Iain Macdougall: Disclosure of Interestskdigo.org/wp-content/uploads/2017/02/1...Feb 01, 2017 ·...
Transcript of Iain Macdougall: Disclosure of Interestskdigo.org/wp-content/uploads/2017/02/1...Feb 01, 2017 ·...
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Controversies Conference on Iron Management in CKD | March 27-30, 2014 | San Francisco, California, USA
Iain Macdougall: Disclosure of Interests
Consultancy, honoraria, research grant income:- • Vifor Pharma
• Vifor FMC Renal Pharma
• Pharmacosmos
• Takeda
• AMAG
• FibroGen
• Astellas
• Glaxo Smith Kline
• Bayer
• Rockwell
• Keryx
• Noxxon
• Pieris
• Amgen
• Janssen Cilag
• Roche
(No employment, stock ownership, legal expert witness)
KDIGO
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Controversies Conference on Iron Management in CKD | March 27-30, 2014 | San Francisco, California, USA
Conference Overview and Objectives
To develop a greater understanding of the role of iron therapy in the management of anemia in patients with chronic kidney disease
-- benefits versus risks
-- balance between ESA therapy and iron KDIGO
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Controversies Conference on Iron Management in CKD | March 27-30, 2014 | San Francisco, California, USA
CKD Anaemia Management
Transfusions
IV Iron ESAs KDIG
O
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Controversies Conference on Iron Management in CKD | March 27-30, 2014 | San Francisco, California, USA
Pre-‐1990
Transfusions
Post-TREAT
IV Iron
ESAs
1990 - 2009
Transfusions Transfusions
IV Iron
ESAs
IV Iron
KDIGO
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Controversies Conference on Iron Management in CKD | March 27-30, 2014 | San Francisco, California, USA
What do we know about IV iron?
• Enhances the erythropoietic response to ESA therapy -- increased Hb response -- reduced ESA doses (economic, ?safety)
• Widespread variability in IV iron usage worldwide
• Very limited robust clinical data on safety -- iron overload -- oxidative stress / cardiovascular toxicity -- infections -- hypersensitivity reactions
-- iron overload
-- reduced ESA doses (economic, ?safety)
• Widespread variability in IV iron usage worldwide
KDIGO
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Controversies Conference on Iron Management in CKD | March 27-30, 2014 | San Francisco, California, USA
Macdougall et al, Kidney Int (1996)
Oral iron
IV iron
14
6
8
10
12
0 4 8 12 16
Hb (g/dL)
*
** * *
** **
Time (weeks)
*
*
*
**
**
**
ESA + IV iron ESA + oral iron ESA + no iron
Fishbane et al, Am J Kidney Dis (1995)
KDIGO
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Controversies Conference on Iron Management in CKD | March 27-30, 2014 | San Francisco, California, USA
n=52 n=37 n=50 n=25 n=228 n=149 n=36 n=36 n=39
-‐46.5%
-‐18.5%
-‐34.4% -‐32.5%
-‐47.1%
-‐25.0%
-‐12.4%
-‐49.4%
-‐23.9%
-‐60%
-‐50%
-‐40%
-‐30%
-‐20%
-‐10%
0% Fishba
ne 199
5
Macdo
ugall
199
6
Sepa
ndj 1996
Descom
bes 2
000
Richardson
200
1
Chan
g 2002
DeVita
2003a
DeVita 2003b
Schiesser 2
006
% cha
nge in ESA
dose
Reduced ESA use with IV iron in dialysis patients
Fishbane S et al. Am J Kidney Dis 1995;26:41–46; Macdougall I et al. Kidney Int 1996;50: 1694–1699; Sepandj F et al. Nephrol Dial Transplant 1996;11:319–322; Descombes E & Fellay G. Nephron 2000;84:196–197; Richardson D et al. Am J Kidney Dis 2001;38:109–117; Chang CH et al. Clin Nephrol 2002;57:136–141; De Vita MV et al. Clin Nephrol 2003;60:335–340; Schiesser D et al. Nephrol Dial Transplant 2006;21:2841–2845; Kapoian T et al. JASN 2008;19:372–379
n=112
-‐17.4%
Kapo
ian2
008
KDIGO
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Controversies Conference on Iron Management in CKD | March 27-30, 2014 | San Francisco, California, USA
Haemoglobin, ESA, and IV iron use in dialysis units in the US (1992−2004)
KDIGO
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Controversies Conference on Iron Management in CKD | March 27-30, 2014 | San Francisco, California, USA
What do we know about IV iron?
• Enhances the erythropoietic response to ESA therapy -- increased Hb response -- reduced ESA doses (economic, ?safety)
• Widespread variability in IV iron usage worldwide
• Very limited robust clinical data on safety -- iron overload -- oxidative stress / cardiovascular toxicity -- infections -- hypersensitivity reactions
-- iron overload
-- reduced ESA doses (economic, ?safety)
• Widespread variability in IV iron usage worldwide
KDIGO
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Mean Ferritin Trends by Country – DOPPS 2-5 (2002-2012)
Mean ferritin (ng/mL)
Non-European Countries European Countries
Confidential
KDIGO
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95th
75th
25th 50th
5th
Patient Percentile
Ferritin Distribution by Country – DOPPS 5 (2012) –
Confidential
KDIGO
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Controversies Conference on Iron Management in CKD | March 27-30, 2014 | San Francisco, California, USA
What do we know about IV iron?
• Enhances the erythropoietic response to ESA therapy -- increased Hb response -- reduced ESA doses (economic, ?safety)
• Widespread variability in IV iron usage worldwide
• Very limited robust clinical data on safety -- iron overload -- oxidative stress / cardiovascular toxicity -- infections -- hypersensitivity reactions
KDIGO
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KDIGO
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Controversies Conference on Iron Management in CKD | March 27-30, 2014 | San Francisco, California, USA
Coyne et al. JASN 2007; 18: 975-984.
134 HD patients – Hb < 11 g/dl – Ferritin = 500–1200 ug/l – TSAT < 25% – EPO dose >225 IU/kg/wk or
>22,500 IU/wk
KDIGO
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KDIGO Guidelines: Summary of Recommendations
Chapter 2: Use of iron to treat anemia in CKD § 2.1.2: For adult CKD patients with anemia not on iron or ESA therapy we suggest a trial of IV iron (or in CKD ND patients alternatively a 1–3 month trial of oral iron therapy) if (2C):
§ an increase in Hb concentration without starting ESA treatment is desired and
§ TSAT is ≤30% and ferritin is ≤500 ng/ml (≤500 µg/l)
§ 2.1.3: For adult CKD patients on ESA therapy who are not receiving iron supplementation, we suggest a trial of IV iron (or in CKD ND patients alternatively a 1–3 month trial of oral iron therapy) if (2C):
§ an increase in Hb concentration or a decrease in ESA dose is desired and
§ TSAT is ≤ 30% and ferritin is ≤ 500 ng/ml (≤ 500 µg/l)
KDIGO
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Controversies Conference on Iron Management in CKD | March 27-30, 2014 | San Francisco, California, USA
Clark PR et al. Magn Reson Med 2003;49:572–5.
Monitoring iron overload by MRI ?
KDIGO
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KDIGO
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Controversies Conference on Iron Management in CKD | March 27-30, 2014 | San Francisco, California, USA
Iron and oxidative stress
Fenton reaction Fe 2+
OH- radical
ROS macromolecules,
e.g. membrane lipids
lipid-derived free radicals
atherosclerosis
Fe 3+
KDIGO
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Controversies Conference on Iron Management in CKD | March 27-30, 2014 | San Francisco, California, USA
Increased ROS-mediated oxidation
Lim C et al. Kidney Int 2004;65:1802–9.
Plasma malondialdehyde (MDA) levels in control rats (CTL), Fe-injected control rats (CTL+Fe), chronic renal failure rats (CRF), and Fe-injected CRF
rats (CRF+ Fe). (N = 6 in each group) ∗P < 0.05 vs. CTL group.
Plas
ma
MD
A c
once
ntra
tion
(µm
ol/L
)
0
0.2
0.4
0.6
0.8
1.0
1.2
CTL CTL+Fe CRF CRF+Fe
*
KDIGO
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Controversies Conference on Iron Management in CKD | March 27-30, 2014 | San Francisco, California, USA
Drueke T et al. Circulation 2002;106:2212–7.
Correlation between iron dose and CCA-IMT in patients <60 years
900
800
700
600
500 750 1500 2250 3000
Fe (mg/year)
CC
A-IM
T (µ
m)
KDIGO
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Controversies Conference on Iron Management in CKD | March 27-30, 2014 | San Francisco, California, USA
Scheiber-Mojdehkar B et al. J Am Soc Nephrol 2004;15:1648–55.
***
***
Tota
l per
oxid
es (µ
mol
/l)
----- IV iron
----- control (-ve iron)
A B C D
200
150
100
50
0
**
KDIGO
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Controversies Conference on Iron Management in CKD | March 27-30, 2014 | San Francisco, California, USA
• – 32,566 HD paSents (Fresenius dialysis centres) – All-‐cause mortality; 2-‐year follow-‐up
– MulSvariate models to account for Sming of IV iron and also co-‐morbidity
KDIGO
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Controversies Conference on Iron Management in CKD | March 27-30, 2014 | San Francisco, California, USA
Iron dose, unlike low albumin, is not linked to increased mortality in HD
Probability of Mortality(Adjusted Hazard Ratio ± 95% CI)
0 1 2 3 4 5
Cumulative6 month
iron dose(mg)
0 - 700700 - 1000
1000 - 1800> 1800
Albumin(g/dl)
< 3.03.0 - < 3.53.5 - < 4.04.0 - < 4.5
Results for both covariates are from unlagged time-dependent model
Feldman H et al. J Am Soc Nephrol 2004;15:1623–32.
KDIGO
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Controversies Conference on Iron Management in CKD | March 27-30, 2014 | San Francisco, California, USA
Kalantar-Zadeh K et al. J Am Soc Nephrol 2005;16:3070-80.
Association between IV iron and all-cause and CV mortality
All-cause mortality CVS-cause mortality
KDIGO
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Controversies Conference on Iron Management in CKD | March 27-30, 2014 | San Francisco, California, USA
Associations between IV iron dose and mortality
Hazard Ratio (95% CI)
KDIGO
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KDIGO
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Controversies Conference on Iron Management in CKD | March 27-30, 2014 | San Francisco, California, USA
IV iron decreases neutrophil killing capacity
Hazard Ratio (95% CI)
Deicher R et al. Kidney Int 2003; 64: 728–36.
KDIGO
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Controversies Conference on Iron Management in CKD | March 27-30, 2014 | San Francisco, California, USA
IV iron and infection
Hoen B et al (2002)
• Prospective study of 985 HD patients
• Risk factors for bacteraemia analysed
• IV iron administration does not significantly ↑ the risk of bacteraemia in chronic HD patients
KDIGO
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Controversies Conference on Iron Management in CKD | March 27-30, 2014 | San Francisco, California, USA
Associations between IV iron dose and mortality
Hazard Ratio (95% CI)
KDIGO
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KDIGO
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IV Iron Salts / Colloids → Carbohydrates
1940s
Goetsch (1946) IV colloidal Fe(OH)3 for anaemia. Severe toxic reactions in patients: ‘preclude use for
therapeutics’
Nissim 1947 Use of IV iron saccharide
IV iron sucrose Launched in Switzerland
Baird & Podmore
(1954) IM iron dextran
(Imferon)
→ IV
Auerbach M et al. Am J Hematol 2008;83:580–8; Macdougall IC & Ashenden M. Adv Chronic Kidney Dis 2009;16:117–30
Hamstra (1980) Anaphylactoid adverse
events (AEs) to iron dextran are ‘serious and unpredictable’. Leads to
black box label and test dose
Iron oxyhydroxide
core
Carbohydrate shell
Anaphylaxis DEATH
KDIGO
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Controversies Conference on Iron Management in CKD | March 27-30, 2014 | San Francisco, California, USA
Hypersensitivity reactions to IV iron
l Anaphylactic l Anaphylactoid
– vasoactive, haemodynamic, and respiratory effects
– role of histamine release from basophils and mast cells
KDIGO