Nephrotic Syndrome for the ABIM
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Nephrotic Syndrome for the ABIM Exam
Definition
- Nephrotic Syndrome: A clinical syndrome characterized by significant proteinuria (>3.5 g/day), hypoalbuminemia (<3 g/dL), hyperlipidemia, and edema. It results from increased permeability of the glomerular filtration barrier, allowing large proteins such as albumin to be lost in the urine.
Pathophysiology
- Glomerular Filtration Barrier Dysfunction: The glomerulus has a filtration barrier composed of the endothelium, basement membrane, and podocytes. Damage to any component, often due to immune-mediated injury or systemic diseases, leads to increased permeability to plasma proteins, particularly albumin.
- Proteinuria: Loss of large amounts of albumin in the urine leads to decreased oncotic pressure, promoting fluid movement into the interstitial spaces and causing edema.
- Hypoalbuminemia: Persistent urinary protein loss depletes serum albumin levels, leading to decreased plasma oncotic pressure, which further exacerbates edema.
- Hyperlipidemia: Hypoalbuminemia stimulates hepatic lipoprotein synthesis, resulting in increased levels of cholesterol, triglycerides, and low-density lipoprotein (LDL).
- Edema: Sodium and water retention occur due to compensatory activation of the renin-angiotensin-aldosterone system (RAAS) and antidiuretic hormone (ADH), leading to worsening fluid overload.
Etiology
- Primary (Idiopathic) Causes:
- Minimal Change Disease (MCD): The most common cause of nephrotic syndrome in children. Characterized by diffuse effacement of podocyte foot processes on electron microscopy. Responds well to corticosteroids.
- Focal Segmental Glomerulosclerosis (FSGS): Characterized by segmental scarring of the glomeruli. Common in adults, particularly African Americans. Associated with obesity, HIV, and heroin use. May progress to end-stage renal disease (ESRD).
- Membranous Nephropathy (MN): Characterized by immune complex deposition in the glomerular basement membrane. Common in adults and associated with malignancies, infections (e.g., hepatitis B, hepatitis C), and autoimmune conditions (e.g., lupus).
- Secondary Causes:
- Diabetic Nephropathy: The leading cause of nephrotic syndrome in the U.S. Results from hyperglycemia-induced glomerular damage, often progressing to ESRD.
- Lupus Nephritis: An autoimmune disorder associated with systemic lupus erythematosus (SLE) leading to glomerular inflammation and nephrotic syndrome.
- Amyloidosis: Characterized by extracellular deposition of amyloid proteins in organs, including the kidneys, leading to nephrotic-range proteinuria.
- Infections: Chronic infections such as hepatitis B, hepatitis C, and HIV are associated with secondary nephrotic syndrome.
- Drugs: Nonsteroidal anti-inflammatory drugs (NSAIDs), penicillamine, and gold can induce nephrotic syndrome.
Clinical Presentation
- Edema: Often the first presenting symptom, including periorbital swelling, peripheral edema, and ascites. Severe cases may lead to pleural effusion or pulmonary edema.
- Fatigue: Due to loss of muscle mass and protein depletion.
- Frothy Urine: Caused by the presence of large amounts of protein in the urine.
- Weight Gain: Rapid increase in weight due to fluid retention.
- Infections: Increased susceptibility to infections, particularly from encapsulated organisms like Streptococcus pneumoniae, due to urinary loss of immunoglobulins and complement factors.
- Thromboembolism: Increased risk of venous thromboembolism (VTE) due to urinary loss of antithrombin III, protein C, and protein S, combined with a hypercoagulable state caused by increased hepatic synthesis of clotting factors.
- Hyperlipidemia: Patients often present with hypercholesterolemia and hypertriglyceridemia.
Diagnosis
- Urinalysis:
- Proteinuria: Nephrotic-range proteinuria (>3.5 g/day) is the hallmark of nephrotic syndrome.
- Urine Microscopy: May show oval fat bodies (lipid droplets) giving a "Maltese cross" appearance under polarized light.
- Serum Studies:
- Hypoalbuminemia: Serum albumin <3 g/dL due to urinary losses.
- Hyperlipidemia: Elevated total cholesterol, LDL, and triglycerides.
- Renal Function Tests: Serum creatinine may be elevated in advanced disease due to glomerular damage.
- Renal Biopsy:
- Indications: Necessary to confirm the diagnosis and determine the underlying cause, especially in adults.
- Findings:
- Minimal Change Disease: Normal appearance on light microscopy; effacement of foot processes on electron microscopy.
- FSGS: Segmental glomerular scarring.
- Membranous Nephropathy: Diffuse thickening of the glomerular basement membrane due to immune complex deposition.
Complications
- Thromboembolism: Hypercoagulability increases the risk of deep vein thrombosis (DVT) and pulmonary embolism (PE). Renal vein thrombosis is also common in nephrotic syndrome.
- Infections: Loss of immunoglobulins in the urine leads to impaired humoral immunity, increasing the risk of bacterial infections, particularly peritonitis, cellulitis, and respiratory infections.
- Acute Kidney Injury (AKI): Severe intravascular volume depletion due to hypoalbuminemia and third spacing of fluids can lead to prerenal AKI.
- Chronic Kidney Disease (CKD): Persistent nephrotic syndrome may lead to progressive loss of renal function and development of CKD.
Management
- General Management:
- Dietary Modifications: Sodium restriction (<2 g/day) to control edema. Fluid restriction may be necessary in severe edema.
- Diuretics: Loop diuretics (e.g., furosemide) to manage edema. In resistant cases, thiazide diuretics may be added.
- ACE Inhibitors/ARBs: Reduce proteinuria and slow the progression of CKD by decreasing intraglomerular pressure.
- Statins: Used to manage hyperlipidemia, though they may not affect overall mortality in nephrotic syndrome.
- Treatment Based on Etiology:
- Minimal Change Disease: First-line therapy is corticosteroids (e.g., prednisone). Most patients, especially children, respond well.
- FSGS: Treatment includes corticosteroids, but many patients require additional immunosuppressive agents (e.g., calcineurin inhibitors) due to steroid resistance.
- Membranous Nephropathy: Immunosuppressive therapy (e.g., cyclophosphamide, calcineurin inhibitors) is indicated for patients at high risk for progression.
- Diabetic Nephropathy: Strict glycemic control and blood pressure management with ACE inhibitors/ARBs are critical. SGLT2 inhibitors may also slow CKD progression.
- Amyloidosis: Management includes treating the underlying cause (e.g., chemotherapy for light-chain amyloidosis).
- Anticoagulation: Prophylactic anticoagulation may be considered in patients with severe hypoalbuminemia (<2 g/dL) and high risk for VTE. Therapeutic anticoagulation is indicated in patients with confirmed thromboembolism.
Prognosis
- Minimal Change Disease: Excellent prognosis, especially in children, with most responding to corticosteroids. Relapses are common but can usually be controlled with treatment.
- FSGS and Membranous Nephropathy: Variable prognosis. Both can progress to CKD if not adequately managed, particularly in steroid-resistant cases.
- Secondary Causes: Prognosis depends on the underlying condition (e.g., diabetic nephropathy, amyloidosis). Treating the primary disease can improve outcomes but may not reverse renal damage.
Key Points
- Nephrotic syndrome is defined by heavy proteinuria (>3.5 g/day), hypoalbuminemia, edema, and hyperlipidemia.
- Primary causes include minimal change disease, FSGS, and membranous nephropathy, while secondary causes include diabetes, lupus, and amyloidosis.
- Diagnosis is based on urinalysis showing nephrotic-range proteinuria, hypoalbuminemia, and renal biopsy to identify the underlying cause.
- Management includes sodium restriction, diuretics for edema, ACE inhibitors/ARBs to reduce proteinuria, and treatment of the underlying disease.
- Complications include thromboembolism, infections, AKI, and progression to CKD.