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MANAGEMENT OF IRON

DEFICIENCY ANEMIA IN CKD

Dharmeizar

KONAS XIII and Annual Meeting


PERNEFRI 2017
ANEMIA IS FREQUENT IN CKD

75.5
80
Hb 12g/dl (% patients)

60 53.6

41.6
40
26.7

20

0
12 3 4 5
CKD stage

Cross-sectional, US multicentre survey of 5,222 adult patients at 237 physician practices


McClellan W et al. Curr Med Res Opin 2004; 20: 1501-1510
ANEMIA:
AN INDEPENDENT RISK FACTOR FOR
MORTALITY
4

3
all-cause mortality

853 male
Hazard ratio for

patients with
CKD stages 3- 2
5 not yet on
dialysis
1

0
<11.0 >11.012.0 >12.013.0 >13.0

Time-averaged Hb ranges (g/dl)

Kovesdy CP et al. Kidney Int 2006; 69: 560-564


IRON DEFICIENCY:
THE LEADING CAUSE
OF ANEMIA IN CKD

48% of anemia in CKD


(stages 3-5, pre dialysis)

Common cause of
hyporesponsiveness to ESA

ESA: Erythropoiesis-stimulating Agent

Stancu S, et al. American J of Kidney Dis.2010;55(4):639-647


CAUSES OF ABSOLUTE IRON
DEFICIENCY IN CKD
Blood loss for lab test

Gastrointestinal loss (ec. Oral anticoagulant,


antiplatelets)

Blood loss during hemodialysis procedure

Reduced intestinal iron absorbsion, increased


hepcidin level

Reduced intake, poor appetite

Kidney International (2016) 89, 2839


EVALUATION OF ANEMIA
IN CKD

Hb concentration is:
Diagnosis of Anemia <13.0 g/dl in males
<12.0 g/dl in females
Initial evaluation:
Complete blood count (CBC) include Hb concentration,
red cell indices, white blood cell count and differential,
and platelet count
Absolute reticulocyte count
Serum ferritin level
Serum transferrin saturation (TSAT)
Serum vitamin B12 and folate levels

KDIGO Clinical practice guideline for Anemia in CKD.2012;2(4)


EVALUATION OF ANEMIA
IN CKD

For CKD patients without anemia, measure Hb concentration


when clinically indicated and:
at least annually in patients with CKD 3
at least twice per year in patients with CKD 45ND
at least every 3 months in patients with CKD 5HD and CKD
5PD

For CKD patients with anemia not being treated with an ESA,
measure Hb concentration when clinically indicated and:
at least every 3 months in patients with CKD 35ND and
CKD 5PD
at least monthly in patients with CKD 5HD

KDIGO Clinical practice guideline for Anemia in CKD.2012;2(4)


DIAGNOSIS OF IRON DEFICIENCY

TSAT <20%
Absolute
Low ferritin
level (<100
g/l)
Iron
deficiency
TSAT <20%
Functional
Normal
Ferritin Level
DIAGNOSIS OF IRON DEFICIENCY

Ferritin
Normal kidney function; Absolute iron deficiency serum ferritin
<15 g/L
CKD Patients: ferritin level 100 g/l influenced by inflammation
Dialysis patient: ferritin level 200 g/L
Serum ferritin >500 g/L excluding iron deficiency

TSAT
The ratio of serum iron to total serum iron-binding capacity
a measure of circulating iron
Iron deficiency: TSAT <15% (Normal 16-40%)
decreases in the presence of acute and chronic inflammation
functional iron deficiency
Diagnostic marker Strengths Limitations

Bone marrow iron Gold standard. Invasive test, semi (but not
content, measured from fully) quantitative.
biopsy
Liver iron content, Gold standard. Invasive test, semi (but not
measured from biopsy fully) quantitative
Serum ferritin Low ferritin levels are highly Moderately high ferritin levels
specific for detection of iron could occur in the setting
deficiency. of non-iron-related
conditions.
Transferrin saturation Higher sensitivity than serum ferritin The denominator (TIBC) can
ratio (iron saturation to detect iron deficiency. be low in malnutrition and/o
Marker of ratio inflammation.
Iron Stores Serum iron Direct measurement of circulating Diurnal fluctuation; can be
iron. low in inflammation.
in CKD Reticulocyte Measures immediate Limited data, reference
haemoglobin content incorporation of iron into levels debatable.
reticulocytes.
Percentage of Similar to reticulocyte Cumbersome specimen
hypochromic red cells haemoglobin content shipment interferes with the
results.
Soluble transferrin Correlates with the number of Mixed applicability data,
receptor transferrin receptors on unknown cut-off levels.
Kovesdy CP. Journal
erythroblasts
of Renal Care
2009;35(S2):14-24 Erythrocyte zinc May be less confounded by Affected by non-iron-related
protoporphyrin inflammation. factors such as lead level.
Hepcidin May detect the presence of Currently there are no
functional iron deficiency due to reliable assays for its
inflammation. measurement.
TREATMENT GOAL OF ANEMIA IN
CKD
Avoidance of blood transfusions and associated risks such as:
sensitisation against future transplantation
iron overload
blood-borne disease
transfusion reactions

Improved quality of life and physical functioning

Improved cognitive and sexual function

Cardiovascular benefits in terms of structure, function, incidence and


prevalence of disease

Reduced hospitalization

Reduced morbidity and mortality

NICE. Anaemia management in CKD. Rapid update 2011. Clinical Guideline


IRON TREATMENT IN CKD: WHEN?

Recommendation:
serum ferritin levels 100 g/L for patients with CKD
serum ferritin levels 200 g/L for dialysis patient
Evaluate Serum ferritin every 3 mo in patients who
are receiving ESA treatment and intravenous iron
supplementation to evaluate iron deficiency or
too much iron supplementation is given
Upper limit of serum ferritin is >500 g/L to avoid
potential complications that are associated with
iron therapy

Horl W. J Am Soc Nephrol 2007;18:382-93


WHAT IS THE OPTIMAL IRON LEVEL?

TSAT <25% was associated with a


significant increase in all-cause
mortality

Kovesdy CP. Journal of Renal Care 2009;35(S2):14-24


WHAT IS THE OPTIMAL IRON LEVEL?

Higher serum ferritin levels were


associated with a trend towards
increased mortality

Kovesdy CP. Journal of Renal Care 2009;35(S2):14-24


When taking into account concomitant TSAT and ferritin levels, low
TSAT was associated with higher mortality even in patients with
elevated serum ferritin

Ferritin as markers of iron excess

Cardiovascular outcomes

Kovesdy CP. Journal of Renal Care 2009;35(S2):14-24


IRON SUPPLEMENTATION STRATEGY

To Do OR Not To Do
IRON REPLACEMENT

Theraputic
Safety
efficacy

Short term
Administration
adverse
oral vs IV
reactions

IV iron
Iron overload
products

Kovesdy CP. Journal of Renal Care 2009;35(S2):14-24


ORAL VS INTRAVENOUS
ADMINISTRATION
ORAL IRON:
LIMITED ABSORPTION IN HD-CKD PATIENTS
Drug interactions
antacids, H2 blockers, omeprazole, PO4-binders,
zinc, quinolones, tetracyclines

Food interactions
Tea

Hepcidin
Upregulation limits effective absorption of the
small bioavailable iron

Limited efficacy and frequent gastrointestinal side effects


IV IRON:
INJECTION BYPASSES THE HEPCIDIN BLOCK
ORAL VS IV IRON
HEAD TO HEAD STUDY IN ASIAN
POPULATION
Randomized, open-label, single-center study

Patients IV Iron (Venofer)


136 Maintenance HD patients: 100 mg iron twice-weekly for 8
Hb 6-9 g/dL & Hct 18%-27% weeks, then weekly for 4 weeks;
Serum ferritin <500 g/L n=70
TSAT <30%
Oral iron
Stable condition 1 month
Ferrous succinate
200 mg t.i.d. for 12 weeks;
n=66

All patients received EPO at a dose of 100-150 IU/Kg/week during the study.
If Hb concentration reached 11 g/dL, the EPO dose was decreased by 25%.

Li H et al. Blood Purif 2008;26:151-6


Oral vs IV iron
IRON SUCROSE enabled targets to be achieved &
reduced ESA

Oral iron
p<0.05 Venofer
p<0.05 p<0.05
600 50 14 7000
6140
496 12.0
500 39.6 12 6000
40 10.0
400 5000 4500
400 10
28.6
30 4000
8
300
20 6 3000
200
4 2000
100 10
2 1000
0 0 0 0
Serum ferritin (g/L) TSAT (%) Hb (g/dL) ESA dose (IU/week)
at week 12 at week 12 at week 12 at week 12*

* EPO reduction significant versus


baseline only in the IV group.

IRON SUCROSE (Venofer) effectively improved iron status and


Hb levels and allowed for a reduction in ESA dose
Li and Wang. Blood Purif. 2008;26(2):151-6.
Oral vs IV iron
Results and Safety

Iron Sucrose effectively improved iron status and Hb


levels and allowed for a reduction in ESA dose

Improvements were significantly greater in the Iron


Sucrose (Venofer) group than oral iron group

There were no reported AEs in the Iron Sucrose


(Venofer) group whereas 22 patients (33%) reported
to have mild GI symptoms in the oral iron group

Li H et al. Blood Purif 2008;26:151-6


IV IRON PRODUCTS
Higher potential possibility of causing life
threatening anaphylactic-type
Iron reactions.
dextran Maximum dose 20 mg/kg body weight
by infusion over 46 hours.

Iron Possibility of toxicity


gluconate Maximum dose 62.5 mg

Possibility of toxicity, Most widely


Iron prescribed IV iron
sucrose Maximum dose up to 200 mg
ADVERSE REACTIONS OF IV
IRON ADMINISTRATION

Short-term Long-term
Anaphylactic rx Iron overload

Hypotension Infections
Gastrointestinal Oxidative stress and CV
symptoms risk

Kovesdy CP. Journal of Renal Care 2009;35(S2):14-24


IV IRON SUPPLEMENTATION:
OXIDATIVE STRESS AND CV RISK

Oxidative stress occurs early in the evolution of impaired


kidney function a poor prognosis and persistent
inflammation

i.v. iron administration:


Promotes oxidative damage to peripheral blood lymphocyte
DNA, protein oxidation, and lipid peroxidation
Promotes cellular apoptosis, endothelial dysfunction, and
monocyte adhesion

i.v. iron doses greater than 400 mg/mo were associated with
higher CV death rates
FERRITIN/ISAT LEVEL AND
OUTCOMES

MICS, malnutrition-inflammation-cachexia syndrome J Am Soc Nephrol 16: 30703080, 2005


RISK AND BENEFITS OF HIGH-
DOSE IRON IN CKD

BENEFITS RISKS
Lower ESA dose and Unknown longterm
treatment costs effect
Posibble prevention of Acute reactions
CV events associated (intravenous):
with high-dose ESA anaphylactoid,
Improvement of heart adbdominal/chest
failure pain, shortness of
breath nausea,
hypotension, pruritus
and rash
Nephron 2015;131:138-144
MANAGEMENT OF REACTIONS TO IV IRON

Kidney International (2016) 89, 2839


CONCLUSIONS
Iron deficiency most common cause of anemia
in CKD
Evaluation of iron status should be routinely
performed
The proper management of iron administration is
important to achieve theraputic effect and to
decrease the adverse reactions
Evaluation of possibility of iron overload should be
done base on combination of ferritin and ISAT level