We recommend that people on ESA or HIF-PHI therapy should remain iron replete before and during therapy either with oral iron or intravenous iron. (1B)
Guideline 2.2.1
We recommend that ESA or HIF-PHI therapy should not be initiated in the presence of absolute iron deficiency (ferritin <100 mcg/L in NDD-CKD and <200 mcg/L in DD-CKD) or functional Iron deficiency (TSAT <20% will normal or elevated ferritin levels) until this is corrected and anaemia persists. Iron supplements should be given prior to or when initiating ESA or HIF-PHI therapy. (1B)
Guideline 2.2.2
We suggest that to define functional iron deficiency (FID) (“iron restricted erythropoiesis”), a TSAT <20% in people with NDD-CKD or maintained on PD, and in those receiving HD be used. Normal or high serum ferritin values do not exclude iron deficiency, as it could be due to other causes such as infection or inflammation. (2B)
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 or HIF-PHI therapy.
- For people with CKD on dialysis (DD-CKD), percentage of HRC >6%, or CHr/RET-He <31 pg are ideal test 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 mcg/L) could be a suitable alternative (1)
A consistent finding in the series of trials using HIF-PHI (Roxadustat) was the effect on iron metabolism. In the non-dialysis trials against placebo (ANDES, ALPS and OLYMPUS), there was a 50% reduction in the requirement for IV iron use, such that the monthly dose of iron required was significantly reduced (2-4). This led to reductions in serum ferritin but no change in TSAT or serum iron. However, the trials did not assess the quantity of oral iron use. This suggests that HIF-PHI therapy may simultaneously correct anaemia and iron depletion. In the DOLOMITES trial, the use of either IV or oral iron was also reduced in the Roxadustat vs darbepoetin alfa groups. While iron administration was left to the investigator’s discretion and/or were based on local clinical practice patterns in the darbepoetin alfa group, oral iron was requested by trial protocol in the Roxadustat group (5).
Another challenge in assessing the impact of HIF-PHI on iron use was that in some trials, iron protocols differed between treatment and comparator groups within a trial while other trials tested similar iron protocols (6, 7, 8). Other potential trial design limitations included differences in Hb targets and the actual achieved Hb between treatment arms, differences in the proportion of participants with baseline iron deficiency and baseline imbalances in iron and hepcidin status and potentially relevant co-morbidities. Therefore, further data from randomised controlled trials is needed to confirm these secondary findings on iron utilisation before definitive guidance can be given.
Iron parameters should be monitored during treatment with HIF-PHI therapy and iron deficiency should be avoided because it is associated with thromboembolic events, impaired red blood cell production (9), lower health related quality of life (HRQoL), higher rates of cardiovascular events and higher mortality (10).
References
- National Collaborating Centre for Chronic Conditions, Royal College of Physicians. Chronic kidney disease assessment and management 2015, updated 2021. National Institute for Clinical Excellence. Available on http://www.nice.org.uk/guidance/NG203 (accessed 04/09/2023)
Coyne DW, Roger SD, Shin SK, et al. Roxadustat for CKD-related anemia in non-dialysis patients. Kidney Intl Rep. 2020;6:624–635.
Fishbane S, El-Shahawy MA, Pecoits-Filho R, et al. Roxadustat for treating anemia in patients with CKD not on dialysis: results from a randomized Phase 3 study. J Am Soc Nephrol. 2021;32:737–755.
Shutov E, Sulowicz W, Esposito C. Roxadustat for the treatment of anemia in chronic kidney disease (CKD) patients not on dialysis: a phase 3, randomized, double-blind, placebo-controlled study (ALPS) [e-pub ahead of print]. Nephrol Dial Transplant. https://doi.org/10.1093/ndt/gfab057. Accessed August 18, 2023.
Barratt J, Andric B, Tataradze A, et al. Roxadustat for the treatment of anaemia in chronic kidney disease patients not on dialysis: a phase 3, randomized, open-label, active-controlled study (DOLOMITES). Nephrol Dial Transplant. 2021;36:1616–1628.
Csiky B, Schomig M, Esposito C, et al. Roxadustat for the maintenance treatment of anemia in patients with end-stage kidney disease on stable dialysis: a European phase 3, randomized, open-label, active controlled study (PYRENEES). Adv Ther. 2021;38:5361–53
Akizawa T, Ueno M, Shiga T, et al. Oral Roxadustat three times weekly in ESA-naive and ESA-converted patients with anemia of chronic kidney disease on hemodialysis: results from two phase 3 studies. Ther Apher Dial. 2020;24:628–641
Ganz T, Locatelli F, Arici M, Akizawa T, Reusch M. Iron Parameters in Patients Treated with Roxadustat for Anemia of Chronic Kidney Disease. Iron Parameters in Patients Treated with Roxadustat for Anemia of Chronic Kidney Disease. J. Clin. Med. 2023;12(13).4217
Guedes M, Muenz D, Zee J, et al. Serum biomarkers of iron stores are associated with worse physical health-related quality of life in nondialysis-dependent chronic kidney disease patients with or without anemia. Nephrol Dial Transplant. 2021;36:1694–1703.
Guedes M, Muenz DG, Zee J, et al. Serum biomarkers of iron stores are associated with increased risk of all-cause mortality and cardiovascular events in nondialysis CKD patients, with or without anemia. J Am Soc Nephrol. 2021;32:2020–2030.