Idiopathic nephrotic syndrome (INS) describes a group of pathologies of the renal glomerulus that result in the classic triad of heavy proteinuria, oedema and hypoalbuminaemia. The disease has historically been defined by evidence of distinctive histological changes in the absence of clinical evidence of a distinct pathological driver. However, the current classification is not based on any systematic mechanistic understanding of biological processes, and therefore current treatment regimens are broad, iterative and nonspecific. Over the past 20 years delineation of the underlying biology of the target cell in INS — the glomerular podocyte — has transformed our understanding of the mechanisms that contribute to breakdown of the glomerular filtration barrier and the development of INS. It is increasingly clear that nephrotic syndrome caused by monogenic mutations is distinct from immune-driven disease, which in some cases is mediated by circulating factors that target the podocyte. The combination of systems biology and bioinformatics approaches, together with powerful laboratory models and ever-growing patient registries has potential to identify disease ‘signatures’ that reflect the underlying molecular mechanism of INS on an individual basis. Understanding of such processes could lead to the development of targeted therapies.
New insights suggest that nephrotic syndrome can be classified according to our understanding of underlying molecular mechanisms into genetic nephrotic syndrome, immune-based nephrotic syndrome and circulating factor disease (CFD); such a classification might aid the identification of patient subgroups who would benefit from targeted therapy.
Genetic advances have shown that at least 33% of cases of childhood-onset steroid-resistant nephrotic syndrome are caused by single gene mutations, and have identified specific biological pathways that could be therapeutically targeted.
CFD is characterized by disease recurrence after transplantation, and is associated with negative genetic testing and often secondary steroid resistance.
Immune-based nephrotic syndrome is acquired, and is likely to be the basis of some forms CFD, but may also account for an immune-mediated non-CFD subtype of disease; some forms of immune-based nephrotic syndrome also have known genetic associations, particularly with HLA-DR alleles.
Biomarkers for CFD can be derived by correlating findings from in vitro models with key clinical features; such approaches may aid the identification of patients at risk of recurrence and provide greater insights into disease processes.
In-depth molecular stratification will be enhanced by systems biology approaches that combine big data methodologies with advanced bioinformatics.
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Funders for studies referenced from the author’s laboratory include the Medical Research Council (UK), Kidney Research UK, Nephrotic Syndrome Trust (NeST), NIHR-TRC, and Kids Kidney Research.
The author declares no competing interests.
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The concept of protein homeostasis, involving protein biogenesis, folding, trafficking and degradation of proteins present within and outside the cell.
- Tryptic peptides
Peptides generated by the action of the protease trypsin.
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Saleem, M.A. Molecular stratification of idiopathic nephrotic syndrome. Nat Rev Nephrol 15, 750–765 (2019). https://doi.org/10.1038/s41581-019-0217-5
The Russian Archives of Internal Medicine (2020)
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