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Nephrotic Syndrome for USMLE Step 2

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Nephrotic Syndrome for the USMLE Step 2 Exam
Definition
  • Nephrotic Syndrome: A clinical syndrome defined by heavy proteinuria (>3.5 g/day), hypoalbuminemia (<3 g/dL), generalized edema, and hyperlipidemia. It results from damage to the glomerular filtration barrier, leading to protein loss in the urine.
Pathophysiology
  • Glomerular Barrier Dysfunction: The glomerulus normally restricts large proteins from filtering into the urine. In nephrotic syndrome, injury to the podocytes, basement membrane, or endothelium increases permeability, allowing proteins (especially albumin) to pass into the urine.
  • Proteinuria: Loss of large amounts of protein in the urine depletes serum protein, causing a drop in plasma oncotic pressure and leading to edema.
  • Hypoalbuminemia: Persistent urinary albumin loss results in low serum albumin, which promotes fluid accumulation in tissues.
  • Hyperlipidemia: Hypoalbuminemia stimulates hepatic synthesis of lipoproteins, leading to elevated levels of cholesterol, triglycerides, and low-density lipoprotein (LDL).
  • Edema: Sodium and water retention occurs due to activation of the renin-angiotensin-aldosterone system (RAAS) and antidiuretic hormone (ADH), worsening fluid overload.
Nephrotic Syndrome Pathophysiology
Etiology
  • Primary Causes:
    • Minimal Change Disease (MCD): The most common cause in children. Characterized by podocyte foot process effacement on electron microscopy, with no significant findings on light microscopy. It responds well to corticosteroids.
    • Focal Segmental Glomerulosclerosis (FSGS): Characterized by segmental glomerular scarring. Common in adults, especially African Americans, and associated with conditions such as obesity and HIV. May lead to chronic kidney disease (CKD).
    • Membranous Nephropathy: Common in adults, it involves immune complex deposition in the glomerular basement membrane, often associated with malignancies, infections (e.g., hepatitis B, C), or autoimmune diseases like lupus.
  • Secondary Causes:
    • Diabetic Nephropathy: The leading cause of nephrotic syndrome in adults, resulting from chronic hyperglycemia and associated glomerular damage.
    • Lupus Nephritis: Nephrotic syndrome due to autoimmune damage in patients with systemic lupus erythematosus (SLE).
    • Amyloidosis: Deposition of amyloid fibrils in the glomeruli, leading to proteinuria.
    • Infections and Drugs: Chronic infections (e.g., hepatitis B, HIV) and nephrotoxic drugs (e.g., NSAIDs) can induce nephrotic syndrome.
Clinical Presentation
  • Edema: Generalized swelling, including periorbital edema, peripheral edema, and ascites, due to fluid retention.
  • Frothy Urine: Due to excessive proteinuria.
  • Fatigue and Weight Gain: Resulting from fluid overload and protein depletion.
  • Increased Risk of Infections: Loss of immunoglobulins and complement factors in the urine increases susceptibility to bacterial infections, particularly from encapsulated organisms like Streptococcus pneumoniae.
  • Hypercoagulability: There is an increased risk of venous thromboembolism (VTE) due to urinary loss of antithrombin III, protein C, and protein S.
Diagnosis
  • Urinalysis:
    • Proteinuria: Nephrotic-range proteinuria (>3.5 g/day).
    • Urine Microscopy: May show oval fat bodies ("Maltese crosses") indicating lipiduria.
  • Serum Studies:
    • Hypoalbuminemia: Serum albumin <3 g/dL due to urinary losses.
    • Hyperlipidemia: Elevated cholesterol and triglyceride levels.
    • Renal Function: Serum creatinine may be elevated if renal function is impaired.
  • Renal Biopsy:
    • Used to confirm the diagnosis and determine the underlying cause in adults.
    • Minimal Change Disease: Shows effacement of foot processes on electron microscopy.
    • FSGS: Shows segmental glomerulosclerosis.
    • Membranous Nephropathy: Shows thickened basement membranes with subepithelial immune deposits.
Complications
  • Thromboembolism: Hypercoagulability increases the risk of deep vein thrombosis (DVT), pulmonary embolism (PE), and renal vein thrombosis.
  • Infections: Due to urinary loss of immunoglobulins, patients are more susceptible to infections such as peritonitis, cellulitis, and pneumonia.
  • Acute Kidney Injury (AKI): Can occur due to hypovolemia from significant fluid shifts into tissues.
  • Chronic Kidney Disease (CKD): Persistent nephrotic syndrome may lead to progressive kidney damage and CKD.
Management
  • General Measures:
    • Sodium Restriction: To manage edema (limit to <2 g/day).
    • Diuretics: Loop diuretics (e.g., furosemide) to manage fluid overload.
    • ACE Inhibitors/ARBs: Reduce proteinuria and slow progression of CKD by decreasing intraglomerular pressure.
  • Specific Treatments Based on Etiology:
    • Minimal Change Disease: First-line treatment with corticosteroids (e.g., prednisone).
    • FSGS: Treated with corticosteroids and, in some cases, immunosuppressive agents (e.g., calcineurin inhibitors).
    • Membranous Nephropathy: May require immunosuppressive therapy in severe cases.
    • Diabetic Nephropathy: Focus on strict glycemic control and blood pressure management.
  • Anticoagulation: May be considered in patients with severe hypoalbuminemia (<2 g/dL) and high risk for thromboembolism.
Prognosis
  • Minimal Change Disease: Excellent prognosis, particularly in children, with most patients responding to corticosteroids.
  • FSGS and Membranous Nephropathy: These conditions have a variable prognosis and can progress to CKD if not adequately managed.
  • Secondary Causes: Prognosis depends on the underlying cause, such as better control of diabetes improving renal outcomes in diabetic nephropathy.
Key Points
  • Nephrotic syndrome is defined by proteinuria >3.5 g/day, hypoalbuminemia, edema, and hyperlipidemia.
  • Common primary causes include minimal change disease, FSGS, and membranous nephropathy, while secondary causes include diabetic nephropathy and lupus.
  • Diagnosis involves urinalysis, serum studies, and renal biopsy to determine the underlying cause.
  • Management includes sodium restriction, diuretics, ACE inhibitors/ARBs, and treatment of the underlying disease.
  • Complications include thromboembolism, infections, acute kidney injury, and progression to CKD.

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