Focal segmental glomerulosclerosis: Difference between revisions

(Created page with "Focal segmental glomerulosclerosis (FSGS) is a pattern of '''glomerular scarring''' in which sclerosis affects '''segments''' (not the entirety) of '''some''' (not all) glomeruli.<ref name="StatPearls">Focal Segmental Glomerulosclerosis. ''StatPearls''. NCBI. 2024.</ref> It is the '''most common cause of primary (idiopathic) nephrotic syndrome in adults''' in the United States and the '''leading glomerular cause of end-stage kidney disease (ESKD)'''.<ref name="CJASN">Ros...")
 
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Focal segmental glomerulosclerosis (FSGS) is a pattern of '''glomerular scarring''' in which sclerosis affects '''segments''' (not the entirety) of '''some''' (not all) glomeruli.<ref name="StatPearls">Focal Segmental Glomerulosclerosis. ''StatPearls''. NCBI. 2024.</ref> It is the '''most common cause of primary (idiopathic) nephrotic syndrome in adults''' in the United States and the '''leading glomerular cause of end-stage kidney disease (ESKD)'''.<ref name="CJASN">Rosenberg AZ, Kopp JB. Focal Segmental Glomerulosclerosis. ''Clin J Am Soc Nephrol''. 2017;12(3):502-517.</ref> FSGS disproportionately affects '''African Americans''' (driven by APOL1 risk alleles). The emergency physician encounters FSGS patients presenting with '''nephrotic syndrome''' (massive edema, proteinuria, hypoalbuminemia) and its '''life-threatening complications''': '''thromboembolism''', '''spontaneous bacterial peritonitis''', '''hypovolemic crisis''', '''acute kidney injury''', and '''severe hypertension'''.
==Background==
==Background==
*'''Diagnosis is histopathologic''' — requires renal biopsy; cannot be diagnosed by clinical features or labs alone<ref name="StatPearls"/>
*Focal segmental glomerulosclerosis (FSGS) is a pattern of glomerular scarring in which sclerosis affects segments (not the entirety) of some (not all) glomeruli<ref name="StatPearls">Focal Segmental Glomerulosclerosis. ''StatPearls''. NCBI. 2024.</ref>
*It is the most common cause of primary (idiopathic) nephrotic syndrome in adults in the United States and the leading glomerular cause of end-stage kidney disease (ESKD)<ref name="CJASN">Rosenberg AZ, Kopp JB. Focal Segmental Glomerulosclerosis. ''Clin J Am Soc Nephrol''. 2017;12(3):502-517.</ref>
*FSGS disproportionately affects African Americans (driven by APOL1 risk alleles)
*The emergency physician encounters FSGS patients presenting with nephrotic syndrome (massive edema, proteinuria, hypoalbuminemia) and its life-threatening complications: thromboembolism, spontaneous bacterial peritonitis, hypovolemic crisis, acute kidney injury, and severe hypertension
* Diagnosis is histopathologic — requires renal biopsy; cannot be diagnosed by clinical features or labs alone<ref name="StatPearls"/>
*FSGS accounts for ~35% of nephrotic syndrome in adults (higher in Black patients) and 7-20% in children
*FSGS accounts for ~35% of nephrotic syndrome in adults (higher in Black patients) and 7-20% in children
*Incidence is increasing worldwide over the past three decades<ref name="MSD">Focal Segmental Glomerulosclerosis. ''MSD Manual Professional Edition''. 2025.</ref>
*Incidence is increasing worldwide over the past three decades<ref name="MSD">Focal Segmental Glomerulosclerosis. ''MSD Manual Professional Edition''. 2025.</ref>
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===Histologic variants (prognostic significance)===
===Histologic variants (prognostic significance)===
*'''NOS (not otherwise specified):''' most common; intermediate prognosis
* NOS (not otherwise specified): most common; intermediate prognosis
*'''Tip lesion:''' best prognosis; most responsive to steroids
* Tip lesion: best prognosis; most responsive to steroids
*'''Collapsing:''' worst prognosis; associated with HIVAN, severe hypertension, rapid progression to ESKD; massive proteinuria; steroid-resistant
* Collapsing: worst prognosis; associated with HIVAN, severe hypertension, rapid progression to ESKD; massive proteinuria; steroid-resistant
*'''Cellular:''' intermediate prognosis
* Cellular: intermediate prognosis
*'''Perihilar:''' associated with adaptive/secondary FSGS
* Perihilar: associated with adaptive/secondary FSGS


==Clinical features==
==Clinical features==
===Nephrotic syndrome (>70% of primary FSGS)===
===Nephrotic syndrome (>70% of primary FSGS)===
*'''Edema:''' generalized or dependent; may develop over weeks or have '''abrupt onset with 15-20 lb weight gain'''<ref name="Medscape_FSGS">Focal Segmental Glomerulosclerosis Clinical Presentation. ''Medscape''. 2024.</ref>
* Edema: generalized or dependent; may develop over weeks or have abrupt onset with 15-20 lb weight gain<ref name="Medscape_FSGS">Focal Segmental Glomerulosclerosis Clinical Presentation. ''Medscape''. 2024.</ref>
**Children: typically begins with '''periorbital/facial swelling''' → progresses to generalized anasarca
**Children: typically begins with periorbital/facial swelling → progresses to generalized anasarca
**Adults: dependent edema (legs, sacrum); periorbital
**Adults: dependent edema (legs, sacrum); periorbital
*'''Foamy urine''' (proteinuria)
* Foamy urine (proteinuria)
*'''Fatigue, anorexia'''
* Fatigue, anorexia
*'''Ascites, pleural effusions''' (from third-spacing; pericardial effusion is rare)
* Ascites, pleural effusions (from third-spacing; pericardial effusion is rare)
*Onset frequently follows an '''upper respiratory tract infection'''
*Onset frequently follows an upper respiratory tract infection
*'''Hypertension''' — may be '''severe''' (diastolic >120 mmHg), especially in Black patients with renal impairment<ref name="StatPearls"/>
* Hypertension — may be '''severe''' (diastolic >120 mmHg), especially in Black patients with renal impairment<ref name="StatPearls"/>


===Subnephrotic presentation (~30%)===
===Subnephrotic presentation (~30%)===
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====Thromboembolism====
====Thromboembolism====
*Nephrotic syndrome is a '''hypercoagulable state''' — urinary loss of antithrombin III, protein C, protein S; elevated fibrinogen, factor V, factor VIII; platelet hyperaggregability<ref name="Complications">Complications of nephrotic syndrome. ''Korean J Pediatr''. 2011;54(8):322-328. PMC3212701.</ref>
*Nephrotic syndrome is a '''hypercoagulable state''' — urinary loss of antithrombin III, protein C, protein S; elevated fibrinogen, factor V, factor VIII; platelet hyperaggregability<ref name="Complications">Complications of nephrotic syndrome. ''Korean J Pediatr''. 2011;54(8):322-328. PMC3212701.</ref>
*Risk: '''deep venous thrombosis, pulmonary embolism, renal vein thrombosis, cerebral sinus thrombosis'''
*Risk: deep venous thrombosis, pulmonary embolism, renal vein thrombosis, cerebral sinus thrombosis
*VTE incidence ~1-5% in adults (higher in membranous nephropathy); risk is highest in the '''first 6 months'''
*VTE incidence ~1-5% in adults (higher in membranous nephropathy); risk is highest in the first 6 months
*'''Sudden gross hematuria or acute flank pain + acute renal failure''' → suspect '''renal vein thrombosis'''
* Sudden gross hematuria or acute flank pain + acute renal failure → suspect renal vein thrombosis
*'''Acute dyspnea + pleuritic chest pain''' → suspect '''pulmonary embolism'''
* Acute dyspnea + pleuritic chest pain → suspect pulmonary embolism
*Children: arterial thrombosis (cerebrovascular) can also occur
*Children: arterial thrombosis (cerebrovascular) can also occur


====Infection====
====Infection====
*'''Immunodeficiency''' from urinary loss of immunoglobulins (especially IgG) and complement proteins
* Immunodeficiency from urinary loss of immunoglobulins (especially IgG) and complement proteins
*Immunosuppressive therapy further increases risk
*Immunosuppressive therapy further increases risk
*'''Most common infections:''' pneumonia, sepsis/bacteremia, cellulitis, '''spontaneous bacterial peritonitis (SBP)''', UTI<ref name="Complications"/>
* Most common infections: pneumonia, sepsis/bacteremia, cellulitis, spontaneous bacterial peritonitis (SBP), UTI<ref name="Complications"/>
*'''SBP in nephrotic syndrome:''' any child with nephrotic syndrome + fever + abdominal pain + ascites should have '''diagnostic paracentesis''' — ''Streptococcus pneumoniae'' is the most common causative organism; ''E. coli'' and gram-negatives also seen
* SBP in nephrotic syndrome: any child with nephrotic syndrome + fever + abdominal pain + ascites should have diagnostic paracentesis — ''Streptococcus pneumoniae'' is the most common causative organism; ''E. coli'' and gram-negatives also seen
*Steroid therapy may '''mask typical signs of infection''' — maintain a high index of suspicion
*Steroid therapy may mask typical signs of infection — maintain a high index of suspicion


====Hypovolemic crisis====
====Hypovolemic crisis====
*Severe hypoalbuminemia (albumin <1.5 g/dL) → decreased oncotic pressure → intravascular volume depletion
*Severe hypoalbuminemia (albumin <1.5 g/dL) → decreased oncotic pressure → intravascular volume depletion
*'''Abdominal pain, vomiting, diarrhea, tachycardia, cool extremities, delayed capillary refill, oliguria''' → '''hypotension''' (a late sign)<ref name="Complications"/>
*Abdominal pain, vomiting, diarrhea, tachycardia, cool extremities, delayed capillary refill, oliguria → hypotension (a late sign)<ref name="Complications"/>
*Can be precipitated by aggressive diuresis or intercurrent illness
*Can be precipitated by aggressive diuresis or intercurrent illness
*'''Risk of AKI from prerenal azotemia'''
* Risk of AKI from prerenal azotemia


====Acute kidney injury====
====Acute kidney injury====
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==Differential diagnosis==
==Differential diagnosis==
===Nephrotic syndrome (other causes)===
===Nephrotic syndrome (other causes)===
*'''Minimal change disease (MCD):''' most common cause in children; clinically indistinguishable from FSGS without biopsy; steroid-responsive; excellent prognosis (distinguishing MCD from FSGS on biopsy is critical because management and prognosis differ)
* Minimal change disease (MCD): most common cause in children; clinically indistinguishable from FSGS without biopsy; steroid-responsive; excellent prognosis (distinguishing MCD from FSGS on biopsy is critical because management and prognosis differ)
*'''Membranous nephropathy:''' most common in white adults; strongly associated with renal vein thrombosis; may be secondary to malignancy, hepatitis B, SLE
* Membranous nephropathy: most common in white adults; strongly associated with renal vein thrombosis; may be secondary to malignancy, hepatitis B, SLE
*'''Diabetic nephropathy:''' most common secondary cause of nephrotic syndrome overall
* Diabetic nephropathy: most common secondary cause of nephrotic syndrome overall
*'''Lupus nephritis''' ([[SLE]])
* Lupus nephritis ([[SLE]])
*'''Amyloidosis'''
* Amyloidosis
*'''IgA nephropathy''' (nephrotic presentation less common)
* IgA nephropathy (nephrotic presentation less common)
*'''HIV-associated nephropathy (HIVAN):''' collapsing FSGS variant; suspect in any HIV-positive patient with nephrotic syndrome
* HIV-associated nephropathy (HIVAN): collapsing FSGS variant; suspect in any HIV-positive patient with nephrotic syndrome


===Generalized edema (non-renal causes to exclude)===
===Generalized edema (non-renal causes to exclude)===
*'''Heart failure''' (elevated JVP, S3 gallop, pulmonary edema)
* Heart failure (elevated JVP, S3 gallop, pulmonary edema)
*'''Cirrhosis/hepatic failure''' (spider angiomata, ascites, jaundice, coagulopathy)
* Cirrhosis/hepatic failure (spider angiomata, ascites, jaundice, coagulopathy)
*'''Protein-losing enteropathy'''
* Protein-losing enteropathy
*'''Severe malnutrition'''
* Severe malnutrition
 
 
{{Periorbital swelling DDX}}


==Evaluation==
==Evaluation==
===ED workup===
===ED workup===
*'''Urinalysis with microscopy:'''
* Urinalysis with microscopy:
**'''Heavy proteinuria''' (3+ or 4+ on dipstick)
** Heavy proteinuria (3+ or 4+ on dipstick)
**Hyaline or broad waxy casts; '''RBC casts are generally absent''' (their presence suggests nephritic syndrome/glomerulonephritis instead)
**Hyaline or broad waxy casts; RBC casts are generally absent (their presence suggests nephritic syndrome/glomerulonephritis instead)
**Oval fat bodies ("Maltese cross" under polarized light) — pathognomonic for nephrotic-range proteinuria
**Oval fat bodies ("Maltese cross" under polarized light) — pathognomonic for nephrotic-range proteinuria
*'''Spot urine protein:creatinine ratio:''' >3.5 mg/mg indicates nephrotic-range proteinuria (faster than 24-hour collection)
* Spot urine protein:creatinine ratio: >3.5 mg/mg indicates nephrotic-range proteinuria (faster than 24-hour collection)
*'''Serum albumin:''' <3.0 g/dL (often <2.0 g/dL in active disease)
* Serum albumin: <3.0 g/dL (often <2.0 g/dL in active disease)
*'''BMP/CMP:''' creatinine (renal function), electrolytes, calcium (low from hypoalbuminemia — correct for albumin)
* BMP/CMP: creatinine (renal function), electrolytes, calcium (low from hypoalbuminemia — correct for albumin)
*'''Lipid panel:''' hyperlipidemia (elevated total cholesterol, LDL, triglycerides) — characteristic of nephrotic syndrome
* Lipid panel: hyperlipidemia (elevated total cholesterol, LDL, triglycerides) — characteristic of nephrotic syndrome
*'''CBC:''' evaluate for infection; anemia (may occur from transferrin loss)
* CBC: evaluate for infection; anemia (may occur from transferrin loss)
*'''Coagulation studies:''' PT/INR, fibrinogen (if thrombosis suspected)
* Coagulation studies: PT/INR, fibrinogen (if thrombosis suspected)
*'''Blood glucose:''' rule out diabetic nephropathy as underlying cause
* Blood glucose: rule out diabetic nephropathy as underlying cause


===Directed testing based on presentation===
===Directed testing based on presentation===
*'''Suspected thromboembolism:''' D-dimer, CT pulmonary angiography (PE), Doppler ultrasound of extremities (DVT), renal vein Doppler (renal vein thrombosis)
* Suspected thromboembolism: D-dimer, CT pulmonary angiography (PE), Doppler ultrasound of extremities (DVT), renal vein Doppler (renal vein thrombosis)
*'''Suspected SBP:''' diagnostic paracentesis (cell count, Gram stain, culture, protein, albumin)
* Suspected SBP: diagnostic paracentesis (cell count, Gram stain, culture, protein, albumin)
*'''Suspected infection:''' blood cultures, urine culture, chest X-ray
* Suspected infection: blood cultures, urine culture, chest X-ray
*'''New diagnosis workup''' (arrange via nephrology; not all ED tests):
* New diagnosis workup (arrange via nephrology; not all ED tests):
**Complement levels (C3, C4) — normal in FSGS (low in SLE, MPGN, post-infectious GN)
**Complement levels (C3, C4) — normal in FSGS (low in SLE, MPGN, post-infectious GN)
**ANA, anti-dsDNA (lupus)
**ANA, anti-dsDNA (lupus)
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**HIV testing
**HIV testing
**Serum free light chains, SPEP/UPEP (amyloidosis, myeloma)
**Serum free light chains, SPEP/UPEP (amyloidosis, myeloma)
**'''Renal biopsy:''' definitive diagnosis; arranged by nephrology
** Renal biopsy: definitive diagnosis; arranged by nephrology


==Management==
==Management==
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====Edema management====
====Edema management====
*'''Salt restriction''' (education; not acute ED intervention)
* Salt restriction (education; not acute ED intervention)
*'''Loop diuretics:''' furosemide 1-2 mg/kg IV (children) or 20-80 mg IV (adults)
* Loop diuretics: furosemide 1-2 mg/kg IV (children) or 20-80 mg IV (adults)
**'''Caution:''' excessive diuresis can precipitate hypovolemic crisis and AKI — monitor volume status carefully
** Caution: excessive diuresis can precipitate hypovolemic crisis and AKI — monitor volume status carefully
**Diuretic resistance is common in severe hypoalbuminemia (furosemide is protein-bound and may not reach tubular lumen effectively)
**Diuretic resistance is common in severe hypoalbuminemia (furosemide is protein-bound and may not reach tubular lumen effectively)
*'''IV albumin 25% (0.5-1 g/kg) followed immediately by IV furosemide:''' for '''severe/refractory edema''' or clinical hypovolemia
* IV albumin 25% (0.5-1 g/kg) followed immediately by IV furosemide: for '''severe/refractory edema''' or clinical hypovolemia
**Albumin temporarily raises oncotic pressure, mobilizes edema fluid into intravascular space, and enhances diuretic delivery to the kidney
**Albumin temporarily raises oncotic pressure, mobilizes edema fluid into intravascular space, and enhances diuretic delivery to the kidney
**'''Monitor closely for pulmonary edema''' — albumin infusion can cause fluid overload if the patient is not truly volume-depleted
**Monitor closely for pulmonary edema — albumin infusion can cause fluid overload if the patient is not truly volume-depleted
*'''Do NOT give albumin without concurrent diuresis''' unless treating confirmed hypovolemia — it will redistribute into the extravascular space and worsen edema
*'''Do NOT give albumin without concurrent diuresis''' unless treating confirmed hypovolemia — it will redistribute into the extravascular space and worsen edema


====Thromboembolism====
====Thromboembolism====
*'''Anticoagulation:''' heparin (UFH or LMWH) followed by warfarin or DOAC per VTE protocols
* Anticoagulation: heparin (UFH or LMWH) followed by warfarin or DOAC per VTE protocols
*'''Thrombolysis or thrombectomy:''' consider for massive PE or limb-threatening DVT per standard protocols
* Thrombolysis or thrombectomy: consider for massive PE or limb-threatening DVT per standard protocols
*Renal vein thrombosis: anticoagulation; rarely requires intervention
*Renal vein thrombosis: anticoagulation; rarely requires intervention


====Infection / SBP====
====Infection / SBP====
*'''Empiric antibiotics:''' broad-spectrum pending cultures
* Empiric antibiotics: broad-spectrum pending cultures
*'''SBP:''' cefotaxime or ceftriaxone (covers ''S. pneumoniae'' and gram-negatives); adjust based on culture
* SBP: cefotaxime or ceftriaxone (covers ''S. pneumoniae'' and gram-negatives); adjust based on culture
*'''Diagnostic paracentesis''' in any nephrotic patient with ascites + fever or abdominal pain — do not wait for imaging
* Diagnostic paracentesis in any nephrotic patient with ascites + fever or abdominal pain — do not wait for imaging


====Hypovolemic crisis====
====Hypovolemic crisis====
*'''IV normal saline 20 mL/kg bolus''' if hemodynamically compromised
* IV normal saline 20 mL/kg bolus if hemodynamically compromised
*'''IV albumin 25% (1 g/kg over 3-5 hours)''' for severe hypovolemia with albumin <1.5 g/dL
* IV albumin 25% (1 g/kg over 3-5 hours) for severe hypovolemia with albumin <1.5 g/dL
*Monitor blood pressure closely; avoid fluid overload
*Monitor blood pressure closely; avoid fluid overload


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===Disease-specific treatment (not typically initiated in ED)===
===Disease-specific treatment (not typically initiated in ED)===
*'''Primary FSGS:''' corticosteroids (prednisone 1 mg/kg/day for 16+ weeks in adults); calcineurin inhibitors (tacrolimus, cyclosporine) for steroid-resistant or intolerant; mycophenolate mofetil; rituximab
* Primary FSGS: corticosteroids (prednisone 1 mg/kg/day for 16+ weeks in adults); calcineurin inhibitors (tacrolimus, cyclosporine) for steroid-resistant or intolerant; mycophenolate mofetil; rituximab
*'''Secondary FSGS:''' treat underlying cause (antiretroviral therapy for HIV, weight loss for obesity, stop offending drug); ACE inhibitor/ARB for proteinuria reduction
* Secondary FSGS: treat underlying cause (antiretroviral therapy for HIV, weight loss for obesity, stop offending drug); ACE inhibitor/ARB for proteinuria reduction
*'''Genetic FSGS:''' does NOT respond to immunosuppression; ACE inhibitor/ARB and supportive care
* Genetic FSGS: does NOT respond to immunosuppression; ACE inhibitor/ARB and supportive care
*All patients: '''ACE inhibitor or ARB''' (reduces proteinuria independent of blood pressure), '''statins''' (for hyperlipidemia), '''sodium restriction'''
*All patients: '''ACE inhibitor or ARB''' (reduces proteinuria independent of blood pressure), '''statins''' (for hyperlipidemia), '''sodium restriction'''


==Disposition==
==Disposition==
*'''Admit:'''
* Admit:
**Severe/symptomatic edema unresponsive to oral diuretics
**Severe/symptomatic edema unresponsive to oral diuretics
**Thromboembolism (PE, DVT, renal vein thrombosis, cerebral sinus thrombosis)
**Thromboembolism (PE, DVT, renal vein thrombosis, cerebral sinus thrombosis)
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**Hypertensive emergency
**Hypertensive emergency
**New diagnosis with severe nephrotic syndrome requiring urgent nephrology evaluation
**New diagnosis with severe nephrotic syndrome requiring urgent nephrology evaluation
*'''Discharge with close follow-up:'''
* Discharge with close follow-up:
**Known FSGS patient with stable mild-moderate edema exacerbation responsive to oral diuretics
**Known FSGS patient with stable mild-moderate edema exacerbation responsive to oral diuretics
**No signs of infection, thrombosis, or AKI
**No signs of infection, thrombosis, or AKI
**Stable renal function
**Stable renal function
**Ensure nephrology follow-up within 24-72 hours
**Ensure nephrology follow-up within 24-72 hours
*'''Always refer to nephrology''' — FSGS requires biopsy for diagnosis and ongoing specialist management; the EM physician's role is to manage complications and ensure timely referral
* Always refer to nephrology — FSGS requires biopsy for diagnosis and ongoing specialist management; the EM physician's role is to manage complications and ensure timely referral
*'''Counsel patients on:'''
* Counsel patients on:
**Sodium restriction
**Sodium restriction
**'''Signs of thromboembolism''' (leg swelling, dyspnea, chest pain) — seek immediate care
**Signs of thromboembolism (leg swelling, dyspnea, chest pain) — seek immediate care
**'''Signs of infection''' (fever, abdominal pain) — low threshold to return
**Signs of infection (fever, abdominal pain) — low threshold to return
**Medication compliance (steroids, immunosuppressants, ACE inhibitors)
**Medication compliance (steroids, immunosuppressants, ACE inhibitors)
**'''Pneumococcal vaccination''' (if not already received — nephrotic patients are at high risk for pneumococcal infection)
**Pneumococcal vaccination (if not already received — nephrotic patients are at high risk for pneumococcal infection)


==See Also==
==See Also==

Latest revision as of 09:36, 22 March 2026

Background

  • Focal segmental glomerulosclerosis (FSGS) is a pattern of glomerular scarring in which sclerosis affects segments (not the entirety) of some (not all) glomeruli[1]
  • It is the most common cause of primary (idiopathic) nephrotic syndrome in adults in the United States and the leading glomerular cause of end-stage kidney disease (ESKD)[2]
  • FSGS disproportionately affects African Americans (driven by APOL1 risk alleles)
  • The emergency physician encounters FSGS patients presenting with nephrotic syndrome (massive edema, proteinuria, hypoalbuminemia) and its life-threatening complications: thromboembolism, spontaneous bacterial peritonitis, hypovolemic crisis, acute kidney injury, and severe hypertension
  • Diagnosis is histopathologic — requires renal biopsy; cannot be diagnosed by clinical features or labs alone[1]
  • FSGS accounts for ~35% of nephrotic syndrome in adults (higher in Black patients) and 7-20% in children
  • Incidence is increasing worldwide over the past three decades[3]

Classification

Type Mechanism Key features
Primary (idiopathic) Presumed circulating permeability factor injuring podocytes Nephrotic-range proteinuria; responds to immunosuppression; recurs in up to 40% of kidney transplants
Secondary Adaptive (hyperfiltration) or toxic podocyte injury Obesity, HIV (HIVAN), heroin, sickle cell, reflux nephropathy, single kidney, anabolic steroids; usually subnephrotic proteinuria
Genetic Mutations in podocyte structural proteins (NPHS1, NPHS2, INF2, TRPC6, others) Steroid-resistant; does NOT recur after transplant; family history
APOL1-associated APOL1 G1/G2 risk alleles (sub-Saharan African ancestry) Explains disproportionate FSGS burden in Black patients; also linked to HIVAN and hypertensive nephrosclerosis
Virus-associated HIV (HIVAN), parvovirus B19, CMV, EBV HIVAN: collapsing variant; almost exclusively in Black patients; responds to antiretroviral therapy

Histologic variants (prognostic significance)

  • NOS (not otherwise specified): most common; intermediate prognosis
  • Tip lesion: best prognosis; most responsive to steroids
  • Collapsing: worst prognosis; associated with HIVAN, severe hypertension, rapid progression to ESKD; massive proteinuria; steroid-resistant
  • Cellular: intermediate prognosis
  • Perihilar: associated with adaptive/secondary FSGS

Clinical features

Nephrotic syndrome (>70% of primary FSGS)

  • Edema: generalized or dependent; may develop over weeks or have abrupt onset with 15-20 lb weight gain[4]
    • Children: typically begins with periorbital/facial swelling → progresses to generalized anasarca
    • Adults: dependent edema (legs, sacrum); periorbital
  • Foamy urine (proteinuria)
  • Fatigue, anorexia
  • Ascites, pleural effusions (from third-spacing; pericardial effusion is rare)
  • Onset frequently follows an upper respiratory tract infection
  • Hypertension — may be severe (diastolic >120 mmHg), especially in Black patients with renal impairment[1]

Subnephrotic presentation (~30%)

  • Incidental proteinuria found on routine urinalysis
  • Microscopic hematuria (occasionally)
  • Mild hypertension
  • Slowly progressive renal insufficiency

EM-relevant complications of nephrotic syndrome

These are the reasons FSGS patients present to the ED:

Thromboembolism

  • Nephrotic syndrome is a hypercoagulable state — urinary loss of antithrombin III, protein C, protein S; elevated fibrinogen, factor V, factor VIII; platelet hyperaggregability[5]
  • Risk: deep venous thrombosis, pulmonary embolism, renal vein thrombosis, cerebral sinus thrombosis
  • VTE incidence ~1-5% in adults (higher in membranous nephropathy); risk is highest in the first 6 months
  • Sudden gross hematuria or acute flank pain + acute renal failure → suspect renal vein thrombosis
  • Acute dyspnea + pleuritic chest pain → suspect pulmonary embolism
  • Children: arterial thrombosis (cerebrovascular) can also occur

Infection

  • Immunodeficiency from urinary loss of immunoglobulins (especially IgG) and complement proteins
  • Immunosuppressive therapy further increases risk
  • Most common infections: pneumonia, sepsis/bacteremia, cellulitis, spontaneous bacterial peritonitis (SBP), UTI[5]
  • SBP in nephrotic syndrome: any child with nephrotic syndrome + fever + abdominal pain + ascites should have diagnostic paracentesis — Streptococcus pneumoniae is the most common causative organism; E. coli and gram-negatives also seen
  • Steroid therapy may mask typical signs of infection — maintain a high index of suspicion

Hypovolemic crisis

  • Severe hypoalbuminemia (albumin <1.5 g/dL) → decreased oncotic pressure → intravascular volume depletion
  • Abdominal pain, vomiting, diarrhea, tachycardia, cool extremities, delayed capillary refill, oliguria → hypotension (a late sign)[5]
  • Can be precipitated by aggressive diuresis or intercurrent illness
  • Risk of AKI from prerenal azotemia

Acute kidney injury

  • Multifactorial: hypovolemia, sepsis, nephrotoxic medications, renal vein thrombosis, or disease progression
  • AKI complicating NS has increased 158% over the past decade in pediatric hospitalizations[6]

Severe/malignant hypertension

  • May present with hypertensive emergency: headache, visual changes, encephalopathy, seizures

Differential diagnosis

Nephrotic syndrome (other causes)

  • Minimal change disease (MCD): most common cause in children; clinically indistinguishable from FSGS without biopsy; steroid-responsive; excellent prognosis (distinguishing MCD from FSGS on biopsy is critical because management and prognosis differ)
  • Membranous nephropathy: most common in white adults; strongly associated with renal vein thrombosis; may be secondary to malignancy, hepatitis B, SLE
  • Diabetic nephropathy: most common secondary cause of nephrotic syndrome overall
  • Lupus nephritis (SLE)
  • Amyloidosis
  • IgA nephropathy (nephrotic presentation less common)
  • HIV-associated nephropathy (HIVAN): collapsing FSGS variant; suspect in any HIV-positive patient with nephrotic syndrome

Generalized edema (non-renal causes to exclude)

  • Heart failure (elevated JVP, S3 gallop, pulmonary edema)
  • Cirrhosis/hepatic failure (spider angiomata, ascites, jaundice, coagulopathy)
  • Protein-losing enteropathy
  • Severe malnutrition


Periorbital swelling

Proptosis

No proptosis

Lid Complications

Other

Evaluation

ED workup

  • Urinalysis with microscopy:
    • Heavy proteinuria (3+ or 4+ on dipstick)
    • Hyaline or broad waxy casts; RBC casts are generally absent (their presence suggests nephritic syndrome/glomerulonephritis instead)
    • Oval fat bodies ("Maltese cross" under polarized light) — pathognomonic for nephrotic-range proteinuria
  • Spot urine protein:creatinine ratio: >3.5 mg/mg indicates nephrotic-range proteinuria (faster than 24-hour collection)
  • Serum albumin: <3.0 g/dL (often <2.0 g/dL in active disease)
  • BMP/CMP: creatinine (renal function), electrolytes, calcium (low from hypoalbuminemia — correct for albumin)
  • Lipid panel: hyperlipidemia (elevated total cholesterol, LDL, triglycerides) — characteristic of nephrotic syndrome
  • CBC: evaluate for infection; anemia (may occur from transferrin loss)
  • Coagulation studies: PT/INR, fibrinogen (if thrombosis suspected)
  • Blood glucose: rule out diabetic nephropathy as underlying cause

Directed testing based on presentation

  • Suspected thromboembolism: D-dimer, CT pulmonary angiography (PE), Doppler ultrasound of extremities (DVT), renal vein Doppler (renal vein thrombosis)
  • Suspected SBP: diagnostic paracentesis (cell count, Gram stain, culture, protein, albumin)
  • Suspected infection: blood cultures, urine culture, chest X-ray
  • New diagnosis workup (arrange via nephrology; not all ED tests):
    • Complement levels (C3, C4) — normal in FSGS (low in SLE, MPGN, post-infectious GN)
    • ANA, anti-dsDNA (lupus)
    • Hepatitis B and C serologies
    • HIV testing
    • Serum free light chains, SPEP/UPEP (amyloidosis, myeloma)
    • Renal biopsy: definitive diagnosis; arranged by nephrology

Management

ED management of nephrotic syndrome complications

Edema management

  • Salt restriction (education; not acute ED intervention)
  • Loop diuretics: furosemide 1-2 mg/kg IV (children) or 20-80 mg IV (adults)
    • Caution: excessive diuresis can precipitate hypovolemic crisis and AKI — monitor volume status carefully
    • Diuretic resistance is common in severe hypoalbuminemia (furosemide is protein-bound and may not reach tubular lumen effectively)
  • IV albumin 25% (0.5-1 g/kg) followed immediately by IV furosemide: for severe/refractory edema or clinical hypovolemia
    • Albumin temporarily raises oncotic pressure, mobilizes edema fluid into intravascular space, and enhances diuretic delivery to the kidney
    • Monitor closely for pulmonary edema — albumin infusion can cause fluid overload if the patient is not truly volume-depleted
  • Do NOT give albumin without concurrent diuresis unless treating confirmed hypovolemia — it will redistribute into the extravascular space and worsen edema

Thromboembolism

  • Anticoagulation: heparin (UFH or LMWH) followed by warfarin or DOAC per VTE protocols
  • Thrombolysis or thrombectomy: consider for massive PE or limb-threatening DVT per standard protocols
  • Renal vein thrombosis: anticoagulation; rarely requires intervention

Infection / SBP

  • Empiric antibiotics: broad-spectrum pending cultures
  • SBP: cefotaxime or ceftriaxone (covers S. pneumoniae and gram-negatives); adjust based on culture
  • Diagnostic paracentesis in any nephrotic patient with ascites + fever or abdominal pain — do not wait for imaging

Hypovolemic crisis

  • IV normal saline 20 mL/kg bolus if hemodynamically compromised
  • IV albumin 25% (1 g/kg over 3-5 hours) for severe hypovolemia with albumin <1.5 g/dL
  • Monitor blood pressure closely; avoid fluid overload

Hypertensive emergency

  • Manage per standard Hypertensive emergency protocols
  • ACE inhibitors/ARBs are first-line for chronic BP control AND reduce proteinuria (but avoid in AKI with hyperkalemia)

Disease-specific treatment (not typically initiated in ED)

  • Primary FSGS: corticosteroids (prednisone 1 mg/kg/day for 16+ weeks in adults); calcineurin inhibitors (tacrolimus, cyclosporine) for steroid-resistant or intolerant; mycophenolate mofetil; rituximab
  • Secondary FSGS: treat underlying cause (antiretroviral therapy for HIV, weight loss for obesity, stop offending drug); ACE inhibitor/ARB for proteinuria reduction
  • Genetic FSGS: does NOT respond to immunosuppression; ACE inhibitor/ARB and supportive care
  • All patients: ACE inhibitor or ARB (reduces proteinuria independent of blood pressure), statins (for hyperlipidemia), sodium restriction

Disposition

  • Admit:
    • Severe/symptomatic edema unresponsive to oral diuretics
    • Thromboembolism (PE, DVT, renal vein thrombosis, cerebral sinus thrombosis)
    • Suspected or confirmed SBP or sepsis
    • Hypovolemic crisis with hemodynamic instability
    • AKI (rising creatinine, oliguria)
    • Hypertensive emergency
    • New diagnosis with severe nephrotic syndrome requiring urgent nephrology evaluation
  • Discharge with close follow-up:
    • Known FSGS patient with stable mild-moderate edema exacerbation responsive to oral diuretics
    • No signs of infection, thrombosis, or AKI
    • Stable renal function
    • Ensure nephrology follow-up within 24-72 hours
  • Always refer to nephrology — FSGS requires biopsy for diagnosis and ongoing specialist management; the EM physician's role is to manage complications and ensure timely referral
  • Counsel patients on:
    • Sodium restriction
    • Signs of thromboembolism (leg swelling, dyspnea, chest pain) — seek immediate care
    • Signs of infection (fever, abdominal pain) — low threshold to return
    • Medication compliance (steroids, immunosuppressants, ACE inhibitors)
    • Pneumococcal vaccination (if not already received — nephrotic patients are at high risk for pneumococcal infection)

See Also

External Links

References

  1. ↑ 1.0 1.1 1.2 Focal Segmental Glomerulosclerosis. StatPearls. NCBI. 2024.
  2. ↑ Rosenberg AZ, Kopp JB. Focal Segmental Glomerulosclerosis. Clin J Am Soc Nephrol. 2017;12(3):502-517.
  3. ↑ Focal Segmental Glomerulosclerosis. MSD Manual Professional Edition. 2025.
  4. ↑ Focal Segmental Glomerulosclerosis Clinical Presentation. Medscape. 2024.
  5. ↑ 5.0 5.1 5.2 Complications of nephrotic syndrome. Korean J Pediatr. 2011;54(8):322-328. PMC3212701.
  6. ↑ Rheault MN, et al. Increasing frequency of AKI amongst children hospitalized with nephrotic syndrome. Pediatr Nephrol. 2014;29(1):139-147. PMC6556228.
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