Renal · Glomerular Diseases
The facts most likely to be tested
Nephrotic syndrome is defined by heavy proteinuria (>3.5 g/day), hypoalbuminemia, peripheral edema, and hyperlipidemia.
Minimal change disease is the most common cause of nephrotic syndrome in children and typically presents with effacement of podocyte foot processes on electron microscopy.
Focal segmental glomerulosclerosis (FSGS) is the most common cause of nephrotic syndrome in African American adults and is strongly associated with HIV, heroin use, and obesity.
Membranous nephropathy is the most common cause of nephrotic syndrome in Caucasian adults and is associated with solid organ malignancies, SLE, and hepatitis B.
Patients with nephrotic syndrome are at high risk for thromboembolism due to the urinary loss of antithrombin III.
Diabetic nephropathy is the most common cause of nephrotic syndrome worldwide and is characterized by Kimmelstiel-Wilson nodules on biopsy.
The initial management for all patients with nephrotic syndrome includes ACE inhibitors or ARBs to reduce proteinuria and slow the progression of renal disease.
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A 54-year-old male presents to the clinic with a two-week history of progressive bilateral lower extremity edema and periorbital swelling. Laboratory studies reveal a serum albumin of 2.2 g/dL, a total cholesterol of 310 mg/dL, and a 24-hour urine protein collection showing 4.5 g of protein. His medical history is significant for adenocarcinoma of the lung diagnosed six months ago. A renal biopsy is performed, showing thickened glomerular basement membranes with subepithelial spikes on silver stain.
What is the most likely diagnosis?
Membranous nephropathy
The patient's presentation of nephrotic syndrome combined with the classic biopsy finding of subepithelial spikes (spike and dome pattern) is pathognomonic for membranous nephropathy, which is frequently secondary to solid organ malignancies.
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High yield triage
Etiology / Epidemiology
Primary causes include Minimal Change Disease (children) and Focal Segmental Glomerulosclerosis (adults). Secondary causes include Diabetes Mellitus and SLE.
Clinical Manifestations
Classic triad: proteinuria >3.5g/24h, hypoalbuminemia, and peripheral edema. Oval fat bodies in urine are pathognomonic.
Diagnosis
24-hour urine collection is the gold standard. Renal biopsy is required for definitive histological diagnosis in adults.
Treatment
ACE inhibitors or ARBs are first-line to reduce proteinuria. Diuretics manage edema; corticosteroids for specific primary etiologies.
Prognosis
High risk of thromboembolism due to loss of Antithrombin III. Monitor for hyperlipidemia and infection.
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Epidemiology & Etiology
Primary nephrotic syndrome is often idiopathic, while secondary causes are driven by systemic disease. Diabetes mellitus remains the most common cause of nephrotic-range proteinuria globally. Minimal change disease is the most frequent cause in pediatric patients, often following viral infections.
Pertinent Anatomy
The glomerular basement membrane and podocyte foot processes are the primary sites of injury. Disruption of the slit diaphragm leads to massive protein leakage. Loss of structural integrity allows large proteins like albumin to cross into the urinary space.
Pathophysiology
Increased glomerular permeability leads to massive proteinuria, causing a compensatory decrease in hepatic albumin synthesis. Low oncotic pressure results in fluid extravasation into the interstitial space, manifesting as edema. The liver attempts to compensate for low oncotic pressure by increasing lipoprotein synthesis, leading to hyperlipidemia.
Clinical Manifestations
Patients present with pitting edema, often periorbital or scrotal. Urine microscopy reveals oval fat bodies with a Maltese cross appearance under polarized light. Hypercoagulability is a major concern due to urinary loss of Antithrombin III, increasing risk for renal vein thrombosis.
Diagnosis
The 24-hour urine collection is the gold standard for quantifying protein excretion, with a threshold of >3.5g/24h. A spot urine protein/creatinine ratio is a reliable screening alternative. Renal biopsy is indicated in adults to differentiate between Minimal Change Disease, FSGS, and Membranous Nephropathy.
Treatment
ACE inhibitors or ARBs are the first-line therapy to decrease intraglomerular pressure and proteinuria. Loop diuretics are used for symptomatic edema, but avoid aggressive diuresis to prevent hypovolemia. Corticosteroids are the treatment of choice for Minimal Change Disease.
Prognosis
Patients are at high risk for thromboembolism and infection due to loss of immunoglobulins. Long-term management requires monitoring for hyperlipidemia and progression to end-stage renal disease. Statins are often required to manage the secondary hyperlipidemia.
Differential Diagnosis
Nephritic Syndrome: hematuria and RBC casts
Congestive Heart Failure: elevated BNP and JVD
Cirrhosis: hypoalbuminemia without massive proteinuria
Acute Tubular Necrosis: muddy brown casts and history of ischemia
Diabetic Nephropathy: history of long-standing hyperglycemia