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Calcium Homeostasis in Health and in Kidney Disease

Sharon M. Moe

10.1002/cphy.c150052

Source: Volume 6, Issue 4, October 2016

Published online: September 2016

Full Article on Wiley Online Library



ABSTRACT

Calcium is an important ion in cell signaling, hormone regulation, and bone health. Its regulation is complex and intimately connected to that of phosphate homeostasis. Both ions are maintained at appropriate levels to maintain the extracellular to intracellular gradients, allow for mineralization of bone, and to prevent extra skeletal and urinary calcification. The homeostasis involves the target organs intestine, parathyroid glands, kidney, and bone. Multiple hormones converge to regulate the extracellular calcium level: parathyroid hormone, vitamin D (principally 25(OH)D or 1,25(OH)2D), fibroblast growth factor 23, and α‐klotho. Fine regulation of calcium homeostasis occurs in the thick ascending limb and collecting tubule segments via actions of the calcium sensing receptor and several channels/transporters. The kidney participates in homeostatic loops with bone, intestine, and parathyroid glands. Initially in the course of progressive kidney disease, the homeostatic response maintains serum levels of calcium and phosphorus in the desired range, and maintains neutral balance. However, once the kidneys are no longer able to appropriately respond to hormones and excrete calcium and phosphate, positive balance ensues leading to adverse cardiac and skeletal abnormalities. © 2016 American Physiological Society. Compr Physiol 6:1781‐1800, 2016.

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Figure 1. Figure 1. Normal calcium balance. The average dietary intake of calcium is 20 mmol of which 16 mmol is excreted in stool. A net of approximately 4 mmol is absorbed (accounting for the obligatory secretion). With a normal glomerular filtration rate, the kidney filters approximately 270 mmol (10 g), and reabsorbs 98%. In neutral balance, the assumption is that the calcium entering the bone and leaving the bone is in steady state, and therefore the kidney maintains neutral balance by excreting any excess calcium.
Figure 2. Figure 2. Regulation of parathyroid hormone secretion and metabolism. Secondary hyperparathyroidism induced acutely by reducing calcium concentration or chronically by reducing calcium and vitamin D intake leads to an increase in PTH(1‐84), a relative decrease in C‐PTH fragment formation, and a lower C‐PTH fragments/PTH(1‐84) ratio. Half parathyroidectomy in dogs leads to a similar situation by decreasing PTH(1‐84) less than C‐PTH fragments. Acute calcium infusion, correction of secondary hyperparathyroidism or injection of 1,25(OH)2D without changing calcium concentration leads to the reverse situation with a high C‐PTH fragments/PTH(1‐84) ratio. Reprinted, with permission, from (46), Figure 2.
Figure 3. Figure 3. Overview of vitamin D metabolism. Vitamin D is obtained from dietary sources, and is metabolized via UVB from 7‐DHC in the skin. Both sources (diet and skin) of vitamin D2 and vitamin D3 bind to DBP and circulate to the liver. In the liver, vitamin D is hydroxylated by CYP27A1 to 25(OH)D, commonly referred to as calcidiol. Calcidiol is then further metabolized to calcitriol by the 1‐αhydroxylase enzyme (CYP27B1) at the level of the kidney. The active metabolite 1,25(OH)2D (calcitriol) acts principally on the target organs of intestine, parathyroid gland, bone cell precursors, and the kidney. Calcitriol is metabolized to the inert 1,24,25(OH)3D through the action of the 24,25‐hydroxylase enzyme (CYP24). Calcidiol is similarly hydroxylated to 24,25(OH)2D (134).
Figure 4. Figure 4. The bone‐kidney‐parathyroid endocrine axes mediated by FGF23 and klotho. Active form of vitamin D (1,25‐dihydroxyvitamin D3) binds to VDR in the bone (osteocytes). The ligand‐bound VDR forms a heterodimer with a nuclear receptor RXR and transactivates expression of the FGF23 gene. FGF23 secreted from bone acts on the klotho‐FGFR complex expressed in the kidney (the bone‐kidney axis) and parathyroid gland (the bone‐parathyroid axis). In the kidney, FGF23 suppresses synthesis of active vitamin D by down‐regulating expression of the Cyp27b1 gene and promotes its inactivation by upregulating expression of the Cyp24 gene, thereby closing a negative feedback loop for vitamin D homeostasis. In the parathyroid gland, FGF23 suppresses production and secretion of PTH. PTH binds to PTHR expressed on renal tubular cells, leading to upregulation of the Cyp27b1 gene expression. Thus, suppression of PTH by FGF23 reduces expression of the Cyp27b1 gene and serum levels of 1,25‐dihydroxyvitamin D3. This closes another long negative feedback loop for vitamin D homeostasis. Reprinted, with permission, from (106).
Figure 5. Figure 5. Location of CaSR in the kidney. CaSR expression along the nephron. For each segment (Glom, glomerulus; MTALH, medullary thick ascending limb of Henle; CTALH, cortical thick ascending limb of Henle; and MD, macula densa; ), the location within the cells of each segment is shown along with the physiologic targets and cell‐specific functions of the CaSR. Localization in red indicates that morphologic studies do not uniformly recognize the CaSR in these locations, but that supporting functional data exist. Localization in green indicates that most or all studies find the CaSR in this location and that physiologic data support the localization. Podo, podocyte; intercal, intercalated. Reprinted, with permission, from (199), Figure 1.
Figure 6. Figure 6. Functions of the CaSR in the thick ascending limb of Henle's loop. The apical electroneutral NKCC2 transporter and ROMK channel (which is the rate‐limiting step for apical K+ recycling) generate a lumen‐positive transepithelial potential difference. This creates the driving force for nonselective, paracellular reabsorption of Ca2 cations. The paracellular transport is through a complex of claudin 16, 19 that is inhibited through physical interaction by a third tight junction protein claudin 14. Activation of the CaSR on the basolateral side of the cell increases claudin 14 expression (yellow) through NFAT signaling, and thus inhibits paracellular transport. Furthermore, activation of the CaSR also inhibits the ROMK channel to further inhibit calcium reabsorption in the setting of hypercalemia, although the mechanism is not understood. Reprinted, with permission, from (195), Figure 1.
Figure 7. Figure 7. Calcium active transport in the DCT. The late part of the DCT and CNT play an important role in fine‐tuning renal excretion of Ca2+. The ephosphatethelial Ca2+ channel (TRPV5) is primarily expressed aphosphatecally in these segments and co‐localizes with calbindin‐D28K (28K), Na+/Ca2+ exchanger (NCX1), and the plasma membrane ATPase (PMCA1b). Upon entry via TRPV5, Ca2+ is buffered by 28K and diffuses to the basolateral membrane, where it is released and extruded by a concerted action of NCX1 and PMCA1b. In addition, the basolateral membrane exposes a parathyroid hormone receptor (PTHR) and the Na+/K+‐ATPase consisting of the α‐, β‐, and γ‐subunit. PTHR activation by PTH stimulates TRPV5 activity, and entered Ca2+ can subsequently control the expression level of the Ca2+ transporters. At the aphosphatecal membrane, there is a bradykinin receptor (BK2) that is activated by urinary TK to activate TRPV5‐mediated Ca2+ influx. In the cell, entered Ca2+ acts as a negative feedback on channel activity, and 28K plays a regulatory role by association with TRPV5 under low intracellular Ca2+ concentrations. Extracellular urinary klotho directly stimulates TRPV5 at the aphosphatecal membrane by modification of the N‐glycan, whereas intracellular klotho enhances Na+/K+‐ATPase surface expression that in turn activates NCX1‐mediated Ca2+ efflux. Reprinted, with permission, from (19).
Figure 8. Figure 8. Physiologic roles of klotho on solute channels and transporters and vitamin D metabolism in the kidney klotho is prominently expressed in DCTs, and less in the proximal convoluted tubules (PCT). In PCT, membrane klotho at the basolateral side functions as coreceptor of FGFRs and drive FGF23 signal transduction to inhibit NaPi cotransporters (NaPi: 2a/c and Pit2) and to suppress cyp27β1 encoding for 1‐hydroxylase,and to stimulate cyp24α1 encoding for 24‐hydoxylase. The role of klotho in the cytoplasm of renal tubules is unclear. Whether membrane klotho at luminal side inhibits NaPi cotransporters (2a/c and Pit2) in an autocrine mode is not known (dash line). In DCT, membrane klotho at basolateral side4 functions as coreceptor of FGFRs to induce FGF23 signal transduction. What intermediate(s) are released from DCT and how intermediate(s) affect on PCT in paracrine mode is not known. One possible candidate is klotho release from the DCT to act on the PCT. Whether membrane klotho at luminal side directly regulates TRPV5 in autocrine mode is unknown. Soluble Klotho in luminal urine derived from either blood or urine exerts regulatory action on NaPi cotransporters in PCT; and on TRPV5 in DCT. Ca: calcium ion; FGF23: NaPi cotransporter: sodium‐phosphate‐dependent cotransporter; Pi: phosphate; 1,25 VD3: 1,25‐(OH)2 vitamin D3, Dash line: suspected action. Reprinted, with permission, from (89).
Figure 9. Figure 9. Overview of calcium and phosphate homeostasis. As (phosphate) levels increase (or there is a chronic phosphate load), both PTH and FGF23 are increased. Both the elevated PTH and FGF23 increase urinary phosphate excretion. The two hormones differ in respect to their effects on the vitamin D axis. PTH stimulates 1‐alpha hydroxylase activity thereby increasing the production of 1,25(OH)2D, which in turn negatively feeds back on the parathyroid gland to decrease PTH secretion. In contrast, FGF23 inhibits 1‐alpha hydroxylase activity, thereby decreasing the production of 1,25(OH)2D feeding back to stimulate further secretion of FGF23. FGF23 and PTH also regulate each other. Finally, low calcium levels stimulate PTH, whereas high calcium levels stimulate FGF23. Lastly, there is some evidence that FGF23 also inhibits PTH secretion (solid line = stimulates; dashed line = inhibits). Reprinted, with permission, from Moe SM, Sprague SM. Chronic kidney disease‐mineral bone disorder (134).
Figure 10. Figure 10. Calcium balance in stage 3/4 CKD patients with and without calcium carbonate. Calcium balance was greater with calcium carbonate compared with placebo. Ca intake was experimentally controlled and statistical analysis does not apply. White bars = placebo; Black bars = calcium carbonate; Ca = calcium; NS = not significant (P > 0.05). Data are presented as least squares mean ± pooled SEM. Reprinted, with permission, from (85).


Figure 1. Normal calcium balance. The average dietary intake of calcium is 20 mmol of which 16 mmol is excreted in stool. A net of approximately 4 mmol is absorbed (accounting for the obligatory secretion). With a normal glomerular filtration rate, the kidney filters approximately 270 mmol (10 g), and reabsorbs 98%. In neutral balance, the assumption is that the calcium entering the bone and leaving the bone is in steady state, and therefore the kidney maintains neutral balance by excreting any excess calcium.


Figure 2. Regulation of parathyroid hormone secretion and metabolism. Secondary hyperparathyroidism induced acutely by reducing calcium concentration or chronically by reducing calcium and vitamin D intake leads to an increase in PTH(1‐84), a relative decrease in C‐PTH fragment formation, and a lower C‐PTH fragments/PTH(1‐84) ratio. Half parathyroidectomy in dogs leads to a similar situation by decreasing PTH(1‐84) less than C‐PTH fragments. Acute calcium infusion, correction of secondary hyperparathyroidism or injection of 1,25(OH)2D without changing calcium concentration leads to the reverse situation with a high C‐PTH fragments/PTH(1‐84) ratio. Reprinted, with permission, from (46), Figure 2.


Figure 3. Overview of vitamin D metabolism. Vitamin D is obtained from dietary sources, and is metabolized via UVB from 7‐DHC in the skin. Both sources (diet and skin) of vitamin D2 and vitamin D3 bind to DBP and circulate to the liver. In the liver, vitamin D is hydroxylated by CYP27A1 to 25(OH)D, commonly referred to as calcidiol. Calcidiol is then further metabolized to calcitriol by the 1‐αhydroxylase enzyme (CYP27B1) at the level of the kidney. The active metabolite 1,25(OH)2D (calcitriol) acts principally on the target organs of intestine, parathyroid gland, bone cell precursors, and the kidney. Calcitriol is metabolized to the inert 1,24,25(OH)3D through the action of the 24,25‐hydroxylase enzyme (CYP24). Calcidiol is similarly hydroxylated to 24,25(OH)2D (134).


Figure 4. The bone‐kidney‐parathyroid endocrine axes mediated by FGF23 and klotho. Active form of vitamin D (1,25‐dihydroxyvitamin D3) binds to VDR in the bone (osteocytes). The ligand‐bound VDR forms a heterodimer with a nuclear receptor RXR and transactivates expression of the FGF23 gene. FGF23 secreted from bone acts on the klotho‐FGFR complex expressed in the kidney (the bone‐kidney axis) and parathyroid gland (the bone‐parathyroid axis). In the kidney, FGF23 suppresses synthesis of active vitamin D by down‐regulating expression of the Cyp27b1 gene and promotes its inactivation by upregulating expression of the Cyp24 gene, thereby closing a negative feedback loop for vitamin D homeostasis. In the parathyroid gland, FGF23 suppresses production and secretion of PTH. PTH binds to PTHR expressed on renal tubular cells, leading to upregulation of the Cyp27b1 gene expression. Thus, suppression of PTH by FGF23 reduces expression of the Cyp27b1 gene and serum levels of 1,25‐dihydroxyvitamin D3. This closes another long negative feedback loop for vitamin D homeostasis. Reprinted, with permission, from (106).


Figure 5. Location of CaSR in the kidney. CaSR expression along the nephron. For each segment (Glom, glomerulus; MTALH, medullary thick ascending limb of Henle; CTALH, cortical thick ascending limb of Henle; and MD, macula densa; ), the location within the cells of each segment is shown along with the physiologic targets and cell‐specific functions of the CaSR. Localization in red indicates that morphologic studies do not uniformly recognize the CaSR in these locations, but that supporting functional data exist. Localization in green indicates that most or all studies find the CaSR in this location and that physiologic data support the localization. Podo, podocyte; intercal, intercalated. Reprinted, with permission, from (199), Figure 1.


Figure 6. Functions of the CaSR in the thick ascending limb of Henle's loop. The apical electroneutral NKCC2 transporter and ROMK channel (which is the rate‐limiting step for apical K+ recycling) generate a lumen‐positive transepithelial potential difference. This creates the driving force for nonselective, paracellular reabsorption of Ca2 cations. The paracellular transport is through a complex of claudin 16, 19 that is inhibited through physical interaction by a third tight junction protein claudin 14. Activation of the CaSR on the basolateral side of the cell increases claudin 14 expression (yellow) through NFAT signaling, and thus inhibits paracellular transport. Furthermore, activation of the CaSR also inhibits the ROMK channel to further inhibit calcium reabsorption in the setting of hypercalemia, although the mechanism is not understood. Reprinted, with permission, from (195), Figure 1.


Figure 7. Calcium active transport in the DCT. The late part of the DCT and CNT play an important role in fine‐tuning renal excretion of Ca2+. The ephosphatethelial Ca2+ channel (TRPV5) is primarily expressed aphosphatecally in these segments and co‐localizes with calbindin‐D28K (28K), Na+/Ca2+ exchanger (NCX1), and the plasma membrane ATPase (PMCA1b). Upon entry via TRPV5, Ca2+ is buffered by 28K and diffuses to the basolateral membrane, where it is released and extruded by a concerted action of NCX1 and PMCA1b. In addition, the basolateral membrane exposes a parathyroid hormone receptor (PTHR) and the Na+/K+‐ATPase consisting of the α‐, β‐, and γ‐subunit. PTHR activation by PTH stimulates TRPV5 activity, and entered Ca2+ can subsequently control the expression level of the Ca2+ transporters. At the aphosphatecal membrane, there is a bradykinin receptor (BK2) that is activated by urinary TK to activate TRPV5‐mediated Ca2+ influx. In the cell, entered Ca2+ acts as a negative feedback on channel activity, and 28K plays a regulatory role by association with TRPV5 under low intracellular Ca2+ concentrations. Extracellular urinary klotho directly stimulates TRPV5 at the aphosphatecal membrane by modification of the N‐glycan, whereas intracellular klotho enhances Na+/K+‐ATPase surface expression that in turn activates NCX1‐mediated Ca2+ efflux. Reprinted, with permission, from (19).


Figure 8. Physiologic roles of klotho on solute channels and transporters and vitamin D metabolism in the kidney klotho is prominently expressed in DCTs, and less in the proximal convoluted tubules (PCT). In PCT, membrane klotho at the basolateral side functions as coreceptor of FGFRs and drive FGF23 signal transduction to inhibit NaPi cotransporters (NaPi: 2a/c and Pit2) and to suppress cyp27β1 encoding for 1‐hydroxylase,and to stimulate cyp24α1 encoding for 24‐hydoxylase. The role of klotho in the cytoplasm of renal tubules is unclear. Whether membrane klotho at luminal side inhibits NaPi cotransporters (2a/c and Pit2) in an autocrine mode is not known (dash line). In DCT, membrane klotho at basolateral side4 functions as coreceptor of FGFRs to induce FGF23 signal transduction. What intermediate(s) are released from DCT and how intermediate(s) affect on PCT in paracrine mode is not known. One possible candidate is klotho release from the DCT to act on the PCT. Whether membrane klotho at luminal side directly regulates TRPV5 in autocrine mode is unknown. Soluble Klotho in luminal urine derived from either blood or urine exerts regulatory action on NaPi cotransporters in PCT; and on TRPV5 in DCT. Ca: calcium ion; FGF23: NaPi cotransporter: sodium‐phosphate‐dependent cotransporter; Pi: phosphate; 1,25 VD3: 1,25‐(OH)2 vitamin D3, Dash line: suspected action. Reprinted, with permission, from (89).


Figure 9. Overview of calcium and phosphate homeostasis. As (phosphate) levels increase (or there is a chronic phosphate load), both PTH and FGF23 are increased. Both the elevated PTH and FGF23 increase urinary phosphate excretion. The two hormones differ in respect to their effects on the vitamin D axis. PTH stimulates 1‐alpha hydroxylase activity thereby increasing the production of 1,25(OH)2D, which in turn negatively feeds back on the parathyroid gland to decrease PTH secretion. In contrast, FGF23 inhibits 1‐alpha hydroxylase activity, thereby decreasing the production of 1,25(OH)2D feeding back to stimulate further secretion of FGF23. FGF23 and PTH also regulate each other. Finally, low calcium levels stimulate PTH, whereas high calcium levels stimulate FGF23. Lastly, there is some evidence that FGF23 also inhibits PTH secretion (solid line = stimulates; dashed line = inhibits). Reprinted, with permission, from Moe SM, Sprague SM. Chronic kidney disease‐mineral bone disorder (134).


Figure 10. Calcium balance in stage 3/4 CKD patients with and without calcium carbonate. Calcium balance was greater with calcium carbonate compared with placebo. Ca intake was experimentally controlled and statistical analysis does not apply. White bars = placebo; Black bars = calcium carbonate; Ca = calcium; NS = not significant (P > 0.05). Data are presented as least squares mean ± pooled SEM. Reprinted, with permission, from (85).
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Article Title: Calcium Homeostasis in Health and in Kidney Disease
 

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Sharon M. Moe. Calcium Homeostasis in Health and in Kidney Disease. Compr Physiol 2016, 6: 1781-1800. doi: 10.1002/cphy.c150052