• Accounts for ~35% of all cases of nephrotic syndrome in adults (the most common cause of primary nephrotic syndrome in adults in many Western series, especially in African Americans) ^[2]
• 2.3% of all ESRD cases ^[2] — though this is likely an underestimate as FSGS is increasingly recognized
• Incidence has been rising over recent decades, partly due to the obesity epidemic (obesity-related secondary FSGS) and improved biopsy rates
• Age distribution: Can occur at any age. Peak incidence in young adults (15–40 years) but also seen in children and elderly
• Sex: Slight male predominance in primary FSGS
• Race/Ethnicity: Markedly more common in Black/African-descent populations (4–5× higher incidence than Caucasians), partly driven by APOL1 risk alleles (G1/G2 variants — evolved for protection against Trypanosoma brucei but increase FSGS risk). Less common in Asians ^[2]

• In Hong Kong and Asia, IgA nephropathy is the most common primary glomerulonephritis overall
• FSGS is less prevalent than in Western populations but is increasing — driven by rising obesity rates and improved diagnostic biopsy
• Minimal change disease (MCD) remains the leading cause of nephrotic syndrome in children in HK; FSGS is the second most common
• In adults in HK, membranous nephropathy and FSGS are the leading causes of primary nephrotic syndrome
• HIV-associated FSGS (collapsing variant) is rare in HK compared to sub-Saharan Africa

Around 1 million nephrons at birth ^[5]. Each nephron consists of:

1. Glomerulus — the filtration unit
2. Renal tubules — proximal tubule → loop of Henle → distal tubule → collecting duct

Normally no plasma protein or red cells in the urine ^[5] — this is because the glomerular filtration barrier is exquisitely designed to prevent their passage.

This is the key structure damaged in FSGS. It has three layers (from capillary lumen outward):

1. Fenestrated endothelium — has pores (~70–100 nm) that allow passage of water and small solutes but retain blood cells. Covered by a glycocalyx layer with negative charge.

2. Glomerular basement membrane (GBM) — a dense extracellular matrix composed of type IV collagen (α3, α4, α5 chains), laminin, nidogen, and heparan sulphate proteoglycans. Acts as both a size barrier and charge barrier (negative charge from heparan sulphate repels negatively charged albumin).

3. Podocytes (visceral epithelial cells) — highly specialized, terminally differentiated cells with interdigitating foot processes connected by a slit diaphragm (the final barrier to protein filtration). Key slit diaphragm proteins include:

   • Nephrin (gene: NPHS1) — the backbone of the slit diaphragm
   • Podocin (gene: NPHS2) — anchors nephrin
   • CD2AP — adaptor protein linking slit diaphragm to actin cytoskeleton
   • TRPC6 — calcium channel in podocyte

Why are podocytes so important in FSGS? Podocytes are terminally differentiated — they cannot regenerate once lost. When podocytes are injured (by circulating factors, genetic defects, drugs, or hyperfiltration), they undergo foot process effacement (retraction/flattening of foot processes), lose slit diaphragm integrity, and eventually detach from the GBM. Loss of podocytes exposes bare GBM → adhesion of capillary tuft to Bowman's capsule (synechia) → sclerosis. This is the fundamental mechanism of FSGS.

The mesangium provides structural support to the glomerular capillary loops and contains mesangial cells (contractile, phagocytic) and mesangial matrix. In FSGS, the mesangium may show expansion and increased matrix deposition in sclerosed segments.

^[2]

Key genetic mutations by functional category ^[2]:

Autosomal recessive (AR) forms are typically early onset (< 1 year old):

• PLCE1 (commonest AR), NPHS1, NPHS2, CD2AP, PTPRO, MYO1E
• Usually completely penetrant

Autosomal dominant (AD) forms are typically late onset (> 1 year old):

• INF2 (commonest AD), TRPC6, WT1, LMX1B, ACTN4

^[2]

The Columbia classification (2004) divides FSGS into five histological variants based on light microscopy patterns. This is important because different variants have different prognoses and treatment responses.

"MCD most responsive to steroid, FSGS least" — and within FSGS, the tip lesion is most responsive and collapsing variant is worst ^[6][4].

The unifying concept across all forms of FSGS is podocyte injury. Here's the step-by-step cascade:

Why is this a vicious cycle? When some glomeruli sclerose and die, the remaining glomeruli must work harder (hyperfiltration). This increased workload puts more stress on the surviving podocytes → more injury → more sclerosis → progressive CKD. This is why FSGS can be relentlessly progressive if untreated.

In primary (idiopathic) FSGS, the prevailing theory is that there is a circulating factor produced by the immune system (likely T cells or B cells) that directly damages podocytes:

• Putative permeability factors include suPAR (soluble urokinase plasminogen activator receptor) and CLCF1 (cardiotrophin-like cytokine factor 1) ^[2]
• Some studies also show upregulation of CD80 (B7-1) in podocytes ^[2]
• Evidence for a circulating factor:
  1. Recurrence post-transplant: FSGS recurs in the transplanted kidney in ~30–40% of cases (sometimes within hours) — the donor kidney was normal, so the problem must be in the recipient's blood ^[7]
  2. Plasmapheresis can temporarily reduce proteinuria — suggesting removal of the circulating factor helps
  3. Cross-transplant: if a kidney with recurrent FSGS is re-transplanted into a patient without FSGS, the disease can resolve

In secondary FSGS (e.g., obesity, reduced nephron mass), the mechanism is fundamentally different:

1. Increased metabolic demand or reduced nephron number → remaining glomeruli must filter more
2. Afferent arteriole vasodilation → increased glomerular capillary pressure (intraglomerular hypertension)
3. Glomerulomegaly (the glomeruli enlarge to handle more filtration)
4. Mechanical stress on podocytes → foot process effacement (but typically less extensive than primary FSGS — often < 50% effacement vs. ≥80% in primary)
5. Gradual podocyte loss → segmental sclerosis, typically at the hilum (perihilar variant)

This is why secondary FSGS typically presents with subnephrotic proteinuria and why the perihilar variant is most commonly seen in adaptive FSGS.

Once the filtration barrier is compromised:

1. Proteinuria → loss of albumin in urine → hypoalbuminaemia (< 30 g/L)
2. Hypoalbuminaemia → decreased intravascular oncotic pressure → fluid shifts to interstitium → generalised oedema (underfill mechanism)
   • Additionally, primary sodium retention in collecting duct (overfill mechanism via ENaC activation by plasmin in nephrotic urine)
3. Hyperlipidaemia → the liver compensates for albumin loss by increasing protein synthesis, and this "revved-up" hepatic synthetic machinery also produces more lipoproteins (especially LDL, VLDL) → hypercholesterolaemia and hypertriglyceridaemia
   • Additionally, decreased lipoprotein lipase activity (reduced catabolism)
   • Lipids spill into urine → lipiduria (oval fat bodies, "Maltese cross" under polarized light)
4. Hypercoagulable state → loss of antithrombin III, protein C, protein S in urine + increased hepatic synthesis of clotting factors (fibrinogen, factors V, VIII) + increased platelet aggregability → risk of venous thromboembolism (especially renal vein thrombosis)
5. Immunodeficiency → loss of immunoglobulins (especially IgG) in urine → increased infection risk (especially encapsulated organisms — Streptococcus pneumoniae)

^[2]

Primary FSGS ^[2]:

• Acute nephrotic syndrome ± haematuria, HTN, ↑serum creatinine
• Diffuse (≥80%) podocyte effacement
• No underlying risk factors for secondary FSGS

Genetic FSGS ^[2]:

• Acute nephrotic syndrome (if early onset) or progressive proteinuria < 5 g/d (if late onset)
• Early onset or FHx of consanguinity
• FHx may be positive (AD/AR inheritance)
• Characteristically steroid-resistant

Secondary FSGS:

• Features of the underlying cause (e.g., obesity, HIV, drug history)
• Proteinuria usually subnephrotic
• Less oedema
• Treatment directed at underlying cause

Two stains on light microscopy that allow visualization of FSGS ^[8]:

Light microscopy: Segmental areas of mesangial matrix expansion, capillary collapse, hyaline deposits (insudation of plasma proteins), and adhesion of tuft to Bowman's capsule (synechia)

Immunofluorescence: Typically shows IgM and C3 trapping in sclerosed segments (nonspecific — represents passive trapping of proteins in damaged areas, not immune complex deposition). Primary FSGS may be "pauci-immune" (negative or minimal staining).

Electron microscopy:

• Diffuse (≥80%) foot process effacement in primary FSGS
• Focal/segmental foot process effacement (< 50%) in secondary FSGS
• This distinction on EM is one of the most reliable ways to differentiate primary from secondary FSGS

IgA nephropathy, membranous nephropathy, and focal segmental glomerulosclerosis are the primary renal pathologies known to recur in the transplanted kidney ^[7]. For FSGS specifically:

• Recurrence rate: ~30–40% for primary FSGS (supports the circulating permeability factor theory)
• Collapsing variant and those with rapid progression to ESRD have highest recurrence risk
• Genetic FSGS does not recur (the transplanted kidney has normal podocyte genes)
• Secondary FSGS does not recur (the insult is removed/not targeting the kidney itself, unless the underlying cause persists e.g., obesity)

These must also be considered when a patient presents with oedema and proteinuria before a glomerular diagnosis is established:

You should suspect FSGS when a patient presents with:

1. Nephrotic syndrome — heavy proteinuria > 3.5 g/day ( > 40 mg/h/m² in children), generalised oedema, hypoalbuminaemia ( < 30 g/L), hyperlipidaemia ± lipiduria ^[3]
2. ± Microscopic haematuria — present in ~50% of FSGS (more common than in MCD)
3. ± Hypertension — more common in FSGS than MCD
4. ± Elevated serum creatinine at presentation — indicates some degree of nephron loss already
5. No obvious secondary cause on initial workup (or alternatively, an identifiable secondary cause such as obesity, HIV, drugs — pointing to secondary FSGS)

In children: steroid trial is given first (90% have MCD); renal biopsy is only performed if there are atypical features or failed response to steroid ^[3]. Atypical features in children that should prompt earlier biopsy include:

• Age < 1 year or > 12 years
• Macroscopic haematuria
• Hypertension
• Low C3/C4
• Renal impairment
• Steroid resistance after 4–6 weeks

In adults: immunological screen and renal biopsy (unless diagnosis is obvious, e.g., DM nephropathy with retinopathy, or PLA2R-positive membranous nephropathy) ^[3]

The definitive diagnosis of FSGS requires renal biopsy demonstrating all three of the following:

Additionally, the histological variant should be classified according to the Columbia classification (NOS, perihilar, tip, cellular, collapsing) — this guides prognosis and management.

Why dysmorphic RBCs indicate glomerular haematuria: When red blood cells squeeze through a damaged glomerular filtration barrier, they get physically distorted — squeezed, fragmented, and morphologically altered. This produces dysmorphic RBCs (irregular shapes, membrane blebs). In contrast, non-glomerular haematuria (e.g., from a stone or tumour in the lower urinary tract) produces isomorphic/eumorphic RBCs (normal biconcave discs). RBC casts form when RBCs get trapped in Tamm-Horsfall protein within the renal tubules — these are pathognomonic of glomerular bleeding.

This is critical to exclude secondary causes and differentiate FSGS from other glomerulopathies:

"The relationship between MCNS, IgM nephropathy, and focal segmental glomerulosclerosis is poorly defined, but responsiveness to steroid therapy is a shared feature. These lesions may form part of a continuum of pathology — spectrum: MCD most responsive to steroid, FSGS least" ^[6].

What this means practically: If you biopsy a patient and find normal LM with diffuse FPE on EM (i.e., "MCD"), but the patient does not respond to steroids, there are two possibilities:

1. The biopsy missed sclerosed glomeruli (sampling error) and the true diagnosis is FSGS → repeat biopsy
2. The patient has MCD that is genuinely steroid-resistant → try second-line agents (cyclophosphamide, cyclosporine)

Management of steroid-resistant MCD: repeat kidney biopsy for alternative diagnosis ^[10].

This is the single most important non-immunosuppressive intervention for FSGS.

ACEI/ARB is indicated in ALL glomerulopathies — not just FSGS — ↓glomerular pressure, ↓proteinuria, which is associated with ↓rate of GFR decline ^[18][3].

For secondary FSGS: ACEI to decrease intra-glomerular pressure by blocking efferent arteriole vasoconstriction + treatment of underlying cause — NO role of steroids or other immunosuppressants ^[11].

Monitoring during RAAS blockade: Check serum creatinine and potassium within 1–2 weeks of starting. A rise of creatinine up to 30% from baseline is acceptable (reflects the desired reduction in intraglomerular pressure). If creatinine rises > 30% → consider renal artery stenosis, volume depletion, or stop ACEI/ARB.

Why corticosteroids? In primary FSGS, the circulating permeability factor is thought to be produced by immune cells (likely T cells). Steroids suppress T-cell function and cytokine production, potentially reducing the permeability factor. However, the response is much worse than in MCD — this is because in FSGS, irreversible structural damage (sclerosis) has already occurred, unlike the purely functional/reversible podocyte effacement in MCD.

"Spectrum: MCD most responsive to steroid, FSGS least" ^[6].

Side effects of long-term corticosteroids (important because FSGS often requires prolonged courses):

• Cushingoid features, weight gain, glucose intolerance/DM
• Osteoporosis → need bone protection (calcium, vitamin D, bisphosphonates)
• Avascular necrosis of femoral head
• Immunosuppression → infection risk
• Cataracts, glaucoma
• Growth retardation in children
• Psychiatric effects (insomnia, mood disturbance)
• Peptic ulcer → gastroprotection with PPI

Used for steroid-resistant, steroid-dependent, or frequently relapsing FSGS.

Why calcineurin inhibitors work in FSGS — dual mechanism:

1. Immunosuppressive: block T-cell activation → reduce production of circulating permeability factors
2. Direct podocyte effect: stabilise the podocyte actin cytoskeleton by protecting synaptopodin from degradation by cathepsin L — this is a non-immune mechanism that directly reduces proteinuria

Contraindications / Cautions:

• Nephrotoxicity — this is the major paradox: CNIs can themselves cause chronic nephrotoxicity and even FSGS. Monitor trough levels closely; do not use if significant renal impairment
• Hypertension (CsA > tacrolimus)
• Hyperkalaemia
• Gingival hyperplasia and hirsutism (CsA)
• DM (tacrolimus > CsA)
• Neurotoxicity (tremor)

Pathophysiology — Why are nephrotic patients hypercoagulable?

Nephrotic syndrome creates a hypercoagulable state through multiple converging mechanisms:

1. Loss of natural anticoagulants through the kidneys — Antithrombin III (AT-III), protein C, and protein S are relatively small proteins that are lost in urine. The loss of anticoagulants is greater than the loss of clotting factors — so they are more likely to clot ^[15]
2. Compensatory hepatic overproduction of clotting factors — The liver upregulates synthesis of large-molecular-weight procoagulant factors (fibrinogen, factors V, VII, VIII, von Willebrand factor) that are too large to be filtered
3. Increased platelet aggregation — Hypoalbuminaemia increases free arachidonic acid → more thromboxane A₂ → platelet hyperreactivity
4. Hyperviscosity — Haemoconcentration from intravascular volume depletion + elevated fibrinogen
5. Immobility — Patients with severe oedema/anasarca are often bedridden

Patients with nephrotic syndrome have an 8 times higher risk of developing venous or arterial thrombosis compared to normal patients ^[15].

Management ^[3]:

Diagnosis: Doppler USG for renal vein/lower limb DVT; CT angiography for PE and renal vein thrombosis ^[3].

Pathophysiology — Why are nephrotic patients prone to infection?

1. Loss of immunoglobulins (especially IgG) in urine ^[3] — IgG is small enough (~150 kDa) to leak through the damaged glomerular barrier. This produces a functional hypogammaglobulinaemia, particularly affecting opsonisation of encapsulated bacteria
2. Loss of complement factors (factor B, factor D) in urine → impaired alternative complement pathway
3. Loss of transferrin in urine → low serum iron → promotes bacterial growth (iron is a bacterial growth factor normally sequestered by transferrin)
4. Immunosuppressive therapy (steroids, CNIs, cyclophosphamide, rituximab) — compounds the problem
5. Oedematous tissues — poor blood supply, skin barrier compromise → cellulitis, wound infection

Management ^[3]:

• SBP → antibiotics (empiric broad-spectrum → narrow based on culture; typically cephalosporins)
• Pneumococcal vaccination indicated for ALL nephrotic syndrome patients ^[18]
• Maintain high index of suspicion for infection in nephrotic patients on immunosuppression
• PCP prophylaxis (trimethoprim-sulfamethoxazole) if on high-dose steroids + cyclophosphamide

This is one of the most practically challenging complications to manage.

Pathophysiology ^[3]:

• Poor drug/diet compliance — patients don't restrict sodium or miss diuretic doses
• Furosemide malabsorption due to gut wall oedema — oral furosemide cannot be absorbed when the intestinal wall is waterlogged
• Albumin-binding of furosemide in tubular lumen — furosemide normally reaches the loop of Henle via tubular secretion and acts from the luminal side. In nephrotic syndrome, heavy proteinuria means furosemide binds to albumin in the tubular lumen, rendering it inactive
• Distal sodium reabsorption — as you block the loop of Henle with furosemide, the distal tubule compensates by increasing sodium reabsorption

Management ^[3]:

AKI in the context of FSGS/nephrotic syndrome can occur through several mechanisms ^[3]:

Pathophysiology:

• In nephrotic syndrome, heavy urinary albumin loss triggers the liver to increase protein synthesis globally — this "revved-up" hepatic machinery also overproduces lipoproteins (LDL, VLDL, Lp(a))
• Simultaneously, lipoprotein lipase (LPL) activity is reduced → decreased clearance of triglyceride-rich lipoproteins
• Additionally, loss of HDL components in urine further worsens the lipid profile
• The net result: ↑total cholesterol, ↑LDL, ↑triglycerides, ↑Lp(a), ↓HDL — a profoundly atherogenic profile

Clinical significance: Chronic nephrotic syndrome (as in FSGS, which is often prolonged) leads to long-term cardiovascular disease ^[3] — accelerated atherosclerosis, coronary artery disease, stroke, and peripheral arterial disease. This is compounded by concomitant hypertension (common in FSGS) and steroid-induced metabolic syndrome.

Management: CV risk modifications ^[3] — statins, BP control, smoking cessation, glycaemic control if diabetic, weight management.

Not a "complication" per se but a hallmark of nephrotic syndrome. When hyperlipidaemia is severe, lipids spill into the urine → oval fat bodies (tubular epithelial cells laden with cholesterol esters) visible on urine microscopy. Under polarised light, cholesterol esters show a characteristic "Maltese cross" birefringence pattern. Also see fatty casts in the sediment.

This is the most feared long-term complication of FSGS.

Key prognostic data ^[2]:

• Clinical course of primary FSGS: usually progressive if untreated, ~50% ESRD within 10 years + < 10% spontaneously remitting
• 30% of patients with steroid-resistant FSGS progress to stage 5 CKD ^[10]
• Collapsing variant has the worst prognosis (33% 3-year renal survival) vs. tip variant (76% 3-year renal survival)

Pathophysiology — The vicious cycle of nephron loss:

As sclerosed glomeruli lose function, the remaining nephrons must compensate by increasing single-nephron GFR (hyperfiltration). This places additional haemodynamic stress on the surviving podocytes → more podocyte injury → more sclerosis → more nephron loss → more hyperfiltration. This self-perpetuating cycle drives inexorable progression to ESRD even after the initial insult is removed.

FSGS is classified with ++ CRF (chronic renal failure) risk ^[20] — unlike MCD which rarely progresses to CRF.

CKD complications (once GFR falls significantly):

• Fluid overload → pulmonary oedema, hypertension
• Hyperkalaemia → cardiac arrhythmia risk
• Metabolic acidosis → compensatory hyperventilation (Kussmaul breathing)
• Renal osteodystrophy — hyperphosphataemia + hypocalcaemia + secondary hyperparathyroidism + ↓1,25-dihydroxyvitamin D
• Anaemia — ↓erythropoietin (EPO) production by diseased kidneys; also EPO loss in nephrotic urine
• Uraemic symptoms — nausea, vomiting, encephalopathy, pericarditis, pruritis

Management: Renal replacement therapy (RRT) — haemodialysis, peritoneal dialysis, or renal transplantation.

IgA nephropathy, membranous nephropathy, and focal segmental glomerulosclerosis are the primary renal pathologies known to recur in the transplanted kidney ^[7]. This makes sense since the antibodies/circulating factors are still being produced — you haven't solved that issue yet ^[7].

Features of recurrence ^[2][7]:

• Can recur within hours to days of transplantation (sometimes in the operating theatre!) — strong evidence for a circulating factor
• Presents with return of proteinuria, sometimes rapidly reaching nephrotic range
• Surveillance: should screen for proteinuria regularly post-transplant ^[2]
• Treatment of recurrent FSGS: optimal Tx unknown, but should rule out secondary FSGS (e.g., CMV, BK-related) ^[2]; plasmapheresis/plasma exchange can remove the circulating factor and induce remission in some cases
• Rituximab may also be effective for recurrent FSGS post-transplant

Long-term complications of transplantation ^[7]:

• Infections: CMV, PJP, BK virus, MTB
• Malignancy: PTLD (B-cell lymphoma, EBV related)
• Cardiovascular disease
• Drug-related side effects (CNI nephrotoxicity, steroid side effects)
• Chronic allograft injury

Prolonged high-dose corticosteroids (often needed for months in FSGS given the slow response) cause a wide array of complications:

Prevention: Gradual taper (never stop abruptly), bone protection (calcium + vitamin D ± bisphosphonates), gastroprotection (PPI), glucose monitoring, regular ophthalmology review.

A particularly cruel irony: CNIs (cyclosporine, tacrolimus), used to treat FSGS, can themselves cause chronic nephrotoxicity and even secondary FSGS.

Monitoring: Trough drug levels (CsA target 100–175 ng/mL; tacrolimus 5–10 ng/mL); serum creatinine; BP; potassium; glucose.