Calcium and Phosphate - Echo360€¦ · Calcium and Phosphate ... metabolism in CKD Cascade of disordered mineral metabolism in CKD Analyte concentration >10,000 1000 90 60 30 4 0

7/20/2015

1

Calcium and Phosphate

Myles Wolf, MD, MMSc

The “Players”

ORGANS:

•Parathyroid

•Bone

•Gut

•Kidney

HORMONES:

•Parathyroid Hormone (PTH)

•(PTH-related Peptide)

•Calcidiol (25-OH-D3)

•Calcitriol (1,25-OH-D3)

•Fibroblast Growth Factor-23

•Klotho

2

Calcium

•Needed for skeleton

•Excitable tissues

•Action potentials

•Cardiac and muscle contractility

3

Calcium balance

4Goltzman D. Endotext

GI absorption: ~20%

Renal reabsorption: ~98%

FeCa: ~2%

7/20/2015

2

Intestinal absorption of calcium

5Bikle, D. Endotext

Transporters are highly dependent

on 1,25D

Tubular handling of calcium: TAL

6Unikowski B. http://alexandria.healthlibrary.ca

Inhibitors: furosemide, activation of CaSR

Tubular handling of calcium: DCT

7

Unikowski B. http://alexandria.healthlibrary.ca

Phosphate

•Phospholipid bilayers

•Cell signaling

•Glycolysis

•ATP

•DNA, RNA synthesis

•Unloading O2 (2,3-BPG)

8

7/20/2015

3

Phosphate Balance

Hruska KA et al. Kidney International (2008) 74, 148–157

Renal reabsorption: ~85-90%

FeP: ~10-15%

Serum P=40 mg/l; GFR 150L/d

800 mg/6000 mg = 13%

GI absorption: ~67%

9

Intestinal Phosphate Absorption

• Linear absorption, nonsaturable function of intake

• Approximately 60-75% of intake

• Primarily in small intestine

• 1,25(OH)2D3 stimulates absorption via NaPi2b

• Most phosphate absorption vitamin D independent

via paracellular transport

10

Prie D et al. Kidney International (2009) 75, 882-889.

Renal Phosphate Handling: Proximal Tubule

Apical

Basolateral

11

Main sodium-phosphate co-transporters

• Gut: NPT2b

− Active transport of phosphate

− Less important than passive phosphate transport

− Human deletion has no phosphate phenotype

• Kidney: NPT2a, NPT2c

− In PCT

− NPT2a mutations: Fanconi syndrome

− NPT2c mutations: HHRH syndrome

− Relative roles vary in mammalian species

12

7/20/2015

4

PTH

• Primarily regulates: ionized calcium

• Main stimulus: hypocalcemia

• Main effects: raise serum calcium

− Stimulates bone resorption

− Stimulates 1,25D production (CYP27B1)

− Inhibits CYP24

− Inhibits calciuria

− Stimulates phosphaturia

• Hyperphosphatemia stimulates parathyroid gland hyperplasia

13

1,25-dihydroxyvitamin D

• Primarily regulates: gut mineral absorption

• Main stimulus: PTH

• Main inhibitor: FGF23

• Main effects:

− Augment gut calcium absorption

− Augment gut phosphate absorption

− Feedback inhibition to suppress PTH

− Stimulates FGF23

− Stimulates 24-hydroxylase

14

Vitamin D synthesis and hydroxylases

15Bikle, D. Endotext

Vitamin D Stores and PTH

PT

H (

pg

/ml)

25 (OH) D (ng/ml)

inflection•N = 1,536 menopausal women on

osteoporosis Rx

•18% had D levels <20

•Inverse association between D

and PTH

RISK FACTORS for D deficiency: older age, non-white race, obesity, low exercise,

low education, insufficient supplementation, certain medications, lack of

discussion with MD about vit DHolick et al, J Clin Endocrinol Metab. 2005; 90: 3215-24. 16

7/20/2015

5

Prevalence of Secondary Hyperparathyroidism by Vitamin D Stores

% w

ith

PT

H >

40

pg

/ml

25 (OH) D (ng/ml)

Holick et al, J Clin Endocrinol Metab. 2005; 90: 3215-24. 17

FGF23

• Primarily regulates: ???

• Main stimulus: 1,25D and high dietary phosphate

• Main effects: lower serum phosphate

− Stimulates phosphaturia

− Inhibits 1,25D production (CYP27B1)

− Stimulates CYP24

− Inhibits PTH

• Direct effects on bone: ???

18

Classic Physiological Actions of FGF23

Wolf M, J Am Soc Nephrol 2010; Wolf M, Kidney Int 2012; Rodriguez-Ortiz ME, JASN 2012

+_

_+

Phosphaturia

+

+

Dietary phosphate

intake+

–?

CaP+?

+?

_+

1,25D

FGF23

PTH

19

FGF23 in normal physiology

• 29 healthy males subjected to

low phosphate diet with

phosphate binder, followed by

phosphate loading

• FGF-23 decreased with low

phosphate and increased with

phosphate load

20Ferrari, J Clin Endocrinol Metab, 2004

Pi

inta

ke

FG

F2

3Tm

Pi/

GF

R

7/20/2015

6

Wolf, J Am Soc Nephrol 2010 21

Illustrative Case Studies: CKD

• Features:

− Low 1,25D

− Variable 25D

− High PTH

− High FGF23

− Low klotho expression

− Low normal calcium

− High normal phosphate

22

23

Calcitriol Deficiency and SHPT in CKD

*Abnormal PTH based on Kidney Disease Outcomes Quality Initiative (K/DOQI) Clinical Practice

Guidelines for Bone Metabolism and Disease in CKD. 2003.Kates et al. Am J Kidney Dis. 1997;30:809-813; Martinez et al. Am J Kidney Dis. 1997;29:496-502; Martinez et al. Nephrol Dial

Transplant. 1996;11(suppl 3):22-28; St. John et al. Nephron. 1992;61:422-427.

GFR (mL/min/1.73 m2)

50

40

30

20

10

0105 95 7585 65 45 35 1555 25

1,25D

Lower range

of 1,25D

10

20

30

40

50

60

70

80

90

100

Pa

tie

nts

Wit

h E

lev

ate

d P

TH

(%

)*

CKD Stage 2 Stage 3

Ca

lcit

rio

l

1,2

5(O

H) 2

D3

(pg

/mL)

Stage 4●●●●

●●●●

●●●●

●●●●

●●●●

●●●●●●●●

●●●●●●●●

●●●●

●●●●

23

FGF23 by CKD stage in CRIC

350

400

300

200

150

50

0

FG

F23,

RU

/ml

105

161

256

145

76

154

96

239

174

388

110

249

All < 30 30 – 44 ≥ 45

100

250

Estimated glomerular filtration rate, ml/min/1.73m2

Isakova et al. Kidney Int 2011

N = 1649

P = 3.5

N = 1472

P = 3.7

N = 752

P = 4.1

N = 3879

P = 3.7

24

7/20/2015

7

FGF23 and PTH in CRIC

25

0

10

20

30

40

50

60

70

80

90

100

<20 20-29 30-39 40-49 50-59 60-69 ≥70

% o

fP

op

ula

tio

n

Estimated glomerular filtration rate, ml/min/1.73 m2

Hyperphosphatemia, serum phosphate ≥ 4.6 mg/dl

Secondary hyperparathyroidism, PTH ≥ 65 pg/ml

FGF23 excess, FGF23 ≥ 100 RU/ml

Isakova et al. Kidney Int 2011

Disordered Mineral Metabolism in Rat CKD

Hasegawa et al. Kidney Int 2010 26

Effects of Anti-FGF23 Antibodies

Normalize 1,25DIncreased serum P

Hasegawa et al. Kidney Int 2010 27

Normal PTH range

1. Increased FGF23 is the earliest alteration in mineral

metabolism in CKD

Cascade of disordered mineral metabolism in CKD

An

aly

te c

on

cen

tra

tio

n

>10,000

1000

90

60

30

40

>90 75 60 45 30 15 0 3 6 >12

GFR (mL/min/1.73 m2)

Time post-transplant (months)

1,25D

(pg/mL)

cFGF23

(RU/mL)

12 3

4

Dialysis

Wolf M. J Am Soc Nephrol 2010

PTH

(pg/mL)

P

(mg/dL)

Normal P range

2. Gradually increasing FGF23 levels cause early decline in 1,25D levels

3. This frees PTH from feedback inhibition, leading to secondary

hyperparathyroidism

4. All these changes occur long before increases in serum P

levels are evident

28

7/20/2015

8

FGF23 and mortality in incident ESRD

Gutierrez et al N Engl J Med 2008 29

FGF23 and mortality in CKD 2-4:266 events, 20.3/1000 person-years

30

Cu

mu

lati

ve

in

cid

en

ce

of

de

ath

, %

Years of follow up

0 1 2 3 4 5

0

10

20

FGF23 Quartile 1: 1.0; Referent

FGF23 Quartile 2: 1.3; 0.8–2.2

FGF23 Quartile 3: 2.0; 1.2–3.3

FGF23 Quartile 4: 3.0; 1.8–5.1

Isakova et al. JAMA 2011.

FGF23-Induced Hypertrophy of NRVM:FGFR-dependent but klotho independent

31

klotho

GAPDH

GAPDH

FGFR1

FGFR4

FGFR2

FGFR3

L CM BlH

Br K CM BlH

10010 25

FGF2

FGF23

Controlng/mL

Faul, Amaral, Oskuei et al. J Clin Invest. 2011.

Blocking FGFRs prevents LVH in uremic rats

32Faul, Amaral, Oskuei et al. J Clin Invest. 2011.

Sham 5/6 nephrectomy5/6 nephrectomy+

PD173074

0

50

100

150

200

250

Sh

am

5/6

5/6

+ P

D

SBP

0

200

400

600

800

1000

1200

1400

1600

Sh

am

5/6

5/6

+ P

D

FGF23

7/20/2015

9

Anti-FGF23 Ab: Increased calcification & mortality

33Shalhoub V, J Clin Invest 2012

Disordered phosphate homeostasis and cardiovascular disease in CKD

34Scialla J, Wolf M. Nat Rev Nephrol 2014

Illustrative monogenic case studies 1

• Biochemical phenotype:

− Rickets

− Hypophosphatemia

− Normal serum calcium

− Low FGF23

− Normal PTH

− Hypercalciuria

− High 1,25D

• Where is the primary lesion?

35

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH)

• Key finding: Hypophosphatemia that is not FGF23 or PTH

mediated

• Primary defect: NaPi2c deficiency

• Phosphate wasting � rickets

• FGF23 suppression � 1,25D activation

• Hypercalciuria

• NaPi2a deficiency was recently described in humans for

the first time (Magen D, N Engl J Med 2010)

36

7/20/2015

10



− Ectopic calcification

− Hyperphosphatemia

− Normal serum calcium

− Low intact FGF23

− Low PTH

− Hypercalciuria

− High 1,25D


37

Tumoral calcinosis: FGF23 deficiency

• Key finding: hyperphosphatemia with low FGF23 and low

PTH

• Absence of biologically active FGF23 or FGF23 action due

to klotho deficiency � elevated 1,25D

• Positive calcium balance + defective phosphate excretion

= calcifications

• Elevated 1,25D and calcium absorption suppress PTH and

permit hyperphosphatemia

38



− Hypercalcemia

− Normal serum phosphate

− High-normal PTH

− Hypocalciuria

− High 1,25D


39

Familial hypocalciuric hypercalcemia (FHH)

• Key finding: hypercalcemia with non-suppressed PTH = primary

hyperparathyroidism

• Inactivating mutation of calcium sensing receptor

− Persistent PTH production despite hypercalcemia

− Upward reset of calcium set point

− PTH induces hypercalcemia

− Activation of TAL and DCT calcium transport by partially

inactive calcium sensing receptor

• Boards claim to fame:

− Looks like primary hyperparathyroidism on serum

− Don’t resect FHH

− Urine calcium differentiates

40

7/20/2015

11



− Hypocalcemia

− Hyperphosphatemia

− Low PTH

− Hypercalciuria

− Low 1,25D


41

Autosomal dominant hypoparathyroidism

• Key finding: Hypocalcemia + low PTH = hypoparathyroidism

• Activating mutation of calcium sensing receptor

• Mirror image disease of FHH

− Absent PTH production despite hypocalcemia

− Downward reset of calcium set point

− Lack of PTH induces hypocalcemia

− Lack of PTH (and likely inappropriately low FGF23)

contribute to hyperphosphatemia

− Reduced TAL and DCT calcium transport by activated

calcium sensing receptor leads to calcium dumping,

hypercalciuria

42

Illustrative monogenic case studies: 5


− Hypocalcemia

− Hypophosphatemia

− High PTH

− Normal 25D

− Undetectable 1,25D


43

Vitamin D-dependent rickets type 1

• Key finding: hypocalcemia + hypophosphatemia with

secondary hyperparathyoridsm = defective vitamin D signaling

• 1-alpha hydroxylase deficiency (autosomal rec)

• Lack of 1,25D � hypocalcemia� secondary hyperpara and

hypophosphatemia

• Vitamin D-dependent rickets type 2 = VDR deficiency

− Difference is 1,25D level and response to 1,25D therapy

• FGF23 should be very low in type 1 and 2

• Vitamin D resistant rickets = primary FGF23 excess (XLH, ADHR,

TIO)

44

7/20/2015

12

Questions

45

Documents

Calcium and Phosphate - Echo360€¦ · Calcium and Phosphate ... metabolism in CKD Cascade of disordered mineral metabolism in CKD Analyte concentration >10,000 1000 90 60 30 4 0