34
FGF23 & Other Emerging Diagnostic Markers Myles Wolf, MD, MMSc Feinberg School of Medicine Northwestern University Disclosures: Abbott, Amgen, Keryx, Luitpold, OPKO, Pfizer, Sanofi, Shire
FGF23 & Other Emerging Diagnostic Markers
Myles Wolf, MD, MMSc Feinberg School of Medicine
Northwestern University
Disclosures: Abbott, Amgen, Keryx, Luitpold, OPKO, Pfizer, Sanofi, Shire
PHYSIOLOGY and
EPIDEMIOLOGY
2
Classic actions and stimuli of FGF23
Stimulates phosphaturia Inhibits CYP27B1 Stimulates CYP24A1 Inhibits PTH Classic actions require “permissive” serum calcium
Stimuli: – phosphate intake, 1,25-dihydoxyvitamin D, PTH, calcium
Lower 1,25-dihydroxyvitamin D
CKD Chickens and Eggs
Early CKD
↓ klotho
↑ FGF-23
Early CKD
↑ FGF-23
↓ klotho
Primary klotho deficiency with FGF23 resistance
Primary FGF23 excess with klotho down regulation
FGF23 by CKD stage in CRIC
350
400
300
200
150
50
0
FGF2
3, R
U/m
l
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
FGF23, phosphate and PTH in CRIC
9
0
10
20
30
40
50
60
70
80
90
100
<20 20-29 30-39 40-49 50-59 60-69 ≥70
% o
fPop
ulat
ion
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 Rats with Anti-GBM Nephritis
Hasegawa et al. Kidney Int 2010
Cr
1,25D
PTH
P
Ca
FGF23
Effects of Anti-FGF23 Antibodies
Normalize 1,25D
Reverse CYP regulation
Decrease phosphaturia:
FEPi
Increase serum P
Hasegawa et al. Kidney Int 2010
Isakova, Wolf, Kidney Int 2010
Emerging views on the pathogenesis of disordered mineral metabolism in CKD
OUTCOMES STUDIES Mortality
CVD Events CKD Progression
14
FGF23 and Mortality in Incident ESRD
Gutierrez et al N Engl J Med 2008
cFGF-23 vs. Phosphate Quartiles & Mortality
0
1
2
3
4
5
6
Odd
s ra
tio o
f mor
talit
y
Q1 Q2 Q3 Q4Quartiles
cFGF-23 Phosphate
Gutierrez et al N Engl J Med 2008
* *
*
*
17
Two-year survival according to FGF23: Prevalent hemodialysis
Quar%le 1= <1100 RU/mL Quar%le 2= 1100–2700 RU/mL Quar%le 3= 2701–8400 RU/mL Quar%le 4= >8400 RU/mL
Jean et al. Nephrol Dial Transplant 2009; e-‐pub ahead of print
100
95
90
85
80
75
70
65
60
Sur
viva
l pro
babi
lity
(%)
Nb at risk 219 186 162 137 Quartile 1 54 48 45 41 Quartile 2 55 48 43 39 Quartile 3 55 46 39 32 Quartile 4 55 44 35 25
0 200 400 600 800 Time (days)
Quar%le 1
Quar%le 2
Quar%le 3
Quar%le 4
FGF23 Tertiles & Composite Risk of Death or Allograft Loss
Wolf et al. J Am Soc Nephrol. 2011
0
10
20
30
40
Cum
ulat
ive
Inci
denc
e, C
ompo
site
Out
com
e (%
)
0 1 2 3Analysis time (years)
FGF23 Tertile 2FGF23 Tertile 3
FGF23 Tertile 1
FGF23 vs. PTH, Phosphate, Hgb as Risk Factor for Composite Outcome
Wolf et al. J Am Soc Nephrol. 2011
0
1
2
3
4
FGF23 PTH Phosphate Hemoglobin
Tertile 1 Tertile 2 Tertile 3
Haz
ard
Rat
io
REF REF REF REF
NS NS NS
<0.001
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Model 1 Model 2 Model 3
Quartile 1 Quartile 2 Quartile 3 Quartile 4
HOST: Higher FGF23 Associated With Greater Risk of All-Cause Mortality in CKD 4
Model 1: age, race, gender. Model 2: Model 1 + smoking status, alcohol intake, DM, HTN, CVD, BMI, SBP, GFR, treatment assignment, homocysteine, hemoglobin, folate, B12, albumin, calcium, 25(OH)D, 1,25(OH)2D, iPTH, phosphorus, HDL, LDL, triglycerides, and total cholesterol. Model 3: Model 2 + use of medications. Kendrick JR, et al. J Am Soc Nephrol. 2011
Haz
ard
Rat
io fo
r Dea
th
≤216 RU/mL 217-380 RU/mL 381-945 RU/mL > 946 RU/mL
R R R
FGF23 and Mortality in CKD 2-4: 266 events, 20.3/1000 person-years
21 Isakova et al. JAMA 2011.
Cum
ulat
ive
inci
denc
e of
dea
th, %
Years of follow up
0 1 2 3 4 50
10
20
FGF23 Quartile 1: 1.0
FGF23 Quartile 2: 1.3
FGF23 Quartile 3: 2.0
FGF23 Quartile 4: 3.0
Parker et al. Ann Intern Med 2010
FGF-23 and CVD in non-CKD: Heart & Soul N=833 with history of CAD
FGF23 and outcomes in CHS
23
• N=3107; 1128 with CKD (eGFR<60 or ACR>30 mg/g) • Strongest association: death, CHF • No association of FGF23 with MI • Greater risks in CKD vs. non-CKD
Ix J et al. JACC 2012
FGF23 and risk of cardiovascular disease events in CKD stages 2 – 4
24 Scialla J et al. J Am Soc Nephrol; In press
N=3860; Median follow-up, 3.7 years
Adjusted for demographics, kidney function, traditional CVD risk factors, medications
Congestive Heart Failure 360 events (27/1000 person-years)
Atherosclerosis 287 events (22/1000 person-years)
LV Geometry According to Ascending Quartiles of FGF23
25
27 24 16 10
3531
3019
1112
16
21
27 33 3850
0102030405060708090
100
Quartile 1 Quartile 2 Quartile 3 Quartile 4
Prev
alen
ce,%
NormalRemodeling
Eccentric LVHConcentric LVH
Fibroblast Growth Factor 23 QuartilesFaul, Amaral, Oskuei et al. J Clin Invest. 2011.
FGF23 vs. phosphate as risk factors for CAC
26
CAC > 400
N=1501 CRIC participants with CKD stage 2-4
Scialla et al. Kidney Int 2013
Disordered phosphate homeostasis and cardiovascular disease in CKD
Hyperphosphatemia
Heart Vessels
High FGF23
LVH Calcification
CVD events
Klotho deficiency
CKD
Fliser et al. J Am Soc Nephrol 2007
Renal progression according to cFGF-23 levels
Interaction between FGF23, eGFR and ESRD
Isakova et al. JAMA 2011.
0.5
1
2
4
All < 30 30 – 44
HR
per
SD
ln F
GF2
3,95
%C
I
≥ 45
Risk of ESRD
eGFR, ml/min/1.73m2
Incidence
N
Events
3879 758 1472 1649
410 231 143 3633.0 111.2 30.6 6.3
FGF23 145 256 161 105
FGF23 is a risk factor for ESRD in AASK
30 Scialla et al. JASN 2012
FGF23 +GFR MV +MM +GFR slope Quartile 1 Ref Ref Ref Ref Quartile 2 1.40 1.47 1.54 1.44 Quartile 3 1.58 1.67 1.79 1.65 Quartile 4 2.17 2.24 2.29 2.22 p-trend <0.01 <0.01 <0.01 <0.01
0.00
0.20
0.40
0.60
0.80
Cum
ulat
ive
inci
denc
e
177 155 132 111 97 79 73 59 37 13Quartile 4198 193 169 150 135 120 109 99 67 30Quartile 3196 189 183 170 150 139 126 117 86 50Quartile 2203 197 195 185 167 156 148 137 88 39Quartile 1
Number at risk
1 2 3 4 5 6 7 8 9 10 11Years since randomization
Quartile 1 Quartile 2Quartile 3 Quartile 4
0.00
0.20
0.40
0.60
0.80
Cum
ulat
ive
inci
denc
e
177 155 132 111 97 79 73 59 37 13Quartile 4198 193 169 150 135 120 109 99 67 30Quartile 3196 189 183 170 150 139 126 117 86 50Quartile 2203 197 195 185 167 156 148 137 88 39Quartile 1
Number at risk
1 2 3 4 5 6 7 8 9 10 11Years since randomization
Quartile 1 Quartile 2Quartile 3 Quartile 4 N = 809
MV: adjusted for: age, sex, Rx group; GFR; UPCR; income, prior heart disease, smoking, albumin, BMI, center +MM: adjusted for PTH, phosphate, 25-hydroxyvitamin D, calcium +GFR slope: adjusted for year 1 GFR slope
ASSAYS and
OTHER ODDS AND ENDS
31
Zisman, Wolf; Curr Opin Nephrol Hypertens 2010
33
Correlation between cFGF-23 & iFGF-23
Gutierrez et al N Engl J Med 2008
Differences in the Proportion of FGF23 Present as C-terminal Fragments
Smith et al. JCEM 2012
Intact Diurnal Variation in Mineral Metabolism in CKD
Isakova T et al. CJASN 2012
37 Isakova T et al. CJASN 2011;6:2688-2695
Within-Subject Variation: FGF23, PTH, Phosphate
3 monthly measurements in 67 PD patients
Factors that Modify FGF23
Raises FGF23 Lowers FGF23 CKD Low GFR AKI
Kidney transplantation
High phosphate diet Low phosphate diet Calcium PTH
Hypocalcemia Non-calcium P-binders
1,25D and analogs Cinacalcet Certain IV iron formulations Certain IV iron formulations
38
Major unanswered questions
What stimulates FGF23 production in early CKD? Does the FGF23 response differ by CKD etiology? What is FGF23 actually regulating? How and where is phosphate sensed? How and where is FGF23 degraded? What are other “off-target” effects of FGF23? What are the ideal therapeutic approaches to lower
(or slow elevation) FGF23? If FGF23 can be modified, can we improve clinical
outcomes?
