Nephrotic Syndrome for USMLE Step 3

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Nephrotic Syndrome for the USMLE Step 3 Exam

Nephrotic syndrome is a kidney disorder characterized by excessive protein loss in the urine (≥3.5 g/day), hypoalbuminemia, edema, hyperlipidemia, and lipiduria. It results from damage to the glomerular filtration barrier, leading to the abnormal leakage of proteins.

Primary Causes:
Minimal Change Disease (MCD): Most common cause in children and often associated with a benign prognosis. Histologically, it shows podocyte foot process effacement without immune deposits.
Focal Segmental Glomerulosclerosis (FSGS): More common in adults. Can be idiopathic or secondary to conditions like obesity, HIV, and heroin use. It shows segmental scarring of the glomeruli.
Membranous Nephropathy: The leading cause of nephrotic syndrome in white adults. It is associated with subepithelial immune complex deposition and thickening of the glomerular basement membrane. May be secondary to hepatitis B, SLE, or malignancies.
Secondary Causes:
Diabetic Nephropathy: The most common cause in the U.S., associated with long-standing diabetes mellitus. Features include thickening of the glomerular basement membrane, mesangial expansion, and Kimmelstiel-Wilson nodules.
Systemic Lupus Erythematosus (SLE): Lupus nephritis can present with either nephrotic or nephritic syndrome, often depending on the class of glomerular involvement (class V commonly causes nephrotic features).
Amyloidosis: Results from extracellular deposition of amyloid fibrils, which damage the glomeruli. Common in multiple myeloma or chronic inflammatory diseases.
Infections: Hepatitis B and C, HIV, and malaria can cause secondary nephrotic syndrome.

The glomerular filtration barrier consists of endothelial cells, the glomerular basement membrane, and podocytes. Damage to any of these components leads to increased permeability to proteins, especially albumin.
Proteinuria: Significant loss of albumin results in hypoalbuminemia, which decreases plasma oncotic pressure and causes fluid to shift into the interstitial space, leading to edema.
Hyperlipidemia: The liver compensates for hypoalbuminemia by synthesizing lipoproteins, resulting in elevated cholesterol and triglycerides.
Thrombosis: Loss of anticoagulant proteins like antithrombin III leads to a hypercoagulable state, increasing the risk of venous thromboembolism (VTE).
Infections: The loss of immunoglobulins in urine weakens the immune system, predisposing patients to infections, especially encapsulated bacteria like Streptococcus pneumoniae.

Edema: The most common presenting symptom, often starting as periorbital edema in the morning and progressing to generalized edema (anasarca).
Frothy Urine: Due to the presence of excessive proteins in the urine.
Hypercoagulability: Increased risk of deep vein thrombosis (DVT) and renal vein thrombosis due to loss of anticoagulant factors.
Increased Susceptibility to Infection: Especially bacterial infections due to urinary loss of immunoglobulins and complement factors.
Hypertension: May be present in advanced or secondary cases, particularly in diabetic nephropathy or amyloidosis.

Urinalysis: Shows proteinuria (>3.5 g/day), often with lipiduria (fatty casts or oval fat bodies).
Blood Tests: Hypoalbuminemia (<2.5 g/dL), hyperlipidemia, and sometimes elevated serum creatinine.
Serologic Testing: Depending on the suspected underlying cause, tests for antinuclear antibodies (ANA), hepatitis B and C, HIV, and complement levels may be indicated.
Renal Biopsy: Necessary in adults to identify the specific histopathologic cause (e.g., MCD, FSGS, membranous nephropathy).

Thromboembolism: Nephrotic syndrome, particularly membranous nephropathy, has a high risk of thromboembolic events, including pulmonary embolism and renal vein thrombosis.
Infections: Patients are susceptible to peritonitis and pneumonia due to immune dysfunction.
Chronic Kidney Disease (CKD): Prolonged proteinuria and glomerular damage can lead to CKD and end-stage renal disease (ESRD).

General Measures:
Dietary Changes: Sodium restriction and moderate protein intake to minimize further kidney damage.
Diuretics: Loop diuretics (e.g., furosemide) for edema control.
Antihypertensive Therapy: Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) to reduce proteinuria and control blood pressure.
Statins: For hyperlipidemia management.
Specific Treatments:
Corticosteroids: Mainstay of treatment for MCD. FSGS may require additional immunosuppressants (e.g., calcineurin inhibitors or cyclophosphamide).
Immunosuppressive Therapy: In membranous nephropathy or lupus nephritis, immunosuppressive agents like rituximab or mycophenolate mofetil may be used.
Anticoagulation: Prophylactic anticoagulation may be indicated in patients with severe hypoalbuminemia (<2 g/dL) or a history of thromboembolism.

MCD: Good prognosis with most children responding to steroids.
FSGS and Membranous Nephropathy: Higher risk of progression to ESRD, especially if proteinuria is uncontrolled.
Secondary Nephrotic Syndrome: Prognosis depends on control of the underlying disease (e.g., diabetes, SLE).

Key Points

Nephrotic syndrome is marked by proteinuria, hypoalbuminemia, edema, hyperlipidemia, and lipiduria.
Primary causes include Minimal Change Disease (children), FSGS, and Membranous Nephropathy (adults).
Secondary causes include diabetic nephropathy, lupus nephritis, and amyloidosis.
Complications include thromboembolism, infections, and progression to CKD or ESRD.
Management involves diuretics, steroids, ACE inhibitors, immunosuppressants, and anticoagulation depending on the underlying etiology.