What is the appropriate work‑up for a patient with suspected nephritic syndrome?

Nephrotic Syndrome Work-Up

Initial Clinical Assessment and Screening

Confirm the diagnosis of nephrotic syndrome by documenting the classic triad: proteinuria >3.5 g/24 hours (or UPCR >300–350 mg/mmol), serum albumin <3.0 g/dL, and peripheral edema. 1, 2, 3

• Exclude benign causes of edema such as menstrual cycle changes, intense exercise, recent sexual activity, or trauma before proceeding with extensive work-up. 1
• Perform dipstick urinalysis as the first screening step; a result of ≥1+ protein mandates quantitative confirmation. 1
• Quantify proteinuria using a first-morning urine protein-to-creatinine ratio (UPCR) or albumin-to-creatinine ratio (ACR); UPCR >300–350 mg/mmol defines nephrotic-range proteinuria. 1, 2
• Confirm with 24-hour urine collection showing total protein excretion >3.5 g/24 hours in adults. 1, 4
• Measure serum albumin; note that assay type matters—bromocresol green (BCG) reads approximately 0.5 g/dL higher than bromocresol purple (BCP). 1

Essential Laboratory Studies

Baseline Renal and Hematologic Assessment

• Obtain complete blood count with differential and platelet count. 1, 5
• Measure serum creatinine, blood urea nitrogen, electrolytes, and calculate estimated glomerular filtration rate (eGFR) to assess renal function. 1, 5
• Check fasting glucose and HbA1c to identify diabetes mellitus, the most common secondary cause of adult nephrotic syndrome. 1

Lipid Profile

• Assess total cholesterol, LDL-C, HDL-C, triglycerides, apolipoprotein B, and lipoprotein(a), as hyperlipidemia is a common feature and cardiovascular risk factor. 1

Urine Sediment Microscopy

• Examine urine sediment for dysmorphic red blood cells (>80% dysmorphic RBCs suggests glomerular hemorrhage) and red-cell casts, which are pathognomonic for glomerulonephritis. 1
• The presence of hematuria with proteinuria suggests nephritic syndrome rather than pure nephrotic syndrome and carries a poorer prognosis. 4

Screening for Secondary Causes

Autoimmune and Systemic Disease Evaluation

• Measure antinuclear antibody (ANA), anti-dsDNA, and complement levels (C3, C4, C1q) to evaluate for systemic lupus erythematosus. 1, 2, 3
• Low C3 levels in nephrotic syndrome should trigger investigation for complement-mediated diseases such as C3 glomerulopathy, lupus nephritis, or infection-related glomerulonephritis. 6
• If C3 is low, measure C4 immediately; if both are low, suspect lupus nephritis or cryoglobulinemia; if only C3 is low, consider C3 glomerulopathy or post-infectious glomerulonephritis. 6
• Persistently low C3 beyond 8–12 weeks after infection mandates kidney biopsy to exclude C3 glomerulopathy. 6

Infectious Disease Screening

• Test for hepatitis B and C serologies to rule out viral-related glomerulopathies. 1, 2
• Perform HIV testing, particularly in high-risk populations, as HIV-associated nephropathy can present with nephrotic syndrome. 1

Paraprotein-Related Disease

• Obtain serum and urine immunoelectrophoresis/immunofixation plus serum free light chains for all adults to exclude paraprotein-related disease such as AL amyloidosis or light-chain deposition disease. 1
• Approximately 60–80% of patients over age 50 with C3 glomerulopathy have monoclonal gammopathy. 6

Medication and Clinical History Review

• Review all medications, including over-the-counter drugs, herbals, and vitamins, to identify potential nephrotoxic agents such as NSAIDs, lithium, or bisphosphonates. 1, 5
• Obtain detailed family history to uncover hereditary kidney diseases. 1
• Document body mass index; obesity (BMI >35 kg/m²) is associated with secondary or maladaptive focal segmental glomerulosclerosis (FSGS). 1
• Document history of prematurity as a potential etiology for reduced nephron number and secondary FSGS. 1

Imaging Studies

• Perform renal ultrasound to assess kidney size and echogenicity, particularly before potential biopsy. 1
• Ultrasound is generally sufficient; more advanced imaging is not routinely needed unless obstruction or structural abnormalities are suspected. 7

Kidney Biopsy: Indications and Timing

Kidney biopsy is the gold-standard diagnostic tool and should be performed within the first month after onset of nephrotic syndrome, ideally before initiating immunosuppressive therapy. 1

Adult Indications

• Biopsy is indicated for all adults with nephrotic syndrome except when serum anti-phospholipase A2 receptor antibodies (PLA2R-Ab) are positive, which is diagnostic of primary membranous nephropathy. 1
• Additional exceptions include MPO-positive or PR3-positive ANCA vasculitis, Fabry disease, and genetically characterized familial FSGS. 1
• Biopsy may still be considered in advanced chronic kidney disease (eGFR <30 mL/min/1.73 m²) if there is evidence of active disease and kidney length is >9 cm. 1

Pediatric Indications

• In children <12 years with typical presentation (periorbital edema, no hematuria, normal blood pressure), routine biopsy is not required at initial presentation, as minimal change disease is most common. 1, 4
• Biopsy is reserved for steroid-resistant disease or for children ≥12 years. 1

Technical Requirements

• Obtain a specimen containing at least 8–10 glomeruli for light microscopy with H&E, PAS, Masson's trichrome, and silver stains. 1
• Perform immunofluorescence for IgG, C3, IgA, IgM, C1q, and κ/λ light chains. 1
• Conduct electron microscopy to detect proliferative or membranous lesions and assess podocyte foot-process effacement. 1

Genetic Testing

• Consider genetic testing for patients with familial kidney disease, syndromic features, steroid-resistant FSGS, or early-onset disease. 1
• Genetic testing helps classify FSGS into primary, genetic, secondary, or undetermined cause, which guides treatment decisions. 1

Complications Assessment

Thromboembolism Risk

• Assess venous thromboembolism (VTE) risk, particularly when serum albumin falls below 2.9 g/dL; membranous nephropathy carries higher VTE risk than other causes. 1
• Additional risk factors include BMI >35 kg/m², heart failure, recent surgery, prolonged immobilization, and proteinuria >10 g/day. 1
• Consider using validated risk assessment tools (e.g., http://www.med.unc.edu/gntools/) to stratify VTE risk. 1
• Consider prophylactic full-dose anticoagulation when serum albumin is <20–25 g/L AND the patient has additional risk factors. 1
• 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

Infection Risk

• Patients with nephrotic syndrome have increased risk of serious bacterial infections, particularly encapsulated organisms, due to urinary loss of immunoglobulins. 3, 7
• Routine prophylactic antibiotics are not recommended, but maintain high clinical suspicion for infection. 7

Common Pitfalls to Avoid

• Do not perform routine serologic testing without clinical suspicion; studies show that serologies (FANA, RF, cryoglobulins, VDRL, ESR) rarely add diagnostic value when clinical features do not suggest secondary causes. 8
• Do not delay biopsy for extensive serologic work-up unless there is strong clinical suspicion for a specific secondary cause that would change immediate management. 1
• Do not use albumin infusion as standard therapy; focus instead on diuretics, RAS inhibition, and disease-specific immunosuppression. 1
• Do not assume normal C3 excludes all glomerular diseases; C3 is typically normal or elevated in nephrotic syndrome unless there is concurrent complement-mediated disease. 6
• Do not forget to monitor for progression to nephritic syndrome; the presence of hematuria, red-cell casts, and declining renal function indicates a more aggressive disease requiring urgent intervention. 4