Unvavelling the pathophysiology and factors leading to red blood cell death in chronic kidney disease

• Applicant: Rosi Bissinger, Ph.D.
• Subject Area: Nephrology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 521775394

Renal anemia is a typical complication of chronic kidney disease and significantly impairs the performance and quality of life of patients. Renal anemia is currently treated using various modalities such as iron substitution, erythropoietin and HIF stabilizer administration. My research has demonstrated that a shortened lifespan of red blood cells also plays an important role in the development of renal anemia. Remarkably, my findings showed that anemia persisted despite the massive formation of the red blood cell generating hormone erythropoietin. A better understanding of why this severe breakdown of red blood cells occurs could provide novel insights into efficient therapeutic strategies in countering renal anemia. In this purview, the overarching aim of this research proposal is to investigate the role of various endogenous environmental factors involved in chronic renal failure in orchestrating premature cell death of red blood cells, leading to renal anemia. More specifically, the research proposed herein aims to elucidate the influence of the uremic milieu, secondary hyperparathyroidism, and hypoxia involving the Rapaport-Luebering cycle and the HIF signaling pathway. In addition, the connection between accelerated red blood cell death and renal anemia in patients before and after kidney transplantation together with the impact of immunosuppressants will be studied. Importantly, the research described in the proposal will highlight the therapeutic modulation of various red blood cell death-triggering mechanisms in vivo. For this purpose, various interventions with drugs (sevelamer, ketoprofen) and special dietary regimens (low-protein diet and low-phosphate diet) recapitulating real-life clinical scenarios will be conducted on established animal models. In addition, relevant signaling pathways (Rapaport-Luebering cycle and HIF signaling pathway) altering red blood cell metabolism and function in renal failure will be examined. Taken together, the knowledge gained from this study shall explain the role of various players contributing to the pathophysiology and hematologic complications of chronic renal failure, as well as provide novel information on efficient therapeutic targeting of renal anemia.

• DFG Programme: Research Grants