Residency · Residency · Pediatrics

Nephrotic Syndrome in Children

Introduction

Nephrotic syndrome is the most common glomerular disease in children, characterized by the classic tetrad of massive proteinuria, hypoalbuminemia, edema, and hyperlipidemia. The annual incidence is approximately 2-7 per 100,000 children, with a peak onset between ages 2 and 6 years. Minimal change disease (MCD) accounts for approximately 80% of cases in children and is typically steroid-responsive. Understanding the pathophysiology, initial management, and long-term complications is essential for every pediatric resident.

Pathophysiology

The glomerular filtration barrier consists of three layers: fenestrated endothelium, glomerular basement membrane (GBM), and podocyte foot processes with slit diaphragms. In nephrotic syndrome, damage to the podocyte and its slit diaphragm leads to loss of the charge-selective and size-selective barrier. Massive urinary protein loss, primarily albumin, leads to hypoalbuminemia. Edema formation has been traditionally attributed to the "underfill" hypothesis, in which low oncotic pressure leads to intravascular volume depletion, triggering RAAS activation and sodium/water retention, though the "overfill" hypothesis (primary renal sodium retention) may contribute in some patients. Hyperlipidemia results from increased hepatic lipoprotein synthesis in response to low oncotic pressure combined with decreased lipoprotein lipase activity reducing lipid clearance. A hypercoagulable state develops from urinary loss of antithrombin III, protein C, protein S, and plasminogen, along with increased hepatic synthesis of procoagulant factors and thrombocytosis.

Clinical Presentation

Edema is the hallmark presentation, beginning as periorbital edema (often first noticed in the morning) and progressing to generalized edema including scrotal or labial edema, ascites, pleural effusions, and anasarca. Weight gain from fluid retention is prominent. Decreased urine output and foamy urine (due to proteinuria) are common. Children typically appear well otherwise, and the absence of hypertension and hematuria supports classic MCD. Patients may present with respiratory distress (pleural effusion) or abdominal discomfort (ascites). Infections, often upper respiratory infections, may trigger the initial presentation or relapses.

<image>Clinical illustration showing the progression of edema in pediatric nephrotic syndrome, from early periorbital puffiness to generalized edema including scrotal/labial swelling, abdominal ascites, and lower extremity pitting edema, alongside a diagram of the glomerular filtration barrier showing normal podocyte foot processes versus effaced foot processes in minimal change disease</image>

Diagnostic Evaluation

Diagnostic Criteria

Proteinuria in the nephrotic range is defined as a urine protein-to-creatinine ratio (UPC) greater than 2 mg/mg, 24-hour urine protein greater than 50 mg/kg/day, or urine dipstick 3+ or greater. Hypoalbuminemia is defined as serum albumin less than 2.5 g/dL. Clinically apparent edema is present. Hyperlipidemia with elevated total cholesterol, LDL, and triglycerides is supportive but not required for diagnosis.

Initial Laboratory Workup

Serum studies include albumin, total protein, BUN, creatinine, electrolytes, lipid panel, and complement levels (C3, C4). Urine studies include urinalysis (proteinuria, evaluation for hematuria and casts), UPC ratio, and microscopy. CBC may show hemoconcentration and thrombocytosis. Serology for hepatitis B/C, HIV, ANA, and anti-dsDNA should be considered if atypical features are present. Complement levels are normal in MCD; low C3 suggests MPGN, post-infectious GN, or lupus nephritis.

When to Suspect Non-MCD Etiology

Features that suggest an etiology other than MCD include age under 1 year or over 12 years at onset, gross hematuria, persistent microscopic hematuria, or RBC casts, hypertension at presentation, low serum complement levels, renal insufficiency (elevated creatinine) at presentation, and steroid resistance (failure to remit after 4-6 weeks of daily corticosteroids). These features warrant renal biopsy.

Management

Initial Treatment: Corticosteroid Therapy

Prednisone or prednisolone is given at 60 mg/m2/day (maximum 60 mg) for 4-6 weeks, followed by 40 mg/m2 on alternate days for 4-6 weeks, then tapered. KDIGO 2021 guidelines recommend a minimum initial course of 12 weeks. Steroid-sensitive nephrotic syndrome (SSNS), defined as complete remission (UPC less than 0.2 or urine dipstick trace/negative for 3 consecutive days) within 4 weeks of daily steroids, accounts for approximately 80-90% of pediatric cases. Steroid-resistant nephrotic syndrome (SRNS), defined as failure to achieve remission after 4-6 weeks of adequate daily steroid therapy, requires renal biopsy and alternative immunosuppression.

Relapse Management

A relapse is defined as UPC greater than 2 or urine dipstick 3+ or greater for 3 consecutive days after previous remission. Infrequent relapses (fewer than 2 in 6 months or fewer than 4 in 12 months) are treated with prednisone 60 mg/m2/day until remission for 3 days, then 40 mg/m2 alternate days for 4 weeks. Frequently relapsing (FRNS) or steroid-dependent nephrotic syndrome (SDNS) warrants steroid-sparing agents.

Steroid-Sparing Agents

Cyclophosphamide at 2 mg/kg/day for 8-12 weeks can induce sustained remission in 60-70% of FRNS, though the risk of gonadal toxicity is cumulative dose-dependent. Calcineurin inhibitors (cyclosporine, tacrolimus) are effective for FRNS, SDNS, and some SRNS but require drug level monitoring and carry a risk of nephrotoxicity with prolonged use. Mycophenolate mofetil (MMF) is an alternative steroid-sparing agent with fewer side effects but a high relapse rate after discontinuation. Rituximab, an anti-CD20 monoclonal antibody, is increasingly used for multiply-relapsing or steroid-dependent disease and can achieve sustained remission off immunosuppression. Levamisole is an immunomodulator used as a steroid-sparing agent in some centers with limited availability.

Supportive Care

Dietary sodium restriction (less than 2 g/day) during active disease is recommended. Fluid restriction is generally not needed unless symptomatic hyponatremia is present. Albumin infusion (1 g/kg over 4-6 hours) with concurrent IV furosemide (1-2 mg/kg) is used for severe symptomatic edema, respiratory compromise, or skin breakdown. Diuretics should be used cautiously, as patients may be intravascularly depleted despite edema; furosemide (1-2 mg/kg) with spironolactone (1-2 mg/kg) is a common approach.

<image>Treatment algorithm flowchart for pediatric nephrotic syndrome showing the initial corticosteroid regimen, assessment of steroid responsiveness at 4-6 weeks, pathways for steroid-sensitive disease (infrequent relapse vs. frequent relapse vs. steroid-dependent), and steroid-resistant disease leading to renal biopsy and second-line immunosuppressive options including calcineurin inhibitors, mycophenolate mofetil, cyclophosphamide, and rituximab</image>

Complications

Infections

Infections are the leading cause of morbidity in nephrotic syndrome. Increased susceptibility results from urinary loss of immunoglobulins (especially IgG), complement factors, and impaired T-cell function from steroid use. Spontaneous bacterial peritonitis (SBP), most commonly caused by Streptococcus pneumoniae or E. coli, should be suspected when a child with ascites develops fever and abdominal pain, and paracentesis should be performed. Pneumococcal vaccination is strongly recommended and should be administered during remission if possible. Varicella is potentially life-threatening in immunosuppressed children; the vaccine should be given during remission, VZIG provided within 96 hours of exposure, and active infection treated with IV acyclovir.

Thromboembolism

There is an increased risk of venous thromboembolism including renal vein thrombosis, deep vein thrombosis, pulmonary embolism, and cerebral venous sinus thrombosis. Risk is higher with severe hypoalbuminemia (less than 2 g/dL), central venous catheters, immobility, and hemoconcentration. Prophylactic anticoagulation is not routinely recommended but should be considered in high-risk situations.

Acute Kidney Injury

AKI may occur from intravascular volume depletion, thrombotic events, or sepsis, and renal function should be monitored closely during active disease.

Clinical Pearls

Minimal change disease accounts for approximately 80% of childhood nephrotic syndrome and has an excellent prognosis with steroid therapy. Periorbital edema, especially in the morning, should prompt urinalysis to screen for proteinuria. Normal complement levels and absence of hematuria support the diagnosis of MCD, while atypical features warrant renal biopsy. Steroid response is the most important prognostic indicator, as steroid-sensitive disease has a favorable long-term renal outcome. Infections (especially pneumococcal) and thromboembolism are the major complications, so pneumococcal vaccination and vigilance for peritonitis are essential. Families should be educated on home urine monitoring with dipstick testing for early detection of relapses.

References

1. Noone DG, Iijima K, Parekh R. Idiopathic nephrotic syndrome in children. Lancet. 2018;392(10141):61-74.
2. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney International. 2021;100(4S):S1-S276.
3. Eddy AA, Symons JM. Nephrotic syndrome in childhood. Lancet. 2003;362(9384):629-639.
4. Iijima K, Sako M, Nozu K, et al. Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet. 2014;384(9950):1273-1281.

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