(Renal Regulation of Potassium and Calcium and Phosphate and Magnesium (Integration of Renal Mechanisms for Control of Blood Volume and Extracellular Fluid Volume pdf - The Body Fluids and Kidneys

kalemia or as a source of potassium during hypokalemia. Thus, redistribution

over 98 per cent of the total body potassium is contained in the cells, they can

compartments also plays an important role in potassium homeostasis. Because

to wide variations in intake, as is also true for most other electrolytes.

of the potassium intake. Thus, the maintenance of normal potassium balance

responses.

(increased plasma potassium concentration). Likewise, a small loss of potassium

between 50 and 200 mEq/day; therefore, failure to rapidly rid the extracellular

is often as high as 50 milliequivalents, and the daily intake usually ranges

lents are in the extracellular fluid. Also, the potassium contained in a single meal

and 14 liters of extracellular fluid (20 per cent of body weight), about 3920 mil-

adult, who has about 28 liters of intracellular fluid (40 per cent of body weight)

and only 2 per cent in the extracellular fluid (Figure 29–1). For a 70-kilogram

concentration of only 3 to 4 mEq/L can cause cardiac arrhythmias, and higher

fluid potassium concentration. For instance, an increase in plasma potassium

0.3 mEq/L. This precise control is neces-

mally is regulated precisely at about 4.2 mEq/L,

Excretion and Potassium

Extracellular Fluid Volume

Control of Blood Volume and

Magnesium; Integration

Calcium, Phosphate, and

Renal Regulation of Potassium,

365

of Renal Mechanisms for

Regulation of Potassium

Concentration in
Extracellular Fluid

Extracellular fluid potassium concentration nor-

seldom rising or falling more than

sary because many cell functions are very sensitive to changes in extracellular

concentrations can lead to cardiac arrest or fibrillation.

A special difficulty in regulating extracellular potassium concentration is the

fact that over 98 per cent of the total body potassium is contained in the cells

liequivalents of potassium are inside the cells and only about 59 milliequiva-

fluid of the ingested potassium could cause life-threatening hyperkalemia

from the extracellular fluid could cause severe hypokalemia (low plasma potas-
sium concentration) in the absence of rapid and appropriate compensatory

Maintenance of potassium balance depends primarily on excretion by the

kidneys because the amount excreted in the feces is only about 5 to 10 per cent

requires the kidneys to adjust their potassium excretion rapidly and precisely

Control of potassium distribution between the extracellular and intracellular

serve as an overflow site for excess extracellular fluid potassium during hyper-

of potassium between the intra- and extracellular fluid compartments pro-
vides a first line of defense against changes in extracellular fluid potassium
concentration.

glucose raise extracellular osmolarity, causing cell

site effect. In diabetes mellitus, large increases in plasma

intracellular potassium concentration, thereby pro-

water out of the cells. The cellular dehydration increases

viduals with insulin deficiency. In rare instances, hyper-

extracellular fluid. Usually the hyperkalemia is mild, but

During prolonged exercise,

cell lysis.

extracellular compartment. This can cause significant

As cells are destroyed, the large amounts of potas-

Cell Lysis Causes Increased Extracellular Potassium Concentra-

(ATPase) pump. This in turn decreases cellular uptake

not completely understood, one effect of increased

extracellular fluid potassium concentration. Although

from the cells, whereas metabolic alkalosis decreases

sium concentration, in part by causing loss of potassium

and creates a tendency toward hyperkalemia.

propranolol, causes potassium to move out of the cells

-adrenergic receptor blockers, such as

-adrenergic receptors. Treatment of hyperten-

extracellular to the intracellular fluid, mainly by activa-

nephrine, can cause movement of potassium from the

Increased secretion of catecholamines, especially epi-

tion (Addison’s disease) often have clinically significant

Conversely, patients with deficient aldosterone produc-

movement of extracellular potassium into the cells.

invariably associated with hypokalemia, due in part to

aldosterone secretion (Conn’s syndrome) is almost

terone, which increases cell potassium uptake. Excess

however, can help to correct the hyperkalemia.

much greater than normal. Injections of insulin,

insulin deficiency owing to diabetes mellitus, the rise in

uptake after a meal is insulin. In people who have

cellular compartments.

until the kidneys can eliminate the excess. Table 29–1

the extracellular compartment. Fortunately, most of

cells. For example, absorption of 40 milliequivalents of

After ingestion of a normal meal, extracellular fluid

Regulation of Internal Potassium

366

Unit V

The Body Fluids and Kidneys

Distribution

potassium concentration would rise to a lethal level if
the ingested potassium did not rapidly move into the

potassium (the amount contained in a meal rich in veg-
etables and fruit) into an extracellular fluid volume of
14 liters would raise plasma potassium concentration
by about 2.9 mEq/L if all the potassium remained in

the ingested potassium rapidly moves into the cells

summarizes some of the factors that can influence the
distribution of potassium between the intra- and extra-

Insulin Stimulates Potassium Uptake into Cells.

One of the

most important factors that increase cell potassium

plasma potassium concentration after eating a meal is

Aldosterone Increases Potassium Uptake into Cells.

Increased

potassium intake also stimulates secretion of aldos-

hyperkalemia due to accumulation of potassium in
the extracellular space as well as to renal retention of
potassium.

b-Adrenergic Stimulation Increases Cellular Uptake of Potassium.

tion of

sion with

Acid-Base Abnormalities Can Cause Changes in Potassium Distri-
bution.

Metabolic acidosis increases extracellular potas-

the mechanisms responsible for the effect of hydrogen
ion concentration on potassium internal distribution are

hydrogen ion concentration is to reduce the activity
of the sodium-potassium adenosine triphosphatase

of potassium and raises extracellular potassium
concentration.

tion.

sium contained in the cells are released into the

hyperkalemia if large amounts of tissue are destroyed,
as occurs with severe muscle injury or with red blood

Strenuous Exercise Can Cause Hyperkalemia by Releasing Potas-
sium from Skeletal Muscle.

potassium is released from skeletal muscle into the

it may be clinically significant after heavy exercise in
patients treated with

b-adrenergic blockers or in indi-

kalemia after exercise may be severe enough to cause
cardiac arrhythmias and sudden death.

Increased Extracellular Fluid Osmolarity Causes Redistribution of
Potassium from the Cells to Extracellular Fluid.

Increased

extracellular fluid osmolarity causes osmotic flow of

moting diffusion of potassium out of the cells and
increasing extracellular fluid potassium concentration.
Decreased extracellular fluid osmolarity has the oppo-

Feces 8 mEq/day

intake

100 mEq/day

output

Urine 92 mEq/day

100 mEq/day

Extracellular

fluid K

4.2 mEq/L

x 14 L

Intracellular

fluid K

140 mEq/L

x 28 L

59 m Eq

3920 mEq

fluids, and potassium output from the body.

Normal potassium intake, distribution of potassium in the body

Figure 29–1

Table 29–1

Factors That Can Alter Potassium Distribution Between the

• Increased extracellular fluid

• Strenuous exercise

• Cell lysis

• Acidosis

• Alkalosis

(Addison’s disease)

-adrenergic stimulation

• Aldosterone deficiency

• Aldosterone

mellitus)

• Insulin

• Insulin deficiency (diabetes

])

(Increase Extracellular [K

into Cells

Factors That Shift K

Intra- and Extracellular Fluid

Factors That Shift K

Out of Cells

(Decrease Extracellular [K

])

•

b-adrenergic blockade

osmolarity

The cells in the late distal and cortical collecting

Collecting Tubules

Cells of Late Distal and Cortical

Potassium Secretion by Principal

ulate this process.

body. In the next section, we consider the basic mech-

reabsorbed or secreted, depending on the needs of the

collecting tubules, where potassium can be either

Thus, most of the day-to-day regulation of potas-

hypokalemia can develop.

With potassium intakes below this level, severe

sium in the distal segments of the nephron, and potas-

in potassium intake, there is net reabsorption of potas-

urinary potassium secretion. With extreme reductions

collecting tubules decreases, causing a reduction in

When potassium intake is reduced below normal,

trate, indicating a powerful mechanism for secreting

potassium diets, the rate of potassium excretion can

and collecting tubules. In fact, with extremely high

With high potassium intakes, the required extra

tubules.

body. With a normal potassium intake of 100 mEq/day,

other times be secreted, depending on the needs of the

segments, potassium can at times be reabsorbed or at

tubules and cortical collecting tubules. In these tubular

The most important sites for regulating potas-

Tubules.

Most Daily Variation in Potassium Excretion Is Caused by

imal tubule or loop of Henle.

these segments can influence potassium excretion, but

is reabsorbed. Changes in potassium reabsorption in

both the proximal tubule and the loop of Henle, a rel-

co-transported along with sodium and chloride. In

sium is reabsorbed in the loop of Henle, especially in

tubule. Another 25 to 30 per cent of the filtered potas-

potassium under normal conditions. About 65 per cent

Figure 29–2 summarizes the tubular handling of

renal diseases, however, can cause serious potassium

tion is regulated. Severe decreases in GFR in certain

plasma potassium, 4.2 mEq/L); this rate of filtration is

about 756 mEq/day (GFR, 180 L/day multiplied by

the tubules. The normal rate of potassium filtration is

tubules, and (3) the rate of potassium secretion by

tion), (2) the rate of potassium reabsorption by the

renal processes: (1) the rate of potassium filtration

Potassium excretion is determined by the sum of three

Overview of Renal Potassium

Renal Regulation; Integration of Renal Mechanisms

Chapter 29

367

dehydration and movement of potassium from the cells
into the extracellular fluid.

Excretion

(GFR multiplied by the plasma potassium concentra-

usually relatively constant because of the autoregula-
tory mechanisms for GFR discussed previously and
the precision with which plasma potassium concentra-

accumulation and hyperkalemia.

of the filtered potassium is reabsorbed in the proximal

the thick ascending part where potassium is actively

atively constant fraction of the filtered potassium load

most of the day-to-day variation of potassium excre-
tion is not due to changes in reabsorption in the prox-

Changes in Potassium Secretion in Distal and Collecting

sium excretion are the principal cells of the late distal

the kidneys must excrete about 92 mEq/day (the
remaining 8 milliequivalents are lost in the feces).
About one third (31 mEq/day) of this amount of
potassium is secreted into the distal and collecting

excretion of potassium is achieved almost entirely by
increasing the secretion of potassium into the distal

exceed the amount of potassium in the glomerular fil-

potassium.

the secretion rate of potassium in the distal and

sium excretion can fall to 1 per cent of the potassium
in the glomerular filtrate (to less than 10 mEq/day).

sium excretion occurs in the late distal and cortical

anisms of potassium secretion and the factors that reg-

tubules that secrete potassium are called principal cells

65%

(491 mEq/day)

(31 mEq/day)

12%

(92 mEq/day)

756 mEq/day

(180 L/day x 4.2 mEq/L)

27%

(204 mEq/day)

secreted into the different tubular seg-

much of the filtered load is reabsorbed or

capillaries. The percentages indicate how

the potassium filtered at the glomerular

the daily excretion is about 12 per cent of

ducts adds to the amount delivered, so that

the distal tubule. Secretion of potassium

8 per cent of the filtered load is delivered to

sorbed in the proximal tubule and in the

tion and secretion. Potassium is reab-

Renal tubular sites of potassium reabsorp-

Figure 29–2

ascending loop of Henle, so that only about

into the late distal tubules and collecting

ments.

which further stimulates potassium secretion, as dis-

membrane. (3) Increased potassium concentration

the epithelial cell; this reduces backleakage of potas-

membrane into the tubule. (2) Increased extracellular

tion, causing potassium to diffuse across the luminal

sium uptake across the basolateral membrane. This in

potassium ATPase pump, thereby increasing potas-

potassium secretion: (1) Increased extracellular fluid

There are three mechanisms by which increased

plasma potassium concentration, therefore, serves as

slightly less than the normal concentration. Increased

potassium concentration rises above about 4.1 mEq/L,

sium excretion, as shown in Figure 29–4. This effect

potassium concentration, leading to increases in potas-

The rate of potassium secre-

and (3) increased tubular flow rate.

potassium concentration, (2) increased aldosterone,

that influence secretion by these cells. The most impor-

collecting tubules, we will discuss the primary factors

Aldosterone, Tubular Flow Rate, and

Potassium Concentration,

Potassium Secretion: Plasma

tion, but under normal conditions it plays a small role

blood. This transporter is necessary to allow potassium

into the tubular lumen, and the potassium then diffuses

located in the luminal membrane. This transporter reab-

hydrogen-potassium ATPase

understood, one mechanism believed to contribute

sium in the late distal and collecting tubules. This

potassium depletion, there is a cessation of potassium

factors discussed later.

brane for potassium. These three determinants of

lumen, and (3) the permeability of the luminal mem-

ATPase pump, (2) the electrochemical gradient for

The

across the membrane.

potassium ions, thus allowing these ions to diffuse

the cell into the tubular lumen. The luminal membrane

cellular potassium concentration, which provides the

sodium-potassium ATPase pump creates a high intra-

from the interior of the cell into the tubular fluid. The

moves potassium to the interior of the cell. The second

membrane of the cell; this pump moves sodium out of

sodium-potassium ATPase pump in the basolateral

tubular lumen is a two-step process, beginning with

cells.

in these regions. Figure 29–3 shows the basic cellular

368

Unit V

The Body Fluids and Kidneys

and make up about 90 per cent of the epithelial cells

mechanisms of potassium secretion by the principal

Secretion of potassium from the blood into the

uptake from the interstitium into the cell by the

the cell into the interstitium and at the same time

step of the process is passive diffusion of potassium

driving force for passive diffusion of potassium from

of the principal cells is highly permeable to potassium.
One reason for this high permeability is that there are
special channels that are specifically permeable to

Control of Potassium Secretion by Principal Cells.

primary factors that control potassium secretion by the
principal cells of the late distal and cortical collecting
tubules are (1) the activity of the sodium-potassium

potassium secretion from the blood to the tubular

potassium secretion are in turn regulated by the

Intercalated Cells Can Reabsorb Potassium During Potassium
Depletion.

In circumstances associated with severe

secretion and actually a net reabsorption of potas-

reabsorption occurs through the intercalated cells;
although this reabsorptive process is not completely

is a

transport mechanism

sorbs potassium in exchange for hydrogen ions secreted

through the basolateral membrane of the cell into the

reabsorption during extracellular fluid potassium deple-

in controlling the excretion of potassium.

Summary of Factors That Regulate

Hydrogen Ion Concentration

Because normal regulation of potassium excretion
occurs mainly as a result of changes in potassium
secretion by the principal cells of the late distal and

tant factors that stimulate potassium secretion by the
principal cells include (1) increased extracellular fluid

One factor that decreases potassium secretion is

increased hydrogen ion concentration (acidosis).

Increased Extracellular Fluid Potassium Concentration Stimu-
lates Potassium Secretion.

tion in the late distal and cortical collecting tubules is
directly stimulated by increased extracellular fluid

is especially pronounced when extracellular fluid

one of the most important mechanisms for increasing
potassium secretion and regulating extracellular fluid
potassium ion concentration.

extracellular fluid potassium concentration raises

potassium concentration stimulates the sodium-

turn increases intracellular potassium ion concentra-

potassium concentration increases the potassium gra-
dient from the renal interstitial fluid to the interior of

sium ions from inside the cells through the basolateral

stimulates aldosterone secretion by the adrenal cortex,

cussed next.

Tubular

ATP

Renal

interstitial

fluid

Renal

interstitial

fluid

lumen

Principal

cells

Principal

cells

0 mV

50 mV

70 mV

Mechanisms of potassium secretion and sodium reabsorption by

Figure 29–3

the principal cells of the late distal and collecting tubules.

normal (blocks 3 and 4). Thus, this feedback mecha-

potassium excretion by the kidneys (block 2). The

blood level of aldosterone (block 1). The increase in

aldosterone secretion and, therefore, increases the

shown in Figure 29–6. In this feedback system, an

back system for regulating potassium excretion, as

The effect of potassium ion concentration to stimu-

nearly 0 to as high as 60 ng/100 ml, a concentration

concentration. Figure 29–5 shows that an increase in

aldosterone-potassium control system, the rate of

feedback effect on the controller. In the case of the

systems, the factor that is controlled usually has a

excretion, as shown in Figure 29–4.

stimulating potassium secretion. Therefore, aldos-

Thus, aldosterone also has a powerful effect to control

is mediated through a sodium-potassium ATPase

the late distal tubules and collecting ducts. This effect

Renal Regulation; Integration of Renal Mechanisms

Chapter 29

369

Aldosterone Stimulates Potassium Secretion.

In Chapter 27,

we discuss the fact that aldosterone stimulates active
reabsorption of sodium ions by the principal cells of

pump that transports sodium outward through the
basolateral membrane of the cell and into the blood at
the same time that it pumps potassium into the cell.

the rate at which the principal cells secrete potassium.

A second effect of aldosterone is to increase the per-

meability of the luminal membrane for potassium,
further adding to the effectiveness of aldosterone in

terone has a powerful effect to increase potassium

Increased Extracellular Potassium Ion Concentration Stimu-
lates Aldosterone Secretion.

In negative feedback control

aldosterone secretion by the adrenal gland is con-
trolled strongly by extracellular fluid potassium ion

plasma potassium concentration of about 3 mEq/L can
increase plasma aldosterone concentration from

almost 10 times normal.

late aldosterone secretion is part of a powerful feed-

increase in plasma potassium concentration stimulates

blood aldosterone then causes a marked increase in

increased potassium excretion then reduces the extra-
cellular fluid potassium concentration back toward

nism acts synergistically with the direct effect of

Effect of extracellular

Effect of aldosterone

Urinary potassium excretion

(times normal)

concentration

Extracellular potassium concentration

(mEq/L)

Extracellular potassium concentration

(mEq/L)

Plasma aldosterone (times normal)

of aldosterone and plasma potassium on potassium excretion. Am

(Drawn from data in Young DB, Paulsen AW: Interrelated effects

secretion by the principal cells of the cortical collecting tubules.

urinary potassium excretion. These factors stimulate potassium

) on the rate of

red line

Effect of plasma aldosterone concentration (

Figure 29–4

) and extra-

cellular potassium ion concentration (black line

J Physiol 244:F28, 1983.)

3.5

4.0

5.0

4.5

6.0

3.0

6.5

Approximate plasma aldosterone

concentration (ng/100 ml plasma)

5.5

Serum potassium concentration (mEq/L)

concentration cause large changes in aldosterone concentration.

aldosterone concentration. Note that small changes in potassium

Effect of extracellular fluid potassium ion concentration on plasma

Figure 29–5

Ald.

excretion

concentration

Aldosterone

concentration

Aldosterone

concentration

intake

sium concentration by aldosterone (Ald.).

Basic feedback mechanism for control of extracellular fluid potas-

Figure 29–6

fore, reduce urinary excretion of potassium. However,

decrease the rate of potassium secretion and, there-

aldosterone secretion, which by itself would tend to

example, with a high sodium intake, there is decreased

excretion during changes in sodium intake. For

The effect of increased tubular flow rate is especially

lated by increased tubular flow rate.

mized. Therefore, net potassium secretion is stimu-

continuously flushed down the tubule, so that the rise

increased tubular flow rate, the secreted potassium is

sium diffusion across the luminal membrane. With

increases, thereby reducing the driving force for potas-

tubular fluid, the luminal concentration of potassium

rate is as follows: When potassium is secreted into the

The mechanism for the effect of high-volume flow

by sodium depletion, reduces potassium secretion.

versely, a decrease in distal tubular flow rate, as caused

drug treatment, stimulates potassium secretion. Con-

with volume expansion, high sodium intake, or diuretic

. A rise in distal tubular flow rate, as occurs

Increased Distal Tubular Flow Rate Stimulates Potassium

aldosteronism (too much aldosterone) or Addison’s

systems, such as occurs in patients with either primary

aldosterone feedback system is blocked. A similar

tration, from 3.8 to almost 4.7 mEq/L. Thus, control of

blocked, the same increases in potassium intake

When the aldosterone feedback system was

intake.

cisely controlled, despite large changes in potassium

functioning normally, potassium concentration is pre-

L. Thus, when the aldosterone feedback system is

crease in potassium concentration, from 4.2 to 4.3 mEq/

Note that in the normal animals, a sevenfold

neither increase nor decrease.

dogs under two conditions: (1) under normal condi-

centration is shown in Figure 29–8. In this experiment,

The special quantitative importance of the aldos-

increased, causing potassium loss by the kidneys and

aldosteronism), potassium secretion becomes greatly

versely, with excess aldosterone secretion (primary

concentration to rise to dangerously high levels. Con-

impaired, thus causing extracellular fluid potassium

Addison’s disease, renal secretion of potassium is

aldosterone secretion, as occurs in patients with

Blockade of Aldosterone Feedback System Greatly Impairs

raised (Figure 29–7).

370

Unit V

The Body Fluids and Kidneys

increased extracellular potassium concentration to
elevate potassium excretion when potassium intake is

Control of Potassium Concentration.

In the absence of

thus leading to hypokalemia.

terone feedback system in controlling potassium con-

potassium intake was increased almost sevenfold in

tions and (2) after the aldosterone feedback system
had been blocked by removing the adrenal glands and
placing the animals on a fixed rate of aldosterone infu-
sion so that plasma aldosterone concentration could

increase in potassium intake caused only a slight in-

caused a much larger increase in potassium concen-

potassium concentration is greatly impaired when the

impairment of potassium regulation is observed in
humans with poorly functioning aldosterone feedback

disease (too little aldosterone).

Secretion

in tubular potassium concentration becomes mini-

important in helping to preserve normal potassium

the high distal tubular flow rate that occurs with a high
sodium intake tends to increase potassium secretion

intake

excretion

Aldosterone

Plasma K

concentration

secretion

Cortical collecting

tubules

raising plasma aldosterone concentration.

lecting tubules and indirectly increases potassium secretion by

centration directly raises potassium secretion by the cortical col-

potassium excretion. Note that increased plasma potassium con-

Primary mechanisms by which high potassium intake raises

Figure 29–7

120 150

180

210

Plasma potassium concentration

(mEq/day)

3.8

4.8

4.6

4.4

4.2

4.0

Potassium intake (mEq/day)

Aldosterone
system
blocked

Normal

Young.)

sium concentration was greatly impaired. (Courtesy Dr. David B.

that after blockade of the aldosterone system, regulation of potas-

after the aldosterone feedback had been blocked (

red line

potassium concentration under normal conditions (

Effect of large changes in potassium intake on extracellular fluid

Figure 29–8

) and

blue line). Note

. When extracellular fluid

decrease.

fluid. The bone, therefore, acts as a large reservoir

stored in the bone, with only about 1 per cent in the

Chapter 79.

major role in calcium homeostasis, as discussed in

the intestinal lumen. Therefore, the gastrointestinal

tions, fecal calcium excretion can exceed calcium

calcium excreted in the feces. Under certain condi-

intake is about 1000 mg/day, with about 900 mg/day of

occurs in the feces. The usual rate of dietary calcium

chloride, however, a large share of calcium excretion

over the long term. Unlike ions such as sodium and

As with other substances in the body, the intake of

calcium is bound to the plasma proteins. Therefore,

proteins. Conversely, in alkalosis, a greater amount of

teins. With acidosis, less calcium is bound to the plasma

that has biological activity at cell membranes. The

(5 mEq/L) exists in the ionized form, which is the form

cular excitability and can lead to cardiac arrhythmias.

spastic skeletal muscle contractions.

. This is characterized by

), the excitability of nerve and muscle

When calcium ion concentration falls to low levels

percentage points of its normal level, 2.4 mEq/L.

this chapter.

fore, calcium ion regulation is discussed only briefly in

parathyroid hormone (PTH) and calcitonin. There-

tration are discussed in detail in Chapter 79, along with

The mechanisms for regulating calcium ion concen-

Excretion and Extracellular

Control of Renal Calcium

Thus, chronic acidosis leads

potassium ATPase pump.

the secretion of potassium. This effect overrides

increases distal volume delivery, thereby stimulating

tubular sodium chloride and water reabsorption, which

excretion. The mechanism for this effect is due in part

several days, there is an increase in urinary potassium

With more prolonged acidosis, lasting over a period of

across the luminal membrane into the tubule.

activity of the sodium-potassium ATPase pump. This

losis) increases potassium secretion. The primary

low sodium intake, there is little change in potassium

little change in potassium excretion. Likewise, with a

flow rate, counterbalance each other, so that there is

Therefore, the two effects of high sodium intake,

(Figure 29–9), as discussed in the previous paragraph.

Renal Regulation; Integration of Renal Mechanisms

Chapter 29

371

decreased aldosterone secretion and the high tubular

excretion because of the counterbalancing effects of
increased aldosterone secretion and decreased tubular
flow rate on potassium secretion.

Acute Acidosis Decreases Potassium Secretion.

Acute

increases in hydrogen ion concentration of the extra-
cellular fluid (acidosis) reduce potassium secretion,
whereas decreased hydrogen ion concentration (alka-

mechanism by which increased hydrogen ion concen-
tration inhibits potassium secretion is by reducing the

in turn decreases intracellular potassium concentra-
tion and subsequent passive diffusion of potassium

to an effect of chronic acidosis to inhibit proximal

the inhibitory effect of hydrogen ions on the sodium-

to a loss of potassium, whereas acute acidosis leads to
decreased potassium excretion.

Calcium Ion Concentration

the endocrinology of the calcium-regulating hormones

Extracellular fluid calcium ion concentration

normally remains tightly controlled within a few

(hypocalcemia
cells increases markedly and can in extreme cases
result in hypocalcemic tetany

Hypercalcemia

(increased calcium concentration) depresses neuromus-

About 50 per cent of the total calcium in the plasma

remainder is either bound to the plasma proteins
(about 40 per cent) or complexed in the non-ionized
form with anions such as phosphate and citrate (about
10 per cent).

Changes in plasma hydrogen ion concentration can

influence the degree of calcium binding to plasma pro-

patients with alkalosis are more susceptible to hypocal-
cemic tetany.

calcium must be balanced with the net loss of calcium

ingestion because calcium can also be secreted into

tract and the regulatory mechanisms that influence
intestinal calcium absorption and secretion play a

Almost all the calcium in the body (99 per cent) is

extracellular fluid and 0.1 per cent in the intracellular

for storing calcium and as a source of calcium when
extracellular fluid calcium concentration tends to

One of the most important regulators of bone uptake

and release of calcium is PTH

intake

Aldosterone

GFR

Unchanged K

excretion

Distal tubular

flow rate

secretion

Cortical collecting

ducts

Proximal

tubular Na

reabsorption

change in potassium excretion.

sodium diet counterbalance each other, so that there is little

increase potassium secretion. The opposing effects of a high-

fluid delivery to the cortical collecting duct, which tends to

tubules. However, the high-sodium diet simultaneously increases

tends to decrease potassium secretion by the cortical collecting

that a high-sodium diet decreases plasma aldosterone, which

Effect of high sodium intake on renal excretion of potassium. Note

Figure 29–9

of phosphate is present in the glomerular filtrate,

about 0.1 mM/min. When less than this amount

explained as follows: The renal tubules have a normal

Regulation of Renal Phosphate

in Table 29–2.

reabsorption in the distal tubule.

bolic acidosis and inhibited by metabolic alkalosis.

reducing calcium excretion. The opposite occurs with

calcium reabsorption by the renal tubules, thereby

in plasma phosphate stimulates PTH, which increases

is the plasma concentration of phosphate. An increase

decreased blood pressure, calcium excretion decreases

Conversely, with extracellular volume contraction or

sequently, increased urinary excretion of calcium.

also reduction in calcium reabsorption and, con-

parallels sodium and water reabsorption. Therefore,

In the proximal tubule, calcium reabsorption usually

distal tubules.

versely, reduction of PTH promotes calcium excretion

which reduces urinary excretion of calcium. Con-

thick ascending loops of Henle and distal tubules,

PTH, there is increased calcium reabsorption in the

calcium reabsorption is PTH. With increased levels of

tion, calcium excretion by the kidneys decreases as a

intake is eliminated in the feces. With calcium deple-

excretion, although much of the increase of calcium

calcium intake, there is also increased renal calcium

adjusted to meet the body’s needs. With an increase in

As is true with the other ions, calcium excretion is

lecting tubules. This pattern of reabsorption is similar

25 to 30 per cent is reabsorbed in the loop of Henle,

filtered calcium is reabsorbed in the proximal tubule,

tered calcium being excreted. About 65 per cent of the

by the tubules, with only about 1 per cent of the fil-

calcium can be filtered at the glomerulus. Normally,

Therefore, only about 50 per cent of the plasma

proteins or complexed with anions such as phosphate.

ionized, with the remainder being bound to the plasma

kidneys but not secreted, the rate of renal calcium

by the Kidneys

Control of Calcium Excretion

cussed elsewhere, and the remainder of this section

29–10). The control of gastrointestinal calcium reab-

(Figure

intestinal reabsorption of calcium; and (3) by directly

ulating activation of vitamin D, which then increases

effects: (1) by stimulating bone resorption; (2) by stim-

Thus, PTH regulates

The most important regulator of calcium reabsorption

excretion by the gastrointestinal tract and the kidneys.

supply of calcium. Therefore, over the long term, the

The bones, however, do not have an inexhaustible

new bone formation. Thus, the day-to-day regulation

that almost no bone resorption now occurs; instead,

concentration is elevated, PTH secretion decreases, so

calcium levels back toward normal. When calcium ion

calcium into the extracellular fluid, thereby returning

bones) and, therefore, to release large amounts of

levels to promote increased secretion of PTH. This

calcium concentration falls below normal, the parathy-

372

Unit V

The Body Fluids and Kidneys

roid glands are directly stimulated by the low calcium

hormone then acts directly on the bones to increase
the resorption of bone salts (release of salts from the

excess calcium is deposited in the bones because of

of calcium ion concentration is mediated in large part
by the effect of PTH on bone resorption.

intake of calcium must be balanced with calcium

at both of these sites is PTH.
plasma calcium concentration through three main

increasing renal tubular calcium reabsorption

sorption and calcium exchange in the bones is dis-

focuses on the mechanisms that control renal calcium
excretion.

Because calcium is both filtered and reabsorbed in the

excretion is calculated as

Renal calcium excretion

= Calcium filtered

- Calcium reabsorbed

Only about 50 per cent of the plasma calcium is

about 99 per cent of the filtered calcium is reabsorbed

and 4 to 9 per cent is reabsorbed in the distal and col-

to that for sodium.

result of enhanced tubular reabsorption.

One of the primary controllers of renal tubular

by decreasing reabsorption in the loops of Henle and

in instances of extracellular volume expansion or
increased arterial pressure—both of which decrease
proximal sodium and water reabsorption—there is

primarily because of increased proximal tubular
reabsorption.

Another factor that influences calcium reabsorption

reduction in plasma phosphate concentration.

Calcium reabsorption is also stimulated by meta-

Most of the effect of hydrogen ion concentration on
calcium excretion results from changes in calcium

A summary of the factors that are known to influ-

ence calcium excretion by the renal tubules is shown

Excretion

Phosphate excretion by the kidneys is controlled
primarily by an overflow mechanism that can be

transport maximum for reabsorbing phosphate of

Vitamin D

activation

PTH

[Ca

]

Intestinal Ca

reabsorption

Renal Ca

reabsorption

release

from bones

concentration mediated by parathyroid hormone (PTH) and

Compensatory responses to decreased plasma ionized calcium

Figure 29–10

vitamin D.

excretion by the kidneys is determined by intake. To

that matter—is that under steady-state conditions,

sodium excretion—or excretion of any electrolyte, for

Matched to Intake Under Steady-State

Sodium Excretion Is Precisely

the amount of extracellular water, so that osmolality

the ADH-thirst mechanisms are functioning normally,

(ADH)-thirst mechanisms are also operative. When

fluid volume, provided the antidiuretic hormone

volume, we also consider the factors that regulate the

conditions.

volume regulation is usually placed on the kidneys,

mechanisms. Therefore, the burden of extracellular

person’s habits rather than by physiologic control

In most cases, salt and fluid intakes are dictated by a

Mechanisms for Control

tion, (2) extracellular volume expansion, and (3)

bances lead to increased magnesium excretion: (1)

are not well understood, but the following distur-

The mechanisms that regulate magnesium excretion

collecting tubules.

the filtered load of magnesium is reabsorbed. Only a

tion is the loop of Henle, where about 65 per cent of

the filtered magnesium. The primary site of reabsorp-

mainly by changing tubular reabsorption. The proxi-

the body, including activation of many enzymes, its

almost nil during magnesium depletion. Because mag-

nesium in the glomerular filtrate.

of magnesium, or 125 to 150 mg/day. The kidneys

absorbed magnesium, about one half the daily intake

magnesium balance, the kidneys must excrete this

absorbed by the gastrointestinal tract. To maintain

to 300 mg/day, but only about one half of this intake is

The normal daily intake of magnesium is about 250

0.8 mEq/L.

is bound to plasma proteins. Therefore, the free

tration is about 1.8 mEq/L, more than one half of this

fluid. Although the total plasma magnesium concen-

in the bones. Most of the rest resides within the cells,

More than one half of the body’s magnesium is stored

Excretion and Extracellular

Control of Renal Magnesium

among phosphate, PTH, and calcium are discussed in

. These interrelations

is lost in the urine.

port maximum for phosphate by the renal tubules,

from the bone salts, and (2) PTH decreases the trans-

promotes bone resorption, thereby dumping large

phate concentration through two effects: (1) PTH

the tendency for phosphate to spill over into the urine.

transport maximum for phosphate, thereby reducing

in phosphate can, over time, increase the reabsorptive

influence phosphate excretion. For instance, a diet low

continual excretion of phosphate into the urine.

maintained above 1 mM/L, a level at which there is

and meat, the concentration of phosphate is usually

assuming a GFR of 125 ml/min. Because most people

a tubular load of phosphate of about 0.1 mM/min,

rises above a threshold of about 0.8 mM/L, which gives

Therefore, phosphate normally begins to spill into the

When more than this is present, the

Renal Regulation; Integration of Renal Mechanisms

Chapter 29

373

essentially all the filtered phosphate is reabsorbed.

excess is excreted.

urine when its concentration in the extracellular fluid

ingest large quantities of phosphate in milk products

Changes in tubular phosphate reabsorption can also

PTH can play a significant role in regulating phos-

amounts of phosphate ions into the extracellular fluid

so that a greater proportion of the tubular phosphate

Thus, whenever plasma PTH is

increased, tubular phosphate reabsorption is decreased
and more phosphate is excreted

more detail in Chapter 79.

Magnesium Ion Concentration

with less than 1 per cent located in the extracellular

ionized concentration of magnesium is only about

normally excrete about 10 to 15 per cent of the mag-

Renal excretion of magnesium can increase

markedly during magnesium excess or can decrease to

nesium is involved in many biochemical processes in

concentration must be closely regulated.

Regulation of magnesium excretion is achieved

mal tubule usually reabsorbs only about 25 per cent of

small amount (usually less than 5 per cent) of the
filtered magnesium is reabsorbed in the distal and

increased extracellular fluid magnesium concentra-

increased extracellular fluid calcium concentration.

Integration of Renal

of Extracellular Fluid

Extracellular fluid volume is determined mainly by the
balance between intake and output of water and salt.

which must adapt their excretion of salt and water to
match intake of salt and water under steady-state

In discussing the regulation of extracellular fluid

amount of sodium chloride in the extracellular fluid,
because changes in extracellular fluid sodium chloride
content usually cause parallel changes in extracellular

a change in the amount of sodium chloride in the
extracellular fluid is matched by a similar change in

and sodium concentration are maintained relatively
constant.

Conditions

An important consideration in overall control of

Table 29–2

Metabolic acidosis

Metabolic alkalosis

Factors That Alter Renal Calcium Excretion

Ø Calcium Excretion

≠ Calcium Excretion

≠ Parathyroid hormone (PTH)

Ø PTH

Ø Extracellular fluid volume

≠ Extracellular fluid volume

Ø Blood pressure

≠ Blood pressure

≠ Plasma phosphate

Ø Plasma phosphate

Vitamin D

therefore, decreases formation of angiotensin II and

after a short time delay, suppresses renin release and,

enhanced because the increased blood pressure also,

these factors. With chronic increases in blood pressure,

as angiotensin II, ADH, or aldosterone, because pres-

pathetic nervous system or of various hormones, such

threefold increase in urinary sodium output. This

urinary sodium output. Note that acute increases in

Figure 29–11 shows the effect of arterial pressure on

as “pressure natriuresis” in the following discussion.

occur in parallel, we refer to these mechanisms simply

sure. Because pressure diuresis and natriuresis usually

discussed in Chapter 19, this feedback between the

mechanisms, respectively. As

fluid balance, is the effect of blood pressure on sodium

volume, as well as for the maintenance of sodium and

Diuresis in Maintaining Body

Natriuresis and Pressure

Importance of Pressure

keep in mind, however, that all these feedback mech-

also to control extracellular fluid volume. We should

equal sodium intake. In the next few sections, we

hormones, that eventually return sodium excretion to

changes in blood pressure and changes in various

other feedback mechanisms come into play, such as

urine sodium and water excretion. When this happens,

the way back to normal, changes in either GFR or

these same intrarenal feedbacks.

and return of GFR toward normal. Likewise, abnor-

, in which increased sodium chloride delivery to

back

, and (2)

much of the extra sodium chloride filtered, called

compensations: (1) increased tubular reabsorption of

tubules, which in turn leads to at least two intrarenal

fever), this raises sodium chloride delivery to the

mized by various buffering mechanisms. For example,

reabsorption, changes in urinary excretion are mini-

of water and electrolytes.

and GFR usually are regulated precisely, so that excre-

volume and sodium excretion. Tubular reabsorption

GFR, would also lead to dramatic changes in urine

tion, in the absence of compensatory adjustments of

volumes. Similarly, small changes in tubular reabsorp-

volume, if tubular compensations did not occur; this

(to 189 L/day) would cause a 9 L/day increase in urine

excretion. For example, a 5 per cent increase in GFR

L/day. Thus, small changes in GFR or tubular reab-

sorption is 178.5 L/day, and urine excretion is 1.5

GFR normally is about 180 L/day, tubular reab-

Tubular

The two variables that influence sodium and water

Tubular Sodium Reabsorption Rates

Altering Glomerular Filtration or

Sodium Excretion Is Controlled by

balance with intake.

vascular collapse within a few days. Thus, one can view

tion or loss of electrolytes and fluid, causing cardio-

compensations, however, are necessary because a

body that may, in the long run, be damaging. These

ations of sympathetic nervous system activity. These

pressure, changes in circulating hormones, and alter-

adjustments must be invoked, such as changes in blood

intrarenal compensations are exhausted, systemic

cellular fluid volume or other systemic adjustments.

severe, sodium balance may be achieved mainly by

a few days.

major changes in kidney function, balance between

ingested. Therefore, even with disturbances that cause

maintain life, a person must, over the long term,

374

Unit V

The Body Fluids and Kidneys

excrete almost precisely the amount of sodium

intake and output of sodium usually is restored within

If disturbances of kidney function are not too

intrarenal adjustments with minimal changes in extra-

But when perturbations to the kidneys are severe and

adjustments are costly in terms of overall homeostasis
because they cause other changes throughout the

sustained imbalance between fluid and electrolyte
intake and excretion would quickly lead to accumula-

the systemic adjustments that occur in response to
abnormalities of kidney function as a necessary trade-
off that brings electrolyte and fluid excretion back in

excretion are the rates of filtration and the rates of
reabsorption:

Excretion

= Glomerular filtration -

reabsorption

sorption potentially can cause large changes in renal

would quickly cause catastrophic changes in body fluid

tion by the kidneys can be exactly matched to intake

Even with disturbances that alter GFR or tubular

if the kidneys become greatly vasodilated and GFR
increases (as can occur with certain drugs or high

glomerulotubular balance

macula densa feed-

the distal tubule causes afferent arteriolar constriction

malities of tubular reabsorption in the proximal tubule
or loop of Henle are partially compensated for by

Because neither of these two mechanisms operates

perfectly to restore distal sodium chloride delivery all

tubular reabsorption can lead to significant changes in

review how these mechanisms operate together to
control sodium and water balance and in so doing act

anisms control renal excretion of sodium and water by
altering either GFR or tubular reabsorption.

Sodium and Fluid Balance

One of the most basic and powerful mechanisms for
control of blood volume and extracellular fluid

and water excretion—called the pressure natriuresis
and pressure diuresis

kidneys and the circulatory system also plays a domi-
nant role in long-term blood pressure regulation.

Pressure diuresis refers to the effect of increased

blood pressure to raise urinary volume excretion,
whereas pressure natriuresis refers to the rise in
sodium excretion that occurs with elevated blood pres-

blood pressure of 30 to 50 mm Hg cause a twofold to

effect is independent of changes in activity of the sym-

sure natriuresis can be demonstrated in an isolated
kidney that has been removed from the influence of

the effectiveness of pressure natriuresis is greatly

increased intake, and further accumulation of fluid

8. The increased fluid excretion balances the

output by way of pressure diuresis. The steepness

7. An increased arterial pressure increases urine

pressure.

6. An increased cardiac output raises arterial

5. An increased pressure gradient for venous return

4. An increase in mean circulatory filling pressure

circulatory filling pressure.

3. An increase in blood volume raises mean

extracellular fluid volume. As discussed later, the

accumulates in the blood and interstitial spaces,

2. As long as fluid intake exceeds urine output, fluid

fluid in the body.

1. An increase in fluid intake (assuming that sodium

fluid volume, and arterial pressure as follows:

to minimize changes in blood volume, extracellular

During changes in sodium and fluid intake, this feed-

volume, cardiac output, arterial pressure, and urine

pressure control. The extracellular fluid volume, blood

output, as shown in Figure 29–12. This is the same

The effect of increased blood pressure to raise urine

Fluid Volumes and Arterial Pressure

Fluid Feedback for Regulating Body

Pressure Natriuresis and Diuresis Are

reabsorption of sodium, thereby amplifying the direct

aldosterone. As discussed previously, decreased levels

Renal Regulation; Integration of Renal Mechanisms

Chapter 29

375

of angiotensin II and aldosterone inhibit renal tubular

effects of increased blood pressure to raise sodium and
water excretion.

Key Components of a Renal-Body

output is part of a powerful feedback system that oper-

ates to maintain balance between fluid intake and

mechanism that is discussed in Chapter 19 for arterial

output are all controlled at the same time as separate
parts of this basic feedback mechanism.

back mechanism helps to maintain fluid balance and

accompanies the fluid intake) above the level of
urine output causes a temporary accumulation of

causing parallel increases in blood volume and

actual increases in these variables are usually
small because of the effectiveness of this
feedback.

raises the pressure gradient for venous return.

elevates cardiac output.

of the normal pressure natriuresis relation
indicates that only a slight increase in blood
pressure is required to raise urinary excretion
severalfold.

is prevented.

80 100 120 140 160 180 200

20 40 60

Urinary sodium or volume

output (times normal)

Chronic
Acute

Arterial pressure (mm Hg)

pressure.

output than those measured during acute increases in arterial

in arterial pressure cause much greater increases in sodium

by the kidneys (pressure natriuresis). Note that chronic increases

Acute and chronic effects of arterial pressure on sodium output

Figure 29–11

Arterial

pressure

Extracellular

fluid volume

Blood

volume

Mean circulatory

filling pressure

Venous

return

Vascular

capacity

Rate of change of

extracellular
fluid volume

Arterial pressure

Renal fluid

excretion

Nonrenal

fluid loss

Fluid

intake

Cardiac

output

Heart strength

Total peripheral

resistance

negative effects.

effects, and dashed lines indicate

volume, and arterial pressure.

mechanism for control of

Basic renal–body fluid feedback

Figure 29–12

blood volume, extracellular fluid

Solid lines indicate positive

spaces act as an “overflow” reservoir for excess fluid,

Thus, under normal conditions, the interstitial

the tissues, is lost once the tissues become highly

factor against edema, owing to a rising interstitial

pressure rising much more. In other words, the safety

spaces become compliant, and large amounts of fluid

tive value to become positive, the tissue interstitial

remains in the blood. This occurs because once the

30 to 50 per cent above normal, almost all the addi-

When the extracellular fluid volume rises more than

remainder is distributed to the interstitial spaces.

in the blood and increases the blood volume. The

renal output of fluid, about 20 to 30 per cent of it stays

and the distribution that occurs in edema states. When

Figure 29–14 shows the normal distribution of fluid

uted to the interstitial spaces.

. In all these conditions, an unusually high

spaces and blood can vary greatly. As discussed in

There are circumstances, however, in which the dis-

usually are controlled simultaneously.

fore, blood volume and extracellular fluid volume

between the interstitial spaces and the plasma. There-

into the blood, but it rapidly becomes distributed

in parallel with each other. Ingested fluid initially goes

From Figure 29–12 it is apparent that blood volume

Spaces and Vascular System

normal despite the low red blood cell mass.

the plasma volume will simply make up the difference,

when there is deficiency of erythropoietin or other

ties of red blood cell volume remain, such as occurs

cells and plasma proteins in the blood. If abnormali-

In this case, fluid is retained by the kidneys, and other

there is a loss of whole blood because of hemorrhage.

The same control mechanisms operate whenever

control of blood volume.

pressure causes a large change in urine output. These

in blood pressure, and (3) a slight change in blood

volume causes a marked change in cardiac output, (2)

this is the following: (1) a slight change in blood

extreme changes in daily fluid intake. The reason for

By studying Figure 29–12, one can see why the blood

Extracellular Fluid Volume Regulation

Precision of Blood Volume and

tion or other inescapable losses.

ficient to make up for fluid losses caused by evapora-

variations in daily intake of water and electrolytes,

strated in Figure 29–13, which shows that changes in

volume. The effectiveness of this mechanism in pre-

blood pressure, blood volume, or extracellular fluid

large decrease in urine output, thereby allowing fluid

lar fluid volume, as well as reduced arterial pressure.

dency toward decreased blood volume and extracellu-

intake falls below normal. In this case, there is a ten-

The opposite sequence of events occurs when fluid

pressure.

extracellular fluid volume, cardiac output, and arterial

modated with only slight changes in blood volume,

pressure diuresis mechanism is operating effectively,

intake. As long as kidney function is normal and the

Thus, the renal-body fluid feedback mechanism

376

Unit V

The Body Fluids and Kidneys

operates to prevent continuous accumulation of salt
and water in the body during increased salt and water

large changes in salt and water intake can be accom-

Even a small decrease in blood pressure causes a

balance to be maintained with minimal changes in

venting large changes in blood volume is demon-

blood volume are almost imperceptible despite large

except when intake becomes so low that it is not suf-

volume remains almost exactly constant despite

a slight change in cardiac output causes a large change

factors work together to provide effective feedback

parallel processes occur to reconstitute the red blood

factors needed to stimulate red blood cell production,

and the overall blood volume will return essentially to

Distribution of Extracellular
Fluid Between the Interstitial

and extracellular fluid volume are usually controlled

tribution of extracellular fluid between the interstitial

Chapter 25, the principal factors that can cause accu-
mulation of fluid in the interstitial spaces include (1)
increased capillary hydrostatic pressure, (2) decreased
plasma colloid osmotic pressure, (3) increased perme-
ability of the capillaries, and (4) obstruction of lym-
phatic vessels
proportion of the extracellular fluid becomes distrib-

between the interstitial spaces and the vascular system

small amounts of fluid accumulate in the blood as a
result of either too much fluid intake or a decrease in

tional fluid goes into the interstitial spaces and little

interstitial fluid pressure rises from its normally nega-

then pour into the tissues without interstitial fluid

fluid pressure that counteracts fluid accumulation in

compliant.

Blood volume (liters)

Blood volume

Normal range

Death

Daily fluid intake

(water and electrolytes) (L/day)

Daily fluid intake

(water and electrolytes) (L/day)

normal range of daily fluid intakes.

volume. Note that blood volume remains relatively constant in the

Approximate effect of changes in daily fluid intake on blood

Figure 29–13

pressures and body fluid volumes.

Thus, changes in activity of the renin-angiotensin

arterial blood pressure that would otherwise occur.

normal, increased levels of angiotensin II cause

Conversely, when sodium intake is reduced below

wise occur when sodium intake increases.

The net result is to minimize the rise in extracellular

increasing the kidneys’ excretion of sodium and water.

tubular reabsorption of sodium and water, thus

Chapter 27, a reduced level of angiotensin II decreases

ing tubular reabsorption of sodium, as explained in

decreased angiotensin II formation.

Because

above normal, renin secretion is decreased, causing

balances. That is, when sodium intake is elevated

angiotensin II formation, and this in turn contributes

excretion is angiotensin II. Changes in sodium and

One of the body’s most powerful controllers of sodium

Role of Angiotensin II In Controlling

contains large amounts of salt and water.

Also, reflex inhibition of renal sympathetic activity

that occurs in acute conditions such as hemorrhage.

and aortic arch. All these reflexes together play an

rial pressure, further activation of the sympathetic

increase tubular reabsorption. And if the reduction in

and aldosterone formation, both of which further

tubular reabsorption of salt and water; and (3) stimu-

rioles, with resultant decreased GFR; (2) increased

and water excretion: (1) constriction of the renal arte-

activity, which has several effects to decrease sodium

system. This in turn increases renal sympathetic nerve

and other low-pressure regions of the thorax decrease,

orrhage, the pressures in the pulmonary blood vessels

For example, when blood volume is reduced by hem-

of extracellular fluid volume under some conditions.

innervation, changes in sympathetic activity can alter

Control of Renal Excretion: Arterial

fluid volumes, as discussed later.

response to day-to-day challenges. However, abnor-

fluid volume, and arterial pressure that occur in

minimizing the changes in blood volume, extracellular

diuresis mechanisms, making them more effective in

and, therefore, renal excretion of salt and water. These

In Chapter 27, we discuss the nervous and hormonal

Fluid Feedback Control

Effectiveness of Renal-Body

Factors Increase the

Nervous and Hormonal

the capillary membranes.

volume are controlled simultaneously, but the quanti-

To summarize, extracellular fluid volume and blood

edema and cardiac failure.

culation, protecting the cardiovascular system against

causes edema, as explained in Chapter 25, but it also

sometimes increasing in volume 10 to 30 liters. This

Renal Regulation; Integration of Renal Mechanisms

Chapter 29

377

acts as an important overflow release valve for the cir-

dangerous overload that could lead to pulmonary

tative amounts of fluid distribution between the
interstitium and the blood depend on the physical
properties of the circulation and the interstitial spaces
as well as on the dynamics of fluid exchange through

factors that influence GFR and tubular reabsorption

nervous and hormonal mechanisms usually act in
concert with the pressure natriuresis and pressure

malities of kidney function or of the various nervous
and hormonal factors that influence the kidneys can
lead to serious changes in blood pressure and body

Sympathetic Nervous System

Baroreceptor and Low-Pressure
Stretch Receptor Reflexes

Because the kidneys receive extensive sympathetic

renal sodium and water excretion as well as regulation

causing reflex activation of the sympathetic nervous

lation of renin release and increased angiotensin II

blood volume is great enough to lower systemic arte-

nervous system occurs because of decreased stretch of
the arterial baroreceptors located in the carotid sinus

important role in the rapid restitution of blood volume

may contribute to the rapid elimination of excess fluid
in the circulation that occurs after eating a meal that

Renal Excretion

fluid intake are associated with reciprocal changes in

greatly to the maintenance of body sodium and fluid

angiotensin II has several important effects in increas-

fluid volume and arterial pressure that would other-

sodium and water retention and oppose reductions in

system act as a powerful amplifier of the pressure
natriuresis mechanism for maintaining stable blood

Blood volume (liters)

Edema

Normal value

Death

Extracellular fluid volume (liters)

interstitial spaces, and edema results.

occurs, the additional extracellular fluid volume resides in the

also showing the failure of blood volume to continue rising when

volume, showing a nearly linear relation in the normal range but

Approximate relation between extracellular fluid volume and blood

Figure 29–14

the extracellular fluid volume becomes excessive. When this

in the urine.

reabsorption and potassium secretion. Therefore, the

in the cortical collecting tubules. The increased sodium

Aldosterone increases sodium reabsorption, especially

Role of Aldosterone in Controlling

this effect, and sodium excretion is once again restored

sodium and water, but the fall in blood pressure offsets

enzyme inhibitor is administered, there is initial loss of

mation, as occurs when an angiotensin-converting

sure. Conversely, after blockade of angiotensin II for-

ing the sodium- and water-retaining effects of the

kidney output of sodium and water, thereby overcom-

increase in extracellular fluid volume. This also initi-

occurs with a renin-secreting tumor of the kidney,

that with large increases in angiotensin II levels, as

volume or blood volume. The reason for this is

sodium- and water-retaining hormones in the body,

Extracellular Fluid Volume Because Increased Arterial Pressure

angiotensin II receptor antagonists.

arterial pressures. This shift of pressure natriuresis

pressures; this indicates an enhanced ability of the

29–15) or an angiotensin II receptor antagonist, the

angiotensin-converting enzyme inhibitor (see Figure

When angiotensin II formation is blocked with an

ing the kidneys’ ability to excrete salt and water.

The use of drugs to block the effects of angiotensin

sis and makes arterial pressure very salt sensitive, as

pressure to rise as much as 50 mm Hg. Thus, the inabil-

sodium, the same rise in sodium intake causes blood

few millimeters of mercury in arterial pressure,

sodium balance. For example, in most people, a 10-fold

raised, much greater increases in arterial pressure are

nearly as steep. Therefore, when sodium intake is

renin secretion, the pressure natriuresis curve is not

(high angiotensin II curve), as occurs in some hyper-

In contrast, when angiotensin levels cannot be

effective is shown in Figure 29–15. Note that when the

The importance of angiotensin II

378

Unit V

The Body Fluids and Kidneys

Importance of Angiotensin II in Increasing Effectiveness of
Pressure Natriuresis.

in making the pressure natriuresis mechanism more

angiotensin control of natriuresis is fully functional,
the pressure natriuresis curve is steep (normal curve),
indicating that only minor changes in blood pressure
are needed to increase sodium excretion when sodium
intake is raised.

decreased in response to increased sodium intake

tensive patients who have impaired ability to decrease

needed to increase sodium excretion and maintain

increase in sodium intake causes an increase of only a

whereas in subjects who cannot suppress angiotensin
II formation appropriately in response to excess

ity to suppress angiotensin II formation when there is
excess sodium reduces the slope of pressure natriure-

discussed in Chapter 19.

II has proved to be important clinically for improv-

renal–pressure natriuresis curve is shifted to lower

kidneys to excrete sodium because normal levels of
sodium excretion can now be maintained at reduced

provides the basis for the chronic blood pressure–

lowering effects in hypertensive patients of the
angiotensin-converting enzyme inhibitors and

Excessive Angiotensin II Does Not Cause Large Increases in

Counterbalances Angiotensin-Mediated Sodium Retention.

Although angiotensin II is one of the most powerful

neither a decrease nor an increase in circulating
angiotensin II has a large effect on extracellular fluid

the high angiotensin II levels initially cause sodium
and water retention by the kidneys and a small

ates a rise in arterial pressure that quickly increases

angiotensin II and re-establishing a balance between
intake and output of sodium at a higher blood pres-

to normal.

Renal Excretion

reabsorption is also associated with increased water

net effect of aldosterone is to make the kidneys retain
sodium and water but to increase potassium excretion

100

120

140

160

Sodium intake and output

(times normal)

Angiotensin blockade

Normal

High angiotensin II

Arterial pressure (mm Hg)

lower blood pressures.

mation shifts pressure natriuresis to

very sensitive to changes in sodium

natriuresis, making blood pressure

mation decrease the slope of pressure

renal–pressure natriuresis curve. Note

angiotensin II formation on the

formation and effect of blocking

Effect of excessive angiotensin II

Figure 29–15

that high levels of angiotensin II for-

intake. Blockade of angiotensin II for-

changes in blood volume during various disturbances,

Changes in ANP levels probably help to minimize

compensate for the excess blood volume.

increased excretion of salt and water, which helps to

ducts. These combined actions of ANP lead to

cardiac atria, ANP enters the circulation and acts on

from excess blood volume. Once released by the

appears to be overstretch of the atria, which can result

muscle fibers. The stimulus for release of this peptide

, released by the cardiac atrial

regulation. One of the most important of the natri-

lular fluid volume. However, several different natri-

and water-retaining hormones in controlling extracel-

Thus far, we have discussed mainly the role of sodium-

in Controlling Renal Excretion

Role of Atrial Natriuretic Peptide

arterial pressure.

to water is prevented, the inability to secrete ADH

enough water to maintain fluid balance. If free access

This is almost always compensated for by ingestion of

lar fluid in the urine through pressure natriuresis.

same time, the small increase in blood pressure that

the kidneys dilutes the extracellular sodium, and at the

. The

high ADH levels can cause severe reduc-

sure, although

Thus, high levels of ADH do not cause major

which ADH levels may be elevated severalfold.

, in

inappropriate ADH syndrome

also elevated by less than 10 mm Hg. The same is true

more than 5 to 10 per cent, and the arterial pressure is

nism. After several days of ADH infusion, the blood

to this increased volume, much of the excess volume

fluid volume. As the arterial pressure rises in response

of ADH into animals initially causes renal retention of

extracellular fluid volume. Infusion of large amounts

extracellular fluid volume, excessive levels of ADH

Although ADH is important in regulating

Extracellular Fluid Volume but Large Decreases in Sodium Con-

volume.

the kidneys, thus helping to rid the body of the excess

Conversely, when there is excess extracellular volume,

both extracellular fluid volume and arterial pressure.

tion in the distal and collecting tubules, the same

nizes the action of ADH to promote water reabsorp-

effects of ADH are blocked with a drug that antago-

fluid volume and arterial pressure. However, if the

otherwise occur. Water deprivation for 24 to 48 hours

deprivation, which strongly elevates plasma levels of

salt. This effect is especially important during water

As discussed in Chapter 28, ADH plays an important

Water Excretion

Role of ADH in Controlling Renal

urine output of salt and water.

terone, the volume depletion may be severe unless the

low blood pressure. In the complete absence of aldos-

in extracellular fluid volume, and a tendency toward

is increased excretion of sodium and water, reduction

secrete enough aldosterone (Addison’s disease), there

In patients with adrenal insufficiency who do not

diuresis that occur when the arterial pressure rises.

presence of high levels of aldosterone. The primary

sodium equal to the daily intake, despite continued

rises sufficiently, the kidneys “escape” from the sodium

in arterial blood pressure. When the arterial pressure

retention, the extracellular fluid volume rises by about

are transient. After 1 to 3 days of sodium and water

(Conn’s syndrome), the increased sodium reabsorp-

aldosterone or excessive formation of aldosterone, as

reabsorption, when there is excessive infusion of

during variations in salt intake.

the kidneys to excrete larger amounts of sodium. Thus,

formation decreases tubular reabsorption, allowing

with high sodium intake, suppression of aldosterone

to the maintenance of sodium balance. Conversely,

reduction in urinary sodium excretion and, therefore,

aldosterone secretion, which in turn contributes to the

angiotensin II. That is, with reduction in sodium intake,

The function of aldosterone in regulating sodium

Renal Regulation; Integration of Renal Mechanisms

Chapter 29

379

balance is closely related to that described for

the increased angiotensin II levels that occur stimulate

changes in aldosterone formation also aid the pressure
natriuresis mechanism in maintaining sodium balance

During Chronic Oversecretion of Aldosterone, Kidneys
“Escape” from Sodium Retention as Arterial Pressure Rises.

Although aldosterone has powerful effects on sodium

occurs in patients with tumors of the adrenal gland

tion and decreased sodium excretion by the kidneys

10 to 15 per cent and there is a simultaneous increase

and water retention and thereafter excrete amounts of

reason for the escape is the pressure natriuresis and

person is allowed to eat large amounts of salt and
drink large amounts of water to balance the increased

role in allowing the kidneys to form a small volume of
concentrated urine while excreting normal amounts of

ADH that in turn increase water reabsorption by the
kidneys and help to minimize the decreases in extra-
cellular fluid volume and arterial pressure that would

normally causes only a small decrease in extracellular

period of water deprivation causes a substantial fall in

decreased ADH levels reduce reabsorption of water by

Excess ADH Secretion Usually Causes Only Small Increases in

centration.

seldom cause large increases in arterial pressure or

water and a 10 to 15 per cent increase in extracellular

is excreted because of the pressure diuresis mecha-

volume and extracellular fluid volume are elevated no

for patients with

increases of either body fluid volume or arterial pres-

tions in extracellular sodium ion concentration
reason for this is that increased water reabsorption by

does occur causes loss of sodium from the extracellu-

In patients who have lost their ability to secrete

ADH because of destruction of the supraoptic nuclei,
the urine volume may become 5 to 10 times normal.

may lead to marked reductions in blood volume and

uretic hormones may also contribute to volume

uretic hormones is a peptide referred to as atrial natri-
uretic peptide (ANP)

the kidneys to cause small increases in GFR and
decreases in sodium reabsorption by the collecting

decreased arterial pressure. The fall in pressure causes

29–12), which leads to decreased cardiac output and

reduces mean circulatory filling pressure (see Figure

capacity. An increase in vascular capacity initially

Increased Blood Volume Caused by

pressure to normal. This allows even the weakened

volume, which helps to return cardiac output and blood

congenital abnormalities of the heart, an important

In myocardial failure, heart valvular disease, and

occurs, the kidneys continue to retain volume until the

enough to restore urine output to normal. When this

weakened, arterial pressure will not be able to increase

pumping adequately. However, if the heart is greatly

rial pressure virtually all the way to normal, and sodium

Indeed, if the heart failure is not too severe, the rise in

fore, the kidneys retain volume in an attempt to return

itself causes the kidneys to retain salt and water. There-

nervous systems. In addition, the low blood pressure

the renin-angiotensin, aldosterone, and sympathetic

activates multiple sodium-retaining systems, especially

consequently, decreases arterial pressure. This in turn

29–12. Initially, heart failure reduces cardiac output and,

this can be understood by re-examination of Figure

times increases by 200 per cent or more. The reason for

15 to 20 per cent, and extracellular fluid volume some-

In congestive heart failure, blood volume may increase

Extracellular Fluid Volume Caused

Increased Blood Volume and

abnormalities.

can cause large increases in both of these variables.

sonably constant, there are abnormal conditions that

Fluid Volume

Volume and Extracellular

Large Increases in Blood

levels.

sodium intake is increased. The opposite changes take

and suppression of sodium- and water-retaining

Thus, the combined activation of natriuretic systems

, especially ANP,

aldosterone secretion, thus further reducing

Also, reduced angiotensin II decreases

volume expansion, decreases tubular sodium

, caused by

pressure natriuresis.

volume expansion, raise sodium excretion through

, caused by

increase in salt and water intake.

This mechanism is most important in the first few

atrium and the pulmonary blood vessels. Signals

Activation of low pressure receptor reflexes

sodium excretion. These mechanisms include the

increase in extracellular fluid volume. It is mainly this

cumulative sodium balance, which causes a slight

intake. The time delay results in a small increase in the

increased, sodium output initially lags slightly behind

High Sodium Intake Suppresses Antinatriuretic Systems and

dietary sodium intake. As discussed previously, the

The integration of the different control systems that

normal, despite continued excess of ANP.

hours, this effect is overcome by a slight decrease in

cause slight decreases in blood volume. In less than 24

natriuresis. For example, infusions of large amounts of

changes in blood pressure, acting through pressure

excessive production of ANP or even complete lack of

such as increased salt and water intake. However,

380

Unit V

The Body Fluids and Kidneys

ANP does not cause major changes in blood volume
because these effects can easily be overcome by small

ANP initially raise urine output of salt and water and

blood pressure that returns urine output toward

Integrated Responses to
Changes in Sodium Intake

regulate sodium and fluid excretion under normal
conditions can be summarized by examining the
homeostatic responses to progressive increases in

kidneys have an amazing capability to match their
excretion of salt and water to intakes that can range
from as low as one tenth of normal to as high as 10
times normal.

Activates Natriuretic Systems.

As sodium intake is

small increase in extracellular fluid volume that trig-
gers various mechanisms in the body to increase

following:
1.

that

originate from the stretch receptors of the right

from the stretch receptors go to the brain stem
and there inhibit sympathetic nerve activity to the
kidneys to decrease tubular sodium reabsorption.

hours—or perhaps the first day—after a large

2. Small increases in arterial pressure

3. Suppression of angiotensin II formation

increased arterial pressure and extracellular fluid

reabsorption by eliminating the normal effect of
angiotensin II to increase sodium reabsorption.

tubular sodium reabsorption.

4. Stimulation of natriuretic systems

contributes further to increased sodium excretion.

systems leads to an increase in sodium excretion when

place when sodium intake is reduced below normal

Conditions That Cause

Despite the powerful regulatory mechanisms that main-
tain blood volume and extracellular fluid volume rea-

Almost all of these conditions result from circulatory

by Heart Diseases

the arterial pressure and cardiac output toward normal.

blood volume can often return cardiac output and arte-

excretion will eventually increase back to normal,
although there will remain excess extracellular fluid
volume and blood volume to keep the weakened heart

person develops severe circulatory congestion and
eventually dies of pulmonary edema.

circulatory compensation is an increase in blood

heart to maintain a life-sustaining level of cardiac
output.

Increased Capacity of Circulation

Any condition that increases vascular capacity will also
cause the blood volume to increase to fill this extra

salt and water retention by the kidneys until the blood

Nephrol 10(Suppl 12):s258, 1999.

ulation: the overriding dominance of the kidney. J Am Soc

Hall JE: Angiotensin II and long-term arterial pressure reg-

2000, pp 1009-1046.

and Pathophysiology, 3rd ed. New York: Raven Press,

Seldin DW, Giebisch G (eds): The Kidney—Physiology

system: renal mechanisms and circulatory homeostasis. In

Hall JE, Brands MW: The renin-angiotensin-aldosterone

kidneys and body fluids. Science 252:1813, 1991.

Guyton AC: Blood pressure control—special role of the

2000, pp 1811-1840.

and Pathophysiology, 3rd ed. New York: Raven Press,

Seldin DW, Giebisch G (eds): The Kidney—Physiology

Guise TA, Mundy GR: Disorders of calcium metabolism. In

sure natriuresis. Curr Hypertens Rep 4:15, 2002.

Granger JP, Alexander BT, Llinas M: Mechanisms of pres-

potassium transport. Pflugers Arch 446:289, 2003.

Giebisch G, Hebert SC, Wang WH: New aspects of renal

62:1498, 2002.

Giebisch GH: A trail of research on potassium. Kidney Int

York: Raven Press, 2000, pp 1153-1174.

Kidney—Physiology and Pathophysiology, 3rd ed. New

and salt appetite. In Seldin DW, Giebisch G (eds): The

Fitzsimmons JT: Physiology and pathophysiology of thirst

Physiol Rev 72:231, 1992.

Cowley AW Jr: Long-term control of arterial pressure.

84:169, 2004.

roendocrine control of body fluid metabolism. Physiol Rev

Antunes-Rodrigues J, de Castro M, Elias LL, et al: Neu-

capacity.

rial pressure are restored to normal. In some cases,

decreased plasma volume. That is, the kidneys continue

from the circulation, the renal responses are similar to

ascites.

leakage of fluid and proteins into the peritoneal cavity,

portal vascular bed, which also contributes to the

This in turn raises capillary pressure throughout the

impedes the flow of portal blood through the liver.

of fibrous tissue in the liver structure, which greatly

proteins. Cirrhosis is also associated with large amounts

results from destruction of the liver cells, thus reducing

rhosis, the reduction in plasma protein concentration

liver as in nephrotic syndrome, except that in liver cir-

by the Kidneys

by the Liver and Sodium Retention

restore the plasma proteins.

into the tissues of the body. The net result is massive

becomes further diluted, causing still more fluid to leak

water retention, the plasma protein concentration

However, because of the large amount of sodium and

system. The kidneys continue to retain sodium and

aldosterone, and possibly the sympathetic nervous

interstitial fluid, including activation of various sodium-

edema and decreases the plasma volume.

of fluid into the various tissues, which in turn causes

colloid osmotic pressure falls to low levels. This causes

decreased plasma protein concentration, the plasma

to less than one-third normal. As a consequence of the

plasma protein can be lost in the urine each day, some-

permeability of the glomerulus. Thirty to 50 grams of

In nephrotic syndrome, the

nephrotic syndrome.

edema are reviewed in Chapter 25. One of the most

The general mechanisms that lead to extracellular

Sodium Retention by the Kidneys

however, leaks into the interstitium, causing further

blood volume toward normal. Much of the extra fluid,

similar to the response after hemorrhage. That is, the

volume. The kidneys’ response to these conditions is

into the interstitium, which tends to decrease the blood

remains normal or even slightly reduced. These condi-

There are several conditions in which extracellular fluid

Blood Volume

Volume but with Normal

Large Increases in

vascular capacity. In these cases, salt and water are

have large varicose veins of the legs, which in rare

volume 15 to 25 per cent. Similarly, in patients who

of the woman’s body regularly increases the blood

ity of the uterus, placenta, and other enlarged organs

For example, in pregnancy the increased vascular capac-

volume increases sufficiently to fill the extra capacity.

Renal Regulation; Integration of Renal Mechanisms

Chapter 29

381

instances may hold up to an extra liter of blood,
the blood volume simply increases to fill the extra

retained by the kidneys until the total vascular bed is
filled enough to raise blood pressure to the level
required to balance renal output of fluid with daily
intake of fluid.

Conditions That Cause

Extracellular Fluid

volume becomes markedly increased but blood volume

tions are usually initiated by leakage of fluid and protein

kidneys retain salt and water in an attempt to restore

edema.

Nephrotic Syndrome—Loss of
Plasma Proteins in Urine and

important clinical causes of edema is the so-called

glomerular capillaries leak large amounts of protein
into the filtrate and the urine because of an increased

times causing the plasma protein concentration to fall

the capillaries all over the body to filter large amounts

Renal sodium retention in nephrotic syndrome

occurs through multiple mechanisms activated by
leakage of protein and fluid from the plasma into the

retaining systems such as the renin-angiotensin system,

water until plasma volume is restored nearly to normal.

fluid retention by the kidneys until tremendous extra-
cellular edema occurs unless treatment is instituted to

Liver Cirrhosis—Decreased
Synthesis of Plasma Proteins

A similar sequence of events occurs in cirrhosis of the

the ability of the liver to synthesize enough plasma

a condition called

Once fluid and protein are lost

those observed in other conditions associated with

to retain salt and water until plasma volume and arte-

plasma volume may actually increase above normal
because of increased vascular capacity in cirrhosis;
the high pressures in the portal circulation can
greatly distend veins and therefore increase vascular

References

Endocr Rev 6:24, 1985.

Young DB: Analysis of long-term potassium regulation.

potassium regulation. Am J Physiol 255: F811, 1988.

Young DB: Quantitative analysis of aldosterone’s role in

. Annu Rev Physiol 64:845, 2002.

Warnock DG. Renal genetic disorders related to K

Kidney, 6th ed. Philadelphia: WB Saunders, 2000, pp 520-

magnesium and phosphate. In: Brenner BM (ed): The

Suki WN, Lederer ED, Rouse D: Renal transport of calcium

2000, pp 1551-1574.

and Pathophysiology, 3rd ed. New York: Raven Press,

Seldin DW, Giebisch G (eds): The Kidney—Physiology

Rosa R, Epstein FH: Extrarenal potassium metabolism. In

Physiol 65:531, 2003.

Na/Pi transporter in the proximal tubule. Annu Rev

Murer H, Hernando N, Forster I, Biber J: Regulation of

382

Unit V

The Body Fluids and Kidneys

574.

and