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
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: > 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 resistance: Inflammation
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 resistance: Iron 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 population—peritoneal 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 (<20%), and high ferritin (>500 or >800 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 CHr<33 have increased iron responsiveness
sTfR not as good as CHr; not as available
Percent hypochromic RBCs: sensitive, specific marker for iron deficiency—drawback: blood does not store well
Jay Wish MD

15. Ferritin should not limit the physician
Before EPO therapy, patients could reach ferritin levels of 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 >500 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 RBCs—indicator of iron delivery to the bone marrow—and serum ferritin
Serum ferritin (ng/mL)
% HRC
Richardson et al. AJKD 2001;38:
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
Probability of mortality
(Adjusted Hazard Ratio ± 95% CI)
0.0
0.5
1.0
1.5
2.0
Cumulative
6-month
iron dose
(mg)
> 1800
Ferritin
(ng/ml)
< 100
> 800 P
= 0.78 =
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 2004;5:

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,

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,

25. IV iron preparations
0.3% side effects with iron gluconate—still 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 iron—cumulative 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 mg increments—several 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 Nov;(87):S Aronson, M.L.  ASN, San Diego, CA., November, 2003
Chaim Charytan MD