Table 2.
Axioms that define FSGS subtypes
| Axiom | Presumed permeability factor-related FSGS (ppfFSGS) | Maladaptive FSGSa | Genetic FSGS | FSGS of undetermined cause |
|---|---|---|---|---|
| Onset of disease | Sudden | Insidious; progression occurs over many years | Dependent on the type of mutation and its interaction with other genetic and environmental factors; often insidious in adults | Insidious; progression occurs over many years; often a history of hypertension |
| Extent of proteinuria | Typically NS level | Variable, can be high; NS is typically absent | Variable; NS is common in children but rare in adults | Variable, can be high; NS is typically absent |
| Findings on LM (beyond the FSGS lesion) | Generally, no other damage unless late in disease course | Often FGGS; varying degrees of chronic damage, perihilar lesions or glomerulomegaly may be present but are not diagnostic in themselves | Varying degrees of chronic damage | Often FGGS; varying degrees of chronic damage |
| Extent of foot process effacement on EM | Generalized (>80%) in non-sclerotic glomeruli | Mild and segmental | Either segmental or diffuse. GBM alterations may be prominent in type IV collagenopathies | Mild and segmental |
| Recurrence rate after kidney transplantation | High (>70%). | Low | Nil, although proteinuria may develop due to recipient versus donor immune response | Low |
| Response to RAS inhibition (or sparsentan) | Poor | Excellent | May be good, but has not been rigorously tested | Good |
| Glucocorticoids and CNIs | May induce remission | Ineffective and potentially harmful | Ineffective. Response to CNIs is anecdotal | Ineffective |
| Genetic tests and family history | Unrevealing | Unrevealing | May reveal mutations in podocyte or GBM proteins. Negative tests do not exclude a genetic cause | Unrevealing |
| Underlying cause | No evidence of a causative factor (e.g. cancer, auto-immunity, viral infection, toxins) | Evidence of a causative factor or process (e.g. unilateral renal dysplasia or agenesis, sickle cell disease, reflux nephropathy, obesity, healing phase of proliferative glomerulonephritis) is present | Mutations in genes that encode proteins involved in glomerular filtration barrier structure and function | Cannot be established, despite comprehensive evaluation |
CNIs, calcineurin inhibitors; EM, electron microscopy; FGGS, focal global glomerulosclerosis; FSGS, focal segmental glomerulosclerosis; GBM, glomerular basement membrane; LM, light microscopy; NS, nephrotic syndrome; RAS, renin–angiotensin system. aToxic and viral forms of secondary FSGS can usually be differentiated from maladaptive FSGS by a careful history and serological studies.