1.
When should iron supplementation in dialysis patients be avoided, minimized or withdrawn?
Rostoker, G
Seminars in dialysis. 2019;(1):22-29
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Abstract
Parenteral iron is used to restore the body's iron pool before and during erythropoiesis-stimulating agent (ESA) therapy; together these agents form the backbone of anemia management in end-stage renal disease (ESRD) patients undergoing hemodialysis. ESRD patients receiving chronic intravenous iron products, which exceed their blood loss are exposed to an increased risk of positive iron balance. Measurement of the liver iron concentration (LIC) reflects total body iron stores in patients with secondary hemosiderosis and genetic hemochromatosis. Recent studies of LIC in hemodialysis patients, measured by quantitative MRI and magnetic susceptometry, have demonstrated a high risk of iron overload in dialysis patients treated with IV iron products at doses advocated by current anemia management guidelines for dialysis patients. Liver iron overload causes increased production of hepcidin and elevated plasma levels, which can activate macrophages of atherosclerotic plaques. This mechanism may explain the results of 3 long-term epidemiological studies which showed the association of excessive IV iron doses with increased risk of cardiovascular morbidity and mortality among hemodialysis patients. A more physiological approach of iron therapy in ESRD is needed. Peritoneal dialysis patients, hemodialysis patients infected with hepatitis C virus, and hemodialysis patients with ferritin above 1000 μg/L without a concomitant inflammatory state, all require specific and cautious iron management. Two recent studies have shown that most hemodialysis patients will benefit from lower maintenance IV iron dosages; their results are applicable to American hemodialysis patients. Novel pharmacometric and economic approaches to iron therapy and anemia management are emerging which are designed to lessen the potential side effects of excessive IV iron while maintaining hemoglobin stability without an increase in ESA dosing.
2.
Iron overload causes osteoporosis in thalassemia major patients through interaction with transient receptor potential vanilloid type 1 (TRPV1) channels.
Rossi, F, Perrotta, S, Bellini, G, Luongo, L, Tortora, C, Siniscalco, D, Francese, M, Torella, M, Nobili, B, Di Marzo, V, et al
Haematologica. 2014;(12):1876-84
Abstract
The pathogenesis of bone resorption in β-thalassemia major is multifactorial and our understanding of the underlying molecular and cellular mechanisms remains incomplete. Considering the emerging importance of the endocannabinoid/endovanilloid system in bone metabolism, it may be instructive to examine a potential role for this system in the development of osteoporosis in patients with β-thalassemia major and its relationship with iron overload and iron chelation therapy. This study demonstrates that, in thalassemic-derived osteoclasts, tartrate-resistant acid phosphatase expression inversely correlates with femoral and lumbar bone mineral density, and directly correlates with ferritin levels and liver iron concentration. The vanilloid agonist resiniferatoxin dramatically reduces cathepsin K levels and osteoclast numbers in vitro, without affecting tartrate-resistant acid phosphatase expression. The iron chelators deferoxamine, deferiprone and deferasirox decrease both tartrate-resistant acid phosphatase and cathepsin K expression, as well as osteoclast activity. Taken together, these data show that transient receptor potential vanilloid type 1 activation/desensitization influences tartrate-resistant acid phosphatase expression and activity, and this effect is dependent on iron, suggesting a pivotal role for iron overload in the dysregulation of bone metabolism in patients with thalassemia major. Our applied pharmacology provides evidence for the potential of iron chelators to abrogate these effects by reducing osteoclast activity. Whether iron chelation therapy is capable of restoring bone health in humans requires further study, but the potential to provide dual benefits for patients with β-thalassemia major -preventing iron-overload and alleviating associated osteoporotic changes - is exciting.
3.
Randomized phase II trial of deferasirox (Exjade, ICL670), a once-daily, orally-administered iron chelator, in comparison to deferoxamine in thalassemia patients with transfusional iron overload.
Piga, A, Galanello, R, Forni, GL, Cappellini, MD, Origa, R, Zappu, A, Donato, G, Bordone, E, Lavagetto, A, Zanaboni, L, et al
Haematologica. 2006;(7):873-80
Abstract
BACKGROUND AND OBJECTIVES Iron accumulation is an inevitable consequence of chronic blood transfusions and results in serious complications in the absence of chelation treatment to remove excess iron. Deferoxamine (Desferal, DFO) reduces morbidity and mortality although the administration schedule of slow, parenteral infusions several days each week limits compliance and negatively affects long-term outcome. Deferasirox (Exjade, ICL670) is an oral chelator with high iron-binding potency and selectivity. In a phase II study, the tolerability and efficacy of deferasirox were compared with those of DFO in 71 adults with transfusional hemosiderosis. DESIGN AND METHODS Patients were randomized to receive once-daily deferasirox (10 or 20 mg/kg; n=24 in both groups) or DFO (40 mg/kg, 5 days/week; n=23) for 48 weeks. Results. Both treatments were well tolerated and no patient discontinued deferasirox due to drug-related adverse events. The reported frequency of transient, mild to moderate gastrointestinal disturbances was higher in the deferasirox group than in the DFO group, but these disturbances settled spontaneously without dose interruption in all patients. Decreases in liver iron concentration (LIC) were comparable in the deferasirox 20 mg/kg/day and DFO groups; baseline values of 8.5 and 7.9 mg Fe/g dw fell to 6.6 and 5.9 mg Fe/g dw, respectively, by week 48. Deferasirox showed a plasma elimination half-life of 8-16 hours, supporting its once-daily administration. INTERPRETATION AND CONCLUSIONS Deferasirox at daily doses of 10 or 20 mg/kg was well tolerated and, at 20 mg/kg, showed similar efficacy to DFO 40 mg/kg in terms of decreases in LIC.