Iron Metabolism in ESRD

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Jun-Ki Park

Sargent et al. Blood Purif 2004

Iron Loss in ESRD • Decreased duodenal iron absorption

• Reduced transferrin concentration leading to decreased iron transport

capacity

• Increased iron loss d/t frequent blood sampling, losses into dialysis tubing and dialyzers

• Occult GI bleeding

• Increased rate of iron turnover to maintain the decreased RBC mass

• Iron losses of 6-7mg daily in addition to physiological iron losses of 1-2mg daily

• Annual loss of 1.5-3g

Iron Malabsorption in ESRD • Acquired GI disease is increasingly recognized as an additional

malabsorptive mechanism of iron deficiency anemia in patients on hemodialysis:

- autoimmune atrophic gastritis and Helicobacter pylori infection are frequently present in such patients - Endoscopic abnormalities incl. chronic and acute gastritis, duodenitis or duodenal ulcer are found in up to 90% of asymptomatic patients on hemodialysis. (Al-Mueilo et al Saudi Med J 2004)

- histological examination of multiple antral gastric biopsy samples documented the presence of chronic active gastritis in these patients

Erythropoiesis

Besarab et Coyne, Nat. Rev. Nephrol 2010

Forms of Iron Deficiency

• Absolute iron deficiency

• Functional iron deficiency

• Iron deficiency d/t inflammation

(‘Reticulo-endothelial blockade’)

Absolute Iron Deficiency

Absolute Iron Deficiency

Fishbane S. et al. JASN 1996

Functional Iron Deficiency • ‘Demand – Supply – Imbalance’

• Adequate iron stores as defined by conventional

criteria, but insufficient mobilization of iron from storage sites to adequately support erythropoiesis with the administration of ESA.

• Serum ferritin level is either normal or elevated, but

the TSAT typically is about 20% or less.

• It responds to iron supplements with an increase in hemoglobin and/or decrease in ESA requirements.

Reticulo-Endothelial Blockade • Refractory anemia due to an underlying inflammatory

state. • Usually characterized with TSAT < 20% and elevated

Ferritin > 200-800 ng/ml • Hepcidin as the key player preventing the intesintal

absorption of iron and release of it from hepatocytes and RES.

• Usually does not respond to iron therapy

Role of Hepcidine

Robert E. Fleming NEJM 2005

Chasis, J. A. & Mohandas, M. Blood 112, 470–478 (2008).

As bone marrow erythropoiesis occurs in erythroblastic islands that surround macrophages, hepcidin inhibition facilitates the mobilization of iron stored in the RES in macrophages to the surrounding maturing red blood cells.

• As the increased cardiovascular risk associated with ESA therapy might be a result of the high doses of these agents rather than of the elevation in hemoglobin levels, increased iron supplementation might reduce the risks associated with ESA therapy.

Multivariate adjusted association between serum iron saturation ratio (ISAT) and all-cause mortality in 58,058 maintenance HD patients in DaVita dialysis facilities between 7/2001 and 6/2003

Kalantar-Zadeh et al. JASN 2005

What is optimal TSAT range? • Randomized controlled study with 42 maintenance HD pts.

• Run-in period of 16 to 20wk: iron dextran and Epo were administered to target average TSAT of 20 to 30% and baseline levels of hemoglobin of 9.5 to 12.0 g/dl

• After the run-in period, 19 pts randomized to the control group received

iron dextran 25 to 150 mg/wk for 6 months • 23 pts randomized to the study group received 4-6 x 100mg loading

doses of iron dextran over 2weeks to achieve TSAT 30% followed by 25 to 150 mg weekly to maintain TSAT between 30 and 50% for 6 months

• Erythropoietin (EPO) dosage was adjusted every 4 wk to maintain Hb at

the same value

Besarab et al. JASN 2000

Besarab et al. JASN 2000

Limitation of Serum Ferritin / TSAT

• Ferritin is acute phase reactant

• There are gender differences (lower in women)

• Transferrin level rises with inflammation and falls with malnutrition/chronic disease.

• Diurnal fluctuations in TSAT described

Kamyar Kalantar-Zadeh CJASN 2006

Reticulocyte Hb Content (CHr)

• Hb in reticulocytes, which are RBCs that are just 1 -2 day old.

• CHr provides a snapshot of how much iron was available for RBC production in a clinically relevant timeframe.

Mittman N et al. AJKD 1997; Chuang et al. NDT 2003

Reticulocyte Hb Content (CHr) • 157 HD patients from 3 centers were randomized to iron

management based on (group 1) serum ferritin and transferrin saturation, or (group 2) CHr. Patients followed for 6 months.

• Treatment with IV iron dextran, 100 mg for 10 consecutive treatments was initiated if (group 1) serum ferritin 100 ng/mL or transferrin saturation 20%, or (group 2) CHr 29 pg.

• In group 1, the investigators treated the patients with serum ferritin levels <100 ng/ml and <TSAT 20%.

• In group 2, the investigators used CHr 29 pg and then explored a subset with a higher cutoff of 30 pg.

Fishbane et al. KI 2001

Fishbane et al. KI 2001

Distribution of reticulocyte hemoglobin content (CHr) values among all subjects.

The mean IV weekly dose of IV iron dextran: Group 1: 47.7 +- 35.5mg Group 2: 22.9 +-20.5 (p+=0.02) Fishbane et al. KI 2001

Fishbane et al. KI 2001

• They found that the CHr was less variable than the TSAT or the ferritin and that it was more accurate.

• In a subsequent study, Fishbane et al. determined that a CHr cutoff of 29 pg tended to miss a number of patients who ultimately responded to intravenous iron.

• The authors concluded that a cutoff of 32 pg showed a much greater utility, and a majority of the patients who had iron therapy on the basis of a CHr 32 pg with an average of 23% reduction in their erythropoietin requirements

Limitation of Serum Ferritin / TSAT • Situation in which the TSAT is low and the serum ferritin is high

occurs often among HD patients.

• Serum ferritin may be elevated in this setting because of functional iron deficiency or RE blockade.

• Therapeutic dilemma: Whether to give additional iron supplements bring the TSAT up into the K/DOQI target range, especially in patients who are not achieving the target Hb in the setting of ESA treatment.

• Risk vs. benefit analysis: What is the risk to the patient’s safety by giving additional intravenous iron versus the benefit of providing additional iron for RBC production so that the patient can enjoy the physiologic and quality of life rewards of a higher Hb level?

DRIVE

Inclusion critria: Hb < 11g/dl ferritin 500-1200ng/ml TSAT <25% Epo dosage >225IU/kg per wk or >22500IU/wk

125mg x 8

Epo increased 25%

Risk for Iron Overload • Iron storage capacity of the RES is about 5 g.

• As per pre-ESA studies, to observe the effects of

hemochromatosis on parenchymal organs, serum ferritin levels had to exceed 2000 to 3000ng/ml and were commonly > 5000ng/ml and TSAT >50% (Bregman et al. Int. J Artif Organs 1981)

• Before the availability of ESAs, iron accumulation occurred in

patients with CKD on dialysis owing to repeated blood transfusions.

• These patients typically had serum ferritin levels >2000ng/ml, high levels of iron in macrophages in the liver and spleen, but very little parenchymal iron accumulation (in hepatocytes or cardiac myocytes). (Ali et al. Lancet 1982)

Ascorbic Acid in EPO-hyporesponsive Anemia and Hyerferritinemia

• Open-label, randomized, prospective study of 42 HD pts with unexplained hyperferritinema not attaining KDOQI Hb level target at EPO doses > 450U/kg/wk.

• Inclusion criteria:

• administration of IV iron and EPO for > 6 months at a dose > 450 U/kg/wk,

• average 3-month Hb level < 11.0 g/dL

• ferritin level > 500 ng/mL

• TSAT < 50%

Attallah, Besarab et al. AJKD 2006

Vit C 300mg IV with each HD session

Attallah, Besarab et al. AJKD 2006

Attallah, Besarab et al. AJKD 2006

Attallah, Besarab et al. AJKD 2006

Attallah, Besarab et al. AJKD 2006

• Possible mechanism for the effect of ascorbate is its effect on iron uptake and iron transport. Ascorbate is a chelator that might mobilize iron from its tissue stores and lead to better responsiveness to EPO.

• Experimental studies indicated that vitamin C is involved in several phases of iron transport, as well as regulation of iron uptake and sequestration. At the molecular level, vitamin C mobilizes iron from the ferritin crystal core in vitro by reducing ferric iron (Fe3) to ferrous iron (Fe2).

Ferritin

Kamyar Kalantar-Zadeh CJASN 2006

Common IV Iron Dosing Regimen

Novel Methods of Iron Delivery

• Ferric Carboxymaltose: macromolecular ferric hydroxide carbohydrate complex. Can be delivered at a replenishment dose of up to 1000 mg of iron during a minimum administration time of </=15 min.

• Administration of iron via dialyzate during each HD is undergoing testing: In a preliminary 6 months study of stable HD pts, soluble ferric pyrophosphate (a chelated iron) added to the dialyzate readily diffused into the blood and was safe and effective

Thank You!