A systems biology approach against renal anemia

World-wide 109 million patients are suffering from anemia in the context of chronic kidney diseases (CKD). The incidence of CKD is rapidly increasing in an aging population. The declining functionality of the kidney in CKD causes persistent inflammation and results in effective iron deficiency as well as an impairment of erythropoietin (Epo) secretion which leads to an impaired capacity to renew red blood cells and thus anemia. CKD patients differ in their inflammation and iron status and show severe fluctuations in hemoglobin levels. Patients suffering from anemia are treated with erythropoiesis stimulating agents (ESAs), which are derivatives of Epo. ESA treatment according to the current guidelines for CKD does not consider individual patient differences. However, a too rapid increase in the number of red blood cells due to high ESA doses results in increased shear stress and thus activation of platelets. 40% of CKD patients in stage G4 have a high risk of thrombovascular events such as thrombosis, heart attack or stroke and for many of them the outcome is fatal. The risk is further elevated at stage G5. To analyse the impact of patient-specific differences in the renal anemia, we will recalibrate the previously developed mechanism-based multiscale model of chemotherapy-associated anemia in lung cancer, which quantitatively describes the interaction of Epo with its receptor in the precursors of the red blood cells. The initial parameters of the mathematical model were determined based on data from clinical trials in lung cancer, and will be recalibrated based on clinical trials in CKD. In addition, new inputs will be examined in the mathematical model to capture the impact caused by persistent inflammation in CKD as well as the dynamics of iron deficiency. Due to the complexity of the multifactorial pathophysiology in renal anemia a multidisciplinary approach is required to disentangle the key elements determining the hemodynamics in renal anemia. To approach this, NephrESA is divided into five subprojects (SP) that focus on the hemodynamics (SP1: Prof. Dr. Jens Timmer, University of Freiburg), inflammation (SP2: Prof. Dr. Ursula Klingmüller, German Cancer Research Center Heidelberg), iron metabolism (SP3: Prof. Dr. Martina Muckenthaler, University Hospital Heidelberg), and platelet activation (SP4: Prof. Dr. Albert Sickmann, Leibniz Institut für analytische Wissenschaften, Dortmund) and is clinically supported by Prof. Dr. Tobias Huber from the University Medical Center Hamburg-Eppendorf (SP5) providing patient data, patient samples and clinical conceptualization.  The results from SP2, SP3 and SP4 will be integrated in the mathematical model in SP1 and will be finally validated in SP5 in the clinical routine of anemia treatment in CKD patients.

Fig 1: NephrESA subprojects and interactions. SP1 is led by Prof. Dr. Jens Timmer at the University of Freiburg. SP2 is led by Prof. Dr. Ursula Klingmüller at the German Cancer Research Center, Heidelberg. SP3 is led by Prof. Dr. Martina U. Muckenthaler at University Hospital Heidelberg. SP4 is led by Prof. Dr. Albert Sickmann at the Leibniz Institut für analytische Wissenschaften, Dortmund. SP5 is led by Prof. Dr. Tobias B. Huber at the University Medical Center Hamburg-Eppendorf.

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