Ca is balanced between total daily intake (800-1000mg), net GIT absorption (20% i.e ~200mg mainly through passive paracellular- tight junction- route with direct relation to intestinal surface area and transit time) which then filtered by the kidneys & net loss (~800mg in feces).
99% of filtered Ca is reabsorbed by the kidneys, 80% mainly through passive para-cellular route (70% in PCT following Na+H2O & 10% in CTALH- following ROMK and NKCC2 activation), small but significant remaining 20% through secondary active trans-cellular transport under PTH control (5-10% in DCT via Na/Ca exchanger & 5-10% in CD which is the major site of regulation)
Ca reabsorption is
*increased by: PTH & 1,25 OH vit D3 & metabolic alkalosis & hypocalcemia & thiazide & amiloride & volume contraction,
*decreased by stimulation of CaSR by hypercalcemia & calcitonin & ECF expansion & metabolic acidosis & loop diuretics
Renal rule in Pi homeostasis
The kidneys are the major regulators of Pi homeostasis, keeping serum Pi level in normal range, in normal adults: ~ 3700-6100mg is filtered per day, where 75-85% is reabsorbed by renal tubules, the net daily renal excretion is ~ 600-1500mg
85% of Pi reabsorption occurs in PCT as 2ry active trans-cellular route via NPta&c, (which is directly related to abundance of these transporters).
Dietary or hormonal changes result in insertion or removal of NaPit2 from the brush border membrane of PCT, which may be rapid (min-hrs) in NaPit2a or slow (hrs-days) in NaPit2c.
NPt2a is Down-regulated: rapidly by {high dietary Pi, PTH, FGF23, glucocorticoids, dopamine, estrogen, acute HTN}, and is up-regulated by {Pi restricted diet, vitamin D3, thyroid hormones}
NPt2c is Down-regulated slowly by {high dietary Pi, PTH, FGF23}, With resultant reduced PCT Pi reabsorption), and is up-regulated by {Pi restricted diet, vitamin D3}.
Renal rule in Mg homeostasis
30% of total serum Mg is protein bound, 70% is available for glomerular filtrate), assuming a normal GFR, the kidney filters ~2000-2400mg/d, 96% of which is reabsorbed as follows:
10-30% in PCT by paracellular tight junction proteins claudin 16 & 19
route following Na and water,
40-70% in CTALH via paracellular route following NKCC2, ROMK, which are regulated also by CaSR
5-10% in DCT via transcellular route mediated by TRPM6
Under normal conditions S.Ca is mentained within normal range due to balance between total daily intake (800-1000mg), net GIT absorption (20% i.e ~200mg mainly through passive paracellular- tight junction- route with direct relation to intestinal surface area and transit time) which then filtered by the kidneys & net loss (~800mg in feces).
99% of filtered Ca is reabsorbed by the kidneys, 80% mainly through passive para-cellular route (70% in PCT following Na+H2O & 10% in CTALH- following ROMK and NKCC2 activation), small but significant remaining 20% through secondary active trans-cellular transport under PTH control (5-10% in DCT via Na/Ca exchanger & 5-10% in CD which is the major site of regulation)
Ca reabsorption is
*increased by: PTH & 1,25 OH vit D3 & metabolic alkalosis & hypocalcemia & thiazide & amiloride & volume contraction,
*decreased by stimulation of CaSR by hypercalcemia & calcitonin & ECF expansion & metabolic acidosis & loop diuretics
Renal rule in Pi homeostasis
The kidneys are the major regulators of Pi homeostasis, keeping serum Pi level in normal range, in normal adults: ~ 3700-6100mg is filtered per day, where 75-85% is reabsorbed by renal tubules, the net daily renal excretion is ~ 600-1500mg
85% of Pi reabsorption occurs in PCT as 2ry active trans-cellular route via NPta&c, (which is directly related to abundance of these transporters).
Dietary or hormonal changes result in insertion or removal of NaPit2 from the brush border membrane of PCT, which may be rapid (min-hrs) in NaPit2a or slow (hrs-days) in NaPit2c.
NPt2a is Down-regulated: rapidly by {high dietary Pi, PTH, FGF23, glucocorticoids, dopamine, estrogen, acute HTN}, and is up-regulated by {Pi restricted diet, vitamin D3, thyroid hormones}
NPt2c is Down-regulated slowly by {high dietary Pi, PTH, FGF23}, With resultant reduced PCT Pi reabsorption), and is up-regulated by {Pi restricted diet, vitamin D3}.
Renal rule in Mg homeostasis
30% of total serum Mg is protein bound, 70% is available for glomerular filtrate), assuming a normal GFR, the kidney filters ~2000-2400mg/d, 96% of which is reabsorbed as follows:
10-30% in PCT by paracellular tight junction proteins claudin 16 & 19
route following Na and water,
40-70% in CTALH via paracellular route following NKCC2, ROMK, which are regulated also by CaSR
5-10% in DCT via transcellular route mediated by TRPM6
Renal Control of Calcium, Phosphate, and Magnesium HomeostasisRenal Regulation of Calcium Balance
Total serum calcium consists of ionized, protein bound, and complexed fractions (approximately 48%, 46%, and 7%, respectively). The complexed calcium is bound to molecules such as phosphate and citrate. The ultrafilterable calcium equals the total of the ionized and complexed fractions. Normal total serum calcium is approximately 8.9–10.1 mg/dl (about 2.2–2.5 mmol/l). Calcium can be bound to albumin and globulins. For each 1.0-g/dl decrease in serum albumin, total serum calcium decreases by 0.8 mg/dl. For each 1.0-g/dl decrease in serum globulin fraction, total serum calcium decreases by 0.12 mg/dl. The amount of calcium excreted in the urine usually ranges from 100 to 200 mg per 24 hours; hence, 98%–99% of the filtered load of calcium is reabsorbed by the renal tubules. Approximately 60%–70% of the filtered calcium is reabsorbed in the proximal convoluted tubule, 20% in the loop of Henle, 10% bythe distal convoluted tubule, and 5% by the collecting duct. The terminal nephron, although responsible for the reabsorption of only 5%–10% of the filtered calcium load, is the major site for regulation of calcium excretionThe reabsorption of calcium in the proximal convolutedtubule parallels that of sodium and water. Proximal tubularcalcium reabsorption is thought to occur mainly by passive diffusion and solvent drag.The passive paracellular pathways account for approximately 80% of calcium reabsorption in this segment of the nephron. A small but significant component of active calcium transport is observed in the proximal tubules. The active transport of calcium proceeds in a two-step process, with calcium entry from the tubular fluid across the apical membrane and exit though the basolateral membrane. This active transport is generally considered to constitute 10%–15% of total proximal tubule calcium reabsorption and it is mainly regulated by parathyroid hormone (PTH) and calcitonin Hormonal and Other Factors Regulating Renal Calcium Handling: PTH, Vitamin D , Metabolic Acidosis, Diuretics
Renal Regulation of Phosphate Balance
The kidney plays a key role in phosphate homeostasis. In normal adults, between 3700 and 6100 mg/d of phosphorus is filtered by the glomerulus. Net renal excretion of phosphorus is between 600 and 1500 mg/d. which means that between 75% and 85% of the daily filtered load is reabsorbed by the renal tubules. Hormonal and Other Factors Regulating Renal Phosphate Handling , PTH, Fibroblast Growth Factor-23, 1,25(OH)2D , Glucocorticoids, Estrogen, Thyroid Hormone, Dopamine, Metabolic Acidosis, Hypertension
Renal Regulation of Magnesium
Assuming a normal GFR, the kidney filters approximately 2000–2400 mg of magnesium per day. This takes into account the fact that only 70% of total serum magnesium (30% is protein-bound) is available for glomerular filtration. Under normal conditions, 96% of filtered magnesium is reabsorbed in the renal tubules by several coordinated transport processes and magnesium transporters Proximal Tubule. 10%–30% of the filtered magnesium is absorbed in the proximal tubule.The exact mechanisms are not known, magnesium is believed to be absorbed via a paracellular pathway aided by a chemical gradient generated by Na gradient– driven water transport that increases intraluminal magnesium as well as lumen-positive potential. Thick Ascending Limb. A paracellular pathway in the thick ascending limb absorbs 40%–70% of filtered magnesium, mostly enhanced by lumen-positive transepithelial voltage, in which claudin-16 and claudin-19 play an important role. The NKCC2 cotransporter mediates apical absorption of Na, K, and Cl. The apical ROMK mediates apical recycling of K back to the tubular lumen and generation of lumen-positive voltage. The Cl channel ClC-Kb mediates Cl exit through the basolateral membrane. Na, K,-ATPase also mediates Na exit through the basolateral membrane and generates the Na gradient for Na absorption. The tight junction proteins claudin-16 and claudin-19 play a prominent role in magnesium absorption. The CaSR has also been determined to regulate magnesium transport in this segment: upon stimulation, magnesium transport is decreased. Basolateral receptor activation inhibits apical K channels and possibly Na-2C1-K cotransport in the rat thick ascending limb Distal Convoluted Tubule. The remaining 5%–10% of magnesium is reabsorbed in the distal convoluted tubule mainly by active transcellular transport mediated by TRPM6. Bone. At least 50% of the total body magnesium content resides in bone as hydroxyapatite crystals. Dietary magnesium restriction causes decreased bone magnesium content
10 g of Ca is filtered /day and 98% is reabsorbed by the renal tubules, the proximal tubules reabsorbs 65% to 70%, by solvent drag following reabsorption of water and urea
20% is reabsorbed in the thick ascending loop of Henle driven by lumen positivity, which in turn is created by NKCC channel and exiting of K via ROMK to the lumen.
10% in Distal Tubule (Active)
5% in Collecting Ducts
Ca Regulation :
Increase Ca absorption
PTH
vit D3
Metabolic alkalosis
Thiazides diuretics
volume depletion.
Decrease Ca absorption
vit- D deficiency
Hypercalcaemia
Extracellular fluid expansion
Metabolic acidosis
Loop diuretics
—————————————————————————————— Renal control of Phosphate
75-85% of filtered PO4 is reabsorbed by kidney
in PCT, PO4 reabsorption is active via Na dependent Npt2a, Npt2c, and PiT-2, and this is the site where control happens
Increased Absorption
PTH
Hypocalcemia
vitD3
Volume contraction
Alkalosis
Decreased absorption
Hypercalcemia
Volume expansion
Acidosis
loop diuretics
———————————————————————– Mg Homeostasis Magnesium (Mg2+) is the fourth most abundant cation in the body. Thus, magnesium homeostasis needs to be tightly regulated, and this is facilitated by intestinal absorption and renal excretion. Magnesium absorption is dependent on two concomitant pathways found in both in the intestine and the kidneys: passive paracellular transport via claudins facilitates bulk magnesium absorption, whereas active transcellular pathways mediate the fine-tuning of magnesium absorption. The identification of genes responsible for diseases associated with hypomagnesaemia resulted in the discovery of several magnesiotropic proteins. Claudins 16 and 19 form the tight junction pore necessary for mass magnesium transport. However, most of the causes of genetic hypomagnesaemia can be tracked down to transcellular magnesium transport in the distal convoluted tubule. Within the distal convoluted tubule, magnesium reabsorption is a tightly regulated process that determines the final urine magnesium concentration. Therefore, insufficient magnesium transport in the distal convoluted tubule owing to mutated magnesiotropic proteins inevitably leads to magnesium loss, which cannot be compensated for in downstream tubule segments. Better understanding of the molecular mechanism regulating magnesium reabsorption will give new opportunities for better therapies, perhaps including therapies for patients with chronic renal failure.
Ca is balanced between total daily intake (800-1000mg), net GIT absorption (20% i.e ~200mg mainly through passive paracellular- tight junction- route with direct relation to intestinal surface area and transit time) which then filtered by the kidneys & net loss (~800mg in feces).
99% of filtered Ca is reabsorbed by the kidneys, 80% mainly through passive para-cellular route (70% in PCT following Na+H2O & 10% in CTALH- following ROMK and NKCC2 activation), small but significant remaining 20% through secondary active trans-cellular transport under PTH control (5-10% in DCT via Na/Ca exchanger & 5-10% in CD which is the major site of regulation)
Ca reabsorption is
*increased by: PTH & 1,25 OH vit D3 & metabolic alkalosis & hypocalcemia & thiazide & amiloride & volume contraction,
*decreased by stimulation of CaSR by hypercalcemia & calcitonin & ECF expansion & metabolic acidosis & loop diuretics
Renal rule in Pi homeostasis
The kidneys are the major regulators of Pi homeostasis, keeping serum Pi level in normal range, in normal adults: ~ 3700-6100mg is filtered per day, where 75-85% is reabsorbed by renal tubules, the net daily renal excretion is ~ 600-1500mg
85% of Pi reabsorption occurs in PCT as 2ry active trans-cellular route via NPta&c, (which is directly related to abundance of these transporters).
Dietary or hormonal changes result in insertion or removal of NaPit2 from the brush border membrane of PCT, which may be rapid (min-hrs) in NaPit2a or slow (hrs-days) in NaPit2c.
NPt2a is Down-regulated: rapidly by {high dietary Pi, PTH, FGF23, glucocorticoids, dopamine, estrogen, acute HTN}, and is up-regulated by {Pi restricted diet, vitamin D3, thyroid hormones}
NPt2c is Down-regulated slowly by {high dietary Pi, PTH, FGF23}, With resultant reduced PCT Pi reabsorption), and is up-regulated by {Pi restricted diet, vitamin D3}.
Renal rule in Mg homeostasis
30% of total serum Mg is protein bound, 70% is available for glomerular filtrate), assuming a normal GFR, the kidney filters ~2000-2400mg/d, 96% of which is reabsorbed as follows:
10-30% in PCT by paracellular tight junction proteins claudin 16 & 19
route following Na and water,
40-70% in CTALH via paracellular route following NKCC2, ROMK, which are regulated also by CaSR
5-10% in DCT via transcellular route mediated by TRPM6
Renal rule in Calcium homeostasis
Ca reabsorption is
*increased by: PTH & 1,25 OH vit D3 & metabolic alkalosis & hypocalcemia & thiazide & amiloride & volume contraction,
*decreased by stimulation of CaSR by hypercalcemia & calcitonin & ECF expansion & metabolic acidosis & loop diuretics
Renal rule in Pi homeostasis
The kidneys are the major regulators of Pi homeostasis, keeping serum Pi level in normal range, in normal adults: ~ 3700-6100mg is filtered per day, where 75-85% is reabsorbed by renal tubules, the net daily renal excretion is ~ 600-1500mg
85% of Pi reabsorption occurs in PCT as 2ry active trans-cellular route via NPta&c, (which is directly related to abundance of these transporters).
Dietary or hormonal changes result in insertion or removal of NaPit2 from the brush border membrane of PCT, which may be rapid (min-hrs) in NaPit2a or slow (hrs-days) in NaPit2c.
NPt2a is Down-regulated: rapidly by {high dietary Pi, PTH, FGF23, glucocorticoids, dopamine, estrogen, acute HTN}, and is up-regulated by {Pi restricted diet, vitamin D3, thyroid hormones}
NPt2c is Down-regulated slowly by {high dietary Pi, PTH, FGF23}, With resultant reduced PCT Pi reabsorption), and is up-regulated by {Pi restricted diet, vitamin D3}.
Renal rule in Mg homeostasis
30% of total serum Mg is protein bound, 70% is available for glomerular filtrate), assuming a normal GFR, the kidney filters ~2000-2400mg/d, 96% of which is reabsorbed as follows:
10-30% in PCT by paracellular tight junction proteins claudin 16 & 19
route following Na and water,
40-70% in CTALH via paracellular route following NKCC2, ROMK, which are regulated also by CaSR
5-10% in DCT via transcellular route mediated by TRPM6
Renal control of Ca, P, Mg
Renal Control of Calcium, Phosphate, and Magnesium HomeostasisRenal Regulation of Calcium Balance
Total serum calcium consists of ionized, protein bound, and complexed fractions (approximately 48%, 46%, and 7%, respectively). The complexed calcium is bound to molecules such as phosphate and citrate. The ultrafilterable calcium equals the total of the ionized and complexed fractions. Normal total serum calcium is approximately 8.9–10.1 mg/dl (about 2.2–2.5 mmol/l). Calcium can be bound to albumin and globulins. For each 1.0-g/dl decrease in serum albumin, total serum calcium decreases by 0.8 mg/dl. For each 1.0-g/dl decrease in serum globulin fraction, total serum calcium decreases by 0.12 mg/dl. The amount of calcium excreted in the urine usually ranges from 100 to 200 mg per 24 hours; hence, 98%–99% of the filtered load of calcium is reabsorbed by the renal tubules. Approximately 60%–70% of the filtered calcium is reabsorbed in the proximal convoluted tubule, 20% in the loop of Henle, 10% bythe distal convoluted tubule, and 5% by the collecting duct. The terminal nephron, although responsible for the reabsorption of only 5%–10% of the filtered calcium load, is the major site for regulation of calcium excretionThe reabsorption of calcium in the proximal convolutedtubule parallels that of sodium and water. Proximal tubularcalcium reabsorption is thought to occur mainly by passive diffusion and solvent drag.The passive paracellular pathways account for approximately 80% of calcium reabsorption in this segment of the nephron. A small but significant component of active calcium transport is observed in the proximal tubules. The active transport of calcium proceeds in a two-step process, with calcium entry from the tubular fluid across the apical membrane and exit though the basolateral membrane. This active transport is generally considered to constitute 10%–15% of total proximal tubule calcium reabsorption and it is mainly regulated by parathyroid hormone (PTH) and calcitonin
Hormonal and Other Factors Regulating Renal Calcium Handling: PTH, Vitamin D , Metabolic Acidosis, Diuretics
Renal Regulation of Phosphate Balance
The kidney plays a key role in phosphate homeostasis. In normal adults, between 3700 and 6100 mg/d of phosphorus is filtered by the glomerulus. Net renal excretion of phosphorus is between 600 and 1500 mg/d. which means that between 75% and 85% of the daily filtered load is reabsorbed by the renal tubules.
Hormonal and Other Factors Regulating Renal Phosphate Handling , PTH, Fibroblast Growth Factor-23, 1,25(OH)2D , Glucocorticoids, Estrogen, Thyroid Hormone, Dopamine, Metabolic Acidosis, Hypertension
Renal Regulation of Magnesium
Assuming a normal GFR, the kidney filters approximately 2000–2400 mg of magnesium per day. This takes into account the fact that only 70% of total serum magnesium (30% is protein-bound) is available for glomerular filtration. Under normal conditions, 96% of filtered magnesium is reabsorbed in the renal tubules by several coordinated transport processes and magnesium transporters
Proximal Tubule. 10%–30% of the filtered magnesium is absorbed in the proximal tubule.The exact mechanisms are not known, magnesium is believed to be absorbed via a paracellular pathway aided by a chemical gradient generated by Na gradient– driven water transport that increases intraluminal magnesium as well as lumen-positive potential.
Thick Ascending Limb. A paracellular pathway in the thick ascending limb absorbs 40%–70% of filtered magnesium, mostly enhanced by lumen-positive transepithelial voltage, in which claudin-16 and claudin-19 play an important role. The NKCC2 cotransporter mediates apical absorption of Na, K, and Cl. The apical ROMK mediates apical recycling of K back to the tubular lumen and generation of lumen-positive voltage. The Cl channel ClC-Kb mediates Cl exit through the basolateral membrane. Na, K,-ATPase also mediates Na exit through the basolateral membrane and generates the Na gradient for Na absorption. The tight junction proteins claudin-16 and claudin-19 play a prominent role in magnesium absorption. The CaSR has also been determined to regulate magnesium transport in this segment: upon stimulation, magnesium transport is decreased. Basolateral receptor activation inhibits apical K channels and possibly Na-2C1-K cotransport in the rat thick ascending limb
Distal Convoluted Tubule. The remaining 5%–10% of magnesium is reabsorbed in the distal convoluted tubule mainly by active transcellular transport mediated by TRPM6.
Bone. At least 50% of the total body magnesium content resides in bone as hydroxyapatite crystals. Dietary magnesium restriction causes decreased bone magnesium content
Renal Control of Ca
Renal handling:
Ca Regulation :
Increase Ca absorption
Decrease Ca absorption
——————————————————————————————
Renal control of Phosphate
———————————————————————–
Mg Homeostasis
Magnesium (Mg2+) is the fourth most abundant cation in the body. Thus, magnesium homeostasis needs to be tightly regulated, and this is facilitated by intestinal absorption and renal excretion. Magnesium absorption is dependent on two concomitant pathways found in both in the intestine and the kidneys: passive paracellular transport via claudins facilitates bulk magnesium absorption, whereas active transcellular pathways mediate the fine-tuning of magnesium absorption. The identification of genes responsible for diseases associated with hypomagnesaemia resulted in the discovery of several magnesiotropic proteins. Claudins 16 and 19 form the tight junction pore necessary for mass magnesium transport. However, most of the causes of genetic hypomagnesaemia can be tracked down to transcellular magnesium transport in the distal convoluted tubule. Within the distal convoluted tubule, magnesium reabsorption is a tightly regulated process that determines the final urine magnesium concentration. Therefore, insufficient magnesium transport in the distal convoluted tubule owing to mutated magnesiotropic proteins inevitably leads to magnesium loss, which cannot be compensated for in downstream tubule segments. Better understanding of the molecular mechanism regulating magnesium reabsorption will give new opportunities for better therapies, perhaps including therapies for patients with chronic renal failure.