Direct suppression/blockade of hepcidin activity
Experiments in vitro and in vivo in a murine model of ACD suggest that suppression or inhibition of hepcidin expression may be a possible means of improving ACD: overexpression of human hepcidin in mice produces a picture of anemia similar to that seen in ACD, with resistance to exogenous EPO therapy, and mice rendered anemic by heat-killed Brucella abortus were effectively treated by hepcidin mRNA suppression. Treatment of mice overexpressing human hepcidin with anti-hepcidin antibodies did not by itself lead to resolution of treated animals, but did restore sensitivity to treatment with EPO.
Indirect suppression of hepcidin
Dorsomorphin is a small molecule inhibitor of BMP signalling that was identified during screening of compounds that dorsalize zebrafish embryos. In vitro experiments showed inhibition by dorsomorphin of BMP, IL-6 and haemojuvelin-stimulated expression of hepcidin, and in vivo inhibition of iron-stimulated expression of hepcidin mRNA in zebrafish, and induction of hyperferremia in iron-replete mice, suggesting a possible role in reducing elevated hepcidin levels in ACD.
Similarly, in a murine model of inflammatory bowel disease, inhibition of BMP by HJV.Fc, a recombinant protein that prevents binding of BMPs to their receptor, LDN-193189, a small molecule inhibitor of BMP signal transduction, and an anti-BMP-6 antibody, inhibited hepcidin expression and increased serum iron levels.
Finally, heparin is known to bind BMPs, and can variably modulate their signalling effects: exogenous heparin has recently been shown to downregulate hepcidin expression by the hepatoma cell line, HepG2 in a dose-dependent manner, and at pharmacological concentrations. Treatment of mice with heparin inhibited liver hepcidin mRNA expression and SMAD phosphorylation, reduced spleen iron concentration, and increased serum iron. Administration of heparin to five patients with deep venous thrombosis also produced reductions in hepcidin levels. The authors postulated that the effects of heparin in their study were mediated by sequestration of BMP proteins, with formation of complexes that are unable to stimulate SMAD signalling and hepcidin expression, and further studies of its potential in improving haemoglobin levels in patients with ACD seem warranted for this widely used agent.
Anti-IL-6 receptor antibodies.
Castleman disease is a rare lymphoproliferative disorder characterized by hyperplastic lymph nodes showing follicular hyperplasia and capillary proliferation associated with endothelial hyperplasia. Dysregulated production of IL-6 has been shown to be responsible for some of the systemic manifestations of the multicentric form of the disease. Five out of six patients receiving longterm treatment with an anti-IL-6 receptor antibody, tocilizumab, showed rapid reductions in serum hepcidin levels, and a more gradual, but progressive, improvement in hematological parameters, including anemia, was observed in nine patients. Anti-IL-6 receptor blockade may represent a future targeted therapy for ACD.
A recent study has shown an association between vitamin D deficiency and ACD in the elderly: the Third National Health and Nutrition Examination Study (NHANES III) examined health and nutritional status of non-institutionalized subjects over 60 years of age in the United States, and hemoglobin and vitamin D levels were obtained in 5100 and 4575 subjects respectively. A significant correlation between hemoglobin and vitamin D levels was found. Further analysis of a subset of 2610 patients, who had more detailed hematological data available, showed that this association was particularly strong for patients with ACD. Individuals with ACD were twice as likely to have vitamin D deficiency as non-anemic subjects. It remains to be seen if there is an etological link between vitamin D deficiency and ACD, and whether vitamin D replenishment will have any therapeutic role to play.
Pentoxifylline is a drug with anti-inflammatory properties, and can suppress production of TNF-alpha and IFN-gamma. Two studies have suggested a beneficial effect for this agent in chronic renal failure patients with anemia resistant to EPO: parallel reductions in pro-inflammatory cytokine levels suggested that the mechanism for this effect was via the anti-inflammatory effects of this agent, and future studies in ACD may be worthwhile.