How do you differentiate between nephritic and nephrotic syndrome in a patient presenting with symptoms such as hematuria, proteinuria, or edema, considering factors like age, underlying medical conditions (e.g. hypertension, diabetes, autoimmune disorders), and family history?

Differentiating Nephritic from Nephrotic Syndrome

Nephrotic syndrome presents with massive proteinuria (≥3.5 g/day), hypoalbuminemia (<3.0 g/dL), and edema, while nephritic syndrome presents with hematuria, hypertension, oliguria, and mild-to-moderate proteinuria (<3.5 g/day). 1, 2

Clinical Presentation Distinguishes the Two Syndromes

Nephrotic Syndrome Features

• Proteinuria ≥3.5 g/day (or urine protein-to-creatinine ratio ≥2 g/g in children) with hypoalbuminemia <3.0 g/dL in adults or ≤2.5 g/dL in children 1
• Peripheral edema that is typically periorbital in the morning and progresses to dependent edema (ankles, legs) throughout the day due to decreased oncotic pressure from albumin loss 2, 3
• Hyperlipidemia as a compensatory mechanism for plasma protein loss, with elevated total cholesterol, LDL-C, and triglycerides 2, 1
• Absence of significant hematuria or only microscopic hematuria (not gross/macroscopic) 4
• Normal or near-normal blood pressure in most cases, unless secondary causes are present 3

Nephritic Syndrome Features

• Hematuria with red blood cell casts on urinalysis, often with gross (macroscopic) hematuria 5, 4
• Hypertension that is often marked and acute in onset 4
• Oliguria with rising serum creatinine indicating acute kidney injury 5
• Mild-to-moderate proteinuria (<3.5 g/day), which is poorly selective 4
• Edema present but typically less severe than nephrotic syndrome 4
• Decreased complement C3 levels in many cases, suggesting immune-mediated glomerular injury 4

Age-Specific Considerations

Children (<12 years)

• Minimal change disease is the most common cause of nephrotic syndrome, accounting for the majority of idiopathic nephrotic syndrome cases 5, 1
• Kidney biopsy is not routinely performed at initial presentation; empiric glucocorticoid therapy is standard 5, 1
• Biopsy is indicated only for steroid resistance, age ≥12 years, or atypical features suggesting nephritic syndrome 1

Adults

• Focal segmental glomerulosclerosis (FSGS) and membranous nephropathy are the most common primary causes of nephrotic syndrome 3, 2
• Diabetes mellitus is the most common secondary cause of nephrotic syndrome in adults 3
• Kidney biopsy is recommended for all adults with nephrotic syndrome to determine the underlying cause, except when serum anti-phospholipase A2 receptor antibodies are positive (diagnostic of membranous nephropathy) 1

Underlying Medical Conditions Guide Secondary Causes

Diabetes Mellitus

• Most common secondary cause of nephrotic syndrome in adults, presenting with gradual onset of proteinuria and typically without hematuria 3
• Diabetic nephropathy rarely requires biopsy if retinopathy is present and proteinuria develops after 10+ years of diabetes 3

Hypertension

• Marked hypertension with acute onset suggests nephritic syndrome or rapidly progressive glomerulonephritis 4
• Chronic hypertension with gradual proteinuria may indicate hypertensive nephrosclerosis or secondary FSGS 5

Autoimmune Disorders (Systemic Lupus Erythematosus)

• Check ANA, anti-dsDNA, and complement levels (C3, C4) in patients with nephrotic or nephritic features 1
• Lupus nephritis Class IV presents with nephritic features: hematuria (20-25 RBCs/hpf), rising creatinine, and proteinuria, often with "full-house" immunofluorescence staining 5
• Consider anticoagulation when serum albumin <20 g/L due to high thromboembolism risk 1

Family History Implications

• Positive family history of kidney disease, especially early-onset nephrotic syndrome, warrants genetic testing for mutations in NPHS1, NPHS2, WT1, or PLCE1 2
• Genetic testing is indicated for patients with familial kidney disease, syndromic features, or steroid-resistant FSGS 2, 1
• History of prematurity should be documented as a potential etiology for secondary FSGS due to reduced nephron number 2

Laboratory Differentiation Algorithm

Initial Workup for All Patients

1. Quantify proteinuria: 24-hour urine collection or spot urine albumin-to-creatinine ratio (uACR ≥300 mg/g indicates severely increased albuminuria) 1
2. Measure serum albumin: <3.0 g/dL in adults or ≤2.5 g/dL in children confirms hypoalbuminemia 1
3. Urinalysis with microscopy: Look for RBC casts (nephritic) vs. fatty casts/oval fat bodies (nephrotic) 4
4. Serum creatinine and eGFR: Rising creatinine suggests nephritic syndrome or acute kidney injury 5
5. Complement levels (C3, C4): Decreased levels suggest immune-mediated nephritic syndrome 1, 4

Additional Testing Based on Clinical Suspicion

• Hepatitis B, C, and HIV serologies to identify secondary causes of nephrotic syndrome 1
• Serum and urine immunoelectrophoresis/immunofixation plus serum free light chains for all adults to exclude paraprotein-related disease 1
• Anti-PLA2R antibodies if membranous nephropathy is suspected (positive result may obviate need for biopsy) 1
• Renal ultrasound to assess kidney size and echogenicity before potential biopsy 1

Critical Pitfalls to Avoid

• Do not dismiss nephrotic syndrome based solely on normal serum albumin, as early or partial nephrotic syndrome may present atypically, particularly with albumin assay variability (bromocresol green vs. bromocresol purple) 1, 6
• Do not assume absence of hematuria rules out glomerular disease; microscopic hematuria can occur in nephrotic syndrome, but RBC casts and gross hematuria strongly suggest nephritic syndrome 4
• Do not delay kidney biopsy in adults with nephrotic syndrome, as biopsy should be performed within the first month after onset, preferably before starting immunosuppressive treatment, to establish a specific histologic diagnosis 1
• Do not overlook thromboembolism risk in nephrotic syndrome, particularly when serum albumin <2.9 g/dL; consider prophylactic anticoagulation with warfarin (target INR 2-3) in high-risk patients, especially those with membranous nephropathy 1, 2
• Do not use Factor Xa inhibitors or direct thrombin inhibitors for anticoagulation in nephrotic syndrome due to unpredictable pharmacokinetics from albumin binding and urinary losses 1