Faint
is not a description
of color
Faint
is
a description
of LIFE
Why are CKD patients prone to develop
iron deficiency?
REDUCED INTAKE
INCREASED LOSSES
•
Poor appetite
•
Occult G-I losses
•
Poor G-I absorption
•
Peptic ulceration
•
Concurrent
•
Blood sampling
•
Dialyser losses
•
Concurrent meds. –
medication – e.g.
omeprazole
•
Food interactions
e.g. aspirin
•
Heparin on dialysis
Iron Management
WHY..?
-Most common cause of an incomplete response to Epoetin
Is iron Deficiency
-Iron is Crucial to the success of Epoetin therapy
-Allow Epoetin to be used more cost-effectively
NKF-DOQI
IDS
IDA
Physical performance
Erythropoiesis
in CKD
Erythropoiesis
Epo
Vit D
SCF, IL-1, IL-3,
IL-6, IL-11
Iron
Erythropoietin
SCF, GM-CSF,
IL-3
About 8 Days
Pluripotent
Stem Cell
Burst-Forming Colony-Forming ProerythroUnit-Erythroid Unit-Erythroid
blasts
Cells (BFU-E)
Cells (CFU-E)
Erythroblasts
Reticulocytes
RBCs
Papayannopoulou T, et al. In: Hoffman R, et al., ed. Hematology: Basic
Principles and Practice. 4th ed. 2005;267-288.
Iron deficiency stages
Early stage
Iron deficiency syndrome
IDS
Late stage
Iron deficiency anemia
IDA
Fatigue
Difficulty concentration
Depressed mood
Sleeping disturbance
Neck tensions
Headache
Dizziness
Loss of hair
Pallor (pale skin)
General malaise
Muscular weakness
Dyspnea
Palpitation
Tachycardia
Low blood pressure
What a body needs iron for
Red blood cell formation
70 % of body iron
Myoglobin formation
Myoglobin occurs in the
cells of the heart muscle
and the skeletal muscles
What a body needs iron for
Hormone formation
formation of hormones can only occur if a
biochemical impulse for their production is sent.
This requires enzymes - substances, also known
as catalysts
these enzymes
need iron to do their job
Serotonin
an endorphin, is also often referred to as
the “happy hormone.”
Dopamine
Like serotonin, dopamine is called
a “happy hormone”
dopamine makes it possible for a person to
recognize relevant stimuli, i.e., those that are
meaningful to him, and ignore unimportant ones
Melatonin
regulates the functioning of what is
known as our inner clock
DSIP
(Delta Sleep Inducing Peptide)
produces the deep sleep, an
important sleep phase that is
responsible for the quality of our
nightly recovery.
Cortisol
controls all of the protein, sugar and
fat metabolisms
As a stress hormone, it is simultaneously
responsible for our body to adapt to
special stresses with appropriate
reactions
Energy production
Each body cell contains a large number of mitochondria We
consider them our “power plants” and they use adenosine
triphosphate (ATP) to produce the necessary chemical cell
energy It is the iron-sulfur molecules, which are the
central constituents in the cascade of chemical reactions
that results in energy being released in the cells
Eicosanoid formation
Eicosanoids are our organism’s ironcontaining signaling molecules, which
directly influence many of our bodily
functions
a) Effect on smooth muscle tension
b) Influence on the stomach
c) Effect on the immune system
a) Effect on smooth muscle tension:
Eicosanoids influence the state of tension of the smooth
muscles. Depending on the impulse that the smooth muscle
cells are exposed to, they change from a state of tension to a
state of relaxation and vice versa These signaling molecules
thereby have a direct effect on important bodily functions,
such as
blood pressure regulation
breathing
intestinal and uterine activities.
b) Influence on the stomach:
In the stomach, an equilibrium typically exists between the
aggressive hydrochloric acid needed for digestion and the
mucous membrane, a layer of cells protecting the stomach
walls.
Here, the iron-containing eicosanoids are co-responsible
for both the acid production and for an adequate quality of
the protective layer.
c) Effect on the immune system:
The eicosanoids also include leukotrienes.
Those are small acid particles in the white blood cells
which are
1. effective in connection with allergic and inflammatory
reactions.
2. It is also the function of leukotrienes to “attract” the
body’s antibodies to the site of an infection.
Basic tissue formation
Iron is co-responsible for the formation and regeneration of our
organism’s basic tissues. These are known to include bone,
cartilage, skin, connective tissue, mucous membranes, hair and
nails. In these building processes, protein chains are
converted to stable fibers by a biochemical process known as
hydroxylation. Iron is indispensable for this process as well.
factors contribute to the development of iron deficiency in CKD
INCREASED LOSSES
• Occult G-I losses
• Peptic ulceration
• Blood sampling
• Dialyser losses
• Concurrent meds.
– e.g. aspirin
• Heparin on
1. National Kidney Foundation. K/DOQI clinical practice guidelines
for chronic kidney disease: evaluation, classification, and stratification.
Am J Kidney Dis 2002;39 (2 Suppl 1):S1-266.
dialysis
EBPG KEY RECOMMENDATIONS
All CRF patients must be iron replete to achieve and
maintain the target Hb.
Almost all HD patients will require IV iron
EBPG KEY RECOMMENDATIONS
Adequate iron status is defined as :
-Serum ferritin
 100mg/l
 200mg/l
-TSAT
-Hypochromic RBCs
> 20%
< 10%
To achieve this target, the population median will be:
Serum ferritin
= 200-500 mg/l
-TSAT
= 30-40%
-Hypochromic RBCs
< 2.5%
Iron Management
Do we match the standards
ESAM Survey
6 month survey
14527 dialysis patients
13 Western European countries
Published in Nephrology Dialysis Transplantation in 2000
ESAM Survey key findings
Absolute iron deficiancy
-15-22% of HD patients
-41% to 45% of PD patients
Iron Store monitor
-41% had iron stores monitored less frequently than is
recommended by the EBPG during Epoetin treatment
in correction phase
Cost effectiveness
Patients with adequate iron status reached a higher Hgb
with lower Epoetin dose
Protocol for dose adjustment
Determine patient Hemoglobin
Hgb< 11-12g/dl
Hgb 11-12g/dl
• Check blood pressure
Monitor Hgb
(if high) control hypertension
If
Serum ferritin
MCH
MCV
high
low
low
Check
CRP for
infection or inflammation
Initiate Epo therapy
• Check iron stores:
-Transferrin saturation  20%
-Serum ferritin 100ng/ml CKD
200ng/ml ESRD
- MCH
low in iron deficiency
- MCV
low in iron deficiency
Supplement to maintain
Adequate iron levels
In practice we aim for
-Transferrin saturation 30-40%
-Serum ferritin 200-500ng/ml
Protocol for dose adjustment
Initiate Epoetin therapy
- 50 IU/Kg/week for CKD Predialysis
-150 IU/kg/week for ESRD DIALYSIS
Optimize dose: monitor Hgb and adjust dose accordingly
Hgb 11-12 g/dl
Maintain same dose
Monitor Hgb once/month
Hgb > 12 g/dl &
if Hgb increases >1 g/dl/in any 2 week period
Withhold the Epoetin dose
Monitor Hgb twice a week
Hgb < 11-12 g/dl &
If Hgb increases < 0.7 g/dl/month
Increase weekly
dose by 25-50%
Monitor Hgb twice a week
For 2-6 weeks after any
dose adjustment
What are the most common
causes for Epo resistance
4
Common causes
• Iron deficiency
•Infection/inflammation
•Chronic blood loss
•Osteitis fibrosa/hyperparathyroidism
What about Iron deficiency
•Most common cause of resistance
•Normal body Iron stores are
800-1200 mg
What about the iron requirements
For CRF patients
•during first 3 months of Epo therapy
1000 mg
Once target Hgb is achieved
400-500 mg of iron/3 month
How can we assess the iron status
Serum Ferritin
‹100 ng/ml
‹200 ng/ml
In practice we aim for
200-500 ng/ml
How can we assess the iron status
Transferrin saturation
‹ 20%
In practice we aim for
30-40%
How can we assess the iron status
Hypochromic RBCs
> 10%
In practice we aim for
< 2.5%
Treatment options
Adequate iron stores readily available for erythropoiesis are
the prerequisite for the correction of anemia in all settings.
Treatment options
Red blood cell transfusions in life threatening anemia
Treatment options
Pharmacological agents for anemia correction
Oral iron therapy
Oral iron salts
- (non-compliance due to GIT upset)
- Intake independent of meals is recommended
Oral Heme iron
- Intestinal iron absorption is 20-30 times more than iron
salts
- Minimal GIT upset-more patient compliance
Intravenous iron preparations
Structure of IV iron agents
- Colloids with spheroidal iron
- Carbohydrate nano particles
- Each particle Consists of
- Iron-oxyhydroxide core (iron (III) hydroxide)
- Carbohydrate shell surrounds & stabilizes the core
This particles structure resemble ferritin that protects against
the toxicity of unbound inorganic ferric iron (iron (III))
Intravenous iron preparations
While the core chemistry is identical in all agents
Core size, shell and global size of the particles
differ for each agent
Differences in core size & carbohydrate chemistry
determine
Pharmacological & biologic differences
Clearance after injection
Iron release in vitro
Early evidence of iron bioactivity in vivo
Maximum tolerated dose
Rate of infusion
Intravenous iron forms
Iron dextran (50mg/ml)
Risk of life-threatening or serious acute hypersensitivity
Test dose of 0.5 ml (25mg)is required prior to first therapeutic dose
One hour should elapse after the test dose
Can be given IV
.
Intravenous iron forms
Ferric gluconate
Lower incidence of lethal hypersensitivity
Iron sucrose (20mg/ml)
No reported lethal reactions
The most commonly used.
Frequency of iron monitor
in CKD patients
Not on Epoetin or IV iron
3-6 Month
Initiation phase of EPO
and No IV iron
4-6 Weeks
Initiation phase of EPO
and taking IV iron
3 Month
Maintenance phase of
EPO and taking iv iron
3-6 Month
Labile Iron
Definition
Defined as the fraction of total intravenous iron
with early biological activity
-Due to a limited pathway seen with all intravenous iron
agents where iron is donated directly from the ironcarbohydrate complex to transferrin
Labile Iron
Fraction of labile iron in (iron–carbohydrate) complexes
varies from 2.5 to 5.8%
iron dextran < iron sucrose < ferric gluconate
2.5% --------------------------------- 5.8%
Molecular weight
- Iron dextran (76 to 265KD) > iron sucrose (43 KD) >
ferric gluconate (38KD)
-The total surface area for iron release is likely the key
factor influencing the rate of iron release.
-A collection of smaller spheres offers a greater total
surface area for iron release than a collection of fewer,
larger spheres with an equal mass
IV iron preparations
Allergic reactions
Fatal anaphylactic reactions reported by FDA (FOI) database
(1997-2002) related to iron sucrose =
0%
Parenteral iron
IM&SC
- IM & SC iron abandoned in many countries due to side effects
Intravenous iron therapy
For patients
- intolerant to oral iron
- oral iron supplementation is not possible
- oral iron therapy fails to provide enough iron for the correction
or prevention of iron-deficiency anemia despite appropriate
patients compliance.