SP1 - NephrESA

Subproject 1: Model capturing the hemodynamics in CKD patients

During the progression of CKD, the status of patients is gradually altered, which impacts the patient hemodynamics. These changes widely vary between patients. To approach these complex and highly dynamic interrelations, the focus in SP1 is on the development of the mechanism-based multiscale model NephrESA that analyzes the impact of patient-specific differences in renal anemia. To capture the hemodynamics in CKD patients, 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 progenitors of red blood cells.
The key objectives are:
1.    Adaptation of the mechanism-based multiscale model for capturing the hemodynamics in CKD
2.    Development of dynamic pathway models capturing iron status, inflammation and platelet activation
3.    Identification of a minimal model sufficient to capture hemoglobin dynamics in CKD
Work plan: Timmer adapts the previously established mechanism-based multiscale model to the anemia dynamics in CKD patients utilizing data (Hb values, ferritin levels, transferrin saturation, ESA dosing) from clinical trials testing different ESAs and ESA doses in CKD patients (n=400). The intensive follow-up of the patients in the clinical trials provides high density and less variability of the data and thus facilitates accurate calibration of model parameters. To extend the model and generate the NephrESAbasic model, Klingmüller formats the clinical data to be applicable for modelling including clinical cofactors like patient weight, CRP values and transferrin saturation. Biomarkers for iron availability (ferritin, iron levels and transferrin saturation) and CRP values are incorporated in the model as additional inputs, and tested whether this enables the model to capture the profiles of hemoglobin in all patients of the clinical trials. Data available from the daily clinical routine differs much in quantity and quality. Lower frequency of data collection and missing values pose a challenge for modelling and require experimental design as well as uncertainty analyses. In cooperation with Huber and the associated partner Dikow, pseudonymized data from 50 CKD patients are provided to Klingmüller. The data is used by Timmer for further calibration of the NephrESAbasic model. This analysis of the CKD patient data by the NephrESAbasic model will help to identify missing aspects. Timmer uses the sub-models generated together with Muckenthaler in SP2 (NephrESAiron model), with Klingmüller in SP3 (NephrESAinflam model) and Sickmann in SP4 (NephrESAthrombo model) to integrate the dynamics of the iron status, of inflammation and of platelet activation into the mechanism-based multiscale model for final calibration. The integrated model (NephrESA) is calibrated based on the patient data to fully capture the hemodynamics in CKD patient. Timmer takes advantage of the well-established modelling pipeline to decide about the structure of the models e.g. regression versus dynamic models or parametric versus non-parametric models. By statistical tests, Timmer infers the presence or absence – and in the former case the nature – of interactions between the sub-models and between the sub-models and the core model, e.g. the effects of inflammatory cytokines on the turnover of the EpoR and the proliferation and differentiation of erythroid progenitor cells as a measure for hemoglobin production. The capacity of the NephrESAbasic model and of the model extended by the sub-models NephreESAiron, NephrESAinflam and NephrESAthromb and their interactions to capture the hemoglobin profiles are compared. The aim is to establish a minimal structure of the NephrESA model that is sufficient to capture the hemodynamics in CKD patient.

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