What is nephrotic syndrome, including its risk factors, patient presentation, physical exam findings, and laboratory results?

Nephrotic Syndrome: Overview, Risk Factors, Presentation, and Laboratory Findings

Nephrotic syndrome is characterized by the triad of nephrotic-range proteinuria (>3.5g/24h), hypoalbuminemia (<30g/L), and edema, often accompanied by hyperlipidemia and increased risk of thromboembolism. 1, 2

Definition and Pathophysiology

• Nephrotic syndrome results from increased glomerular permeability to proteins due to podocyte dysfunction, leading to substantial protein loss in urine 1
• The primary pathophysiological mechanism involves alterations in the glomerular filtration barrier, allowing proteins (primarily albumin) to leak into the urine 3
• Loss of albumin leads to decreased oncotic pressure, causing fluid shift from intravascular to interstitial spaces, resulting in edema 1
• Hyperlipidemia occurs as a compensatory mechanism for the loss of plasma proteins 1

Risk Factors and Etiology

• Primary (idiopathic) causes:

  • Minimal change disease (most common in children) 2
  • Focal segmental glomerulosclerosis (most common in African ancestry populations) 2
  • Membranous nephropathy (most common in white adults) 2

• Secondary causes:

  • Diabetes mellitus (most common systemic cause) 2
  • Systemic lupus erythematosus 2
  • Amyloidosis 4
  • Infections 5
  • Medications 5
  • Genetic disorders (particularly in congenital nephrotic syndrome) 6

• Genetic factors:

  • Congenital nephrotic syndrome is primarily caused by genetic defects in podocytes 6
  • Common genetic mutations include NPHS1 (encoding nephrin), NPHS2 (encoding podocin), WT1, and PLCE1 6

Clinical Presentation

• Edema:

  • Periorbital edema (most noticeable in the morning) 2
  • Dependent pitting edema (more common later in the day) 2
  • Can progress to involve limbs and abdomen with severe disease 4

• Other symptoms:

  • Fatigue 3
  • Decreased urine output 4
  • Weight gain due to fluid retention 5

• Physical examination findings:

  • Pitting edema (periorbital, lower extremities, sacral, abdominal) 4
  • Pleural effusions and ascites in severe cases 5
  • Hypertension (may be present in some cases) 1

Laboratory Findings

• Urinary findings:

  • Proteinuria >3.5g/24h (measured by 24-hour urine collection) 2
  • Protein:creatinine ratio (PCR) >300-350 mg/mmol indicates nephrotic range proteinuria 2
  • Lipiduria (oval fat bodies, fatty casts) 2

• Serum findings:

  • Hypoalbuminemia (<30 g/L, often <20 g/L in severe cases) 2
  • Hyperlipidemia (elevated total cholesterol, LDL, triglycerides) 4
  • Normal or mildly elevated serum creatinine (unless complicated by acute kidney injury) 2

• Other laboratory abnormalities:

  • Low levels of binding proteins for ions, vitamins, hormones 7
  • Altered coagulation profile (loss of anticoagulant proteins) 7
  • Vitamin D deficiency 5

Complications

• Thromboembolism:

  • High risk of venous thrombosis (29% for renal vein thrombosis, 17-28% for pulmonary embolism) 1
  • Due to loss of anticoagulant proteins and increased procoagulant factors 7

• Infections:

  • Increased susceptibility due to loss of immunoglobulins and complement factors 5
  • Common sites include skin, respiratory tract, and urinary tract 7

• Acute kidney injury:

  • Can occur due to hypovolemia, nephrotoxic medications, or progression of underlying disease 7

• Progression to chronic kidney disease:

  • Patients with nephrotic-range proteinuria >3.8g/day have a 35% risk of end-stage renal disease within 2 years 1

Diagnostic Approach

• Quantitative measurement of proteinuria (24-hour collection or spot urine protein/creatinine ratio) 2
• Serum albumin, lipid profile, and renal function tests 2
• Referral to a nephrologist is necessary (ideally within 2 weeks) 2
• Renal biopsy is usually performed to establish the specific form of glomerular disease 2
• Additional tests to identify secondary causes (e.g., diabetes, lupus, amyloidosis) 2