What is the initial workup and treatment for a patient presenting with nephrotic range proteinuria?

Workup for Nephrotic Range Proteinuria

Perform kidney biopsy in all adults with nephrotic-range proteinuria (>3.5 g/24 hours or UPCR >3500 mg/g) to establish the underlying diagnosis, except when serum anti-phospholipase A2 receptor antibodies are positive, which is diagnostic of membranous nephropathy. 1, 2

Initial Diagnostic Evaluation

Confirm Nephrotic Syndrome

• Quantify proteinuria using spot urine protein-to-creatinine ratio (UPCR >3500 mg/g or >3.5 g/24 hours defines nephrotic range) 3, 4
• Measure serum albumin (expect <30 g/L in nephrotic syndrome) 3
• Assess lipid panel (hyperlipidemia is characteristic) 3, 2
• Evaluate for edema (periorbital in morning, dependent pitting later in day) 3

Essential Laboratory Tests

• Complete metabolic panel including serum creatinine and estimated GFR to assess renal function 4
• Urinalysis with microscopic examination to evaluate for hematuria, pyuria, and cellular casts (suggests glomerulonephritis) 4
• Hepatitis B and C serology to exclude viral-associated glomerular disease 4
• HIV testing to exclude HIV-associated nephropathy 4
• Antinuclear antibody (ANA) to screen for systemic lupus erythematosus 4
• Complement levels (C3, C4) to evaluate for complement-mediated glomerular disease 4
• Serum and urine protein electrophoresis if age >40 years or suspecting paraproteinemia/amyloidosis 4, 3
• Anti-phospholipase A2 receptor antibodies (positive result is diagnostic of membranous nephropathy and may obviate need for biopsy in adults) 2

Imaging

• Renal ultrasound to evaluate kidney size, structural abnormalities, and exclude obstruction 4

Kidney Biopsy: The Diagnostic Gold Standard

Indications for Biopsy

• All adults with nephrotic-range proteinuria should undergo kidney biopsy to determine the specific glomerular disease, unless anti-phospholipase A2 receptor antibodies are positive 1, 5, 2
• Children who fail to respond to initial glucocorticoid therapy (typically after 4-8 weeks) require biopsy and genetic testing 1, 2
• Biopsy is indispensable and cannot be substituted by clinical or laboratory variables alone 1

Pathological Assessment

• Use International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification for lupus nephritis 1
• Assess activity and chronicity indices to guide treatment decisions 1
• Evaluate for thrombotic and vascular lesions particularly if antiphospholipid antibodies are present 1

Genetic Testing in Specific Populations

• Perform massively parallel sequencing (whole-exome sequencing preferred) as first-line diagnostic in infants with congenital nephrotic syndrome (onset within first 3 months of life) 1
• Genetic screening establishes etiology, informs management regarding potential Wilms tumor or neurological involvement, and enables family counseling 1

Age-Specific Diagnostic Approaches

Pediatric Patients

• Children <12 years with typical presentation (edema, nephrotic-range proteinuria, no hematuria, normal blood pressure, normal complement): initiate empiric glucocorticoid therapy without biopsy, as minimal change disease is most common 2
• If steroid-responsive, no biopsy needed; if steroid-resistant or atypical features present, proceed with genetic testing and kidney biopsy 1, 2

Adult Patients

• White adults: membranous nephropathy is most common primary cause 3
• African ancestry populations: focal segmental glomerulosclerosis (FSGS) is most common 3
• Diabetic nephropathy is the most common secondary cause across all populations 3
• African-American patients with poorly controlled hypertension: consider hypertensive nephrosclerosis in differential, though biopsy remains necessary 6

Adjunctive Management During Workup

Blood Pressure Control

• Initiate ACE inhibitor or ARB for all patients with nephrotic-range proteinuria or arterial hypertension 1
• Target blood pressure <125/75 mmHg in patients with nephrotic-range proteinuria 4

Thromboembolism Prophylaxis

• Consider anticoagulation in patients with high thromboembolism risk, particularly those with membranous nephropathy 2

Edema Management

• Dietary sodium restriction is essential 2
• Diuretics as needed for symptomatic edema management 2

Referral to Nephrology

Urgent referral to nephrologist (ideally within 2 weeks) is necessary for all patients with confirmed nephrotic-range proteinuria 3

Specialized Care Requirements

• Infants with congenital nephrotic syndrome must be referred to specialized tertiary pediatric nephrology centers with multidisciplinary teams including neonatologists, pediatric nephrologists, dieticians, and surgeons 1
• Early introduction to transplant center is recommended for children with congenital nephrotic syndrome to minimize dialysis time 1

Common Pitfalls to Avoid

• Do not delay biopsy in adults assuming diabetic nephropathy without histological confirmation, as other treatable causes may coexist 3, 5
• Do not perform biopsy in children <12 years with typical minimal change disease presentation before trial of glucocorticoids 2
• Do not overlook secondary causes: always screen for diabetes, lupus, amyloidosis, infections (HIV, hepatitis), and hematologic malignancies 3, 2
• Do not forget to assess for urinary tract obstruction before initiating treatment, particularly if considering cyclophosphamide 7