Abstract
Podocytes are the key target cells for injury across the spectrum of primary and secondary proteinuric kidney disorders, which account for up to 90% of cases of kidney failure worldwide. Seminal experimental and clinical studies have established a causative link between podocyte depletion and the magnitude of proteinuria in progressive glomerular disease. However, no substantial advances have been made in glomerular disease therapies, and the standard of care for podocytopathies relies on repurposed immunosuppressive drugs. The past two decades have seen a remarkable expansion in understanding of the mechanistic basis of podocyte injury, with prospects increasing for precision-based treatment approaches. Dozens of disease-causing genes with roles in the pathogenesis of clinical podocytopathies have been identified, as well as a number of putative glomerular permeability factors. These achievements, together with the identification of novel targets of podocyte injury, the development of potential approaches to harness the endogenous podocyte regenerative potential of progenitor cell populations, ongoing clinical trials of podocyte-specific pharmacological agents and the development of podocyte-directed drug delivery systems, contribute to an optimistic outlook for the future of glomerular disease therapy.
Key points
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Kidney podocytes are the key target cell for injury across the spectrum of proteinuric kidney diseases; genetic, immunological, infectious, metabolic and other insults contribute to podocyte injury and loss.
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The treatment of podocytopathies has traditionally relied on repurposed agents such as antihypertensive agents and immunosuppressive drugs.
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The last two decades have witnessed an expansion in clinical trials of potential podocyte-protective therapies, including strategies that target Apol1 variants, endothelin 1 and endothelin receptors, transient receptor potential channels, complement, cytokines, mitochondrial dysfunction and aberrant lipid metabolism.
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Remaining challenges include the identification of approaches to regenerate podocytes, the development of strategies for podocyte-specific drug delivery and the identification of biomarkers to guide personalized therapy for proteinuric kidney diseases.
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K.M. reports consulting fees from Chinook and funds to her department for being a site principal investigator for a study sponsored by Vertex outside the submitted work. K.N.C. reports consulting fees from Travere, Goldfinch, Chinook, ANI, Sanofi, and Aurinia and funds to his department for being a site principal investigator for studies sponsored by Vertex, Chinook and Travere outside the submitted work. J.C.H. reports consulting fees from Yingli Pharmaceutics and serves as founder of Rila Therapeutics and member of the Scientific Advisory Board for Renalytix.
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Nature Reviews Nephrology thanks Fernando Fervenza, Alessia Fornoni, who co-reviewed with Rachel Njeim, Moin Saleem and Catherine Meyer-Schwesinger for their contributions to the peer review of this work.
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Meliambro, K., He, J.C. & Campbell, K.N. Podocyte-targeted therapies — progress and future directions. Nat Rev Nephrol (2024). https://doi.org/10.1038/s41581-024-00843-z
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DOI: https://doi.org/10.1038/s41581-024-00843-z
