalcemic tetany. Conversely, hypercalcemia reduces excitability leading to lethargy and even cardiac arrhythmias.
In plasma, how much of Ca2+ is free in solution? How much is unable to be filtered by the kidneys and why?
What percentage of filtered Ca2+ is reabsorbed in the proximal tubule? Via what route is Ca2+ absorbed in the proximal tubule?
What rpercentage of filtered Ca2+ is excreted in urine?
~40% Ca2+ in plasma is bound to proteins and thus not filtered. ~10% is complexed with anions. Rest of the Ca2+ (50%) is freely filtered.
About 60% of the filtered Ca2+ load is reabsorbed in the proximal tubule. This is largely passive via the paracellular route (analogous to Cl- , urea, K+ ) through tight junctions. Thus, proximal Ca2+ reabsorption is indirectly dependent on Na+ and H2O reabsorption (because these must occur to generate a driving force for the passive paracellular transport). In later nephron segments, Ca2+ is also reabsorbed and normally 1-3% of filtered Ca2+ is actually excreted in the urine.
Explain the mechanism of Ca2+ reabsorption in the distal tubule.
What hormone regulates Ca2+ reabsorption in this segment of the nephron?
Ca2+ reabsorption in the distal nephron is via the transcellular route. In the distal convoluted tubule, Ca2+ diffuses through channels in the apical membrane and is then transported across the basolateral membrane by the Ca-ATPase (pump) or the Na-Ca exchanger. As illustrated in Figure 6.11, PTH (attached) controls renal Ca2+ handling in the distal tubule by stimulating the apical Ca2+ channel.
What is the precursor to vitamin D? What must be done to vit D to activate it?
Where in the body is activation of vit D done? (2 places)
What is the name for the active form of vit D?
What is the primary action of the active form of vit D? Where else in the body does it have minor effects on Ca2+ regulation?
Vitamin D (specifically its D3 form) is derived in the body from cholesterol and this process requires sun light (i.e. UV radiation). Vitamin D (its D2 form) can also be ingested perhaps in the form of a daily multi-vitamin pill. Vitamin D (D3 or D2) must be hydroxylated twice to become biologically active. One of these hydroxylation steps occurs in the kidney (the other in the liver). The active form of vitamin D is called calcitriol. As stated previously, the primary role of calcitriol is to promote Ca2+ uptake by the GI tract. The actions of calcitriol on bone and kidney are far less important. Vitamin D deficiency can decrease gut Ca2+ uptake to the extent that bone formation/reformation is impaired. In children, this can lead to a disease called rickets.
Where is PTH released from? What stimulates its release?
What are the 3 effects of PTH action?
PTH is released from the parathyroid gland. It is released in response to changes in plasma Ca2+ level. Decreased plasma Ca2+ stimulates PTH release. Increased plasma Ca2+ inhibits it. PTH has many functions in the body.
PTH ONE: PTH promotes the kidney-based hydroxylation step that generates active vitamin D (or calcitriol). Thus, increased PTH release induced by low plasma Ca2+ acts to increase the plasma Ca2+ pool by promoting calcitriol-stimulated Ca2+ uptake in the gut.
PTH TWO: PTH increases movement of Ca2+ from bone to blood. Again, increased PTH release induced by low plasma Ca2+ acts to increase the plasma Ca2+ pool by promoting Ca2+ release from bone. This is a fast transfer that makes the vast Ca2+ store in bone available to help maintain plasma Ca2+ levels at desirable levels.
PTH THREE: PTH increases renal-tubular Ca2+ reabsorption mainly by acting on the distal convoluted tubule. Increased PTH release induced by low plasma Ca2+ acts to increase plasma Ca2+ by limiting the amount of Ca2+ excreted in the urine (hence the negative action of PTH depicted in Figure 6.12-attached).
How much phosphate is unavailable for filtration by the kidneys?
What percentage of filtered phosphate is reabsorbed in the proximal tubule? Via what route?
About 10% of plasma phosphate is bound to protein so that 90% is freely filtered into the nephron. About 75% of the filtered phosphate load is reabsorbed mostly in the proximal tubule. This proximal phosphate reabsorption is via the transcellular route mediated by an apical Na-Phosphate-symporter (see Figure 4.3 in one of my previous lectures, if you like). Thus, phosphate reabsorption requires a Na gradient and is thus linked to Na+ reabsorption.
Phosphate reabsorption is a TM process. The normal filtered load is just higher than the TM. What does this mean for phosphate reabsorption?
What does phosphate in tubular fluid do?
Phosphate reabsorption is a TM process (TM = transport maximum). The normal filtered load is just higher than the TM and thus most phosphate is reabsorbed and only a little ends up in the urine. Working so close to the TM means that any increase in filtered phosphate simply adds to the amount excreted in the urine. Phosphate in the tubular fluid of the collecting duct complexes with hydrogen ions and is the primary titratable pH buffer present in urine (as we will learn later). Interestingly, systemic acidosis promotes phosphate release from bone into the plasma. This phosphate is filtered and provides more titratable pH buffer in the collecting tubule to help remove excess hydrogen ion from the body.
What hormone does a rise in plasma phosphate stimulate the release of?
Where does this hormone act in the nephron? What are its effects on phosphate?
A rise in plasma phosphate stimulates PTH release from the parathyroid gland (but remember changes in plasma Ca2+ is the primary PTH release signal). PTH acts on the proximal tubule to reduce the reabsorption of phosphate. PTH IS THE ONLY HORMONE THAT ACTS ON THE PCT. Thus, more phosphate is delivered to the collecting tubule where it can act as a pH buffer. Regardless of whether the remaining tubular phosphate gets complexed with hydrogen ions or not, the PTH inhibition of proximal phosphate reabsorption results in more phosphate being excreted, normalizing the elevated plasma phosphate levels that triggered PTH release in the first place. Thus, this PTH action of inhibiting proximal phosphate reabsorption can be included in the list of PTH actions above. This would then be PTH FOUR in the previous list.