Renal Handling of Calcium

Afferent arteriole

Afferent arteriole

Afferent Arteriole
Efferent arteriole

FIGURE 5-13

Glomerular filtration of calcium (Ca). Total serum Ca consists of ionized, protein bound, and complexed fractions (47.5%, 46.0%, and 6.5%, respectively). The complexed Ca is bound to molecules such as phosphate and citrate. The ultrafilterable Ca equals the total of the ionized and complexed fractions. Normal total serum Ca is approximately 8.9 to 10.1 mg/dL (about 2.2-2.5 mmol/L). Ca can be bound to albumin and globulins. For each 1.0 gm/dL decrease in serum albumin, total serum Ca decreases by 0.8 mg/dL; for each 1.0 gm/dL decrease in serum globulin fraction, total serum Ca decreases by 0.12 mg/dL. Ionized Ca is also affected by pH. For every 0.1 change in pH, ionized Ca changes by 0.12 mg/dL. Alkalosis decreases the ionized Ca [1,6,7].

| | Parathyroid hormone and 1,25(OH)2D3 I I Calcitonin I | Thiazides

Ca2+ ATPase, VDR, CaBP-D, Na+/Ca2+ exchanger colocalized here

| | Parathyroid hormone and 1,25(OH)2D3 I I Calcitonin I | Thiazides

Ca2+ ATPase, VDR, CaBP-D, Na+/Ca2+ exchanger colocalized here

FIGURE 5-14

Renal handling of calcium (Ca). Ca is filtered at the glomerulus, with the ultrafilterable fraction (UFca) of plasma Ca entering the proximal tubule (PT). Within the proximal convoluted tubule (PCT) and the proximal straight tubule (PST), isosmotic reabsorption of Ca occurs such that at the end of the PST the UF^ to TFCa ratio is about 1.1 and 60% to 70% of the filtered Ca has been reabsorbed. Passive paracellular pathways account for about 80% of Ca reabsorption in this segment of the nephron, with the remaining 20% dependent on active transcellular Ca movement. No reabsorption of Ca occurs within the thin segment of the loop of Henle. Ca is reabsorbed in small amounts within the medullary segment of the thick ascending limb (MAL) of the loop of Henle and calcitonin (CT) stimulates Ca reabsorption here. However, the cortical segments (cTAL) reabsorb about 20% of the initially filtered load of Ca. Under normal conditions, most of the Ca reabsorption in the cTAL is passive and paracellular, owing to the favorable electrochemical gradient. Active transcellular Ca transport can be stimulated by both parathyroid hormone (PTH) and 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3) in the cTAL. In the early distal convoluted tubule (DCT), thiazide-activated Ca transport occurs. The DCT is the primary site in the nephron at which Ca reabsorption is regulated by PTH and 1,25(OH)2D3. Active transcellular Ca transport must account for Ca reabsorption in the DCT, because the transepithelial voltage becomes negative, which would not favor passive movement of Ca out of the tubular lumen. About 10% of the filtered Ca is reabsorbed in the DCT, with another 3% to 10% of filtered Ca reabsorbed in the connecting tubule (CNT) by way of mechanisms similar to those in the DCT [1,2,6, 7,18]. ATPase—adenosine triphosphatase; CaBP-D—Ca-binding protein D; DT—distal tubule; VDR—vitamin D receptor. (Adapted from Kumar [1].)

Renal Handling Calcium
FIGURE 5-15

Effects of hypercalcemia on calcium (Ca) reabsorption in the cortical thick ascending limb (cTAL) of the loop of Henle and urinary concentration. (1) Hypercalcemia stimulates the Ca-sensing receptor (CaSR) of cells in the cTAL. (2) Activation of the G-pro-tein increases intracellular free ionized Ca (Ca2+) by way of the inositol 1,4,5-trisphosphate (IP3) pathway, which increases the activity of the P450 enzyme system. The G-protein also increases activity of phospholipase A2 (PLAa), which increases the concentration of arachidonic acid (AA). (3) The P450 enzyme system increases production of 20-hydroxy-eicosatetraenoic acid (20-HETE) from AA. (4) 20-HETE inhibits hormone-stimulated production of cyclic adenosine monophosphate (cAMP), blocks sodium reabsorption by the sodium-potassium-chloride (Na-K-2Cl) cotransporter, and inhibits movement of K out of K-channels. (5) These changes alter the electrochemical forces that would normally favor the paracellular movement of Ca (and Mg) such that Ca (and Mg) is not passively reabsorbed. Both the lack of movement of Na into the renal interstitium and inhibition of hormonal (eg, vaso-pressin) effects impair the ability of the nephron to generate maximally concentrated urine [3,4,14]. ATP—adenosine triphosphate; PK-C—protein kinase C.

FIGURE 5-16

Postulated mechanism of the Ca transport pathway shared by PTH and 1,25(OH)2D3. Cyclic adenosine monophosphate (cAMP) generated by PTH stimulation leads to increased influx of Ca into the apical dihydropyridine-sensitive Ca channel. There also is increased activity of the basolateral Na-Ca exchanger and, perhaps, of the plasma membrane-associated Ca-adenosine triphosphatase (PMCA), which can rapidly extrude the increased intracellular free Ca (Ca2+). Calcitriol (1,25(OH)2D3), by way of the vitamin D receptor (VDR), stimulates transcription of calbindin D28k (CaBP2g) and calbindin D9k (CaBPg). CaBP28 increases apical uptake of Ca by both the dihydropyridine- and thiazide-sensitive Ca channels by decreasing the concentration of unbound free Ca2+ and facilitates Ca movement to the basolateral membrane. CaBP9 stimulates PMCA activity, which increases extrusion of Ca by the cell. Similar hormonally induced mechanisms of Ca transport are believed to exist throughout the cortical thick ascending limb, the DCT, and the connecting tubule (CNT) [6]. ATP—adenosine triphosphate; Na+—ionized sodium.

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