Focal Segmental Glomerulosclerosis (FSGS)

Content of This Page

1- Definition & Types

2- Causes (Aetiology)

3- Pathophysiology

4- Clinical Features & Examination

5- Investigations

6- Management

7- Complications

8- Core Concepts

Definition & Types

Definition:
FSGS is a non-inflammatory glomerular disease characterized by:

  • Focal (some glomeruli involved)

  • Segmental (only a portion of each glomerulus affected)

  • Sclerosis (scarring)

Commonly presents with nephrotic syndrome and progressive renal impairment.

Types of FSGS:

  • Primary (Idiopathic): abrupt onset of nephrotic syndrome with diffuse podocyte injury.

  • Secondary: due to a known cause or stressor (e.g. HIV, obesity).

  • Genetic: due to podocyte gene mutations (e.g. nephrin, podocin, APOL1).

  • Collapsing variant: aggressive subtype seen in HIV; rapid progression to ESRD.

© image from Wikimedia Commons

Causes (Aetiology)

Primary:

  • Unknown trigger → immune-mediated podocyte injury

  • Seen in young adults or children with sudden nephrotic syndrome

 Secondary:

  • HIV infection

  • Heroin use

  • Morbid obesity

  • Chronic hypertension

  • Prior glomerular disease (e.g. IgA nephropathy)

  • Reflux nephropathy

  • Sickle cell anaemia

  • Vesico-ureteric reflux

 Genetic:

  • Mutations in podocyte-related proteins (e.g. NPHS1, NPHS2, ACTN4)

  • APOL1 gene variants in individuals of West African ancestry increase risk

Pathophysiology

  • Podocyte injury → loss of filtration barrier integrity

  • Leads to segmental collapse and sclerosis of glomerular tufts

  • Non-inflammatory process → no proliferative lesions

  • Progressive nephron loss → glomerular hyperfiltration → further injury

  • Results in proteinuria, nephrotic syndrome, and renal failure

Clinical Features & Examination

Typical Presentation:

  • Nephrotic syndrome:

    • Heavy proteinuria (>3.5 g/day)

    • Hypoalbuminaemia

    • Generalised oedema (esp. periorbital, lower limbs)

    • Hyperlipidaemia

  • Hypertension and microscopic haematuria may be present

  • May progress to CKD or ESRD

Secondary FSGS:

  • Slower onset

  • Less severe proteinuria

  • Often lacks full nephrotic features

Investigations

Urine:

  • Dipstick: +3/+4 proteinuria

  • 24-hr or spot protein-to-creatinine ratio

  • Microscopic haematuria may be present

 Bloods:

  • ↓ Albumin

  • ↑ Lipids (cholesterol, triglycerides)

  • Normal or impaired renal function (↑ creatinine)

🔬 Renal Biopsy:

  • Essential for diagnosis:

    • Segmental sclerosis in some glomeruli

    • Foot process effacement on electron microscopy

    • IgM and C3 sometimes seen in sclerotic areas (non-specific)

Management

Primary FSGS:

  • High-dose corticosteroids (1 mg/kg/day prednisone equivalent)

  • Assess response over weeks to months

  • Calcineurin inhibitors (e.g. tacrolimus) if steroid-resistant

  • Cyclophosphamide / MMF in some cases

 Secondary FSGS:

  • Manage underlying cause (e.g. HIV, obesity)

  • ACE inhibitors or ARBs: reduce proteinuria and protect kidneys

  • Blood pressure control

  • Lipid-lowering agents

  • Lifestyle: weight loss, avoid NSAIDs/nephrotoxins

Complications

  • Progression to end-stage renal disease (ESRD)

  • Thromboembolism (due to nephrotic state)

  • Infections (e.g. peritonitis, cellulitis)

  • Recurrent FSGS in renal transplants (especially primary form)

  • Steroid side effects: weight gain, diabetes, infections

Core Concepts

  • FSGS = focal, segmental scarring of glomeruli, non-inflammatory

  • Nephrotic syndrome with poor steroid response suggests FSGS

  • Biopsy is essential—segmental lesions may be missed if sampling is inadequate

  • Check for secondary causes—especially HIV, obesity, reflux nephropathy

  • APOL1 gene variants increase risk in Black patients

  • Requires early treatment to prevent progression to ESRD

  • Even with therapy, many cases progress to CKD

 
 
 
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