Hepcidin in diagnosis and therapy of anemia

Both, anemia of chronic disease (ACD) and anemia in chronic kidney disease (CKD) are prevalent in a general Western population. Erythropoiesis-Stimulating Agents (ESAs) are frequently used in the treatment of ACD and anemia due to CKD. However, the response rate to ESA-therapy is highly variable depending on the underlying disease. In addition, during the last years different studies raised concerns about the safety of ESAs when dosed to target higher haemoglobin levels, particularly when using higher doses and in patients who are poorly responsive. Predictors of responsiveness to ESA-therapy as well as alternative therapy strategies for ACD and anemia of CKD are hence desirable, in order to avoid the emotional and financial burden of ineffective medical intervention and possible negative side effects of ESA therapy. The primarily liver derived peptide hepcidin, a key regulator of iron homeostasis, is increased in ACD and CKD patients. Increased serum hepcidin levels lead to intracellular iron retention in macrophages and relative iron deficiency, making iron unavailable for erythropoiesis. Only one available human study in patients suffering from ACD due to malignancy has suggested that a poor response to ESA-therapy is associated, among other causes, with poor iron availability due to increased serum hepcidin levels. In CKD patients, data on a possible association of hepcidin levels and response to ESA therapy, although a higher number of studies have been conducted, is conflicting. Therefore we are planning to investigate the link between serum hepcidin levels and responsiveness to ESA- therapy in a well-established rodent model of ACD and CKD as well as in a mixed model. These experiments are promising as preliminary data show a correlation between serum hepcidin levels and responsiveness to ESA- therapy in ACD rats. Animal models give us the possibility to study the response to ESA-therapy in rats suffering from ACD and CKD with different inflammation and iron status as well as different serum hepcidin levels in a prospective manner. In addition we will further investigate the hepcidin lowering effect of LDN-193189, a small- molecule inhibitor of BMP type I receptors, on ESA-therapy responsiveness in a high inflammation state. The proof of efficacy of LDN-193189 to reverse ACD has been recently published. In conclusion, using our rodent models, a standardized evaluation of serum hepcidin as a predictor of responsiveness to ESA-therapy in ACD and CKD under different inflammation conditions and iron status is possible. This is desperately needed as conflicting data is available on serum hepcidin as a predictor of responsiveness to ESA-therapy in humans which tends to be due to differences in baseline inflammation and iron status in the reported clinical studies. Especially in a time of exploding health care system costs and raised concerns about the safety of ESAs, a reliable and robust predictor of responsiveness to ESA-therapy as well as alternative therapy options are desperately needed.

Within this project, we unveiled new mechanistic interactions of different treatments for anemia of chronic disease. These results directly influenced the design of clinical trials testing new drugs for the treatment of anemia of chronic disease. Both, anaemia of chronic disease (ACD) and anaemia in chronic kidney disease (CKD) are prevalent in a general Western population. Erythropoiesis-Stimulating Agents (ESAs) are frequently used in the treatment of ACD and anemia due to CKD. However, the response rate to ESA-therapy is highly variable depending on the underlying disease. Predictors of responsiveness to ESA-therapy as well as alternative therapy strategies for ACD and anemia of CKD are hence desirable, to avoid the emotional and financial burden of ineffective medical intervention and possible negative side effects of ESA therapy. The primarily liver derived peptide hepcidin, a key regulator of iron homeostasis, is increased in ACD and CKD patients. Increased serum hepcidin levels lead to intracellular iron retention in macrophages and relative iron deficiency, making iron unavailable for erythropoiesis. As a first step, we could show, using two well established models of ACD and CKD, that there is a clear functional link between hepcidin levels and response to ESA therapy.Suggesting that hepcidin may be a good biomarker to predict response to ESA therapy as well as that an anti-hepcidin therapy may affect and improve response to ESA therapy in ACD and CKD patients.We found, as anticipated, that a combination of both ESA and hepcidin block (using LDN-193189, a small molecule) lead to an improved erythropoietic response. ESA and anti-hepcidin therapy seem to work even synergistically. We could show that this is mainly due to an anti-inflammatory effect of this combination therapy. In a next step, we could show that the combination therapy allowed a significant reduction in ESA dosing. This is important, as it has been suggested that ESA dose is directly linked to negative side effects of ESA therapy. Based on these results clinical trials have been designed focusing on ESA reduction because of a combination therapy. The reported effect of the combination therapy on innate immunity lead to an additional side spin of the project and resulted in a publication in Nature Medicine, describing the interaction between iron metabolism, hepcidin and innate immunity as well as showing that modulation of the innate immunity may be a therapeutic option for different forms of anemia.Within this project, we could not only show the important synergistic effect of ESA and anti-hepcidin strategies, influencing the design of planed clinical trials but also discovered a new mechanism involved in anemia development in different diseases.