Focal Segmental Glomerulosclerosis

Abstract

Focal segmental glomerulosclerosis (FSGS) is a leading cause of kidney disease worldwide. The presumed etiology of primary FSGS is a plasma factor with responsiveness to immunosuppressive therapy and a risk of recurrence after kidney transplant-important disease characteristics. In contrast, adaptive FSGS is associated with excessive nephron workload due to increased body size, reduced nephron capacity, or single glomerular hyperfiltration associated with certain diseases. Additional etiologies are now recognized as drivers of FSGS: high-penetrance genetic FSGS due to mutations in one of nearly 40 genes, virus-associated FSGS, and medication-associated FSGS. Emerging data support the identification of a sixth category: APOL1 risk allele-associated FSGS in individuals with sub-Saharan ancestry. The classification of a particular patient with FSGS relies on integration of findings from clinical history, laboratory testing, kidney biopsy, and in some patients, genetic testing. The kidney biopsy can be helpful, with clues provided by features on light microscopy (e.g, glomerular size, histologic variant of FSGS, microcystic tubular changes, and tubular hypertrophy), immunofluorescence (e.g, to rule out other primary glomerulopathies), and electron microscopy (e.g., extent of podocyte foot process effacement, podocyte microvillous transformation, and tubuloreticular inclusions). A complete assessment of renal histology is important for establishing the parenchymal setting of segmental glomerulosclerosis, distinguishing FSGS associated with one of many other glomerular diseases from the clinical-pathologic syndrome of FSGS. Genetic testing is beneficial in particular clinical settings. Identifying the etiology of FSGS guides selection of therapy and provides prognostic insight. Much progress has been made in our understanding of FSGS, but important outstanding issues remain, including the identity of the plasma factor believed to be responsible for primary FSGS, the value of routine implementation of genetic testing, and the identification of more effective and less toxic therapeutic interventions for FSGS.

Keywords: Alleles; Biopsy; Body Size; Electron; Fluorescent Antibody Technique; Focal Segmental; Genetic Testing; Glomerulosclerosis; Humans; Kidney Diseases; Kidney Glomerulus; Microscopy; Mutation; Penetrance; Podocytes; Segmental glomerulosclerosis; Workload; hypertrophy; immunosuppression; kidney; kidney transplantation; nephrotic syndrome.

Figure 1.

Histopathology of minimal change disease and focal segmental glomerulosclerosis. Minimal change disease shows patent glomeruli in the absence of tubulointersitial scarring (silver stain, ×40). The tip lesion represents a focal adhesion of the glomerular tuft to Bowman’s capsule near the proximal tubule takeoff (silver stain, ×400). The most common forms of FSGS seen in adaptive FSGS and across all etiologies of FSGS are the perihilar variant (periodic acid–Schiff stain, ×40) and not otherwise specified pattern (silver stain, ×400). The most distinctive variant is the collapsing variant (collapsing glomerulopathy; silver stain, ×40). A specific instance of collapsing variant can be appreciated in the setting of endothelial tubuloreticular inclusions seen on ultrastructural analysis. These may be observed in high IFN states, including viral infection and exogenous IFN. The red arrowhead indicates the relative response to therapy and propensity of progression of these various forms, with minimal change disease and tip lesion being most responsive and least progressive and collapsing glomerulopathy being most therapy resistant and rapidly progressing.

Figure 2.

The six forms of FSGS. These syndromes include three forms that are most common, including primary FSGS, adaptive FSGS, and APOL1 FSGS. These forms are probably of approximately equal prevalence in the United States adult population. Three forms are less common, including genetic FSGS (by which is meant high-penetrance genetic causes), medication-associated FSGS, and viral FSGS. The approximate relative distribution of these variants in the United States population at present is shown by the size each cloud, although firm data on prevalence are lacking. The absolute frequency of these FSGS forms is influenced by race/ethnicity (particularly in the frequency of APOL1 risk variants), age (children are less likely to have adaptive FSGS), and the frequency of exposures to toxins (e.g., heroin) and medications and having viruses (e.g., HIV).