Calcium and Phosphate

Function Ca2+, Mg2+ PO2- in ECF, Know physiologocal and pathological states for mineral regulation, PTH, calcitriol,calcitonin reg of Ca2+ and PO42-

Calcium summary

Hypocalaemia

• Hypocalaemia

• PTH secreted

  • Bone → increased resorption

    • (both calcium and phosphate released into blood)

  • Kidney → increase reabsorption PCT

    • less phosphate reabsorption → increased secretion

  • Kidney increases 1,25 D3 → increased gut absorption

    • both reabsorped from gut but phosphate excreted

  • 1,25 D3 → acts on bone (synergistic with PTH)

  • higher plasma calcium → negative feedback

    • Parathyroid gland → inhibits PTH secretion

    • 1, 25 D3 → inhibiting PTH secretion

Calcium summary

Hypercalaemia

• Hypercalaemia

• Calcitonin released (parafollicular C cells)

  • acts on bone → reduce resorption → less Ca2+ & phosphate released to blod

• → low PTH secretion due to low calcium

• hence low phosphate → FGF-23 made

• means inactive 24,25DHCC (D3) produced

  • stimulates PTH inhibition (via phosphate and FGF-23)

  • bone inhibition

  • decreases gut absorption → lost to faeces

  • DCT reabsorption inhibition → decreased transport protein expression

    • decreased activity of Na+/Ca2+ exchanger basolaterally

    • PCT influenced by PTH in terms of phosphate but DCT for more calcium reabsorption

• Decreased plasma Ca2+ levels

• when phosphate higher due to no PTH → FGF-23 broken down

Calcium role

• Stabilises excitable cell membranes

  • Ca²⁺ binds to negative charges CSM → neutralises CSM → less likely small depolarisations reach the threshold potential

• Second messenger via ER release

• Clotting cascade → CF activation

3 forms

• albumin bound

  • alkaline → Ca2+ bind to albumin (less ionised (H+) molecules in plasma)

  • acidic → H+ and ions bound to albumin

    • competition btw anions and cations

• complexed → plasma phosphate (least → 10%)

• ionised (majority)→ free form → closely regulated (hormones)

Mineral homeostasis

intake = requirement + excretion

• high requirements: growth, lactation, pregnancy

• more difficult for Ca2+ and PO42- absorbed from GI (Na+ easier)

• compartment distribution → deficit uses bone storage → redistribution

• mostly kidney excretion

Dietary calcium

• upper small intestine absorption (caltriol upregulates absorption)

  • Calcitriol → expression of Ca2+ binding protein in intestinal cells

• inefficient → 80% lost in faeces

• lactation → stimulates increased uptake

• ‘steaming up’ TOO EARLY in dairy cows (leading up to peak lactation)

  • milk fever = hypocalcaemia

  • reduced Ca2+ if stimulation too early

  • diet provides high Ca2+ → PTH and calcitriol never stimulated

Release of Ca2+ from bone

Osteoclasts

• release Ca2+ and PO42-

• osteoblasts → osteoid → mineralisation

• bone turnover = balance

Ca2+ and Kidney

free and COMPLEXED filtered

70% passive cotransport in PCT

high blood pressure → higher GFR → increased Ca2+ excretion

active reabsorption via PTH in DCT

No tubular sectetion

Stones = calcium oxalate or sulfate

• free Ca2+ solubility aided by presence of anions (competing for albumin)

Phosphate 1&2

Role → organic molecules → phosphorylation → ATP energy store

• urinary buffer

• plasma conc not as tightly controlled as Ca2+

• high phosphate → less Ca2+ dissolved → form complexes

  • more solid Ca2+ → mineralisation

• Phosphate and Ca2 daily turnover → lost in faeces, urine, milk

  • or stored in bone

• Ca2+ and phosphate close to limit (being complexed) in ECF

  • soft tissue calcification/precipitation

  • Protection → calciprotein particle evolution

    • CPPs trap the minerals in a safe, soluble form → phagocytosis (macrophages + liver) → before deposited in tissue

      • Kidney failure

        • more phosphate + fewer factors for suspension → precipitation

        • vascular calcification → hard to control phosphate

          • what kills dialysis patients

• absorbed → active vit D from diet

• bound to proteins (organic phosphate)→ digested before phosphates release → no rise on phosphate after meal

• UNBOUND → passive diffusion → rise following meal

  • Multivalent cation (aluminium) → complexes to phosphate → inhibits phosphate absorption from the gut

• After feeding → insulin → glucose phosphorylation

• PTH release Ca2+ and phosphate from bone

Renal handling of phosphate & Phosphate excretion rate factors

urine: H+ + monohydrogen phosphate → dihydrogen phosphate → increases pH

• Na2HPO4 + H+ → NaH2PO4 + Na

60% phosphate in diet → absorbed active transport → PCT cotransport with Na

• Na/K (baslolateral) - maintains electrochemical gradient

• normallt in urine

PTH → reduces phosphate transport → more excreted in urine → lowers phosphate plasma levels

• load of ions → PTH decreases NUMBER of phosphate transporters in PCT

  • excess phosphate in filtrate excreted → transporters saturated

  • high GFR → more excretion

    • high plasma phosphate → more excreted

• but conserves Ca2+ in DCT → promotes reabsorption

Parathyroid tumour → more PO42- excreted

FGF-23 - may become diagnostic marker in mineralised bone disorder with kidney disease

Magnesium 1&2

Major intracellular cation

60% → bone

40% in plasma

• protein bound

• complexed to small cations (least)

• 64% free → hydrated cations

Balance not well understood

• small intestinal absorption → normally passive

• active in ruminants → grass staggers if deficient

Renal

• only 20-30% filtered load absorbed in PCT

• thick ascending loop → major site of absorption → PTH reg perhaps?

• Aldosterone increases Mg excretion

  • Hypomagnesemia associated with hypocalaemia and high Na+ in blood → digoxin poisoning

Hormone summary

• regulates plasma conc → Ca2+ important (narrow range)

  • gut absorption, distribution, excretion

• PTH

  • increases Ca2+ reabsorption

  • decreases PO42- absorption (reducing cotransporter numbers)

• Active D3 → gut absorption

  • expression of Ca2+ binding protein in intestinal cells

  • multivalent cation → inhibits phosphate absorption

  • protein bound not absorbed

  • unbound is passive diffusion

• Calcitonin

  • protects against hypercalaemia

  • active in young animals and salmon (potent calcitonin salt water → fresh water)

• FGF-23

  • mechanism for sensing specific phosphate levels unknown

  • needed for negative feedback to reduce or increase → not clear

PTH

84 amino acids

• chief cells of parathyroid gland

• 2 internal, 2 external (bilateral)

• externals on cranial thryoid

  • high risk hypocalaemia when removal of thyroids → removes internals + BLOOD SUPPLY to externals

Effects

• secretion regulated by Ca2+ conc

• Calcitriol and FGF-23 inhibit PTH via -ve feedback

  • severe hypomagnesemia → may inhibit PTH secretion → hypocalcaemia in ruminants

• promotes high Ca2+ reabsorption, PO42- excretion

• bone resorption

• stimulates SYNTHESIS of calcitriol → gut absorption

• promotes Mg absorption from loop of Henle

Vit D} cholecalciferol → calcediol (liver)→ calcetriol (kidney)

• cats cannot synthesis from skin → diet only

• D2 → calciferol → irradiation of ergo-sterol (plant form)

• D3 → cholecalciferol → irradiation (sunlight) of 7-dehydrocholesterol [provitD]

Main role → calcium and phosphate intestinal absorption

Diet/skin → cholecalciferol

• → calcidiol (liver - unregulated)

  • 25-hydroxycholecaciferol

• → calcitriol (kidney - regulated)

  • active calcitriol = 1 alpha hydroxylation process

    • 1,25 de-hydroxy-cholecalciferol

      • phosphate or FGF-23 may inhibits 1 alpha hydroxylation enzyme

      • PTH enhances reaction

  • inactive = 24 hydroxylation process

    • 24,25 de-hydroxy-cholecalciferol

      • phosphate or FGF-23 stimulation

      • PTH inhibition

Stimulates synthesis of osteocalcin → major Ca2+ binding protein

Negative feedback - inhibts PTH

But synergistic with PTH in bone and kidney

Calcitonin

• C cells of thyroid or ultimobranchial bodies

• reduces blood Ca2+ → decreases osteolysis and increases osteogenesis

• important in growing mammals

• not as important in adults

FGF-23

• produced by osteoblasts and osteocytes in response in order to increase ECF phosphate (and calcium)

  • not immediate increase in response to high ECF

  • not stored only processed

  • stimulated by low phosphate

    • negative feedback → high phosphate → FGF-23 broken down

• Inhibits phosphate entry

  • from gut → inhibiting calcitriol (1,25 + formation of 24,25)

  • bone → PTH inhibition (prevents resorption)

  • inhibits proximal tubular reabsorption (PTH inhibited)

• Needs cofactor klotho to work

  • calcification + early death due to excess PO4

  • Klotho antiaging

  • regulation knowledge incomplete

Kidney pathology → disease

Cat endstage kidney disease → emasciated

white chalky deposits →nephrocalcinosis

• unable to control phosphate while GFR falls → build up of phosphate in plasma

• reduces Ca2+ → complexes form

• stimulates PTH production

• bone resorption releases Ca2+ and more phosphate (repeats)

• kideys progresses to end stage