Kidney-Bone and Beyond: An Academic Career

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

Chief, Division of Pediatric Nephrology Director, Clinical Translational Research Center

Associate Dean of Clinical Research David Geffen School of Medicine at UCLA

Holick MF, Lancet 6:357, 2001

With Hectorol® (doxercalciferol) Therapy

HO 25 (OH)D2

OH

HO VITAMIN D2

LIVER KIDNEY

OH

Normal Metabolic Pathway

LIVER KIDNEY FAILURE

In Kidney Failure

No Active Vitamin D Hormone

LIVER

Active Vitamin D Hormone HO 25 (OH)D2

HO 1,25 D2

OH

OH

HO VITAMIN D2

HO HECTOROL

OH

HO

HO

1.24 D2 Minor Active Vitamin D Hormone

OH

HO

OH

1.25 D2 Major Active Vitamin D Hormone

OH

Feedback Loops in SHPT

Ca = calcium; CVD = cardiovascular disease; P = phosphorus. Courtesy of Kevin Martin, MB, BCh.

↑ PTH

Bone Disease Fractures Bone pain

Marrow fibrosis Erythropoietin resistance

↑ Serum P ↓1,25D Calcitriol

Renal Failure

↑ PTH

Systemic Toxicity CVD

Hypertension Inflammation Calcification

Immunological

↓25D

↓ Ca++

Decreased Vitamin D Receptors and Ca-Sensing Receptors

Progression to Renal Failure

Normal Diffuse

Nodular Hyperplasia

Adenomatous Hyperplasia

Early Nodular

Progressive loss of kidney function

VDR Expression

CaSR Expression

Partial 1,25(OH)2D resistance

Progressive loss of 1,25(OH)2D has a profound effect on the structure and function of the parathyroid glands

1α-Hydroxylase

Murayama A, Takeyama K, Kitanaka S, et al. Endocrinology. 1999;140(5):2224-2231; Fukagawa M, Yi H, Fukuda N, et al. Artif Organs. 1995;19(12):1210-1214; Satomura K, Seino Y, Yamaoka K, et al. Kidney Int. 1988; 34:712–716.

Alteration of Parathyroid Gland Function

Spectrum of Renal Osteodystrophy

Normal bone formation Mild

Adynamic

Osteomalacia

PTH

Al+3

Mixed lesion

Osteitis fibrosa

Calcium, Vitamin D

High turnover Low turnover Vascular Calcification Process

Therapeutic Options for the Treatment of Renal Osteodystrophy

Phosphate Binders Active Vitamin D Analogues

Calcimimetic Drugs

Cinacalcet

Oxacalcitrol - Japan Paracalcitol - USA Stage 5 Doxercalciferol - USA Stage 3-5 Aluminum

Ca-Salts

Salusky IB et al NEJM 1990

Change in Plasma Al levels During the Course of the Study

Salusky IB et al NEJM 1990

Change in Plasma Aluminum Levels after DFO

A

Therapeutic Options for the Treatment of Renal Osteodystrophy

Phosphate Binders Active Vitamin D Analogues

Calcimimetic Drugs

Cinacalcet

Oxacalcitrol - Japan Paracalcitol - USA Stage 5 Doxercalciferol - USA Stage 3-5 Sevelamer:

Ca free – Metal Free Lanthanum Ca: Ca free - Metal +

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

Reduced Kidney Function and SHPT

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

Progression of CKD and Indices of Bone Metabolism

Martinez I et al. NDT S-11 3:22-28, 1996, Walters et al, D&I, 31: 735, 2002

Clinical Features of Childhood ROD

Height < -2 SD 153 (61.9%) Clinical manifestations of bone disease 91 (36.8%) Deformities 63 (25.5%) Pathological fractures 33 (13.4%) Aseptic bone necrosis 32 (13.0%) Mild disabling bone disease 26 (10.5%) Severe disabling bone disease 18 (7.3%) Invalidating bone disease (all) 44 (17.8%)

Groothoff JW KI 63 (2003) 266–275

STUDY DESIGN

Calcitriol

+

CaCO3

Calcitriol

+

Sevelamer 1-α D2

+

CaCO3

1-α D2

+

Sevelamer

500

3500

2500

1500

Bon

e Fo

rmat

ion

Rat

e (u

m2 /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

Bone Gene Expression in Calcified Plaque

Bostrom K et al JCI 1993

Extra-Skeletal Calcification in Chronic Renal Failure

Courtesy of Kevin Martin, M.D.

Lumen

Intimal Atherosclerotic Plaque

(Giachelli et al 2004)

Process of Vascular Calcification

Coronary Artery Calcification in Young Dialysis Patients

0.1

1

10

100

1000

10000

0 5 10 15 20 25 30 35 Age (years)

Cal

cific

atio

n Sc

ore*

N=39

*Determined by EBT. Goodman WG, et al. N Engl J Med. 2000;342:1478-1483.

Calcification scores doubled in patients with positive initial scan when rescanned at 20 months

Risk Factors Associated With Increased Risk for Cardiac Calcification in Young Dialysis Patients

* Modifiable. Serum calcium was not significant. Goodman WG, et al. N Engl J Med. 2000;342:1478-1483.

Coronary No Calcification Calcification Factor (n=14) (n=25) P Value

Ca from 6456 ± 4278 3325 ± 1490 0.02 calcium binders (mg/day)*

Serum P (mg/dL) 6.9 ± 0.9 6.3 ± 1.2 0.06

Ca × P product (mg2/dL2)* 65.0 ± 10.6 56.4 ± 12.7 0.04

Age (years) 26 ± 3 15 ± 5 <0.001

Mean duration of dialysis (years) 14 ± 5 4 ± 4 <0.001

Risk of Cardiovascular Calcification Is Increased in Dialysis Patients

*Determined by EBT. CAD = coronary artery disease; CV = cardiovascular. †Rumberger JA, et al. Mayo Clin Proc. 1999;74:243-252. Braun J, et al. Am J Kidney Dis. 1996;27:394-401.

0

500

1000

1500

2000

2500

28-39 40-49 50-59 60-69 Age (years)

Mea

n C

oron

ary

Arte

ry

Cal

cium

Sco

re*

Nondialysis, No CAD (n = 22) Nondialysis, CAD (n = 80) Dialysis (n = 49)

Very high CV risk†

Coronary Artery Calcification by Presence of CKD and Diabetes: The Dallas Heart Study Population

Kramer et al. J Am Soc Nephrol. 2005;16:507-513.

Total

No CKD (n=2449)

Stage 1-2 CKD (n =170)

Stage 3-5 CKD (n = 41)

Non-Diabetic

No CKD (n = 2182)

Stage 1-2 CKD (n = 108)

Stage 3-5 CKD (n = 28)

Diabetic

No CKD (n = 267)

Stage 1-2 CKD (n = 62)

Stage 3-5 CKD (n = 13)

CAC≤10 CAC 11-100 CAC 101-400 CAC >400

0% 20% 40% 60% 80% 100%

Arterial Media Calcification in ESRD

London GM, et al. Nephrol Dial Transplant. 2003;18:1731-1740

Cardiovascular disease (CVD) mortality general population versus ESRD patients

Foley et al. Am J Kidney Dis. 1998;32:S112-S119

GP=general population

Age (years)

Annu

al C

VD m

orta

lity

(%)

0.001

0.01

0.1

1

10

100

25-34 35-44 45-54 55-64 65-74 75-84 >85

GP male GP female GP black GP white dialysis male dialysis female dialysis black dialysis white

Charles Nolan, MD

Vascular Calcification in Patients With CKD

Patients with Stage 5 CKD are at high risk for vascular calcification Vascular calcifications are present in almost 50% of patients with

stage 4 CKD and new dialysis patients Vascular calcification can be quantified Vascular calcification is associated with modifiable risk factors

– Ca intake from calcium-based binders – S-P, S-Ca and Ca × P product – Therapy with vitamin D

Vascular calcification results in arterial stiffening and increased pulse pressure and adynamic bone disease

Goodman WG, et al. N Engl J Med. 2000;342:1478-1483. Guérin AP, et al. Nephrol Dial Transplant. 2000;15:1014-1021. Ribeiro S, et al. Nephrol Dial Transplant. 1998;13:2037-2040. Raggi P, et al. J Am Coll Cardiol. 2002b;39:695-701.

New Definition of ROD: 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 Kidney International June 2006

A

Therapeutic Options for the Treatment of Renal Osteodystrophy

Phosphate Binders Active Vitamin D Analogues

Calcimimetic Drugs

Cinacalcet

Oxacalcitrol - Japan Paracalcitol - USA Stage 5 Doxercalciferol - USA Stage 3-5 Sevelamer:

Ca free – Metal Free Lanthanum Ca: Ca free - Metal +

FGF-23 and Rickets

ADHR (Autosomal Dominant Hypophosphatemic rickets) TIO (Tumor Induced Osteomalacia) XLH (X-linked hypophosphatemia) ARHP (Autosomal Recessive Hypophosphatemia)

Hypophosphatemia Renal phosphate wasting Low (or inappropriately normal) 1,25D Normal 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

Pituitary Choroid

DCT PCT

Klotho

OB OC

BONE MARROW

OCY

BONE OSTEOID

OCY

Traditional Bone Histomorphometry

Connections between blood vessels and osteocyte-lacunocanaliculi

Feng JQ. et al. Curr Opin.Nephrol.Hypertens. 18:285, 2009

Novel Regulators of Phosphate and Bone Metabolism

MARKER

Phex Early and late osteocytes

Phosphate metabolism

OF45/MEPE Late osteoblast through osteocytes

Inhibitor of bone formation/regulator of phosphate metabolism

DMPI Early and mature osteocytes

Sclerostin Late embedded osteocyte

Inhibitor of bone formation

FGF23 Early and mature osteocytes

Induces hypophosphatemia

Phosphate metabolism and mineralization

EXPRESSION FUNCTION

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

GFR (ml/min/1.73 m2)

Perc

enta

ge

Portale A et al CJASN 2013

Bone FGF-23 Expression (50x)

Healthy Control CKD (Stage 2)

Pereira RC et al Bone 2009 in press

Bone DMP1 Expression (200x)

Healthy Control CKD (Stage 2)

Pereira RC et al Bone 2009 in press

FGF23 Associated with LVH in Patients with CKD

(Faul C et al. JCI 2012)

cFGF-23 Quartiles and Mortality in Dialysis Patients (Gutierrez et al. NEJM 2008)

Temporal aspects of disordered mineral metabolism in CKD

Anal

yte

conc

entr

atio

n

>10,000

1000

90 60

30 4 0 >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

Wolf, J Am Soc Nephrol 2010

UCLA Renata Pereira, Ph.D., Pediatrics

Joel Hernandez M.D., Pediatrics

Barbara Gales, R.N., Pediatrics

Jonathan Goldin, M.D.,Ph.D., Radiology

Robert Elashoff, Ph.D, Biomathematics

Katherine Wesseling, M.D., Pediatrics

Collaborators

Immutopics Jeffrey Lavigne Richard Zahranik Loma Linda Med. Ctr. Shobha Sahney, M.D. Mass. General Hospital Harald Jüppner, M.D.

Support: NIDDK, NCRR