Focal Segmental Glomerulosclerosis

The contract between this chapter and the reader.

1. 1. Define FSGS as a lesion with multiple causes.
2. 2. Classify FSGS into primary, secondary, and genetic.
3. 3. Explain the mechanisms of each.
4. 4. Recognise the clinical features and distinguish the subtypes.
5. 5. Diagnose FSGS and its variants on biopsy.
6. 6. Treat primary FSGS with immunosuppression.
7. 7. Treat secondary and genetic FSGS without immunosuppression.
8. 8. Recognise recurrence after transplantation.
9. 9. Understand the prognosis and the evidence.

A sixty-second reading. Each bullet stands alone.

• FSGS is a pattern of focal, segmental glomerulosclerosis with podocyte injury, not a single disease.
• Distinguishing primary, secondary, and genetic FSGS is the central task because it changes treatment.
• Primary (idiopathic) FSGS is driven by a circulating permeability factor and presents with nephrotic syndrome.
• Secondary (adaptive) FSGS results from hyperfiltration (obesity, reduced nephron mass) with sub-nephrotic proteinuria.
• Genetic FSGS results from podocyte gene mutations and is usually steroid-resistant.
• Diffuse foot-process effacement on electron microscopy suggests primary; segmental effacement suggests secondary.
• Biopsy shows segmental sclerosis; the collapsing variant (HIV, APOL1) has the worst prognosis.
• Primary FSGS is treated with corticosteroids, then calcineurin inhibitors if steroid-resistant.
• Secondary FSGS is treated by addressing the cause and with RAAS blockade — not immunosuppression.
• Genetic FSGS does not respond to immunosuppression and is managed supportively.
• All forms receive supportive therapy (RAAS blockade, statin).
• Primary FSGS recurs after transplant and is treated with plasma exchange.
• Unremitting primary FSGS carries a significant risk of kidney failure; remission improves the prognosis.

The medical core. An expert should agree focal segmental glomerulosclerosis is fully covered here.

Why it matters at the bedside

FSGS is a trap for the unwary, because the same scar on the biopsy can mean three completely different diseases needing three completely different treatments. Immunosuppress a primary FSGS and you may save the kidney; immunosuppress a secondary or genetic one and you only add toxicity. The whole chapter turns on one question asked well: which kind of FSGS is this?

What FSGS is: a lesion, not a disease

• FSGS names a pattern, not a single entity: focal (some glomeruli) and segmental (part of the tuft) glomerulosclerosis, underpinned by podocyte injury. The crucial insight is that this one lesion has several distinct causes, and identifying the cause — not just the lesion — is what determines treatment. ‘FSGS’ on a report is the beginning of the diagnostic work, not the end.

The classification: primary, secondary, genetic

• FSGS divides into three mechanistic categories. Primary (idiopathic) FSGS is immune-mediated — a circulating permeability factor injures podocytes diffusely, producing nephrotic syndrome, and it responds to immunosuppression. Secondary (adaptive) FSGS arises from hyperfiltration — obesity, reduced nephron mass, reflux, prior injury — a maladaptive response that scars segmentally, usually with sub-nephrotic proteinuria, and is not immune. Genetic FSGS comes from podocyte gene mutations (such as nephrin and podocin), is usually steroid-resistant, and does not respond to immunosuppression. Viral (HIV) and drug causes add further secondary forms.

Clinical features and distinguishing the subtypes

• The categories present differently, and the differences are the diagnostic levers. Primary FSGS tends to abrupt, heavy, nephrotic-range proteinuria with a low albumin; secondary FSGS tends to insidious, sub-nephrotic proteinuria with a preserved albumin. The clinical context helps — obesity or reduced nephron mass points to secondary, early onset or family history to genetic — and the electron microscopy is pivotal: diffuse foot-process effacement favours primary, segmental or limited effacement favours secondary.

Diagnosis and variants

• Biopsy shows segmental sclerosis on light microscopy — and because the lesion is focal, a small sample can miss it (the overlap with minimal change). Electron microscopy subtypes it by the extent of effacement. The histologic variants carry prognostic weight: the collapsing variant (associated with HIV and APOL1 risk variants) has the worst outcome; the tip lesion is often the most favourable; cellular, perihilar (typically adaptive), and not-otherwise-specified complete the set. APOL1 risk variants, common in those of African ancestry, raise FSGS risk.

Treating primary FSGS

• Primary FSGS is the form that earns immunosuppression: corticosteroids are first-line (though it is more steroid-resistant than minimal change), with calcineurin inhibitors for steroid-resistant or steroid-dependent disease and rituximab as an option. The goal is remission of proteinuria, which markedly improves the prognosis — making the correct identification of primary disease genuinely consequential.

Treating secondary and genetic FSGS

• Secondary and genetic FSGS must not be immunosuppressed — immunosuppression does not help and only adds harm. Secondary (adaptive) FSGS is treated by addressing its cause (weight loss, removing the nephrotoxic driver) and with RAAS blockade to reduce intraglomerular pressure. Genetic FSGS is managed supportively, again with RAAS blockade, plus genetic counselling. Mislabelling either as primary is the central, avoidable error.

Supportive therapy

• Every form of FSGS receives supportive therapy aimed at the proteinuria and its consequences: RAAS blockade (an ACE inhibitor or ARB) to lower intraglomerular pressure and proteinuria, increasingly an SGLT2 inhibitor, a statin for hyperlipidemia, and attention to the nephrotic state's thrombosis risk in primary disease — the supportive backbone of the dedicated chapter.

Recurrence after transplantation

• Primary FSGS famously recurs after transplantation — the circulating permeability factor is still present — often early and with heavy proteinuria, and is treated with plasma exchange (with rituximab in some). This is the bridge to the transplant volume's recurrent-disease chapter, and it is one of the treatable recurrences that must not be missed.

Prognosis

• Prognosis tracks the category and the response. Unremitting primary nephrotic FSGS carries a significant risk of progression to kidney failure, whereas achieving remission — spontaneous or treated — markedly improves it. The collapsing variant does worst; secondary FSGS generally progresses more slowly. The lesson is that the same biopsy diagnosis spans a wide range of outcomes, set largely by the subtype and the proteinuric response.

The evidence and its uncertainties

• FSGS sits on genuinely unsettled ground. The circulating permeability factor of primary disease is still not definitively identified; the primary-versus-secondary distinction, though central, is blurred at the margins and rests partly on the effacement pattern and the response to treatment; and the role of APOL1 in ancestry-related risk is an active and evolving story. The clinician works with a classification that is clinically indispensable yet scientifically incomplete.

Five fully-built tables.

Table A — The categories of FSGS

Table B — Primary versus secondary

Table C — Histologic variants

Table D — Treatment by category

Table E — Prognosis and recurrence

Visualise & Map

Causal chains, each ending in a named action.

Chain 1 — The permeability factor

A circulating permeability factor → diffuse podocyte injury → nephrotic-range proteinuria with diffuse effacement → primary FSGS → ACTION: treat with immunosuppression.

Chain 2 — The maladaptive response

Hyperfiltration (obesity, reduced nephron mass) → raised intraglomerular pressure → adaptive segmental sclerosis → secondary FSGS → ACTION: treat the cause and use RAAS blockade, not immunosuppression.

Chain 3 — The broken podocyte gene

A podocyte gene mutation → an intrinsically defective slit diaphragm → steroid-resistant genetic FSGS → ACTION: manage supportively (immunosuppression does not help) and counsel.

Chain 4 — The collapsing extreme

APOL1 risk variants or HIV → severe podocyte injury → the collapsing variant → worst prognosis → ACTION: recognise it, treat the cause, and counsel on the poor outlook.

Chain 5 — The factor that travels

The permeability factor persists after transplant → it injures the new graft's podocytes → recurrent FSGS with early heavy proteinuria → ACTION: treat recurrence with plasma exchange.

Numbered rules. These numbers are the cross-reference handle for the cases and flowcharts.

Clinical Reasoning

Five cases. Each stops you at a decision before it answers it.

Every mechanism from Level 3 earns a bedside consequence and an action.

Exhaustive. Every rule in the chapter is here.

Safety & Evidence

Panel A — Red flags

Panel B — NEVER DO

Anti-patterns clinicians fall into. Each becomes a Level 22 distractor.

The grade reflects strength of evidence, not importance.

Patient Decisions

Outcomes as natural frequencies. Figures are representative; the direction of effect is given where precise numbers are uncertain.

Apply & Test

Copy-paste chart notes that map to the real decisions in this chapter.

Template 1 — FSGS classification / diagnosis note

• Biopsy: segmental sclerosis; variant (collapsing/tip/cellular/perihilar/NOS) ___.
• Proteinuria (nephrotic vs sub-nephrotic); albumin ___.
• Electron microscopy: diffuse vs segmental foot-process effacement ___.
• Context: hyperfiltration (obesity/reduced mass), family history, HIV/APOL1 ___.
• Category: primary / secondary / genetic ___.

Template 2 — Treatment-by-subtype note

• Primary: corticosteroids; calcineurin inhibitor if steroid-resistant; rituximab ___.
• Secondary: cause addressed (weight loss, etc.); RAAS blockade — no immunosuppression ___.
• Genetic: supportive; genetic counselling — no immunosuppression ___.
• Supportive (all): RAAS, statin, SGLT2; thrombosis risk if nephrotic ___.
• Transplant recurrence (if applicable): plasma exchange ___.

Pre-rounds compression. Rules only.

Active recall. At least one card per objective.

Micro-teaching for rounds. Two scenarios, five steps each.

Metacognition anchored to this chapter's tensions. No answers provided.

1. 1. The primary/secondary distinction decides whether to immunosuppress, yet it is blurred at the margins; how do you act decisively on a classification you know is imperfect?
2. 2. We treat primary FSGS by removing an immune driver we cannot name; how comfortable should you be immunosuppressing against an unidentified permeability factor?
3. 3. APOL1 risk variants tie a kidney disease to ancestry; how do you use that knowledge clinically without letting it become a crude racial heuristic?
4. 4. Recurrence after transplant is predictable in primary FSGS; how much should the risk of recurrence shape the decision to transplant at all?
5. 5. The same biopsy word spans an excellent and a dismal prognosis; how do you counsel a patient when ‘FSGS’ alone tells them so little?

Nine items, each anchored in this chapter. At least one per objective.