We recommend that ESA therapy should NOT be initiated in the presence of absolute iron deficiency, (ferritin <100 mcg/L in people with non-dialysis dependent CKD (NDD-CKD) and <200 mcg/L in people who are dialysis dependent) until this is corrected and it is determined that anaemia persists in conjunction to a shared decision of the advantages and risks of ESA therapy. In people with functional iron deficiency iron supplements should be given prior to or when initiating ESA therapy. (1B)
Rationale
Iron is required for production of new red cells. Iron must be supplied to the erythropoietic tissue at an adequate rate, particularly if stimulated by ESA therapy. If iron stores are low ESAs can still be used if anaemia of CKD is a likely contributor, as long as iron is made directly available to the erythropoietic tissues coincident with the initiation of ESA therapy.
- For people with CKD, percentage of hypochromic red blood cells >6% or reticulocyte Hb content < 31 pg are good tests to assess iron status.
- If these tests are not available or the person has thalassaemia or thalassaemia trait, a combination of transferrin saturation (less than 20%) and serum ferritin measurement (less than 100 microgram/L) are a suitable alternative (1).
The PIVOTAL trial has shown that in people receiving haemodialysis on a high-dose proactive iron regimen (400 mg a month after an initial dose of 600 mg in the first month) require smaller ESA doses to maintain desirable Hb level between 100-120 g/L, when compared to those patients on low dose iron regimen (0-400 mg monthly when required to maintain ferritin >200 μg/L and a transferrin saturation >20%). The median monthly dose of erythropoiesis-stimulating agent was 19.4% lower in people receiving the high-dose regimen (29,757 IU per month; interquartile range, 18,673 to 48,833) than in patients receiving the low-dose regimen (38,805 IU per month; interquartile range, 24,377 to 60,620) (median difference, −7539 IU per month; 95% CI, −9485 to −5582). The people in the high dose arm experienced less cardiovascular events, which may be contributed to lower ESA doses use due to pro-active iron therapy (2).
Several smaller prospective trials have also been carried out to confirm what was found in the PIVOTAL trial. One study compared the ESA requirements in Iranian people receiving haemodialysis receiving regular low dose iron (100 mg/month, n=30) and high dose iron (400 mg/month, n=30) regimens. It was found that the ESA dosage to maintain hemoglobin level between 100 and 120 g/L was significantly decreased in the high dose iron arm (52,129.03 ± 23,810 vs. 45,760 ± 20,978.71, P ≤ 0.02) (3).
Another study also compared ESA requirements in Thai people receiving haemodialysis prescribed regular low dose iron (100 mg/month, n=40) and regular high dose iron (200 mg/month, n=39). Similarly, this showed reduced ESA requirements, to maintain a desirable Hb level of 100-120 g/L, in those patients on the high dose iron regiment. The mean monthly ESA dose at month 12, was 35,706 ± 21,637 IU in the 100-mg IV iron group compared with 26,382 ± 14,983 IU in the 200-mg IV iron group (P = 0.03). No significance was seen between the two groups when looking at the death rate, cardiovascular events, blood transfusions or EQ-5D quality of life measurements (4).
References
- National Collaborating Centre for Chronic Conditions, Royal College of Physicians. Chronic kidney disease: assessment and management. 2021. National Institute for Clinical Excellence.
- Macdougall IC, White C, Anker SD, et al. Intravenous Iron in Patients Undergoing Maintenance Hemodialysis [published correction appears in N Engl J Med. 2019 Jan 14
- Zununi Vahed, S., Ahmadian, E., Hejazian, S.M. et al. The Impact of Intravenous Iron Supplementation on Hematinic Parameters and Erythropoietin Requirements in Hemodialysis Patients. Adv Ther 38, 4413–4424 (2021).
- Anumas S, Chatkrailert A, Tantiyavarong P. Maintenance intravenous iron in hemodialysis patients to minimize erythropoietin doses: a double-blinded, randomized controlled trial (the MAINTAIN IRON trial). Sci Rep. 2023;13(1):1287. Published 2023 Jan 23