Page 141 - Fluid, Electrolyte, and Acid-Base Disorders in Small Animal Practice

Disorders of Calcium: Hypercalcemia and Hypocalcemia 131

monocytic hematopoietic precursors in the bone marrow CALCITRIOL IN CANCER THERAPY?
into osteoclasts. 549 This relationship between calcitriol Many studies focus on the benefits of calcitriol therapy in
and osteoclasts explains the dependence of PTH on cancer. 222,254 Part of the great interest stems from the
calcitriol for optimal bone resorption. 403 25
antiproliferative role of calcitriol, with specific effects
Effects of Calcitriol on the Kidneys on DNA replication genes 164 and with a potentially
important effect on proliferation of blood vessel endothe-
An important effect of calcitriol in the kidneys is 42
lial cells. Studies are focused on human prostate can-
direct inhibition of 25-hydroxyvitamin D-1a-hydroxylase 312 254
cer and also on breast and colon cancers.
in the renal tubule, preventing overproduction Although a discussion is beyond the scope of this chapter,
of calcitriol. 467 In addition, calcitriol facilitates calcium its dynamic character indicates it will be important for
and phosphorus reabsorption from the glomerular fil- many years to come.
trate. 318 Calcitriol is necessary to work with PTH to reab-
sorb urinary calcium into blood. Glomerular podocytes CALCITONIN
contain the VDR for calcitriol and respond to low
doses of calcitriol with decreased injury and loss of Calcitonin is a 32-amino acid polypeptide hormone that
podocytes. 316 In glomerulonephritis, low doses of 389,478
is synthesized by C cells in the thyroid gland. An
calcitriol decreased mesangial proliferative nephritis,
important role of calcitonin is to limit the degree of post-
which involved calcitriol abrogation of inflammatory prandial hypercalcemia. This effect, in concert with PTH,
mediators interleukin (IL)-1a, tumor necrosis factor-a acts to maintain serum iCa concentration within a narrow
(TNF-a), and IL-6 in the mesangium. 430 Although
range. Calcitonin is secreted in response to hypercalcemia
calcitriol hasgenerallybeen thoughttoprotect the kidneys and also to a calcium-rich meal. Calcitonin secretion
during CRF by preventing the damage from excess increases during hypercalcemia, but the effects of calcito-
PTH, 403,635 it is becoming clear that calcitriol has direct nin on normal calcium homeostasis are considered to be
beneficial effects on the diseased kidney as well.
minor. The major target site for calcitonin is bone, where
it inhibits osteoclastic bone resorption. The effects of cal-
Effects of Calcitriol on the Parathyroid
Gland citonin in bone are transitory, which has limited the use-
fulness of calcitonin as a treatment for hypercalcemia. At
Calcitriol inhibits the production of PTH in the parathy- high doses, calcitonin may promote urinary calcium
roid gland by direct and indirect means. 531,537 Binding of excretion. 81
calcitriol to its receptor in parathyroid chief cells directly
inhibits PTH synthesis. Second, calcitriol stimulates NORMAL HOMEOSTATIC
intestinal calcium absorption, which indirectly reduces RESPONSE TO
PTH secretion by increasing serum iCa concentration. HYPOCALCEMIA
Calcitriol suppression of PTH synthesis is dose depen-
dent and occurs before serum iCa concentration is Hypocalcemia elicits corrective responses that are
increased by the delayed effects of calcitriol on intestinal mediated by PTH and calcitriol. 478 Acute effects occur
calcium transport. 540 Calcitriol may be considered the in seconds to minutes; subacute effects occur over several
primary controlling factor for transcription of the PTH hours; and chronic effects occur over days to weeks. A
gene and subsequent synthesis of PTH because suppres- marked increase in PTH secretion occurs in response to
sion of PTH synthesis cannot occur in the absence mild hypocalcemia, and this response occurs in seconds.
of calcitriol even in the presence of hypercalcemia Acute secretion of preformed PTH can maintain PTH
(see Fig. 6-6). 402,537 PTH secretion decreases 12 to 24 concentrations for 1 to 1.5 hours during hypocalcemia.
hours after exposure to calcitriol. Whereas PTH stimulates Hypocalcemia decreases the proportion of PTH that is
renal calcitriol synthesis, calcitriol is a negative regulator of degraded in the parathyroid chief cells, making more
PTH. Long-standing calcitriol deficiency results in chief PTH available for secretion. This effect is relatively rapid
cell hypertrophy and hyperplasia, demonstrating that (approximately 40 minutes). During increased PTH
calcitriol is important in limiting cellular proliferation in secretion, renal calcium reabsorption and phosphorus
the parathyroid gland. 537 Calcitriol treatment of uremia excretion are increased within minutes, whereas bone
in dogs and humans has resulted in regression of parathy- mobilization of calcium and phosphate occurs within
roid gland hyperplasia. 202,404 Calcitriol can beusedtopre- 1 to 2 hours.
ventdevelopment ofhyperparathyroidismindogsand cats After several hours of hypocalcemia, increased PTH
with early stages of CRF. 401 This has proved to be highly secretion stimulates the synthesis and secretion of
successful and is consistent with developing thinking in calcitriol. Increased intestinal transport of calcium and
the human medical profession. 642 phosphorus into blood follows, providing an external