CKD-MBD: New Insights into Pathogenesis and Current Aspects of

Treatment

Isidro B. Salusky, M.D.Distinguished Professor of Pediatrics

Chief, Division of Pediatric NephrologyDirector, Clinical Translational Research Center

Associate Dean of Clinical ResearchDavid Geffen School of Medicine at UCLA

New Definition of Renal Osteodystrophy CKD-Mineral Bone Disease (CKD-MBD)

A systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following:• Abnormalities of calcium, phosphorus, PTH or

vitamin D metabolism • Abnormalities in bone turnover, mineralization,

volume, linear growth, or strength• Vascular or other soft tissue calcification

Moe et al KI 2006

KDIGO—Definition of Renal Osteodystrophy

“…an alteration of bone morphology in patients with CKD. It is one measure of the skeletal component of the systemic disorder of CKD-MBD that is quantifiable by histomorphometry of bone biopsy..."

New Classification of ROD

Mineralization

NormalAbnormal

TurnoverHigh

NormalLow

VolumeHigh

NormalLow

Slide courtesy of Susan Ott

KI 2006 69(11):1945-53

TMV ClassificationHistologic Classification of Renal Osteodystrophy Based on TMV (Turnover/Mineralization/Volume)

KI 2006 69(11):1945-53

Osteitis fibrosa

Mild 2oHPT

Osteomalacia

Mixed uremic osteodystrophy

Adynamic bone

Prevalence of Abnormal Turnover and Mineralization Across CKD 2-4

(n=14)

Stage 4

Patie

nts

with

Abn

orm

al

Hist

olog

y (%

)

BFR/BS

O.Th

Stage 3Stage 2

(n=24)

(n=14)

OMT

Wesseling K et al. CJASN 2012

Traditional Pathogenesis of Secondary Hyperparathyroidism in CKD

Decreased Vitamin D Receptors

Decreased Ca-Sensing Receptors

Parathyroid Glands

Increased PTH Secretion

Hypocalcemia

Reduced Renal Mass

Decreased Serum 1,25(OH)2D

(Active Vitamin D Calcitriol)

Increased Serum Phosphate

National Kidney Foundation. Am J Kidney Dis. 2003;42:S1-S201.Cheng S, et al. Ther Clin Risk Manag. 2006;2:297-301.

FGF23 and Rickets

ADHR (Autosomal Dominant Hypophosphatemic rickets)

TIO (Tumor Induced Osteomalacia)

XLH (X-linked hypophosphatemia)

ARHP (Autosomal Recessive Hypophosphatemia)

HypophosphatemiaRenal phosphate wastingLow (or inappropriately normal) 1,25DNormal serum Ca levels

Increased FGF-23 values

FGF-23 is Produced in Osteocytes and Regulates Phosphorus and Vitamin D

Osteoblast Osteocyte

DMP-1

MEPE-ASARM

PHEX

FGF-23

1,25(OH)2D Pi

Dietary animals + humans +CKD

PituitaryChoroid

DCT PCT

Klotho

OBOC

BONE MARROW

OCY

BONE OSTEOID

OCY

Traditional Bone Histomorphometry

Osteocytes: Regulators of phosphate, vitamin D and bone metabolism

Feng et al Curr Opin.Nephrol.Hypertens (2009) 18:285

MARKER

Phex Early and lateosteocytes

Phosphate metabolism

OF45/MEPE Late osteoblastthrough osteocytes

Inhibitor of bone formation/regulator of phosphate metabolism

DMPI Early and matureosteocytes

Sclerostin Late embeddedosteocyte

Inhibitor of bone formation

FGF23 Early and matureosteocytes

Induceshypophosphatemia

Phosphatemetabolism andmineralization

EXPRESSION FUNCTION

Osteocytes

Adapted Feng JQ. et al (2006-2007)

Calcium, Phosphorus & PTH by iGFR in 447 Children with CKD

Ser

um

Cal

ciu

m (

mg

/dl)

Ser

um

Ph

osp

ho

rus

(mg

/dl)

Inta

ct P

TH

(p

g/m

l)

Iohexol GFR (ml/min/1.73 m2)

>70 60-69 50-59 40-49 30-39 20-29 <200

2

4

6

8

10

12

0

60

120

180

Corrected Calcium Phosphorus iPTH

**

*

*

*vs GFR >70, P<0.05 by ANOVA

Portale A et al CJASN in press

25OHD, 1,25(OH)2D, & FGF23 by iGFR in 447 Children with CKDS

eru

m 2

5OH

D (

ng

/dl)

Ser

um

1,2

5(O

H) 2

D (

pg

/dl)

FG

F23

(R

U/m

l)

Iohexol GFR (ml/min/1.73 m2)

>70 60-69 50-59 40-49 30-39 20-29 <200

10

20

30

40

0

100

200

300

400

500

25OHD 1,25(OH)2D FGF23

*

**

*

*

*

Median valuesVitamin D, N=370

*vs GFR >70, P<0.05 by ANOVA

FGF23 & Phosphorus SD Scores by iGFR in 447 CKiD Children

Ph

osp

ho

rus

SD

Ph

osp

ho

rus

SD

Iohexol GFR (ml/min/1.73 m2)Iohexol GFR (ml/min/1.73 m2)

-3

-2

-1

0

1

2

3

0

100

200

300

400

500

Phosphorus FGF23

Median values

*

*

>70 69-60 59-50 49-40 39-30 29-20 <20

*

**

*

*

*

FG

F23

(R

U/m

l)

Portale A et al CJASN in press

>70 60-69 50-59 40-49 30-39 20-29 <200

10

20

30

40

50

60

70

80

90

100 Phos >95% iPTH >65 pg/ml FGF23 >100 RU/ml

GFR (ml/min/1.73 m2)

Increased Serum Pi, PTH and FGF23 by GRF in 447 CKiD Children

Increased Serum Pi, PTH and FGF23 by GRF in 447 CKiD Children

Pe

rce

nta

ge

Glomerular Non-Glomerular P (n=91) (n=356)

Age, years 14 ± 3 11 ± 4 <0.001GFR, ml/min/1.73 m2 49 ± 21 45 ± 17 NSSerum calcium, mg/dl 9.3 ± 0.4 9.4 ± 0.4 NSSerum phosphorus, mg/dl 4.4 ± 1.0 4.6 ± 0.8 <0.05*Serum iPTH, pg/ml 50 (28-116) 52 (30-84) NSPlasma FGF23, RU/ml 169 (96-273) 131 (90-192) 0.005*Serum 25OHD, ng/ml 18 ± 12 29 ± 11 <0.001Serum 1,25(OH)2D, pg/ml 27 ± 12 31 ± 11 0.001

Data are means ± SD or medians (25th-75th percentile)

Mean (median) values were compared using the t-test or *Wilcoxon rank-sum test

Comparison of Glomerular vs Non-Glomerular Disease

FGF23 in CKD-MBD

• FGF23 is the first detectable abnormality in mineral metabolism

• Early increases in serum FGF23 concentrations reduced S-P levels and subsequently maintain serum P levels within the normal range until advanced CKD stages

• Early increases in FGF23 account for early decreases in 1,25D and the development of 2oHPT

• Phosphate balance is neutral in CKD stages 2-3

FGF23 and Progressive Renal Dysfunction

Fliser D. et al. JASN 18:2600, 2007

FGF23 Associated with LVH in Patients with CKD (Faul C et al. JCI 2012)

Prevalence of LVH by FGF23 Quartile in 317 CKiD Children

FGF23 QuartileFGF23 Quartile

LVH

Pe

rce

nta

geLV

H P

erc

ent

age

<90 90-135 135-200 >2000

5

10

15

20

25P for linear trend = 0.038

Data from Visit 1b

Determinants of LVH

Odds Ratio [95% CI] P

Systolic BP %tile (AGH) 1.02 [1.02 – 1.03] 0.002

Log FGF23 1.54 [1.03 – 2.33] 0.038

Multivariable logistic regression of LVH as categorical variable. (N=317)

Odds Ratio [95% CI] P

Systolic BP %tile (AGH) 1.01 [1.02 – 1.03] 0.007

Log FGF23 1.34 [0.87 – 2.06] 0.178

Serum Phos Z score 1.29 [1.05 – 1.57] 0.014

Bone FGF23 Expression (50x)

Healthy Control CKD (Stage 2)

Pereira RC et al Bone 2009

Bone DMP1 Expression (200x)

Healthy Control CKD (Stage 2)

Pereira RC et al Bone 2009

Therapeutic Options for the Treatment of CKD-MBD

Cinacalcet

Calcitriol

Paricalcitol

DoxercalciferolErgocalciferol

Sevelamer:Ca free – Metal Free

Ca-Salts

Lanthanum Ca:Ca free - Metal +

0

200

400

600

800

1000

1200

0 1 2 3 4 5 6 7 8

Effects on Serum PTH Levels

Time (months)

PTH

[1st P

TH-IM

A] (p

g/m

l)

1-α (OH)D2 + CaCO3

1-α (OH)D2 + Sevelamer

1,25 (OH)2D3 + CaCO3

1,25 (OH)2D3 + Sevelamer

p < 0.01 from baseline*

*

Wesseling K. et al KI 2010

500

3500

2500

1500

Bo

ne

Fo

rmat

ion

Rat

e (

um

2/m

m2/d

ay)

1 α(OH)D2 +CaCO3

1,25(OH)2D3 +CaCO3

1 α(OH)D2 +Sevelamer

1,25(OH)2D3 +Sevelamer

Effects of Therapy on Bone Turnover

6000

Initial

Final

* *

*

*

* p<0.001

Wesseling K. et al KI 2010

Effects of 1,25(OH)2D3 Therapy on Bone Turnover, Mineralization and FGF23 in

Dialyzed Patients with 2oHPT

Wesseling-Perry K et al. KI 79:112, 2011

(n=51)

Effects of 1,25(OH)2D3 Therapy on Bone Osteocytic Proteins in Dialyzed Patients

(Pereira R et al. ASN 2011)

Temporal aspects of disordered mineral metabolism in CKD

An

alyt

e co

nce

ntr

atio

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)

cFGF-23(RU/mL)

1 2 3

4

Dialysis

Wolf M. J Am Soc Nephrol 2010;21. [Epub ahead of print]

cFGF-23, C-terminal Fibroblast Growth Factor-23

PTH(pg/mL)

Normal PTH range

P(mg/dL)

Normal P range

1. Increased FGF-23 is the earliest alteration in mineral

metabolism in CKD

2. Gradually increasing FGF-23 levels cause early

decline in 1,25D levels

3 .This frees PTH from feedback inhibition, leading to

SHPT

4. All these changes occur long before increases in

serum P levels are evident

Oliveira CJASN 2010;5:286-291

Effects of Sevelamer and CaCO3 on 2oHPT and FGF23 in CKD 2-4

UCLA

Katherine Wesseling, M.D., Pediatrics

Renata Pereira, Ph.D., Pediatrics

Joshua Zaritsky, M.D., Pediatrics

Barbara Gales, R.N., Pediatrics

Justine Bacchetta, M.D., Pediatrics

Robert Elashoff, Ph.D, Biomathematics

Children’s Hospital Los Angeles. Kevin Lemley, M.D.

CollaboratorsMass. General HospitalHarald Jüppner, M.D.

Immutopics Jeffrey LavigneRichard Zahranik

UCSFTony Portale, M.D.

Northwestern U. M. Wolf, M.D.

Loma Linda Med. Ctr. Shobha Sahney, M.D.

Support: NIDDK, NCRR

Thank You

UCLA Renata Pereira

Joshua Zaritsky

Navdeep TumberBarbara GalesGina RamosOra YadinIsidro Salusky

Mass Gen HospitalHarald Jüppner

ImmutopicsJeff Lavigne

Richard ZaradnikChris Harkins

Loma Linda UniversityShoba Sahney