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Causes and pathogenesis of focal segmental glomerulosclerosis

Key Points

  • Podocyte injury and loss are key events in the development of progressive glomerulosclerosis

  • The term focal segmental glomerulosclerosis (FSGS) refers to a disease of primary podocyte injury, or a lesion caused by secondary scarring processes in any type of chronic kidney disease

  • FSGS lesions can occur as a result of many causes, including circulating factors, underlying mutations in key podocyte genes, drug use, infection and maladaptive responses to nephron loss

  • Premature birth, profibrotic molecules, autophagy and proteinuria might have roles in the pathogenesis of FSGS

  • Parietal epithelial cells are potential podocyte progenitors that, depending on the microenvironment, might replace injured podocytes or contribute to the scarring response and podocyte loss

Abstract

Focal segmental glomerulosclerosis (FSGS) describes both a common lesion in progressive kidney disease, and a disease characterized by marked proteinuria and podocyte injury. The initial injuries vary widely. Monogenetic forms of FSGS are largely due to alterations in structural genes of the podocyte, many of which result in early onset of disease. Genetic risk alleles in apolipoprotein L1 are especially prevalent in African Americans, and are linked not only to adult-onset FSGS but also to progression of some other kidney diseases. The recurrence of FSGS in some transplant recipients whose end-stage renal disease was caused by FSGS points to circulating factors in disease pathogenesis, which remain incompletely understood. In addition, infection, drug use, and secondary maladaptive responses after loss of nephrons from any cause may also cause FSGS. Varying phenotypes of the sclerosis are also manifest, with varying prognosis. The so-called tip lesion has the best prognosis, whereas the collapsing type of FSGS has the worst prognosis. New insights into glomerular cell injury response and repair may pave the way for possible therapeutic strategies.

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Figure 1: FSGS lesions have varying morphologic appearances.
Figure 2: Possible pathways for regeneration of podocytes from PEC migration to the glomerular tuft and for the development of sclerosis.

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Jeffrey B. Kopp, Hans-Joachim Anders, … Paola Romagnani

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Acknowledgements

The author's work is supported in part by NIDDK grant R01 DK445757. She also thanks Dr Haichun Yang for his technical assistance and helpful comments.

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Correspondence to Agnes B. Fogo.

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Fogo, A. Causes and pathogenesis of focal segmental glomerulosclerosis. Nat Rev Nephrol 11, 76–87 (2015). https://doi.org/10.1038/nrneph.2014.216

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