Nephritic Syndrome in Children

Overview

Definition

Nephritic syndrome is defined as renal disease caused by immune-mediated inflammation and injury of the glomeruli with classic features of:

• Hematuria
• Proteinuria (subnephrotic range)
• Hypertension
• RBC casts in the urine
• Edema

Epidemiology

• Acute post-streptococcal glomerulonephritis (PSGN):
  • The most common glomerulonephritis (GN) in children
  • Worldwide:
    • > 400,000 cases per year
    • 5,000 deaths annually
    • More common in developing countries
  • Most common between the ages of 2 and 15 years
• Affected demographics depends on the cause:
  • Henoch-Schönlein purpura (HSP) nephritis:
    • Usually affects children < 10 years of age
    • Slightly higher prevalence in boys
  • Lupus nephritis is more common in girls.
  • Alport syndrome predominantly affects boys.

Etiology

Primary (renal) causes of nephritic syndrome in children:

• IgA nephropathy (Berger’s disease)
• Membranoproliferative glomerulonephritis (MPGN) (nephrotic syndrome often also present) 
• Idiopathic crescent GN (rapidly progressive GN)
• Anti-glomerular basement membrane (GBM) or Goodpasture’s disease (rare in children)

Secondary causes of nephritic syndrome in children:

• Post-infectious GN:
  • Post-streptococcal GN
  • May occur with other bacterial (e.g., Staphylococcus aureus), viral (e.g., rubella), and parasitic (e.g., Toxoplasma gondii) infections 
• IgA vasculitis (HSP)
• Alport syndrome
• Lupus nephritis
• Granulomatosis with polyangiitis (formerly Wegener’s granulomatosis)
• Nephritis associated with infective endocarditis

Pathophysiology

• Immune-mediated inflammatory injury to glomeruli leading to basement cell membrane damage by either:
  • Immunoglobulin directly binding to specific antigens within the glomeruli (e.g., Goodpasture’s disease: glomerular basement antigen) 
  • Immune complexes (antigen-antibody) deposited in the glomeruli (e.g., post-infectious/streptococcal GN)
• Cascade of immune-mediated inflammation is triggered, leading to:
  • Complement system activation                        
  • Leukocyte activation                          
• Immune-mediated inflammatory effects:
  • Basement cell membrane damage: impaired glomerular barriers
  • Hematuria: from leakage of RBCs, RBC casts
  • Proteinuria: from leakage of proteins 
  • Hypertension: from salt and water retention, with renin production
  • Edema: from the proteinuria, with salt and water retention
  • Oliguria: decline in glomerular filtration 
• Genetic modifiers play a role in the pathogenesis of some nephritic syndromes.

Clinical Presentation

Signs and symptoms

• Acute GN:
  • Sudden-onset gross/microscopic hematuria
  • Edema (usually mild lower extremity or periorbital edema)
  • Oliguria
  • Hypertension
  • Dull abdominal or flank tenderness
  • Fever (about 50% of the time in acute PSGN)
• Chronic GN:
  • May be asymptomatic and found incidentally on routine urinalysis
  • Hypertension
  • Can have features of nephrotic syndrome or mixed nephritic-nephrotic syndrome
• Rapidly progressive GN:
  • Relatively more rapid progression of acute GN over days or weeks
  • Rare in children
• Recurrent macroscopic hematuria:
  • Can be seen in IgA nephropathy 12–72 hours after a mild upper respiratory infection (URI)
  • Can also be seen in Alport syndrome

Physical exam

• Mild edema in lower extremities
• Periorbital edema
• Scrotal edema
• Abdominal or flank pain
• Palpable purpuric rash seen in HSP with distribution from lower extremities to buttocks

Complications

Patients can also present with manifestations of severe disease:

• Overlap with or progression to nephrotic syndrome
• Hypertensive encephalopathy
• End-stage renal disease (ESRD)
• CKD

Diagnosis

Diagnostic approach

Clinical findings are specific to the underlying causes.

Laboratory data:

• Urine studies:
  • Urinalysis and urine microscopy: hematuria with dysmorphic RBCs and/or RBC casts
  • Proteinuria > 150 mg/day but < 3.5 mg/day in older children and teens
  • Proteinuria defined as between 4 and 40 mg/m²/hr in babies and younger children
  • Sterile pyuria also seen
• Renal function:
  • Elevated BUN
  • Elevated serum creatinine
  • BUN/creatinine ratio > 15
• Complement levels: dependent on underlying cause of nephritis

Imaging (renal ultrasound):

• Detects other causes of hematuria (e.g., stones)
• Shows renal changes, especially of long-standing disease

Disease-specific tests:

• Acute PSGN:
  • Elevated antistreptococcal-O titers
  • Elevated anti-DNase B antibodies
  • Decrease in serum complement C3 due to consumption
• Systemic lupus erythematosus:
  • ANA
  • Anti-double-stranded DNA
• Granulomatosis polyangiitis: 
  • Antineutrophil cytoplasmic autoantibody (ANCA)
  • Pulmonary and sinus investigation with CT 
• Anti-GBM (Goodpasture’s) disease:
  • ANCA
  • Anti-GBM antibodies
  • Pulmonary workup for symptoms of hemoptysis or dyspnea
• MPGN: As this is a pathologic diagnosis with multiple possible etiologies, workup depends on presentation and includes HIV and hepatitis B and C.

Glomerular disease differentiation

• Nephritic and nephrotic syndromes are common presentations of glomerular diseases, which can be a diagnostic challenge.
• Nephritic syndrome is characterized by glomerular inflammation, while the nephrotic type has deranged glomerular capillary walls resulting in increased permeability.
• There are overlapping findings including proteinuria and edema, but the extent differs.
• Additionally, some diseases have a mixed picture: nephritic-nephrotic syndrome
• Knowledge of the differences aids in arriving at the possible diagnoses.

Renal biopsy

• To confirm diagnosis
• To determine extent of renal injury and help direct therapy
• Characteristic features can be seen on histopathology using:
  • Light microscopy: may not be specific, with the same morphologic pattern for several diseases
  • Immunofluorescence microscopy: demonstrates immune complex deposition and pattern, which can be disease specific
  • Electron microscopy: may be useful confirmation tool

Management

Management depends on the cause and severity.

• Initial approach: Treat the underlying cause.
• In cases where renal function is preserved (e.g., IgA nephropathy) or disease self-resolves (e.g., PSGN), monitoring is done and no further intervention is needed.
• Treat throat or skin culture-positive streptococcal infections to eliminate reservoir.
• Symptomatic treatment:
  • Renal insufficiency: 
    • Supportive management and proper hydration
    • Monitor progression. 
  • Hypertension: 
    • Salt/fluid restriction 
    • Antihypertensives for chronic persistent HTN
  • Edema: salt and fluid restriction +/- diuretics
• Corticosteroids and/or immunosuppressive medications if indicated (e.g., lupus nephritis)
• If severe renal insufficiency or kidney failure: renal replacement therapy (e.g., hemodialysis, renal transplantation)

Clinical Relevance

• Systemic lupus erythematosus: chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Deposition of immune complexes in glomerulus leads to lupus nephritis. This condition is more common in Asian and African American females. Renal injury can be mild to progressive GN. Diagnosis is made with renal biopsy.
• Post-streptococcal glomerulonephritis: the most common cause of nephritic syndrome in children, and is preceded by an infection from group A beta-hemolytic streptococcus of the throat or skin. Renal biopsy is usually not needed to establish the diagnosis. The condition is usually self-limited.
• IgA nephropathy: also known as Berger’s disease. Presents as gross or microscopic hematuria shortly after onset of URI symptoms. The disease is characterized by IgA deposition in the mesangium. Berger’s disease is the most common cause of primary glomerulonephritis in most developed countries. 
• HSP: also known as IgA vasculitis. Clinical features include characteristic rash, arthralgias, abdominal pain, and nephritis. The condition can be triggered by an upper respiratory or GI infection. Usually occurs in children < 10 years old. 
• Granulomatosis with polyangiitis: formerly known as Wegener’s granulomatosis. This condition is under the antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) autoimmune disorders, which is characterized by inflammation of small vessels and granuloma formation. Granulomatosis with polyangiitis is associated with crescentic, pauci-immune glomerulonephritis. The ear, nose, and throat area, along with the airways, are also involved.
• Alport syndrome: also known as hereditary nephritis. Alport syndrome is a genetic condition that is commonly X linked and encompasses glomerular disease, sensorineural hearing loss, and abnormal ocular findings. Genetic variants affect collagen IV alpha chains found in impacted target organs (basement membrane of kidney, cochlea, and eye).