We recommend that inadequate response (‘resistance’) to ESA therapy is defined as failure to reach the target Hb range despite SC epoetin dose >300 IU/kg/week (450 IU/kg/week IV epoetin), or darbepoetin dose >1.5 mcg/kg/week, or equivalent dose of methoxy ethylene glycol epoetin beta following investigation and treatment of other causes. (1A)
Guideline 3.14.1
We suggest clinicians consider accepting lower aspirational haemoglobin target range in those on high, escalating ESA doses with inadequate response or consider alternative therapy such as a trial use of HIF-PHI for non-dialysis dependent CKD (NDD-CKD). (2C)
Rationale
Extensive publications are available on the topic of resistance to ESA therapy including the Revised European Best Practice Guidelines (1) which defines ESA resistance as above. Failure to respond at an earlier stage in therapy should however raise suspicion of ESA resistance. Comparison of the individual Hb outcome achieved and the dose of ESA used can provide a useful way of highlighting individuals that are ESA resistant during local unit audit (2, 3). ESA therapy is efficacious in most people. However, many conditions and treatment variables can cause or explain apparent resistance to ESA therapy. Adequate investigation and management of these underlying conditions is crucial in achieving satisfactory outcome haemoglobin values as well as requiring therapy in their own right.
It is suggested to consider accepting lower Hb target levels in individuals who require high escalating doses of ESA, where the aspirational range cannot be achieved. High doses are defined as:
- >175 IU/kg per week for people on HD
- >125 IU/kg per week for people on PD
- >100 IU/kg per week for people who have CKD and aren’t dialysis dependent (NDD-CKD)
Individuals on these doses, should start to receive investigations into potential other reversible causes of low haemoglobin levels (4).
Suggested approaches to investigate ESA hypo-responsiveness:
- Check adherence If poor, attempt to improve (if self-injection)
- Check reticulocyte count If >100,000/microL (> 3 %), look for blood loss or hemolysis: endoscopy, colonoscopy, hemolysis screen
- Check serum vitamin B12 and folate, if low, replenish
- Check iron status, if low, replenish iron
- Check serum PTH, if elevated, manage hyperparathyroidism
- Check Serum CRP, if elevated, check for and treat infection or inflammation
- Check efficiency of dialysis. If underdialysed, improve dialysis efficiency
- Check if on ACEi/ARB use If yes, consider reducing dose or discontinuing drug
- Perform bone marrow biopsy and manage any condition diagnosed e.g., dyscrasia, infiltration, fibrosis (5).
References
- Horl WH, Jacobs C, Macdougall IC et al. European best practice Guidelines 14-16: inadequate response to epoetin. Nephrol Dial Transplant 2000; 15 Suppl 4: 43-50.
- Winearls CG. Recombinant human erythropoietin: 10 years of clinical experience. Nephrol Dial Transplant 1998; 13 Suppl 2: 3-8. Jacobs C, Horl WH, Macdougall IC et al.
- European best practice Guidelines 5: target haemoglobin. Nephrol Dial Transplant 2000; 15 Suppl 4: 15-19.
- National Collaborating Centre for Chronic Conditions, Royal College of Physicians. Chronic kidney disease: assessment and management. 2021. National Institute for Clinical Excellence.
- KDIGO Clinical Practice Guideline for Anaemia in Chronic Kidney Disease. Kidney Int Suppl 2012;2:279-335.