Focal segmental glomerulosclerosis

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

FSGS is the scar pattern left by different types of podocyte stress. A primary immune-mediated permeability process, a pathogenic genetic variant, viral or drug injury, and adaptive hyperfiltration can all converge on segmental sclerosis. Because the therapeutic directions diverge, reading the biopsy label as a complete diagnosis is unsafe. The clinician must classify cause using nephrotic phenotype, electron-microscopy effacement, family and exposure history, nephron mass and systemic context.

Primary FSGS usually presents with full nephrotic syndrome and widespread foot-process effacement. Secondary adaptive forms may have substantial proteinuria but preserved serum albumin and patchier effacement. These are tendencies rather than absolute rules. A lesion missed on a small biopsy can initially be reported as minimal change disease, and advanced global scarring can conceal the original process. Specialist renal-pathology review is valuable when phenotype and tissue disagree.

Treatment seeks complete or partial proteinuria remission because either improves prognosis. Immunosuppression is reserved for primary disease: glucocorticoid first when appropriate, then a calcineurin inhibitor for steroid resistance. Secondary and genetic forms receive cause removal and kidney-protective care because immunosuppression adds infection, metabolic, reproductive and malignancy harm without addressing the driver. Unclassified persistent disease may justify genetics, repeat biopsy or an expert glomerular clinic rather than serial unstructured drug trials.

Key points

Focal segmental glomerulosclerosis is a biopsy lesion, not one disease: focal means only some glomeruli and segmental means only part of an affected tuft is scarred.
Primary FSGS is a circulating-factor podocytopathy typically causing abrupt nephrotic syndrome with diffuse foot-process effacement after secondary causes are excluded.
Secondary adaptive FSGS follows reduced nephron mass, obesity, reflux, sickle disease or longstanding hyperfiltration and often produces proteinuria without profound hypoalbuminaemia.
Genetic FSGS is more likely with childhood or young-adult onset, family history, syndromic features, consanguinity or treatment resistance and rarely benefits from immunosuppression.
HIV, parvovirus, interferon, pamidronate, anabolic steroids, heroin and other exposures can produce secondary patterns; testing follows individual probability.
A biopsy can miss FSGS because lesions are focal and juxtamedullary glomeruli may be affected first; adequate tissue and electron microscopy are essential.
Pathology variants such as collapsing, tip, cellular, perihilar and not-otherwise-specified add prognostic context but do not replace aetiological classification.
Primary FSGS receives high-dose glucocorticoid under specialist care for up to the defined response limit if tolerated; genetic and secondary disease should not receive this reflexively.
Steroid-resistant primary FSGS is treated with tacrolimus or ciclosporin for at least six months before response is judged, using trough and kidney-toxicity monitoring.
Supportive care for every cause includes blood-pressure and proteinuria reduction, salt management, suitable SGLT2 inhibition, cardiovascular prevention and nephrotoxin avoidance.
Remission of proteinuria strongly predicts kidney survival; persistent proteinuria and falling eGFR require adherence, cause and chronicity review rather than repeated empiricism.
Primary FSGS can recur within hours or days after kidney transplantation, so native-disease classification and previous graft history guide transplant counselling and surveillance.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Primary podocytopathy

A presumed circulating permeability factor causes abrupt diffuse podocyte injury and nephrotic syndrome after adaptive, genetic and secondary causes have been excluded.

Adaptive hyperfiltration

Reduced nephron mass, obesity, reflux, sickle disease or longstanding hyperfiltration overloads remaining glomeruli and produces secondary segmental scarring.

Genetic disease

Pathogenic podocyte or basement-membrane variants are more likely with early onset, family history, syndromic features, consanguinity or resistance to immunosuppression.

Infection and exposure-associated disease

HIV, parvovirus, interferon, pamidronate, anabolic steroids, heroin and other exposures can produce secondary FSGS patterns requiring cause-directed rather than reflex immunosuppressive care.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Podocyte stress
Primary permeability injury, genetic variants, viral or medicine injury and adaptive hyperfiltration can all stress podocytes and converge on segmental sclerosis.
2
Focal segmental scar
Focal means only some glomeruli are affected, while segmental means only part of an affected glomerular tuft is scarred.
3
Foot-process effacement
Diffuse foot-process effacement in primary disease accompanies abrupt nephrotic syndrome, whereas adaptive forms often cause proteinuria without profound hypoalbuminaemia.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Primary nephrotic phenotype

Sudden heavy proteinuria, low albumin and generalised oedema without an adaptive or secondary driver supports primary FSGS but still requires clinicopathological agreement.

Adaptive hyperfiltration pattern

Obesity, reflux scarring, solitary kidney or reduced nephron mass with hypertension and proteinuria but limited oedema suggests secondary perihilar or adaptive FSGS.

Genetic warning

Early onset, family kidney failure, consanguinity, deafness, eye or skeletal features, or steroid resistance prompts genomic evaluation and careful counselling.

Collapsing glomerulopathyRed flag

A rapid creatinine rise with heavy proteinuria and collapsing capillary tufts may be associated with viral infection, medicine exposure or high-risk genotype and needs urgent cause assessment.

Nephrotic thrombosisRed flag

Pleuritic pain, hypoxia, unilateral swelling or flank pain during severe hypoalbuminaemia requires immediate assessment for pulmonary, limb or renal-vein thrombosis.

Post-transplant recurrenceRed flag

Very early heavy proteinuria after transplantation in someone with presumed primary FSGS raises recurrence and needs immediate transplant-centre biopsy and treatment review.

Calcineurin toxicity

A creatinine rise with hypertension, hyperkalaemia, tremor or high trough during therapy may reflect drug haemodynamics or chronic toxicity rather than FSGS progression.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Urine PCR, ACR and microscopyFirst step
Why
Quantify total and albumin protein, identify haematuria and establish response baselines.
Interpretation and limitations
Protein burden and albumin define phenotype; an active nephritic sediment suggests another or additional glomerular lesion.
02
Creatinine, electrolytes, albumin and lipid profile
Why
Grade kidney impairment, nephrotic physiology and cardiovascular complications.
Interpretation and limitations
Trend eGFR before and after haemodynamic therapy; preserved albumin despite heavy protein can support an adaptive rather than primary nephrotic process.
03
Kidney biopsy with electron microscopy
Why
Identify segmental scar, variant, chronic damage and the distribution of podocyte foot-process effacement.
Interpretation and limitations
Adequate glomerular sampling is crucial because focal lesions are missed; diffuse effacement supports but does not by itself prove primary FSGS.
04
Renal imaging and nephron-mass assessment
Why
Find reflux scarring, asymmetry, a solitary kidney or other adaptive structural driver.
Interpretation and limitations
Structural loss can explain hyperfiltration-mediated lesions and redirects treatment away from immunosuppression.
05
Targeted infection testing
Why
Assess HIV, hepatitis, parvovirus or other infection when phenotype and exposure make it plausible.
Interpretation and limitations
Positive infection changes both cause-specific treatment and immunosuppression safety; collapsing morphology alone does not identify the organism.
06
Medicine and substance history
Why
Identify interferons, bisphosphonates, lithium, anabolic agents, heroin and other podocyte-toxic exposures.
Interpretation and limitations
Record dose and chronology and coordinate safe withdrawal; a remote exposure should not be blamed without temporal compatibility.
07
Genetic testing
Why
Find a monogenic podocytopathy and inform therapy, family screening and transplant recurrence risk.
Interpretation and limitations
Use an accredited renal-genetics pathway with consent because variants of uncertain significance do not establish causation and ancestry requires careful interpretation.
08
Calcineurin trough and toxicity profile
Why
Ensure therapeutic exposure and separate under-treatment from drug toxicity during steroid-resistant care.
Interpretation and limitations
Interpret trough with exact dose timing, interactions, creatinine, potassium, magnesium and blood pressure through renal pharmacy.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Minimal change disease

Both show diffuse foot-process effacement and nephrosis, but adequate light microscopy reveals segmental scars in FSGS; early focal lesions may still be missed.

Membranous nephropathy

Subepithelial immune deposits, capillary-wall thickening and disease-associated antibodies support membranous disease rather than a segmental sclerosing pattern.

Diabetic glomerulosclerosis

Longstanding diabetes, characteristic mesangial nodules and arteriolar hyalinosis suggest diabetic disease, though secondary segmental scars may coexist.

Collagen IV nephropathy

Persistent familial haematuria, hearing or ocular disease and basement-membrane abnormalities favour Alport-spectrum disease, which can acquire secondary FSGS lesions later.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Biopsy says FSGSClassify cause before immunosuppressionFirst stepNative kidney pathology identifies a focal segmental sclerotic lesion.

1Confirm full nephrotic syndrome, review electron-microscopy effacement and adequacy, and ask renal pathology to describe variant, activity and chronicity.
2Search systematically for reduced nephron mass, obesity, reflux, infection, medicine or substance exposure, family history, early onset and syndromic features.
3Classify as primary, secondary, genetic or undetermined in the specialist record and explain how that category determines benefit or harm from immunosuppression.

02Primary FSGSInduce proteinuria remissionClinicopathological review supports primary podocytopathy with nephrotic syndrome and no secondary driver.

1Assess infection, glucose, bone, eye, mental-health and reproductive risk and begin the specialist high-dose glucocorticoid course with an explicit maximum duration.
2Monitor quantitative protein and albumin, oedema and eGFR; taper after response and avoid continuing full dose when intolerance or the response boundary is reached.
3If resistant, confirm adherence and diagnosis, then use tacrolimus or ciclosporin for at least six months at therapeutic exposure before judging failure.

03Secondary or geneticRemove stress and protect nephronsAdaptive, viral, medicine-related or genetic evidence outweighs a primary circulating-factor process.

1Treat infection, withdraw a culprit safely, manage weight and sleep apnoea, or address reflux and nephron-loss consequences with the relevant specialist teams.
2Optimise one ACE inhibitor or ARB, pressure, dietary sodium and eligible SGLT2 therapy with creatinine and potassium monitoring and cardiovascular prevention.
3Avoid empirical immunosuppression, offer genetic counselling or family assessment where appropriate, and follow proteinuria and eGFR for progression.

04Transplant planningAnticipate recurrence accuratelyKidney failure develops and transplantation is being considered after an FSGS diagnosis.

1Revisit native-disease classification, genetics, age of onset, speed of progression, prior remission and any previous allograft recurrence before estimating risk.
2Explain that primary FSGS can recur very early whereas monogenic and adaptive forms usually have different recurrence patterns; avoid a single generic percentage.
3Arrange transplant-centre proteinuria surveillance from implantation and an urgent biopsy and recurrence pathway if heavy protein appears.

Key medicines and prescribing safety5 treatments · regimens, roles and cautions

First-line immunosuppression for suitable adults with primary FSGS and a true nephrotic phenotype.

Prednisolone

Specialist high-dose daily or alternate-day treatment continues until remission, intolerance or the maximum 16-week response period.

Do not use for secondary or genetic FSGS; infection, diabetes, mood, bone, eye and adrenal toxicity require prevention and a planned taper.

Stabilises podocytes and suppresses immunity to induce remission when primary FSGS resists glucocorticoid.

Tacrolimus or ciclosporin

Use a trough-guided specialist regimen for at least six months in steroid-resistant primary disease before judging response.

Nephrotoxicity, hypertension, hyperkalaemia, neurotoxicity and CYP interactions require renal-pharmacy review; slow taper after sustained response reduces relapse.

Reduces intraglomerular pressure and proteinuria across primary, secondary and genetic forms when haemodynamically suitable.

ACE inhibitor or ARB

Start one licensed agent cautiously and titrate to the highest tolerated dose with potassium and creatinine checks.

Never combine the classes; review during AKI, hypovolaemia or hyperkalaemia and replace before pregnancy through a specialist plan.

Provides haemodynamic kidney protection and slows progression in eligible chronic proteinuric kidney disease regardless of diabetes status.

SGLT2 inhibitor

Use the licensed daily CKD dose when current NICE eGFR and albuminuria eligibility criteria are satisfied.

Counsel on sick-day withholding, genital infection and ketoacidosis risk and expect a small early eGFR dip without ignoring larger deterioration.

Controls fluid overload during active nephrotic primary FSGS while definitive therapy reduces the protein leak.

Loop diuretic

Individualise route and dose to symptomatic oedema, perfusion, kidney function and prior treatment response.

Over-diuresis causes hypotension, electrolyte loss and AKI; adaptive FSGS without oedema may not require substantial diuresis.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Nephrotic oedema and thrombosis

Heavy protein loss lowers oncotic pressure and alters coagulation proteins, producing generalised oedema and increased venous thromboembolism risk.

Serious infection

Urinary immunoglobulin loss, oedematous tissue and immunosuppressive treatment can combine to impair host defence and blunt infection presentation.

Progressive kidney failure

Persistent proteinuria and expanding glomerular scarring predict declining filtration, particularly when remission is not achieved or adaptive stress continues.

Post-transplant recurrence

Primary FSGS can recur rapidly in an allograft, causing abrupt heavy proteinuria and threatening graft survival; secondary and genetic risks differ.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Trend urine PCR, serum albumin and eGFR using comparable samples; complete and partial remission should be documented quantitatively.
During nephrosis monitor weight, oedema, fluid symptoms, blood pressure, thrombosis and infection, adjusting diuresis as albumin recovers.
During glucocorticoid therapy monitor glucose, infection, mood, pressure, bone, eye and muscle toxicity and stop at the planned response boundary for review.
During calcineurin therapy follow trough, creatinine, potassium, magnesium, blood pressure and interactions, distinguishing drug effect from disease progression.
In secondary disease confirm removal or control of the driver and monitor cardiovascular and CKD risks even if proteinuria falls only partially.
Revisit genetics and pathology when onset, family history, extra-renal features or treatment response no longer fits the original classification.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

The lesion is an endpoint

Many injuries converge on segmental scar, so the causal classification is more therapeutically important than the pathology word FSGS by itself.

Albumin helps classify cause

Heavy proteinuria with preserved serum albumin is more typical of adaptive hyperfiltration than a primary permeability-factor nephrotic syndrome, though exceptions require expert review.

Sampling creates false minimal change

A small biopsy may contain no affected glomerulus, particularly when lesions begin near the corticomedullary junction, and can be misread as MCD.

Collapsing is a pattern too

Collapsing glomerulopathy signals severe podocyte injury but still requires assessment for infection, medicines, autoimmune disease and genetic susceptibility.

Partial remission matters

A substantial durable proteinuria reduction without complete normalisation improves kidney prognosis and can be a meaningful endpoint in resistant primary FSGS.

Recurrence tests the classification

Very early allograft recurrence supports a circulating-factor primary disease, whereas absence of recurrence is common in many genetic and adaptive forms.

11Common pitfallsFrequent interpretation and management errors.

01
Treating every biopsy report of FSGS with high-dose glucocorticoid before classifying its cause.
02
Calling obesity-associated proteinuria primary FSGS without assessing serum albumin, nephron mass and electron microscopy.
03
Assuming a negative family history excludes a pathogenic variant or that a variant of uncertain significance proves one.
04
Declaring calcineurin treatment failure before adequate therapeutic exposure and at least six months of specialist therapy.
05
Missing calcineurin nephrotoxicity when creatinine rises during an apparent proteinuria response.
06
Quoting transplant recurrence risk without revisiting whether native disease was primary, genetic or secondary.