Background and Purpose: Selective endothelin A (ETA) antagonism has shown promise as a potential treatment for chronic kidney disease (CKD), but the adverse effect of fluid retention associated with ETA antagonists has limited their clinical utility. Combination of low doses of the selective ETA antagonist zibotentan with a fixed-dose sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin is currently being evaluated in the Zibotentan and Dapagliflozin for the Treatment of CKD (ZENITH-CKD) clinical trial as an approach to maximize kidney protection via ETA antagonism and SGLT2 inhibition in combination. Approach: This study utilized a quantitative systems pharmacology modeling approach to simulate the dose-response relationship of zibotentan alone and in combination with dapagliflozin in a virtual CKD patient population. Key Results: Simulations predict that interstitial fluid volume (IFV) changes will remain below baseline for zibotentan doses below 0.5 mg when combined with dapagliflozin, while the combination therapy will provide substantial additional improvements in urinary albumin-to-creatinine ratio (uACR), glomerular hypertension, and proximal tubule energy demand, indicating enhanced renoprotection. The simulation also indicate that patients with higher baseline eGFR (>30 mL/min/1.73m2) and baseline uACR (>800 mg/g) may experience greater kidney protective response to the combination therapy with less potential for detrimental fluid retention. Conclusions and impact: If the predicted results are confirmed by the ZENITH-CKD trial, this analysis will enhance mechanistic understanding of the balance between albuminuria reduction and fluid retention with this combination treatment strategy, and will provide a tool to inform optimal population selection for late phase clinical studies and lifecycle management planning.