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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


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


CKD Anaemia Management

Transfusions

IV Iron ESAs KDIG

O


Pre-‐1990

Transfusions

Post-TREAT

IV Iron

ESAs

1990 - 2009

Transfusions Transfusions

IV Iron

ESAs

IV Iron

KDIGO


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)


KDIGO


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


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


Haemoglobin, ESA, and IV iron use in dialysis units in the US (1992−2004)

KDIGO






-- iron overload

-- reduced ESA doses (economic, ?safety)


KDIGO

Mean Ferritin Trends by Country – DOPPS 2-5 (2002-2012)

Mean ferritin (ng/mL)

Non-European Countries European Countries

Confidential

KDIGO

95th

75th

25th 50th

5th

Patient Percentile

Ferritin Distribution by Country – DOPPS 5 (2012) –

Confidential

KDIGO






KDIGO

KDIGO


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

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


Clark PR et al. Magn Reson Med 2003;49:572–5.

Monitoring iron overload by MRI ?

KDIGO

KDIGO


Iron and oxidative stress

Fenton reaction Fe 2+

OH- radical

ROS macromolecules,

e.g. membrane lipids

lipid-derived free radicals

atherosclerosis

Fe 3+

KDIGO


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


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)

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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


•  – 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

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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


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


Associations between IV iron dose and mortality

Hazard Ratio (95% CI)

KDIGO

KDIGO


IV iron decreases neutrophil killing capacity


Deicher R et al. Kidney Int 2003; 64: 728–36.

KDIGO


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


Associations between IV iron dose and mortality


KDIGO

KDIGO

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


Hypersensitivity reactions to IV iron

l  Anaphylactic l  Anaphylactoid

– vasoactive, haemodynamic, and respiratory effects

– role of histamine release from basophils and mast cells

KDIGO

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Iain Macdougall: Disclosure of Interestskdigo.org/wp-content/uploads/2017/02/1...Feb 01, 2017 · Iain Macdougall: Disclosure of Interests ... cause and CV mortality All-cause mortality