From the Guidelines
Focal segmental glomerulosclerosis (FSGS) is a complex disease that develops through podocyte injury and dysfunction, leading to sclerosis in segments of some glomeruli, and can be primary (idiopathic) or secondary to various conditions, including viral infections, medication toxicity, and genetic mutations. The pathogenesis of FSGS involves damage to podocytes, specialized cells that form the glomerular filtration barrier, leading to their detachment from the glomerular basement membrane, and triggering a cascade of events including foot process effacement, disruption of the slit diaphragm, and proteinuria 1.
Primary and Secondary FSGS
FSGS can be classified into four subclasses: primary FSGS, genetic FSGS, secondary FSGS, and FSGS of undetermined cause (FSGS-UC) 1. Secondary FSGS is mediated by viral injury, medication-related injury, or adaptive changes, and can be caused by conditions such as hypertension, obesity, viral infections (particularly HIV), drug toxicity, or genetic mutations affecting podocyte proteins such as nephrin, podocin, and TRPC6 1.
Key Factors in FSGS Pathogenesis
The progression of FSGS involves hyperfiltration in remaining functional nephrons, leading to further podocyte stress and loss, creating a vicious cycle of ongoing damage. Inflammation and activation of the renin-angiotensin-aldosterone system contribute to progressive fibrosis 1.
Clinical Implications
Understanding the pathogenesis of FSGS is crucial for developing effective treatment strategies, which target reducing proteinuria, controlling hypertension, and modulating the immune system in primary forms of the disease 1. Distinguishing primary from secondary FSGS is essential, as immunosuppressive therapy may not be indicated in secondary FSGS, and other treatments, such as antiretroviral therapy for HIV infection or weight loss for obesity, may be more appropriate.
From the Research
Pathogenesis of FSGS
The pathogenesis of Focal Segmental Glomerulosclerosis (FSGS) is a complex process involving various clinicopathological entities with different mechanisms of injury, primarily targeting the podocyte and leading to characteristic sclerotic lesions in parts of some glomeruli 2, 3, 4, 5, 6.
- Primary FSGS: Thought to be caused by circulating permeability factors that have a main role in podocyte foot process effacement, usually presenting with nephrotic syndrome 2.
- Secondary FSGS: Includes maladaptive FSGS secondary to glomerular hyperfiltration, virus-associated FSGS, and drug-associated FSGS, which can result in direct podocyte injury 2, 4.
- Genetic FSGS: Caused by alterations in structural genes of the podocyte, with genetic risk alleles in apolipoprotein L1 being especially prevalent in African Americans 4.
- Podocyte Injury: The initial injury in FSGS, which can be caused by various factors including genetic alterations, circulating factors, infection, drug use, and secondary maladaptive responses 2, 4, 5.
- Role of Parietal Epithelial Cells (PECs): PECs have been highlighted as playing a role in the pathogenesis of FSGS, with activated PECs migrating along adhesion to the glomerular tuft and contributing to the progression of sclerosis 5.
- Complex Interplay: The pathogenesis of FSGS involves a complex interplay between etiologic and pathogenic factors, progression factors, and intervention, with genetic predisposition, environmental influences, and pharmacologic intervention all impacting the phenotypic expression of FSGS 6.
Key Factors
Key factors involved in the development and progression of FSGS include: