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Calcium Phosphorus and Vitamin D metabolism in Renal Disease

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					Calcium, Phosphorus, and Vitamin D metabolism in Renal Disease and Chronic Renal Failure

萬芳醫院‧李盈靜
2008/8/12 Y.C.Li

94.07.26
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Definition of chronic kidney disease (CKD)
 Kidney damage for > 3 months, as defined by structural or functional abnormalities of the kidney, with or without  GFR, manifest by either:
 Pathological abnormalities, or  Markers of kidney damage, including abnormalities in the composition of the blood or urine, or abnormalities in imaging tests


GFR < 60 ml/min/1.73m2 for > 3 months, with or without kidney damage
K/DOQI (2002) Am J Kidney Dis
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Stages of CKD
Stage Description GFR (ml/min/1.732m2)

1
2 3

Kidney damage with normal or  GFR
Kidney damage with mild  GFR Moderate  GFR

>90
60-89 30-59

4
5

Severe  GFR
Kidney failure

15-29
<15

K/DOQI (2002) Am J Kidney Dis
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Kidney function test
• Inulin clearance – GFR=(UinXV)/(SinX1440) • Radioisotope • Serum creatinine – SCr=(GCr-TSCr-Ecr)/GFR • Urinary creatinine clearance – CCr= (UCrXV)/(SCrX1440) • Estimated GFR from equations – Cockcroft-Gault equation • CCr(ml/min)= (140-age)X(BW)X(0.85 if female)/(72XSCr) – MDRD study equation • GFR(ml/min/1.73m2)=170X(SCr)-0.999X(Age)0.176X(SUN)-0.170 X(Alb)+0.318X(0.762 if female)
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Stage Description

GFR (ml/min/1.73m2)

SCr (mg/dl) /(60 kg,170cm, 50y/o, M)

1
2

Kidney damage with normal or  GFR
Kidney damage with mild  GFR

>90
60-89

<0.9
1-1.3

3
4 5

Moderate  GFR
Severe  GFR Kidney failure

30-59
15-29 <15

1.4-2.6
2.7-5.2 >5.2

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What are calcium and phosphate
• The calcium and phosphate levels in the blood are kept in careful balance by the body’s hormones and chemicals. • This balance is like a see-saw (as one rises, the other often falls )

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Normal calcium metabolism
• DRIS:1000mg • Absorption of between 20 and 70%  Most efficient absorption: duodenum  bulk of absorption : jejunum and ileum (anatomic length) • Absorption by active transport ( duodenum, control of 1,25-(OH)2D3) facilitated diffusion
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• PTH mobilize calcium from bones to serum protect the serum ionized calcium. • Ca-reabsorption 65% -proximal tubule(independent hormone) 20~25% -ascending limb of loop of Henle (promoted by PTH)
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Normal phosphorus metabolism
• Phosphorus absorption occurring throughout the small intestine.(60~80%) • Uptake from the gut is due to a combination of an inhibitable sodium-phosphate cotransporter and diffusion down a concentration gradient. • Phosphate absorption : 1,25-(OH)2D3 on calcium transport enhanced intestinal alkaline phosphase actitity. PTH is lowering the tubular resorption of phosphate
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Normal vitamin D metabolism
• A group of steroid hormone • Two major provitamines  Ergosterol: derived from plants  7-dehydorchlesterol:derived from animal sterols • Absorption: upper duodenum with chylomicrons • Storage :associated with anα-globulin binding protein
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1,25-(OH)2D3 stimulates the formation of a calcium binding
protein (calbindin-D) in the intestinal mucosa

7-dehydorchlesterol Sunlight Previtamin D
1α-hydrxylase

25-hydrxylase 24-hydrxylase

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Normal parathyroid hormone (PTH) metabolism
• A polypeptide hormone (MW 9500;84AA), • Maintain the serum [Ca2+] with a relatively narrow (8.4~10.2mg/dl,10mg/dl=2.5mmol/l) • Set point of calcium pro-PTH PTH(84AA) • Pre-proPTH 6AA 25AA
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• PTH

In
liver

c-terminal peptide cleared by glomerular filtration

N-terminal peptide (intact PTH) • Ways of increasing [Ca2+] renal 1-αhydroxylase :increase 1,25-(OH)2D3 enhance GI absorption of Ca Ca resorption from bone (osteoblasts & osteoclasts which contain the PTH receptors) reabsorption from the distal nephron
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Effects of the failing kidney on mineral metabolism
• Secondary hyperparathyroidism • Hyperphosphatemia • Deficiency of 1,25-(OH)2D3

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Secondary hyperparathyroidism
Blood phosphorus rises too high
Excess phosphorus forms salts with calcium (metabolic calcification) Ca × P > 70

phosphorus and calcium ↓ Release of PTH
GRF progressively declines More PTH is needed Markedly elevated levels of PTH (hyperparathyroidism)
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The deposition of phosphorus and calcium salts in soft tissue (eyes, skin, lungs, heart, and blood vessels )

Phosphorus remains high and calcium remains low
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Hyperphosphatemia
• The fractional excretion of phosphate is maintained until the GFR falls below 30ml/min(CKD stage 4) • As renal failure advance, the serum phosphate levels rise • Hypocalcemia will occur both as a consequence of hyperparathyroidism (as a result of impaired GI calcium absorption on the face of falling 1,25-(OH)2D3 )
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Deficiency of 1,25-(OH)2D3
• At levels of GFR less than 20ml/min, 1,25(OH)2D3 levels are decreased or undetectable • It is important in the feedback inhibition of PTH formation and secretion • There might be have 1,25-(OH)2D3 receptors within the parathyroid gland (rat)

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Therapeutic interventions in predialysis patients
• Low protein diet(0.6g/kg/d) with lower phosphorus intake(6.5mg/kg/d) had a slower progression of renal disease • In practical terms it is difficult to gain complication with diets containing less than 800 mg/day

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Control of phosphate retention and secondary hyerparathyroidism in dialysis patients • Dietary intervention
phosphorus intake is closely related to the protein intake
(better way to estimate:17mg/kgBW/d regression equation:128+14(grams of protein in diet) all patients who undergo dialysis will require phosphatebinding medication

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Phosphorus binders
• Must be taken with meals • Aluminum-containing gels:carry a risk of toxicity and are therefore avoided (expect: hyperphosphatemia >12mg/d) • Magnesium - containing compound:concern over development of hypermagnesium in dialysis patient long term study:insufficient (but parathyroid hormone activity diminished)
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• Calcium - containing compound: Calcium carbonates (most widely, 6-20g/d) hypercalcemia: HD 25% PD 60% Calcium citrate : not used with aluminum salts (enhance aluminum absorption) Calcium acetate:bind phosphorus over a wide range of PH values • Severe constipation is a potential ris of excessive consumption • Constipation is often the reason why patients do not take the prescribed phosphorus binders
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New medicine of Phosphorus binders
• Sevelamer hydochloride---Renagel(磷能解) (1998 FDA) reduce serum phosphorus without raising serum calcium because of its composition (no Aluminum, calcium and other metals ion) • it exchanges the ion way and absorbs the phosphoric acid in the intestines by the similar resin. • National Health Administration has already authorized this listing licence of medicines. It is expected that Renagel will be listed formally inTaiwan in August of 2005 of this year.
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Dialysis
• Do not achieve adequate phosphorus clearance to maintain normal serum phosphorus
Daily clearance of P

• Daily intake:1000~1200mg (felman) CAPD 324mg HD 252mg 1200~1400mg(man) • Calcium concentration of dialysis solutions has an important role to play in maximizing other therapeutic modalities .(↓ambient dialysate calcium concentration to 2.5 mEq/L)
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The use of 1,25-(OH)2D3
• Oral 1,25-(OH)2D3 acts to increase calcium and phosphate absorption form the GI tract in dose dependent. • Oral 1,25-(OH)2D3 was fraught with problems related to hypercalcemia and an elevated calcium/phosphate product

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Parathyroidectomy
• Indications for parathyroidectomy systemic calciphylaxis (peripheral ischemic necrosis involving digits, skin over the thighs and buttocks, with associated medial calcinosis of arteries) • Patients who are considered to have high operative risk, it may be possible to embolize the parathyroid glands radiocontrast media
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<30mg/dl

>30mg/dl

5.2mg/dl
5.9mg/dl

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10~65pg/ml

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