Renal/Urology · PANCE / PANRE

Nephrotic Syndrome

Heavy proteinuria (>3.5 g/day) with hypoalbuminemia, edema, and hyperlipidemia.

Also known as: nephrotic syndrome, minimal change disease, FSGS, membranous nephropathy, diabetic nephropathy

Overview

A glomerular disorder characterized by proteinuria >3.5 g/day (or UPCR >3.5 g/g), hypoalbuminemia (<3.0 g/dL), peripheral edema, and hyperlipidemia. Reflects increased glomerular basement membrane permeability to plasma proteins.

Epidemiology

Annual incidence ~3 per 100,000 adults. Minimal change disease is the most common cause in children; FSGS and membranous nephropathy dominate in adults. Diabetic nephropathy is the most common secondary cause overall.

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Risk factors

Diabetes mellitus (diabetic nephropathy — leading secondary cause)
Infections: HIV (collapsing FSGS), hepatitis B (membranous), hepatitis C (membranoproliferative)
Malignancy: solid tumors (membranous), lymphoma (minimal change)
Medications: NSAIDs (minimal change, membranous), gold, penicillamine
Autoimmune: SLE (any pattern), amyloidosis
Genetic: APOL1 (FSGS), Alport, congenital nephrotic syndrome

Pathophysiology

Damage to the glomerular filtration barrier (podocytes, GBM, endothelium) increases permeability to albumin and larger proteins. Proteinuria drives hypoalbuminemia → reduced oncotic pressure → edema. Hepatic compensatory synthesis raises lipoproteins (hyperlipidemia). Loss of antithrombin III, protein C/S, and immunoglobulins predisposes to thrombosis and infection.

Clinical presentation

Symptoms

Insidious or rapid-onset peripheral edema — periorbital in morning, dependent later
Foamy or frothy urine (proteinuria)
Weight gain, abdominal distention (ascites)
Dyspnea (pleural effusions), fatigue
Symptoms of underlying cause: rash, joint pain (SLE), polyuria/polydipsia (diabetes)

Signs / physical exam

Pitting edema (lower extremities, periorbital, scrotal/labial)
Ascites, pleural effusions in severe cases
Hypertension (variable, more common in FSGS)
Muehrcke lines (transverse white nail bands), xanthelasma

Classic findings

Periorbital edema in a child = consider minimal change disease until proven otherwise.

Differential diagnosis

Minimal change disease — Most common in children; abrupt nephrotic onset; normal light microscopy; podocyte effacement on EM; steroid-responsive
Focal segmental glomerulosclerosis (FSGS) — Common in adults, especially Black patients (APOL1); HIV, obesity, heroin; segmental sclerosis on biopsy
Membranous nephropathy — Most common primary nephrotic syndrome in white adults; anti-PLA2R antibody positive in ~70% primary; subepithelial deposits, 'spike and dome'
Diabetic nephropathy — Long-standing diabetes, retinopathy, gradual albuminuria; Kimmelstiel-Wilson nodules
Membranoproliferative GN — Mixed nephrotic/nephritic; low complement; hep C, cryoglobulinemia, complement dysregulation
Amyloidosis — Older adults; AL (myeloma) or AA (chronic inflammation); Congo red apple-green birefringence
Lupus nephritis (class V) — SLE with membranous pattern; ANA, anti-dsDNA, low complement

Diagnostic workup

Diagnostic criteria

Nephrotic syndrome diagnosed by: proteinuria >3.5 g/day, hypoalbuminemia <3.0 g/dL, edema, hyperlipidemia. Kidney biopsy is standard in adults to determine specific pathology and guide therapy (excepting clear diabetic nephropathy).

Labs

24-h urine protein OR spot UPCR (>3.5 g/g diagnostic)
Urinalysis with microscopy — oval fat bodies, fatty casts, 'Maltese cross' under polarized light
Serum albumin (<3.0 g/dL), lipid panel (elevated), creatinine, BMP
Hep B, Hep C, HIV serologies
ANA, complement (C3, C4), SPEP/UPEP with free light chains
Anti-PLA2R antibody (primary membranous), anti-THSD7A
A1c, glucose

Imaging

Renal ultrasound — assess size, exclude obstruction
Echocardiogram if HF suspected as alternative edema cause

Diagnostic algorithm

Cause	Population	Light Microscopy	EM/IF	First-line Therapy
Minimal change	Children, NSAIDs, lymphoma	Normal	Podocyte effacement on EM	Prednisone
FSGS	Black adults, HIV, obesity	Segmental sclerosis	Focal podocyte effacement	Prednisone, CNI, rituximab
Membranous	White adults, hep B, malignancy	Thickened GBM, 'spike and dome'	Subepithelial deposits, IgG/C3	Rituximab (KDIGO 2021)
Diabetic nephropathy	Long-standing diabetes	Kimmelstiel-Wilson nodules	GBM thickening	RAAS + SGLT2i + finerenone
Amyloidosis	Older adults, myeloma, chronic inflammation	Acellular deposits	Apple-green birefringence (Congo red)	Treat underlying (myeloma)

Major causes of nephrotic syndrome with characteristic biopsy findings and first-line therapy.

Treatment

First-line

Treat underlying cause — glycemic control in diabetes, antiviral for hepatitis, withdraw offending drug
ACEi (lisinopril, ramipril, enalapril) or ARB (losartan, valsartan, irbesartan) — reduce proteinuria, slow progression
SGLT2 inhibitor — dapagliflozin, empagliflozin — added benefit in proteinuric CKD
Loop diuretic — furosemide, torsemide, bumetanide — for edema; may need higher doses due to albumin binding loss
Statin (atorvastatin, rosuvastatin) for hyperlipidemia
Sodium restriction (<2 g/day)

Second-line / adjunct

Minimal change disease: prednisone 1 mg/kg/day × 8-16 weeks; cyclophosphamide or rituximab for relapses
FSGS: prednisone trial; cyclosporine, tacrolimus, or rituximab for steroid-resistant/dependent
Membranous nephropathy: rituximab first-line (KDIGO 2021); alternative cyclophosphamide + steroid (Ponticelli) or calcineurin inhibitor
Diabetic nephropathy: maximize RAAS blockade + SGLT2i + finerenone
Anticoagulation (warfarin or DOAC) if albumin <2.5 g/dL with membranous (highest VTE risk) or prior thrombosis
Pneumococcal vaccination; consider prophylactic antibiotics if recurrent infections

Complications

Venous thromboembolism — especially renal vein thrombosis in membranous nephropathy (highest risk)
Increased infection risk (loss of immunoglobulins, complement; immunosuppression)
Acute kidney injury from volume depletion (over-diuresis) or thrombosis
Progression to CKD/ESRD
Accelerated atherosclerosis from chronic dyslipidemia
Vitamin D deficiency (urinary loss of vitamin D binding protein)

PANCE pearls

'Maltese cross' = oval fat bodies under polarized light = nephrotic-range proteinuria.
Membranous nephropathy has the highest VTE risk of any nephrotic disease — especially renal vein thrombosis (flank pain, hematuria, AKI).
Anti-PLA2R antibody is diagnostic for primary membranous; positive in ~70%. Negative anti-PLA2R should prompt malignancy workup.
Children with new-onset nephrotic syndrome (age 1-10) are presumed minimal change — empiric steroids without biopsy unless atypical features.
Avoid over-diuresis: rapid volume loss with low albumin can precipitate AKI and worsen edema rebound.

References

KDIGO 2021 — KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases (Kidney Int 2021)
Beck 2009 — M-type Phospholipase A2 Receptor as Target Antigen in Idiopathic Membranous Nephropathy (Beck et al., NEJM 2009)

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