Lisa Daniel-Fischer

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.

Focal segmental glomerulosclerosis (FSGS) is a glomerular lesion often associated with nephrotic syndrome. It is also associated with a high risk of progression to end-stage kidney disease. Current treatment of FSGS is limited to systemic corticosteroids or calcineurin inhibition, along with inhibitors of the renin-angiotensin-aldosterone system. FSGS is heterogeneous in etiology, and novel therapies targeting specific, dysregulated molecular pathways represent a major unmet medical need. By leveraging big data, we have generated a network-based molecular model of FSGS pathophysiology using previously established systems biology workflows to allow computational evaluation of compounds for their predicted interference with molecular processes contributing to FSGS. We identified repurposing the anti-platelet drug clopidogrel as a therapeutic option to counterbalance dysregulated FSGS pathways. This prediction of our computational screen was validated by testing clopidogrel in the adriamycin FSGS mouse model. Clopidogrel improved key FSGS outcome parameters and significantly reduced urinary albumin to creatinine ratio (p<0.01) and weight loss (p<0.01), and ameliorated histopathological damage (p<0.05). Clopidogrel is used to treat several cardiovascular diseases linked to chronic kidney disease. Clopidogrel's favorable safety profile and its efficacy in the adriamycin mouse FSGS model thus recommend it as an attractive drug repurposing candidate for clinical trial in FSGS. This proof-of-concept study demonstrates the feasibility of translating compounds from our computational technology platform via pre-clinical verification to clinical phase II readiness.

Lithium added to peritoneal dialysis fluid protects mesothelial cells and attenuates peritoneal fibrosis and angiogenesis by reducing αB-crystallin.