Faculty version with model answers

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1 Faculty version with model answers Fluid & Electrolytes Bruce M. Koeppen, M.D., Ph.D. University of Connecticut Health Center 1. A 40 year old, obese man is seen by his physician, and found to be hypertensive. He is instructed to decrease his salt intake, and begins a diet in which Na + content is approximately 60 meq/day (previously his Na + intake was estimated at 200 meq/day). The man also begins a vegetarian diet, and his potassium intake increases from 80 meq/day to 200 meq/day. Prior to beginning his new dietary regimen his serum [Na + ] was 140 meq/l (nl = meq/l) and his serum [K + ] was 3.5 meq/l (nl = meq/l). A. What effect will the decrease in Na + intake from 200 to 60 meq/day have on his weight, and why? The decrease in Na + intake will result in a decrease in the volume of the ECF, and in so doing result in a decrease in his weight. This lose of weight occurs relatively quickly, as compared to the weight loss associated with decreased caloric intake. B. What effect will the decrease in Na + intake from 200 to 60 meq/day have on serum [Na + ] and his urinary Na + excretion rate? In your explanation describe the changes that are expected occur in Na + handling along the nephron. Urinary Na + excretion is expected to decrease from 200 meq/day to 60 meq/day, thus paralleling the change in intake (under normal conditions the kidneys are the primary route of Na + excretion from the body, and thus Na + excretion is approximately equal to Na + intake in the steady-state). When on the high Na + diet (200 meq/day) it is likely that the renin-angiotensin-aldosterone system (RAAS) is suppressed, as is sympathetic input to the kidneys. In addition, atrial natriuretic peptide (ANP) levels may be increased. The decreased angiotensin-ii levels and the decreased sympathetic input to the kidneys may reduce proximal tubule reabsorption, but this would only be a minor consideration. More importantly, the reduced aldosterone levels, and elevated ANP levels will reduce the reabsorption of Na + by the collecting duct. Thus, a greater fraction of the Na + delivered to the collecting duct will not be absorbed. This will allow the excretion of 200 meq/day of Na+, which will maintain Na + balance. Additional background information: When on the low Na + diet (60 meq/day) the RAAS will likely be stimulated, as will sympathetic input to the kidneys. Also, ANP secretion will be suppressed. The increased angiotensin-ii levels and the increased sympathetic input to the kidneys may increase proximal tubule reabsorption, but this would only be a minor consideration. More importantly, the increased aldosterone levels, and reduced ANP levels will increase the reabsorption of Na + by the collecting duct. Thus, a greater fraction of the Na + delivered to the collecting duct will be absorbed. This will allow the excretion of Na + to be reduced from 200 meq/day to 60 meq/day as needed to maintain steady-state balance. ANP acts on the medullary portion of the collecting duct through guanyly cyclase. The increased cgmp levels in the cells result in inhibition (decreased open time) of Na+ channels in the apical membrane of the cell. Aldosterone acts to stimulate Na + reabsorption by altering the transcription a number of proteins involved in transepithelial Na + transport (aldosterone induced proteins). Aldosterone increases collecting duct Na + reabsorption in about 1 hour. This effect appears to reflect activation of pre-existing Na + channels (amiloride-sensitive Na + channels: ENac) in the apical Bruce M. Koeppen, M.D., Ph.D., University of Connecticut Health Center -1-

2 membrane of the principal cells. This is followed over the next several hours with increased transcription of the ENac gene, and thus increased expression of ENac in the cell. In addition, aldosterone increases the transcription of the genes encoding the components of the Na + -K + - ATPase. The following cell diagram summarizes the mechanisms of Na + and K + transport by the principal cells of the collecting duct. Na + K + ATP Na + C. What would be the effect of this man s change in diet, especially the increase in K + intake, on his serum [K + ]? In your answer be sure to include a description of the expected changes in K + transport along the length of the nephron. If his renal function is normal, it is not expected that the increase in K + intake in this man will alter his serum [K + ]. His kidneys are the primary route for K + excretion from the body, and they should be able to efficiently and adequately increase the excretion of K +. Thus, an increase in K + intake must be matched by an increase in K + excretion. The mechanism for this adaptive increase in excretion is as follows. K + is freely filtered at the glomerulus. Most of the filtered load is reabsorbed in the proximal tubule and thick ascending limb of Henle s loop. The amount of K + excreted in the urine reflects in large part the amount that is secreted by the late distal tubule and the collecting duct (primarily the cortical portion). The ability to excrete the additional K + ingested is a result of increased delivery of K + from the proximal tubule and loop of henle, and increased secretion by the principal cells of the collecting duct. The principal cells secretes K + as illustrated in the diagram shown above (1.C.). The following table summarizes factors that regulate and alter K + secretion by the principal cells of the collecting duct. Stimulates K + Secretion Inhibits K + secretion Physiological Regulators Serum [K + ]?[K + ] [K + ] Aldosterone?Aldo?Aldo Other Factors Flow rate?flow rate?flow rate Acid-Base Acute Acidosis Acute Alkalosis It is important to emphasize that the two physiological regulators of K + secretion are the serum [K + ] and aldosterone. Although not physiological regulators, changes is tubular fluid flow rate Bruce M. Koeppen, M.D., Ph.D., University of Connecticut Health Center -2-

3 and systemic acid-base balance also affect K + secretion. In this man the increased ingestion of K + will result in a slight increase in serum [K + ] (the increase would probably not be detectable on routine analysis). This increase in [K + ] will directly stimulate K + secretion by the principal cells, and also cause increase secretion of aldosterone by the adrenal gland. Aldosterone then acts on the principal cells to stimulate K + secretion. The precise mechanism by which serum [K + ] and aldosterone stimulate K + secretion are not known, except that both conditions increase the K + permeability of the apical membrane. This may result from activation of existing K + channels or the synthesis and insertion of new channels into the membrane. Because aldosterone also increases Na + reabsorption by the principal cell, which in turn increases the magnitude of the lumen negative transepithelial voltage, there is a voltagedependent increase K + secretion as well. This is illustrated below. Increased Aldosterone V T V T K + Apic a l Solut io n Basolat er al So lut ion Apic al Solut i on Ba solat eral Solut io n Additional background information: In the proximal tubule, K + is reabsorbed in the primarily by solvent drag, although there is also a component of transcellular reabsorption. In the thick ascending limb of Henle s loop, K + is reabsorbed via the apical membrane Na + -2Cl - -K + symporter, and through the paracellular pathway driven by the lumen positive transepithelial voltage. 2. A 48 year old women sees her physician because of diarrhea. She was well prior to developing diarrhea 3 days ago (4-5 watery stools per day). She now feels weak, and becomes dizzy when she stands. On physical examination her blood pressure is 90/60 mmhg, and the systolic pressure decreases by 15 mm Hg when she stands. Her pulse rate also increases from 100/min to 120/min upon standing. The following data is obtained: Serum [Na + ] = 107 meq/l (nl = meq/l) Serum [K + ] = 3.9 meq/l (nl = meq/l) Serum BUN = 20 mg/dl (nl = 7-18 mg/dl) Bruce M. Koeppen, M.D., Ph.D., University of Connecticut Health Center -3-

4 Serum [glucose] = 108 mg/dl (nl = mg/dl) Serum osmolality = 220 mosm/kg H 2 O (nl = mosm/kg H 2 O) Urine [Na + ] = 3 meq/l (nl = depends on Na + and H 2 O intake) Urine [glucose] = 0 (nl = 0) Urine osmolality = 405 mosm/kg H 2 O (nl = depends on H 2 O intake) A. What is the status of this woman s extracellular fluid (ECF) volume? What evidence supports your conclusion? The ECF volume in this woman is decreased. Her symptoms of dizziness when standing up, the postural fall in blood pressure, and the reflex tachycardia support this conclusion. The elevated urine osmolality at a time when the serum osmolality is low also is consistent with a decreased ECF volume (i.e., ADH secretion is stimulated by a decreased ECF volume). The ECF volume is decreased as a result of the loss of fluid she has experienced. The elevated serum [BUN] found in this woman is further evidence of a decreased ECF volume. Urea is normally filtered at the glomerulus, and then partially reabsorbed by the proximal tubule. As described in more detail below, GFR will be decreased and proximal tubule reabsorption enhanced in the setting of a decreased ECF volume. As a result the serum [BUN] increases. Additional background information: In considering the response of the kidneys to changes in Na+ balance it is important to discuss the concept of effective circulating volume (ECV). Effective circulating volume, is not a defined body fluid compartment, but a useful physiological concept for understanding the regulation of renal salt and water excretion. Essentially, the effective circulating volume relates the adequacy of tissue perfusion. Therefore, it is related to cardiac output, blood volume and blood pressure. In many situations effective circulating volume changes in parallel with ECF volume, blood pressure, blood volume and cardiac output. However, in some important clinical situations this is not the case (e.g., congestive heart failure and hepatic cirrhosis). The most important volume sensors in the body are those in the high pressure (carotid sinus, aortic arch and juxtaglomerular apparatus of the kidney) and low pressure (cardiac atria, pulmonary vessels) sides of the vascular system. The kidneys respond to signals from these sensors to alter salt and water excretion in an adaptive manner. In this case, effective circulating volume, ECF volume, blood pressure, and cardiac output are all decreased. Both high and low pressure volume sensors detect this decrease and send signals to the kidneys to decrease excretion of salt and water; a response designed to re-establish normal volume. Conversely, an increase in these parameters will lead to enhanced renal salt and water excretion. This concept will be revisited in several of the following questions and cases in this conference. B. Why did this woman develop hyponatremia? In your answer also discuss why the urine [Na + ] is low, and the urine osmolality is elevated above the plasma osmolality. Hyponatremia: It is important to emphasize that hyponatremia represents a disorder of water balance. In this situation there is positive water balance (intake > excretion). There are several reasons for the decreased ability of this woman s kidneys to excrete solute-free water: The loss of fluid has decreased this woman s ECV (ECF volume, blood pressure, blood volume and cardiac output), and as a result ADH secretion is stimulated (non-osmotic secretion of ADH). The ADH will cause water reabsorption by the collecting duct, rather than water excretion (note the urine osmolality is elevated above what would be expected given the very low serum osmolality). Bruce M. Koeppen, M.D., Ph.D., University of Connecticut Health Center -4-

5 The decreased volume status of this woman results in a decrease in the GFR, and enhanced proximal tubule reabsorption of NaCl and water. The mechanisms involved in the enhanced proximal tubule reabsorption include: 1. Increased activity of the sympathetic nervous system. Renal sympathetic nerves innervate the cells of the proximal tubule, and stimulate the reabsorption of Na +. The cellular mechanisms are not known, but appear to be mediated via α1-adrenoceptors. 2. Increased activity of the renin-angiotensin-aldosterone system. A-II acts directly on the cells of the proximal tubule to stimulate Na + reabsorption (and H + secretion via the Na + /H + antiporter). A-II exerts its effect on the cells of the proximal tubule via AT 1 receptors. These receptors are G-protein linked to phospholipase C. As a result, there is generation of IP3 and diacylglycerol. Ultimately intracellular Ca ++ levels increase (released from intracellular stores), and activity of the Na + /H + antiporter is increased, although the precise effect on the transporter (e.g., phosphorylation) is not known. 3. Alteration in the peritubular Starling forces. GFR decreases and the filtration fraction increases in this situation. This in turn decreases the hydrostatic pressure and increases the oncotic pressure in the peritubular capillaries, and thereby enhances overall reabsorption of fluid by the proximal tubule. As a result there will less NaCl and water delivered to the loop of Henle, and therefore less separation of solute and water (i.e., dilution) by the thick ascending limb. Because the thick ascending limb is the primary urine dilution site, there will be less generation of solute-free water. The above factors all stimulate the reabsorption of Na +. Therefore, the urine excretion of Na + is reduced as indicated by the low urinary [Na + ]. Urine [Na+]: Because of the decrease in effective circulating volume, the kidneys will reduce their excretion of Na +. Na + excretion is determined by the filtered load, and tubular reabsorption. U Na X V = GFR X P Na Tubular Reabsorption With a decrease effective circulating volume the GFR is reduced and tubular reabsorption of Na+ is enhanced. As noted above, the high-pressure and low-pressure detect the decrease in cardiac output, blood pressure and blood volume, and activate the sympathetic nervous system and the renin-angiotensin-aldosterone system. Activation of these effector systems results in the following. The mechanisms involved are: GFR decreases as a result of increased sympathetic nerve activity, which constricts the afferent arterioles. Angiotensin II levels are also elevated, and A-II also constricts the afferent arteriole. Na + reabsorption along the entire nephron is enhanced. The mechanism for enhanced proximal tubule reabsorption is described above. Reabsorption by the thick ascending limb of Henle s loop is also stimulated by sympathetic nerves and aldsoetrone. Finally, the reabsorption of Na + by the collecting duct is stimulated by aldsoterone (see question #1 for details). Together these adjustments in renal function dramatically reduce the excretion of Na + in the urine. Bruce M. Koeppen, M.D., Ph.D., University of Connecticut Health Center -5-

6 Urine osmolality: The urine osmolality is greater than that of the plasma reflecting that ADH levels are elevated. It is important to recognize that ADH levels are elevated as a result of the decrease in cardiac output, blood pressure and blood volume (i.e., non-osmotic secretion of ADH). The high-pressure and low-pressure baroreceptors send afferent fibers to the brain, which cause the cells in the paraventricular and supraoptic nuclei of the hypothalamus to produce and secrete ADH. Note that this non-osmotic stimulus overrides the osmotic stimulus, which in this women would act to inhibit ADH secretion (i.e., body fluid osmolality is low, which would inhibit ADH secretion). C. The woman is treated with intravenous isotonic saline (0.9% NaCl). What effect will this have on her ECF volume and her serum [Na + ]? The isotonic saline will re-expand her ECF volume, and the kidneys in responding to her Na + deficit will retain most of the infused Na +. As volume is restored, ADH secretion will be turned off and the capacity of the kidneys to excrete solute-free water will be increased. As a result she will re-establish water balance, and correct the hyponatremia. 3. A 49 year old woman sees her physician because of weakness, easy fatigability, and loss of appetite. During the past month she has lost 7 kg (15 lb.). On physical examination she is found to have hyperpigmentation especially of the oral mucosa and gums. She is hypotensive, and her blood pressure falls when she assumes an upright posture (BP = 100/60 mmhg supine & 80/50 mmhg erect). The following laboratory data are obtained. Serum [Na + ] = 132 meq/l (nl = meq/l) Serum [K + ] = 6.5 meq/l (nl = meq/l) Urine [Na + ] = 20 meq/l (nl = depends on Na + and H 2 O intake) A. The plasma level of what hormone(s) would be expected to be below normal in this woman? This woman s symptoms and the electrolyte disturbances are most characteristic of decreased levels of adrenal cortical steroids, and especially the mineralocorticoid hormone aldosterone. This is a patient with Addison's disease. The presence of hyperpigmentation suggests that the primary problem is at the level of the adrenal gland (i.e., non-responsive to ACTH). ACTH levels are elevated in response to the decreased circulating levels of adrenal cortical steroids. Because ACTH is synthesized as preproopiomelanocortin, and when this molecule is processed to ACTH several of the cleavage products have melanocyte stimulating properties. These cleavage products are secreted with the ACTH and act on the epidermal melanocytes leading to the hyperpigmentation of the gums and skin. B. How do you explain the urine [Na + ] of 20 meq/l in this woman. What would you expect the urine [Na + ] would be in an individual who is volume depleted? What relationship does this have to the hypotension in this woman? Normally, the kidneys would respond to the decreased ECF volume present in this woman by dramatically reducing the excretion of Na + (see question #2 for comparison). The urine [Na + ] is unexpectedly high in this woman, because of the inability of her kidneys to reabsorb Na + in the thick ascending limb and collecting duct (collecting duct is more important in this regard). This Na + wasting is a result of the low levels of aldosterone (see question #1 for details on the action of aldosterone on the principal cells of the collecting duct). Although the angiotensin II Bruce M. Koeppen, M.D., Ph.D., University of Connecticut Health Center -6-

7 levels would be elevated in this woman, her adrenal glands are not secreting aldosterone in response to the angiotensin II. The hypotension is a result of the negative Na + balance present in this woman, which in turn reflects the decreased circulating levels of aldosterone. With hypoaldosteronism, Na + reabsorption by the thick ascending limb of Henle s loop and the collecting duct is reduced, and negative Na + balance develops (Na + excretion > Na + intake). Because ECF volume reflects Na + balance, ECF volume will be decreased. Since plasma is a component of the ECF, vascular volume and hence blood pressure will be decreased. C. What is the mechanism for development of hyponatremia in this woman? Hyponatremia indicates a problem in water balance. Thus, the ability of this woman's kidneys to excrete solute-free water is impaired, and she is in positive water balance (solute-free water ingestion > solute-free water excretion). There are several reasons for the decreased ability of this woman s kidneys to excrete solute-free water (see 2.B.) Note: In this problem as well as in problem #2, hyponatremia developed in the setting of negative Na + balance with a decreased ECF volume. Hyponatremia can also develop in the setting of positive Na + balance with an increased ECF volume. This is most commonly seen in patients with congestive heart failure. With congestive heart failure the decreased cardiac performance (decreased cardiac output and reduced blood pressure) is sensed by the highpressure baroreceptors as a decrease in effective circulating volume. As a result, the sympathetic nervous system and the renin-angiotensin-aldosterone are activated. Non-osmotic release of ADH also occurs. As described above, Na + excretion is reduced and positive Na + balance results. The retention of Na + expands the ECF volume, and ultimately leads to the development of edema. The non-osmotic secretion of ADH reduces the ability of the kidneys to excrete solute-free water, and if water intake exceeds the kidneys capacity to excrete solutefree water, positive water balance and thus hyponatremia results. D. Why does this woman have hyperkalemia? Urinary K + excretion is determined in large part by the amount of K + secreted into tubular fluid by the distal tubule and cortical collecting duct. K + secretion at these nephron sites is reduced by the low levels of plasma aldosterone (see 1.B. for mechanism). Therefore, K + excretion by the distal tubule and cortical collecting duct will be reduced in this woman, and she will be in positive K + balance (intake > excretion). In addition, aldosterone causes the uptake of K + into cells (e.g., skeletal muscle). In the absence of aldosterone there will be less cellular uptake. This will contribute to the development of hyperkalemia. 4. A 70 year old man with lung cancer develops the syndrome of inappropriate antidiuretic hormone secretion (SIADH). He is admitted to the hospital, and the following data are obtained. His vital signs are normal, as is the physical examination. There is no evidence of ECF volume contraction or ECF volume expansion. Body Weight = 70 kg Serum [Na + ] = 120 meq/l (nl = meq/l) Urine Osmolality = 600 mosm/kg H 2 O Urine [Na + ] Excretion = 80 meq/day Bruce M. Koeppen, M.D., Ph.D., University of Connecticut Health Center -7-

8 A. What determines the amount of Na + that is excreted in the urine, and is Na + excretion in this patient normal (assume that he ingests approximately 80 meq/day of Na + )? Na + excretion is determined by diet and volume status (i.e., effective circulating volume). In a euvolemic individual, the amount of Na + excreted each day equals the amount ingested in the diet. Measurement of the [Na + ] in a single urine sample cannot provide an indication of whether Na + excretion is normal. Also, the plasma [Na + ] does not reflect Na + balance. Instead, it reflects water balance. The hyponatremia of this man indicates he is in positive water balance (i.e., intake > excretion). B. 1 L of isotonic sa line is administered intravenously believing it would raise the serum [Na + ]. How much of the infused NaCl will be excreted in the urine (for simplicity assume that 1L of isotonic saline contains 150 mmol/l of NaCl)? What effect will this infusion have on the plasma [Na + ]? Infusion of 1L of isotonic saline will add 300 mosmoles of NaCl (150 mmoles of NaCl = 300mOsmole) to his ECF together with 1L of water. This will transiently increase the ECF volume and raise the plasma osmolality and [Na + ]. However, over time the entire amount of NaCl will be excreted, because he is in steady-state Na + balance (excretion = intake). However, because of the inappropriate secretion of ADH he will not be able to excrete the water. With a Uosm of 600 mosm/kg H 2 O, he will excrete the infused NaCl (300 mosmoles) in 0.5 L of urine. Thus, 0.5 L of solute-free water will be added to the body, and the plasma [Na + ] will decrease. For this man, the addition of 0.5 L of solute-free water to his body fluid will reduce the plasma [Na + ] to 119 meq/l. Total Body Osmoles (unchanged) = 240 mosmoles/l x 42 L = 10,080 mosmoles New Total Body Water = 42 L +0.5 L = 42.5 L New Plasma Osmolality = 10,080 mosmoles 42.5 L = 237 mosm/kg H 2 O New Plasma [Na + ] = 237 mosm/kg H2O 2 = 119 meq/l C. What effect would the administration of 1 L of hypertonic saline (3% NaCl solution) have on the plasma [Na + ]? A 3% saline solution contains 513 mmol/l of NaCl (MW = 58.5 g/mole), which is 1,026 mosmole/l. Thus, 1L of fluid and 1,026 mosmoles of solute are added to the body fluids. With the establishment of a new steady state, the infused NaCl will be excreted with 1.7 L of urine. 1,026mOsmole 600 mosm/kg H2O = 1.7 L (Uosm = 600 mosm/kg H 2 O because of the unregulated secretion of ADH. Therefore, 1 liter of infused water is excreted together with an additional 0.7 L of solute-free water. This will result in Bruce M. Koeppen, M.D., Ph.D., University of Connecticut Health Center -8-

9 a new plasma [Na + ] of 122 meq/l. Total Body Osmoles (unchanged) = 240 mosmoles/l x 42 L = 10,080 mosmoles New Total Body Water = 42 L L = 41.3 L New Plasma Osmolality = 10,080 mosmoles 41.3 L = 244 mosm/kg H 2 O New Plasma [Na + ] = 244 mosm/kg H2O 2 = 122 meq/l D. What other therapies could be used to treat this man s hyponatremia? The simplest treatment option would be to restrict his intake of fluids, so that intake does not exceed the ability of his kidneys to excrete solute-free water (i.e., he should drink only in response to thirst). Another treatment option would be block the effect of ADH on the collecting duct. Currently, ADH receptor antagonists are being developed, that can be used for this purpose. 5. A 55 year old is prescribed a thiazide diuretic as part of his therapy for hypertension. On a routine blood sample obtained 3 months after starting the diuretic his serum [K + ] is found to be 2.5 meq/l. Prior to starting the diuretic his serum [K+] was 4.0 meq/l. On physical examination he has orthostatic changes in blood pressure and pulse. What is the mechanism for the development of hypokalemia in this man? Thiazides act on the early portion of the distal tubule, which is upstream from the portion of the nephron where K + is secreted (late distal tubule and cortical portion of the collecting duct). By inhibiting reabsorption at this site there is increased delivery of Na + and fluid to the K + secretory site. This in turn stimulates K + secretion by the principal cells. See cell diagram below: Na + K + ATP Na + The increased flow rate keeps the [K + ] in the lumen low thus favoring K + exit from the cell across the apical membrane. The enhanced Na + delivery contributes to this process, since as more Na + is reabsorbed, more K + is brought into the cell by the Na + -K + -ATPase, and thus more Bruce M. Koeppen, M.D., Ph.D., University of Connecticut Health Center -9-

10 enters the lumen across the apical membrane. Any diuretic that acts upstream to the K + secretory site has the potential to cause increased K + secretion, and thus the development of hypokalemia. Because aldosterone levels are also likely to be elevated in this lady (secondary to decreased ECV), K + secretion is further stimulated. Aldosterone has several effects on the principal cells: 1. Increases the permeability of the apical membrane to Na +. This is thought to involve activation of pre-existing Na + channels in the apical membrane, and the synthesis and insertion of new channels. 2. Increases the synthesis and insertion of Na + -K + -ATPase into the basolateral membrane. This increases cellular uptake of K + (also the extrusion of Na + ). 3. Increases the permeability of the apical membrane to K +. Although not as well studied as the Na+ channels, the response to aldosterone is thought to be similar. 4. Increases the lumen negative transepithelial voltage. This effect is secondary to the stimulation of Na+ reabsorption. The increase in the lumen negative transepithelial voltage creates a more favorable electrochemical gradient for the passive movement of K + out of the principal cell into the tubular fluid. 6. A 78 year old woman has been diagnosed as having osteoporosis, and is placed on supplemental calcium. Her serum [Ca ++ ] is normal prior to starting the calcium supplements. What will be the effect of increased calcium intake on her serum [Ca ++ ]? The increased dietary intake would not be expected to cause an appreciable change in her serum [Ca ++ ]. To understand why this is so, the students should first review the normal regulation of calcium balance, and the role of PTH and 1,25-dihydroxy vitamin D 3 (calcitriol) in this process. Diet 1000 mg Calcitriol & PTH stimulate Cortisol inhibits Androgens, Estrogens Growth Hormone stimulate Intestine 400 mg 200 mg Serum [Ca ++ ] 9-10 mg/dl 300 mg 300 mg Bone Feces 800 mg PTH stimulates 9800 mg Kidneys 10,000 mg PTH, Calcitriol, Cortisol, T3, T4 stimulate Calcitonin inhibits Urine 200 mg Bruce M. Koeppen, M.D., Ph.D., University of Connecticut Health Center -10-

11 In this woman, much of the increased calcium she ingests will simply be excreted in the feces. Initially, there will be some increase in intestinal absorption. This will increase the serum [Ca ++ ], which in turn will suppress PTH secretion. The decreased PTH will then suppress the renal formation of calcitriol, and thereby reduce intestinal calcium absorption. Also, with lower PTH levels less of the filtered load of calcium would be absorbed by the cortical portion of the thick ascending limb of Henle s loop and the early portion of the distal tubule (site of action of PTH for the regulation of Ca ++ reabsorption). The net result is that there will be no appreciable change in the serum [Ca ++ ]. Other therapy (e.g., bisphosphonates, calcitonin) is required in order to decrease the bone turnover associated with osteoporosis. These agents can also increase bone mass. Additional background information: The calcium-sensing receptor (CaSR) is a receptor expressed in the plasma membrane of cells involved in regulating Ca ++ homeostasis. The CaSR senses small changes in extracellular [Ca ++ ]. Ca ++ binds to the CaSR receptors in PTHsecreting cells of the parathyroid gland, calcitonin-secreting parafollicular cells in the thyroid gland, and 1,25-dihydroxyvitamen D 3 (calcitriol) producing cells of the proximal tubule. The receptor is also found in the cortical portion of the thick ascending limb of henle s loop and the early portion of the distal tubule; sites where Ca ++ reabsorption is regulated by PTH. An increase in plasma [Ca ++ ] inhibits the secretion of PTH and calcitriol production (the decrease in PTH secretion also contributes to the decreased production of calcitriol), and stimulates calcitonon secretion. The opposite occurs with a decrease in plasma [Ca ++ ]. CaSRs in the thick ascending limb and distal tubule respond directly to changes in plasma [Ca ++ ] and regulate Ca ++ absorption by these nephron segments (PTH also stimulates reabsorption). An increase in plasma [Ca ++ ] activates the CaSR and inhibits Ca ++ absorption (increased Ca ++ excretion). The opposite occurs with a decrease in plasma [Ca ++ ]. Bruce M. Koeppen, M.D., Ph.D., University of Connecticut Health Center -11-