Focal Segmental Glomerulosclerosis

Podocyte Cytoskeletal Disruption and Loss

• Podocytes, highly specialized visceral epithelial cells with limited regenerative capacity, maintain the glomerular filtration barrier through a complex network of actin cytoskeletal proteins
• Injury to podocytes causes cytoskeletal rearrangement, foot process effacement (visible on electron microscopy), and loss of cellular integrity
• This leads to increased glomerular permeability, allowing massive urinary losses of plasma proteins, particularly albumin
• Progressive podocyte apoptosis and detachment from the basement membrane reduce the functional nephron population; detached podocytes are visible in urine as "podocyturia"
• The loss of podocytes is largely irreversible, as mature podocytes have minimal capacity for mitotic division and regeneration, leading to permanent glomerular damage

Proteinuria-Mediated Secondary Injury

• Massive proteinuria (often >3.5 g/day) itself becomes pathogenic through multiple mechanisms
• Filtered proteins overwhelm proximal tubule reabsorptive capacity, leading to toxic effects on tubular epithelial cells
• Albumin and other proteins bind to megalin-cubilin receptors on proximal tubule cells, activating inflammatory cascades and oxidative stress pathways
• Complement activation (particularly the alternative pathway) occurs both within glomeruli and in tubules, perpetuating inflammation
• This creates a vicious cycle: podocyte injury → proteinuria → tubular damage → interstitial inflammation → fibrosis

Glomerulosclerosis and Progressive Fibrosis

• Initial podocyte injury triggers activation of surviving podocytes and infiltrating cells (macrophages, pericytes) to produce excessive extracellular matrix components
• Transforming growth factor-beta (TGF-β), a master fibrogenic cytokine, is upregulated in response to proteinuria and inflammation
• Excessive collagen deposition within the glomerular tuft leads to hardening and sclerosis, which further impairs filtration and promotes glomerular collapse
• Epithelial-to-mesenchymal transition (EMT) of podocytes contributes to myofibroblast populations that perpetuate fibrosis
• Unlike the initial focal segmental pattern, progressive disease often leads to global glomerulosclerosis affecting entire glomeruli

Hemodynamic Maladaptation

• In diseased glomeruli, compensatory hemodynamic changes occur in remaining patent capillaries
• Increased intraglomerular pressure through vasodilation of afferent arterioles and relative vasoconstriction of efferent arterioles
• These changes amplify proteinuria and accelerate glomerular injury in the remaining functional nephrons
• Angiotensin II plays a critical role in this process, making renin-angiotensin-aldosterone system (RAAS) inhibition therapeutically important

Genetic and Molecular Defects in Primary FSGS

• Mutations in genes encoding critical podocyte structural proteins have been identified in familial and some sporadic FSGS cases
• NPHS2 gene mutations (encoding podocin) account for ~10-15% of childhood FSGS and some adult cases; autosomal recessive inheritance
• TP53 mutations and ACTN4 (α-actinin-4) mutations affecting cytoskeletal dynamics
• TRPC6 mutations causing abnormal calcium signaling in podocytes
• These genetic defects impair the structural integrity of the slit diaphragm and foot process cytoskeleton, predisposing to collapse under stress
• The presence of genetic mutations may explain why some patients are steroid-resistant and have poor prognosis

Circulating Permeability Factors in Primary FSGS

• Evidence supports the existence of circulating, non-immunoglobulin "permeability factors" that directly injure podocytes
• These factors (including soluble urokinase receptor [suPAR] and others) directly activate podocyte integrin signaling pathways
• They cause rapid podocyte foot process effacement and increased glomerular permeability
• This mechanism explains why FSGS can recur rapidly after kidney transplantation (occurring in 20-50% of transplant recipients), as circulating factors persist
• Plasma exchange therapy, which removes these factors, has shown benefit in steroid-resistant disease and post-transplant recurrence

Complement and Immune Activation

• Complement deposition may be present (especially C3 in some variants) despite lack of significant immunoglobulin deposits
• Alternative pathway activation and dysregulation occurs in some forms (C3-FSGS)
• This immune activation perpetuates inflammation independent of antibody-mediated mechanisms

• No identifiable systemic disease or secondary cause
• Represents intrinsic kidney disease affecting podocyte function and structure
• Subdivided into variants based on light microscopy location of sclerosis (tip lesion, perihilar, cellular, collapsing) which have prognostic implications
• Associated with circulating permeability factors in a subset of patients
• Genetic mutations identified in 15-30% of childhood cases and 5-10% of adult cases

Obesity-Related FSGS

• Increasingly recognized with rising obesity prevalence; affects ~35% of FSGS patients in some series
• Obesity induces podocyte dysfunction through multiple mechanisms: hyperfiltration in remaining functioning nephrons, increased production of adipokines (leptin), systemic inflammation, and oxidative stress
• Body mass index >30 kg/m² is a significant risk factor
• Often presents with nephrotic-range proteinuria
• May show glomerular enlargement (glomerulomegaly) on histology

Heroin and Drug-Associated FSGS

• Historically important cause, particularly in 1970s-1980s epidemics; remains relevant in areas of active drug use
• Heroin causes direct podocyte toxicity through oxidative stress and inflammatory pathways
• Can present acutely with nephrotic syndrome
• Often associated with normal kidney size unlike other FSGS forms
• Interstitial edema and inflammation often prominent on biopsy
• Risk relates to route of administration and duration of use

HIV-Associated FSGS (HIV-Associated Nephropathy, HIVAN)

• Collapsing variant of FSGS is characteristic in HIV patients, especially African Americans
• Incidence has decreased dramatically with highly active antiretroviral therapy (HAART)
• Direct HIV infection of podocytes and tubular cells proposed mechanism (HIV genomes detected in kidney tissue)
• Usually presents with rapid onset nephrotic syndrome and acute kidney injury
• Progression to ESRD is rapid (months to 1-2 years) without treatment
• Immune reconstitution with CD4 count recovery is associated with disease stabilization

Viral Infections

• Hepatitis C virus (HCV) associated with FSGS, particularly in HCV genotype 1
• Hepatitis B virus (HBV) can cause FSGS (less common than membranoproliferative patterns)
• Parvovirus B19 and other viral infections documented as triggers
• Immune complex deposition and viral antigen-specific podocyte injury proposed mechanisms

Familial/Genetic FSGS

• Autosomal recessive inheritance common in childhood onset (NPHS2, NPHS1)
• Autosomal dominant inheritance in adult-onset familial cases (ACTN4, TRPC6, TP53)
• X-linked variants (LICAM mutations)
• Genetic testing increasingly recommended in childhood-onset and familial forms
• Genetic mutations associated with steroid resistance in most cases

Adaptive FSGS (Hyperfiltration-Induced)

• Development in setting of reduced nephron mass from any cause
• Occurs in 5-10% of kidney donors post-donation; increased risk if donation from elderly donors
• Seen in solitary kidney, severe hypertension, morbid obesity, advanced age
• Progressive reduction in GFR despite initially preserved function
• Glomerular hypertrophy and increased intraglomerular pressure drive progressive sclerosis
• Better prognosis than primary FSGS; often slower progression to ESRD

Pamidronate-Associated FSGS

• Rare complication of bisphosphonate therapy for bone disease
• Collapsing pattern often seen
• Risk factors include high cumulative doses and repeated infusions
• May be related to direct toxicity or immune dysregulation

Lupus-Associated FSGS

• Superimposed FSGS pattern on lupus nephritis (Class III or IV)
• Associated with worse prognosis and more rapid progression to ESRD
• Requires dual immunosuppressive therapy targeting both lupus and FSGS

Other Secondary Associations

• Diabetes mellitus (type 2): FSGS pattern superimposed on diabetic changes
• Hypertension: Long-standing severe hypertension can cause FSGS through hyperfiltration injury
• Reflux nephropathy: Chronic tubulointerstitial scarring predisposes to FSGS in remaining functional nephrons
• Sickle cell disease: Sickling episodes cause hemodynamic injury leading to FSGS pattern
• Multiple myeloma: Light chain disease causing direct podocyte toxicity

Cardinal Manifestation: Nephrotic Syndrome

• FSGS is the most common primary cause of nephrotic syndrome in adults in developed countries (>40% of adult nephrotic syndrome cases)
• Classic tetrad present in varying degrees: proteinuria >3.5 g/day (often massive, range 4-12 g/day), hypoalbuminemia, edema, and hyperlipidemia
• Onset is typically sudden, but can be insidious with gradual proteinuria increase
• Nephrotic-range proteinuria (>3.5 g/day) present in ~80% at diagnosis

Peripheral Edema (Pitting Edema)

• Results from proteinuria-induced hypoalbuminemia reducing plasma oncotic pressure
• Albumin <2.0 g/dL typical; total serum albumin <3.0 g/dL common
• Fluid accumulates in dependent areas first (ankles when standing/ambulatory, sacrum when bedridden)
• Edema can be massive and limb-threatening; anasarca may develop
• Onset correlates with degree of proteinuria and rate of plasma protein loss

Dyslipidemia

• Hyperlipidemia results from both decreased catabolism (reduced plasma proteins inhibit lipase function) and increased hepatic synthesis (response to hypoalbuminemia)
• Total cholesterol typically >300 mg/dL (often >400 mg/dL)
• LDL elevated, HDL reduced
• Hypertriglyceridemia common (triglycerides often >200 mg/dL)
• Increased cardiovascular risk; lipid abnormalities persist even with disease remission

Nephrotic-Range Proteinuria

• Urinary protein excretion typically 4-12 g/day, sometimes >20 g/day
• Selective proteinuria (predominantly albumin) typical of primary FSGS
• Proteinuria is the driving force for other manifestations and progression
• Degree of proteinuria correlates with severity of podocyte injury
• May be present before edema develops or laboratory abnormalities become apparent

Hematuria

• Microscopic hematuria present in 25-40% of patients
• Gross hematuria rare; if present, should prompt investigation for other causes
• Suggests more active glomerular inflammation
• May be intermittent and mild

Hypertension

• Present in 30-50% at diagnosis, becomes more common with disease progression
• Results from fluid retention (sodium-avid state due to activation of RAAS and sympathetic nervous system), proteinuria-induced glomerular injury, and reduced GFR
• Often worsens as renal function declines
• May be severe (>160/100 mmHg in 10-15%)
• Accelerates progression to ESRD if untreated

Acute Kidney Injury Presentation (Variable)

• Some patients present with rapid decline in GFR, occasionally with oliguria
• More common in collapsing variant and HIV-associated FSGS
• May mimic acute post-infectious or lupus nephritis
• Can progress to dialysis-dependent ESRD in weeks to months if untreated

Asymptomatic Urinary Abnormalities

• Some patients detected through routine screening with proteinuria and hematuria
• May have minimal or no edema despite nephrotic-range proteinuria
• More common in adaptive FSGS forms
• Discovered on physical examination or laboratory testing for unrelated reasons

Physical Examination Findings

• Periorbital edema: Puffiness around eyes, often most apparent on waking
• Pitting edema: Lower extremity edema (ankles, shins), sacral edema in hospitalized patients
• Ascites: Fluid accumulation in peritoneal cavity with massive nephrotic syndrome; shifting dullness to percussion
• Pulmonary edema: Crackles on lung auscultation in setting of fluid overload and pulmonary edema
• Hypotension (orthostatic): May develop despite edema due to intravascular volume depletion from aggressive diuresis
• Pleural effusion: Dullness to percussion, decreased breath sounds
• Elevated JVP: Indicates significant fluid retention

Important Clinical Variants with Distinct Presentations

• Tip Lesion FSGS: Better prognosis, more responsive to steroids, more female predominance, better outcomes with treatment
• Collapsing FSGS: Most aggressive form, rapid progression, worse prognosis; associated with HIV, heroin, pamidronate; presents with highest proteinuria and most rapid GFR decline; notable glomerular collapse on microscopy
• Perihilar FSGS: Sclerosis in perihilar region; intermediate prognosis; more common in African Americans; may have better steroid response than collapsing form
• Cellular FSGS: Endocapillary cellularity prominent; intermediate prognosis; more common in children
• Not-Otherwise-Specified (NOS): Default category; intermediate outcomes

Age-Related Presentations

• Children (2-6 years): Often present with frank edema and nephrotic syndrome; steroid-responsive in 85-90% (minimal change disease more common)
• Adolescents and young adults: Variable presentation, higher rate of steroid resistance; genetic mutations more likely
• Older adults (>50 years): May present with asymptomatic proteinuria; adaptive form more common; comorbidities complicate management

Clinical Suspicion and History

• Presentation with nephrotic syndrome in a patient without prior kidney disease warrants FSGS consideration
• Historical features that increase suspicion:
• Recent intravenous drug use (heroin)
• Known HIV infection
• Obesity (BMI >30 kg/m²)
• Single kidney or solitary kidney from donation
• Family history of kidney disease or ESRD
• African American or Hispanic ethnicity (higher prevalence)
• Timeline of symptom development and presence of hypertension at presentation

Laboratory Tests

• 24-Hour Urine Protein Quantification: Gold standard; nephrotic range = >3.5 g/day (or >40 mg/kg/day in children); FSGS typically 4-12 g/day

Initial stabilisation and supportive care (all FSGS, primary or secondary)

• Loop diuretics: furosemide for symptomatic edema/anasarca; hypoalbuminemia impairs delivery of drug to the tubular secretory site, so higher or IV dosing is often needed. Watch for over-diuresis in the intravascularly depleted nephrotic patient.
• RAAS blockade: an ACE inhibitor (lisinopril) or ARB (losartan) is the cornerstone antiproteinuric therapy per KDIGO 2021 Glomerular Diseases guideline — efferent arteriolar dilation lowers intraglomerular pressure and reduces proteinuria independent of blood pressure. Titrate to the maximum tolerated dose; contraindicated in pregnancy (all ACE inhibitors, including captopril, and ARBs are fetotoxic).
• SGLT2 inhibitor: dapagliflozin is added for residual proteinuric CKD per KDIGO 2024 CKD guideline; restores tubuloglomerular feedback and afferent tone. Note that the pivotal CKD outcome trials excluded patients receiving active immunosuppression for glomerular disease, so use in actively treated primary FSGS is extrapolated rather than FSGS-specific.
• Statin therapy for nephrotic dyslipidemia; dietary sodium restriction; treat hypertension to guideline BP targets.

Primary (immune/permeability-factor) FSGS — first line

• Corticosteroids: high-dose oral prednisone (roughly 1 mg/kg/day, capped near 80 mg) is the KDIGO-recommended initial immunosuppression, continued for a prolonged course before declaring steroid resistance. Response is slow — months, not weeks.

Escalation / steroid-resistant or steroid-dependent disease

• Calcineurin inhibitors: cyclosporine or tacrolimus — stabilise the podocyte actin cytoskeleton (synaptopodin preservation) in addition to T-cell suppression; KDIGO lists these as preferred second-line.
• Mycophenolate mofetil with dexamethasone, or rituximab, are alternatives with weaker evidence.
• Plasma exchange is used chiefly for post-transplant recurrence, where circulating permeability factors are implicated.

Secondary and genetic FSGS — treat the cause, not the immune system

• HIVAN: antiretroviral therapy is the definitive treatment (DHHS HIV guidelines) plus RAAS blockade.
• Obesity-related: weight reduction, including bariatric surgery in selected patients.
• Drug-associated (pamidronate, heroin, interferon): withdraw the agent.
• Genetic FSGS (NPHS2, ACTN4, TRPC6): immunosuppression is ineffective — genetic testing spares futile steroid toxicity.

Complications of nephrotic-range proteinuria

• Venous thromboembolism: urinary loss of antithrombin III with compensatory hepatic overproduction of fibrinogen and factors V/VIII creates a hypercoagulable state. Suspect renal vein thrombosis with sudden flank pain, gross hematuria, an acute rise in proteinuria, or a falling GFR. Pulmonary embolism is an emergency — dyspnea and hypoxemia in a nephrotic patient mandate immediate imaging and anticoagulation, usually CT pulmonary angiography (weigh contrast exposure against renal function; ventilation–perfusion scanning is the alternative when GFR is significantly reduced). Risk rises steeply as serum albumin falls (highest in membranous nephropathy, but real in FSGS).
• Infection: urinary loss of IgG and complement factor B impairs opsonisation of encapsulated organisms. Spontaneous bacterial peritonitis from Streptococcus pneumoniae in a child with ascites is the classic emergency; fever with abdominal pain requires diagnostic paracentesis.
• Progressive CKD and ESRD: the dominant long-term outcome; heralded by persistent nephrotic-range proteinuria that fails to remit — remission of proteinuria is the strongest predictor of renal survival.
• Acute kidney injury: from over-diuresis, RAAS blockade, interstitial edema, or renal vein thrombosis; disproportionately common in the collapsing variant.
• Metabolic losses: hypocalcemia and vitamin D deficiency (loss of vitamin D–binding protein), anemia (principally urinary transferrin loss, producing an iron-therapy–resistant microcytic anemia; urinary erythropoietin loss is a proposed and less well-substantiated contributor), abnormal thyroid function tests (thyroxine-binding globulin loss), and protein malnutrition with muscle wasting.
• Accelerated atherosclerosis from sustained hyperlipidemia.

Complications of therapy

• Corticosteroids: hyperglycemia, osteoporosis, avascular necrosis of the femoral head, cataracts, adrenal suppression, and opportunistic infection with prolonged high-dose courses.
• Calcineurin inhibitors: dose-dependent nephrotoxicity producing striped interstitial fibrosis and arteriolar hyalinosis — a rising creatinine on cyclosporine or tacrolimus may be drug toxicity rather than disease progression; also hyperkalemia, hypertension, tremor, and gingival hyperplasia (cyclosporine).
• Rituximab: hypogammaglobulinemia, infusion reactions, and hepatitis B reactivation — screen HBsAg/anti-HBc before dosing.
• Post-transplant recurrence: proteinuria returning within hours to days of engraftment implicates a circulating permeability factor.

• Biopsy buzzwords: focal (some glomeruli) and segmental (part of the tuft) sclerosis with hyalinosis on light microscopy; negative or nonspecific immunofluorescence (IgM and C3 trapped in sclerotic segments); electron microscopy shows foot process effacement. Negative IF is the finding that separates FSGS from immune-complex glomerulonephritis.
• The association examiners test: APOL1 G1/G2 high-risk genotype is associated with markedly increased FSGS and HIVAN risk in people of West African ancestry and with faster progression to ESKD; its effect on steroid responsiveness is not established.
• HIV → collapsing variant (HIVAN): nephrotic-range proteinuria with rapid GFR decline and enlarged, echogenic kidneys on ultrasound despite advanced disease. Best next step is starting antiretroviral therapy, not steroids.
• The classic single best next step: an adult with new nephrotic syndrome gets a renal biopsy. A child under ~10 with typical nephrotic syndrome gets empiric prednisone first — FSGS is the diagnosis you make when that child fails to respond, so steroid-resistant nephrotic syndrome in a child is an FSGS stem until biopsy proves otherwise.
• Primary vs secondary is the management fork: primary FSGS presents with abrupt full nephrotic syndrome (hypoalbuminemia, edema) and diffuse effacement, and earns immunosuppression. Secondary/adaptive FSGS (obesity, reflux, solitary kidney, sickle cell) presents with subnephrotic-to-nephrotic proteinuria but preserved albumin and no edema, with only segmental effacement — treat the cause and use RAAS blockade; steroids are the wrong answer.
• Variant prognosis: tip lesion best and most steroid-responsive; collapsing worst (HIV, heroin, pamidronate, interferon).
• Transplant pearl: recurrence in 20–50%, sometimes within hours to days, from a circulating permeability factor — plasmapheresis is the intervention.
• Common distractor: minimal change disease also shows effacement and negative IF, but has normal light microscopy and near-universal steroid responsiveness; sampling error can make early FSGS look like MCD.