Inhibition of eryptosis - a new strategy in the treatment of renal anemia

• Applicant: Rosi Bissinger, Ph.D.
• Subject Area: Nephrology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 426724658

Chronic kidney disease (CKD) leads to renal anemia, thereby affecting patients´ quality of life. Although renal anemia is often treated by application of erythropoietin (EPO), anemia cannot be fully compensated despite administration of EPO. In addition, the application of EPO promotes thrombosis formation and tumor growth. According to preliminary data from the applicant, it has been shown that the anemia in patients with CKD is due to an increased eryptosis which leads to an accelerated clearance of the erythrocytes from the bloodstream. As eryptotic erythrocytes adhere to the vessel wall, the increased eryptosis contributes not only to the genesis of renal anemia but also favors vascular occlusion. The mechanisms leading to increased eryptosis in patients with end-stage renal disease (ESRD) as well as in patients with non-dialysis chronic kidney disease (CKD) have not been understood yet. A common mechanism that plays a role in both ESRD and CKD is complement activation, as complement is active in both types of renal failure. Other possible causes of eryptosis could be uremic toxins. Furthermore, dysproteinemia due to proteinuria may also play a role. To be able to specifically treat renal anemia by inhibiting eryptosis, it is absolutely necessary to know the causes of its development. According to further preliminary data of the applicant and other colleagues, substances have already been found which inhibit eryptosis in vitro. The present application therefore seeks to elucidate the mechanisms of eryptosis contributing to renal anemia. Furthermore, the substances already effective in vitro are to be tested for their ability to inhibit the eryptosis in CKD in vivo. For this purpose, plasma samples from patients with ESRD and CKD will be used. Finally, the substances should be tested in an experimental approach in mice with doxorubicin-induced nephropathy and 5/6th nephrectomy. Upon successful testing of one or more substances, the substances could be considered a therapeutic option for the treatment of renal anemia in humans.

• DFG Programme: Research Grants