Nephrotic Syndrome in Children

Overview

Definition

Nephrotic syndrome is a renal disorder characterized by increased permeability of the glomerular filtration barriers significantly leading to severe proteinuria.

Classic features include:

• Nephrotic-range proteinuria of > 40 mg/m²/hour
• Hypoalbuminemia, often < 2.5 g/dL
• Elevated cholesterol and triglycerides
• Edema

Epidemiology

• Occurs at any age but more commonly seen in school-aged children and adolescents
• Worldwide incidence 16 cases per 100,000 children
• Male > female (2:1) in younger children but evens out in adolescence
• 90% of cases in children are due to primary causes (e.g., minimal change disease (MCD)).
• Higher incidence of chronic glomerular disease in children ≥ 12 years of age

Classification

Different general classification systems can overlap:

• Based on onset in those ≤ 1 year of age:
  • Congenital (< 3 months of age)
  • Infantile (3 months to 1 year of age)
• Based on presence of systemic disease or underlying process:
  • Primary nephrotic syndrome (includes idiopathic)
  • Secondary nephrotic syndrome

Idiopathic nephrotic syndrome is further classified on the basis of steroid responsiveness:

• Steroid-responsive (majority of cases)
• Steroid-resistant 
• Steroid-dependent

Etiology

Congenital/infantile:

• Denys–Drash syndrome (associated with high risk for Wilms’ tumor)
• Congenital nephrotic syndrome of the Finnish type (autosomal recessive)
• Autosomal recessive familial focal segmental glomerulosclerosis (FSGS)
• Autosomal dominant FSGS
• Frasier syndrome
• Diffuse mesangial sclerosis
• Nail–patella syndrome
• Pierson syndrome
• Schimke immuno-osseous dysplasia
• Nongenetic causes (also classified as secondary): 
  • Congenital syphilis
  • Congenital toxoplasmosis
  • Other: cytomegalovirus, HIV

Primary (90% idiopathic):

• MCD: most common presentation and histologic finding of nephrotic syndrome in school-aged children
• FSGS
• Mesangial proliferation
• Membranoproliferative glomerulonephritis (MPGN)
• Membranous nephropathy (rare in children)

Secondary:

• Diseases or conditions:
  • Systemic lupus erythematosus (can be nephritic or nephrotic)
  • Henoch–Schönlein purpura  (can be nephritic or nephrotic)
  • Amyloidosis
  • IgA nephropathy (more often nephritic)
  • Lymphoma
  • Diabetes mellitus
• Medications, such as NSAIDs
• Infections:
  • Poststreptococcal glomerulonephritis (PSGN; can be nephritic or nephrotic)
  • Hepatitis B
  • Hepatitis C
  • HIV
  • Malaria
• Renal scarring

Pathophysiology

The structure of the glomerulus creates a filtration system, the glomerular filtration barrier, composed of:

• Fenestrated endothelium
• Glomerular basement membrane (GBM)
• Epithelial layer:
  • Podocytes and foot processes
  • Filtration slits
  • Slit diaphragm

Under normal circumstances, the passage of proteins across the glomerular filtration barrier is controlled by their size or charge.

• Size of the molecules:
  • Barrier is permeable only to water, small proteins, and ions.
  • Proteins with high molecular weight cannot cross the GBM.
• Charge of the molecules:  
  • The GBM is negatively charged owing to the presence of polyanions, such as heparan sulfate proteoglycans.
  • Anions such as albumin are repelled.

Genetic or immune-mediated factors lead to:

• Structural or functional damage to components of the glomerular filtration barrier such as the podocytes
• Loss of negative charge enables the filtration of anions such as albumin
• Increased permeability of the membrane 
• Subsequent loss of proteins from plasma into the urinary space

Effects:

• Heavy proteinuria → loss of albumin (hypoalbuminemia) → ↓ intravascular osmotic pressure → edema
• ↑ Hepatic lipogenesis (a nonspecific response to hypoalbuminemia) + abnormal regulatory enzymes → hyperlipidemia
• Loss of endogenous anticoagulants (antithrombin III) → thrombotic and thromboembolic complications
• Loss of immunoglobulins → increased risk for infections, especially from encapsulated bacteria

Clinical Presentation

• Edema:
  • Pitting
  • Gravity-dependent:
    • Starts with periorbital edema (which decreases during the day)
    • Lower-extremity edema then noted during the day
    • When reclining, back and sacral edema are noted.
  • Often sudden onset after a recent illness such as an upper respiratory infection
• Dyspnea due to:
  • Pleural effusion
  • Ascites
  • Pneumonia
  • Pulmonary embolism
• Nonspecific: headache, fatigue, irritability, abdominal pain
• May present with hematuria (mixed nephritic and nephrotic syndrome)
• May have hypertension
• May present with complications:
  • Infections (due to impaired immune response)
  • Thromboembolic event (due to hypercoagulable state)

Diagnosis

Urine studies

• 24-hour urine collection (gold standard): 
  • Protein quantification
  • Nephrotic syndrome is protein excretion > 40 mg/m²/hour (> 50 mg/kg/day).
• First morning spot urine protein/urine creatinine ratio:  
  • Useful in children in whom a timed 24-hour collection is not always possible
  • Persistent proteinuria: 
    • Defined as spot urine protein/creatinine ratio of > 0.2 mg/mg (> 0.5 for children 6 to 24 months of age) noted on several occasions
    • Requires further evaluation to determine any underlying renal pathology
  • Nephrotic syndrome is urine protein/creatinine ratio of > 2 mg/mg. 
• Urinalysis:
  • Dipstick urine protein:
    • 3+ (consistent with > 300 mg/dL)
    • 4+ (consistent with > 2000 mg/dL)
  • Fatty casts (“Maltese cross” under polarized light)
  • Hematuria (RBCs) or RBC casts in mixed nephritic–nephrotic syndrome

Additional tests

• CMP:
  • Electrolytes:
    • Often normal
    • Hyponatremia may occur owing to underlying condition, inappropriate antidiuretic hormone release, or aggressive diuretic therapy.
    • Calcium may be low owing to hypoalbuminemia, but ionized calcium is usually normal.
  • BUN/creatinine:
    • May be normal
    • May be elevated in renal insufficiency
  • Serum albumin < 2.5 g/dL
• Hypogammaglobulinemia
• Elevated cholesterol and triglycerides
• Complement levels (C3, C4)
• Other effects from low binding proteins:
  • Decreased vitamin D (due to reduced vitamin D–binding protein)
  • Reduced thyroxine (due to decreased thyroid-binding protein)
• Disease-specific tests:
  • PSGN:
    • Elevated antistreptolysin O (ASO) titers
    • Elevated anti DNase B antibodies
    • Decrease in serum complement C3 due to consumption
  • Systemic lupus erythematosus:
    • ANA
    • Anti–double-stranded DNA (dsDNA)
  • Diabetes mellitus: fasting glucose, glycosylated hemoglobin (A1c)
  • Additional: HIV (membranoproliferative glomerulonephritis (MPGN), FSGS); hepatitis B and C (MPGN); serologic test for syphilis
• Genetic testing if steroid-resistant or < 1 year of age
• Imaging: renal ultrasound to determine size and exclude obstructive causes

Glomerular disease differentiation

• Nephritic and nephrotic syndromes are common presentations of glomerular diseases that 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 aid in arriving at the possible diagnoses.

Biopsy

• Often not necessary to establish diagnosis
• Indications:
  • < 1 year of age or > 10–12 years of age at onset
  • No response to steroids (steroid-resistant)
  • Relapse with steroid taper (steroid-dependent)
  • History and other findings suggest secondary nephrotic syndrome or primary nephrotic syndrome other than minimal change disease.
  • Family history of kidney disease

Management

Treatment approach

• As the majority of pediatric nephrotic cases are due to MCD (which is often steroid-responsive), steroid treatment is initiated even without biopsy in the following cases:
  • Patients 1–12 years of age
  • History and findings not suggestive of systemic disease
  • Normal kidney function
  • No macroscopic hematuria
  • Normal complement levels
  • Negative viral tests: active or latent infection ruled out
  • No family history of kidney disease
• Additionally, FSGS responds to steroids in 10%–20% of cases.

Immunosuppressive treatment

• Steroids: need to rule out active or latent infection before initiation
• Steroid responses:
  • Steroid-sensitive: 
    • Remission (disappearance of proteinuria) with 4–8 weeks of treatment
    • Seen in majority of pediatric patients
  • Steroid-resistant: 
    • No remission after completion of steroid treatment
    • Additional evaluation: biopsy and genetic testing
  • Steroid-dependent: 
    • Experience relapse during tapering
    • Reinitiation of steroids required (longer course)
• 2nd-line agents:
  • Given if there are major steroid side effects (e.g., cushingoid features, excess weight, psychiatric disturbances, cataracts)
  • Options:
    • Mycophenolate mofetil
    • Cyclosporine
    • Tacrolimus
    • Levamisole (not available in the United States)
    • Cyclophosphamide (has serious side effects)

Additional management

• Edema:
  • Salt restriction
  • Diuretic therapy: often furosemide
  • In anasarca/severe edema/pleural effusion: furosemide + albumin 
• Hypercoagulable state:
  • Encourage regular ambulation.
  • Avoid volume depletion (to reduce risk of hemoconcentration).
  • Anticoagulation prophylaxis is not proven.
  • Venous thromboembolism is treated with low-molecular-weight heparin and then warfarin.
• Risk of infection:
  • Risk of encapsulated bacteria such as Streptococcus pneumoniae: Vaccinate children ≥ 2 years of age with 23-valent pneumococcal vaccine.
  • Annual inactivated influenza vaccination
  • Avoid live vaccine while on immunosuppressive treatment (or in relapse).
  • High index of suspicion if there are signs of infection
• Hypertension:
  • Diuretics may control blood pressure.
  • ACE inhibitors or angiotensin II receptor blockers (ARBs):
    • Decrease proteinuria
    • Caution in setting of volume depletion (may worsen kidney function)
  • Calcium channel blockers may also be used. 
• Transplantation can be curative in some cases (e.g., Finnish-type congenital nephrotic syndrome).

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 manifestations include nephritic or nephrotic syndrome, gross or microscopic hematuria, and/or chronic renal failure. Diagnosis is made with renal biopsy.
• Poststreptococcal glomerulonephritis: renal disorder in children preceded by an infection with group A beta-hemolytic streptococcus of the throat or skin: PSGN commonly presents as a nephritic syndrome, but nephrotic syndrome occurs in 5% of cases. Renal biopsy is typically not needed to establish diagnosis. The condition is usually self-limited.
• Henoch-Schönlein purpura (HSP): also known as IgA vasculitis: Clinical features include characteristic rash, arthralgias, abdominal pain, and nephritis.  This IgA-mediated glomerulonephritis can be triggered by an upper respiratory or GI infection. HSP usually occurs in children < 10 years old. This condition can also present as nephritic syndrome.
• Amyloidosis: a pathologic extracellular tissue deposition of fibrils composed of various misfolded low-molecular-weight protein subunits: Misfolded proteins deposit in various tissues, interfere with normal organ functions, and cause tissue-specific disease (e.g., renal amyloidosis). Manifestations for renal disease range from mild proteinuria to frank nephrosis. Diagnosis is established with renal biopsy. Dialysis or transplantation improves prognosis.
• Congenital and infantile nephrotic syndrome: affect children < 1 year of age: Mutations that lead to nephrotic syndrome include NPHS1, NPHS2, NPHS3, LAMB2, and WT1. NPHS1 (encodes nephrin and mutation causes Finnish-type congenital nephrotic syndrome) and NPHS2 (encodes podocin and mutation leads to familial FSGS) are the most frequent genes affected (95% of cases). These disorders are not responsive to steroid or other immunosuppressive therapy, and workup should include genetic testing.