Ganong's Review of Medical Physiology, 23rd Edition

654 SECTION VIII Renal Physiology

vasopressin V 2 receptor, cyclic adenosine 5-monophosphate
(cAMP) and protein kinase A. Cytoskeletal elements are in-
volved, including microtubule-based motor proteins (dynein
and dynactin) as well as actin filament-binding proteins such
as myosin-1.
In the presence of enough vasopressin to produce maximal
antidiuresis, water moves out of the hypotonic fluid entering
the cortical collecting ducts into the interstitium of the cortex,
and the tubular fluid becomes isotonic. In this fashion, as
much as 10% of the filtered water is removed. The isotonic
fluid then enters the medullary collecting ducts with a TF/P
inulin of about 20. An additional 4.7% or more of the filtrate
is reabsorbed into the hypertonic interstitium of the medulla,
producing a concentrated urine with a TF/P inulin of over

300. In humans, the osmolality of urine may reach 1400
     mOsm/kg of H 2 O, almost five times the osmolality of plasma,
     with a total of 99.7% of the filtered water being reabsorbed
     (Table 38–7). In other species, the ability to concentrate urine
     is even greater. Maximal urine osmolality is about 2500
     mOsm/kg in dogs, about 3200 mOsm/kg in laboratory rats,
     and as high as 5000 mOsm/kg in certain desert rodents.
     When vasopressin is absent, the collecting duct epithelium
     is relatively impermeable to water. The fluid therefore remains
     hypotonic, and large amounts flow into the renal pelvis. In
     humans, the urine osmolality may be as low as 30 mOsm/kg
     of H 2 O. The impermeability of the distal portions of the
     nephron is not absolute; along with the salt that is pumped
     out of the collecting duct fluid, about 2% of the filtered water
     is reabsorbed in the absence of vasopressin. However, as much
     as 13% of the filtered water may be excreted, and urine flow
     may reach 15 mL/min or more.

THE COUNTERCURRENT MECHANISM

The concentrating mechanism depends upon the mainte-

nance of a gradient of increasing osmolality along the medul-

lary pyramids. This gradient is produced by the operation of

the loops of Henle as countercurrent multipliers and main-

tained by the operation of the vasa recta as countercurrent ex-

changers. A countercurrent system is a system in which the

inflow runs parallel to, counter to, and in close proximity to

the outflow for some distance. This occurs for both the loops

of Henle and the vasa recta in the renal medulla (Figure 38–3).

The operation of each loop of Henle as a countercurrent mul-

tiplier depends on the high permeability of the thin descending

limb to water (via aquaporin-1), the active transport of Na+ and

Cl– out of the thick ascending limb, and the inflow of tubular

fluid from the proximal tubule, with outflow into the distal

tubule. The process can be explained using hypothetical steps

FIGURE 38–15 NaCl transport in the thick ascending limb of
the loop of Henle. The Na–K–2Cl cotransporter moves these ions into
the tubular cell by secondary active transport. Na+ is transported out
of the cell into the interstitium by Na, K ATPase in the basolateral mem-
brane of the cell. Cl– exits in basolateral ClC-Kb Cl– channels. Barttin, a
protein in the cell membrane, is essential for normal ClC-Kb function.
K+ moves from the cell to the interstitium and the tubular lumen by
ROMK and other K+ channels (see Clinical Box 38–2).

Interstitial

fluid

Tubular

lumen

K+

Na+

Renal tubule cell

K+

Cl−

Barttin

Na+

2Cl−

K+

ROMK

K+

ROMK

K+

K+

CLINICAL BOX 38–2

Genetic Mutations in Renal Transporters

Mutations of individual genes for many renal sodium trans-

porters and channels cause specific syndromes such as

Bartter syndrome, Liddle syndrome, and Dent disease. A

large number of mutations have been described.

Bartter syndrome is a rare but interesting condition

that is due to defective transport in the thick ascending

limb. It is characterized by chronic Na+ loss in the urine,

with resultant hypovolemia causing stimulation of renin

and aldosterone secretion without hypertension, plus hy-

perkalemia and alkalosis. The condition can be caused by

loss-of-function mutations in the gene for any of four key

proteins: the Na–K–2Cl cotransporter, the ROMK K+ chan-

nel, the ClC–Kb Cl– channel, or barttin, a recently described

integral membrane protein that is necessary for the normal

function of ClC–Kb Cl– channels.

The stria vascularis in the inner ear is responsible for

maintaining the high K+ concentration in the scala media

that is essential for normal hearing. It contains both ClC–Kb

and ClC–Ka Cl– channels. Bartter syndrome associated with

mutated ClC–Kb channels is not associated with deafness

because the Clc–Ka channels can carry the load. However,

both types of Cl– channels are barttin-dependent, so pa-

tients with Bartter syndrome due to mutated barttin are

also deaf.

Another interesting example involves the proteins poly-

cystin-1 (PKD-1) and polycystin-2 (PKD-2). PKD-1 appears to

be a Ca2+ receptor that activates a nonspecific ion channel

associated with PKD-2. The normal function of this appar-

ent ion channel is unknown, but both proteins are abnor-

mal in autosomal dominant polycystic kidney disease,

in which the renal parenchyma is progressively replaced by

fluid-filled cysts until there is complete renal failure.