Focal Segmental Glomerulosclerosis
A progressive kidney disease characterized by focal and segmental scarring of glomeruli, commonly presenting as nephrotic syndrome and leading to renal failure if untreated.
- Sudden onset flank pain or macroscopic hematuria (concern for Renal Vein Thrombosis).
Emergency Management: Severe anasarca leading to pulmonary edema or respiratory compromise; acute kidney injury secondary to severe hypovolemia.
Focal Segmental Glomerulosclerosis (FSGS) is a pattern of kidney injury characterized by sclerosis in some (focal) but not all glomeruli, and involving only segments (segmental) of the affected glomeruli. It is a common cause of primary nephrotic syndrome in adults, presenting with heavy proteinuria and progressive renal decline. The core pathology involves podocyte injury and depletion, leading to foot process effacement and subsequent glomerular scarring.
Detailed Overview
FSGS represents a diverse clinical entity that can be primary (idiopathic), genetic, or secondary to viral infections, drugs, or adaptive hemodynamic responses (e.g., obesity, reduced nephron mass). Its clinical significance lies in its frequent progression to end-stage renal disease (ESRD), particularly in primary forms with massive proteinuria. Distinguishing between primary and secondary forms is critical as primary FSGS typically responds to immunosuppression, whereas secondary forms are treated with hemodynamic modulation and treating the underlying cause.
Epidemiology & Demographics
Incidence is roughly 7 per 1 million population annually in the US. It is the most common cause of primary nephrotic syndrome in adults, accounting for up to 40% of cases. Prevalence is significantly higher in Black populations (often linked to APOL1 gene risk alleles). Male to female ratio is approximately 1.5-2:1. Peak age of onset for primary FSGS is 45-65 years.
Etiological Mechanism
Primary FSGS is idiopathic, believed to be caused by a circulating permeability factor (e.g., suPAR). Genetic causes involve mutations in slit diaphragm proteins (e.g., NPHS1, NPHS2) or podocyte cytoskeleton (ACTN4). Viral causes include HIV (HIV-associated nephropathy) and Parvovirus B19. Drug-induced causes include heroin, pamidronate, and anabolic steroids.
Primary Causes
Primary: Idiopathic (circulating factor). Secondary: Hemodynamic stress (obesity, solitary kidney, sickle cell disease), viral infections (HIV-1, SARS-CoV-2), toxins/drugs (lithium, interferon). Genetic: APOL1 risk alleles in individuals of African descent, TRPC6 mutations.
- African Ancestry: Presence of APOL1 high-risk genotypes (G1/G2 variants) significantly increases the risk of developing FSGS and progression to ESRD.
- Obesity: Severe obesity causes glomerular hyperfiltration, leading to adaptive secondary FSGS.
- HIV Infection: HIV can directly infect podocytes, leading to the collapsing variant of FSGS (HIVAN).
The initiating event is podocyte injury, leading to disruption of the actin cytoskeleton and foot process effacement. This detachment of podocytes from the glomerular basement membrane (GBM) exposes the bare GBM to Bowman's capsule, forming synechiae. Plasma proteins leak into Bowman's space and mesangium, stimulating mesangial cell proliferation and extracellular matrix deposition. Progressive hyalinosis and sclerosis obliterate the glomerular capillary tuft, eventually leading to global sclerosis, tubular atrophy, and interstitial fibrosis.
Characteristic Clinical Presentation
- Severe Edema: Pitting edema primarily in the lower extremities (ankles, pretibial area) and periorbital regions, worse in the morning.
- Frothy Urine: Noticeable foaming in the toilet bowl due to high concentrations of albumin in the urine.
- Fatigue: Profound tiredness due to anemia, malnutrition from protein loss, and underlying uremia if renal function has declined.
Physical Examination Signs
- Anasarca (generalized edema) in severe nephrotic syndrome
- Hypertension (BP > 140/90 mmHg, often volume-dependent)
- Xanthelasma (cholesterol deposits around eyelids) due to hyperlipidemia
- End-Stage Renal Disease (ESRD): Progressive loss of kidney function requiring dialysis or transplantation, occurring in up to 50% of patients within 5-10 years.
- Thromboembolism: High risk of deep vein thrombosis (DVT) and renal vein thrombosis due to urinary loss of antithrombin III and increased hepatic synthesis of procoagulant factors.
Diagnostic Criteria & Guidelines
Diagnosis requires a percutaneous renal biopsy showing focal and segmental sclerosis with podocyte foot process effacement on electron microscopy. Clinically defined nephrotic syndrome: proteinuria > 3.5 g/24h, serum albumin < 3.0 g/dL, edema, and hyperlipidemia.
Differential Diagnosis
- Minimal Change Disease (MCD)
- Membranous Nephropathy
- Diabetic Nephropathy
Laboratory Tests & Biomarkers
- 24-Hour Urine Protein: > 3.5 g/day (often > 5-10 g/day in primary FSGS)
- Serum Albumin: < 3.0 g/dL (often < 2.0 g/dL)
- Lipid Panel: Total cholesterol often > 300 mg/dL, LDL > 160 mg/dL
Imaging Modalities & Findings
- Renal Ultrasound:
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Columbia Classification: NOS (Not Otherwise Specified)
Most common variant, segmental sclerosis without distinct features of other variants.
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Columbia Classification: Collapsing
Global capillary tuft collapse with podocyte hypertrophy/hyperplasia; rapid progression to ESRD (classic for HIVAN).
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Columbia Classification: Tip Lesion
Sclerosis localized to the tubular pole of the glomerulus; best prognosis and high steroid responsiveness.
For primary FSGS with nephrotic syndrome: Oral Prednisone 1 mg/kg/day (maximum 80 mg/day) for 4 to 16 weeks, followed by a slow taper over 6 months if responsive. Plus maximally tolerated ACE inhibitor (e.g., Lisinopril 10-40 mg daily) or ARB (e.g., Losartan 50-100 mg daily) for blood pressure control and antiproteinuric effect.
Second-Line & Adjunctive Therapy
For steroid-resistant or dependent FSGS: Calcineurin inhibitors (Tacrolimus 0.05-0.1 mg/kg/day targeting trough 4-8 ng/mL OR Cyclosporine 3-5 mg/kg/day targeting trough 100-200 ng/mL) for at least 6 months. Alternative: Mycophenolate mofetil 1000 mg BID.
Surgical & Procedural Management
Renal transplantation for patients who progress to ESRD. Note: Primary FSGS has a 30-50% risk of recurrence in the allograft.
Recommended Lifestyle Changes
- Dietary sodium restriction to < 2000 mg/day to manage edema and hypertension.
- Moderate dietary protein intake (0.8-1.0 g/kg/day) – do not overconsume protein despite urinary losses.
Patient Counseling & Advice
Counsel regarding the slow response to steroids (up to 16 weeks). Emphasize the importance of adherence to immunosuppressive regimens and blood pressure medications. Warn about signs of infection while on immunosuppression.
Follow-Up & Monitoring Schedule
Monthly clinic visits initially to monitor weight, blood pressure, serum creatinine, eGFR, serum albumin, and urine protein-to-creatinine ratio (UPCR). Monitor glucose and bone density while on prolonged steroids.
Preventive Strategies
No definitive prevention for primary FSGS. For secondary FSGS: optimal weight management, strict glycemic control, and viral suppression (e.g., HAART for HIV).
Variable. Tip variant has >70% remission rate. Collapsing variant progresses to ESRD in >50% within 2 years. Overall, untreated nephrotic primary FSGS reaches ESRD in 5-10 years.
Frequently Asked Questions
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