Ca2+ PO4-homeostasis med apr 2011 LO 1102/Ca2_PO4... · Dr. J. Mohan 18 April, 2011 2 Physiology Objectives 1. Describe how the kidneys regulate the quantity and concentration of

Dr. J. Mohan

18 April, 2011 1

Renal Physiology

April, 2011

J. Mohan, PhD.

Lecturer,

Physiology Unit,

Faculty of Medical Sciences,

U.W.I., St Augustine.

Office : Room 105, Physiology Unit.

References:

�Koeppen B.E. & Stanton B.A. (2010). Berne & Levy Physiology. 6th

Edition. Mosby, Elsevier.

�Marieb, E. & Hoehn, K. (2010). Human Anatomy & Physiology. 8th

Edition, Pearson, Benjamin Cummings.

�Costanzo L.S. (2006) Physiology. 3rd Edition, Elsevier, Saunders.

�Stanfield, C.L. & Germann W.J. (2008). Principles of Human

Physiology. 3rd Edition, Pearson, Benjamin Cummings.

�Hall, J.E. (2011). Guyton and Hall Textbook of Medical Physiology.

12th Edition, Elsevier, Saunders.

Dr. J. Mohan

18 April, 2011 2

Physiology Objectives

1. Describe how the kidneys regulate the quantity and

concentration of most ECF ions. E.g. Ca2+, PO4-.

2. Describe the role of the kidney in the production of 1,25

dihydroxycholecalciferol (active form of vitamin D).

3. Discuss the effects of diuretics on the excretion of calcium

and phosphate.

Today’s Topics

• Calcium homeostasis

• Renal handling of Ca2+

• Phosphate homeostasis

• Renal handling of Phosphate

Dr. J. Mohan

18 April, 2011 3

Calcium & Phosphate : Functions

Calcium (Ca2+)

• critical component of bone, cartilage, teeth

• other functions : co factor in enzymatic reactions; 2nd

messenger, blood clotting, neuromuscular transmission, muscle

contraction

Phosphate (Pi)

• important component of organic molecules e.g. DNA, RNA,

ATP, intermediates of metabolic pathways

• critical component of bone

• urinary buffer for H+ (maintenance of acid-base balance)

Calcium Distribution

Total Body Calcium

• Bone (99%)

• ICF ~(1%) - ER & mitochondria; bound to proteins; low amt free

• ECF (0.1%)

– Plasma [Ca2+] ~ 5 mEq/L

– 50% of plasma Ca2+ - bound form, 40% bound to plasma

proteins ; 10% bound to anions e.g. Pi, citrate, HCO3-,

SO42-

– 50% - free- ionised

– < 5 mEq/L = hypocalcemia; > 5 mEq/L = hypercalcemia

• concentration gradient for [Ca2+] across cell membranes

maintained by a Ca2+-ATPase pump (PMCa1b) in all cells and

by a 3Na+-1Ca2+ antiporter (NCX1) in some cells

Dr. J. Mohan

18 April, 2011 4

Calcium & Phosphate Homeostasis

• in a normal adult, renal excretion of Ca2+ & Pi = GI absorption

• � plasma [ Ca2+ & Pi ] � � GI absorption, bone resorption

(i.e., loss of Ca2+ & Pi from bone), & renal tubular reabsorption

� � plasma [ Ca2+ & Pi]

• during growth & pregnancy, GI absorption > urinary excretion,

and these ions accumulate in newly formed fetal tissue & bone

• kidneys, GI tract & bone, play a major role in maintaining

plasma Ca2+ & Pi levels, as well as Ca2+ & Pi balance

Calcium Homeostasis

• maintenance of Ca2+ homeostasis depends on 2 factors:

– (1) the amount of Ca2+ in the body

– (2) the distribution of Ca2+ between the bone & ECF

• What determines the amount of Ca2+ in the body ?

– total body [Ca2+ ] is determined by the relative amount of

Ca2+ absorbed by the GI tract vs the amount excreted by

the kidneys

– absorption of Ca2+ by the GI tract occurs via active carrier-

mediated transport mechanism that is stimulated by

calcitriol, a metabolite of vitamin D3

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18 April, 2011 5

Calcium Homeostasis

– despite variations in Ca2+ intake (200 - 1500 mg/day), the

kidneys keep total body Ca2+ balance constant by excreting

an amount of Ca2+ in urine = the amount absorbed by the

GI tract

– Ca2+ balance = Ca2+ intake (diet) = Ca2+ lost in GI tract +

Ca2+ lost in urine

Calcium Homeostasis

• what determines the distribution of Ca2+ among the bone & ECF?

– PTH, calcitriol, & calcitonin regulate the distribution of Ca2+between bone & ECF

– PTH• secreted by the parathyroid glands

• secretion is regulated by the [Ca2+] in ECF; plasma membrane

of the chief cells of the parathyroid glands contains the

calcium-sensing receptor (CaSR), which monitors the [Ca2+] in

ECF

• � plasma [Ca2+] � � PTH gene expression and release by

the chief cells

• � plasma [Ca2+] � � PTH release by the chief cells

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18 April, 2011 6

Calcium Homeostasis

• PTH increases plasma [Ca++] by :

– (1) stimulating bone resorption

– (2) increasing Ca2+ reabsorption by the kidneys

– (3) stimulating the production of calcitriol, a metabolite

of vitamin D3 produced in the PT of the kidney

• � Ca2+ absorption by the GI tract

• with PTH, causes � bone resorption

Calcium Homeostasis

• Calcitonin

– secreted by thyroid C cells (a.k.a., parafollicular cells)

– secretion is stimulated by hypercalcemia

– decreases plasma [Ca2+] mainly by stimulating bone

formation (i.e., deposition of Ca2+ in bone)

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18 April, 2011 7

Calcium Homeostasis

Figure 35-10, Koeppen & Stanton, 2010

Today’s Topics





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18 April, 2011 8

Renal handling of Calcium


• 99% of filtered Ca2+ (i.e., ionized & complexed) is reabsorbed

by the nephron

• PT – reabsorbs ~ 70% of filtered load

– 2 pathways - transcellular (20%) & paracellular (80%)

– transcellular : 2 steps :

• (1) Ca2+ diffuses down its electrochemical gradient across

the apical membrane through Ca2+ channels and into the

cell

• (2) at the basolateral membrane, Ca2+ is extruded from

the cell against its electrochemical gradient by a Ca2+-

ATPase


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18 April, 2011 9

• PT – reabsorbs ~ 70% of filtered load

– paracellular :

– passive, reabsorption of Ca2+ occurs via solvent drag along

the entire length of the PT and is also driven by the +ve

luminal voltage in the 2nd half of PT (i.e., diffusion)

– (see slide on “Paracellular Na+ reabsorption in the 2nd half of

PT)

– Ca2+ reabsorption occurs in parallel with Na+ reabsorption in

PT


• LoH – thick ALoH - 20%

– 2 pathways - transcellular & paracellular like in PT

– similar transcellular mechanism to PT

– BUT no solvent drag by the paracellular mechanism

– paracellular reabsorption of Ca2+ & Na+ occurs in parallel

because :

• most of Ca2+ reabsorption is via passive paracellular

mechanisms secondary to reabsorbtion of Na+

• +ve luminal voltage- (see slide on “solute transport in the

thick ALoH”


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18 April, 2011 10

• LoH – thick ALoH - 20%

– therefore, loop diuretics e.g. furosemide, which inhibit

reabsorption of Na+ by the thick ALoH � also � the +ve

luminal voltage � � driving force for Ca2+ reabsorption �

� reabsorption of Ca2+ via the paracellular pathway

– Ca2+ reabsorption occurs in parallel with Na+ reabsorption

in the thick ALoH


• DT – reabsorbs ~ 9%

– active reabsorption; transcellular only

– Ca2+ enters the cell across the apical membrane through

Ca2+-permeable epithelial ion channels (TRPV5/TRPV6)

– inside the cell, Ca2+ binds to calbindin

– calbindin-Ca2+ complex carries Ca2+ across the cell &

delivers Ca2+ to the basolateral membrane, where it is

extruded from the cell by either Ca2+-ATPase (PMCA1b) or

the 3Na+-1Ca++ antiporter (NCX1)


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18 April, 2011 11

• DT

– urinary Na+ and Ca2+ excretion usually changes in parallel, but not always because reabsorption of Ca2+ and Na+ by the DT is independent and differentially regulated

• e.g. 1. in the DT, Ca2+ reabsorption is regulated by its own hormone, PTH

• e.g. 2. thiazide diuretics � reabsorption of Na+ by the DT, BUT � reabsorption of Ca2+ by this segment

– NB : different effect of loop diuretics because of parallel reabsorption of Na+ & Ca2+ in thick ALoH

• CD – reabsorbs < 1%

• 1% excreted


Mechanism of Calcium

Reabsorption in the DT


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18 April, 2011 12

Regulation of Urinary Calcium Excretion

• several hormones and factors regulate urinary Ca2+ excretion (See Table 35-4; Koeppen & Stanton, 2010)

– PTH = the most important hormone that controls Ca2+ excretion, � reabsorption of Ca2+ by kidneys�� Ca2+ excretion

– changes in [Ca2+] in ECF also regulate urinary Ca++ excretion

• hypercalcemia �� excretion • hypocalcemia � � excretion


• hypercalcemia �� excretion by :

– (1) � PT Ca2+ reabsorption• reduced paracellular reabsorption because of increased

interstitial fluid [Ca2+]

– (2) � Ca2+ reabsorption by the thick ALoH• mediated by the CaSR located in the basolateral

membrane of these cells (the activity of the 1Na+-1K+-2Cl- symporter is decreased, thereby reducing the magnitude of the +ve luminal voltage)

– (3) suppressing reabsorption of Ca2+ by the DT by reducing PTH levels

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18 April, 2011 13


• Calcitonin

– stimulates reabsorption of Ca2+ by the thick ALoH & DT – less effective than PTH– importance in humans unknown

• Calcitriol

– either directly or indirectly � Ca2+ reabsorption by DT– less effective than PTH


• Changes in plasma [Pi]

– � plasma [Pi] (e.g., caused by increased dietary intake of Pi) ��PTH levels and thereby � Ca2+ excretion

– � plasma [Pi] (e.g., caused by dietary Pi depletion) has the opposite effect

• Changes in ECF volume

– alter excretion of Ca++ mainly by affecting reabsorption of NaCl and fluid in the proximal tubule.

– � ECF volume (volume contraction) �� NaCl and water reabsorption by the PT �� reabsorption of Ca2+ � �urinary Ca++ excretion

– � ECF volume (volume expansion) has the opposite effect

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18 April, 2011 14


• Acid – Base Status

– acidosis �� Ca2+ excretion

• acidosis inhibits the apical membrane Ca2+ channel

(TRPV5), �� reabsorption of Ca2+

– alkalosis �� Ca2+ excretion

• alkalosis stimulates the apical membrane Ca2+ channel

(TRPV5), �� reabsorption of Ca2+

Today’s Topics





Dr. J. Mohan

18 April, 2011 15

Phosphate : Functions

Phosphate

• important component of organic molecules e.g. DNA, RNA,

ATP, intermediates of metabolic pathways

• critical component of bone

• urinary buffer for H+ (maintenance of acid-base balance)

Phosphate : Distribution

Total Body Phosphate

• Bone matrix (86%)

• ICF (14%) – component of DNA & RNA; ATP & other metabolic

intermediates

• ECF (0.03%) - inorganic form- serves as buffer for H+

- normal plasma [Pi] = 4 mg/dL

- 10% in plasma = protein bound – unavailable

for ultrafiltration at glomerulus

Dr. J. Mohan

18 April, 2011 16

Phosphate Homeostasis

• maintenance of Pi homeostasis depends on 2 factors:

– (1) the amount of Pi in the body

– (2) the distribution of Pi between the ICF & ECF

• What determines the amount of Pi in the body ?

– total body [Pi] is determined by the relative amount of Pi

absorbed by the GI tract vs the amount excreted by the

kidneys

– absorption of Pi by the GI tract occurs via active & passive

mechanisms; Pi absorption increases as dietary Pi rises, and

it is stimulated by calcitriol


– despite variations in Pi intake (800 -1500 mg/day), the

kidneys keep total body Pi balance constant by excreting an

amount of Pi in urine = the amount absorbed by the GI tract

– renal Pi excretion is the primary mechanism by which the

body regulates Pi balance and thereby Pi homeostasis

Dr. J. Mohan

18 April, 2011 17


• what determines the distribution of Pi among the bone, the ICF &

ECF?

– PTH, calcitriol, and calcitonin regulate the distribution of Pi

between bone & ECF

– PTH & calcitriol � � release of Pi from bone (same hormones

that release Ca2+ from this pool)

– calcitonin � � bone formation and � �plasma [Pi]

– kidneys also regulate plasma [Pi] :

• � plasma [Pi] � � the amount of Pi filtered by the

glomerulus; kidneys normally reabsorb Pi at a maximum

rate, so, any increase in the amount filtered � � urinary Pi

excretion > GI reabsorption � � in net loss of Pi from the

body � � plasma [Pi]



Dr. J. Mohan

18 April, 2011 18

Today’s Topics





Renal handling of Phosphate


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18 April, 2011 19

Renal handling of Phosphate

• Phosphate that is not bound to plasma proteins = filtered acrossglomerular capillaries

• PT – reabsorbs ~ 80% of filtered load– mainly transcellular mechanism

– Na+ - phosphate cotransport (NPT) in apical membrane of PT cells : 3 symporters

• 1 transports 2Na+ with each Pi (NPT1)• 2 transport 3Na+ with each Pi (NPT2 & NPT3)• NPT2 is the most important • Pi exits across the basolateral membrane by a Pi-inorganic

anion antiporter

• DT – reabsorbs ~ 10% – mechanism of transport not yet known

• LoH & CD – negligible

• 10% excreted

Mechanism of Phosphate

Reabsorption in the PT


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18 April, 2011 20

Regulation of Urinary Phosphate Excretion

• several hormones and factors regulate urinary Pi excretion ( See Table 35-5; Koeppen & Stanton, 2010)

• PTH = the most important hormone that controls Pi excretion, �reabsorption of Pi by the PT � � Pi excretion

• PTH reduces Pi reabsorption by stimulating the endocytic removal of NPT2 from the brush border membrane of the PT

• dietary Pi intake also regulates Pi excretion by mechanisms unrelated to changes in PTH levels

– Pi loading � �excretion– Pi depletion � � excretion– changes in dietary Pi intake modulate Pi transport by altering the

transport rate of each NPT2 symporter & the # of transporters


• Changes in ECF volume

– alter excretion of Pi indirectly; may involve changes in levels of hormones other than PTH

– � ECF volume (volume contraction)� urinary Pi excretion

– � ECF volume (volume expansion) has the opposite effect

• Acid – Base Status

– acidosis �� Pi excretion

– alkalosis �� Pi excretion

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18 April, 2011 21

• Glucocorticoids

– glucocorticoids �� Pi excretion

– glucocorticoids � � delivery of Pi to the DT/CD by

inhibiting reabsorption of Pi by the PT

– this � delivery of Pi to the DT/CD enables the DT/CD to

secrete more H+ & generate more HCO3- ( Pi is an

important urinary buffer)


• Growth hormone

– growth hormone �� Pi reabsorption in the PT � �

excretion of Pi

• Dietary Pi

– � in dietary Pi enhances plasma FGF-23 (fibroblast growth

factor 23) levels, which by reducing NPT2 expression in the

apical membrane of the PT � � urinary Pi excretion and

also � � calcitriol levels


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18 April, 2011 22

• Chronic renal failure

– the kidneys cannot excrete Pi, BUT Pi absorption by the GI

continues � � accumulation of Pi in the body � � plasma [Pi]

– the � plasma [Pi] complexes with Ca2+ � �plasma [Ca2+]

– � plasma [Pi] � � production of calcitriol

– � production of calcitriol � � absorption of Ca2+ by the GI

tract, which further � plasma [Ca2+]

– � plasma [Ca2+] � � PTH secretion & Ca2+ release from

bone � osteitis fibrosa cystica (i.e., increased bone resorption

with replacement by fibrous tissue, which renders bone more

susceptible to fracture)


Actions of PTH

Figure 19-21, Germann & Stanfield, 2008

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18 April, 2011 23

Activation of Calcitriol

Figure 19-22, Germann & Stanfield, 2008

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Ca2+ PO4-homeostasis med apr 2011 LO 1102/Ca2_PO4... · Dr. J. Mohan 18 April, 2011 2 Physiology Objectives 1. Describe how the kidneys regulate the quantity and concentration of