Focal Segmental Glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is a histological pattern of segmental scarring of some glomeruli, representing a podocytopathy with several causes.

• Primary FSGS: circulating permeability factor (suPAR, anti-nephrin), nephrotic syndrome, recurs after transplant in 30 to 40%.
• Genetic FSGS: NPHS1, NPHS2 (podocin), WT1, INF2, ACTN4, TRPC6, COL4A genes; APOL1 high-risk genotypes in people of African ancestry (collapsing variant and HIVAN).
• Secondary adaptive FSGS: obesity, reduced nephron mass (low birth weight, reflux, unilateral agenesis, nephrectomy), hypertension, sickle cell disease.
• Secondary toxic and viral: HIV, parvovirus B19, pamidronate, interferon, lithium, heroin, COVID-19 (collapsing variant).
• Variants: NOS, tip, perihilar, cellular, collapsing (worst prognosis).
• Complications: ESKD in 50% within 5 to 10 years for nephrotic FSGS; recurrence in allografts.

• Primary: nephrotic syndrome with abrupt onset, microscopic haematuria, hypertension, reduced GFR.
• Secondary (adaptive): gradual subnephrotic proteinuria with preserved albumin, obesity, enlarged glomeruli.
• Genetic: familial, steroid resistant nephrotic syndrome in childhood, syndromic features.
• Collapsing FSGS: rapid renal failure, heavy proteinuria.

• Proteinuria (subnephrotic to nephrotic), low albumin in primary form, bland or haematuric sediment.
• Renal biopsy: segmental sclerosis and hyalinosis, foot process effacement (diffuse in primary, segmental in secondary), variant typing; sampling error is common.
• Exclude secondary causes: BMI, HIV, hepatitis B/C, drug history, reflux imaging, family history.
• Genetic testing for steroid resistant disease, early onset, family history, syndromic disease.
• APOL1 genotyping in patients of African ancestry.
• Baseline eGFR, lipids, HbA1c.

• All patients: sodium restriction, ACE inhibitor or ARB (ramipril 5 to 10 mg, losartan 50 to 100 mg) titrated to blood pressure below 130/80 mmHg and proteinuria reduction, SGLT2 inhibitor (dapagliflozin 10 mg), statin, weight loss in obesity-related disease, avoid NSAIDs.
• Primary FSGS with nephrotic syndrome: prednisolone 1 mg/kg (maximum 80 mg) daily for 8 to 16 weeks until remission, then taper over 6 months. Remission in about 40 to 50%.
• Steroid dependent, intolerant or resistant disease: tacrolimus 0.05 to 0.1 mg/kg/day (trough 5 to 10 ng/mL) or ciclosporin 3 to 5 mg/kg/day for at least 6 months with low-dose prednisolone, then taper. Mycophenolate mofetil 1 g twice daily and rituximab are options. Sparsentan 400 mg daily (endothelin and angiotensin receptor antagonist) lowers proteinuria.
• Genetic and adaptive forms: supportive therapy only; avoid immunosuppression.
• Collapsing FSGS from HIV: antiretroviral therapy plus ACE inhibitor.
• Recurrence after transplant: plasmapheresis with high-dose ciclosporin, rituximab.
• Manage complications: lipids, thromboprophylaxis, infection.
• Dialysis and transplantation for ESKD; living related donors with genetic disease require screening.