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Nephrotic Syndrome, Pediatric

Basics

Description

- Inquire about known atopy or food intolerance. - Inquire about drug exposure (especially NSAID agents). - Inquire about any recent infections. - Signs and symptoms: - Fatigue and general malaise - Reduced appetite - Weight gain and facial swelling - Puffy eyes - Abdominal swelling or pain - Foamy urine - Atopy - Pitting, dependent edema - Fluid accumulation in body spaces (ascites, pleural effusions, scrotal swelling) - Mild hypertension (10 " 20% of patients)

Nephrotic syndrome (NS) is defined by nephrotic-range proteinuria, hypoalbuminemia, edema, and hypercholesterolemia. Nephrotic-range proteinuria is typically found when there is 3 " 4+ protein on the urine dipstick and is defined as >40 mg/m2/h or a spot protein-to-creatinine ratio >2 mg protein/mg creatinine.

Epidemiology

  • Minimal change nephrotic syndrome (MCNS) is the most frequent cause of NS in younger children:Occurs mainly between 2 and 8 years of age, with a peak at 3 yearsBoys are more commonly affected than girls (3:2).Atopy and MCNS have an association.
  • Focal segmental glomerulosclerosis (FSGS) is the 2nd most frequent cause of NS in childhood:Children with FSGS are more likely than children with MCNS to have steroid-resistant nephrotic syndrome (SRNS).
  • Less common than MCNS and FSGS are congenital NS (<3 months) and infantile NS (<1 year).
  • Black and Hispanic children have a higher incidence of FSGS than do white and Asian children.
  • Prevalence of 16 cases per 100,000 in children <16 years

Pathophysiology

  • Disruption of podocyte architecture composing the glomerular filtration barrier leads to proteinuria, hypoalbuminemia, and subsequently edema.
  • Hypercholesteremia occurs due to increased liver production of cholesterol in response to hypoalbuminemia as well as to loss of lipoprotein lipase in urine.
  • MCNS PathologyThe glomerular tuft and size are normal.Mesangial expansion is absent or minimal.Immunofluorescence is usually negative, although mild staining for C3, IgM, and IgA may occasionally be found.Electron microscopy reveals effacement of the visceral (podocyte) epithelial foot processes, which is reversible.

Etiology

  • Most pediatric cases are primary; 5 " 10% are secondary to other diseases.
  • The most common primary cause of NS in childhood is MCNS. It is characterized by minimal histologic changes on light microscopy and is usually steroid-sensitive nephrotic syndrome (SSNS).
  • Other causes of primary NS include FSGS, membranous, and membranoproliferative glomerulonephritis (GN).
  • Secondary causes of NS include infections, vasculitis, diabetes, drugs (e.g., NSAIDs), and hereditary disorders.
  • Examples of congenital NS include Finnish type, diffuse mesangial sclerosis (DMS), and syphilitic nephrosis.
  • NS can also be caused by inherited mutations in proteins involved in the podocyte cytoskeleton, which often results in SRNS and FSGS.

Diagnosis

History

  • Inquire about known atopy or food intolerance.
  • Inquire about drug exposure (especially NSAID agents).
  • Inquire about any recent infections.
  • Signs and symptoms:Fatigue and general malaiseReduced appetiteWeight gain and facial swellingPuffy eyesAbdominal swelling or painFoamy urineAtopyPitting, dependent edemaFluid accumulation in body spaces (ascites, pleural effusions, scrotal swelling)Mild hypertension (10 " 20% of patients)

Physical Exam

Look for edema in the most dependent area of the child:

  • Legs
  • Lumbar spine
  • Scalp
  • Soft ear cartilage
  • Scrotum/labia

Diagnostic Tests & Interpretation

Lab

Initial Lab Tests

  • The urine dipstick usually shows 2,000 mg/dL (4+) of protein:In small children with NS, the urine dipstick may show <4+.
  • Timed or spot urine protein collection24-hour urine shows >40 mg/kg/day.Spot urine protein-to-creatinine ratio >2 mg/mg.
  • Microscopic hematuria is present in 10 " 20% of cases: The presence of RBC casts is more suggestive of glomerulonephritis.
  • Serum creatinine usually normal
  • Serum albumin usually <2.5 g/dL
  • Total cholesterol elevated, usually >200 mg/dL but can be as high as 500 mg/dL
  • Home testingThe 1st morning urine is tested for protein with urine dipsticks daily.

Imaging

In complicated cases, renal ultrasound to evaluate for kidney size, parenchymal architecture, and renal venous thrombosis.

Differential Diagnosis

  • EdemaCHFLiver failureProtein-losing enteropathyProtein-energy malnutrition (Kwashiorkor)
  • NS:MCNSFSGSMembranous GNMembranoproliferative GNDiffuse mesangioproliferative GN

Treatment

Medication

First Line

  • Corticosteroids are used as 1st-line therapy in suspected MCNS.On presentation: prednisone 2 mg/kg/day for 4 " 6 weeks (maximum: 60 mg); then prednisone 1.5 mg/kg on alternate days (maximum: 40 mg) and continued for 2 " 5 months with tapering of the dose.On relapse: prednisone 2 mg/kg/day until urine protein test results are negative or trace for 3 consecutive days; then prednisone 1.5 mg/kg on alternate days for at least 4 weeks.Inadequate duration of corticosteroid therapy is associated with increased risk of relapse

Second Line

  • Alkylating agents (cyclophosphamide, chlorambucil)
  • Mycophenolate mofetil (MMF)
  • Calcineurin inhibitors (cyclosporine A, tacrolimus)
  • Rituximab

Supportive Medications

  • Diuretics
  • ACE inhibitors or angiotensin receptor blockers
  • Statins for hypercholesterolemia in persistent NS

Alert

  • Live vaccines are contraindicated while daily corticosteroids or alkylating agents are being given.
  • Children in relapse, on corticosteroids, or on alkylating agents and who are nonimmune and exposed to varicella should receive VZIG.
  • Albumin and/or furosemide must be used cautiously to prevent pulmonary edema from rapid fluid shifts or intravascular dehydration.

Additional Treatment

General Measures

  • Influenza vaccination yearly
  • Full pneumococcal vaccination with PCV13 when needed and 23-valent pneumococcal vaccine
  • PPD and chest x-ray at initial presentation prior to starting corticosteroids if risk factors for tuberculosis present

Ongoing Care

Follow-up Recommendations

  • When to expect improvement:Remission occurs 2 " 4 weeks after starting corticosteroids in MCNS.
  • Signs to watch for:Fever, abdominal pain, oliguria, respiratory distress
  • Pitfalls:Recognize situations in which hypovolemia may occur and trigger thrombosis and/or acute kidney injury.
  • Monitor for complications of glucocorticoid therapy:Growth failureCataractsHypertensionOsteopeniaSteroid-induced gastritis

Diet

Restrict salt intake while in relapse or on daily corticosteroids.

Patient Education

Educate the family about urine testing, complications, diet, and prognosis.

Prognosis

  • The prognosis for MCNS is excellent, with a mortality rate of <1%:80 " 90% of MCNS are steroid-sensitive.20 " 30% of MCNS will never relapse.40% of MCNS become steroid-dependent or frequent relapsers.Remaining 30 " 40% MCNS have infrequent relapses.
  • Patients with FSGS, genetic forms of NS, or other secondary causes are more likely to be steroid-resistant and may progress to develop chronic kidney disease.

Complications

  • Risk factors for hypovolemia in NS:Severe relapse, GI illness, diuretic use, or sepsis
  • Risk factors for thrombosis in patients with NS:Hypovolemia, immobilization, thrombocytosis; urinary losses of protein C, protein S, and antithrombin III
  • Risk factors for acute kidney injury in patients with NS:Hypovolemia, bilateral renal vein thrombosis, diuretics, or ACE inhibitors
  • Most complications are secondary to steroid therapy and include growth retardation, glaucoma, posterior lens cataracts, obesity, mood changes, hirsutism, osteoporosis, and infection.
  • Spontaneous bacterial peritonitis (SBP) is an important and potentially life-threatening complication of NS.Symptoms include fever, abdominal pain, vomiting, and diarrhea.Diagnosis is confirmed by ascitic fluid polymorphonuclear cell count of ≥250 cells/mm3 and positive bacterial culture.Rapid institution of antibiotic therapy is crucial in any patient with NS and suspected SBP.
  • Diarrhea and vomiting may result in rapid, severe hypovolemia.
  • Vascular thromboses are found with NS in relapse, especially if hypovolemia is present.Sites of thrombosis include lower extremities, IVC, renal veins, cerebral sinuses, and pulmonary emboli.
  • Viral infections (measles, varicella) may be life threatening in immunocompromised patients.
  • Acute reversible renal failure is an uncommon complication of NS of childhood.

Additional Reading

  • Chesney RW. The idiopathic nephrotic syndrome. Curr Opin Pediatr. 1999;11(2):158 " 161. [View Abstract]
  • Eddy AA, Symons JM. Nephrotic syndrome in childhood. Lancet. 2003;362(9384):629 " 639. [View Abstract]
  • Gipson DS, Massengill SF, Yao L, et al. Management of childhood onset nephrotic syndrome. Pediatrics. 2009;124(2):747 " 757. [View Abstract]
  • Hodson EM, Knight JF, Willis NS, et al. Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database Syst Rev. 2000;(4):CD001533. [View Abstract]
  • Hodson EM, Knight JF, Willis NS, et al. Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database Syst Rev. 2003;(1):CD001533. [View Abstract]
  • Lombel RM, Gibson DS, Hodson EM. Treatment of steroid-sensitive nephrotic syndrome: new guidelines from KDIGO. Pediatr Nephrol 2013;28:415 " 426.
  • Robson WLM, Leung AKC. Nephrotic syndrome in childhood. Adv Pediatr. 1993;40:287 " 323. [View Abstract]
  • Van Husen M, Kemper MK. New therapies in steroid-sensitive and steroid-resistant idiopathic nephrotic syndrome. Pediatr Nephrol. 2011; 26(6):881 " 892. [View Abstract]

Codes

ICD09

  • 581.9 Nephrotic syndrome with unspecified pathological lesion in kidney
  • 581.3 Nephrotic syndrome with lesion of minimal change glomerulonephritis
  • 582.1 Chronic glomerulonephritis with lesion of membranous glomerulonephritis
  • 581.2 Nephrotic syndrome with lesion of membranoproliferative glomerulonephritis

ICD10

  • N04.9 Nephrotic syndrome with unspecified morphologic changes
  • N04.0 Nephrotic syndrome with minor glomerular abnormality
  • N05.1 Unsp neph syndrome w focal and segmental glomerular lesions
  • N04.5 Nephrotic syndrome w diffuse mesangiocapillary glomrlneph

SNOMED

  • 52254009 Nephrotic syndrome (disorder)
  • 44785005 Minimal change disease (disorder)
  • 236403004 Focal segmental glomerulosclerosis (disorder)
  • 197661001 Glomerulosclerosis (disorder)
  • 236380004 Steroid-sensitive nephrotic syndrome (disorder)
  • 197591002 Nephrotic syndrome with membranoproliferative glomerulonephritis (disorder)

FAQ

  • Q: Will the MCNS recur?
  • A: The clinical course tends to be one of multiple remissions and relapses. Relapses usually improve around the time of puberty.
  • Q: Can the NS return in adult life?
  • A: Yes. This does occur.
  • Q: Is macroscopic hematuria ever found with MCNS?
  • A: Gross hematuria suggests a renovascular event or a diagnosis other than MCNS. Microscopic hematuria occurs in ’ Ό10 " 20% of cases.
  • Q: What other agents are used to treat NS?
  • A: Cyclosporin A, tacrolimus, MMF, cyclophosphamide, and ACE inhibitors/angiotensin receptor blockers are used in children with steroid-dependent or steroid-resistant NS.