Physiology I ‫ ﻋ ﻠ ﻲ ﻓ ﺎر س ﺣ ﺳ ن‬. ‫د‬. ‫ م‬.

‫ا‬

Renal Functions
The kidneys process the plasma portion of blood by removing substances from it
and, in a few cases, by adding substances to it. In so doing, they perform a variety
of functions, as summarized in Table 14.1 .

Basic Renal Processes

Urine formation begins with the filtration of plasma from the glomerular capillaries
into Bowman’s space. This process is termed glomerular filtration, and the
filtrate is called the glomerular filtrate. It is cell-free and, except for larger
proteins, contains all the substances in virtually the same concentrations as in
plasma. This type of filtrate is also termed an ultra-filtrate.
During its passage through the tubules, the filtrate’s composition is altered by
movements of substances from the tubules to the peritubular capillaries, and vice
versa ( Figure 14.6 ).

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When the direction of movement is from tubular lumen to peritubular capillary

plasma, the process is called tubular reabsorption or, simply, reabsorption.
Movement in the opposite direction—that is, from peritubular plasma to tubular
lumen—is called tubular secretion or, simply, secretion. Tubular secretion is also
used to denote the movement of a solute from the cell interior to the lumen in the
cases in which the kidney tubular cells themselves generate the substance.
The amount of any substance excreted in the urine is equal to the amount filtered
plus the amount secreted minus the amount reabsorbed.
Amount excreted =amount filtrate +amount secreted –amount re-absorbed
It is important to stress that not all these processes— filtration, secretion, and
reabsorption—apply to all substances.
To emphasize the general principles of renal function, Figure 14.7 illustrates the
renal handling of three hypothetical substances that might be found in blood.

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Approximately20% of the plasma that enters the glomerular capillaries is filtered

into Bowman’s space. This filtrate, which contains X, Y, and Z in the same
concentrations as in the capillary plasma, enters the proximal tubule and begins to
flow through the rest of the tubule. Simultaneously, the remaining 80% of the
plasma, containing X, Y, and Z, leaves the glomerular capillaries via the efferent
arteriole and enters the peritubular capillaries.
Assume that the tubule can secrete 100% of the peritubular capillary substance X
into the tubular lumen but cannot reabsorb X. Therefore, by the combination of
filtration and tubular secretion, the plasma that originally entered the renal artery is
cleared of all of its substance X, which leaves the body via the urine. Logically,
this tends to be the pattern for renal handling of foreign substances that are
potentially harmful to the body.
By contrast, assume that the tubule can reabsorb but not secrete Y and Z. The
amount of Y reabsorption is moderate so that some of the filtered material is not
reabsorbed and escapes from the body. For Z, however, the re-absorptive
mechanism is so powerful that all the filtered Z is reabsorbed back into the plasma.
Therefore, no Z is lost from the body.

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Hence, for Z, the processes of filtration and reabsorption have canceled each other
out and the net result is as though Z had never entered the kidney. Again, it is
logical to assume that substance Y is important to retain but requires maintenance
within a homeostatic range; substance Z is presumably very important for health
and is therefore completely reabsorbed.
A specific combination of filtration, tubular reabsorption, and tubular secretion
applies to each substance in the plasma.
The critical point is that, for many substances, the rates at which the processes
proceed are subject to physiological control. By triggering changes in the rates of
filtration, reabsorption, or secretion whenever the amount of a substance in the
body is higher or lower than the normal limits, homeostatic mechanisms can
regulate the substance’s bodily balance.
Forces Involved in Filtration
Once again we return to the general principle that physiological processes are
dictated by the laws of chemistry and physics; the importance of physical forces is
critical to understanding the fundamental processes of homeostasis. Filtration
across capillaries is determined by opposing Starling forces. To review, Starling
forces are
1. The blood pressure in the glomerular capillaries—the glomerular capillary
hydrostatic pressure ( PGC )—is a force favoring filtration.
2. The fluid in Bowman’s space exerts a hydrostatic pressure ( PBS ) that
opposes this filtration.
3. opposing force is the osmotic force (π GC ) that results from the presence of
protein in the glomerular capillary plasma.

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Recall that there is usually no protein in the filtrate in Bowman’s space because
of the unique structure of the areas of filtration in the glomerulus, so the osmotic
force in Bowman’s space ( πBS ) is zero. The unequal distribution of protein causes
the water concentration of the plasma to be slightly less than that of the fluid in
Bowman’s space, and this difference in water concentration favors fluid movement
by osmosis from Bowman’s space into the glomerular capillaries—that is, it
opposes glomerular filtration.
Note that, in Figure 14.8 , the value given for this osmotic force(29 mmHg)is
slightly larger than the value( 28 mmHg)for the osmotic force for plasma in all
arteries and non-renal capillaries(why??). The reason is that, unlike the situation
elsewhere in the body, enough water filters out of the glomerular capillaries that
the protein left behind in the plasma becomes more concentrated than in arterial
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plasma. In other capillaries, in contrast, little water filters out and the capillary
protein concentration remains essentially unchanged from its value in arterial
plasma. In other words, unlike the situation in other capillaries, the plasma protein
concentration and, therefore, the osmotic force increase from the beginning to the
end of the glomerular capillaries. The value given in Figure 14.8 for the osmotic
force is the average value along the length of the capillaries. Normally, the net
filtration pressure is always positive because the glomerular capillary hydrostatic
pressure ( P GC ) is larger than the sum of the hydrostatic pressure in Bowman’s
space ( P BS ) and the osmotic force opposing filtration ( π GC ). The net glomerular
filtration pressure initiates urine formation by forcing an essentially protein-free
filtrate of plasma out of the glomerulus and into Bowman’s space and then down
the tubule into the renal pelvis
Rate of Glomerular Filtration

The volume of fluid filtered from the glomeruli into Bowman’s space per unit
time is known as the glomerular filtration rate (GFR). GFR is determined not only
by the net filtration pressure but also by the permeability of the corpuscular
membranes and the surface area available for filtration. In other words, at any
given net filtration pressure, the GFR will be directly proportional to the membrane
permeability and the surface area. The glomerular capillaries are much more
permeable to fluid than most other capillaries.

Therefore, the net glomerular filtration pressure causes massive filtration of fluid
into Bowman’s space. In a 70 kg person, the GFR averages 180 L/day (125
mL/min)! This is much higher than the combined net filtration of 4 L/day of fluid
across all the other capillaries in the body.

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When we recall that the total volume of plasma in the cardiovascular system is
approximately 3 L, it follows that the kidneys filter the entire plasma volume about
60 times a day. This opportunity to process such huge volumes of plasma enables
the kidneys to regulate the constituents of the internal environment rapidly and to
excrete large quantities of waste products.

GFR is not a fixed value but is subject to physiological regulation. This is achieved
mainly by neural and hormonal input to the afferent and efferent arterioles, which
causes changes in net glomerular filtration pressure ( Figure 14.9 ).

The glomerular capillaries are unique in that they are situated between two sets of
arterioles—the afferent and efferent arterioles. Constriction of the afferent

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arterioles decreases hydrostatic pressure in the glomerular capillaries ( P GC ).

This is similar to arteriolar constriction in other organs and is due to a greater loss
of pressure between arteries and capillaries ( Figure 14.9a ).

In contrast, efferent arteriolar constriction alone has the opposite effect on P GC in

that it increases it ( Figure 14.9b ). This occurs because the efferent arteriole lies
beyond the glomerulus, so that efferent arteriolar constriction tends to “dam back”
the blood in the glomerular capillaries, raising P GC . Dilation of the efferent
arteriole ( Figure 14.9c ) decreases P GC and thus GFR, whereas dilation of the
afferent arteriole increases P GC and thus GFR ( Figure 14.9d ). Finally,
simultaneous constriction or dilation of both sets of arterioles tends to leave P GC
un changed because of the opposing effects. The control of GFR is an example of
the general principle of physiology that most physiological functions are controlled
by multiple regulatory systems, often working in opposition. In addition to the
neural and endocrine input to the arterioles, there is also neural and humoral input
to the mesangial cells that surround the glomerular capillaries.
Contraction of these cells reduces the surface area of the capillaries, which causes
a decrease in GFR at any given net filtration pressure.
It is possible to measure the total amount of any non-protein or non-protein-bound
substance filtered into Bowman’s space by multiplying the GFR by the plasma
concentration of the substance. This amount is called the filtered load of the
substance. For example, if the GFR is 180 L/day and plasma glucose concentration
is 1 g/L, then the filtered load of glucose is 180 L/day × 1 g/L = 180 g/day.
Once the filtered load of the substance is known, it can be compared to the amount
of the substance excreted. This indicates whether the substance undergoes net
tubular reabsorption or net secretion. Whenever the quantity of a substance
excreted in the urine is less than the filtered load, tubular reabsorption must have

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occurred. Conversely, if the amount excreted in the urine is greater than the filtered
load, tubular secretion must have occurred.
Tubular Reabsorption
Table 14.2 summarizes data for a few plasma components that undergo filtration
and reabsorption. It gives an idea of the magnitude and importance of re-absorptive
mechanisms.

The values in this table are typical for a healthy person on an average diet. There
are at least three important conclusions we can draw from this table:
(1) The filtered loads are enormous, generally larger than the amounts of the
substances in the body. For example, the body contains about 40 L of water, but
the volume of water filtered each day is 180 L.
(2) Reabsorption of waste products is relatively incomplete (as in the case of urea),
so that large fractions of their filtered loads are excreted in the urine.
(3) Reabsorption of most useful plasma components, such as water, inorganic ions,
and organic nutrients, is relatively complete so that the amounts excreted in the
urine are very small fractions of their filtered loads.
An important distinction should be made between re-absorptive processes that can
be controlled physiologically and those that cannot. The reabsorption rates of most
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organic nutrients, such as glucose, are always very high and are not physiologically
regulated. Thus, the filtered loads of these substances are normally completely
reabsorbed, with none appearing in the urine. For these substances, like substance
Z in Figure 14.7 , it is as though the kidneys do not exist because the kidneys do
not eliminate these substances from the body at all. Therefore, the kidneys do not
regulate the plasma concentrations of these organic nutrients. Rather, the kidneys
merely maintain whatever plasma concentrations already exist.
Recall that a major function of the kidneys is to eliminate soluble waste products.
To do this, the blood is filtered in the glomeruli. One consequence of this is that
substances necessary for normal body functions are filtered from the plasma into
the tubular fluid. To prevent the loss of these important non-waste products, the
kidneys have powerful mechanisms to reclaim useful substances from tubular fluid
while simultaneously allowing waste products to be excreted. The re-absorptive
rates for water and many ions, although also very high, are under physiological
control. For example, if water intake is decreased, the kidneys can increase water
reabsorption to minimize water loss.
In contrast to glomerular filtration, the crucial steps in tubular reabsorption (those
that achieve movement of a substance from tubular lumen to interstitial fluid) do
not occur by bulk flow because there are inadequate pressure differences across the
tubule and inadequate permeability of the tubular membranes. Instead, two other
processes are involved.
(1) The reabsorption of some substances from the tubular lumen is by diffusion,
often across the tight junctions connecting the tubular epithelial cells ( Figure
14.10 ).
(2) The reabsorption of all other substances involves mediated transport, which
requires the participation of transport proteins in the plasma membranes of tubular
cells.
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The final step in reabsorption is the movement of substances from the interstitial
fluid into peritubular capillaries that occurs by a combination of diffusion and bulk
flow. We will assume that this final process occurs automatically once the
substance reaches the interstitial fluid.

Reabsorption by Diffusion

The reabsorption of urea by the proximal tubule provides an example of passive

reabsorption by diffusion. An analysis of urea concentrations in the proximal
tubule will help clarify the mechanism. Because the corpuscular membranes are
freely filterable to urea, the urea concentration in the fluid within Bowman’s space
is the same as that in the peritubular capillary plasma and the interstitial fluid
surrounding the tubule. Then, as the filtered fluid flows through the proximal
tubule, water reabsorption occurs. This removal of water increases the
concentration of urea in the tubular fluid so it is higher than in the interstitial fluid
and peritubular capillaries. Therefore, urea diffuses down this concentration
gradient from tubular lumen to peritubular capillary.

Urea reabsorption is thus dependent upon the reabsorption of water. Reabsorption

by diffusion in this manner occurs for a variety of lipid-soluble organic substances,
both naturally occurring and foreign (e.g., the pesticide DDT).

Reabsorption by Mediated Transport

Substance reabsorbed by mediated transport must first cross the luminal
membrane (also called the apical membrane) that separates the tubular lumen
from the cell interior. Then, the substance diffuses through the cytosol of the cell
and, finally, crosses the basolateral membrane, which begins at the tight
junctions and constitutes the plasma membrane of the sides and base of the cell.
The movement by this route is termed transcellular epithelial transport.

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A substance does not need to be actively transported across both the luminal and
basolateral membranes in order to be actively transported across the overall
epithelium, thus moving from lumen to interstitial fluid against its electrochemical
gradient. For example, Na moves “downhill” (passively) into the cell across the
luminal membrane either by diffusion or by facilitated diffusion and then is
actively transported “uphill” out of the cell across the basolateral membrane via Na
/K -ATPase in this membrane. The reabsorption of many substances is coupled to
the reabsorption of Na. The co-transported substance moves uphill into the cell via
a secondary active cotransporter as Na moves downhill into the cell via this same
cotransporter. This is precisely how glucose, many amino acids, and other organic
substances undergo tubular reabsorption. The reabsorption of several inorganic
ions is also coupled in a variety of ways to the reabsorption of Na.
Many of the mediated-transport-re-absorptive systems in the renal tubule have a
limit to the amounts of material they can transport per unit time known as the
transport maximum (Tm). This is because the binding sites on the membrane
transport proteins become saturated when the concentration of the transported
substance increases to a certain level. An important example is the secondary
active-transport proteins for glucose, located in the proximal tubule. As noted
earlier, glucose does not usually appear in the urine because all of the filtered
glucose is reabsorbed. This is illustrated in Figure 14.11 , which shows the
relationship between plasma glucose concentrations and the filtered load,
reabsorption, and excretion of glucose.

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Tubular Secretion
Tubular secretion moves substances from peritubular capillaries into the tubular
lumen. Like glomerular filtration, it constitutes a pathway from the blood into the
tubule. Like reabsorption, secretion can occur by diffusion or by transcellular
mediated transport. The most important substances secreted by the tubules are H
and K . However, a large number of normally occurring organic anions, such as
choline and creatinine, are also secreted; so are many foreign chemicals such as
penicillin. Active secretion of a substance requires active transport either from the
blood side (the interstitial fluid) into the tubule cell (across the basolateral
membrane) or out of the cell into the lumen (across the luminal membrane). As in
reabsorption, tubular secretion is usually coupled to the reabsorption of Na .
Secretion from the interstitial space into the tubular fluid, which draws substances
from the peritubular capillaries, is a mechanism to increase the ability of the
kidneys to dispose of substances at a higher rate rather than depending only on the
filtered load.

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Micturition
Urine flow through the ureters to the bladder is propelled by contractions of the
ureter wall smooth muscle. The urine is stored in the bladder and intermittently
ejected during urination, or micturition.
The bladder is a balloon like chamber with walls of smooth muscle collectively
termed the detrusor muscle. The contraction of the detrusor muscle squeezes on the
urine in the bladder lumen to produce urination. That part of the detrusor muscle at
the base (or “neck”) of the bladder where the urethra begins functions as the
internal urethral sphincter. Just below the internal urethral sphincter, a ring of
skeletal muscle surrounds the urethra. This is the external urethral sphincter , the
contraction of which can prevent urination even when the detrusor muscle
contracts strongly.

The neural controls that influence bladder structures during the phases of filling
and micturition are shown in Figure 14.13 .

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Regulation of Ion and Water Balance

Total-Body Balance of Sodium and Water

Water composes about 55% to 60% of the normal body weight, and that water is
distributed throughout different compartments of the body.
Since water is of such obvious importance to homeostasis, the regulation of total-
body-water balance is critical to survival. This highlights two important general
principles of physiology:
(1)Homeostasis is essential for health and survival;
(2)Controlled exchange of materials—in this case, water— occurs between
compartments and across cellular membranes.
Table 14.3 summarizes total-body-water balance. These are average values that
are subject to considerable normal variation.

There are two sources of body water gain:

(1) Water produced from the oxidation of organic nutrients,
(2) Water ingested in liquids and food (a rare steak is approximately 70% water).
Four sites lose water to the external environment: skin, respiratory airways,

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gastrointestinal tract, and urinary tract. Menstrual flow constitutes a fifth potential
source of water loss in women.
The loss of water by evaporation from the skin and the lining of the respiratory
passageways is a continuous process. It is called insensible water loss because the
person is unaware of its occurrence. Additional water can be made available for
evaporation from the skin by the production of sweat. Normal gastrointestinal loss
of water in feces is generally quite small, but it can be significant with diarrhea and
vomiting.
Under normal conditions salt and water losses equal salt and water gains, and no
net change in body salt and water occurs. This matching of losses and gains is
primarily the result of the regulation of urinary loss, which can be varied over an
extremely wide range. For example, urinary water excretion can vary from
approximately 0.4 L/day to 25 L/day, depending upon whether one is lost in the
desert or drinking too much water. Similarly, some individuals ingest 20 to 25 g of
sodium chloride per day, whereas a person on a low-salt diet may ingest only 0.05
g. Healthy kidneys can readily alter the excretion of salt over this range to balance
loss with gain.
Basic Renal Processes for Sodium and Water

Both Na and water freely filter from the glomerular capillaries into Bowman’s
space because they have low molecular weights and circulate in the plasma in the
free form (unbound to protein). They both undergo considerable reabsorption
(normally more than 99%) but no secretion. Most renal energy utilization is used in
this enormous re-absorptive task. The bulk of Na and water reabsorption (about
two-thirds) occurs in the proximal tubule, but the major hormonal control of
reabsorption is exerted on the distal convoluted tubules and collecting ducts.

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The mechanisms of Na and water reabsorption can be summarized in two

generalizations:

(1) Na reabsorption is an active process occurring in all tubular segments except

the descending limb of the loop of Henle

(2) Water reabsorption is by osmosis and is dependent upon Na reabsorption.

Primary Active Na Re-absorption

The essential feature underlying Na re-absorption throughout the tubule is the

primary active transport of Na out of the cells and into the interstitial fluid, as
illustrated for the proximal tubule and cortical collecting duct in Figure 14.14 .

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This transport is achieved by Na /K -ATPase pumps in the basolateral membrane

of the cells. The active transport of Na out of the cell keeps the intracellular
concentration of Na low compared to the tubular lumen, so Na moves “downhill”
out of the tubular lumen into the tubular epithelial cells.

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The mechanism of the downhill Na movement across the luminal membrane into
the cell varies from segment to segment of the tubule depending on which channels
and/or transport proteins are present in their luminal membranes.

For example, the luminal entry step in the proximal tubule cell occurs by
cotransport with a variety of organic molecules, such as glucose, or by counter-
transport with H. In the latter case, H moves out of the cell to the lumen as Na
moves into the cell (Figure 14.14a). Thus, in the proximal tubule, Na reabsorption
drives the reabsorption of the co-transported substances and secretion of H. In
actuality, the luminal membrane of the proximal tubular cell has a brush border
composed of numerous microvilli (for clarity, not shown in Figure 14.14a ). This
greatly increases the surface area for reabsorption. The luminal entry step for Na in
the cortical collecting duct occurs primarily by diffusion through Na 1 channels (
Figure 14.14b ).

The movement of Na downhill from lumen into cell across the luminal membrane
varies from one segment of the tubule to another. By contrast, the basolateral
membrane step is the same in all Na -reabsorbing tubular segments—the primary
active transport of Na out of the cell is via Na /K - ATPase pumps in this
membrane. It is this transport process that decreases intracellular Na concentration
and so makes possible the downhill luminal entry step.

Coupling of Water Reabsorption to Na Reabsorption

As Na , Cl, and other ions are reabsorbed, water follows passively by osmosis .
Figure 14.15 summarizes this coupling of solute and water reabsorption.

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(1) Na is transported from the tubular lumen to the interstitial fluid across the
epithelial cells. Other solutes, such as glucose, amino acids, and HCO3 , whose
reabsorption depends on Na transport, also contribute to osmosis.

(2) The removal of solutes from the tubular lumen decreases the local osmolarity
of the tubular fluid adjacent to the cell (i.e., the local water concentration
increases). At the same time, the appearance of solute in the interstitial fluid just
outside the cell increases the local osmolarity (i.e., the local water concentration
decreases).

(3) The difference in water concentration between lumen and interstitial fluid
causes net diffusion of water from the lumen across the tubular cells’ plasma
membranes and/or tight junctions into the interstitial fluid.

(4) From there, water, Na , and everything else dissolved in the interstitial fluid
move together by bulk flow into peritubular capillaries as the final step in

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reabsorption. Water movement across the tubular epithelium can only occur if the
epithelium is permeable to water. No matter how large its concentration gradient,
water cannot cross an epithelium impermeable to it. Water permeability varies
from tubular segment to segment and depends largely on the presence of water
channels, called aquaporins , in the plasma membranes.

The water permeability of the proximal tubule is always very high, so this segment
reabsorbs water molecules almost as rapidly as Na. As a result, the proximal tubule
reabsorbs large amounts of Na and water in the same proportions. We will
describe the water permeability of the next tubular segments—the loop of Henle
and distal convoluted tubule—later. Now for the really crucial point—the water
permeability of the last portions of the tubules, the cortical and medullary
collecting ducts, can vary greatly due to physiological control. These are the only
tubular segments in which water permeability is under such control.
The major determinant of this controlled permeability and, therefore, of passive
water reabsorption in the collecting ducts is a peptide hormone secreted by the
posterior pituitary gland and known as vasopressin, or antidiuretic hormone .
Renal Sodium Regulation
In healthy individuals, urinary Na excretion increases when there is an excess of
sodium in the body and decreases when there is a sodium deficit. These
homeostatic responses are so precise that total-body sodium normally varies by
only a few percentage points despite a wide range of sodium intakes and the
occasional occurrence of large losses via the skin and gastrointestinal tract.
As we have seen, Na is freely filterable from the glomerular capillaries into
Bowman’s space and is actively reabsorbed but not secreted. Therefore,
Na excreted = Na filtered - Na reabsorbed.

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The body can adjust Na excretion by changing both processes on the right side of
the equation. For example, when total-body sodium decreases for any reason, Na
excretion decreases below normal levels because Na reabsorption increases.
The first issue in understanding the responses controlling Na reabsorption is to
determine what inputs initiate them; that is, what variables are receptors actually
sensing? Surprisingly, there are no important receptors capable of detecting the
total amount of sodium in the body. Rather, the responses that regulate urinary Na
excretion are initiated mainly by various cardiovascular baroreceptors, such as the
carotid sinus, and by sensors in the kidneys that monitor the filtered load of Na .
baroreceptors respond to pressure changes within the cardiovascular system and
initiate reflexes that rapidly regulate these pressures by acting on the heart,
arterioles, and veins. The new information in this chapter is that regulation of
cardiovascular pressures by baroreceptors also simultaneously achieves
regulation of total-body sodium.
Na is the major extracellular solute constituting, along with associated anions,
approximately 90% of these solutes.
Therefore, changes in total-body sodium result in similar changes in extracellular
volume. Because extracellular volume comprises plasma volume and interstitial
volume, plasma volume is also directly related to total-body sodium.
Thus, the chain linking total-body sodium to cardiovascular pressures is
completed: Low total-body sodium leads to low plasma volume, which leads to a
decrease in cardiovascular pressures. These lower pressures, via baroreceptors,
initiate reflexes that influence the renal arterioles and tubules so as to decrease
GFR and increase Na reabsorption. These latter events decrease Na excretion,
thereby retaining Na in the body and preventing further decreases in plasma
volume and cardiovascular pressures. Increases in total-body sodium have the
reverse reflex effects.
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To summarize, the amount of Na in the body determines the extracellular fluid

volume, the plasma volume component of which helps determine cardiovascular
pressures, which initiate the responses that control Na excretion.
Control of GFR
Figure 14.22 summarizes the major mechanisms by which an example of
increased Na loss elicits a decrease in GFR.

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The main direct cause of the reduced GFR is a reduced net glomerular filtration
pressure. This occurs both as a consequence of a decreased arterial pressure in the
kidneys and, more importantly, these reflexes are the basic baroreceptor reflexes a
decrease in cardiovascular pressures causes neutrally mediated reflex
vasoconstriction in many areas of the body. As we will see later, the hormones

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angiotensin II and vasopressin also participate in this renal vasoconstrictor

response.
Conversely, an increase in GFR is usually elicited by neuroendocrine inputs when
an increased total-body-sodium level increases plasma volume. This increased
GFR contributes to the increased renal Na loss that returns extracellular volume to
normal.

Control of Na Re-absorption

For the long-term regulation of Na excretion, the control of Na reabsorption is

more important than the control of GFR. The major factor determining the rate of
tubular Na reabsorption is the hormone aldosterone.

Aldosterone and the Renin–Angiotensin System The adrenal cortex produce a

steroid hormone, aldosterone, which stimulates Na reabsorption by the distal
convoluted tubule and the cortical collecting ducts. An action affecting these late
portions of the tubule is just what one would expect for a fine-tuning input because
most of the filtered Na has been reabsorbed by the time the filtrate reaches the
distal parts of the nephron.

When aldosterone is completely absent, approximately 2% of the filtered Na

(equivalent to 35 g of sodium chloride per day) is not reabsorbed but excreted. In
contrast, when the plasma concentration of aldosterone is high, essentially all the
Na reaching the distal tubule and cortical collecting ducts is reabsorbed. Normally,
the plasma concentration of aldosterone and the amount of Na excreted lie
somewhere between these extremes.

As opposed to vasopressin, which is a peptide and acts quickly, aldosterone is a

steroid and acts more slowly because it induces changes in gene expression and

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protein synthesis. In the case of the nephron, the proteins participate in Na 1

transport.

Look again at Figure 14.14b . Aldosterone induces the synthesis of all the channels
and pumps shown in the cortical collecting duct. When a person eats a diet high in
sodium, aldosterone secretion is low, whereas it is high when the person ingests a
low-sodium diet or becomes sodium-depleted for some other reason. What controls
the secretion of aldosterone under these circumstances? The answer is the hormone
angiotensin II, which acts directly on the adrenal cortex to stimulate the secretion
of aldosterone.

Angiotensin II is a component of the renin– angiotensin system, summarized in

Figure 14.23 .

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Renin is an enzyme secreted by the juxtaglomerular cells of the juxtaglomerular

apparatuses in the kidneys. Once in the bloodstream, renin splits a small
polypeptide, angiotensin I , from a large plasma protein, angiotensinogen , which is
produced by the liver. Angiotensin I, a biologically inactive peptide, then

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undergoes further cleavage to form the active agent of the renin– angiotensin
system, angiotensin II. This conversion is mediated by an enzyme known as
angiotensin-converting enzyme ( ACE ), which is found in very high concentration
on the luminal surface of capillary endothelial cells. Angiotensin II exerts many
effects, but the most important are the stimulation of the secretion of aldosterone
and the constriction of arterioles. Plasma angiotensin II is high during salt
depletion and low when salt intake is high. It is this change in angiotensin II that
brings about the changes in aldosterone secretion. What causes the changes in
plasma angiotensin II concentration with changes in salt balance? Angiotensinogen
and angiotensin-converting enzyme are usually present in excess, so the rate-
limiting factor in angiotensin II formation is the plasma renin concentration. Thus,
the chain of events in salt depletion is increased renin secretion → increased
plasma renin concentration → increased plasma angiotensin I concentration →
increased plasma angiotensin II concentration → increased aldosterone release →
increased plasma aldosterone concentration.

What are the mechanisms by which sodium depletion causes an increase in renin
secretion ( Figure 14.24 )

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There are at least three distinct inputs to the juxtaglomerular cells:

(1) The renal sympathetic nerves,

(2) Intrarenal baroreceptors,
(3) The macula densa.
This is an excellent example of the general principle of physiology that most
physiological functions (like renin secretion) are controlled by multiple regulatory
systems, often working in opposition.

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The renal sympathetic nerves directly innervate the juxtaglomerular cells, and an
increase in the activity of these nerves stimulates renin secretion. This makes sense
because these nerves are reflexively activated via baroreceptors whenever a
reduction in body sodium (and, therefore, plasma volume) decreases
cardiovascular pressures (see Figure 14.22 ).

The other two inputs for controlling renin release— intrarenal baroreceptors and
the macula densa—are contained within the kidneys and require no external
neuroendocrine input (although such input can influence them). As noted earlier,
the juxtaglomerular cells are located in the walls of the afferent arterioles. They are
sensitive to the pressure within these arterioles and, therefore, function as
intrarenal baroreceptors.

When blood pressure in the kidneys decreases, as occurs when plasma volume is
decreased, these cells are stretched less and, therefore, secrete more renin (see
Figure 14.24 ). Thus, the juxtaglomerular cells respond simultaneously to the
combined effects of sympathetic input, triggered by baroreceptors external to the
kidneys, and to their own pressure sensitivity.

The other internal input to the juxtaglomerular cells is via the macula densa, which,
as noted earlier, is located near the ends of the ascending loops of Henle (see
Figure 14.2 ). The macula densa senses the amount of Na 1 in the tubular fluid
flowing past it. A decreased salt delivery causes the release of paracrine factors
that diffuse from the macula densa to the nearby JG cells, thereby activating them
and causing the release of renin. Therefore, in an indirect way, this mechanism is
sensitive to changes in sodium intake. If salt intake is low, less Na 1 is filtered and
less appears at the macula densa. Conversely, a high salt intake will cause a very

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low rate of release of renin. If blood pressure is significantly decreased, glomerular

filtration rate can decrease.

This will decrease the tubular flow rate such that less Na 1 is presented to the
macula densa. This input also results in increased renin release at the same time
that the sympathetic nerves and intrarenal baroreceptors are doing so (see Figure
14.24 ).

The importance of this system is highlighted by the considerable redundancy in the

control of renin secretion. Furthermore, as illustrated in Figure 14.24 , the various
mechanisms can all be participating at the same time. By helping to regulate
sodium balance and thereby plasma volume, the renin–angiotensin system
contributes to the control of arterial blood pressure. However, this is not the only
way in which it influences arterial pressure. angiotensin II is a potent constrictor of
arterioles in many parts of the body and that this effect on peripheral resistance
increases arterial pressure.

Drugs have been developed to manipulate the angiotensin II and aldosterone

components of the system. ACE inhibitors, such as lisinopril , reduce angiotensin
II production from angiotensin I by inhibiting angiotensin-converting enzyme.
Angiotensin II receptor blockers, such as losartan , prevent angiotensin II from
binding to its receptor on target tissue (e.g., vascular smooth muscle and the
adrenal cortex). Finally, drugs such as eplerenone block the binding of aldosterone
to its receptor in the kidney. Although these classes of drugs have different
mechanisms of action, they are all effective in the treatment of hypertension. This
highlights that many forms of hypertension can be attributed to the failure of the
kidneys to adequately excrete Na and water.

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Renal Water Regulation

Water excretion is the difference between the volume of water filtered (the GFR)
and the volume reabsorbed. Thus, the changes in GFR initiated by baroreceptor
afferent input described in the previous section tend to have the same effects on
water excretion as on Na excretion. As is true for Na, however, the rate of water
reabsorption is the most important factor for determining how much water is
excreted. As we have seen, this is determined by vasopressin; therefore, total-body
water is regulated mainly by reflexes that alter the secretion of this hormone.
vasopressin is produced by a discrete group of hypothalamic neurons whose axons
terminate in the posterior pituitary gland, which releases vasopressin into the
blood. The most important of the inputs to these neurons come from osmo-
receptors and baroreceptors.
Baroreceptor Control of Vasopressin Secretion

The minute-to-minute control of plasma osmolality is primarily by the

osmoreceptor-mediated vasopressin secretion already described. There are,
however, other important controllers of vasopressin secretion. The best understood
of these is baroreceptor input to vasopressinergic neurons in the hypothalamus.

A decreased extracellular fluid volume due, for example, to diarrhea or

hemorrhage, elicits an increase in aldosterone release via activation of the renin–
angiotensin system. However, the decreased extracellular volume also triggers an
increase in vasopressin secretion. This increased vasopressin increases the water
permeability of the collecting ducts. More water is passively reabsorbed and less is
excreted, so water is retained to help stabilize the extracellular volume.

This reflex is initiated by several baroreceptors in the cardiovascular system (

Figure 14.27 ).

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The baroreceptors decrease their rate of firing when cardiovascular pressures

decrease, as occurs when blood volume decreases. Therefore, the baroreceptors
transmit fewer impulses via afferent neurons and ascending pathways to the
hypothalamus, and the result is increased vasopressin secretion. Conversely,
increased cardiovascular pressures cause more firing by the baroreceptors,
resulting in a decrease in vasopressin secretion. The mechanism of this inverse
relationship is an inhibitory neurotransmitter released by neurons in the afferent
pathway.

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In addition to its effect on water excretion, vasopressin, like angiotensin II, causes
widespread arteriolar constriction. This helps restore arterial blood pressure toward
normal .

The baroreceptor reflex for vasopressin, as just described, has a relatively high
threshold—that is, there must be a sizable reduction in cardiovascular pressures to
trigger it. Therefore, this reflex, compared to the osmoreceptor reflex described
earlier, generally plays a lesser role under most physiological circumstances, but it
can become very important in pathological states, such as hemorrhage.

Potassium Regulation
K is the most abundant intracellular ion. Although only 2% of total-body
potassium is in the extracellular fluid, the K concentration in this fluid is extremely
important for the function of excitable tissues, notably, nerve and muscle.
The resting membrane potentials of these tissues are directly related to the relative
intracellular and extracellular K concentrations. Consequently, either increases (
hyperkalemia ) or decreases ( hypokalemia ) in extracellular K concentration can
cause abnormal rhythms of the heart ( arrhythmias ) and abnormalities of skeletal
muscle contraction and neuronal action potential conduction. A healthy person
remains in potassium balance in the steady state by daily excreting an amount of
potassium in the urine equal to the amount ingested minus the amounts eliminated
in feces and sweat.
Like Na losses, K losses via sweat and the gastrointestinal tract are normally quite
small, although vomiting or diarrhea can cause large quantities to be lost. The
control of urinary K excretion is the major mechanism regulating body potassium.

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Renal Regulation of K

K is freely filterable in the glomerulus. Normally, the tubules reabsorb most of this
filtered K so that very little of the filtered K appears in the urine. However, the
cortical collecting ducts can secrete K and changes in K excretion are due mainly
to changes in K secretion by this tubular segment (Figure 14.30).

During potassium depletion, when the homeostatic response is to minimize

potassium loss, there is no K secretion by the cortical collecting ducts. Only the
small amount of filtered K that escapes tubular reabsorption is excreted. With
normal fluctuations in potassium intake, a variable amount of K is added to the
small amount filtered and not reabsorbed. This maintains total-body potassium
balance.

Figure 14.14b illustrated the mechanism of K secretion by the cortical collecting

ducts. In cortical collecting ducts tubular segment, the K pumped into the cell
across the basolateral membrane by Na /K -ATPases diffuses into the tubular
lumen through K channels in the luminal membrane. Thus, the secretion of K by
the cortical collecting duct is associated with the reabsorption of Na 1 by this

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tubular segment. K secretion does not occur in other Na -reabsorbing tubular

segments because there are few K channels in the luminal membranes of their
cells. Rather, in these segments, the K pumped into the cell by Na /K - ATPase
simply diffuses back across the basolateral membrane through K channels located
there (see Figure 14.14a ).

What factors influence K secretion by the cortical collecting ducts to achieve

homeostasis of bodily potassium? The single most important factor is as follows.
When a high potassium diet is ingested (Figure 14.31 ), plasma K concentration
increases, though very slightly, and this drives enhanced basolateral uptake via the
Na /K -ATPase pumps.

Thus, there is an enhanced K secretion. Conversely, low potassium diet or a

negative potassium balance, such as results from diarrhea, decreases basolateral K
uptake. This reduces K secretion and excretion, thereby helping to reestablish
potassium balance.

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A second important factor linking K secretion to potassium balance is the hormone

aldosterone (see Figure 14.31 ).
Besides stimulating tubular Na reabsorption by the cortical collecting ducts,
aldosterone simultaneously enhances K secretion by this tubular segment.
The homeostatic mechanism by which an excess or deficit of potassium controls
aldosterone production (see Figure 14.31) is different from the mechanism
described earlier involving the renin–angiotensin system. The aldosterone secreting
cells of the adrenal cortex are sensitive to the K concentration of the extracellular
fluid. Thus, an increased intake of potassium leads to an increased extracellular K
concentration, which in turn directly stimulates the adrenal cortex to produce
aldosterone. The increased plasma aldosterone concentration increases K secretion
and thereby eliminates the excess potassium from the body.
Conversely, a decreased extracellular K concentration decreases aldosterone
production and thereby reduces K secretion. Less K than usual is excreted in the
urine, thereby helping to restore the normal extracellular concentration.
Figure 14.32 summarizes the control and major renal tubular effects of
aldosterone. The fact that a single hormone regulates both Na and K excretion
raises the question of potential conflicts between homeostasis of the two ions.

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For example, if a person was sodium-deficient and therefore secreting large

amounts of aldosterone, the K –secreting effects of this hormone would tend to
cause some K loss even though potassium balance was normal to start with.
Usually, such conflicts cause only minor imbalances because there are a variety of
other counteracting controls of Na and K excretion.
Hydrogen Ion Regulation

The understanding of the regulation of acid–base balance requires appreciation of a

general principle of physiology that physiological processes are dictated by the
laws of chemistry and physics. Metabolic reactions are highly sensitive to the H
concentration of the fluid in which they occur. This sensitivity is due to the
influence that H has on the shapes of proteins, such as enzymes, such that their
function can be altered. Not surprisingly, then, the H concentration of the
extracellular fluid is tightly regulated.
This regulation can be viewed in the same way as the balance of any other ion—
that is, as matching gains and losses. When loss exceeds gain, the arterial plasma
hydrogen ion concentration decreases and pH exceeds 7.4. This is termed alkalosis

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. When gain exceeds loss, the arterial plasma hydrogen ion concentration increases
and the pH is less than 7.4. This is termed acidosis .
Sources of Hydrogen Ion Gain or Loss
Table 14.6 summarizes the major routes for gains and losses of H .
a huge quantity of CO2 — about 20,000 mmol—is generated daily as the result of
oxidative metabolism.

These CO2 molecules participate in the generation of H during the passage of

blood through peripheral tissues via the following reactions:

This source does not normally constitute a net gain of H. This is because the H
generated via these reactions is reincorporated into water when the reactions are
reversed during the passage of blood through the lungs. Net retention of CO2 does
occur in hypoventilation or respiratory disease and in such cases causes a net gain
of H. Conversely, net loss of CO2 occurs in hyperventilation, and this causes net
elimination of H.

The body also produces both organic and inorganic acids from sources other than
CO2. These are collectively termed nonvolatile acids. They include phosphoric acid

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and sulfuric acid, generated mainly by the catabolism of proteins, as well as lactic
acid and several other organic acids. Dissociation of all of these acids yields anions
and H. Simultaneously, however, the metabolism of a variety of organic anions
utilizes H and produces HCO3. Thus, the metabolism of “nonvolatile” solutes both
generates and utilizes H. With the high-protein diet typical in the United States, the
generation of nonvolatile acids predominates in most people, with an average net
production of 40 to 80 mmol of H per day. A third potential source of the net gain
or loss of H in the body occurs when gastrointestinal secretions leave the body.

Vomitus contains a high concentration of H and so constitutes a source of net loss.

In contrast, the other gastrointestinal secretions are alkaline. They contain very
little H, but their concentration of HCO3 is higher than in plasma. Loss of these
fluids, as in diarrhea, in essence constitutes a gain of H. Given the mass-action
relationship shown in equation 14–1, when HCO3 is lost from the body, it is the
same as if the body had gained hydrogen ion. This is because loss of the HCO3
causes the reactions shown in equation 14–1 to be driven to the right, thereby
generating hydrogen ion within the body. Similarly, when the body gains HCO3, it
is the same as if the body had lost hydrogen ion, as the reactions of equation 14–1
are driven to the left. Finally, the kidneys constitute the fourth source of net
hydrogen ion gain or loss. That is, the kidneys can either remove H from the
plasma or add it.

Buffering of Hydrogen Ion in the Body

Any substance that can reversibly bind H is called a buffer. Most H is bound by
extracellular and intracellular buffers.

The normal extracellular fluid pH of 7.4 corresponds to a hydrogen ion

concentration of only 0.00004 mmol/L (40 nmol/L). Without buffering, the daily

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turnover of the 40 to 80 mmol of H produced from nonvolatile acids generated in

the body from metabolism would cause huge changes in body fluid hydrogen ion
concentration.

H Buffer is a weak acid in that it can dissociate to buffer H or it can exist as the un-
dissociated molecule (H Buffer). When H concentration increases for any reason,
the reaction is forced to the right and more H is bound by buffer to form H Buffer.
For example, when H concentration is increased because of increased production
of lactic acid, some of the H combines with the body’s buffers, so the hydrogen ion
concentration does not increase as much as it otherwise would have. Conversely,
when H concentration decreases because of the loss of H or the addition of alkali,
equation 14–2 proceeds to the left and H is released from H Buffer. In this manner,
buffers stabilize H concentration against changes in either direction.
The major extracellular buffer is the CO2 /HCO3 system summarized in equation
14–1. This system also plays some role in buffering within cells, but the major
intracellular buffers are phosphates and proteins.
This buffering does not eliminate H from the body or add it to the body; it only
keeps the H “locked up” until balance can be restored. How balance is achieved is
the subject of the rest of our description of hydrogen ion regulation.
Integration of Homeostatic Controls
The kidneys are ultimately responsible for balancing hydrogen ion gains and losses
so as to maintain plasma hydrogen ion concentration within a narrow range. Thus,
the kidneys normally excrete the excess H from nonvolatile acids generated from
metabolism—that is, all acids other than carbonic acid. An additional net gain of H
can occur with increased production of these nonvolatile acids, with

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hypoventilation or respiratory malfunction, or with the loss of alkaline

gastrointestinal secretions. When this occurs, the kidneys increase the elimination
of H from the body to restore balance. Alternatively, if there is a net loss of H from
the body due to hyperventilation or vomiting, the kidneys replenish this H.
Although the kidneys are the ultimate hydrogen ion balancers, the respiratory
system also plays a very important homeostatic role. We have pointed out that
hypoventilation, respiratory malfunction, and hyperventilation can cause a
hydrogen ion imbalance. Now we emphasize that when a hydrogen ion imbalance
is due to a non-respiratory cause, then ventilation is reflexively altered so as to help
compensate for the imbalance.
An increased arterial hydrogen ion concentration stimulates ventilation, which
lowers arterial PCO2 that, by mass action, reduces hydrogen ion concentration.
Alternatively, a decreased plasma hydrogen ion concentration inhibits ventilation,
thereby increasing arterial PCO2 and the hydrogen ion concentration.
In this way, the respiratory system and kidneys work together. The respiratory
response to altered plasma hydrogen ion concentration is very rapid (minutes) and
keeps this concentration from changing too much until the more slowly responding
kidneys (hours to days) can actually eliminate the imbalance. If the respiratory
system is the actual cause of the hydrogen ion imbalance, then the kidneys are the
sole homeostatic responder. Conversely, malfunctioning kidneys can create a
hydrogen ion imbalance by eliminating too little or too much hydrogen ion from
the body, and then the respiratory response is the only one in control.

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Renal Mechanisms

The kidneys eliminate or replenish H from the body by altering plasma bicarbonate
concentration. The key to understanding how altering plasma bicarbonate
concentration eliminates or replenishes H was stated earlier. That is, the excretion
of HCO3 in the urine increases the plasma hydrogen ion concentration just as if a
hydrogen ion had been added to the plasma. Similarly, the addition of HCO3 to the
plasma decreases the plasma hydrogen ion concentration just as if a hydrogen ion
had been removed from the plasma.

Thus, when the plasma hydrogen ion concentration decreases (alkalosis) for
whatever reason, the kidneys’ homeostatic response is to excrete large quantities of
HCO3. This increases plasma hydrogen ion concentration toward normal. In
contrast, when plasma hydrogen ion concentration increases (acidosis), the kidneys
do not excrete HCO3 in the urine. Rather, kidney tubular cells produce new HCO3
and add it to the plasma. This decreases the plasma hydrogen ion concentration
toward normal.

HCO3 Handling

HCO3 is completely filterable at the renal corpuscles and undergoes significant

tubular reabsorption in the proximal tubule, ascending loop of Henle, and cortical
collecting ducts.

For simplicity, we will ignore the secretion of HCO3 because it is always much less
than tubular reabsorption and we will treat HCO3 excretion as the difference
between filtration and reabsorption.

HCO3 reabsorption is an active process, but it is not accomplished in the

conventional manner of simply having an active pump for HCO3 at the luminal or

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basolateral membrane of the tubular cells. Instead, HCO3 reabsorption depends on

the tubular secretion of H, which combines in the lumen with filtered HCO3.

Figure 14.33 illustrates the sequence of events. Begin this figure inside the cell
with the combination of CO2 and H2O to form H2CO3, a reaction catalyzed by the
enzyme carbonic anhydrase.

The H2CO3 immediately dissociates to yield H and HCO3. The HCO3 moves down
its concentration gradient via facilitated diffusion across the basolateral membrane
into interstitial fluid and then into the blood. Simultaneously, the H is secreted into
the lumen. Depending on the tubular segment, this secretion is achieved by some
combination of primary H -ATPase pumps, primary H /K -ATPase pumps, and Na
/H counter-transporters.

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The secreted H, however, is not excreted. Instead, it combines in the lumen with a
filtered HCO3 and generates CO2 and H2O, both of which can diffuse into the cell
and be available for another cycle of hydrogen ion generation. The overall result is
that the HCO3 filtered from the plasma at the renal corpuscle has disappeared, but
its place in the plasma has been taken by the HCO3 that was produced inside the
cell. In this manner, no net change in plasma bicarbonate concentration has
occurred. It may seem inaccurate to refer to this process as HCO3 “reabsorption”
because the HCO3 that appears in the peritubular plasma is not the same HCO3 that
was filtered. Yet, the overall result is the same as if the filtered HCO3 had been
reabsorbed in the conventional manner like Na or K.

Except in response to alkalosis, discussed in the next section, the kidneys normally
reabsorb all filtered HCO3, thereby preventing the loss of HCO3 in the urine.
Addition of New HCO3 to the Plasma
An essential concept shown in Figure 14.33 is that as long as there are still
significant amounts of filtered HCO3 in the lumen, almost all secreted H will
combine with it. But what happens to any secreted H once almost all the HCO3 has
been reabsorbed and is no longer available in the lumen to combine with the H ?
The answer, illustrated in Figure 14.34, is that the extra secreted H combines in
the lumen with a filtered non-bicarbonate buffer, the most important of which is
HPO4 . The hydrogen ion is then excreted in the urine as part of the HPO4 ion.

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Now for the critical point: Note in Figure 14.34 that, under these conditions, the
HCO3 generated within the tubular cell by the carbonic anhydrase reaction and
entering the plasma constitutes a net gain of HCO3 by the plasma, not merely a
replacement for filtered HCO3. Therefore, when secreted hydrogen ion combines in
the lumen with a buffer other than HCO3 , the overall effect is not merely one of
HCO3 conservation, as in Figure 14.33 , but, rather, of addition to the plasma of
new HCO3 . This increases the HCO3 concentration of the plasma and alkalinizes it.
To repeat, significant amounts of H combine with filtered non-bicarbonate buffers
like HPO4 only after the filtered HCO3 has virtually all been reabsorbed. The main
reason is that there is such a large load of filtered HCO3— 25 times more than the
load of filtered non-bicarbonate buffers—competing for the secreted H.

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There is a second mechanism by which the tubules contribute new HCO 3 2 to the
plasma that involves not hydrogen ion secretion but, rather, the renal production
and secretion of ammonium ion (NH4 ) ( Figure 14.35 ).

Tubular cells, mainly those of the proximal tubule, take up glutamine from both
the glomerular filtrate and peritubular plasma and metabolize it. In the process,
both NH4 and HCO3 are formed inside the cells. The NH4 is actively secreted via
Na /NH4 counter-transport into the lumen and excreted, while the HCO3 moves
into the peritubular capillaries and constitutes new plasma bicarbonate.
A comparison of Figures 14.34 and 14.35 demonstrates that the overall result—
renal contribution of new HCO3 to the plasma—is the same regardless of whether
it is achieved by
(1) H secretion and excretion on non-bicarbonate buffers such as phosphate
(2) By glutamine metabolism with excretion.

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It is convenient; therefore, to view the latter as representing H excretion “bound”

to NH 3, just as the former case constitutes H excretion bound to non-bicarbonate
buffers. Thus, the amount of H excreted in the urine in these two forms is a
measure of the amount of new HCO3 added to the plasma by the kidneys. Indeed,
“urinary H excretion” and “renal contribution of new HCO3 to the plasma” are
really two sides of the same coin. The kidneys normally contribute enough new
HCO3 to the blood by excreting H to compensate for the H from nonvolatile acids
generated in the body.
Classification of Acidosis and Alkalosis
The renal responses to the presence of acidosis or alkalosis are summarized in
Table 14.7.

To repeat, acidosis refers to any situation in which the hydrogen ion concentration
of arterial plasma is increased above normal whereas alkalosis denotes a decrease.

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All such situations fit into two distinct categories (Table 14.8): (1) respiratory
acidosis or alkalosis and (2) metabolic acidosis or alkalosis.

As its name implies, respiratory acidosis results from altered alveolar ventilation.
Respiratory acidosis occurs when the respiratory system fails to eliminate carbon
dioxide as fast as it is produced. Respiratory alkalosis occurs when the respiratory
system eliminates carbon dioxide faster than it is produced. As described earlier,
the imbalance of arterial hydrogen ion concentrations in such cases is completely
explainable in terms of mass action. Thus, the hallmark of respiratory acidosis is an
increase in both arterial and hydrogen ion concentration, whereas that of
respiratory alkalosis is a decrease in both. Metabolic acidosis or alkalosis includes
all situations other than those in which the primary problem is respiratory.

Some common causes of metabolic acidosis are excessive production of lactic acid
(during severe exercise or hypoxia) or of ketone bodies. Metabolic acidosis can
also result from excessive loss of HCO3, as in diarrhea. Another cause of metabolic
alkalosis is persistent vomiting, with its associated loss of H as HCl from the
stomach.
What is the arterial PCO2 in metabolic acidosis or alkalosis?
By definition, metabolic acidosis and alkalosis must be due to something other
than excess retention or loss of carbon dioxide, so you might have predicted that
arterial PCO2 would be unchanged, but this is not the case. As emphasized earlier
in this chapter, the increased hydrogen ion concentration associated with metabolic

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acidosis reflexively stimulates ventilation and decreases arterial PCO2. By mass

action, this helps restore the hydrogen ion concentration toward normal.
Conversely, a person with metabolic alkalosis will reflexively have ventilation
inhibited. The result is an increase in arterial PCO2 and, by mass action, an
associated restoration of hydrogen ion concentration toward normal.
To reiterate, the plasma PCO2 changes in metabolic acidosis and alkalosis are not
the cause of the acidosis or alkalosis but the result of compensatory reflexive
responses to non-respiratory abnormalities. Thus, in metabolic as opposed to
respiratory conditions, the arterial plasma PCO2 and hydrogen ion concentration
move in opposite directions, as summarized in Table 14.8 .

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