Pediatric Nephrotic Syndrome is a renal disorder of children, characterized by nephrotic range proteinuria, hypoalbuminemia, hyperlipidemia and edema. The most common type is primary (idiopathic) associated with minimal change disease, which responds very well to steroid therapy and has a good long-term prognosis. Other causes, clinical presentation, laboratory findings and management are discussed in this article.
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Definition

Nephrotic syndrome in children have different nephrotic-range protein (urine protein value is 2-3 mg/mg).  Hypoalbuminemia means low levels of albumin in blood. 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 but, in children, it occurs most commonly between 3 to 9 years of age. Boys are more affected by the disease than girls under the age of 8 years; however, the disease shows an equal male to female incidence in older children, adolescents and adults. Global incidence of pediatric nephrotic syndrome is 2–7/100000 children. Congenital nephrotic syndrome presents before three months of age.

Etiology of Childhood Nephrotic Syndrome

The etiology of the pediatric nephrotic syndrome can be understood by the following points:

Primary (idiopathic) nephrotic syndrome

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

Secondary nephrotic syndrome

  • Infections/post-infectious: Hepatitis B (MN or membranoproliferative glomerulonephritis – MPGN), hepatitis C (MPGN), 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.
  • Immunologic disorders: Castleman disease, Kimura disease, bee sting, food allergens.
  • Hematologic disorders: Sickle cell disease, lymphoma, leukemia.
  • Drugs like penicillamine (MN), gold (MN), lithium, 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 COL4A5, COL4A3 or COL4A4 genes.
  • Nail-Patella syndrome (osteo-onychodysplasia): mutations in 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), TRPC6.
  • Diffuse mesangial sclerosis: Mutations in laminin β2 chain.
  • Denys-Drash syndrome: Mutations in WT1 transcription factor.

Pathophysiology of Childhood Nephrotic Syndrome

Normally, a 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 of GBM also prevents filtration of anions like albumin.

Edema

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

Hyperlipidemia

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

The hypercoagulable state is produced due to:

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

The susceptibility to infections is increased due to a loss of immunoglobulins; complement factor C3b and properdin factor B in 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 the T-cell dysfunction which causes an increased permeability of GFB, or immune dysfunction that leads to the release of circulating factors (e.g., soluble urokinase plasminogen activator receptor) which affects the podocyte structure/function.

Light microscopy is usually normal in MCNS, but effacement of the foot processes of epithelial cells (podocytes) is seen on electron microscopy. There is no deposit of immunoglobulin or complement on immunofluorescent examination, except insignificant IgM deposits.

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 characteristic.

MPGN

More than half of the patients with MPGN have autoantibodies (nephritic factors – NeF) that activate C3 convertase. A thickening of the capillary walls (due to subendothelial extension of mesangium), increased mesangial matrix and mesangial hypercellularity are present in MPGN.

MPGN type I (the most common type) is characterized by subendothelial deposits due to the activation of the classical complement pathway. MPGN type II (10–20%, also called dense deposit disease) is associated with partial lipodystrophy, characterized by intramembranous deposits due to the activation of the alternate complement pathway. MPGN type III (< 5%) is 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 or endo-extra-capillary glomerulonephritis may also be seen.

Symptoms of Childhood Nephrotic Syndrome

Pitting edema is the most important symptom; it is soft and gravity dependent. Initially, edema is periorbitali.e. observed only in eyelids and is more marked in the mornings. It later progresses to edema of other areas (feet, genitalia, etc.), ascites or anasarca.

The child may complain about abdominal pain due to stretching, ascites or complications like:

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

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

The Alport syndrome is characterized by progressive nephritis with sensorineural hearing loss. Hematuria is always present with the syndrome. The presence of proteinuria or nephrotic syndrome, along withal port syndrome, suggests a poor prognosis.

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

The Alport syndrome is characterized by progressive nephritis with sensorineural hearing loss. Hematuria is always present, and an additional presence of proteinuria or nephrotic 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, 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 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 the nephrotic syndrome is peritonitis. Other infections include meningitis, pneumonitis, cellulitis and sepsis. The most common organism is pneumonia. Other bacterial infections include group B streptococci. H. influenzaeE. coli and other Gram-negative organisms are also common. The varicella infection is quite common as well.
  4. Thromboembolic complications (generally 3%) include:
  • Pulmonary embolism
  • Renal vein thrombosis
  • Deep vein thrombosis
  • Sagital sinus thrombosis
  • Arterial thrombosis (rarely)
  1. Urinary loss of vitamin D-binding protein may lead to a vitamin D deficiency.
  2. Hypothyroidism due to a loss of thyroid-binding globulin is rarely seen.

Diagnosis of Childhood Nephrotic Syndrome

  1. Urine analysis
    • Nephrotic range proteinuria is important for the diagnosis of nephrotic syndrome. Urinary protein excretion > 50 mg/kg/day or 40 mg/m2/h, first morning urine protein to creatinine ratio > 2:1 or 3+ or 4+ proteinuria on dipstick urine analysis suggests nephrotic range proteinuria.
    • In minimal change disease, proteinuria is selective (loss of predominantly albumin and low molecular weight proteins), while non-selective proteinuria suggests severe histological lesions. Cameron Index (ratio of IgG to transferrin clearances) between 0.05–0.10 suggests selective proteinuria, while a value of > 0.15 suggests non-selective proteinuria.
    • Macroscopic hematuria (20% of children) may be present.
    • A microscopic examination of urine may show fat bodies and hyaline casts. Glomerular casts are seen only in the presence of acute renal failure or acute tubular necrosis. Urine sodium is 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-globulins 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 ca. 50% of the patients with IgA nephropathy.
  2. Lipid profile
  • Lipid profile shows increased total cholesterol, increased LDL level, unchanged or low HDL level 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 usually normal unless there is renal failure.

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

  1. Blood tests
  • Hyponatremia (reduced Na levels in the blood due to hyperlipemia and fluid retention), hyperkalemia (reduced K levels in blood in presence of renal insufficiency) and hypocalcemia (reduced Ca levels due to hypoalbuminemia) may be present, but serum ionized calcium is 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 in microscopic polyangiitis and C-ANCA in Wegener’s granulomatosis.
  1. Renal biopsy
  • A renal biopsy should be considered when MCNS is less likely to progress – the presence of gross hematuria, hypertension, renal failure, hypocomplementemia, age < 1 year or > 8 years, a family history of kidney disease and positive viral screen are criteria required for a 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 MCNS and some children with FSGS. The American Academy of Pediatrics (AAP) suggests oral prednisone 60 mg/m2/day (maximum 80 mg/day) for six weeks, followed by 40 mg/m2on alternate days for 6 weeks. In ISKDC regimen, same doses are administered for four weeks instead of six weeks.
  • A response is seen within 10–15 days of initiating steroid therapy. Remission is defined by urine protein:creatinine ratio < 0.2 or negative or trace proteinuria on dipstick for three consecutive days.
  • Relapse is defined by first-morning urine protein:creatinine ratio ≥ 2 or ≥ 2+ proteinuria on dipstick for three of five consecutive days. Children experiencing one to three relapses per 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 tapering of steroids or 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) are effective. Spironolactone (5-10 mg/kg) and amiloride are also effective.

Note- Important risks associated with diuretics in nephrotic syndrome include:

  • Hypovolemia
  • Acute renal failure
  • Thromboembolism

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

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

3.   Alternative treatments

These 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. Important side effects are:

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

b. Alkylating agents (cyclophosphamide, 2 mg/kg/day or chlorambucil, 0.2 mg/kg) 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 to reduce or withdraw steroids 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 to allow a withdrawal of steroids in steroid-dependent or frequently relapsing patients, but relapse is following common discontinuation.

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 with or without thrombolytic agents.
  3. For treatment of acute episodes of elevated blood pressure, a β-blocker or calcium channel blocker is preferred, while angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) is preferred for the treatment of long-term hypertension.
  4. Children with nephrotic syndrome should receive pneumococcal vaccination on clinical presentation of nephrotic syndrome, followed by revaccination every five years. A yearly influenza vaccination is also recommended. If the child is not immunized to varicella, the varicella vaccine can be given during low-dose alternate day 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 show good prognosis by medication. 90% of MCNS responds to corticosteroids with an excellent prognosis. Some children with FSGS may respond to steroid therapy better with a favorable long-term prognosis, while most of others and those with diffuse mesangial proliferation do not respond well to steroid therapy. Some children with minimal changes on the initial renal biopsy may show changes of FSGS later.

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

Prognosis of MN depends on the underlying disease. More than 50% of MPGN patients progress to renal failure in the long run. Permanent proteinuria suggests poor prognosis in IgA nephropathy.

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

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

Review Questions

1. Which of the following is the most common bacteria causing peritonitis in children with nephrotic syndrome?

  1. Streptococcus pyogenes
  2. Streptococcus pneumoniae
  3. Streptococcus bovis
  4. Escherichia coli
  5. Pseudomonas aeruginosa

2. Which of the following conditions is associated with normal serum complement levels?

  1. Minimal change disease
  2. Membranoproliferative glomerulonephritis
  3. Post-infectious glomerulonephritis
  4. Lupus nephritis

3. Mutations in which of the following genes is associated with classical Finnish-type congenital nephrotic syndrome?

  1. NPHS1
  2. NPHS2
  3. ACTN4
  4. TRPC6
  5. WT1
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