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) |
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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