Nephritic syndrome

Nephritic syndrome is characterized by glomerular inflammation that causes glomerular hematuria (e.g., with red blood cell casts), sterile pyuria, and mild to moderate proteinuria leading to hypertension, oliguria, and/or fluid retention with mild to moderate peripheral edema. In adults, this syndrome can be caused by a variety of conditions, including autoimmune, hereditary, and infectious diseases, leading to glomerulonephritis. The majority of cases of pediatric nephritic syndrome are due to poststreptococcal glomerulonephritis (PSGN). Nephritic diseases can manifest with varying degrees of severity, ranging from asymptomatic hematuria to systemic involvement and end-stage renal disease (ESRD), such as in rapidly progressive glomerulonephritis (RPGN). Diagnosis of the underlying disease is often based on presentation and laboratory values, although renal biopsy is usually required for diagnostic confirmation in adults. Various forms of microscopy are frequently used to distinguish features and assist with diagnosis. These include light microscopy (LM), immunofluorescence microscopy (IM), and electron microscopy (EM). Treatment depends on the underlying cause and is usually managed by nephrology.

See “Glomerular diseases” for more information on the pathophysiology of glomerulonephritis and differentiating between nephritic and nephrotic syndrome.

• Nephritic syndrome ^[1][2]
  • Clinical syndrome characterized by glomerular hematuria (e.g., RBC casts or acanthocytes in urine), proteinuria (usually < 3.5 g/day), hypertension, and mild to moderate peripheral edema
  • Additional features include:
    • ↓ Kidney function, e.g., oliguria, azotemia, ↓ GFR
    • Sterile pyuria
• Glomerulonephritis: acute glomerular inflammation or one of several diseases in which it occurs
  • Primary glomerulonephritis: due to a pathological process isolated within the glomerulus (e.g., IgA nephropathy)
  • Secondary glomerulonephritis: due to a systemic condition affecting the glomerulus (e.g., lupus nephritis)
• Rapidly progressive glomerulonephritis: glomerulonephritis that manifests as nephritic syndrome with rapid decline in renal function in days to weeks ^[1][3]

NephrItic syndrome indicates glomerular Inflammation.

Glomerulonephritis ^[1][4]

Glomerulonephritis was traditionally classified according to histopathological patterns but is now more commonly classified by etiology. ^[4]

• ANCA-associated glomerulonephritis (pauci-immune glomerulonephritis)
  • Granulomatosis with polyangiitis
  • Microscopic polyangiitis
  • Eosinophilic granulomatosis with polyangiitis
• Anti-glomerular basement membrane (GBM) associated glomerulonephritis
  • Anti-GBM disease (Goodpasture disease)
  • Anti-GBM glomerulonephritis (no lung involvement)
• Immune complex-mediated glomerulonephritis
  • Low C3 levels
    • Lupus nephritis
    • Infection-related glomerulonephritis
      • Poststreptococcal glomerulonephritis (PSGN)
      • Postinfectious glomerulonephritis
      • Glomerulonephritis associated with an active infection like endocarditis
      • Cryoglobulinemic glomerulonephritis (polyclonal)
  • Normal C3 levels
    • IgA nephropathy
    • IgA vasculitis
    • Fibrillary glomerulonephritis
• Monoclonal immunoglobulin (Ig) glomerulonephritis
  • Monoclonal Ig deposition disease
  • Proliferative glomerulonephritis with monoclonal Ig deposits
  • Cryoglobulinemic glomerulonephritis (monoclonal)
• C3 glomerulopathy
  • C3 glomerulonephritis
  • Dense deposit disease

Pulmonary-renal syndromes ^[5]

Conditions that can simultaneously involve the kidneys and lungs are classified as pulmonary-renal syndromes; causes include:

• Granulomatosis with polyangiitis
• Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)
• Microscopic polyangiitis
• Anti-GBM disease
• Systemic lupus erythematosus

• General pathophysiology
  • Inflammation → cytokine release → glomerular capillary damage
    • Porous glomerular basement membrane → leakage of proteins and RBCs → nephritic sediment (all blood components are detectable on urinalysis)
      • Proteinuria (< 3.5 g/24h): leakage of proteins
      • Hematuria: leakage of RBCs, which stick together and form red blood cell casts in the renal tubules
    • Oliguria: Inflammatory infiltrates reduce fluid movement across the membrane (↓ GFR).
    • Azotemia: Inflammation prevents sufficient filtering and excretion of urea.
    • Salt retention → intravascular volume expansion → hypertension and edema
• Rapidly progressive glomerulonephritis
  • Breaks in the glomerular capillary wall and dysfunction of the glomerular basement membrane (GBM) → leakage of plasma proteins (e.g., coagulation factors) and passage of inflammatory cells (macrophages, T cells) into Bowman space
  • Release of inflammatory cytokines → damage to the membrane of Bowman space and passage of cells from the interstitium into Bowman space
  • This causes the formation of fibrin clots and proliferation of cells (e.g., macrophages, fibroblasts, neutrophils, epithelial cells) → crescent moon formation → compression of the glomerulus → renal dysfunction.

• Intermittent gross hematuria (red or brown urine, i.e., cola-colored urine)
• Hypertension
• Pitting edema
• In ↓ GFR: oliguria and uremic symptoms (see “Uremia”)
• Fatigue

Approach ^[4][6]

Nephritic syndrome is diagnosed based on clinical presentation and the presence of nephritic sediment on urinalysis.

• Consult nephrology and other specialists as needed (e.g., rheumatologist, infectious disease specialist).
• Perform a thorough clinical evaluation, and obtain guided diagnostics to determine the underlying cause.
• Renal biopsy is usually required for diagnostic confirmation.
• Management is disease-specific; see “Diseases associated with nephritic syndrome.”
• Start general management for complications (e.g., supportive care for AKI).

Suspect RPGN in patients with nephritic sediment who have rapidly rising serum creatinine levels, and start diagnostic testing immediately. A renal biopsy is vital for quick diagnosis and initiation of appropriate treatment.

Laboratory studies ^[4][6][7]

• Urinalysis with microscopy: nephritic sediment ^[7]
  • Glomerular hematuria
    • Red blood cell casts: RBC casts form through the congregation of proteins and RBCs inside the tubules.
    • Acanthocytes
  • Sterile pyuria and sometimes WBC casts
  • Mild to moderate proteinuria of > 150 mg/24 h but < 3.5 g/24 h (nonselective glomerular proteinuria) ^[8]
• 24-hour urine profile: preferred to spot urine protein:creatinine ratio for quantifying protein in the urine
• BMP: ↑ Creatinine, ↓ GFR, azotemia with ↑ BUN
• CBC
  • To assess for anemia and leukocytosis (e.g., due to infection-related glomerulonephritis)
  • Thrombocytopenia (e.g., in thrombotic microangiopathy)
• Inflammatory markers: ↑ ESR, ↑ CRP in inflammatory conditions (e.g., lupus nephritis)
• Liver enzymes
  • Transaminitis suggests hepatitis; see “Transaminitis workup.”
  • Serum albumin: to rule out liver disease as a cause of proteinuria

Glomerular hematuria is a typical finding in nephritic syndrome and is characterized by acanthocytes, RBC casts, and mild to moderate proteinuria. Nonglomerular hematuria is characterized by bright red or pink urine, normal RBC morphology, the absence of RBC casts, and the possible occurrence of blood clots.

Additional studies ^[4][6][7]

Obtain additional studies to establish the cause of nephritic syndrome.

• Autoimmunity workup includes:
  • ANCA
  • ANA and anti-dsDNA
  • Anti-GBM antibodies
  • Complement levels
  • Cryoglobulins
  • Rheumatoid factor
• Infectious disease workup includes:
  • Blood cultures
  • Screening for GAS infection: anti-streptolysin O and anti-deoxyribonuclease B
  • Hepatitis B screening
  • Hepatitis C screening
  • HIV screening
• Other
  • Malignancy workup (i.e., SPEP, UPEP, and serum free light chain assay) for monoclonal Ig glomerulonephritis
  • Hemolysis workup for thrombotic microangiopathy

Low serum C3 levels are seen in poststreptococcal glomerulonephritis, lupus nephritis, and membrane proliferative glomerulonephritis.

Renal biopsy ^[9]

• Indications include:
  • Diagnostic confirmation (gold-standard test)
    • Red flags for RPGN
    • Nonspecific disease patterns
  • To determine prognosis and/or guide management
• Supportive findings depend on the underlying cause and include:
  • Immunofluorescence microscopy pattern
    • Linear: anti-GBM disease
    • Granular: immune complex-mediated glomerulonephritis
    • Negative: ANCA-associated glomerulonephritis (pauci-immune glomerulnonephritis)
  • See also “Terminology of glomerular diseases,” “Diffuse proliferative glomerulonephritis,” and “Membranoproliferative glomerulonephritis.”

A renal biopsy is usually required to determine the underlying cause of nephritic syndrome. In some cases (e.g., in infection-related glomerulonephritis or hereditary glomerulonephritis), renal biopsy may be deferred if the diagnosis is clear based on laboratory studies. ^[4][6][9]

• Management is disease-specific; see “Diseases associated with nephritic syndrome.”
• Assess for red flags for RPGN and manage as indicated; see "Rapidly progressive glomerulonephritis" for details.
• Start general management for complications (e.g., supportive care for AKI).

Supportive care for nephritic syndrome ^[9][9]

• Supportive care for AKI, e.g., low-sodium diet (< 2 g/day), fluid restriction
• ACE inhibitors or ARBs for proteinuria and/or hypertension (first-line therapy)
• Diuretics (e.g., furosemide) for edema and/or severe hypertension
• Consider indications for renal replacement therapy, e.g., ESRD.

Red flags for RPGN ^[3]

• Rapid rise in BUN and creatinine in a patient with nephritic sediment
• Decrease in urine output within days to weeks, possibly leading to anuria
• Additional pulmonary symptoms (e.g., hemoptysis in pulmonary-renal syndrome)

Management ^[3]

• Renal biopsy: recommended for all patients
  • Light microscopy
    • Crescent formation (moon-shaped) made of plasma proteins (e.g., C3b) and fibrin
    • Monocytes, macrophages, glomerular parietal cells
  • Additional findings depend on the underlying cause.
• Pharmacotherapy ^[3]
  • Glucocorticoids: IV methylprednisolone pulses followed by oral prednisone
  • PLUS cyclophosphamide (or rituximab for ANCA-associated vasculitis) ^[10]
• Plasmapheresis
  • Indicated for Anti-GBM disease (in combination with immunosuppression) ^[9]
  • Can be considered for IgA nephropathy and ANCA-associated vasculitis ^[9][10][11]

Prognosis ^[3]

• Full recovery of renal function occurs in most patients who receive early treatment.
• Without proper treatment, the prognosis is unfavorable with rapid progression to ESRD and high mortality.

In RPGN, renal function is lost within 3 months of clinical onset. ^[3]

• Allergic interstitial nephritis
• Diabetic nephropathy
• Warfarin-related nephropathy
• Cholesterol embolization syndrome
• For a comparison of nephrotic and nephritic syndromes, see “Nephrotic vs. nephritic syndrome.”
• See also “Common causes of hematuria.”

The differential diagnoses listed here are not exhaustive.

Diseases commonly associated with nephritic syndrome and their characteristics are summarized below.

• Anti-GBM disease (Goodpasture disease) refers to a condition in which autoantibodies form against basement membranes in the kidneys and lungs. ^[4]
• Glomerular involvement alone is referred to as anti-GBM glomerulonephritis.

Etiology ^[6][25]

The etiology of nephritic syndrome is similar in adults and children with the following considerations:

• PSGN is the most common acute cause in children.
• Membranoproliferative glomerulonephritis is more common in children than adults.
• ANCA-associated vasculitis is rare in children.

Clinical features ^[6]

Clinical features of nephritic syndrome are the same in adults and children.

In PSGN, renal symptoms are often preceded by an upper respiratory tract or soft tissue infection. ^[6]

Diagnosis ^[6]

Diagnosis is similar in adults and children (see “Diagnosis of nephritic syndrome”).

• In children, estimate GFR using the modified Schwartz formula. ^[9]
• If PSGN is suspected, see “Diagnosis of PSGN.” ^[6]
• Refer to pediatric nephrology for additional diagnostic testing for the following: ^[6][9]
  • Diagnostic uncertainty
  • A cause other than PSGN is suspected.

Evaluation for underlying genetic conditions may be obtained by a specialist in noninfectious causes of nephritis. ^[25]

Management

• Reassure caregivers that 90% of children with acute nephritis recover fully. ^[6]
• Consult pediatric nephrology for management, including: ^[6][9]
  • Treatment of the underlying cause
  • Supportive care for nephritic syndrome as needed.
  • Disease monitoring