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Image: “The Test Urine Container Urine Inflammation” by frolicsomepl. License: Public Domain


Definition

Nephrotic syndrome in children is characterized by nephrotic-range proteinuria (urine protein loss of 2–3 g/day). It is accompanied by hypoalbuminemia (low levels of albumin) and hyperlipidemia. Hyperlipidemia represents disordered lipid metabolism with an increase in the triglyceride levels in the blood.

Epidemiology of Childhood Nephrotic Syndrome

Nephrotic syndrome can present at any age; however, in children, it mostly occurs between 3–9 years of age. Boys < 8 years of age are more affected by the disease than girls at this age, although the disease shows an equal incidence in both genders in older children, adolescents, and adults. The global incidence of pediatric nephrotic syndrome is 2–7/100000 children. Congenital nephrotic syndrome presents in infants < 3 months of age.

Etiology of Childhood Nephrotic Syndrome

The etiology of pediatric nephrotic syndrome can be highlighted as follows:

Primary (idiopathic) nephrotic syndrome

  • Minimal change nephrotic syndrome (MCNS, minimal change disease) is the most common cause of primary nephrotic syndrome accounting for > 90% of cases in children < 10 years of age and in > 50% of the cases in children > 10 years of age
  • Focal segmental glomerulosclerosis (FSGS)
  • Membranous nephropathy (MN) is more common in adults

Secondary nephrotic syndrome

  • Infections/post-infectious: Hepatitis B [leading to MN or membranoproliferative glomerulonephritis (MPGN)], hepatitis C, human immunodeficiency virus (HIV)-1, toxoplasmosis, syphilis, malaria, shunt nephritis, acute post-streptococcal glomerulonephritis
  • Autoimmune disorders: Systemic lupus erythematosus (MN), renal vasculitis (microscopic polyangiitis; rarely Wegener’s granulomatosis), anti-GBM nephritis
  • Immunological disorders: Castleman disease, Kimura disease, bee sting, food allergens
  • Hematological disorders: Sickle cell disease, lymphoma, leukemia
  • Penicillamine, drugs containing gold or lithium salts, non-steroidal anti-inflammatory drugs (NSAIDs), heroin, pamidronate, mercury, and interferon
  • Henoch-Schönlein purpura (HSP)
  • Atypical hemolytic-uremic syndrome (HUS)
  • IgA nephropathy (Berger disease)
  • Amyloidosis: Secondary to chronic juvenile arthritis, Crohn’s disease, tuberculosis, bronchiectasis, chronic osteomyelitis, cystic fibrosis, familial Mediterranean fever

Genetic disorders

  • Alport syndrome: Mutations in the COL4A5, COL4A3, or COL4A4 genes
  • Nail-patella syndrome (osteo-onychodysplasia): Mutations in the LMX1B gene on chromosome 9
  • Finnish-type congenital nephrotic syndrome (autosomal recessive): mutations in nephrin (NPHS1)
  • FSGS: Mutations in podocin (NPHS2), α-actinin-4 (ACTN4), or TRPC6
  • Diffuse mesangial sclerosis: Mutations in the laminin β2 chain
  • Denys-Drash syndrome: Mutations in the WT1 gene

Pathophysiology of Childhood Nephrotic Syndrome

The glomerular filtration barrier (GFB) is composed of fenestrated endothelial cells, glomerular basement membrane (GBM), and epithelial cells (podocytes) with their foot processes. A thin membrane, called a slit diaphragm, closes the pores between the foot processes. The GBM prevents albumin from being filtered out into the urine.

Edema

The pathogenesis of edema can be explained by the underfill hypothesis (decreased intravascular oncotic pressure, movement of fluid into interstitial spaces, and edema) and the overfill hypothesis (proteinuria, sodium retention, fluid retention, and edema).

Hyperlipidemia

Hyperlipidemia is caused by the stimulation of hepatic lipoprotein synthesis due to hypoalbuminemia and decreased lipid catabolism due to the urinary loss of lipoprotein lipase.

The hypercoagulable state is produced due to the following factors:

  • Increased hepatic production of fibrinogen and clotting factors V, VII, VIII, and X
  • Decreased anticoagulant levels (antithrombin III, heparin cofactor, and factors XI and XII)
  • Thrombocytosis
  • Increased platelet aggregation
  • Vascular stasis
  • Prolonged immobilization
  • Hypovolemia
  • Infections

The susceptibility to infections is increased owing to a loss of immunoglobulins, complement factor C3b, and properdin factor B in the urine, as well as immunosuppressive therapy.

MCNS

The proposed hypothesis for the pathogenesis of idiopathic nephrotic syndrome is that the condition is caused by MCNS, including T-cell dysfunction, which causes increased permeability of GFB or immune dysfunction. This leads to the release of circulating factors (e.g., soluble urokinase plasminogen activator receptor), which affects podocyte structure and function.

Light microscopy evaluation of renal biopsy samples shows no change in MCNS; however, electron microscopy reveals the effacement of podocytes. Other than insignificant IgM deposits, an immunofluorescence examination shows no deposits of immunoglobulin or complement components.

FSGS

FSGS is characterized by focal and segmental areas of sclerosis with the presence of other normal glomeruli.

MN

In MN, diffuse thickening of capillary walls (due to IgG-containing immune deposits on the epithelial side of GBM) is a characteristic feature.

MPGN

More than half of the patients with MPGN have autoantibodies (nephritic factors) that activate C3 convertase. Thickening of the capillary walls (due to a subendothelial extension of the mesangium), increased mesangial matrix, and mesangial hypercellularity are features of MPGN.

MPGN type I is most common and characterized by subendothelial deposits due to the activation of the classical complement pathway. MPGN type II is also called dense deposit disease and accounts for 10–20% of all cases. It is associated with partial lipodystrophy and characterized by intramembranous deposits due to the activation of the alternate complement pathway. MPGN type III is the least common (< 5%) and characterized by subepithelial and subendothelial deposits.

IgA nephropathy is characterized by the presence of mesangial deposits (mainly IgA > IgG and C3) and mesangial hypercellularity. FSGS, endocapillary glomerulonephritis, or extracapillary glomerulonephritis may also be present.

Symptoms of Childhood Nephrotic Syndrome

Pitting edema is the most common symptom. Initially, edema is periorbital, i.e. observed only in the eyelids and more marked in the mornings. It later progresses to other areas (feet, genitalia, etc.) and may cause ascites or anasarca.

The child may experience abdominal pain due to ascites and may present with complications including the following:

  • Severe hypovolemia
  • Peritonitis
  • Venous thrombosis
  • Steroid-induced gastritis
  • Pancreatitis

Hematuria is rare in MCNS, but microscopic hematuria may be present in 20% of cases. Macroscopic hematuria is present in 60–80% of the cases of FSGS, MN, and MPGN.

Alport syndrome is characterized by progressive nephritis with sensorineural hearing loss. Hematuria is always present in Alport syndrome. The presence of proteinuria or nephrotic syndrome and Alport syndrome suggests a poor prognosis.

Nail-patella syndrome is an autosomal dominant disorder characterized by dystrophic nails, hypoplastic or absent patella, and renal manifestations like proteinuria, nephrotic syndrome, and hematuria.

Complications of Childhood Nephrotic Syndrome

  1. Hypovolemia can be precipitated by a loss of intravascular volume, the use of diuretics, sepsis, or diarrhea. It presents with abdominal pain, hypotension, cold extremities, and raised hematocrit.
  2. Acute renal failure may occur in nephrotic syndrome due to hypovolemia, bilateral renal vein thrombosis, and the aggressive use of diuretics, drug-induced interstitial nephritis, or severe histologic lesions. In minimal change disease, it is usually reversible with appropriate management.
  3. The most common infection caused due to nephrotic syndrome is peritonitis. Other infections include meningitis, pneumonitis, cellulitis, and sepsis. The most common causative organism is Streptococcus pneumoniae. Bacterial infections caused by Group B streptococci, H. influenzaeE. coli, and other Gram-negative organisms are also common. Varicella is of concern, especially in immunosuppressed patients.
  4. Thromboembolic complications (generally 3%) include the following:
  • Pulmonary embolism
  • Renal vein thrombosis
  • Deep vein thrombosis
  • Sagital sinus thrombosis
  • Arterial thrombosis (rare)
  1. Urinary loss of vitamin D-binding protein may lead to a deficiency of vitamin D.
  2. Hypothyroidism due to a loss of thyroid-binding globulin is rare.

Diagnosis of Childhood Nephrotic Syndrome

  1. Urinalysis
    • Nephrotic-range proteinuria is an important indicator in the diagnosis of nephrotic syndrome. Urinary protein excretion > 50 mg/kg/day or > 40 mg/m2/h, first-morning urine (FMU) protein:creatinine ratio > 2:1, or dipstick urinalysis > 3+ or 4+ proteinuria is suggestive of nephrotic range proteinuria.
    • Selective proteinuria (excessive loss of albumin and low molecular weight proteins) suggests minimal change disease, while non-selective proteinuria suggests severe histological lesions. Cameron Index (CI) (ratio of IgG to transferrin clearances) ranging from 0.05–0.10 is suggestive of selective proteinuria, while CI > 0.15 indicates non-selective proteinuria.
    • Macroscopic hematuria may be present in 20% of children.
    • Microscopic examination of urine may show fat bodies and hyaline casts. Glomerular casts are seen only in acute renal failure or acute tubular necrosis. Urine sodium levels are low.
  1. Serology
    • Hypoproteinemia (< 5 g/dL) and hypoalbuminemia (< 3 g/dL) are present. Serum protein electrophoresis shows low albumin and increased globulins (↑ α2-globulins > ↑ β-globulins; γ-globulin levels vary according to etiology).
    • Serum IgG levels are decreased in minimal change disease and increased in systemic lupus erythematosus.
    • Serum IgA levels are elevated in approximately 50% of patients with IgA nephropathy.
  2. Lipid profile
    • Lipid profile shows increased total cholesterol, increased LDL, unchanged or low HDL, and increased LDL:HDL ratio. Serum triglycerides and VLDL are increased in patients with severe hypoalbuminemia. Serum lipoprotein (a), apoproteins, and apolipoproteins B, CII, and CIII are also raised.

Note: Serum creatinine is normal unless there is renal failure.

Low serum C3 levels are seen in MPGN and post-infectious GN, while low serum C3 and C4 levels are seen in lupus nephritis.

  1. Blood tests
  • Hyponatremia (reduced sodium levels in the blood due to hyperlipemia and fluid retention), hypokalemia (reduced potassium levels in the blood due to renal insufficiency), and hypocalcemia (reduced calcium levels due to hypoalbuminemia) may be present; however, serum ionized (free) calcium levels are normal.
  • In complete blood counts, increased hemoglobin and hematocrit are seen due to a volume contraction. Thrombocytosis is also common.
  • The presence of circulating anti-GBM IgG antibodies confirms the diagnosis of anti-GBM nephritis. ANCA (anti-neutrophil cytoplasmic antibodies) are present in renal vasculitis; P-ANCA are observed in microscopic polyangiitis and C-ANCA in Wegener’s granulomatosis.
  1. Renal biopsy
  • Renal biopsy should be considered when MCNS is less likely to progress. The presence of gross hematuria, hypertension, renal failure, hypocomplementemia, a family history of kidney disease, positive viral screen, and patients < 12 months old or > 8 years of age may be indicated renal biopsy.

Note: A Mantoux test should be performed before starting corticosteroid therapy.

Differential Diagnoses of Childhood Nephrotic Syndrome

  • Causes of edema: Cardiac disease, hepatic disease, angioedema
  • Causes of abdominal distension: Other causes of ascites, intestinal obstruction, abdominal tumors
  • Other causes of proteinuria
  • Other causes of hypoalbuminemia: Kwashiorkor
  • Acute nephritic syndrome

Treatment of Childhood Nephrotic Syndrome

  1. Oral prednisone is the mainstay of treatment in most cases of nephrotic syndrome, especially in MCNS and some children with FSGS. The American Academy of Pediatrics suggests oral prednisone at a dose of 60 mg/m2/day (maximum 80 mg/day) for six weeks, followed by 40 mg/m2 on alternate days for six weeks. The ISKDC regimen indicates similar doses to be administered for four instead of six weeks.
  • A response is seen within 10–15 days of initiating steroid therapy. Remission is defined by a urine protein:creatinine ratio < 0.2, or negative or trace proteinuria in dipstick urinalysis for three consecutive days.
  • Relapse is defined by an FMU protein:creatinine ratio ≥ 2 or dipstick urinalysis ≥ 2+ proteinuria for three of five consecutive days. Children experiencing one to three relapses/year are called infrequent relapsers, while those experiencing ≥ 2 relapses within six months or ≥ 4 relapses in any one-year period are called frequent relapsers.
  • Corticosteroid resistance is defined as a failure to induce a remission within four weeks of daily steroid therapy. Corticosteroid dependence is defined as relapse during the tapering of steroids or recurrence of symptoms within two weeks of the discontinuation of steroid therapy.
  1. Diuretics should be used only when there is severe edema after the correction of hypovolemia. Furosemide (1–2 mg/kg) with or without salt-poor albumin (1 g/kg infusion over four hours) is effective. Spironolactone (5–10 mg/kg) and amiloride are also effective.

Note: The risks associated with the use of diuretics in nephrotic syndrome include:

  • Hypovolemia
  • Acute renal failure
  • Thromboembolism

Head-out immersion may be helpful in refractory edema with ascites or pleural effusion.

Diet: In cases of edema, salt restriction is highly recommended. Protein restriction is not indicated except in renal failure.

3.   Alternative treatments

The following agents are used in the treatment of steroid-dependent nephrotic syndrome, steroid-resistant nephrotic syndrome, or when corticosteroids are contraindicated or cause side effects:

a. Levamisole (2.5 mg/kg on alternate days) reduces the risk of relapse in steroid-dependent patients. The significant side effects are as follows:

  • Neutropenia
  • Skin rash
  • Vomiting
  • Sleep disturbances
  • Hyperactivity
  • Seizures

b. Alkylating agents (2 mg/kg/day cyclophosphamide or 0.2 mg/kg chlorambucil) are used to induce a long-lasting remission in frequently relapsing or steroid-dependent patients.

c. Mycophenolate mofetil (MMF, 450–600 mg/m2/day) is useful in withdrawing or reducing the steroid dose in steroid-dependent patients. Side effects include abdominal pain, diarrhea, and hematologic disturbances; however, the rate of relapse following cessation of treatment is high.

d. Cyclosporine (5 mg/kg/day) is also useful in withdrawing steroid therapy in steroid-dependent or frequently relapsing patients, although relapse is common after the discontinuation of cyclosporine.

Treatment of complications

  1. Symptomatic hypovolemia is treated by rapid intravenous infusion of plasma (20 mL/kg) or 20% albumin (1 g/kg).
  2. Thromboembolic complications can be prevented by mobilization, correction of hypovolemia, and early treatment of sepsis. Prophylactic warfarin may be considered when plasma albumin < 20 g/L, serum fibrinogen > 6 g/L, or serum antithrombin III level < 70% of normal. Thrombosis should be treated with heparin and/or thrombolytic agents.
  3. For the treatment of acute episodes of hypertension, β blockers or calcium channel blockers are preferred, while angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB) are preferred for the treatment of long-term hypertension.
  4. Children with nephrotic syndrome should receive pneumococcal vaccination upon the clinical presentation of nephrotic syndrome, followed by revaccination every five years. Annual influenza vaccination is also recommended. If the child is not immunized to varicella, this vaccine should be considered along with steroid therapy.
  5. Peritonitis should be treated with antibiotics that are effective against S. pneumoniae and Gram-negative organisms.

Progression and Prognosis of Childhood Nephrotic Syndrome

Pediatric or childhood nephrotic syndrome shows a good prognosis with drug therapy. Most cases (up to 90%) of MCNS respond to corticosteroids with an excellent prognosis. Some children with FSGS may respond better to steroid therapy with a favorable long-term prognosis unlike those with diffuse mesangial proliferation who do not respond well to steroids. Children with minimal changes in the initial renal biopsy may later show changes in FSGS.

Among children who respond to steroids, approximately 30% have no further relapse, about 10–20% are infrequent relapsers, while 50–60% are frequent relapsers or steroid-dependent.

The prognosis of MN depends on the underlying disease. In the long run, renal failure develops in > 50% of patients with MPGN. Permanent proteinuria suggests a poor prognosis in IgA nephropathy.

In steroid-resistant nephrotic syndrome, the risk of progression to end-stage renal failure is high. About 30% of patients may have a recurrence of proteinuria even after a renal transplant. Risk factors for such recurrence include an age of onset > 6 years, rapid progression to renal failure, and diffuse mesangial proliferation observed in the first renal biopsy.

Familial nephrotic syndrome caused by mutations in the NPHS1, NPHS2, or WT1 genes does not respond to immunosuppression with corticosteroids or alternative drugs.

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