Focal Segmental Glomerulosclerosis (FSGS)

📋 Key Information Summary

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Focal segmental glomerulosclerosis (FSGS) is a histological pattern of glomerular injury characterised by focal (some glomeruli) and segmental (part of a glomerulus) scarring, leading to nephrotic-range proteinuria and progressive chronic kidney disease (CKD).
Primary (idiopathic) FSGS is mediated by circulating permeability factors causing podocyte injury and slit-diaphragm disruption; secondary FSGS arises from adaptive, genetic, or toxin-mediated glomerular overload.
Key secondary causes include obesity-related glomerulomegaly, HIV-associated nephropathy (HIVAN), heroin nephropathy, reflux nephropathy, reduced nephron mass, and drug exposures (e.g., lithium, sirolimus, pamidronate, interferon-α).
Incidence in Australia is approximately 7 per million population per year; FSGS is the leading cause of nephrotic syndrome in Aboriginal and Torres Strait Islander (ATSI) adults and accounts for ~15–20 % of primary glomerulonephritis biopsies nationally.
Renal biopsy is essential for definitive diagnosis; light microscopy shows segmental sclerosis, immunofluorescence is typically negative or shows non-specific IgM/C3 in sclerotic segments, and electron microscopy confirms foot-process effacement in primary FSGS.
The Columbia classification (not otherwise specified [NOS], perihilar, tip, cellular, collapsing variants) guides prognosis and, to a lesser extent, treatment response.
Primary FSGS with nephrotic syndrome is treated with oral prednisone 1 mg/kg/day (max 60 mg) for a minimum of 16 weeks (minimum 4 weeks at full dose after remission) before considering treatment failure.
Calcineurin inhibitors (cyclosporin or tacrolimus) are first-line steroid-sparing agents or second-line therapy for steroid-dependent, steroid-resistant, or steroid-intolerant disease; cyclosporin 3–5 mg/kg/day or tacrolimus 0.05–0.1 mg/kg/day with trough monitoring.
Secondary FSGS management targets the underlying cause — weight loss for obesity-related FSGS, antiretroviral therapy (ART) for HIVAN, drug cessation for toxin-mediated disease — rather than immunosuppression.
ACE inhibitors or ARBs are recommended for all patients with proteinuria to reduce intraglomerular pressure and slow CKD progression; target BP <130/80 mmHg (<125/75 if protein >1 g/day).
Rituximab, mycophenolate mofetil (MMF), and cyclophosphamide are used as second- or third-line agents in refractory primary FSGS; plasmapheresis may be considered for recurrent FSGS post-transplant.
Approximately 30–50 % of patients with primary FSGS progress to end-stage kidney disease (ESKD) within 10 years; recurrence post-transplant occurs in 20–40 % of cases, often within days to weeks.
ATSI Australians have disproportionately higher rates of FSGS, driven by higher prevalence of obesity, diabetes, low birth weight (reduced nephron mass), and socioeconomic barriers to specialist nephrology care.

Introduction & Australian Epidemiology

Focal segmental glomerulosclerosis (FSGS) is a clinico-pathological entity characterised by a pattern of glomerular injury in which some (focal) glomeruli show scarring of a portion (segment) of the capillary tuft. It represents a final common pathway of podocyte injury from diverse aetiologies and is classified histologically rather than as a single disease. FSGS is a leading cause of the nephrotic syndrome in adults and an increasingly important cause of progressive chronic kidney disease (CKD) worldwide.

Australian Epidemiology

Data from the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) and Australian kidney biopsy registries indicate that FSGS accounts for approximately 15–20 % of all primary glomerulonephritis biopsies. The overall population incidence is estimated at 7 per million per year, but this figure is rising, reflecting increasing obesity and metabolic syndrome prevalence. In Aboriginal and Torres Strait Islander populations, FSGS is disproportionately more common and is frequently associated with secondary aetiologies including obesity, type 2 diabetes, and low birth weight. FSGS is the most common primary glomerular disease leading to ESKD in Indigenous Australians under 50 years of age.

The male-to-female ratio is approximately 2:1 for primary FSGS. Peak incidence occurs in the third to fourth decades for primary FSGS, while secondary forms are seen across all age groups. The incidence of FSGS in children in Australia is approximately 2 per 100,000 per year, accounting for 10–15 % of childhood nephrotic syndrome.

Primary vs Secondary FSGS

Distinguishing primary (idiopathic) FSGS from secondary FSGS is critical because treatment strategies differ fundamentally. Primary FSGS is presumed immune-mediated and responds to immunosuppression; secondary FSGS requires management of the underlying cause.

Feature	Primary FSGS	Secondary FSGS
Aetiology	Circulating permeability factor(s); idiopathic	Adaptive, genetic, viral, or toxin-mediated
Presentation	Nephrotic syndrome (oedema, hypoalbuminaemia, hyperlipidaemia)	Subnephrotic or nephrotic proteinuria; oedema less prominent
Proteinuria	Usually >3.5 g/day (nephrotic range)	Variable; often 1–3 g/day
Serum albumin	Low (<25 g/L)	Often near-normal or mildly reduced
Electron microscopy	Diffuse foot-process effacement (>80 %)	Focal or mild foot-process effacement
Treatment	Immunosuppression (steroids, CNIs)	Treat underlying cause; avoid unnecessary immunosuppression
Prognosis	30–50 % progress to ESKD within 10 years	Depends on aetiology and response to cause-specific therapy

Secondary FSGS — Key Causes in Australia

Obesity-Related Glomerulopathy (ORG)

With over 65 % of Australian adults classified as overweight or obese (AIHW 2023), ORG is the most common secondary cause of FSGS in Australia. Glomerulomegaly with or without FSGS lesions results from increased glomerular capillary pressure driven by hyperfiltration in a setting of excess body mass. Characteristic findings include glomerulomegaly (glomerular volume >3.5 × normal), relatively preserved foot processes, and a perihilar pattern of sclerosis. Treatment centres on weight loss (target BMI <30 kg/m²), ACE inhibitor or ARB therapy, and management of metabolic comorbidities. Bariatric surgery may be considered for BMI >40 kg/m² (or >35 with significant comorbidity) with refractory proteinuria.

HIV-Associated Nephropathy (HIVAN)

HIVAN, caused by direct viral infection of renal tubular epithelial cells and podocytes, presents with collapsing FSGS — the most aggressive histological variant. Australia has approximately 29,000 people living with HIV (Kirby Institute 2023); HIVAN is more common in those of African descent and in people with advanced immunosuppression (CD4 <200 cells/µL). The single most effective intervention is combination antiretroviral therapy (cART), which dramatically reduces progression to ESKD. Immunosuppression with corticosteroids is not recommended for HIVAN. ACE inhibitors or ARBs provide additional renoprotection.

Drug-Induced FSGS

Several drugs are recognised causes of FSGS or FSGS-like injury in the Australian context:

Lithium: Long-term lithium use (common in Australian psychiatric practice) can cause chronic tubulointerstitial nephropathy with secondary FSGS. Monitor serum creatinine and eGFR every 6–12 months; consider switching mood stabiliser if eGFR declines significantly.
Pamidronate / zoledronic acid: Bisphosphonate-associated collapsing FSGS is rare but well described. Discontinue the offending agent; kidney function may partially recover.
Sirolimus / everolimus (mTOR inhibitors): Used in transplant immunosuppression; may cause de novo or worsening FSGS, particularly in those with pre-existing proteinuria.
Interferon-α: Historically used in hepatitis C treatment; causes podocyte dedifferentiation and collapsing FSGS. With the advent of direct-acting antivirals, this exposure has decreased.
Anabolic steroids and heroin: Heroin-associated nephropathy (now uncommon in Australia) classically produces FSGS; anabolic steroid use in bodybuilding communities is an under-recognised cause.

Adaptive / Maladaptive FSGS

Reduced nephron number (low birth weight, unilateral renal agenesis, reflux nephropathy, cortical necrosis, surgical nephrectomy) or increased metabolic demand (sickle cell disease, cyanotic congenital heart disease) leads to compensatory glomerular hyperfiltration, capillary hypertension, and eventual segmental sclerosis. Management involves treating the primary condition, ACE inhibitor/ARB therapy, and avoiding nephrotoxins.

Pathophysiology — Podocyte Injury

Podocytes are terminally differentiated visceral epithelial cells that interdigitate with foot processes bridged by the slit diaphragm, forming the final size-selective barrier of the glomerular filtration apparatus. FSGS pathogenesis converges on podocyte injury, detachment, and depletion below a critical threshold, triggering segmental adhesion (synechia) to Bowman's capsule, capillary collapse, and sclerosis.

Primary FSGS — Circulating Permeability Factor Hypothesis

Evidence from rapid recurrence of FSGS post-transplant (within hours to days), the efficacy of plasmapheresis, and in vitro assays demonstrating increased albumin permeability of isolated glomeruli exposed to patient sera supports the existence of one or more circulating factors. Candidates include soluble urokinase plasminogen activator receptor (suPAR), cardiotrophin-like cytokine factor 1 (CLCF-1), and angiopoietin-like 4 (Angptl4). suPAR has received the most attention, although its specificity remains debated. These factors target the podocyte slit-diaphragm complex, disrupting αvβ3 integrin signalling and nephrin expression, leading to foot-process effacement, cytoskeletal rearrangement, and podocyte detachment.

Genetic FSGS

Monogenic causes account for approximately 5–10 % of adult and 20–30 % of paediatric FSGS. Key genes encode slit-diaphragm proteins (NPHS1/nephrin, NPHS2/podocin), cytoskeletal regulators (ACTN4/α-actinin-4, INF2/inverted formin-2), mitochondrial proteins (COQ2, COQ6), and nuclear lamina components (LMNA/lamin A/C). Genetic testing is indicated in familial FSGS, steroid-resistant nephrotic syndrome in children, or when histology suggests a genetic aetiology (e.g., diffuse mesangial sclerosis). In Australia, genomic testing can be accessed through the Medicare-funded Genomic Medicine programme (MBS item 73343) at participating genetic health services.

Secondary FSGS — Haemodynamic Mechanisms

In secondary FSGS, the primary insult is glomerular hypertension and hyperfiltration rather than a circulating permeability factor. Obesity, reduced nephron mass, and conditions increasing metabolic demand lead to afferent arteriolar vasodilation, increased glomerular capillary pressure, and mechanical stress on podocytes. This manifests histologically as glomerulomegaly with perihilar sclerosis and relatively preserved foot processes — contrasting with the diffuse foot-process effacement of primary FSGS.

The Sclerosis Cascade

Stage 1

Podocyte injury and foot-process effacement → proteinuria

Stage 2

Podocyte detachment and parietal epithelial cell activation → adhesion to Bowman's capsule

Stage 3

Segmental capillary tuft collapse with hyalinosis and foam-cell infiltration

Stage 4

Fibrosis, complete glomerular sclerosis, tubulointerstitial fibrosis → CKD progression

Stage 5

Adaptive hyperfiltration in remaining nephrons → further podocyte loss → accelerating decline → ESKD

Investigations & Biopsy Findings

Baseline Investigations

Essential Urinalysis and urine protein-to-creatinine ratio (uPCR) or urine albumin-to-creatinine ratio (uACR) Quantify proteinuria; nephrotic-range defined as uPCR >300 mg/mmol or uACR >200 mg/mmol. Available at all pathology providers (MBS item 66869 for uACR).

Essential Serum creatinine, eGFR (CKD-EPI equation) Assess baseline kidney function. MBS item 66510 (combined urea, creatinine, eGFR).

Essential Serum albumin, total protein, lipid profile Hypoalbuminaemia (<25 g/L) supports nephrotic syndrome; hyperlipidaemia is common.

Essential Full blood examination (FBE) Rule out secondary causes; assess for thrombocytosis (thrombotic risk in nephrotic syndrome).

Essential Hepatitis B and C serology, HIV serology Mandatory to exclude viral-associated FSGS. MBS item 69481 (HIV) / 69486 (HCV).

Available Complement levels (C3, C4) Typically normal in FSGS; low C3 may suggest membranoproliferative pattern or lupus nephritis mimicking FSGS.

Available ANA, dsDNA, ANCA, anti-PLA2R antibodies Exclude lupus nephritis, ANCA vasculitis, membranous nephropathy if clinical suspicion exists.

Available Serum and urine protein electrophoresis with immunofixation Exclude myeloma-associated amyloidosis or monoclonal immunoglobulin deposition disease (MBS item 66841).

Specialist Genetic testing (targeted panel or whole-exome sequencing) Indicated for familial FSGS, steroid-resistant NS in children, or early-onset disease. Access via genetic health services (MBS item 73343).

Renal Biopsy

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Renal biopsy is the gold standard for FSGS diagnosis and is indicated in all adults with unexplained nephrotic-range proteinuria or nephrotic syndrome. Biopsy is performed under real-time ultrasound guidance (MBS item 36523). At least 10 glomeruli should be obtained for adequate assessment.

Light Microscopy

Segmental solidification of the glomerular tuft with increased extracellular matrix, obliteration of capillary lumina, and frequently hyalinosis (insudation of plasma proteins). In early disease, only a minority of glomeruli are affected (hence "focal"), and only a portion of each glomerulus is involved (hence "segmental"). As the disease progresses, global sclerosis supervenes. Tubulointerstitial fibrosis and tubular atrophy correlate more strongly with prognosis than the percentage of globally sclerosed glomeruli.

Immunofluorescence (IF)

Typically negative or shows non-specific trapping of IgM and C3 within sclerotic segments. Granular capillary-loop staining for IgG should prompt consideration of membranous nephropathy or IgA nephropathy superimposed on FSGS. Staining for IgA in mesangial areas is characteristic of IgA nephropathy, not primary FSGS.

Electron Microscopy (EM)

The key finding distinguishing primary from secondary FSGS is the extent of foot-process effacement: >80 % diffuse effacement favours primary FSGS; focal or mild effacement (<50 %) with glomerulomegaly favours secondary FSGS. EM also identifies immune-complex deposits, fibrillary structures, or organised deposits that may suggest an alternative or superimposed diagnosis.

Columbia Histological Classification of FSGS

Variant	Key Features	Prognosis
Not Otherwise Specified (NOS)	Segmental increase in matrix without qualifying for other variants	Intermediate; most common variant
Perihilar	Segmental sclerosis at the vascular pole; hyalinosis common	Better prognosis; associated with secondary FSGS
Tip	Sclerotic lesion at the urinary pole (tip of proximal tubule)	Best prognosis; highest steroid response rate (60–70 %)
Cellular	Endocapillary hypercellularity with foam cells; no sclerosis required	Variable; may progress rapidly
Collapsing	Collapse of glomerular tuft with hypertrophic podocytes	Worst prognosis; associated with HIVAN, viral infections

Clinical Presentation & Diagnostic Criteria

Primary FSGS

Primary FSGS most commonly presents with the full nephrotic syndrome: generalised peripheral oedema (often periorbital and lower limb), frothy urine, weight gain from fluid retention, and features of hypoalbuminaemia (ascites, pleural effusions). Hypertension is present in approximately 30–50 % of patients at diagnosis. Haematuria (microscopic) may be present in up to 40 %. Kidney function at presentation ranges from normal to severely impaired; elevated serum creatinine at presentation is a poor prognostic sign. Thromboembolic complications (renal vein thrombosis, pulmonary embolism) occur in 10–30 % of patients with nephrotic syndrome.

Secondary FSGS

Secondary FSGS often presents insidiously with asymptomatic proteinuria detected on routine health screening or during investigation of declining eGFR. Overt nephrotic syndrome is less common. Clinical clues to a secondary aetiology include obesity (BMI >30 kg/m²), known HIV infection, history of reflux nephropathy or solitary kidney, and medication history (lithium, bisphosphonates, mTOR inhibitors).

Diagnostic Approach

1

Confirm nephrotic-range proteinuria

uPCR >300 mg/mmol or 24-hour urine protein >3.5 g/day on at least two occasions.

2

Exclude secondary causes

HIV, hepatitis B/C, obesity, drug history, family history of kidney disease, sickle cell trait.

3

Perform renal biopsy

Ultrasound-guided percutaneous biopsy (MBS item 36523). Light microscopy, IF, and EM are essential.

4

Classify and subtype

Apply Columbia classification; determine primary vs secondary based on clinical, histological, and EM findings.

Risk Stratification

Prognosis in FSGS is determined by histological variant, degree of proteinuria, kidney function at presentation, tubulointerstitial fibrosis on biopsy, and treatment response.

Lower Risk

Favourable Histology, Responds to Therapy

Tip variant, perihilar variant, eGFR >60 mL/min/1.73 m² at presentation, proteinuria <5 g/day, minimal tubulointerstitial fibrosis, achieves complete or partial remission with first-line therapy.

Renal survival >90 % at 10 years

Intermediate Risk

NOS Variant, Delayed or Partial Response

NOS variant, eGFR 30–60 mL/min/1.73 m² at presentation, proteinuria 5–10 g/day, moderate tubulointerstitial fibrosis (20–50 %), achieves only partial remission.

Renal survival 50–70 % at 10 years

Higher Risk

Collapsing Variant or Steroid-Resistant

Collapsing variant, eGFR <30 mL/min/1.73 m² at presentation, proteinuria >10 g/day, severe tubulointerstitial fibrosis (>50 %), persistent nephrotic syndrome despite immunosuppression, genetic FSGS.

High risk of ESKD within 3–5 years; discuss RRT planning

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Collapsing FSGS carries the worst prognosis of all FSGS variants. Median time to ESKD is 13–15 months despite treatment. Early nephrology referral and RRT planning are essential.

Management — Immunosuppressive Therapy

Immunosuppressive therapy is indicated for primary FSGS with nephrotic syndrome. Secondary FSGS should be managed by treating the underlying cause; immunosuppression is generally not beneficial and may be harmful.

First-Line: Corticosteroids

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Prednisone (Prednisolone)

Panafcortelone® · Solone® · Panafcort® · Corticosteroid

Adult dose 1 mg/kg/day PO (max 60 mg/day) for minimum 16 weeks (minimum 4 weeks at full dose after remission, then taper over 4–6 months)

Paediatric dose 2 mg/kg/day PO (max 60 mg/day) for 4–8 weeks, then alternate-day taper over 4–6 months

Renal adjustment No dose adjustment required; monitor for fluid retention, hyperglycaemia, and hypertension

PBS status ✔ PBS General Benefit

⚠️

Steroid treatment course must be continued for a minimum of 16 weeks before declaring steroid resistance in FSGS. This differs from minimal change disease (where 8 weeks is sufficient). Premature discontinuation leads to relapse and potential treatment failure.

Second-Line: Calcineurin Inhibitors (CNIs)

CNIs are first-line steroid-sparing agents for steroid-dependent, steroid-resistant, or steroid-intolerant primary FSGS. They are also used as initial therapy when corticosteroids are contraindicated.

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Cyclosporin

Neoral® · Sandimmun® · Calcineurin inhibitor

Adult dose 3–5 mg/kg/day PO in 2 divided doses; target trough 100–200 ng/mL

Paediatric dose 4–6 mg/kg/day PO in 2 divided doses; trough 100–200 ng/mL

Duration Minimum 12 months after remission; slow taper over 6–12 months

Renal adjustment Use with caution if eGFR <30; risk of nephrotoxicity. Monitor serum creatinine closely.

Hepatic adjustment Reduce dose by 50 % in severe hepatic impairment

PBS status ⚠ PBS Authority Required

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Tacrolimus

Prograf® · Calcineurin inhibitor

Adult dose 0.05–0.1 mg/kg/day PO in 2 divided doses; target trough 5–10 ng/mL

Paediatric dose 0.1–0.2 mg/kg/day PO in 2 divided doses; trough 5–10 ng/mL

Renal adjustment No specific dose reduction; closely monitor trough levels and serum creatinine

PBS status ⚠ PBS Authority Required

Third-Line and Refractory Disease

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Mycophenolate Mofetil (MMF)

CellCept® · Myfortic® · Immunosuppressant

Adult dose 1 g PO BD (2 g/day); used in combination with low-dose prednisone or as CNI-sparing agent

PBS status ⚠ PBS Authority Required (renal transplant indication)

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Rituximab

MabThera® · Riximyo® · Anti-CD20 monoclonal antibody

Adult dose 375 mg/m² IV × 4 weekly doses, or 1000 mg IV × 2 doses 2 weeks apart

Indication Steroid- and CNI-resistant primary FSGS; recurrent FSGS post-transplant

PBS status ✘ Not PBS for FSGS (may require Authority application)

Supportive Therapy (All Patients)

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ACE Inhibitor or ARB

Ramipril · Perindopril · Losartan · Irbesartan · Antihypertensive

Indication All patients with proteinuria regardless of blood pressure; reduces intraglomerular pressure and proteinuria by 30–50 %

Target BP <130/80 mmHg; <125/75 if proteinuria >1 g/day

Renal adjustment Start low, titrate slowly; hold if hyperkalaemia (K⁺ >5.5 mmol/L) or acute eGFR decline >25 % within 4 weeks

PBS status ✔ PBS General Benefit

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Statin therapy

Atorvastatin · Rosuvastatin · HMG-CoA reductase inhibitor

Indication Nephrotic hyperlipidaemia; reduces cardiovascular risk. Atorvastatin 10–40 mg PO nocte or rosuvastatin 5–20 mg PO nocte.

PBS status ✔ PBS General Benefit

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Anticoagulation

Warfarin · LMWH · Direct oral anticoagulant

Indication Consider prophylactic anticoagulation if serum albumin <20 g/L with additional thrombotic risk factors (obesity, immobilisation, prior VTE). Enoxaparin 40 mg SC daily or warfarin targeting INR 2.0–2.5.

PBS status ✔ PBS General Benefit (warfarin)

SGLT2 Inhibitors

Emerging evidence from DAPA-CKD and EMPA-KIDNEY trials supports the use of SGLT2 inhibitors (dapagliflozin 10 mg PO daily or empagliflozin 10 mg PO daily) in non-diabetic CKD with proteinuria. SGLT2 inhibitors reduce intraglomerular pressure through tubuloglomerular feedback and have shown benefit in slowing eGFR decline and reducing proteinuria in a broad range of proteinuric kidney diseases, including FSGS. They are now recommended by Kidney Health Australia for CKD with uACR >22 mg/mmol regardless of diabetic status.

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Dapagliflozin

Forxiga® · SGLT2 inhibitor

Adult dose 10 mg PO daily; can be used in non-diabetic CKD with eGFR ≥20 mL/min/1.73 m²

PBS status ⚠ PBS Authority Required (non-diabetic CKD indication may require co-morbidity criteria)

Monitoring

Definitions of Treatment Response

Response Category	Definition
Complete remission (CR)	uPCR <50 mg/mmol (proteinuria <0.3 g/day) with stable or improving eGFR
Partial remission (PR)	uPCR 50–300 mg/mmol (proteinuria 0.3–3.5 g/day) with ≥50 % reduction from baseline and stable or improving eGFR
Relapse	Return to nephrotic-range proteinuria after prior complete remission
Steroid-dependent	Relapse during steroid taper or within 2 weeks of cessation
Steroid-resistant	Failure to achieve CR or PR after ≥16 weeks of high-dose prednisone
Frequently relapsing	≥2 relapses within 6 months or ≥3 relapses within 12 months

Recommended Monitoring Schedule

Parameter	Frequency (Active Treatment)	Frequency (Remission Maintenance)
uPCR or uACR	Every 2–4 weeks	Every 1–3 months for 2 years, then every 6 months
Serum creatinine / eGFR	Every 2–4 weeks	Every 1–3 months
Serum albumin	Every 2–4 weeks	Every 3 months
Lipid profile	At diagnosis, then every 3–6 months	Every 6–12 months
Fasting glucose / HbA1c	Monthly during steroid therapy	As per standard diabetic care
CNI trough levels	Every 1–2 weeks initially, then monthly	Every 1–3 months
Blood pressure	Every visit	Every visit; home BP monitoring encouraged

ℹ️

Steroid side-effect monitoring: During corticosteroid therapy, monitor blood glucose (risk of steroid-induced diabetes), blood pressure, weight, bone density (DEXA scan if >3 months of prednisone), and screen for avascular necrosis if hip or knee pain develops. Prescribe calcium/vitamin D supplementation and consider bisphosphonate prophylaxis for high-risk patients.

Special Populations

🤰 Pregnancy

FSGS in pregnancy

Nephrotic syndrome in pregnancy increases the risk of pre-eclampsia, preterm delivery, and fetal growth restriction. Target BP <140/90 mmHg (ACOG/RANZCOG). ACE inhibitors and ARBs are contraindicated in pregnancy (teratogenic — discontinue before conception or as soon as pregnancy is confirmed). Labetalol, nifedipine, or methyldopa are preferred antihypertensives. Prednisone and cyclosporin are classified as Category A (safe in pregnancy). Tacrolimus is Category B3. MMF is contraindicated (teratogenic — switch to azathioprine at least 6 weeks before conception). Rituximab is Category D (avoid in pregnancy).

👶 Paediatrics

Childhood FSGS

FSGS accounts for 10–15 % of childhood nephrotic syndrome in Australia. Prednisone 2 mg/kg/day (max 60 mg) for 4–8 weeks followed by alternate-day taper for 4–6 months is first-line. Genetic testing (NPHS1, NPHS2, WT1, LMX1B) should be performed early in steroid-resistant cases — up to 30 % of paediatric SRNS has a monogenic cause. Calcineurin inhibitors are the mainstay of second-line therapy in children. Children with genetic FSGS do not respond to immunosuppression and should avoid unnecessary exposure.

👴 Elderly (>65 years)

Older adults with FSGS

Older patients are at increased risk of steroid complications (diabetes, infection, osteoporosis, myopathy). Consider lower starting doses of prednisone (0.5 mg/kg/day) or earlier introduction of CNIs as steroid-sparing agents. Monitor closely for infection; Pneumocystis jirovecii prophylaxis (trimethoprim-sulfamethoxazole 160/800 mg PO thrice weekly) should be considered during intensive immunosuppression. Fall prevention and bone protection (calcium, vitamin D, bisphosphonate if indicated) are essential.

🫘 Renal Impairment

Advanced CKD (eGFR <30)

If eGFR <30 mL/min/1.73 m² at presentation, the likelihood of achieving remission with immunosuppression is low, and the risk of treatment toxicity is high. Cyclosporin nephrotoxicity risk increases significantly. Consider supportive care only (ACEi/ARB, SGLT2i, BP control, statin, manage complications of CKD). If eGFR continues to decline, early discussion of RRT options (dialysis, pre-emptive transplant) is recommended. Renal transplant is the treatment of choice for ESKD secondary to FSGS.

🫁 Hepatic Impairment

Liver disease

Hepatitis B and C can cause secondary FSGS-like glomerular injury (MPGN pattern). Treat underlying viral hepatitis before considering immunosuppression. Cyclosporin is metabolised hepatically; reduce dose by 50 % in Child-Pugh B/C cirrhosis. Tacrolimus also requires dose reduction. Prednisone dose adjustment is not required, but monitor for fluid retention and hepatorenal syndrome.

🛡️ Immunocompromised

HIV and immunosuppressed patients

HIVAN (collapsing FSGS) is managed primarily with cART — do not use corticosteroids. Immunosuppression in other immunocompromised states (post-transplant, autoimmune disease on biologics) requires careful risk-benefit analysis. PML risk with rituximab in JC-virus-positive patients. Screen for latent TB (Quantiferon-Gold), hepatitis B, and Strongyloides before initiating immunosuppression in at-risk populations (including ATSI Australians and immigrants from endemic regions).

FSGS Recurrence Post-Transplant

Recurrent FSGS is a significant complication following renal transplantation and is the most common cause of early graft failure in FSGS patients. Recurrence rates are 20–40 % for primary FSGS and can be as high as 80–100 % after a prior graft lost to recurrence.

Risk Factors for Recurrence

Prior recurrence in a previous transplant graft
Rapid progression to ESKD (<3 years from diagnosis)
Younger age at onset
White race
Collapsing FSGS variant
Absence of FSGS in native kidneys (donor-derived FSGS is rare)

Management of Recurrent FSGS

1

Plasmapheresis

First-line treatment for early recurrence; typically 6–9 sessions over 2–3 weeks. Removes circulating permeability factors. Response rate 50–70 %.

2

Optimise immunosuppression

High-dose CNIs (tacrolimus trough 10–12 ng/mL in the early post-transplant period). Consider adding or intensifying corticosteroids.

3

Rituximab

Used in plasmapheresis-resistant or dependent recurrence. 375 mg/m² IV × 1–4 doses.

4

Abatacept (experimental)

CTLA-4 Ig (abatacept) has shown benefit in some cases of B7-1 (CD80) positive recurrent FSGS. Off-label use; consider in refractory cases.

✅

Pre-emptive plasmapheresis: Some Australian transplant centres offer pre-emptive plasmapheresis peri-operatively for patients at very high risk of recurrence (e.g., prior graft loss to recurrence). Evidence is limited to case series, but this approach may delay or prevent early recurrence.

🇦🇹 Aboriginal and Torres Strait Islander Health Considerations

Aboriginal and Torres Strait Islander Health

Disease burden

FSGS is disproportionately more common in ATSI Australians, particularly in remote and very remote communities. ATSI Australians have 2–3 times the rate of CKD compared with non-Indigenous Australians (AIHW 2023). FSGS secondary to obesity-related glomerulopathy, diabetic nephropathy, and low birth weight (reduced nephron mass) is highly prevalent. ATSI Australians account for a disproportionate share of ESKD cases attributed to glomerulonephritis nationally.

Low birth weight impact

ATSI children have significantly higher rates of low birth weight and intrauterine growth restriction, resulting in reduced nephron endowment. This predisposes to compensatory glomerular hyperfiltration and secondary FSGS in later life — particularly when combined with obesity and metabolic syndrome, which are highly prevalent in ATSI communities. The "Barker hypothesis" of developmental origins of disease is strongly relevant.

Access to nephrology care

ATSI Australians in remote areas face significant barriers to specialist nephrology services, including long travel distances, limited availability of nephrologists, and lack of access to renal biopsy services. Telehealth nephrology consultations through the Australian Government's telehealth programme (MBS items 91822/91823) can facilitate specialist review, but renal biopsy still requires transfer to a regional or tertiary centre.

Cultural safety

Nephrology services must integrate cultural safety principles, including Aboriginal Health Worker involvement, yarning-based education, gender-sensitive care (same-gender clinician for biopsy consent where possible), and recognition of sorry business and other cultural obligations that may affect appointment attendance. Engagement with local Aboriginal Community Controlled Health Organisations (ACCHOs) is essential for care coordination.

Obesity and metabolic syndrome

Obesity prevalence in ATSI adults is approximately 40 % (compared with ~30 % non-Indigenous), with significantly higher rates in remote communities. Obesity-related FSGS is likely underdiagnosed. Culturally appropriate weight management programmes, supported by dietitians experienced in ATSI nutrition (e.g., MBS item 10956 for allied health chronic disease management), should be prioritised.

Medication access

Under the Closing the Gap PBS Co-payment Programme, eligible ATSI patients can access PBS medicines at reduced or no cost. This is particularly important for long-term medications including ACE inhibitors, ARBs, statins, immunosuppressants, and SGLT2 inhibitors. Ensure patients are registered for Closing the Gap PBS benefits through their community pharmacy.

RHDAustralia guidelines

For ATSI patients with FSGS, consider screening for rheumatic heart disease (RHD) and its renal complications, particularly in high-prevalence regions (Northern Territory, Far North Queensland, Western Australia). RHD-related immune-complex-mediated glomerulonephritis can mimic or coexist with FSGS. Consult RHDAustralia clinical guidelines for cardiac-renal overlap management.

📚 References

1. D'Agati VD, Kaskel FJ, Falk RJ. Focal segmental glomerulosclerosis. New England Journal of Medicine. 2011;365(25):2398–2411.
2. Rosenberg AZ, Kopp JB. Focal segmental glomerulosclerosis. Clinical Journal of the American Society of Nephrology. 2017;12(3):502–517.
3. De Vriese AS, Sethi S, Nath KA, Glassock RJ, Fervenza FC. Differentiating primary, genetic, and secondary FSGS in adults: a clinicopathologic approach. Journal of the American Society of Nephrology. 2018;29(3):759–774.
4. Kidney Disease: Improving Global Outcomes (KDIGO). KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney International. 2021;100(4S):S1–S276.
5. Briganti EM, Dowling J, Finlay M, et al. The incidence of biopsy-proven glomerulonephritis in Australia. Nephrology Dialysis Transplantation. 20