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The distribution of Ca++ between bone and ECF is regulated by two hormones, PTH and calcitriol, along with the kidneys. PTH is released by the parathyroid glands and its secretion is triggered by a decrease in plasma [Ca++] (hypocalcemia). The calcium sensing receptor (CaSR) present in the plasma membrane of parathyroid chief cells is activated by plasma Ca++, leading to a decrease in PTH release during hypercalcemia and an increase during hypocalcemia. PTH raises plasma [Ca++] by promoting bone resorption, enhancing Ca++ reabsorption in the distal tubule of the kidney, and stimulating the production of calcitriol. Calcitriol, in turn, increases Ca++ absorption in the intestines and supports PTH-induced bone resorption. Hypocalcemia and hypophosphatemia stimulate the production of calcitriol in the kidneys. Calcitriol primarily boosts plasma [Ca++] by facilitating Ca++ absorption from the intestines. It also aids PTH in bone action and increases Ca++ reabsorption in the kidneys by enhancing the expression of important Ca++ transport and binding proteins. Calcitonin, secreted by thyroid C cells, is stimulated by hypercalcemia. It reduces plasma [Ca++] by promoting bone formation. In humans, however, calcitonin plays a minor role in Ca++ homeostasis.

Activation of the CaSR in the TAL of Henle’s loop by hypercalcemia inhibits Ca++ reabsorption, leading to increased urinary Ca++ excretion and decreased plasma [Ca++]. The opposite effect occurs during hypocalcemia. Regulation of Ca++ excretion by the kidneys is a major mechanism for maintaining plasma [Ca++].

Reduced PTH levels due to conditions like hypoparathyroidism after parathyroidectomy can lower plasma [Ca++] and result in hypocalcemic tetany, characterized by intermittent muscular contractions. In severe cases, hypocalcemic tetany can be fatal due to asphyxiation. Hypercalcemia can cause life-threatening cardiac arrhythmias and decreased neuromuscular excitability. Primary hyperparathyroidism, often caused by a benign tumor of the parathyroid glands, and malignancy-associated hypercalcemia are the most common clinical causes of hypercalcemia. Malignancy-associated hypercalcemia, observed in 10% to 20% of cancer patients, is caused by the secretion of parathyroid hormone–related peptide (PTHrP) by carcinomas in various organs. Increased levels of PTH and PTHrP lead to hypercalcemia and hypercalciuria.

Transport of calcium along the nephron is regulated as described above.

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Fig. 36.14 ). Two hormones (PTH and calcitriol ) regulate the distribution of Ca++ between bone and ECF and thereby, in concert with the kidneys, regulate plasma [Ca++]. PTH is secreted by the parathyroid glands, and its secretion is stimulated by a decline in plasma [Ca++] (i.e., hypocalcemia). Plasma Ca++ is an agonist of the calcium sensing receptor (CaSR), which is located in the plasma membrane of chief cells in parathyroid glands (discussed later). Hypercalcemia activates the CaSR, which decreases PTH release, whereas hypocalcemia reduces CaSR activity that in turn increases PTH release. PTH increases plasma [Ca++] by: (1) stimulating bone resorption, (2) increasing Ca++ reabsorption by the distal tubule of the kidney, and (3) stimulating the production of calcitriol, which in turn increases Ca++ absorption by the intestinal tract and facilitates PTH-mediated bone resorption. Production of calcitriol in the kidney is stimulated by hypocalcemia and hypophosphatemia. Calcitriol increases plasma [Ca++], primarily by stimulating Ca++ absorption from the intestinal tract. It also facilitates the action of PTH on bone and enhances Ca++ reabsorption in the kidneys by increasing expression of key Ca++ transport and binding proteins in the kidneys (details discussed later). In addition, cCalcitonin is secreted by thyroid C cells (parafollicular cells), and its secretion is stimulated by hypercalcemia. Calcitonin decreases plasma [Ca++], mainly by stimulating bone formation (i.e., deposition of Ca++ in bone). Although it plays an important role in Ca++ homeostasis in lower vertebrates, calcitonin plays only a minor role in Ca++ homeostasis in humans, so it will not be discussed further.
hypercalcemia activates the CaSR in the TAL of Henle’s loop, inhibiting Ca++ reabsorption in this segment, resulting in an increase in urinary Ca++ excretion and thereby a reduction in plasma [Ca++]. Hypocalcemia has the opposite effect. Importantly, regulation of Ca++ excretion by the kidneys is one of the major ways the body regulates plasma [Ca++].
Conditions that lower PTH levels (i.e., hypoparathyroidism after parathyroidectomy for an adenoma) reduce plasma [Ca++], which can cause hypocalcemic tetany (intermittent muscular contractions). In severe cases, hypocalcemic tetany can cause death by asphyxiation. Hypercalcemia can also cause lethal cardiac arrhythmias and decreased neuromuscular excitability. Clinically the most common causes of hypercalcemia are primary hyperparathyroidism and malignancy-associated hypercalcemia. Primary hyperparathyroidism results most often from overproduction of PTH caused by a benign tumor of the parathyroid glands. In contrast, malignancy-associated hypercalcemia, which occurs in 10% to 20% of all patients with cancer, is caused by secretion of parathyroid hormone–related peptide (PTHrP), a PTH-like hormone secreted by carcinomas in various organs. Increased levels of PTH and PTHrP cause hypercalcemia and hypercalciuria.
Calcium Transport Along the Nephron