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Resistance to erythropoietin-stimulating agents: etiology, evaluation, and therapeutic considerations

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Abstract

Routine clinical and laboratory assessments facilitate diagnosis of erythropoietin (EPO) resistant anemia by allowing early identification of patients with non-adherence. Any new event that impairs response to EPO (e.g., catheter sepsis) must be promptly controlled. Because of the confounding interaction of its risk factors, initial evaluation should include nutrition, dialysis adequacy, hemorrhage, bone mineral metabolism, and inflammation. Prevention of EPO resistance is more cost effective and should include adequate dialysis and nutritional supplements. Blood loss during hemodialysis (HD) procedures should be minimized. If there is laboratory proof of iron deficit intravenous repletion is most effective. Oxidative stress may be attenuated by vitamins E and C, while optimal control of hyperparathyroidism will enhance EPO stimulation. Contaminated dialysates should be suspected if there is EPO-stimulating agents (ESA) resistance at the same time among most members of a dialysis program. Heavy metal toxicity should be suspected in high-risk patients. The impact of co-morbidities such as hemoglobinopathy, glucose 6 phosphate dehydrogenase (G6PD) deficiency and connective tissue diseases must be excluded in an appropriate setting. In conclusion, given the multiple risk factors of EPO resistance promotion of the overall health status will most likely yield an enduring benefit. Finally, there are experimental trials of gene-based (therapy) to stimulate endogenous EPO synthesis with the goal of avoiding the off-target effect of excessive dosing.

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Acknowledgements

I thank Dr. Matti Vehaskari for assistance in editorial reproof of this manuscript.

Author information

Authors and Affiliations

  1. Percy Rosenbaum Professorship of Pediatric Nephrology, Children’s Hospital/LSU Health Science Center, New Orleans, LA, USA

    Oluwatoyin Bamgbola

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  1. Oluwatoyin Bamgbola
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Correspondence to Oluwatoyin Bamgbola.

Additional information

Answers:

1. A

2. E

3. A

4. E

5. A

6. C

7. C

Questions (answers appear following the reference list)

Questions (answers appear following the reference list)

  1. 1.

    One of the following is not a risk factor for ESA resistance:

    1. A.

      Primary hyperparathyroidism

    2. B.

      Occult GI bleeding

    3. C.

      Folate deficiency

    4. D.

      Parvovirus B19

    5. E.

      Chlorinated dialysis water

  2. 2.

    Microcytic anemia occurs in all of the following except:

    1. A.

      Lead toxicity

    2. B.

      Iron deficiency

    3. C.

      Ascorbic acid deficiency

    4. D.

      Copper deficiency

    5. E.

      Diphyllobothrium worm infestation

  3. 3.

    Which of the following statements concerning the association of fatality and use of ESA is correct?

    1. A.

      Larger doses of ESA required to increase hemoglobin within the KDOQI target

    2. B.

      Larger doses of ESA required to increase hemoglobin in excess of 40%

    3. C.

      No change in ESA requirement, but unable to attain the K/DOQI target

    4. D.

      Lower doses of ESA while there is an increase in Hb above the K/DOQI target

    5. E.

      Attain K/DOQI target hemoglobin with intravenous iron only

  4. 4.

    The mechanism of ESA resistance in CKD includes all the following except:

    1. A.

      Impaired EPO synthesis

    2. B.

      Erythroid cell deficiency

    3. C.

      Oxidative stress

    4. D.

      Inflammatory cytokine

    5. E.

      Circulating antibodies

  5. 5.

    All are reasons for larger doses of ESA requirement in children except:

    1. A.

      Lower bone marrow response to EPO

    2. B.

      Greater incidence of infection

    3. C.

      Greater inflammatory status

    4. D.

      Greater ESA prescription by physicians

    5. E.

      Use of HD catheters

  6. 6.

    All are effective interventions in the modulation of oxidative stress except:

    1. A.

      Vitamin C

    2. B.

      Discontinuation of the hemodialysis catheter

    3. C.

      Angiotensin-converting enzyme inhibition

    4. D.

      Folate therapy

    5. E.

      Transplant nephrectomy

  7. 7.

    Mechanism of anemia due to mycophenolate mofetil (MMF):

    1. 1.

      Inhibition of type II inosine monophosphate dehydrogenase

    2. 2.

      Single nucleotide polymorphisms (SNPs) for uridine glucuronosyl-transferase 1A9

    3. 3.

      Suppression of catalase enzyme

    4. 4.

      Mitochondrial injury

    1. A.

      1, 2, 3

    2. B.

      1, 2

    3. C.

      3 only

    4. D.

      2 only

    5. E.

      2, 4

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Bamgbola, O. Resistance to erythropoietin-stimulating agents: etiology, evaluation, and therapeutic considerations. Pediatr Nephrol 27, 195–205 (2012). https://doi.org/10.1007/s00467-011-1839-4

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