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Actualités sur l’Hyperphosphatémie et

le Métabolisme Minéralo-Osseux de

l’Insuffisance Rénale Chronique

Dr Pablo Ureña TorresClinique du Landy23, rue du Landy. 93400 Saint [email protected]

Phosphate Metabolism

Phosphorus

- One of the most abundant anions in the body

(500 to 800 g or 20-30 moles)

- Mostly bound to oxygen (PO4 or Phosphate)

Functions- Mineral : Teeth/Bone. Hydroxyapatite (Ca10(PO4)6(OH)2

85% in bone (500 à 800 g)- Reserve and transfer of energy (ATP)- pH regulation- Intracellular signal transduction (second messenger)- Cellular membrane composition (phospholipids)- Nucleic acids constituent- Oxygen dissociation from Hb (2-3 DPG),NAD coenzyme, etc

Phosphate Distribution

Bone

500

0

1000A

mo

un

t (g

)

Cells(Intracellular)

Fluids(Extracellular)

600 g20 000 mmol

63 g 0.5 g

- The most abundant anion in the body (700 g = 23 000 mmol)- Intracellular (80-120 mmol/l IC and only 1-1.5 mmol/l plasma)

- Minimum needs in a healthy adult : 300 mg/day

85-90 %

Plasma = 0.02% = 130 mg

Hydroxyapatite

9 % 1 %

De Boer IH, et al., NHANES III. AJKD 53:399-407, 2009

Serum Phosphate Concentration

0,80 0,80 0,80 0,80 –––– 1,45 mmol/L1,45 mmol/L1,45 mmol/L1,45 mmol/L (2.6 to 4.6 m/dL)(2.6 to 4.6 m/dL)(2.6 to 4.6 m/dL)(2.6 to 4.6 m/dL)Inorganic Phosphate =Orthophosphate et pyrophosphosphate

Total Plasma Phosphate = 3,9 mmol/l

15,513 subjects

3.2

3.7

Fasting

Non fasting

Serum phosphorus (mg/dL)

Morning Afternoon Evening

3.3

3.4

3.5

3.6

Serum Phosphate Concentration

De Boer IH, et al., NHANES III. AJKD 53:399-407, 200915,513 subjects

NHW

Serum phosphorus (mg/dL)

3.2

NHB

Age Gender Race/Ethnicity

3.3

3.4

3.5

3.6

H

Men

Women20-29

30-39

40-49

50-5960-69

70-79

80-90

Plasma Phosphate Regulation

- Parathyroid hormone (PTH)

- Vitamin D

HORMONES

- Phosphatonins (FGF23)(Fibroblast Growth Factor 23)

sFRP4, FGF7, MEPE

- Klotho

ORGANS

Bone

Intestine Kidney

Parathyroid glands

Plasma Phosphate Regulation

Intestine

1400 mg/d(Diet)

500 mg(Feces)

1100 mg

200 mg

900 mg(Net

absorption )

ExtracellularPool 550 mg

(Plasma pool130 mg or

0.80-1.45 mmol/L)

60-70%

(NPT2b)

?2Na+

HPO42-

85%

15%

PO4

Kidney

Bone

FGF23

Parathyroid glands

PTH

Active Vitamin D

NPT2aNPT2cKlotho

1400 mg900 mg(Urine)

NET INTESTINAL PO4 ABSORPTION

mmol/day

0 10 20 30 40 50 60 70 80 90 100

0

-10

-20

10

20

30

40

50

60

70

NET IN

TESTINAL PO4 ABSORPTION

mg/day

-500

0

500

1000

1500

2000

DIET PO4, mg/day

0 500 1000 1500 2000 2500 3000

Net PO4 Abs, mmol/day = -5 + 0.77*diet PO4, mmol/dayr = 0.95

DIET PO4, mmol/day

Lemann J and Favus M, Primer JBMR 1999

Intestinal Phosphate Absorption

Rufino M., et al., Nephrol Dial Transplant 61:94, 1998

Relationship between Protein Intake and Phosphate Intake

APPORTS PHOSPHATES

(mmol/jour)

0 50 100 150 200 250 300 350

0

20

40

60

80

100

120

140

y = 0,4316xR2 = 0,8252N = 559

APPORTS PROTIDIQUES(g/jour)

100 g protéines = 43 mmol phosphates

Phosphate Intake,

Demography, Cardiovascular Risk Factors, and Kidney Function Explain Only

12% of Variation in Serum

Phosphate Levels

(NHANES III)

De Boer IH, et al., AJKD 53:399-407, 200915,513 subjects

Frequence of Hyperphosphatemia in CKD Patients

PTH > 60 pg/ml Hb < 11.0 g/dL Bicarbonate < 22 mM Potassium > 5.0 mM Phosphate > 1.38 mM

Moranne O. , and the Nephrotest Study Group. JASN 2008

25 %

Hyperphosphatemia in CKD Patients

Martinez I et al. Am J Kidney Dis 1997;29:496–502

*P < 0.05, compared with CrCl ≥ 50 mL/min

0

mm

ol/

L

Creatinine clearance (mL/min)

0.75

1.00

1.25

1.50

Serum ionized calcium

Phosphorus

0.50

0

5.4

10.8

16.2

21.6

pm

ol/

L

iPTH

*

*** *

*

Creatinine clearance (mL/min)

CKD Patients not on Dialysis Show a Greater Prevalence of Coronary Artery Calcification than Non CKD Patients

1- Kramer H et at., J Am Soc Nephrol 16:507-513, 2005

2- Russo et al. Am J Kidney Dis 44:1024-1030, 2004

Prevalence (%)

0General

Population

20

40

60

80

CKDStage 4

IncidentCKD Stage 5

PrevalentCKD Stage 5

100

18

40

66

83

Mean age (yrs) 44 52 58 57

3- Block G et at., Kidney Int 68:1815-1824, 2005

4- Chertow G et al. Kidney Int 62:245-252, 2002

Serum Phosphate Levels and Coronary Artery Calcification

Tomiyama C et al. Nephrol Dial Transplant 21:2464-2471, 2006

Serum Phosphate Levels (mg/dL)

5.5

3.0

3.5

4.0

4.5

5.0

CACS ≤ 400n = 74

3.7 mg/dL(1.20 mmol/L

4.2 mg/dL(1.40 mmol/L

P = 0.013

CACS ≥ 400N = 22

Patients with CKD Stages 2-4

- Nishioka et al. N Engl J Med349:e12, 2003

- Phosphatemia and CAC ScoreTomiyama C et al. NDT 21:2464-2471, 2006

Hyperphosphatemia and Vascular Calcifications

CKD Patients not on Dialysis Are More Likely to Die than Progress to ESRD Dialysis Therapy

RRT = Renal Replacement Therapy

Keith D et al., Arch Intern Med 164:659-663, 2004

High Serum Phosphate Levels are Associted with Increased Risk of Mortality in CKD Patients not on Dialysis

Kestenbaum B et al., J Am Soc Nephrol 16:520-528, 2005

L’Axe Fibroblast Growth Factor 23-

Klotho dans l’Homéostasie du

Phosphate en Cas de MRC

Rein : FGF23/Klotho/NPT2a

Intestin : NPT2b

Parathyroïde : Klotho/FGFR1/FGF23

Circulating FGF23 Molecules

Urena P et al. Kidney Int 73:102-107, 2008Dr D. Prié, personal data

- Circulating at low concentration in normal subjects

0 10 20 30 40 50

FGF-23 intact (pg/ml)

% of subjets

0

5

10

15

20

25

30

Intact FGF23 by ELISA from Kainos Lab.Normal mean values : 29 ± 28 pg/ml

Normal range 0-40 pg/ml

C-terminal FGF23 by ELISA from Immutopics Lab.Normal mean values : 57 ± 43 rU/ml

Normal range 0-130 rU/ml

50

75

25

0

100

FGF23 (rU/ml)

C-Terminal FGF-23

Circulating FGF23 in CKD is Mainly the Intact Molecules

Shimada et al. WCN-ERA-EDTA 2009. Unpublished data

Dr D. Prié, personal data

DFG < 80 ml/min, l’augmentation du FGF23 est corrélée à l’augmentation de la phosphatémie et à la diminution de la calcitriolémie.

Serum FGF23 Levels Increases Very Early Patients with Chronic Kidney Disease

Log(FGF23)

DFG ml/mn

0,5

1,5

2,5

3,5

4,5

5 35 65 95 125 155 185

The Renal Expression of Klotho mRNA isDown-Regulated in CKD Patients

Koh N et al. BBRC 280:1015-1020, 2001

RNAse protection assay

kl s = secreted formKl m : membrane form

F1-F9 = CRF kidneysC1-C3 : Control kidneys

Hasegawa et al. ASN 2003 (JASN 2003 14 40A)Shigematsu T et al., Am J Kidney Dis 44:250-256, 2004

Serum FGF23 Levels Correlate with the Urinary Fractional Excretion of Phosphate (DFG < 80 ml/mn)

The maximum tubular reabsorptive rate of phosphate correlated negatively with serum FGF-23 concentrations(r2= 0.460). However, the amount of daily urinary phosphate excretion was significantly less in patients with a Ccrless than 30 mL/min (<0.50 mL/s; P < 0.01), whereas their circulating FGF-23 levels were significantly greater.

In CKD animals the injection of antibodies against FGF-23 normalizes serum calcitriol levels

Serum FGF23 Levels Correlate Negatively with Calcitriol and Positively with PTH (DFG < 80 ml/mn)

Hasegawa et al. ASN 2003 (JASN 2003 14 40A)

Manipulating Serum Phosphate with Phosphate Binders Can Reduce Serum FGF23 Levels in Uremic Rats

Nagano N et al. Kidney Int 69;531-537, 2006

Mineral Metabolism in Patients with Mild Chronic Kidney Disease: Origin of Secondary Hyperparathyroidism

Isakova T et al. JASN, 2008

PTH

CKD II-III

Calcemia

Normal

FE Ca

FGF23Normal = 50 pg/mlCKD II-III = 75 pg/ml

Non Progressors Progressors

FGF23 35± 58 69± 70

(pg/ml)

Phosphate 1.04 ± 0.38 1.25 ± 0.27

(mmol/ml)

PTH 6± 5 22 ± 20

(pg/ml)

Fliser D et al. JASN 18:2601-2608, 2007





Intestin : NPT2b


NPT2b and Intestinal Phosphate Absorption in CKD

Phosphate (P32) Uptake NPT2b mRNA

Marks J et al. Kidney Int 72:166-173, 2007

Sabbagh Y et al., ASN 2008

Intestinal Phosphate Absorption in NPT2b-/-Mice

[SA-FC343] Importance of Npt2b in Phosphate Homeostasis: Characterization

of the Conditional Npt2b Knockout MouseYves Sabbagh, Stephen P. O'Brien, Wenping

Song, Adam Stockmann, Cynthia Arbeeny, Susan C. Schiavi. Renal Sciences, Genzyme Corporation,Framingham, MA

Standard diet (0.6% of Phosphate)NPT2b-/- mice have : - hypophosphatemia

- hypophosphaturia2 folds more phosphate in the feces than the WT mice

Under low phosphate diet (0.02% of Phosphate), after intestinal administration of 1.6 M of phosphate

- NPT2b-/- mice absorb 40-50% less phosphate than WT- Nicotinamide decrease by 40% intestinal phosphateabsorption in WT mice but have no effect in NPT2b-/-

Nicotinamide Decreases Serum Phosphate Concentration in Dialysis Patients

Takahashi Y et al. Kidney Int 65:1099-1104, 2004

Eto N et al., Nephrol Dial Transplant 20:1378-1385, 2004

2Na+

HPO42-

?

(NPT2b)

2Na+HPO42-

SGLT-1

Evidence For a Intestinal Phosphate Sensor

Berndt T et al. PNAS 104:11085-11090, 2007





Intestin : NPT2b


FGF23/FGFR1/Klotho on Parathyroid Glands

Ben-Dov I et al. JCI 117:4003-4008, 2007

Diminution de l’Expression de la Protéine Klotho dans les Glandes Parathyroïdes

Komabe, Fugakawa, et al. WCN-ERA-EDTA 2009. Unpublished data

Diminution de l’Expression de la Protéine FGFR1 dans les Glandes Parathyroïdes

Komabe, Fugakawa, et al. WCN-ERA-EDTA 2009. Unpublished data

Serum FGF23 Levels Predict the Severity of Secondary Hyperparathyroidism and Its Response to Vitamin D

100 patients followed for 2 years

Nakanishi et al. Kidney Int 67:1171, 2005

62 patients

24 weeks of calcitriol

treatment

FGF23 before treatment

Response + -

Kazama et al. Kidney Int 67:1120, 2005

Schematic Representation of Factors Regulating Serum Phosphate Levels

Urena P., el al.Kidney Int 71:730-737, 2007

Parathyroids

Kidney

Intestine

Bone

Phosphorus

PhosphorusElimination

PTH

FGF23

?

DominiquePrié Marie

Courbebaisse

ChristineSalaün Alice

RousseauChristineLeroy

DavidDeBrauwere

ValérieBoitez

LaurentBeck

GérardFriedlander

PabloUreña

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