View source for Focal segmental glomerulosclerosis

==Background==
*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
*Incidence is increasing worldwide over the past three decades<ref name="MSD">Focal Segmental Glomerulosclerosis. ''MSD Manual Professional Edition''. 2025.</ref>

===Classification===
{| class="wikitable"
|-
! 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<ref name="Medscape_FSGS">Focal Segmental Glomerulosclerosis Clinical Presentation. ''Medscape''. 2024.</ref>
**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<ref name="StatPearls"/>

===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<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
*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<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
*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)<ref name="Complications"/>
*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<ref name="AKI_NS">Rheault MN, et al. Increasing frequency of AKI amongst children hospitalized with nephrotic syndrome. ''Pediatr Nephrol''. 2014;29(1):139-147. PMC6556228.</ref>

====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 DDX}}

==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==
*[[Nephrotic syndrome]]
*[[Nephritic syndrome]]
*[[Acute kidney injury]]
*[[Pulmonary embolism]]
*[[Deep venous thrombosis]]
*[[Spontaneous bacterial peritonitis]]
*[[Hypertensive emergency]]
*[[HIV]]

==External Links==
*[https://www.ncbi.nlm.nih.gov/books/NBK532272/ StatPearls — Focal Segmental Glomerulosclerosis]
*[https://journals.lww.com/cjasn/fulltext/2017/03000/focal_segmental_glomerulosclerosis.18.aspx CJASN — Focal Segmental Glomerulosclerosis (Rosenberg & Kopp, 2017)]
*[https://emedicine.medscape.com/article/245915-overview Medscape — Focal Segmental Glomerulosclerosis]
*[https://www.msdmanuals.com/professional/genitourinary-disorders/glomerular-disorders/focal-segmental-glomerulosclerosis MSD Manual — Focal Segmental Glomerulosclerosis]
*[https://www.kidney.org/kidney-topics/focal-segmental-glomerulosclerosis-fsgs NKF — Focal Segmental Glomerulosclerosis]
*[https://pmc.ncbi.nlm.nih.gov/articles/PMC3212701/ Korean J Pediatr — Complications of nephrotic syndrome (2011)]

==References==
<references/>

[[Category:Renal]]