About FSGS

Focal segmental glomerulosclerosis (FSGS) is a rare, progressive podocytopathy^1-3

FSGS is a rare, progressive kidney condition characterized by a shared histologic pattern of podocyte injury and focal glomerular sclerosis, resulting in variable proteinuria and frequently presents with nephrotic syndrome.^1-3

Unaffected podocyte

Injured podocyte in FSGS

Epidemiology and disease burden

FSGS is a rare condition, yet it is one of the leading causes of kidney failure, affecting adults and children⁴

• US prevalence of FSGS is 212.6 per 1,000,000*, with ~50,000 adults currently living with progressive kidney disease due to FSGS⁴
• Approximately 68% of patients are already at chronic kidney disease (CKD) Stage 3 or higher at time of biopsy, meaning many patients have advanced disease progression at diagnosis⁵
• Approximately half of patients progress to end-stage kidney disease (ESKD) within 10–20 years of diagnosis⁶

FSGS disproportionately impacts certain populations^2,7

• ~2x more males are affected than females²
• 2-3x more prevalent in African American patients versus White patients⁷

The disease burden extends beyond kidney outcomes and includes nephrotic syndrome complications, cardiovascular risk, and reduced quality of life^1,8-10

• FSGS accounts for nephrotic syndrome in 20% of children and 40% of adults^1,11

Podcast Episode Nephrology FSGS

Introduction to FSGS

Hear Dr. Howard Trachtman discuss FSGS classification, the role of podocyte injury, and the treatment challenges that patients face

Listen now

Classification of FSGS

The 2021 Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Disease Guideline classifies FSGS by proteinuria, etiology, and histologic presentation 
on biopsy.³

Primary FSGS

• Most common form of FSGS in adolescents and young adults¹²
• Thought to be the result of putative circulating permeability factors that cause podocyte injury^3,12,13

Diagnostic characteristics³

Diagnostic characteristics³

 

• Often sudden onset
• Nephrotic syndrome^† generally present (e.g. hypoalbuminemia, hyperlipidemia, edema)
• Proteinuria >3.5 g/day
• Diffuse podocyte foot process effacement

Genetic FSGS

• Genetic forms of FSGS arise from genetic variants affecting podocyte biology, the glomerular basement membrane, or related kidney developmental pathways.¹⁴ These may present as renal-limited disease, with manifestations confined to the kidneys, or as syndromic disease, with extra-renal manifestations.¹⁴

Diagnostic characteristics³

Diagnostic characteristics³

 

• Often younger in age
• Proteinuria generally without nephrotic syndrome^†
• Family history of kidney disease
• May have syndromic features

Key associated genes¹⁵

Key associated genes³

 

• Renal-limited: APOL1-associated FSGS, NPHS1, NPHS2, CD2AP, and TRPC6
• Syndromic: COL4A3-5 variants (Alport syndrome), LMX1B (Nail-Patella syndrome), WT1 (Frasier syndrome), and INF2 (Charcot-Marie-Tooth disease)

Secondary FSGS

• FSGS lesion found in the setting of an established pathophysiologic process known to cause FSGS³
• May occur due to adaptive changes associated with an underlying condition, viral infections, or may be drug-induced³

Diagnostic characteristics³

Diagnostic characteristics³

 

• Proteinuria generally without nephrotic syndrome^†
• With or without diffuse podocyte foot process effacement
• Normal or reduced nephron mass

FSGS of undetermined cause

• Presence of FSGS lesions with no identified underlying etiology of primary, genetic, or secondary FSGS³

Diagnostic characteristics³

Diagnostic characteristics³

 

• Proteinuria generally without nephrotic syndrome^†
• Segmental foot process effacement
• Clinical and histologic manifestations that do not resemble primary FSGS based on current understanding

Pathophysiology: A shared mechanism of podocyte injury

Although FSGS can arise from diverse causes, all forms share a common glomerular lesion resulting from podocyte injury.^1,12

In FSGS, early podocyte stress can promote enhanced endothelin-1 (ET-1) and angiotensin II (Ang II) signaling, activating inflammatory pathways that perpetuate glomerular damage and disease progression.^15-18

Within this cycle, Ang II activates ET-1 production in a positive feedback loop, promoting perpetual upregulation and continuous pathway activation.^15,17,19
Signaling through the endothelin type A (ET_A) and angiotensin type 1 (AT₁) receptors then propagates further podocyte injury, leading to^15,20,21:

As podocyte loss accumulates, integrity of the glomerular filtration barrier declines, resulting in worsening proteinuria.^15,20,21

Collectively, these mechanisms sustain a self-perpetuating cycle of ongoing podocyte injury, persistent proteinuria, and progressive kidney damage that drives long-term disease progression and poor clinical outcomes.^{8,16-18,21-25}

Early recognition of disease manifestations and prompt diagnosis are essential for implementing strategies to reduce proteinuria and mitigate further kidney injury.^3,11,26

Podcast Episode Nephrology FSGS

From Podocyte to Patient: The Pathophysiology of FSGS

Listen to Dr. Huber discuss the role of ET-1 and Ang II signaling in FSGS disease progression

Listen now

MA-SP-25-0077 | May 2025