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

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

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

Erythropoietin resistance Loss of response or limited response to EPO Excessive dose requirement: >30 000 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

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

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

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

IV iron is superior to oral iron in managing anemia of NDD-CKD Source: Iron Sucrose US Clinical Trials Group; Kidney Int: in press

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

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

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

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

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

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

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 >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

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;38:109-117 Jay Wish MD

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

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

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

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) 0 - 700 700 - 1000 1000 - 1800 > 1800 Ferritin (ng/ml) < 100 100 -800 > 800 P = 0.78 = 0.0005 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;5:1623-32.

Safety of IV iron Higher risk with undertreatment Benefits of correcting anemia far outweigh the theoretical risk of CV toxicity Chaim Charytan MD

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

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

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

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

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

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 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

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