IgA Nephropathy

IgA nephropathy (Berger’s disease) is a renal disease characterized by IgA deposition in the mesangium. It is the most common cause of primary glomerulonephritis in most developed countries. Patients frequently present in the second and third decades of life and, historically, with a preceding upper respiratory or GI infection. Common presenting features are gross hematuria or asymptomatic, microscopic hematuria on urinalysis. The course is often benign, with the definitive diagnostic procedure, renal biopsy, performed only in cases of severe, progressive renal disease. Treatment depends on the severity of proteinuria, renal function, and pathologic changes. ACE inhibitors or angiotensin-receptor blockers (ARBs) are given to reduce disease progression. Persistent proteinuria and increasing creatinine are indications for immunosuppressive therapy that includes glucocorticoids and, possibly, cytotoxic agents.

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Overview

Definition

IgA nephropathy (Berger’s disease) is a renal disease characterized by IgA deposition in the mesangium, causing glomerular inflammation (glomerulonephritis (GN)).

Epidemiology

  • Most common cause of primary GN in developed countries
  • Often presents in the second to third decades of life
  • Seen more commonly among Caucasians and East Asians
  • Both sexes affected equally among East Asians; approximately 2:1 male-to-female predominance among Caucasians

Etiology

  • Unknown in most cases
  • Often preceded by an upper respiratory or GI infection
  • Exercise can be a trigger (worsens hematuria in patients with IgA nephropathy).
  • Can be associated with conditions such as:
    • Cirrhosis
    • Celiac disease
    • HIV infection
    • Minimal change disease
    • Membranous nephropathy
    • Granulomatosis with polyangiitis

Pathophysiology

  • Preceding mucosal infection → impaired regulation of synthesis and metabolism of IgA (abnormal O-galactosylation of the hinge region of primarily polymeric IgA1)
  • Poorly galactosylated IgA1 increases recognition by circulating antibodies → immune complexes → mesangial deposition of immune complexes → type III hypersensitivity reaction → mesangial inflammation and GN

Clinical Presentation

IgA nephropathy presents with recurrent gross hematuria or asymptomatic microscopic hematuria as the most common manifestations.

Recurrent hematuria

  • Up to 50% of cases
  • Usually presents with recurring episodes of:
    • Gross hematuria accompanied by upper respiratory infection (synpharyngitic hematuria)
    • Flank pain
    • Low grade fever

Microscopic hematuria

  • Up to 40% of cases
  • Presents with asymptomatic, microscopic hematuria
  • Occasionally accompanies mild proteinuria

Rare manifestations

  • Less than 10% of cases
  • Patients can present with:
    • Nephrotic syndrome: kidney excretes > 3.5 g/day of protein
    • Acute, rapidly progressive GN:
      • Hematuria
      • Edema
      • Proteinuria
      • Renal insufficiency
    • Malignant hypertension:
      • Extremely high BP (typically > 180/120 mm Hg) with acute end-organ damage
      • Rare presentation
      • Disease was not detected early enough as patient did not have typical hematuria.

Diagnosis

The diagnosis is usually based on the clinical presentation and suspicion arising from a preceding infectious event.

Initial workup

  • Urinalysis (findings consistent with nephritic syndrome):
    • Hematuria
    • RBC casts, occasional dysmorphic RBCs
    • May have mild to moderate proteinuria
  • Other laboratory results:
    • Normal complement levels
    • May have increased creatinine
    • Increased serum IgA concentration (in 30%–50% of patients) but without correlation with disease activity

Biopsy

  • Renal biopsy provides the definitive diagnosis.
  • Because of the benign course of GN, the invasive test of renal biopsy is indicated only in severe or progressive disease:
    • Persistent urine protein excretion > 500 mg/day
    • Increased serum creatinine
    • New-onset hypertension or significant elevation in BP over baseline
  • Biopsy results: 
    • Light microscopy → mesangial hypercellularity
    • Electron microscopy → electron-dense deposits in the mesangium
    • Immunofluorescence microscopy → mesangial deposits of IgA

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Management and Prognosis

Management

  • For patients with hematuria, normal renal function, and minimal proteinuria: 
    • No active treatment
    • Monitoring of kidney function (including proteinuria) and BP
  • For patients with proteinuria > 500 mg/day and/or hypertension:
    •  Goal: proteinuria < 500 mg/day and BP < 130/80 mm Hg
    • Treatment:
      • ACE inhibitors or angiotensin-receptor blockers (ARBs) decrease disease progression.
      • Statin therapy decreases cardiovascular risk (but has no effect on renal progression).
      • Other options, such as fish oil treatment and tonsillectomy, have conflicting results.
  • For severe, active, or progressive disease:
    •  Features:
      • Increasing serum creatinine
      • Persistent proteinuria (> 1 g/day) despite ACE inhibitor or ARB intake
      • Biopsy findings of active disease
    • Therapy: glucocorticoids
  • For rapidly progressive disease: Consider combination therapy using glucocorticoids + cyclophosphamide, then azathioprine.

Prognosis

  • In up to 50% of patients, slow progression to end-stage renal failure noted over 20–25 years.
  • In others, complete remission or persistent low grade hematuria but preserved renal function
  • Predictors of progressive renal disease:
    • Elevated serum creatinine
    • Hypertension
    • Persistent proteinuria for more than 6 months (> 1 g/day)

Differential Diagnosis

The following conditions are among the differential diagnoses for IgA nephropathy.

  • Henoch–Schönlein purpura (HSP) or IgA vasculitis: another IgA-mediated GN that can be triggered by an upper respiratory or GI infection: HSP usually occurs in children < 10 years old. Patients present with palpable purpura on the buttocks and lower extremities, abdominal pain, and arthralgias. HSP disease is identical in histology to IgA nephropathy.
  • Alport syndrome (hereditary nephritis): also presents with isolated hematuria: Alport syndrome is a commonly X-linked inherited disease resulting in defective type IV collagen; this disorder is associated with sensorineural hearing loss and ocular abnormalities. Patients often present during infancy with episodic gross hematuria. Renal biopsy reveals splitting of the glomerular basement membrane.
  • Thin basement membrane nephropathy: can also present with isolated hematuria as well as gross hematuria with flank pain: This hereditary disease is characterized by mutations of type IV collagen. Renal biopsy reveals diffuse thinning of the glomerular basement membrane.
  • Membranoproliferative GN: a pattern of glomerular disease detected on biopsy that can be seen in association with hepatitis B and C infections: Hematuria is the most common presentation, but nephrotic syndrome and abnormal renal function are also seen. Renal biopsy shows hypercellularity with thickening and splitting of the glomerular basement membrane.
  • Poststreptococcal GN: a self-limited type of GN that occurs in children: Poststreptococcal GN is an immune-complex–mediated condition that is often preceded by group A beta-hemolytic streptococcal pharyngitis or skin infections. Laboratory results show decreased complement levels, elevated antistreptolysin-O and anti-DNase B levels. Renal biopsy reveals granular glomerular basement membrane on immunofluorescence microscopy and subepithelial humps on electron microscopy.

References

  1. Cattran DC, Appel GB. Treatment and prognosis of IgA nephropathy. UpToDate. Retrieved February 10, 2021, from https://www.uptodate.com/contents/treatment-and-prognosis-of-iga-nephropathy
  2. Chueng CK, Barratt J. Clinical presentation and diagnosis of IgA nephropathy. UpToDate. Retrieved February 10, 2021, from https://www.uptodate.com/contents/clinical-presentation-and-diagnosis-of-iga-nephropathy
  3. Cheung CK, Barratt J. Pathogenesis of IgA nephropathy. UpToDate. Retrieved February 10, 2021, from https://www.uptodate.com/contents/pathogenesis-of-iga-nephropathy
  4. Lewis JB, Neilson EG. Glomerular Diseases. In: Jameson J, et al. (Eds.). Harrison’s Principles of Internal Medicine, 20th ed. McGraw-Hill.

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