The Kidneys and Regulation of Water and Inorganic Ions
497
Regulation of Membrane Channels
and Transporters
Tubular reabsorption and/or secretion of many substances
is under physiological control. For most of these substances,
control is achieved by regulating the activity or concentrations
of the membrane channel and transporter proteins involved in
their transport. This regulation is achieved by hormones and
paracrine/autocrine factors.
The recent explosion of information concerning the
structure, function, and regulation of renal tubular-cell ion
channels and transporters has made it possible to explain the
underlying defects in some genetic diseases. For example, a
genetic mutation can lead to an abnormality in the Na
+
/glu-
cose cotransporter that mediates active reabsorption of glu-
cose in the proximal tubule. This can lead to the appearance
of glucose in the urine (
familial renal glucosuria
). Contrast
this condition to diabetes mellitus, in which the ability to
reabsorb glucose is usually normal, but the fi ltered load of glu-
cose exceeds the threshold for the tubules to reabsorb glucose
(see Figure 14–11).
“Division of Labor” in the Tubules
To excrete waste products adequately, the GFR must be very
large. This means that the fi ltered volume of water and the fi l-
tered loads of all the nonwaste plasma solutes are also very large.
The primary role of the proximal tubule is to reabsorb most of this
ltered water and these solutes.
Furthermore, with potassium as
the one major exception, the proximal tubule is the major site
of solute secretion. Henle’s loop also reabsorbs relatively large
quantities of the major ions and, to a lesser extent, water.
Extensive reabsorption by the proximal tubule and Henle’s
loop ensures that the masses of solutes and the volume of
water entering the tubular segments beyond Henle’s loop are
relatively small. These distal segments then do the fi ne-tuning
for most substances, determining the fi nal amounts excreted
in the urine by adjusting their rates of reabsorption and, in
a few cases, secretion. It should not be surprising, therefore,
that most homeostatic controls act upon the more distal seg-
ments of the tubule.
The Concept of Renal Clearance
A useful way of quantifying renal function is in terms of clear-
ance. The renal
clearance
of any substance is the volume
of plasma from which that substance is completely removed
(“cleared”) by the kidneys per unit time. Every substance has
its own distinct clearance value, but the units are always in
volume of plasma per unit of time. The basic clearance formula
for any substance
S
is
Clearance of
S
=
Mass of
S
excreted per unit time
Plasma concentration of
S
Thus, the clearance of a substance is a measure of the volume
of plasma completely cleared of the substance per unit time.
This accounts for the mass of the substance excreted in the
urine.
Because the mass of
S
excreted per unit time is equal to
the urine concentration of
S
multiplied by the urine volume
during that time, the formula for the clearance of
S
becomes
C
S
=
U
S
V
P
S
where
C
S
= clearance of
S
U
S
= urine concentration of
S
V
= urine volume per unit time
P
S
= plasma concentration of
S
Let us take the particularly important example of a poly-
saccharide named
inulin
(
not
insulin). This substance is an
important research tool because its clearance is equal to the
glomerular fi ltration rate. It is not normally found in the body,
but we will administer it intravenously to a person at a rate suf-
fi cient to maintain a constant plasma concentration of 4 mg/L.
Urine collected over a one-hour period has a volume of 0.1 L
and an inulin concentration of 300 mg/L. Thus, inulin excre-
tion equals 0.1 L/h
×
300 mg/L, or 30 mg/h. How much
plasma had to be completely cleared of its inulin to supply this
30 mg/h? We simply divide 30 mg/h by the plasma concentra-
tion, 4 mg/L, to obtain the volume cleared: 7.5 L/h. In other
words, we are calculating the inulin clearance (
C
In
) from the
measured urine volume per unit time (
V
), urine inulin concen-
tration (
U
In
), and plasma inulin concentration (
P
In
):
C
In
=
U
In
V
P
In
C
In
=
300 mg/L
×
0.1 L/h
4 mg/L
C
In
= 7.5 L/h
Now for the crucial points. It is known that inulin is
readily fi ltered at the renal corpuscle but is not reabsorbed,
secreted, or metabolized by the tubule. Therefore, the mass of
inulin excreted in our example—30 mg/h—must be equal to
the mass fi ltered over that same time period (
Figure 14–12
).
Thus, the clearance of inulin (
C
In
) must equal the volume of
plasma originally fi ltered (GFR):
C
In
is equal to GFR.
The clearance of any substance handled by the kidneys in
the same way as inulin—fi ltered, but not reabsorbed, secreted,
or metabolized—would equal the GFR. Unfortunately, there
are no substances normally present in the plasma that per-
fectly meet these criteria. For clinical purposes, the
creatinine
clearance (
C
Cr
)
is commonly used to approximate the GFR as
follows. The waste product creatinine produced by muscle is
fi ltered at the renal corpuscle and does not undergo reabsorp-
tion. It does undergo a small amount of secretion, however,
so that some peritubular plasma is cleared of its creatinine by
secretion. Therefore,
C
Cr
slightly overestimates the GFR but is
close enough to be highly useful in most clinical situations.
This leads to an important generalization. When the clear-
ance of any substance is greater than the GFR, that substance
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