Focal Segmental Glomerulosclerosis (FSGS)

FSGS is a pattern of injury, not a single disease. Under the microscope, parts (segmental) of some (focal) glomeruli show scarring. Caused by damage to podocytes — the specialised cells that form the kidney's filter barrier.

FINDING THE CAUSE matters more than the biopsy pattern:

1. PRIMARY (idiopathic) FSGS:

• Driven by a circulating 'permeability factor' (target of research)
• Sudden-onset nephrotic syndrome
• Diffuse podocyte foot process effacement on electron microscopy
• May respond to steroids

2. Genetic FSGS

• Mutations in podocyte genes: NPHS1 (nephrin), NPHS2 (podocin), INF2, ACTN4, COL4A3/4/5, APOL1 (in African ancestry)
• Often childhood onset but adult presentations exist
• Does NOT respond to immunosuppression — important to identify
• Genetic counselling for family

3. SECONDARY FSGS (adaptive or maladaptive):

• Obesity (BMI > 35)
• Solitary kidney, reflux nephropathy, low birth weight (reduced nephron number)
• Sickle cell disease
• HIV-associated nephropathy (HIVAN)
• Heroin, anabolic steroids, lithium, pamidronate, interferon
• Healed previous injury (post-AKI, post-ANCA vasculitis)
• Slower onset, less heavy proteinuria, lower albumin drop

4. Apol1-mediated

• High-risk APOL1 variants (G1, G2) in African ancestry — major US/UK problem
• Drug trials with APOL1 inhibitors are advancing

Typical FSGS Presentations

• Frothy urine
• Ankle and leg swelling (oedema)
• Periorbital puffiness in mornings
• Weight gain from fluid
• Sometimes acute kidney injury
• Sometimes asymptomatic proteinuria found on routine dip

Investigations

• Urine ACR (often very high, > 300, sometimes > 1,000)
• Serum albumin (low — nephrotic if < 30 g/L)
• Cholesterol (typically very high)
• eGFR / creatinine
• HIV, hepatitis B/C, syphilis serology
• ANA, ANCA, complement
• Sickle solubility (if relevant)
• Genetic panel — especially if young, family history, or no clear secondary cause
• KIDNEY BIOPSY — diagnostic

BIOPSY VARIANTS (Columbia classification):

• Tip lesion — best prognosis
• NOS (not otherwise specified) — most common
• Perihilar — typical of secondary forms
• Cellular — often primary
• Collapsing — worst prognosis (HIV, APOL1, parvovirus)

Primary FSGS

• High-dose prednisolone 1 mg/kg (max 60-80 mg) daily for 12-16 weeks
• Then slow taper over 6 months
• If steroid-resistant or relapsing: tacrolimus or ciclosporin for 6-12 months
• Refractory: rituximab, MMF
• Add SPARSENTAN (NICE-approved 2024) for persistent proteinuria

Genetic FSGS

• Avoid immunosuppression (doesn't work, harms)
• Maximal ACE/ARB + SGLT2 inhibitor + sparsentan
• Genetic counselling, family screening
• Plan for transplant — low recurrence risk

Secondary FSGS

• TREAT THE CAUSE:
• Obesity: weight loss (GLP-1, bariatric surgery)
• HIV: HAART — often dramatic improvement
• Reflux: urological assessment
• Drug-induced: stop the drug
• Maximal ACE/ARB + SGLT2 inhibitor
• Avoid immunosuppression

ALL FSGS — SUPPORTIVE:

• ACE inhibitor or ARB to maximum tolerated dose
• SGLT2 inhibitor (dapagliflozin)
• Salt restriction < 5 g/day
• Statin (high cholesterol)
• Anticoagulation if albumin < 20 g/L and very high proteinuria (clot risk)
• Vitamin D (lost in urine)
• Pneumovax if heavy proteinuria

Prognosis Depends Heavily On Response

• Complete remission (urine ACR < 30): 10-year kidney survival > 90%
• Partial remission (50% reduction, ACR < 300): 10-year survival ~70%
• No remission: 10-year survival 30-50%

Factors Predicting Worse Outcome

• Heavy proteinuria > 10 g/day
• Reduced eGFR at diagnosis
• Collapsing variant
• Tubular atrophy/interstitial fibrosis on biopsy
• APOL1 high-risk genotype
• African ancestry
• Steroid resistance

Kidney Transplant

• Primary FSGS recurs in 30-40% of grafts — usually within days/weeks
• Recurrence rate even higher in second transplant if first was lost to recurrence
• Pre-emptive plasma exchange + rituximab may reduce recurrence
• Genetic FSGS rarely recurs (< 5%)
• Secondary FSGS rarely recurs
• Living donor decisions need careful genetic and risk discussion

Daily

• Take medications consistently
• Monitor weight, BP daily during active disease
• Low salt cooking — < 5 g/day
• Moderate protein 0.8 g/kg/day
• Avoid NSAIDs (worsen proteinuria)

Flag To Your Team

• Sudden weight gain > 2 kg in a few days
• New or worsening leg swelling
• Frothy urine returning after remission
• Calf pain or chest pain (clot risk in nephrotic syndrome)
• Severe infection (immunosuppression)

Long-term

• Annual flu, COVID, 5-yearly pneumococcal vaccines
• Bone protection if long steroids
• Cardiovascular risk factor optimisation
• Mental health support — nephrotic syndrome is debilitating
• Pregnancy planning with team — usually possible in remission