Renal calcium reabsorption

The kidney plays a crucial role in calcium homeostasis.
To maintain a net calcium balance, more than 98%
of the fi ltered load of calcium must be reabsorbed
along the nephron. Tubular reabsorption of calcium
can take place via the transcellular and paracellular
routes by mechanisms similar to those described for
calcium transport in the intestine.
Paracellular, diffusional movement predominates
in the proximal convoluted tubule and thick ascending
limb of Henle’s loop, in which the epithelium has a
low electrical resistance and hence high permeability.
Transcellular, active transport takes place in the distal
nephron where the epithelia are less permeable. The
rate of active calcium reabsorption is controlled by
PTH and 1α,25(OH)2D3. The involvement of calbindin-
D28k in active calcium transport is suggested
by its exclusive presence in the distal nephron and its
increased production in response to 1α,25(OH)2D3
treatment of collecting duct cells (Bindels, 1993).
8.6.4 Na+/Pi co-transporters
Three families of vertebrate Na+/Pi co-transporter
have been identifi ed: type I, type II (IIa and IIb isoforms)
and type III. Type I proteins have been found
in the apical membrane of renal proximal tubules,
but their function is not yet clearly established. Type
II proteins are also located in apical membranes – type
IIa in renal proximal tubules and type IIb in small
intestinal enterocytes. Type III co-transporters are
found in many tissues and appear to be located at the
basolateral membrane. Type II (IIa and IIb) Na+/Pi
co-transporters mediate secondary active phosphate
transport in which the immediate energy source is the
downhill concentration gradient for Na+ maintained
by the action of the sodium pump at the basolateral
membrane. The parallel operation of other sodiumcoupled
transport systems will indirectly affect the
Na+/Pi co-transport rate due to competition for
driving forces (Danisi & Murer, 1991). Type II cotransporters
operate with a 3Na+ to 1Pi stoichiometry
(Murer et al., 2001). In the presence of divalent phosphate,
these transporters interact with the substrate
(Pi) followed by the loading of two Na+ ions. Thus
the translocation of the fully loaded transporter is an
electroneutral process. The observed negative charge
Vitamin D 213
transfer within the transport cycle is the result of the
reorientation of the unloaded transporter (Murer et
al., 2002).
8.6.5 Intestinal phosphate absorption
Dietary phosphorus is a mixture of inorganic phosphate
and organic phosphorus. The phosphorus in
meat and fi sh exists largely in the form of phosphoproteins
and phospholipids; over 80% of the phosphorus
in grains such as wheat, rice and maize is found as
phytic acid (hexaphosphoinositol); about 33% of the
phosphorus in milk exists as inorganic phosphate; milk
protein (casein) is particularly highly phosphorylated.
Regardless of its dietary form, most phosphorus is
absorbed in inorganic form. Organically bound phosphorus
is hydrolysed enzymatically in the lumen of the
small intestine. The phosphorus within phytic acid has
poor bioavailability owing to incomplete hydrolysis.
Phosphate absorption takes place mainly in the
jejunum by an energy-dependent transcellular route
that is regulatable and a passive paracellular route that
is not regulatable. The transcellular pathway involves
secondary active transport at the brush-border membrane
mediated by the type IIb Na+/Pi co-transporter.
Both the monovalent and divalent forms of phosphate
are transported (Quamme, 1985). The capacity (Vmax)
of the transport system is signifi cantly greater at pH
6.1 than at 7.4, thus the acidic environment of the
unstirred layer favours Pi uptake (Borowitz & Ghishan,
1989). The basolateral membrane also contains
a Na+/Pi co-transporter, which has a lower capacity
and a higher affi nity compared to the brush-border
co-transporter (Kikuchi & Ghishan, 1987).
A low-phosphorus diet leads to a rapid decrease of
plasma Pi concentration and activation of the renal
25(OH)D-1α-hydroxylase. The resultant increase
in circulating 1α,25(OH)2D3 induces an increased
capacity of the type IIb Na+/Pi co-transporter in the
brush border of the intestinal epithelium. The hormonal
response requires several hours and involves
protein synthesis. The rapid adaptive response observed
in the kidney (see below) does not take place in
the intestine (Hattenhauer et al., 1999).
8.6.6 Renal phosphate reabsorption
Renal reabsorption of phosphate takes place in the
proximal convoluted tubule and, under normal physiological
conditions, ~80% of phosphate contained in
the glomerular fi ltrate is reabsorbed. The brush-border
uptake, which is mediated by the type IIa Na+/Pi
co-transporter, is rate-limiting in most situations
and the target of physiological control mechanisms.
Basolateral exit is ill-defi ned, but may involve another
Na+/Pi co-transporter (Schwab et al., 1984). Transport
of phosphate in the opposite direction (from the peritubular
interstitium into the tubular cell) can take
place across the basolateral membrane if apical entry
is insuffi cient to satisfy the cell’s metabolic requirements.
The existence of multiple systems for transporting
phosphate across the brush-border membrane
of the tubular epithelium has been recognized since
1977. Walker et al. (1987) demonstrated two sodium-
dependent systems in the early segments of
the proximal tubule: a high-capacity, low-affi nity
system and a low-capacity, high-affi nity system. A
third transport system in the late proximal segments
was found by the same group to be independent of sodium
and mediated by an hydroxyl ion/Pi exchanger
or a proton/Pi co-transport system (Yan et al., 1988).
The renal control of acid–base balance requires secretion
of hydrogen ions into the tubular lumen by the
tubular epithelial cells, causing a progressive decrease
in luminal pH from 7.4 to 6.8 along the length of the
proximal tubule. Such a decline in pH results in a fall
of the divalent to monovalent phosphate ratio from
4:1 to 1:1 at any given Pi concentration (Quamme &
Wong, 1984). It has been demonstrated that the two
sodium-dependent systems mentioned above transport
the divalent form of phosphate, whereas the
sodium-independent system located in the late proximal
tubule has a preference for the monovalent form
(Yan et al., 1988). Accordingly, the multiple transport
systems act in concert to reclaim fi ltered phosphate
along the proximal tubule.
The rate of renal phosphate reabsorption is adjusted
in response to deviations in plasma Pi concentration to
achieve a correct phosphate homeostasis. A low-phosphorus
diet induces a rapid (2–4 hour) non genomic
response followed by a long-term genomic response
if phosphorus deprivation persists. Both types of
response involve stimulation of sodium-dependent
phosphate transport by 1α,25(OH)2D3. The rapid
response may be mediated by a microtubule-dependent
translocation of the Na+/Pi co-transporter protein
from intracellular compartments to the brush-border
214 Vitamins: their role in the human body
membrane (Lötscher et al., 1996). Rapid down-regulation
of the co-transporter in response to acute administration
of a large dose of phosphate is probably
mediated by endocytosis of the protein (Lötscher et
al., 1996). The long-term response involves transactivation
of the Na+/Pi co-transporter gene (Taketani
et al., 1997).
8.6.7 Calcium movement in bone
Bone contains a fl uid compartment that is separated
from the extracellular fl uid by the lining cells on the
surface of bone. As shown in Fig. 8.9, the bone fl uid
compartment comprises the fl uid-fi lled space between
the lining cells and bone matrix, around the
protoplasmic extensions in the canaliculi, and around
osteocytes in their lacunae. The bone fl uid is therefore
in direct contact with bone crystals or amorphous
calcium phosphate deposits (Talmage, 1970).
The Ca2+ concentration in the bone fl uid compartment
is normally about one-third that in the extracellular
fl uid. The lining cells exert the primary control
on extracellular calcium homeostasis. These cells have
open channels between them, permitting paracellular
entry of Ca2+ into the bone fl uid compartment down
the concentration gradient. The uphill movement of
Ca2+ from the bone fl uid compartment to the extracellular
fl uid involves active pump-driven transport
through the lining cells.
In the presence of vitamin D, parathyroid hormone
(PTH) increases the calcium permeability of the
lining cell plasma membrane facing the bone fl uid,
allowing Ca2+ to diffuse into the cells from the bone
fl uid. The increase in intracellular Ca2+ then activates
the calcium pump on the opposite membrane. This
action of PTH results in the rapid removal of Ca2+,
accompanied by Pi, from amorphous calcium phosphate
deposits in the vicinity of the lining cells and
transference of these ions to the extracellular fluid.