Nephritic Syndrome in Children

Nephritic syndrome is a renal condition with signs and symptoms produced by inflammation of the glomeruli (glomerulonephritis) and increased permeability of the glomerular barriers. Defining features include hematuria, proteinuria (but below nephrotic range), RBC casts with dysmorphic RBCs on urine microscopy, and increased serum creatinine. Causes can be genetic, autoimmune, idiopathic, or post-infectious. The most common cause is acute post-streptococcal glomerulonephritis. General clinical findings include edema, hypertension, and oliguria. Diagnosis is made based on history, physical exam, and laboratory data. A renal biopsy is sometimes necessary to establish the underlying cause. There can be a combined nephritic-nephrotic picture, especially in the chronic presentation. Treatment and prognosis depend on cause and severity.

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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

Urinary sample with hematuria: dark or tea-colored urine

Image: “hematuria” by omicsonline.org. License: CC BY 4.0

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

Severe case of IgA vasculitis or Henoch-Schönlein purpura:
Palpable purpura is noted on on the child’s foot, leg, and arm.

Image: “More severe case of HSP on child’s foot” by Okwikikim. License: Public Domain

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.
Table: Differences between nephrotic and nephritic syndrome
Nephrotic syndromeNephritic syndrome
Edema++++++
Blood pressureNormal/raisedRaised
Proteinuria++++++
Hematuria– or microscopic+++
Other features
  • Hypoalbuminemia
  • Hyperlipidemia
  • Hypercoagulability
  • RBC casts
  • Sterile pyuria

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
Table: Summary of laboratory and biopsy results of specific nephritic syndromes
Nephritic syndromeLaboratory and additional testsRenal biopsy results
Acute post-streptococcal GN
  • ASO
  • Anti-DNase B
  • ↓ C3
  • LM: endocapillary proliferation, leukocytic infiltrates
  • IF: C3 and IgG depositions, “starry sky” pattern C3 deposition
  • EM: subepithelial electron dense “humps”
Membranoproliferative GN (a pattern of glomerular injury, not a specific disease; has types I-III)↓ C3
  • LM: mesangial hypercellularity, endocapillary proliferation, double-contour/”tram track” appearance of GBM
  • IF:
    • I: IgG, C3, C1q, C4
    • II: C3
    • III: C3
  • EM:
    • I: subendothelial deposits
    • II: dense deposits
    • III: subepithelial and subendothelial deposits
Lupus GN
  • ANA
  • Anti-dsDNA
  • ↓ C3
  • IF: IgG, IgA, IgM, C3, C1q can be seen; known as “full house” deposition
  • EM: tubuloreticular inclusions, subendothelial deposits
IgA nephropathyNormal C3
  • LM: mesangial hypercellularity
  • IF: mesangial IgA depositions
  • EM: mesangial dense deposits
HSA/IgA vasculitis
  • Normal C3
  • Skin biopsy: shows IgA
  • LM: mesangial proliferation
  • IF: mesangial IgA depositions
  • EM: electron-dense deposits in mesangium
Alport syndrome (hereditary GN)Skin biopsy: monoclonal Ab against the alpha-5 (IV) chain (protein is absent)EM: splitting of the GBM, basketweave appearance
Rapidly progressive GN (denotes severe glomerular injury, but has different etiologies)Depends on the underlying causeMost common histology: crescent formation in glomeruli
Ab: antibody
GN: glomerulonephritis
GBM: glomerular basement membrane
Ig: immunoglobulin
LM: light microscopy
IF: immunofluorescence
EM: electron microscopy

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).

References

  1. Chang, A., Laszik, Z. (2020). The Kidney. In Kumar, V., Abbas, A., Aster, J. & Robbins, S. Robbins and Cotran. Pathologic Basis of Disease (10th Ed., pp. 895–930). Elsevier, Inc.
  2. Floege, J., & Feehally, J. (2019). Introduction to glomerular disease: Clinical presentations. In Feehally, John, DM, FRCP, Floege, Jürgen, MD, FERA, Tonelli, Marcello, MD, SM, MSc, FRCPC & R. J. Johnson MD (Eds.), Comprehensive clinical nephrology (pp. 18-198). https://www.clinicalkey.es/#!/content/3-s2.0-B9780323479097000159
  3. Flores, F. X. (2020). Isolated glomerular diseases associated with recurrent gross hematuria. In R. M. Kliegman MD et al. (Eds.), Nelson textbook of pediatrics (pp. 272-2728.e1). https://www.clinicalkey.es/#!/content/3-s2.0-B978032352950100537X
  4. Landry, D. W., & Bazari, H. (2017). Aproximación al paciente con enfermedad renal. In L. Goldman MD, & A. I. Schafer MD (Eds.), Goldman-Cecil. tratado de medicina interna (pp. 728-736). https://www.clinicalkey.es/#!/content/3-s2.0-B9788491130338001142
  5. Lewis, J. B., & Neilson, E. G. (2018). Glomerular diseases. In J. L. Jameson, A. S. Fauci, D. L. Kasper, S. L. Hauser, D. L. Longo & J. Loscalzo (Eds.), Harrison’s principles of internal medicine, 20e. New York, NY: McGraw-Hill Education. accessmedicine.mhmedical.com/content.aspx?aid=1156520317
  6. Kehr, K. Acute Glomerular Diseases in Children. openurologyandnephrologyjournal.com/VOLUME/8/PAGE/104/FULLTEXT/
  7. Niaudet, P. Overview of the pathogenesis and causes of glomerulonephritis in children. Retrieved February 16, 2021, from https://www.uptodate.com/contents/overview-of-the-pathogenesis-and-causes-of-glomerulonephritis-in-children
  8. O’Brien, D. Overview of nephritic syndrome. Retrieved February 25, 2021, from https://www.merckmanuals.com/professional/genitourinary-disorders/glomerular-disorders/overview-of-nephritic-syndrome

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