RENAL HANDLING OF CALCIUM, PHOSPHATE,
AND MAGNESIUM
Calcium
More than 98% of total body calcium is in bones, whereas the remainder is located in intracellular and extracellular fluid. Normal plasma
concentrations, which range from 8.8
to 10.3 mg/dL, are maintained by the
actions of PTH, 1,25-hydroxy vitamin D, and calcitonin
on bones, the gastrointestinal tract, and the kidneys.
About half of the extracellular calcium load is in an active, ionized form, whereas the
remainder complexes with albumin and
other anions. The ionized calcium is freely
filtered at the glomerulus, and normally almost all of it is reabsorbed.
In the proximal tubule, 50% to 60% of the filtered load is reabsorbed along a paracellular route. A chemical gradient is established as sodium and
water are reabsorbed, concentrating
calcium in the tubular fluid. Meanwhile,
an electrical gradient is established by the paracellular reabsorption of chloride, which leaves a positive charge in the lumen. Specialized
tight junction proteins, such as
claudin-2, may form a cation-specific paracellular
pathway.
In the thick ascending limb, 15% of the filtered load is reabsorbed along a paracellular route.
An electrical gradient, formed
secondary to K+ recycling, drives this process. Claudin-16, another tight junction protein, is an important component of this
paracellular pathway, and mutations
are associated with familial hypomagnesemia with
hypocalciuria.
In the distal convoluted and connecting tubules, 10% to 15% of the filtered load is reabsorbed
along a transcellular route. Calcium
crosses the apical membrane through TRPV5
channels, binds to calbindin, then exits the basolateral membrane on the NCX1 Na+/Ca2+ exchanger and, to a lesser degree, a Ca2+ ATPase (PMCA).
The collecting duct makes an unknown, but likely minor, contribution to calcium reabsorption.
Hypocalcemia triggers release of PTH, which has numerous effects on renal function. In the proximal tubule, it inhibits the NHE-3 Na+/H+
exchanger, reducing the gradient for
paracellular calcium reabsorption. (This
seemingly paradoxical effect allows PTH
to increase phosphate excretion, as discussed later.) In the distal nephron, however, it up-regulates the apical TRPV5 calcium channel, causing
a net increase in calcium reabsorption.
Meanwhile, hypercalcemia both
suppresses PTH release and directly inhibits calcium reabsorption. In the thick ascending limb, for example, the increased load of
reabsorbed calcium activates a
basolateral calcium-sensing receptor (CaSR), which then inhibits NKCC2 transporters and ROM-K channels, reducing the electrical gradient
for calcium reabsorption.
Finally, acidosis inhibits the TRPV5 calcium channel, whereas alkalosis has the opposite effect.
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| RENAL HANDLING OF CALCIUM AND PHOSPHATE |
Phosphate
About 85% of total body phosphate is stored in bones, 14% in soft tissues, and 1% in extracellular fluid. Normal plasma concentrations, which range
from 3 to 4.5 mg/dL, are maintained
by the actions of PTH, 1,25-hydroxyvitamin
D, and phosphatonins on the parathyroid glands,
bones, gastrointestinal tract, and kidneys.
About 90% of plasma phosphate is unbound and freely filtered at the glomerulus. About 85% of the filtered load is normally reabsorbed.
In the proximal tubule, 80% of the filtered load is reabsorbed along a transcellular route. Phosphate crosses the apical membrane on Na+/Pi
symporters. The pathway of
basolateral exit is poorly understood but
may involve a phosphate/anion exchanger.
In the distal convoluted tubule and connecting tubule, 5% of the filtered
load is reabsorbed along a transcellular
route that remains poorly understood.
Hyperphosphatemia promotes release of PTH, which down-regulates Na+/Pi symporters and basolateral Na+/K+ ATPases in
the proximal tubule. As a result,
phosphate reabsorption is suppressed. Additionally, hyperphosphatemia causes the release of FGF-23 from osteocytes and osteoblasts in bone,
which causes decreased Na+/Pi
expression. Finally, increased dietary
phosphate intake appears to directly downregulate Na+/Pi transport through a PTH-independent mechanism. Hypophosphatemia, meanwhile,
causes the opposite effects.
Magnesium
About half of total body magnesium is in bone, and nearly all of the remainder is in intracellular fluid. Only 1% is in the extracellular space, with
normal plasma concentrations ranging
from 1.8 to 2.3 mg/dL. About 80% of
the extracellular load is unbound to proteins and freely filtered at the glomerulus. About 95% to 98% of the filtered load is normally
reabsorbed. 20% is reabsorbed in the
proximal tubule via an unknown, likely
passive, mechanism. Another 60% to 70% is reabsorbed
in the thick ascending limb through a paracellular route, driven by the electrical gradient resulting from K+ recycling. Claudin 16
is thought to form the pore for
paracellular magnesium reabsorption. Finally, 5% to 10% of the filtered load is reabsorbed in the distal nephron through an apical Mg2+
channel known as TRPM6. The pathway
for basolateral exit is not known.
