What is the most likely diagnosis and initial management for a 28‑year‑old patient presenting with bilateral leg edema, leg pain, and dipstick 3+ proteinuria?

Bilateral Leg Edema with Pain and 3+ Proteinuria in a 28-Year-Old

This patient most likely has nephrotic syndrome, and you must urgently quantify the proteinuria, measure serum albumin, obtain a renal biopsy within the first month, and initiate supportive management with loop diuretics and ACE inhibitor/ARB therapy while awaiting histologic diagnosis. 1, 2, 3

Immediate Diagnostic Confirmation

Quantify proteinuria immediately using either a 24-hour urine collection (nephrotic range = >3.5 g/24 hours) or spot urine protein-to-creatinine ratio (UPCR >300-350 mg/mmol indicates nephrotic-range proteinuria). 1, 4 A dipstick showing 3+ protein requires quantitative confirmation before proceeding. 1

Measure serum albumin to confirm hypoalbuminemia (<3.0 g/dL in adults), which combined with heavy proteinuria and edema establishes the diagnosis of nephrotic syndrome. 5, 1, 3 Note that albumin assay variability exists—bromocresol green versus bromocresol purple methods can differ by approximately 0.5 g/dL. 1

Obtain baseline laboratory assessment including complete blood count, serum creatinine, electrolytes, eGFR, lipid profile (total cholesterol, LDL, HDL, triglycerides), and complement levels (C3, C4). 1, 2

Critical Secondary Cause Screening

At age 28, you must exclude secondary causes before assuming primary glomerular disease:

• Check fasting glucose and HbA1c to rule out diabetes mellitus, the most common secondary cause in adults. 1
• Obtain autoimmune serologies: ANA, anti-dsDNA, and complement levels (C3, C4, C1q) to evaluate for systemic lupus erythematosus. 1, 3
• Test hepatitis B and C serologies and consider HIV testing to identify viral-related glomerulopathies. 1
• Review all medications for potential nephrotoxic agents. 1
• Document family history of kidney disease and assess BMI (obesity with BMI >35 kg/m² suggests secondary/maladaptive FSGS). 1

Kidney Biopsy: Essential and Time-Sensitive

Perform kidney biopsy within the first month after nephrotic syndrome onset, ideally before starting immunosuppressive therapy. 1, 3 This is the gold-standard diagnostic tool that determines specific histologic diagnosis and guides treatment selection. 2

The biopsy is indicated for all adults with nephrotic syndrome except when serum anti-phospholipase A2 receptor antibodies are positive (diagnostic of membranous nephropathy). 1, 3

Technical requirements for adequate biopsy: 1

• Minimum 8-10 glomeruli for light microscopy (H&E, PAS, Masson's trichrome, silver stain)
• Immunofluorescence for IgG, C3, IgA, IgM, C1q, κ and λ light chains
• Electron microscopy to detect proliferative/membranous lesions and podocyte foot-process effacement

Immediate Supportive Management (Start Before Biopsy Results)

Edema Control

Initiate loop diuretics as first-line therapy for bilateral leg edema. 2 Start furosemide 40-80 mg twice daily (not once daily—twice-daily dosing achieves optimal diuretic effect). 2 Loop diuretics maintain efficacy even with impaired renal function, unlike thiazides which lose effectiveness when creatinine clearance falls below 40 mL/min. 2

Accept modest increases in serum creatinine (up to 30%) during diuresis—this reflects appropriate volume reduction, not kidney injury. 2 For resistant edema, add metolazone 2.5-5 mg daily for synergistic effect. 2

Restrict dietary sodium to <2 g/day to maximize diuretic effectiveness. 2

Proteinuria Reduction and Renal Protection

Start ACE inhibitor or ARB therapy immediately despite any elevation in creatinine, as these agents provide critical proteinuria reduction and renal protection in nephrotic syndrome. 2 Target blood pressure <130/80 mmHg, or even <125/75 mmHg given the likely massive proteinuria. 5, 2

Monitor serum creatinine and potassium closely after initiation; accept up to 30% increase in creatinine if it stabilizes, but discontinue if progressive rise occurs. 2

Critical Thromboembolism Risk Assessment

Assess thromboembolism risk urgently, particularly if serum albumin falls below 2.9 g/dL. 1, 3 Patients with nephrotic syndrome have a 29% risk of renal vein thrombosis, 17-28% risk of pulmonary embolism, and 11% risk of deep vein thrombosis. 5

Consider prophylactic anticoagulation when serum albumin is <20-25 g/L (2.0-2.5 g/dL) AND the patient has additional risk factors such as proteinuria >10 g/day, BMI >35 kg/m², or prolonged immobilization. 1, 3 Warfarin is the anticoagulant of choice with target INR 2-3; avoid Factor Xa inhibitors and direct thrombin inhibitors due to unpredictable pharmacokinetics from albumin binding and urinary losses. 1, 3

Disease-Specific Immunosuppression (After Biopsy)

Defer immunosuppressive therapy until kidney biopsy establishes the diagnosis, as treatment regimens differ substantially between minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and secondary causes. 2

If Biopsy Shows Minimal Change Disease or Primary FSGS:

Prednisone 1 mg/kg/day (maximum 80 mg) or alternate-day dose of 2 mg/kg (maximum 120 mg) is first-line therapy. 5, 1, 6 Continue high-dose corticosteroids for a minimum of 4 weeks and up to 16 weeks as tolerated, or until complete remission is achieved. 5 Taper slowly over 6 months after achieving complete remission. 5

Consider cyclosporine as alternative first-line therapy if the patient has contraindications to corticosteroids (uncontrolled diabetes risk, psychiatric conditions, severe osteoporosis). 5, 1 Cyclosporine may be preferred over tacrolimus due to lesser tendency to precipitate diabetes. 5, 1

If Biopsy Shows Membranous Nephropathy:

Immunosuppression should only be initiated if proteinuria persistently exceeds 4 g/day and remains >50% of baseline despite 6 months of conservative therapy with ACE inhibitor/ARB and blood pressure control. 2

Common Pitfalls to Avoid

Do not dismiss nephrotic syndrome based solely on normal serum albumin—early or partial nephrotic syndrome may present atypically, and albumin assay variability can be misleading. 3 Rare cases of nephrotic syndrome with concurrent liver disease may present with proteinuria <3.5 g/day yet still have severe glomerular permeability defects. 7

Do not delay kidney biopsy in adults—biopsy should be performed within the first month, preferably before immunosuppressive treatment, to establish specific histologic diagnosis. 1, 3

Do not overlook the leg pain component—while edema causes discomfort, significant leg pain raises concern for deep vein thrombosis, which occurs in 11% of nephrotic syndrome patients. 5 Consider Doppler ultrasound if pain is unilateral or disproportionate to edema.

Avoid NSAIDs, potassium supplements, and potassium-based salt substitutes, which can precipitate hyperkalemia or reduce diuretic efficacy. 2

Monitoring Parameters

Monitor serum potassium, sodium, and creatinine 1-2 weeks after initiating or adjusting diuretics and ACE inhibitor/ARB therapy. 2 Once immunosuppression begins, monitor patients every 2-4 weeks for the first 2-4 months, then every 3-6 months for renal and extra-renal disease activity. 1