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For patients with kidney failure, peritoneal dialysis (PD) is an alternative kidney replacement therapy to hemodialysis. Long-term PD efficacy is limited by multicellular pathologies induced by the hyperosmotic PD fluids, including vasculopathy and fibroangiogenic remodeling of the peritoneum, which lack targeted pharmacological interventions. We developed a deep secretome profiling workflow in a coculture system using a human peritoneal mesothelial cell line and primary human lymphatic endothelial cells to characterize the influence of PD fluid on communication between these cell types. This approach uncovered extracellular and intracellular signaling patterns absent in standard monocultures and identified 1910 human proteins that revealed extracellular regulatory processes central to PD-associated peritoneal pathology. Integration of the coculture secretome and cellular proteomes with effluent and plasma proteomes derived from patients with PD revealed cell type-specific signaling networks and groups of proteins correlating with clinical parameters such as ultrafiltration capacity, transport kinetics, and inflammation. Functional validation demonstrated that lithium chloride supplementation partially counteracted fibroangiogenic signaling and affected key PD fluid-induced processes, including PDGFC-driven lymphangiogenesis, syndecan-4 ectodomain shedding by endothelial cells, and a mesothelial switch from NOTCH1 to NOTCH3 synthesis. These findings suggest new potential pharmacological strategies to mitigate peritoneal fibrosis and vasculopathy, offering a framework for future therapeutic innovation in PD and beyond.