652 SECTION VIII Renal Physiology
tubuloglomerular feedback, tends to maintain the constancy
of the load delivered to the distal tubule.
The sensor for this response is the macula densa. The
amount of fluid entering the distal tubule at the end of the
thick ascending limb of the loop of Henle depends on the
amount of Na+ and Cl– in it. The Na+ and Cl– enter the mac-
ula densa cells via the Na–K–2Cl cotransporter in their apical
membranes. The increased Na+ causes increased Na,^ K
ATPase activity and the resultant increased ATP hydrolysis
causes more adenosine to be formed. Presumably, adenosine
is secreted from the basal membrane of the cells. It acts via
adenosine A 1 receptors on the macula densa cells to increase
their release of Ca2+ to the vascular smooth muscle in the
afferent arterioles. This causes afferent vasoconstriction and a
resultant decrease in GFR. Presumably, a similar mechanism
generates a signal that decreases renin secretion by the adja-
cent juxtaglomerular cells in the afferent arteriole (see Chap-
ter 39), but this remains unsettled.
Conversely, an increase in GFR causes an increase in the
reabsorption of solutes, and consequently of water, primarily
in the proximal tubule, so that in general the percentage of the
solute reabsorbed is held constant. This process is called
glomerulotubular balance, and it is particularly prominent
for Na+. The change in Na+ reabsorption occurs within sec-
onds after a change in filtration, so it seems unlikely that an
extrarenal humoral factor is involved. One factor is the
oncotic pressure in the peritubular capillaries. When the GFR
is high, there is a relatively large increase in the oncotic pres-
sure of the plasma leaving the glomeruli via the efferent arte-
rioles and hence in their capillary branches. This increases the
reabsorption of Na+ from the tubule. However, other as yet
unidentified intrarenal mechanisms are also involved.
WATER TRANSPORT
Normally, 180 L of fluid is filtered through the glomeruli each
day, while the average daily urine volume is about 1 L. The same
load of solute can be excreted per 24 h in a urine volume of 500
mL with a concentration of 1400 mOsm/kg or in a volume of
23.3 L with a concentration of 30 mOsm/kg (Table 38–7). These
figures demonstrate two important facts: First, at least 87% of
the filtered water is reabsorbed, even when the urine volume is
23 L; and second, the reabsorption of the remainder of the fil-
tered water can be varied without affecting total solute excre-
tion. Therefore, when the urine is concentrated, water is
retained in excess of solute; and when it is dilute, water is lost
from the body in excess of solute. Both facts have great impor-
tance in the regulation of the osmolality of the body fluids. A key
regulator of water output is vasopressin acting on the collecting
ducts.AQUAPORINS
Rapid diffusion of water across cell membranes depends on
the presence of water channels, integral membrane proteins
called aquaporins. To date, 13 aquaporins have been cloned;
however, only 4 aquaporins (aquaporin-1, aquaporin-2, aqua-
porin-3, and aquaporin-4) play a key role in the kidney. The
roles played by aquaporin-1 and aquaporin-2 in renal water
transport are discussed below.PROXIMAL TUBULE
Active transport of many substances occurs from the fluid in the
proximal tubule, but micropuncture studies have shown that
the fluid remains essentially iso-osmotic to the end of the prox-
imal tubule (Figure 38–9). Aquaporin-1 is localized to both the
basolateral and apical membrane of the proximal tubules and its
presence allows water to move rapidly out of the tubule along
the osmotic gradients set up by active transport of solutes, and
isotonicity is maintained. Because the ratio of the concentration
in tubular fluid to the concentration in plasma (TF/P) of the
nonreabsorbable substance inulin is 2.5 to 3.3 at the end of the
proximal tubule, it follows that 60–70% of the filtered solute and
60–70% of the filtered water have been removed by the time the
filtrate reaches this point (Figure 38–14).
When aquaporin-1 was knocked out in mice, proximal tubu-
lar water permeability was reduced by 80%. When the mice
were subjected to dehydration, their urine osmolality did not
increase (<700 mOsm/kg), even though other renal aquaporins
were present. In humans with mutations that eliminate aqua-
porin-1 activity, the defect in water metabolism is not as severe,
though their response to dehydration is defective.TABLE 38–7 Alterations in water metabolism produced by vasopressin in humans. In each case, the osmotic load
excreted is 700 mOsm/d.
GFR
(mL/min)Percentage of Filtered
Water Reabsorbed Urine V olume (L/d)Urine Concentration
(mOsm/kg H 2 O)Gain or Loss of Water in
Excess of Solute (L/d)
Urine isotonic to plasma 125 98.7 2.4 290...
Vasopressin (maximal
antidiuresis)125 99.7 0.5 1400 1.9 gainNo vasopressin
(“complete” diabetes
insipidus)125 87.1 23.3 30 20.9 loss