What is nephrotic syndrome in pediatric patients?

What is Nephrotic Syndrome in Pediatric Patients?

Nephrotic syndrome is a glomerular disorder characterized by the tetrad of heavy proteinuria (≥40 mg/h/m² or first morning urine protein-to-creatinine ratio ≥2 g/g), hypoalbuminemia (serum albumin ≤2.5 g/dL), edema, and hyperlipidemia, resulting from increased glomerular permeability to proteins due to podocyte dysfunction. 1

Core Diagnostic Features

The diagnosis requires documentation of all four cardinal features:

• Proteinuria: In children, this is defined as ≥40 mg/h/m² or first morning UPCR of ≥2 g/g, which is substantially higher than the normal ratio of 0.2 g/g 2, 1
• Hypoalbuminemia: Serum albumin ≤2.5 g/dL in children (compared to <3.0 g/dL in adults), with the lower threshold reflecting pediatric-specific criteria 1
• Edema: Typically presents as periorbital swelling (most noticeable in the morning) or dependent pitting edema in the legs and generalized body swelling 3, 4
• Hyperlipidemia: Occurs as a compensatory hepatic response to protein losses, with elevated cholesterol and triglycerides 5, 6

Pathophysiological Mechanism

The primary defect involves podocyte dysfunction leading to loss of the glomerular filtration barrier's integrity:

• A T-cell-driven circulating "glomerular permeability factor" interferes with glomerular permselectivity to albumin, particularly in minimal change disease and focal segmental glomerulosclerosis 5
• Loss of albumin decreases oncotic pressure, causing fluid shift from intravascular to interstitial spaces, producing edema 5
• The liver increases unselective protein synthesis to compensate for urinary losses, resulting in hyperlipidemia and increased production of prothrombotic factors 7
• Beyond albumin, children lose immunoglobulins, complement factors, anticoagulant proteins, and binding proteins for vitamins and hormones in their urine 5, 7

Common Causes in Children

Minimal change disease is the most common primary glomerular disease in children, particularly those under 12 years of age 1, 8:

• Idiopathic minimal change disease: Accounts for the majority of cases in young children, characterized by normal-appearing glomeruli on light microscopy but diffuse foot process effacement on electron microscopy 5, 6
• Focal segmental glomerulosclerosis (FSGS): The second most common idiopathic cause, which can be primary, genetic, secondary, or of undetermined cause 5, 6
• Genetic disorders: Congenital nephrotic syndrome results from genetic defects in podocytes, with common mutations including NPHS1, NPHS2, WT1, and PLCE1 5
• Secondary causes: Include infections (particularly in HIV-infected children where 15 of 164 pediatric AIDS patients developed nephrotic syndrome in one cohort), drugs, systemic diseases, and history of prematurity leading to reduced nephron number 2, 5, 8

Clinical Presentation

Children typically present with:

• Periorbital edema and generalized body swelling, often accompanied by decreased urine output 3
• The degree of proteinuria may vary from minimal to nephrotic-range, with 15 pediatric patients in one series presenting with nephrotic-range proteinuria 2
• Some children may have hematuria in addition to proteinuria, or develop complications like renal tubular acidosis 2
• Ultrasound may show echogenic kidneys that are large for the patient's age and height, though findings can be normal 2

Serious Complications

Nephrotic syndrome carries significant morbidity risks that require vigilant monitoring:

• Thromboembolism: 29% risk for renal vein thrombosis and 17-28% risk for pulmonary embolism due to loss of anticoagulant proteins, with risk particularly elevated when albumin falls below 2.9 g/dL 5, 1
• Infections: Increased susceptibility results from loss of immunoglobulins and complement factors in urine 5, 8
• Progressive kidney disease: Patients with proteinuria >3.8 g/day have a 35% risk of end-stage renal disease within 2 years 5
• Accelerated coronary heart disease: Four times greater risk due to severe hypercholesterolemia and metabolic complications 1

Diagnostic Evaluation in Children

For children under 12 years, kidney biopsy is not routinely performed at initial presentation, as minimal change disease is presumed and treatment with glucocorticoids is initiated empirically 1, 6:

• Measure serum albumin, complete metabolic panel including total protein, and lipid profile 2, 1
• Perform serological testing for hepatitis B, C3, C4, and antinuclear antibody if systemic disease is suspected 2
• Obtain renal ultrasound to assess kidney echogenicity and size 2, 1
• Kidney biopsy is indicated only for: children ≥12 years, steroid-resistant cases, frequent relapses with severe hypoalbuminemia, or atypical presentations 9, 1
• Consider genetic testing in cases with family history, early onset, syndromic features, or steroid resistance 5, 1

Initial Management Approach

The Kidney International recommends treating the initial episode with oral prednisone at 60 mg/m² per day until remission, then decreasing to 40 mg/m² per day on alternate days for 1 week, and tapering by 10 mg/m² per week to complete a total of 4 weeks 9:

• Steroid-responsiveness is of greater prognostic value than renal histology, with most steroid-responsive patients having a chronic relapsing course 8
• If the child improves with steroid treatment, no biopsy is needed; if no improvement occurs, genetic testing and kidney biopsy are warranted 6
• Albumin infusion should be considered only if there are clinical indicators of hypovolemia (not based solely on low albumin level), with furosemide administered at the end of infusion to enhance diuresis 9
• Supportive care includes dietary sodium restriction, edema management with diuretics (furosemide), and blood pressure control with ACE inhibitors like enalapril 3, 1