Marshall L. Stoller, Maxwell V. Meng-Urinary Stone Disease

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92 Stackhouse and Stoller

CELLULAR CALCIUM

Calcium is used as a cellular activator throughout the body. The concentration of free

ionized calcium within the cell is regulated by protein binding, chelation, transport into

cellular organelles, and transport out of the cells. Primary organelles with large calcium

stores include the mitochondria, the Golgi apparatus, the sarcoplasmic reticulum, and

the endoplasmic reticulum. A full review of intracellular calcium handling is beyond the

scope of this chapter, but useful reviews are published (23,24).

Fig. 2. Osteoblast/osteoclast interaction. Osteoblasts express RANKL, but also actively secrete

OPG, which serves as a competitive inhibitor or “decoy” to bind RANKL. Expression of OPG

is under hormonal control, and serves to regulate the availability of RANKL. Osteoclast precur-

sors express RANK. When RANKL is available to bind to RANK, osteoclast differentiation and

maturation is promoted. OPG, osteoprotegrin; RANK, receptor activator of NF-κB; RANKL,

receptor activator of NF-κB ligand (21).

Chapter 6 / Calcium Physiology 93

Extracellular Calcium

Extracellular calcium is available for use by multiple systems in the body, and is

tightly regulated within a narrow window of concentration. Serum levels reflect the

extracellular plasma level of calcium and are generally 8.6–10.5 mg/dL. Calcium in

plasma is 45% ionized, 40% bound to protein, and 15% complexed to anions. Ionized

and complexed calcium are diffusible across membranes and are filtered at the renal

glomerulus. Albumin accounts for 90% of the protein-binding of calcium. This protein

binding is pH dependent, with acidosis leading to decreased binding sites and increased

serum ionized calcium, and alkalosis yielding increased protein binding sites and

decreased ionized calcium.

Ionized calcium is detected by the CaR and is the regulated form of calcium. It is the

active form in neuromuscular function and in other organs.

CALCIUM EXCRETION FROM THE KIDNEYS

Overview of Calcium Excretion

Calcium is not actively secreted by the nephron; thus calcium excretion is the differ-

ence between the amount of calcium filtered and the amount reabsorbed. Filtration is a

more passive process, so excretion is controlled by regulation of reabsorption. Reabsorp-

tion occurs from the proximal tubule to the collecting duct. The bulk of this is a passive

paracellular process, but in the distal tubule and collecting duct active processes requir-

ing cellular energy expenditure predominate. In these distal segments, hormonal control

of the active processes determines net calcium excretion.

Glomerular Filtration of Calcium

The ionized calcium and the calcium complexed to small anions are filterable at the

renal glomerulus. The majority (98–99%) of this filtered calcium is then reabsorbed in

the nephron. The remainder that is not reabsorbed represents the excreted fraction. The

filtered load is the product of the glomerular filtration rate and the serum calcium con-

centration.

Renal Reabsorption of Calcium

Most (85%) of calcium reabsorptive activity takes place in the proximal tubule and

in the thick ascending limb of the loop of Henle (25), through paracellular pathways. In

this portion of the nephron, sodium is actively reabsorbed, and is followed passively by

chloride and water. Calcium also appears to be passively reabsorbed through paracellular

pathways in this portion of the collecting tubule. A small amount of calcium is actively

reabsorbed in this region as well. Active transport moves calcium against its concentra-

tion gradient and requires expenditure of energy. In the proximal tubule, active transport

is provided by Ca

ATPase and a Na

–Ca

exchanger, which is a carrier protein that

relies on the intracellularly directed sodium gradient. In the thin loop of Henle there is

little calcium transport. The thick ascending limb of the loop of Henle uses both passive

and active reabsorption. In this region, movement of anions out of the tubular fluid leaves

an electrical gradient that promotes passive movement of positively charged calcium

ions through paracellular channels.

Fifteen percent of the filtered load is reabsorbed in the distal portion of the nephron

and collecting duct. In this portion of the nephron, calcium is reabsorbed against an elec-

94 Stackhouse and Stoller

trochemical gradient. The tight junctions in this distal region are impermeable to cal-

cium, so paracellular transport is not possible. The active reabsorption appears to occur

in three parts. The first is at the apical or luminal surface of the cell, and involves calcium

movement through membrane bound protein channels. The second step involves move-

ment of calcium through the cytosol to the basolateral membrane of the cell. The final

step involves extrusion of the calcium out into the extracellular fluid compartment.

The membrane bound protein channels were at first only putative. These were origi-

nally described as CaT1 channels, but two of these have now been identified and cloned,

named TRPV5 (26) and TRPV6

(8). It appears that in renal tissue, TRPV5 is the more

metabolically active and important form. These TRPVs allow entry of calcium from the

tubular fluid into the cell. They are subject to negative feedback inhibition by calcium

(27). The calcium transported into the cell via TRPV5 and TRPV6 is then bound by

calbindin D proteins. The specific calbindin protein thought to be involved is CaBP28K.

These proteins serve to transport the calcium from the apical to the basolateral surface

of the cell. Because the calcium is bound to them, they also serve as a buffer to prevent

the intracellular calcium levels from rising. The CaBP28K moves the calcium to the

basolateral membrane, where they are extruded via a Na

–Ca

exchanger (NCX1) and

by PMCA. In renal tissue, NCX1 appears to be the predominant mechanism of calcium

extrusion through the basolateral membrane, unlike in intestinal tissue where PMCA

dominates.

CALCIUM REGULATING HORMONES

Introduction

Calcium regulating hormones (calciotropic hormones) include vitamin D, PTH, and

calcitonin (28). PTH serves as the serum calcium raising hormone. Calcitonin serves

as a serum calcium lowering hormone. Each of these calcium regulating hormones will

be discussed in detail under its own heading following. Table 1 summarizes the effects

of calcium regulating hormones.

Vitamin D

Vitamin D, not a true vitamin, is actually a steroid derived hormone critical for

calcium regulation, immune system function, and may play a role in tumor preven-

tion. Vitamin D was discovered during investigations into the etiology of rickets and

osteomalacia. It is essential for optimal calcium and phosphate metabolism, and

insufficient vitamin D is epidemiologically associated with rickets, hypertension,

diabetes mellitus, autoimmune disease, and cancer. Comprehensive reviews of vita-

min D metabolism are available (21,29).

The active forms of vitamin D are 1,25

dihydroxy vitamin D

(calcitriol) and 24R,25(OH)

-vitamin D

(24R,25(OH)

Calcitriol is the dominant metabolically active form of vitamin D in terms of calcium

homeostasis. 24R,25(OH)

is important in bone fracture healing, but has not been

implicated in day-to-day calcium homeostasis (30). Calcitriol is formed from vitamin

D in the diet or from the action of ultraviolet light converting 7-dehydrocholesterol

to vitamin D

in the skin. Hydroxylation to 25, hydroxy vitamin D

then occurs in the

liver. This step is mediated by parts of the cytochrome P-450 system; in particular

CYP2R1 is the most likely 25-hydroxylase (31). In the kidney proximal tubule, this

25 hydroxy vitamin D3 is further hydroxylated by 1-α-hydroxylase to 1,25

dihydroxyvitamin D

(calcitriol) (21). 1-α-Hydroxylase is found in other tissues (32)

Chapter 6 / Calcium Physiology 95

Table 1

Effects of Calcium Regulating Hormones

Hormone Serum calcium Intestinal absorption Renal calcium excretion

Bone metabolism

Calcitriol • Elevates • Increases calcium absorption by

• Works with PTH to increase • Promotes osteoclast activity,

enterocytes reabsorption, decreasing releasing calcium and phosphate

excretion into the serum

Parathyroid • Elevates • Most researchers believe no • Works with calcitriol to increase

• Promotes osteoclast activity,

direct effect, but serves to reabsorption, decreasing releasing calcium and phosphate

increase calcitriol levels,

excretion into the serum

leading indirectly to increased

intestinal absorption

Calcitonin • Lowers

• Inhibits osteoclast activity,

leading to a net increase in bony

apatite formation

96 Stackhouse and Stoller

and may perform this function outside the kidney in certain physiologic and patho-

logic states such as pregnancy and renal failure. 1-α-Hydroxylase activity is regu-

lated by PTH and by serum calcium levels. Tight regulation of calcitriol production

is necessary because of calcitriol’s potent role in calcium homeostasis. For this rea-

son, measurement of 25 hydroxy vitamin D

is a more useful indicator of dietary

vitamin D status, as the hepatic 25-hydroxylation is not tightly regulated (33).

After release in the plasma, calcitriol is bound to vitamin D binding protein and is

delivered to target organ cells. Calcitriol effects are mediated through two separate

VDRs. The nuclear receptor, VDR

nuc

is responsible for regulating gene transcription

when stimulated by calcitriol. VDR

nuc

is a 50-kDa receptor bound to the nuclear mem-

brane, and has been cloned and studied. There is also a putative membrane receptor,

VDR

mem1,25

, that is a rapid-reacting receptor that opens calcium and chloride ion chan-

nels and activates MAP-kinase. This receptor has not yet been cloned, but research

indicates that it is 60 kDa and it is expressed in enterocytes (34), chondrocyte matrix

vesicles (35), and elsewhere. Calcitriol causes increased gastrointestinal absorption of

calcium and phosphate, resorption of bone by osteoclasts, and also induces formation of

calcibindin D in cells throughout the body. Calbindin D refers to a group of proteins that

promote binding and transmembrane transport of calcium in the intestinal cells and in

the proximal tubule of the kidney. Calcitriol appears to work in concert with PTH in bone

and in the renal tubule to achieve its effects. The net effect of calcitriol on calcium

metabolism is to increase ionized calcium availability in the extracellular space.

Parathyroid Hormone

PTH is a peptide hormone secreted by chief cells of the parathyroid gland. It is

composed of 84 amino acids. The actions of PTH are complex and have been summa-

rized in the literature (36). A closely related hormone, parathyroid hormone-related

peptide (PTHrP), is important in lactation, early development (37), and placental trans-

port of calcium (38), but does not appear to play an important regulatory role in calcium

homeostasis. Release of PTH is stimulated in response to low circulating calcium levels,

and also in response to elevated extracellular phosphate levels. This release of PTH from

chief cells is mediated by CaR discussed later in this chapter.

PTH acts on the target cells through the PTH/PTHrP receptor. This receptor has been

characterized (39), and is the predominant PTH receptor used for extracellular calcium

homeostasis. Other PTH receptors have been described but they appear to have func-

tions apart from extracellular calcium regulation (40,41). The 34 amino acids at the

N-terminus of PTH and PTHrP appear to form the stimulatory region for the PTH/

PTHrP receptor. The secondary and tertiary structure of this N-terminus region has been

investigated and conflicting evidence is present regarding the active conformation. In

any event, receptor ligand binding appears to result in the synthesis of cyclic adenosine

monophosphate and activation of protein kinase A. There is also evidence in rat cell

models that activation of the PTH/PTHrP receptor results in activation of phospholipase

C and elevates intracellular levels of inositol triphosphate and free calcium (42), and

evidence of signaling through the mitogen-activated protein kinase pathway (43). Taken

together, the presence of multiple signal cascades resulting from stimulation of the

PTH/PTHrP receptor and the existence of at least two agonists (PTH and PTHrP) for the

receptor may point to multiple functions mediated by the PTH/PTHrP receptor in dif-

ferent organs.

Chapter 6 / Calcium Physiology 97

In the kidney, PTH stimulates 1-α-hydroxylase in proximal tubules to convert vita-

min D

to calcitriol. PTH indirectly increases intestinal absorption of calcium and phos-

phate through activation of calcitriol, but also experimentally through direct action on

PTH receptors in intestinal villi. This direct action of PTH on the intestine is controver-

sial at present and not accepted by all researchers (44). PTH is a direct agonist of

osteoclast activity, raising extracellular calcium levels by osteoclastic breakdown of

apatite crystals in bone. In the kidney, PTH increases calcium reabsorption at the distal

convoluted tubule. In the proximal tubule PTH acts to decrease expression of sodium-

phosphate co-transporters (NPT-2a and NPT-2c). This decreased expression serves to

inhibit phosphate reabsorption.

Thus, the net effect of PTH release is to elevate serum calcium and phosphate levels

through bone resorption, and to decrease renal calcium excretion but increase renal

phosphate excretion.

Calcitonin

Recent research regarding calcitonin has been well summarized (45). Calcitonin is a

32-amino acid peptide hormone made by the parafollicular (C cells) of the thyroid gland.

There is significant divergence of calcitonin amino acid sequence across different spe-

cies, resulting in differing potencies of calcitonins and care must be made when applying

nonhuman research to human clinical conditions. Elevated serum calcium levels cause

parafollicular cells of the thyroid gland to release calcitonin. Calcitonin is active in

multiple tissues and organs, and has biologically diverse roles. Calcitonin is also synthe-

sized in several other nonthyroid organ tissues, but these other sites do not link calcitonin

synthesis with serum calcium levels, and they do not appear to participate in calcium

homeostasis.

Calcitonin interacts with the calcitonin receptor (CTR). The CTR gene has been

identified in humans, and has at least 14 exons (46). The messenger RNA transcript is

subject to multiple alternative splicings, leading to several different isoforms of the

receptor in humans. The most common isoforms appear to have similar binding affinities

to human calcitonin, but differ in their intracellular signaling.

Activation of CTR leads to coupling with different G proteins, largely dependent on

cellular function. This coupling can activate adenylate cyclase and leads to elevated

cyclic adenosine monophosphate levels, and can also activate phospholipase C, leading

to elevated intracellular inositol triphosphate, free calcium, and activated protein kinase

C (43).

Just as was seen in the discussion of PTH/PTHrP receptors in the preceding

section, this multiplicity of cellular signaling pathways probably reflects the various

roles of calcitonin in stimulating different cell types.

In regards to extracellular calcium homeostasis, calcitonin inhibits osteoclast activity

(47), inhibits osteoclast precursor cell differentiation, and increases renal calcium excre-

tion. By inhibiting osteoclast activity, calcitonin causes serum calcium levels to fall.

This osteoclast inhibition appears to be a slower process in adult humans than in growing

animals, and calcitonin may be less involved in minute-to-minute calcium homeostasis

in adults than other calcium regulating hormones. Administration of large doses of

calcitonin to normal human adults has little effect on serum calcium levels. On the other

hand, administration of calcitonin to human adults with pathologic states involving

increased bone resorption such as Paget disease has been shown to significantly lower

serum calcium levels (48). Interestingly, calcitonin causes lysosomal degradation of

98 Stackhouse and Stoller

CTRs in osteoclasts, making them more “resistant” to the effects of calcitonin. Clinically

this is seen as therapeutic loss of responsiveness to exogenously administered calcito-

nin (49).

CALCIUM RECEPTORS AND CHANNELS

Calcium sensing receptor (CaR) is a G-coupled protein receptor (GCPR) found

throughout the body (50). An excellent review of this receptor is available (51). This

receptor serves to sense the level of extracellular calcium concentration. It is active in

the chief cells of the parathyroid, where it helps regulate release of PTH. It is also

expressed in bone, renal, and intestinal tissues. It is a 1078-amino acid protein with an

extracellular domain with the N-terminus, and transmembrane domain, and an intracel-

lular domain with the carboxyl-terminus (52,53). Calcium is the major agonist for this

receptor throughout the body, and it is sensitive to very slight changes in concentration.

Magnesium is also an agonist at high concentration, although in most parts of the body

this would be a supraphysiologic effect. In the renal tubule approaching the thick ascend-

ing limb of the loop of Henle, the magnesium concentration may be great enough to allow

it to act as an agonist (54). Spermine and spermidine are also weak agonists of this

receptor. This may be important in the central nervous system where spermine concen-

trations are high enough to be agonistic (55).

Because calcium is an agonist, extracellular calcium ions can serve as calcium regu-

lating hormones. The parathyroid glands express CaR on the cell surface membrane. The

CaR in the chief cells of the parathyroid gland serve to induce the inverse relationship

between serum calcium levels and serum PTH levels. This allows rapid correction of

variation in extracellular calcium levels by immediate secretion of PTH. In this regard,

the CaR acts analogously to a thermostat, regulating calcium within a very narrow range.

The CaR belongs to the GCPR family C, group II. Mutations in CaR lead to metabolic

derangements of calcium metabolism. Heterozygous mutations involving loss of func-

tion in CaR result in familial hypocalciuric hypercalcemia. Homozygous mutations

involving loss of CaR function cause neonatal severe primary hyperparathyroidism.

Mutations of CaR may also lead to gain of function, resulting in autosomal dominant

hypoparathyroidism.

CONCLUSION

Calcium metabolism is critical to homeostasis, and understanding calcium metabo-

lism will be crucial to understanding the pathophysiology of nephrolithiasis. Current

research is expanding our knowledge of these key pathways at an increasing rate. As we

understand more about calcium metabolism, more therapeutic targets will be identified.

Medical management of stone formers is focused on interventions to urinary constitu-

ents and urine physical properties. As clinicians seek to change urinary calcium excre-

tion, urinary pH, urinary sodium excretion, urine volume production, and use other

medical therapeutic interventions, the complex regulatory pathways of calcium metabo-

lism must be understood.

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