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Guideline 2.1 – Treatment of Anaemia with Iron therapy – Iron Repletion

Guideline 2.1 – Treatment of Anaemia with Iron therapy – Iron Repletion

We recommend that people should be iron replete to achieve and aim to maintain target Hb range whether receiving ESA or HIF PHI or not. (1B)

Iron repletion is usually defined as:

  • %HRC <6% / CHr or RET-He >31 pg / ferritin and TSAT (>100 microgram/L and >20%) in people with non-dialysis dependent CKD (NDD-CKD) or on PD and >200 microgram/L in people receiving HD. (2B)
  • For children, aim for a target ferritin level greater than 100 microgram/L for children with CKD receiving dialysis as well as children with CKD not on ESA or HIF-PHI therapy. (not graded)
  • In ensuring iron repletion iron should be considered when ferritin is <500 mcg/L and/or the TSAT <30%.

Rationale

The definition of “adequate” iron status (1) is:

  • Serum ferritin
    • 200-700 microgram/L in people receiving HD
    • 100-600 microgram/L in people with NDD-CKD and
  • HRC <6%, or CHr/RET-He >31 pg
  • TSAT 20%-40%

It must be noted that the above ranges are not the optimum values to target with treatment as observed in some trials, if the treatment aims to minimise ESA dosage to maintain target Hb and maximising Hb levels and minimising the need to initiate ESA therapy. However, the aim of iron treatment targets is to optimise anaemia therapy while minimising potential toxicity. Therapy targets aim at:

  1. Minimising the ESA or HIF PHI dose required to maintain target Hb levels in those on ESA or HIF PHI therapy and;
  2. Maximising the Hb level and minimising the need to initiate ESA or HIF PHI therapy to achieve target-range Hb levels in those not on ESA or HIF PHI therapy.

Increasing the Hb in anaemic people with CKD places the greatest demand for iron in the erythropoietic tissues. During ESA or HIF-PHI induction therapy iron requirements will depend on the rate of erythropoiesis, the Hb deficit, and ongoing iron losses. Once the target Hb has been reached and Hb stabilised, the iron requirements will be dependent on ongoing iron losses. When adequate iron status is achieved, those on ESA or HIF-PHI therapy should be given maintenance iron treatment as required.

Several studies have reported that the dose of ESA required to achieve and maintain a given Hb level is inversely related to iron stores (2-7). Iron deficiency (absolute or functional) was the main cause of ESA resistance in the UK, but this has now been solved by parenteral iron replacement strategies (8). The evidence behind the statement that TSAT generally should be maintained at greater than 20% stems from a single RCT comparing higher to lower TSAT targets; participants randomised to a target TSAT of 30% to 50% demonstrated a 40% reduction in ESA dose compared with those assigned to a target of 20% to 30% (9).

In a randomised controlled study involving 157 haemodialysis participants comparing iron management based on serum ferritin and transferrin saturation versus CHr, CHr was a markedly more stable analyte than serum ferritin or transferrin saturation. Iron management based on CHr resulted in similar haematocrit and epoetin dosing while significantly reducing IV iron exposure (10).

In another study involving 164 people with CKD on HD, low CHr (<26 pg) was suggestive of functional iron deficiency. When a subgroup of participants was randomly assigned to receive a single dose of IV iron dextran (1000 mg), a CHr <26 pg at baseline predicted iron deficiency with a sensitivity of 100% and specificity of 80%. The serum ferritin, transferrin saturation and percentage of hypochromic red blood cells were all less accurate. The time to correction of iron deficiency at the level of the reticulocyte was found to be within 48 hours as measured by correction of the mean CHr to >26 pg, and by the shift of the majority of the reticulocyte population to CHr >26 pg within this time span (11).

In a study comparing TSAT versus CHr as a guide of parenteral iron therapy in 197 Japanese people with CKD-PD, although CHr reflected the iron status more sensitively, TSAT was a better clinical marker for iron supplementation therapy (12). A cross-sectional study of 72 DD-CKD (HD) was performed in which the mean haemoglobin was 9.6 ± 0.16 g/dL. Mean haemoglobin content of reticulocytes (CHr) was normally distributed and correlated with MCV, MCH and red cell ferritin. A low CHr identified iron deficiency with normal serum ferritin or transferrin saturation (13).

Tessitore et al (14) compared the diagnostic efficiency of different iron markers in HD. Although percentage hypochromia >6% was the best marker to identify responsiveness to intravenous iron; CHr was 78% efficient at cut-off ≤ 29 pg.

TSAT and serum ferritin were evaluated in 47 people with HD with baseline serum ferritin levels <600 mcg/L. Participants were treated with IV dextran (1000 mg over ten haemodialysis treatments). Participants were classified as having iron deficiency if haematocrit value increased by 5% or if their erythropoietin dose decreased by 10% by 2 months. Receiver operator curves (ROC) demonstrated that none of the iron indices had a high level of utility (both sensitivity and specificity >80%). As such it was concluded that both tests should be interpreted in the context of the participant’s underlying EPO responsiveness. In participants who are responsive to EPO, a TSAT <18% or serum ferritin level <100 mcg/L should be used to indicate inadequate iron. When EPO resistance is present, TSAT<27% or ferritin <300 mcg/L should be used to guide iron management (15).

A study of 209 participants with solid tumours or haematological malignancy using a threshold of CHr 32 pg ruled out iron deficiency with a negative predictive value of 98.5% (16). An American study of 556 participants who were referred for anaemia management yielded a receiver operating characteristic analysis CHr cut-off of 30.7 pg to identify IDA with 68.2% sensitivity and 69.7% specificity (17). A further study of 40 people with CKD-HD in the maintenance phase of erythropoietin therapy compared for each person: baseline after an iron-free period and a second sample after 4 weeks of IV iron. For a CHr cut-off of 30.8 pg the area under curve (AUC) was 0.84 (95% CI 0.64– 0.93), sensitivity 78.7%, and specificity 87.2%. %HRC AUC was 0.78 (95% CI 0.64–0.91), at cutoff 2.4%, sensitivity 72.2%, and specificity 88.1% (18).

A cross-sectional study by Karunarathne et al of 100 people with CKD in Sri Lanka demonstrated for the already defined cut-off value of CHr 29 pg showed a sensitivity and specificity of 54% and 73% respectively, but from the ROC coordinates they suggest an increase to 31 pg will increase the sensitivity and specificity to 63% and 61% respectively (19).

NICE guidelines on the evaluation of iron therapy in people with CKD suggests that for people on haemodialysis, %HRC >6% dominated all other iron evaluation strategies (it led both to more QALYs and lower cost) (1). For the other people, TSAT<20% alone or serum ferritin <100 mcg/L alone were the least cost-effective strategy, but %HRC was the most cost-effective (1).

NICE guidelines on anaemia management in people with CKD suggest to:

  • Use percentage of hypochromic red blood cells (% HRC; > 6%), but only if processing of blood sample is possible within 6 hours. Since a fresh blood sample is needed, this test may be difficult to use routinely in clinical practice.
  • If using percentage of hypochromic red blood cells is not possible, use reticulocyte Hb content (CHr <31 pg- revised in these guidelines but NICE remains currently at 29 pg) or equivalent tests – for example, reticulocyte Hb equivalent.
  • If these tests are not available or the person has thalassaemia or thalassaemia trait, use a combination of transferrin saturation (less than 20%) and serum ferritin measurement (less than 100 microgram/L).
  • If these tests are not available or the person has thalassaemia or thalassaemia trait, use a combination of transferrin saturation (less than 20%) and serum ferritin measurement (less than 100 microgram/L).

We believe that CHr (<31 pg) is more sensitive in determining iron depletion than %HRC (17-19). This is because CHr reflects haemoglobin content of young reticulocytes, and therefore reflects iron availability in the preceding few days; while %HRC reflects haemoglobin contents of whole erythrocyte pool, and since senescent erythrocyte tend to get smaller in volume, the test may be affected by the overall rate of erythropoiesis.

  • If neither test is available, we recommend testing both serum ferritin and transferrin saturation rather than relying on either test separately unless the serum ferritin is <100 mcg/L and suggests absolute iron deficiency (1,15).
  • For children, a target ferritin >100 mcg/L for dialysis and NDD-CKD, not on ESA therapy is appropriate (20). There is no evidence that a higher ferritin target of 200 mcg/L is beneficial or safe in paediatric HD.

References

  1. National Collaborating Centre for Chronic Conditions, Royal College of Physicians. Chronic kidney disease assessment and management. 2015, last updated November 2021. National Institute for Clinical Excellence. Available on http://www.nice.org.uk/guidance/NG203 (accessed 05/09/2023)
  2. 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.
  3. Besarab A, Dalton CL. Maintaining higher TSATs and other iron indices is beneficial in management of anaemic haemodialysis patients. Nephrol Nurs J 2001; 28: 429-434.
  4. Coladonato JA, Frankenfield DL, Reddan DN et al. Trends in anaemia management among US haemodialysis patients. J Am Soc Nephrol 2002; 13: 1288-1295.
  5. Kalantar-Zadeh K, McAllister CJ, Lehn RS et al. Effect of malnutrition-inflammation complex syndrome on EPO hyporesponsiveness in maintenance haemodialysis patients. Am J Kidney Dis 2003; 42: 761-773.
  6. McClellan WM, Frankenfield DL, Wish JB et al. Subcutaneous erythropoietin results in lower dose and equivalent hematocrit levels among adult haemodialysis patients: Results from the 1998 End-Stage Renal Disease Core Indicators Project. Am J Kidney Dis 2001; 37:E36.
  7. Richardson D, Bartlett C, Will EJ. Optimizing erythropoietin therapy in haemodialysis patients. Am J Kidney Dis 2001; 38: 109-117.
  8. UK Renal Registry. UK Renal Registry Report: The Seventeenth Annual Report.2014 https://www.renalreg.org/wp-content/uploads/2014/12/07-Chap-07.pdf (accessed 15/06/2017).
  9. Besarab A, Amin N, Ahsan M et al. Optimization of epoetin therapy with intravenous iron therapy in haemodialysis patients. J Am Soc Nephrol 11:530-538, 2000.
  10. Fishbane S, Shapiro W, Dutka P et al. A randomized trial of iron deficiency testing strategies in haemodialysis patients. Kidney International. 2001; 60(6):2406-2411.
  11. Fishbane S, Galgano C, Langley RC, Jr et al. Reticulocyte haemoglobin content in the evaluation of iron status of haemodialysis patients. Kidney International. 1997; 52(1):217- 222.
  12. Kaneko Y, Miyazaki S, Hirasawa Y et al. Transferrin saturation versus reticulocyte haemoglobin content for iron deficiency in Japanese haemodialysis patients. Kidney International. 2003; 63:1086-109.
  13. Bhandari S, Turney JH, Brownjohn AM et al. Reticulocyte indices in patients with end stage renal disease on haemodialysis. Journal of Nephrology 1998; 11: 2, 78-82.
  14. Tessitore N, Solero GP, Lippi G et al. The role of iron status markers in predicting response to intravenous iron in haemodialysis patients on maintenance erythropoietin. Nephrology Dialysis Transplantation. 2001; 16(7):1416-1423.
  15. Chen YC, Hung SC, Tarng DC. Association between transferrin receptor-ferritin index and conventional measures of iron responsiveness in haemodialysis patients. American Journal of Kidney Diseases. 2006; 47(6):1036-1044.
  16. Ellinor I. B. Peerschke, PhD and others, Using the Hemoglobin Content of Reticulocytes (RET-He) to Evaluate Anemia in Patients with Cancer, American Journal of Clinical Pathology, Volume 142, Issue 4, October 2014, Pages 506–512, https://doi.org/10.1309/AJCPCVZ5B0BOYJGN
  17. Michael Auerbach, Steven J. Staffa, Carlo Brugnara, Using Reticulocyte Hemoglobin Equivalent as a Marker for Iron Deficiency and Responsiveness to Iron Therapy, Mayo Clinic Proceedings, Volume 96, Issue 6, 2021, Pages 1510-1519, ISSN 0025-6196, https://doi.org/10.1016/j.mayocp.2020.10.042.
  18. Urrechaga, E., Boveda, O., Aguayo, F.J., de la Hera, P., Muñoz, R.I., Gallardo, I. and Escanero, J.F. (2016), Percentage of hypochromic erythrocytes and reticulocyte hemoglobin equivalent predictors of response to intravenous iron in hemodialysis patients. Int. Jnl. Lab. Hem., 38: 360-365. https://doi.org/10.1111/ijlh.12496
  19. Karunarathne P, Kulathilake C, Wijesiriwardena I, Hewageegana A, Marasinghe A. Evaluation of Iron Status by Reticulocyte Haemoglobin Content (Chr) in Chronic Kidney Disease Patients on Haemodialysis and Erythropoietin. Indian J Hematol Blood Transfus. 2022 Apr;38(2):359- 365. doi: 10.1007/s12288-021-01464-3
  20. National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anaemia in Chronic Kidney Disease. Section III. Clinical practice recommendations for anaemia in chronic kidney disease in children. Am J Kidney Dis 2006; 47: S86–108.