Differentiating the etiologies of focal segmental glomerulosclerosis (FSGS): unraveling differences in disease epidemiology and single-cell pathophysiology

Abstract:Focal segmental glomerulosclerosis (FSGS) is a histopathological pattern of kidney injury defined by the microscopical appearance of scar tissue ('sclerosis') in segments of some ('focal') kidney glomeruli. Historically, FSGS was incorrectly defined as a separate disease entity, while it is now recognized that FSGS lesions may occur in a wide range of clinical conditions that are all characterized by severe podocyte injury and loss, called podocytopathies. Despite the heterogeneous etiology of the different FSGS subtypes, the first clinical and histopathological presentation may be very similar. Moreover, there are no biomarkers that reliably discriminate between subtypes, making the diagnosis of the underlying etiology challenging. Importantly, a misclassification will lead to inappropriate and potentially harmful therapy. Furthermore, in previous studies, patient stratification according to the underlying FSGS subtype was often flawed, possibly invalidating the reported research results. Clearly, our current understanding of the pathophysiology and epidemiology of FSGS is inadequate to reliably diagnose and treat the right underlying podocytopathy. This PhD project consists of three chapters. First, glomerular disease in Flanders is studied on a macroscopic epidemiological level by analyzing data from the Flemish Collaborative Glomerulonephritis Group (FCGG) registry. This database captures all native kidney biopsies performed in the Flemish population of 6.5 million inhabitants. It therefore allows to identify all FSGS patients across Flanders and serves as a starting point for further research into the epidemiology of the different subtypes. Next, we perform an in-depth epidemiological analysis of a Flemish FSGS cohort that is well stratified according to the underlying podocytopathy. Finally, by performing single-nucleus RNA-sequencing on kidney biopsies of different FSGS subtypes, we zoom in into the pathophysiology to unravel subtype-specific gene expression signatures at the single-cell level.

Publication year:2024

Accessibility:Embargoed