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Profound Effects On Immune Function Of Iron Therapy In End-Stage Renal Disease

Iron therapy, given to treat anaemia in combination with recombinant human erythropoietin (rhEPO) in patients with end-stage renal disease (ESRD), depresses immune function by inhibiting TNF-a production and increasing IL-4. It might also effect the risk of cardiac events.

The randomised clinical study, led by Günter Weiss, MD, University Hospital of Innsbruck, Austria, enrolled 31 patients with ESRD who received regular haemodialysis. Before the study began, all patients received rhEPO 3 times weekly, and iron saccharate iv (dependent on serum ferritin levels). Iron was withdrawn 1 week prior to study initiation. Of the 28 patients who completed the study, 13 received rhEPO plus iron (100 mg/week) and 15 received rhEPO alone.

In the group receiving iron, TNF- a levels declined during the study and were significantly lower than in the group receiving rhEPO, in which TNF- a (as well as interleukin (IL)-6 and haptoglobin) levels increased. These cytokines are associated with induction of cytotoxic immune effector mechanisms of macrophages. Levels of IL-4, an anti-inflammatory T-helper cell-derived cytokine, decreased in the rhEPO-alone group but increased significantly in those receiving iron.

The effect could increase the susceptibility of ESRD patients to infection and tumour by modification of the immune response. This was "especially relevant in ESRD patients since immune effector function in these subjects is already impaired", the researchers said. Furthermore, they noted that high iron availability might enhance the growth of invading pathogens and malignant tumours, since the metal was an essential nutrient.

Another hypothesis investigated in the study was that iron catalysed the formation of oxygen radicals. This was assessed by measuring total peroxide activity, but it was found that while this increased slightly in those receiving rhEPO alone, it decreased (although not significantly) in the group receiving rhEPO plus iron.

The researchers said that iron might limit peroxide formation by inhibiting the production of its main inducer, TNF-a. Iron might therefore decrease susceptibility to cardiac events by decreasing cytokine-induced oxidative stress. The researchers noted that they could not rule out the possibility that iron did indeed induce free radicals and lead to tissue damage via pathways that did not involve TNF- a.

Iron therapy might have "important implications for the pathophysiology and therapy in renal anaemia", the researchers said. They suggested that prospective studies to assess the long-lasting clinical effects of iron supplements and resulting immune modulation in ESRD were necessary.

Determination of the amount of metabolically active iron that exerts a biological effect on immunity and free radical formation would be useful. Investigations were warranted to determine the optimal concentration of iron to give to ESRD patients in order to correct anaemia while minimising the risk of infection and cardiac complications.
Kidney Int 2003;64:2:572-8. "Effect of iron treatment on circulating cytokine levels in ESRD patients receiving recombinant human erythropoietin"

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