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To review in detail some of the most important factors affecting responsiveness to recombinant human erythropoietin.

Article inclusion criteria not defined.

Not specified.

Recruitment:  Article inclusion methods not described. 

Design: Narrative Review.

Blinding used (if applicable): not applicable

Intervention (if applicable): not applicable

Statistical Analysis: statistical analysis not performed.

Timing of Measurements: not applicable

Dependent Variables: not applicable

Independent Variables: not applicable

Control Variables: not applicable

Initial N:  19 references included.

Attrition (final N): 19 references

Age:  not mentioned

Ethnicity:  not mentioned

Other relevant demographics: n/a

Anthropometrics:  n/a

Location:  Worldwide studies

Other Findings

Potential causes of inadequate response to rh-Epo

1. Major factors

   a. iron deficiency

    b. infection

    c. non-infectious inflammatory states

    d. chronic blood loss

2. Minor factors

    a. hyperparathyroidism

    b. inadequate dialysis

    c. aluminum overload

    d. folic acid or vitamin B-12 deficiency

    e. vitamin C deficiency

    f. malignancy

    g. drug intake (ACE inhibitors?)

    h. hemolysis and bone marrow disorders

Iron deficiency

1. The most common cause of inadequate response to rh-EPO therapy is iron deficiency as defined by serum ferritin <20 µg/L and functional iron deficiency when serum ferritin is normal, but insufficient iron can be made available to meet the needs of erythropoiesis and Hb fails to increase as expected with usual doses of rh-EPO.

2.  Iron deficiency can also occur as a result of interference with normal iron metabolism by aluminium toxicity.

Inflammation

1. Erythropoiesis is inhibited by cytokines such as tumor necrosis factor, interleukin 1, and interferon- gamma; in addition the marker for inflammation, high serum levels of C-reactive protein predicts resistance to rh-EPO treatment.

    a. cytokines are directly produced by macrophages and thus are a refection of the inflammatory process.

    b. cytokines also disrupt iron metabolism, probably through impaired release of iron from the monocyte-macrophage system.

Quality of dialysis

1.  Two studies found that rh-Epo dose requirement decreased as the urea reduction rate increased.

Hyperparathyroidism

1. There are several potential mechanisms by which hyperparathyroidism can exacerbate anemia in CRF.  These include a direct toxic effect of PTH on erythropoietin synthesis as well as on RBC production and survival and an indirect effect via the induction of marrow fibrosis and interference with erythropiesis.

Parathyroidectomy:  result of 1 study

	Before	2 months	P
No rh-EPO (n=20)
PTH (pg/ml)	948+501	54+42	n.a.
Hb (g/dl) + rh=EPO (n=19)	10.0+1.3	11.1+1.1	<0.01
PTH (pg/ml)	1023+515	55+41	n.a.
Hb (g/dl)	8.6+1.0	10.4+1.2	<0.005
Rh-EPO dose/wk	170+67	112+48	<0.005

 

Other factors affecting rh-EPO responsiveness

1. Aluminum overload can interfere with iron metabolism and with the enzymes of heme synthesis resulting in microcytic anemia.

2. Vitamin deficiencies such as folic acid or B-12 can aggravate anemia of CRF and contribute to resistance to rh-EPO treatment.

3. There is some evidence that vitamin C deficiency is associated with decreased availability of stored iron, and systematic administration of vitamin C supplements can improve iron availability, although large exogenous doses of vitamin C may increase the risk of oxalate deposition.

4.  Blood loss is a common factor in rh-Epo hyporesponsiveness.

5.  Patients with various forms of solid tissue malignancy may show chronic anemia that is resistant to rh-Epo.

Iron deficiency is considered the most important factor influencing rh-Epo response.  It is widely accepted that maintaining adequate iron levels reduces dosage requirement and improves efficacy in HD patients.

Many other factors can influence resistance to rh-Epo therapy, especially inflammation and infection, quality of dialysis and hyperparathyroidism.

Optimizing response to rh-Epo therapy is important for both patient outcoes and the cost of treatment, and requires consideration of a growing number of factors, some well established and others more controversial.

University/Hospital:

Necker Hospital (Paris France)

This paper is a good review of factors that can interfere with rh-EPO therapy, including nutritional deficiencies of folate, vitamin B-12 and vitamin C as well as iron.

Only 19 references listed.