IgA nephropathy

IgA nephropathy (IgAN), also known as Berger disease, is the most common primary glomerulonephritis worldwide. It most frequently affects male individuals in the second to third decades of life. Clinical manifestations are usually triggered by upper respiratory tract or gastrointestinal infections and include gross hematuria and flank pain; however, most individuals with IgAN are asymptomatic. Rarely, IgAN may manifest as rapidly progressive glomerulonephritis (RPGN). Urinalysis usually shows persistent microhematuria and proteinuria, while more severe IgAN may manifest with recurrent episodes of nephritic syndrome. Kidney biopsy is required for definitive diagnosis and is usually indicated in patients with severe or progressive kidney disease. Treatment consists of measures to slow the progression of the disease (e.g., ACE inhibitors); immunosuppressive therapy is reserved for more severe IgAN. Even with treatment, up to 40% of patients progress to end-stage renal disease (ESRD) within 20 years.

IgA nephropathy is the most common primary glomerulonephritis in adults. ^[1]

• Peak incidence: second to third decades of life ^[2]
• Sex: ♂ > ♀ (2:1) ^[3]
• Ethnicity: more common in the Asian population (worldwide) ^[4]

Epidemiological data refers to the US, unless otherwise specified.

• The cause is still not entirely understood.
• Most likely mechanism: an increased number of defective, circulating IgA antibodies are synthesized (often triggered by mucosal infections, i.e., upper respiratory tract and gastrointestinal infections) → IgA antibodies form immune complexes that deposit in the renal mesangium → mesangial cell and complement system activation → glomerulonephritis (type III hypersensitivity reaction) ^[5]

The course and presentation of IgAN are highly variable.

• Asymptomatic with urinalysis abnormalities, e.g., microhematuria, proteinuria (most common presentation) ^[6][7]
• Symptomatic episodes, usually during or immediately following a respiratory or gastrointestinal infection or following strenuous exercise ^[6][8]
  • Gross or microscopic hematuria ^[6][8]
  • Flank pain
  • Low-grade fever
• Nephritic syndrome (including hypertension)
• RPGN and/or nephrotic syndrome (∼ 5% of individuals with IgAN) ^[6][7]
• ESRD ^[8]

Manifestations of IgAN usually begin < 5 days after the onset of URTI or GI infection symptoms. ^[6][9]

IgAN and IgA vasculitis are both IgA-mediated vasculitides triggered by a mucosal infection. IgA vasculitis most commonly occurs in children < 10 years of age and affects multiple organs (palpable purpura, abdominal pain, arthralgia). IgAN is limited to the kidneys and typically affects adults.

General principles

• Suspect IgAN in patients with:
  • Suggestive clinical features, e.g., gross hematuria during or following a URTI or gastrointestinal infection
  • Incidental hematuria and proteinuria
  • Declining kidney function (especially in patients < 40 years of age)
• Consult nephrology for all patients with suspected IgAN.
• A renal biopsy is needed for a definitive diagnosis of IgAN. ^[6][10]
• Additional laboratory studies (e.g., serum IgA, C3 complement level) can help exclude differential diagnoses and secondary causes.

IgAN is the most common cause of kidney failure in individuals < 40 years of age. ^[6]

Urine studies ^[6]

• Urinalysis: nephritic sediment
  • Hematuria: episodic gross or microscopic
  • Proteinuria: usually accompanies hematuria ^[9][11]
  • Red blood cell casts may be present.
• 24-hour urine profile: proteinuria
  • Ranges from mild (< 1 g/24 h) to severe (> 3 g/24 h) ^[6][7]
  • More severe proteinuria is associated with an increased likelihood of IgAN progression. ^[6]

Renal biopsy ^[6][9]

• Indications
  • The decision to perform a renal biopsy is often based on regional and institutional practices. ^[6][9][12]
  • Usually warranted if there are signs of severe or progressive kidney disease, e.g.:
    • ↑ Serum creatinine
    • Proteinuria > 0.5–1 g/24 h
    • Secondary hypertension
• Findings ^[1][6]
  • Light microscopy: mesangial proliferation and matrix expansion
  • Immunofluorescent microscopy: mesangial IgA deposits with C3 and occasionally IgM and/or IgG ^[6]
  • Electron microscopy: mesangial immune complex deposits
  • Histological classification using the revised Oxford classification (MEST-C score) helps determine prognosis. ^[10]

If findings would not impact management decisions, a biopsy may not be indicated in patients with nonsevere kidney disease.

The renal manifestation of IgA vasculitis is histologically indistinguishable from IgAN. ^[6][7]

Additional laboratory studies ^[6][9]

The following studies may support the diagnosis of IgAN but are not required in the diagnostic workup.

• BMP: Creatinine may be elevated. ^[6]
• ↑ IgA in serum: in 50% of patients; not specific to IgAN ^[6]
• C3 level: typically normal
• Consider further studies to assess for secondary causes of IgAN (e.g., IgAN associated with chronic liver disease, IgA vasculitis) if clinically suspected. ^[6][10]

• Poststreptococcal glomerulonephritis
  • Associated with low complement levels
  • Clinical features take longer to appear (typically 10–20 days) following an infection ^[9]
• IgA vasculitis nephritis
• Lupus nephritis
• Membranoproliferative glomerulonephritis

The differential diagnoses listed here are not exhaustive.

General principles

• Consult nephrology for all patients.
• Management consists mainly of supportive measures, i.e.:
  • Management of proteinuria and hypertension
  • ASCVD risk reduction
  • Lifestyle modifications
• Use of immunosuppressive therapy for severe or progressive kidney disease is controversial.
• Long-term monitoring of blood pressure, urine protein, and GFR is required for all patients. ^[10]

Even with treatment, 20–40% of patients with IgAN develop ESRD within 20 years. ^[8][10]

Supportive measures ^[6][10][13]

Indicated for all patients to slow disease progression.

• Management of hypertension and proteinuria > 0.5 g/24 h ^[10]
  • First line: ACE inhibitors or angiotensin II receptor blockers at maximally tolerated doses ^[6][10]
  • SGLT-2 inhibitors may be added to RAASi.
  • Dual endothelin angiotensin receptor antagonists (e.g., sparsentan) may be considered if other agents are not effective. ^[6][14]
  • See “Antihypertensive treatment by comorbidities.”
• ASCVD risk reduction
  • Management of hyperlipidemia
  • Management of ASCVD risk factors in chronic kidney disease
• Lifestyle modifications
  • Obesity management
  • Tobacco cessation
  • Exercise
  • Dietary sodium restriction

Immunosuppressive therapy ^[6][10]

A nephrology consultation is required before starting immunosuppressive therapy.

• Glucocorticoids may be considered for severe or progressive disease (i.e., proteinuria > 1 g/24 h despite supportive measures for ≥ 3 months). ^{[10][15] [10][13]}
  • A short course (≤ 6 months) is recommended. ^[10]
  • Implement preventive measures for adverse effects of glucocorticoids (e.g., infections, osteoporosis).
  • Consider PCP prophylaxis.
• Cyclophosphamide: for rapidly progressive IgAN, in addition to glucocorticoids ^[10]

• Symptoms resolve spontaneously in 5–30% of patients. ^[6][16]
• 20–40% of patients with IgAN develop ESRD within 20 years. ^[8][10]

One-Minute Telegram 51-2022-3/3: Are glucocorticoids a safe and effective treatment for IgA nephropathy?

Interested in the newest medical research, distilled down to just one minute? Sign up for the One-Minute Telegram in “Tips and links” below.