What is the diagnosis, diagnostics, and treatment for puffy eyes, slight facial edema, and occasional pedal edema with normal creatinine and estimated Glomerular Filtration Rate (eGFR) levels?

Diagnosis: Nephrotic Syndrome Until Proven Otherwise

The presentation of puffy eyes, facial edema, and pedal edema with previously normal renal function strongly suggests nephrotic syndrome, and you must immediately check urinalysis with spot urine albumin-to-creatinine ratio (UACR) and serum albumin to confirm or exclude this diagnosis. 1

Immediate Diagnostic Workup

Essential First-Line Tests

• Spot urine albumin-to-creatinine ratio (UACR) on a random urine sample—this is the preferred screening test over 24-hour collections 2
• Serum albumin level—hypoalbuminemia (<3.5 g/dL) combined with proteinuria defines nephrotic syndrome 1
• Urinalysis with microscopy to look for proteinuria, hematuria, red blood cell casts, or dysmorphic RBCs that indicate glomerular disease 3
• Repeat serum creatinine and calculate eGFR using a validated equation (CKD-EPI preferred) to assess current kidney function 2
• Lipid panel—hyperlipidemia is part of the nephrotic syndrome tetrad 4

Confirming Nephrotic Syndrome

Nephrotic syndrome is diagnosed when UACR ≥300 mg/g (or ≥3000 mg/24h) is present along with hypoalbuminemia, edema, and typically hyperlipidemia 2, 4. Two of three UACR specimens collected within 3-6 months should be abnormal to confirm persistent albuminuria, though with clinical nephrotic syndrome you proceed immediately 2.

Establishing Chronicity vs. Acute Presentation

Determine Timeline

• Review any prior creatinine/eGFR values from the past 3+ months—the fact that values were normal 6 months ago suggests this may be a relatively acute process 3
• Chronic kidney disease requires ≥3 months of abnormalities, so if this presentation is recent (<3 months), you're dealing with either acute nephrotic syndrome or acute kidney injury 3
• Repeat eGFR within days to weeks to distinguish acute kidney injury from chronic kidney disease progression 3

Differential Diagnosis Based on Clinical Context

Primary Glomerular Diseases (Most Common in Adults)

• Membranous nephropathy—most common cause of primary nephrotic syndrome in adults; check anti-PLA2R antibodies 2
• Focal segmental glomerulosclerosis (FSGS)
• Minimal change disease—more common in children but can occur in adults 1

Secondary Causes to Evaluate

• Diabetes mellitus—check HbA1c and fasting glucose, though diabetic nephropathy typically develops gradually over years with retinopathy 2
• Systemic lupus erythematosus—check ANA, anti-dsDNA, complement levels
• Amyloidosis—check serum and urine protein electrophoresis with immunofixation, serum free light chains 2
• Medication-induced—review all medications including NSAIDs, thiazolidinediones (which cause edema but not true nephrotic syndrome) 5

Red Flags Requiring Urgent Nephrology Referral

Refer immediately to nephrology if any of the following are present: 3

• Nephrotic-range proteinuria (UACR ≥300 mg/g) with edema
• Rapidly decreasing eGFR (>5 mL/min/1.73 m²/year)
• eGFR <30 mL/min/1.73 m²
• Uncertainty about etiology of kidney disease
• Active urinary sediment (RBC casts, dysmorphic RBCs suggesting glomerulonephritis)

Initial Management While Awaiting Nephrology Evaluation

Conservative Management

• Sodium restriction (<2 g/day) to reduce edema 2
• Loop diuretics (furosemide) for symptomatic edema relief—dose may need to be higher in nephrotic syndrome due to protein binding 2
• ACE inhibitor or ARB if hypertension is present (target BP <130/80 mmHg with albuminuria ≥30 mg/g), but monitor creatinine and potassium within 1-2 weeks of initiation 2, 3
• Dietary protein restriction to approximately 0.8 g/kg/day if CKD is confirmed 2

Critical Monitoring

• Check serum potassium within 1-2 weeks if starting ACE inhibitor/ARB 3
• Monitor for complications of nephrotic syndrome including thromboembolism (consider prophylactic anticoagulation if albumin <2.5 g/dL), infection, and acute kidney injury 2
• Assess volume status carefully—avoid aggressive diuresis that could precipitate acute kidney injury 3

Kidney Biopsy Consideration

Kidney biopsy is the gold standard for definitive diagnosis and should be performed in most adults with nephrotic syndrome to guide treatment decisions, as different glomerular diseases require different immunosuppressive regimens 2. The biopsy is typically performed by nephrology using ultrasound guidance and examined by light microscopy, immunofluorescence, and electron microscopy 2.

When to Defer Biopsy

• Minimal change disease suspected in children (can treat empirically with corticosteroids) 1
• Clear diabetic nephropathy with long-standing diabetes, retinopathy, and gradual onset 2
• Severe coagulopathy or other contraindications to biopsy

Common Pitfalls to Avoid

• Don't attribute periorbital edema to allergy without checking urinalysis—this is a classic presentation of nephrotic syndrome, especially in children 1
• Don't assume normal creatinine 6 months ago excludes significant kidney disease now—nephrotic syndrome can develop relatively acutely 4, 6
• Don't start immunosuppression before biopsy (except in clear minimal change disease in children)—the histologic diagnosis determines treatment 2
• Don't use ACE inhibitors/ARBs for "primary prevention" if BP is normal and UACR is <30 mg/g—they're only indicated when albuminuria or hypertension is present 2