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Guideline 2.4 – Treatment of Anaemia with Iron Therapy – Upper Limit for Iron Therapy

Guideline 2.4 – Treatment of Anaemia with Iron Therapy – Upper Limit for Iron Therapy

For people not on HD, we recommend that serum ferritin should not exceed 600 mcg/L in those treated with iron. To achieve this, iron management should be reviewed when ferritin is >500 mcg/L, recognising that a level of >800 mcg/L may reflect iron toxicity. (1B)

Guideline 2.4.1

For people receiving HD, we recommend that proactive high-dose IV iron, initially 600 mg in divided doses in the first month and then 400 mg every month (or equivalent) should be given unless ferritin >700 mcg/L or TSAT >40%. (1A)

Guideline 2.4.2

We suggest a tailored approach by clinicians to assess the risk and benefit of starting a proactive IV iron protocol in people who have been established on HD for >12 months. (2B)

Rationale

Iron overload is defined as increased total body iron content with the possible risk of organ dysfunction (1). There is no clinically available method that accurately determines total body iron content. An elevated serum ferritin does not always correlate with elevations in liver iron content (2, 3). Magnetic resonance imaging provides a reliable assessment of tissue iron content in people on HD regularly treated with parenteral iron (4). However, the clinical relevance of increased liver iron remains unclear.

Elevated serum ferritin together with elevated serum transferrin saturation remain the most clinically accurate parameter of iron overload in people with CKD.

Discontinuation of adequate maintenance IV iron when an individual‘s ferritin is >500 mcg/L produces a population mean that straddles the 600 mcg/L ceiling (5). Ongoing iron therapy with ferritin >500 mcg/L results in a higher median ferritin outcome (6).

Interpretation of iron status results and deciding on the need for further iron therapy should include a concomitant assessment of changes in Hb level and ESA or HIF-PHI dose over time. Examples:

  • A dropping ferritin as well as decreasing Hb levels signifies blood loss e.g., on HD or bowel related anaemia: iron therapy is indicated; further investigation may be required depending on the clinical scenario.
  • A decreasing ferritin level after initiation of ESA therapy, with a concomitant rise in Hb level indicates a response to ESA with a shift of iron from stores to bone marrow: further iron therapy is guided by target ferritin level.
  • An increasing ferritin level after reduction of ESA dose to bring Hb level down to target range indicates ferritin level is rising as Hb synthesis is dropping further iron therapy may be postponed.
  • A rising ferritin level and a drop in TSAT suggest an inflammatory condition: a source of inflammation may be sought such as sepsis, vascular access, surgery, recent hospitalisation: further iron therapy depends on target ferritin level and clinical scenario.
  • Ongoing high requirements for IV iron to maintain a given ferritin level also point to ongoing blood loss which may require further investigation.

The finding of a TSAT <20% coupled with a ferritin >500 mcg/L poses a particularly difficult problem for clinicians. This situation may be caused by iron test variability (7), inflammation, or reticulo-endothelial iron blockade. Evidence on the risks and benefits of IV iron therapy in this population is not well established. The effect of iron therapy in this group was assessed in the DRIVE trial (8), which evaluated the efficacy of IV ferric gluconate in 134 participants with high ferritin (500–1200 mcg/L) and low TSAT levels (≤ 25%) who were anaemic despite a high rHuEPO dose (≥225 IU/kg/week or ≥22500 IU/week). After 6 weeks the participants receiving ferric gluconate (125 mg IV at eight consecutive HD sessions) showed a significant increase in Hb in comparison with controls. However, the study has a number of limitations because, given the small sample size and short follow-up, it provides no information about safety and iron overload.

The PIVOTAL trial compared a high-dose, proactive IV iron sucrose regimen to a low-dose, reactive IV iron sucrose regimen in 2141 adult people in their first year of HD receiving an ESA (9). The high-dose group received 600 mg of IV iron initially in the first month and then 400 mg IV iron sucrose proactively every month unless serum ferritin was >700 μg/L or transferrin saturation (TSAT) ≥40%. The low-dose group received 0 to 400 mg monthly, with a serum ferritin of <200 μg/L or a TSAT of <20% being a trigger for iron administration. The primary end point was the composite of nonfatal myocardial infarction, nonfatal stroke, hospitalisation for heart failure, or death, assessed in a time-to-first-event analysis. Secondary end points included death, hospitalisation for any cause, infection rate and ESA dose. The median follow-up period was 2.1 years. The high-dose group received a median monthly iron dose of 264 mg, compared with 145 mg in the low-dose group. The median monthly dose of an ESA was 29,757 IU in the high-dose group and 38,805 IU in the low-dose group. Hence the trial found that patients in the proactive arm who achieved ferritin levels ~600 mcg/L required lower ESA doses overall than those patients who were in the reactive arm where ferritin levels were maintained ~ 200 mcg/L. A total of 320 (29.3%) in the high-dose group had a primary end-point event, compared with 338 (32.3%) in the low-dose group (HR, 0.85; 95% CI, 0.73 to 1.00; P<0.001 for noninferiority; P=0.04 for superiority). There was no significant difference in infection rates or hospitalisation for any cause between the two groups. The authors concluded that a high-dose IV iron regimen administered proactively was superior to a low-dose regimen administered reactively; resulting in a lower risk of death or major adverse cardiovascular events and requiring lower doses of ESA and a lower incidence of blood transfusions (9).

Therefore, intravenous iron administered at a low dose and high frequency may be more appropriate for adults who are receiving in-centre haemodialysis. It should be noted that the PIVOTAL trial investigated incident HD participants only, those who were already established on HD for >12 months were excluded from recruitment. We recommend an individualised approach by clinicians to assess the risk and benefit of starting a proactive iv iron protocol in people who have been established on HD for >12 months but it seems likely to have similar benefits.

The FIND-CKD study assessed the 12-month efficacy and safety of IV ferric carboxymaltose (FCM) compared with oral iron in ND-CKD participants with anaemia and iron deficiency. Two different target ferritin levels were studied: higher (400–600 mcg/L) or lower (100–200 mcg/L). This RCT found that IV FCM targeting a higher ferritin is more effective than oral iron in delaying or reducing the ESA requirement and the occurrence of 2 consecutive Hb levels <10 g/dL (10).

References

  1. Macdougall IC, Bircher AJ, Eckardt KU, et al; Conference Participants. Iron management in chronic kidney disease: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference. Kidney Int. 2016 Jan;89(1):28-39.
  2. Canavese C, Bergamo D, Ciccone G, et al. Validation of serum ferritin values by magnetic susceptometry in predicting iron overload in dialysis patients. Kidney Int. 2004 Mar;65(3):1091-8.
  3. Ghoti H, Rachmilewitz EA, Simon-Lopez R, et al. Evidence for tissue iron overload in long-term haemodialysis patients and the impact of withdrawing parenteral iron. Eur J Haematol. 2012 Jul;89(1):87-93.
  4. Rostoker G, Griuncelli M, Loridon C, et al. Haemodialysis-associated hemosiderosis in the era of erythropoiesis-stimulating agents: a MRI study. Am J Med. 2012 Oct;125(10):991-999.
  5. Richardson D, Bartlett C, Will EJ. Optimizing erythropoietin therapy in haemodialysis patients. Am J Kidney Dis 2001; 38: 109-117.
  6. Besarab A, Amin N, Ahsan M et al. Optimization of epoetin therapy with intravenous iron therapy in haemodialysis patients. J Am Soc Nephrol 2000; 11: 530-538.
  7. Fishbane S, Shapiro W, Dutka P et al. A randomized trial of iron deficiency testing strategies in haemodialysis patients. Kidney Int 2001; 60:2406-2411.
  8. Coyne DW, Kapoian T, Suki W et al. DRIVE Study Group. Ferric gluconate is highly efficacious in anaemic haemodialysis patients with high serum ferritin and low transferrin saturation: results of the Dialysis Patients‘ Response to IV Iron with Elevated Ferritin (DRIVE) Study. J Am Soc Nephrol 2007; 18: 975–984.
  9. Macdougall I.C, White C, Anker S et al. intravenous iron in patients undergoing maintenance haemodialysis. N Engl J Med. 2019 Jan 3 1;380 (5):447-458.
  10. Macdougall IC, Bock AH, Carrera F, Eckardt KU, Gaillard C, Van Wyck D, Roubert B, Nolen JG, Roger SD; FIND-CKD Study Investigators. FIND-CKD: a randomized trial of intravenous ferric carboxymaltose versus oral iron in patients with chronic kidney disease and iron deficiency anaemia. Nephrol Dial Transplant. 2014 Nov;29(11):2075-84. doi: 10.1093/ndt/gfu201