Page 140 - Fluid, Electrolyte, and Acid-Base Disorders in Small Animal Practice

130 ELECTROLYTE DISORDERS

Stimulation of Calcitriol Synthesis up-regulation of calcitriol receptors in patients with ure-
Serum PTH, calcitriol, phosphorus, and calcium mia, regulation of PTH synthesis and secretion by the
concentrations are the principal regulators for renal parathyroid gland, 635 and prevention or reversal of para-
calcitriol synthesis. 243 Chronic changes in serum calcium thyroid gland hyperplasia in the uremic patient. 202,401
concentration regulate the synthesis of calcitriol, and these
calcium changes can override signals from serum phospho- THE CALCITRIOL RECEPTOR
rus and PTH concentrations. 267 Deficiencies of phospho- The VDR for calcitriol is present in many tissues in addi-
rus, calcium, and calcitriol lead to increased calcitriol tion to bone, kidneys, intestine, and parathyroid
formation. 402 Low calcium orcalcitriol concentrationslead gland. 237 The importance of calcitriol in tissue is propor-
to increased serum PTH concentrations. In the kidneys, tional to the abundance of the VDR in the cells, and this is
PTH mediates dephosphorylation of renal ferredoxin highly regulated. 311 Intestinal epithelial cells and parathy-
(renoredoxin) and results in increased synthesis of roid gland chief cells have equal and high concentrations
calcitriol. 212,533 Renoredoxin is the regulatory constituent of VDR. VDR genetic polymorphisms are thought to
of the 1a-hydroxylase enzyme system and is inhibited by generate variation of efficiency of the VDR. 84,110
phosphorylation in the presence of high concentrations of Calcitriol initially dissociates from its serum binding pro-
phosphorusorcalciumintherenaltubule. 243 PTHnotonly tein, diffuses across the cell membrane, and binds with its
activatestherenal1a-hydroxylasebutalsoinducessynthesis receptor.
of the enzyme from the renal gene encoding it. 158,159
Several drugs and hormones have effects on vitamin D Effects of Calcitriol on the Intestine
metabolism, some of which are stimulatory. 65 Hypocalce- Calcitriol enhances the transport of calcium and phos-
mia and calcitonin directly stimulate 1a-hydroxylation phate from the intestinal lumen to plasma across the
independent of PTH. 70 Estrogens increase calcitriol enterocyte. 73,601 Energy in the form of adenosine triphos-
synthesis after up-regulation of PTH receptors in the phate (ATP) is required to transport calcium from the
kidneys, 70 and testosterone may also increase calcitriol enterocytes into the blood and to absorb phosphate from
synthesis. 640 Reduced dietary calcium intake can lead to the intestinal lumen. Calcitriol induces synthesis of the
stimulation of renal 1a-hydroxylase in the absence of plasma membrane calcium pump (ATPase) that removes
þ
detectable hypocalcemia. 640 calcium from the enterocytes 432 and the Na -phosphate
cotransport protein that transports phosphorus into the
Inhibition of Calcitriol Synthesis enterocyte. In addition, calcitriol increases the brush bor-
Calcitriol synthesis is inhibited by calcitriol, hypercalce- der permeability to calcium and induces the synthesis of
mia, FGF-23, and phosphate loading. 70,203,243 Calcium calbindin-D 9k. 125,567 Calbindins serve as buffers to pro-
directly and indirectly inhibits calcitriol synthesis. 175 tect enterocytes from toxic concentrations of calcium ion
The indirect action is caused by inhibition of PTH syn- while ferrying calcium across the cell. 601 Calcitriol also
thesis and secretion, thus removing the stimulus provided directly stimulates rapid calcium transport (transcaltachia)
by PTH. The inhibitory effects of chronic hypercalcemia across the enterocyte. 418 Normal dogs have a progressive
can override the stimulatory effects of increased PTH decrease in the number of calcitriol receptors and
concentrations in calcitriol production, as may occur in calbindin concentrations that regulate the efficiency of
primary hyperparathyroidism. 267 The inhibitory effects calcium absorption in enterocytes from the duodenum
of high concentrations of phosphorus on calcitriol syn- to the ileum. 307 Longer transit times in certain portions
thesis are important and affect the activity of existing of the intestinal tract (e.g., ileum) can still lead to
enzyme molecules. 401,402 significant calcium absorption despite low transport
efficiency. 601
Actions of Calcitriol
Effects of Calcitriol on Bone
Calcitriol is the only natural form of vitamin D with sig-
139,467
nificant biologic activity. It is approximately 1000 Calcitriol is necessary for bone formation and mineraliza-
times as effective as parent vitamin D and 500 times as tion because it ensures an adequate source of calcium and
effective as its precursor calcidiol (25-hydroxyvitamin phosphorus from the intestinal tract. Deficiencies in vita-
D) in binding to the natural calcitriol receptor (VDR) min D lead to impaired bone growth, such as rickets in
in target cells. 404 Calcitriol increases serum calcium and growing animals and osteomalacia in adults. 478 Calcitriol
phosphorus concentrations, and its major target organ is necessary for normal bone development and growth
for these effects is the intestine. 72 However, there is also because it regulates the production of multiple bone
an important contribution from bone, 549 and calcitriol proteins produced by osteoblasts, including alkaline
stimulates the kidneys to reabsorb both calcium and phosphatase (ALP), collagen type I, osteocalcin, and
phosphorus from the glomerular filtrate. Calcitriol has osteopontin. 19,544 Calcitriol is also necessary for normal
multiple indirect effects on calcium balance, including bone resorption because it promotes differentiation of