Iron in patients with chronic kidney disease

1
Iron in patients with chronic kidney disease

• Jay Wish MD
• Director, Dialysis Unit
• University Hospitals of Cleveland
• Professor, Case Western Reserve University
• Cleveland, OH
• Chaim Charytan MD
• Chief, Renal Division
• Director, Dialysis Unit
• New York Hospital Medical Center of Queens
• Clinical Professor of Medicine, Cornell
  University College of Medicine
• New York, NY

2
A currently hot topic

• New K/DOQI guidelines on anemia management
• Four areas of interest
• Erythropoietin resistance
• Patients with low TSAT and high ferritin
• Safety of different iron preparations
• The use of iron in CKD

Jay Wish MD
3
Erythropoietin therapy

• Important step in the treatment of CKD
• Benefits
• Regression of LVH / Improved CV Function
• Decreased hospitalization rate
• Improved survival
• Improved exercise capacity
• Improved cognition
• Improved sexual function
• Improved quality of life
• Decreased transfusion requirements

Chaim Charytan MD
4
Erythropoietin resistance

• Loss of response or limited response to EPO
• Excessive dose requirement gt30 000 units of EPO
  per week
• Causes of resistance
• Inflammation
• Infection
• Malnutrition
• Underdialysis
• GI bleeding
• Neoplasia

• Vitamin or trace element deficiency
• Aluminum toxicity
• Osteitis fibrosa
• Anti-erythropoeitin antibodies
• Iron deficiency

Chaim Charytan MD
5
Erythropoietin resistanceInflammation

• Often called the malnutrition inflammation
  anemia syndrome
• Anemia not a cause but a marker of severe
  metabolic disturbances resulting from an
  inflammatory process
• Causes EPO resistance
• Limits response to iron therapy and EPO therapy

Chaim Charytan MD
6
Erythropoietin resistanceIron deficiency

• Major treatable cause of EPO resistance
• Hemodialysis population
• Blood losses into the dialyzer, dialysis tubing,
  venipuncture
• Losses of 3-9 mL of blood / 3-9 mg of iron/day
• Predialysis CKD populationperitoneal dialysis
  patients
• Iron deficiency related to anorexia, decreased
  intake, chronic GI bleeding, nonsteroidal
  ingestion, menstruation and pregnancy in women.

Chaim Charytan MD
7
Oral vs parenteral iron

• Oral iron is not as effective as parenteral iron
  in hemodialysis, peritoneal dialysis, and CKD
  patients
• Causes include
• Iron malabsorption
• Lack of patient compliance due to GI effects

Chaim Charytan MD
8
IV iron is superior to oral iron in managing
anemia of NDD-CKD
Source Iron Sucrose US Clinical Trials Group
Kidney Int in press
9
In terms of iron management

• We must determine
• How much iron to use
• What target level to aim for
• What parameters to use (TSAT, ferritin, or other)
• Increasing number of patients with high EPO
  requirements, low TSATs (lt20), and high ferritin
  (gt500 or gt800 ng/mL)

Jay Wish MD
10
K/DOQI updates

• Target ferritin ceiling changed from 800 ng/mL
  to 500 ng/mL
• Modification will affects patients who are
  currently well managed
• Current mean is 600 ng/mL, so half of patients
  will now receive less iron
• Problems achieving target hemoglobin levels

Jay Wish MD
11
Reevaluating traditional parameters

• Ferritin
• Storage iron
• Also an acute-phase reactant
• Should focus less on high ferritin levels and
  more on indicators of iron available for
  erythropoiesis
• Newer measurements
• Reticulocyte hemoglobin content
• Percent hypochromic RBCs
• Soluble transferrin receptors (sTfR)

Jay Wish MD
12
Which iron marker to use?

• Patient needs increased EPO to meet target
  hemoglobin levels
• Significant iron requirement
• Oral iron not enough, IV iron necessary
• TSAT is the best marker for iron available for
  erythropoiesis
• Iron should be given to increase TSAT to the
  20-30 range

Jay Wish MD
13
Decreasing EPO use

• Will be a common trend as EPO becomes a cost
  center rather than a profit center
• Decrease EPO use by bringing TSAT to the 30
  range

Jay Wish MD
14
If a patient has low TSAT and high ferritin

• Further tests can be done
• Reticulocyte hemoglobin content (CHr)
• Steve Fishbane et al patients with CHrlt33 have
  increased iron responsiveness
• sTfR not as good as CHr not as available
• Percent hypochromic RBCs sensitive, specific
  marker for iron deficiencydrawback blood does
  not store well

Jay Wish MD
15
Ferritin should not limit the physician

• Before EPO therapy, patients could reach ferritin
  levels of 4000-5000 ng/mL
• Physicians should not be too focused on ferritin
  level
• K/DOQI guideline updates
• Based on studies showing that iron responsiveness
  decreases with ferritin gt500 ng/mL
• Distinction between
• Patient with low TSAT and high ferritin with
  inflammation
• Patient with functional iron deficiency
• The latter can benefit from iron therapy

Chaim Charytan MD
16
Hypochromic red blood cells
Scatter plot of median ferritin level (ng/mL) vs
median HRC for each respective month of study
Inverse linear relationship between the
percentage of hypochromic RBCsindicator of iron
delivery to the bone marrowand serum ferritin
Serum ferritin (ng/mL)
HRC
Richardson et al. AJKD 200138109-117
Jay Wish MD
17
Adverse events with IV iron?

• No reported cases of hemochromatosis or
  hemosiderosis with IV iron in the erythropoietin
  era
• Guidelines were updated for physicians not to use
  iron indiscrimately
• Acute infusion of IV iron on immune system
• Avoid in infected patients
• Avoid in patients with high CRP and high ferritin

Chaim Charytan MD
Jay Wish MD
18
Safety of IV iron Areas of concern

• Tissue overload no evidence in the literature
  since the introduction of EPO
• Infectious complications
• In vitro iron interferes with white cell function
  and phagocytosis
• Has not been translated into clinical consequences

Chaim Charytan MD
19
Safety of IV iron CV morbidity?

• In vitro iron can be proinflammatory and induce
  lipid peroxidation
• Could parenteral iron lead to accelerated
  atherosclerosis, inflammation and thus CV
  morbidity?
• In vitro doses required to have an effect are
  much higher than used in IV iron
• Feldman et al saw no correlation between iron use
  and CV mortality and morbodity

Chaim Charytan MD
20
High ferritin, not cumulative iron dose, linked
to increased mortality in HD patients
Results for both covariates are from unlagged
time-dependent model. Ferritin is from month
prior to iron dosing period.
Adapted from Feldman HI et al. JASN
200451623-32.
21
Safety of IV iron

• Higher risk with undertreatment
• Benefits of correcting anemia far outweigh the
  theoretical risk of CV toxicity

Chaim Charytan MD
22
IV iron preparations

• Three types of IV iron preparations
• Iron dextran
• Iron sucrose
• Iron gluconate
• Iron dextran has the highest incidence of modest
  and severe life-threatening side effects
• Iron sucrose and iron gluconate are newer and
  safer
• No head-to-head analysis of the different
  preparations

Chaim Charytan MD
23
FDA reported allergic reactions to IV iron
Jan 1997-Sep 2002
Reports/million 100 mg dose equivalents
Bailie et al. NDT 2005,20,1443-1449
24
FDA reported allergic reactions to IV iron
Jan 1997-Sep 2002
Dextran has highest reporting rates in all
clinical categories
Reports/million 100 mg dose equivalents
Bailie et al. NDT 2005,20,1443-1449
25
IV iron preparations

• 0.3 side effects with iron gluconatestill very
  low
• Patients who have had a reaction to iron dextran
  are more likely to have a reaction to iron
  gluconate than to iron sucrose
• Iron sucrose and iron gluconate are used in
  similar total doses per course of therapy,
  generally 1 gram per course
• Iron sucrose may be given at 500 mg/4 hours iron
  gluconate can only be given at 300 mg/4 hours

Chaim Charytan MD
26
Infusing the newer iron preparations

• ESRD population patients come in three times a
  week for small doses of ironcumulative 1 g
• Adverse reactions with iron sucrose or iron
  gluconate seen at higher doses only
• No anaphylactic death from either preparation in
  35 years

Jay Wish MD
27
Drawbacks of the newer iron preparations

• Iron deficiency-related anemia in stage 3-4 CKD
• Repleting the iron
• Oral iron
• Potential intolerance due to GI side effects
• IV iron
• Iron sucrose and iron gluconate can only be given
  in 100-150 mg incrementsseveral infusions
  required
• Problem for intravascular access
• Iron dextran can be administered at a 1-g dose.
  Is saving the vein worth the 1 in 100,000 risk of
  anaphylactic shock?

Jay Wish MD
28
No question, no anaphylaxis!

• There is no need to go to IV dextran and expose
  the patient to that risk
• Article in press in AJKD
• 500 mg sucrose infusions generally safe
• Blaustein, DA Kidney Int Suppl. 2003
  Nov(87)S72-7. Aronson, M.L.  ASN, San Diego,
  CA., November, 2003

Chaim Charytan MD