Immunoglobulin A Nephropathy Flashcards
Immunoglobulin A Nephropathy
Background
Most common glomerulonephropathy (GN) worldwide
Highest incidence among Eastern Asians, common in Native Americans, and very low incidence in African Americans
Immunoglobulin A Nephropathy
Among biopsy-proven immunoglobulin A nephropathy (IgAN), 15% to 25% reach end-stage renal disease (ESRD) within 10 years and 20% to 40% by 20 years.
Immunoglobulin A Nephropathy
Despite being slowly progressive, IgAN comprises 10% to 20% of ESRD due to high prevalence.
Immunoglobulin A Nephropathy
Pathogenesis (Multistep Model)
Elevated circulating levels of galactose-deficient at hinge region of IgA1 (Gd-IgA1) are produced, presumably due to genetic factors; mistrafficking of B cells from mucosal to systemic compartments may also be responsible (likely influenced by genotype).
Immunoglobulin A Nephropathy
Antibodies directed against the underglycosylated hinge region of Gd-IgA1 are produced, likely driven by molecular mimicry.
Immunoglobulin A Nephropathy
Antibodies directed against Gd-IgA1 are produced. Antibodies may be of IgA or IgG class.
The immune complexes (IC) are deposited in the kidneys (the IC are either preformed in circulation or formed in situ against previously deposited Gd-IgA1).
Immunoglobulin A Nephropathy
Deposited IC activate complement cascade (C3) and induce mesangial cell proliferation, matrix deposition, and activation, all leading to irreversible kidney damage.
Immunoglobulin A Nephropathy
Common Associations/Etiologies
IgAN may occur as a primary or secondary glomerulonephritis.
Immunoglobulin A Nephropathy
Primary isolated IgAN:
May occur at any age, but typically in older patients
Kidney involvement only
IgA rheumatoid factor may be positive in 30% of affected patients.
Immunoglobulin A Nephropathy
Primary systemic Henoch–Schonlein purpura (HSP):
Typically occurs in first decade of life, but may occur at any age
Immunoglobulin A Nephropathy
Primary systemic Henoch–Schonlein purpura (HSP):
Systemic manifestations: palpable purpura affecting extensor surfaces (>90%), abdominal pain +/− (bloody) diarrhea (50%), arthritis, positive IgA rheumatoid factor (50% to 60%), IgA ANCA titers
Immunoglobulin A Nephropathy
Secondary causes generally involve organs that produce or clear IgA, conditions that stimulate IgA production, or autoimmune diseases:
Skin: dermatitis herpetiformis, psoriasis, psoriatic arthritis
Immunoglobulin A Nephropathy
Secondary causes generally involve organs that produce or clear IgA, conditions that stimulate IgA production, or autoimmune diseases:
Liver: alcoholism, primary biliary cirrhosis, cirrhosis; hepatitis B, chronic schistosomiasis. Cirrhotic liver has reduced capacity to metabolize/clear IgA.
Immunoglobulin A Nephropathy
Secondary causes generally involve organs that produce or clear IgA, conditions that stimulate IgA production, or autoimmune diseases:
Gastrointestinal tract: inflammatory bowel disease, celiac disease, ulcerative colitis, Crohn’s
Immunoglobulin A Nephropathy
Secondary causes generally involve organs that produce or clear IgA, conditions that stimulate IgA production, or autoimmune diseases:
Pulmonary: sarcoidosis, idiopathic hemosiderosis, cystic fibrosis, bronchiiiolitis obliterans, ANCA disease involving upper respiratory tract.
Immunoglobulin A Nephropathy
Secondary causes generally involve organs that produce or clear IgA, conditions that stimulate IgA production, or autoimmune diseases:
Neoplasia: lung, larynx, pancreas, mycosis fungoides
Infection: HIV, leprosy
Immunoglobulin A Nephropathy
Secondary causes generally involve organs that produce or clear IgA, conditions that stimulate IgA production, or autoimmune diseases:
Systemic or immunologic disorders: systemic lupus erythematosus, rheumatoid arthritis, cryoglobulinemia, ankylosing spondylitis, Sjogren’s, Behcet’s, Reiter’s, familial immune-mediated thrombocytopenia, autoantibody IgA-mediated Goodpasture’s
Immunoglobulin A Nephropathy
Clinical Manifestations
IgAN may present with various patterns of clinical presentation:
Episodic macroscopic “gross” hematuria:
More common in children
Immunoglobulin A Nephropathy
Clinical Manifestations
IgAN may present with various patterns of clinical presentation:
Association with upper respiratory tract infection or gastroenteritis (gross hematuria occurs concurrently or within 3 days of onset of infection and typically resolves by 3 days) with or without accompanying flank or loin pain
Immunoglobulin A Nephropathy
Clinical Manifestations
IgAN may present with various patterns of clinical presentation:
Prolonged remission of clinical signs is common.
Asymptomatic (incidental finding) hematuria and proteinuria:
Immunoglobulin A Nephropathy
Clinical Manifestations
IgAN may present with various patterns of clinical presentation:
More common in adults
Hypertension and impaired kidney function may be present at diagnosis.
Immunoglobulin A Nephropathy
Clinical Manifestations
IgAN may present with various patterns of clinical presentation:
Remission is uncommon.
Gross hematuria with concurrent AKI
Immunoglobulin A Nephropathy
Clinical Manifestations
IgAN may present with various patterns of clinical presentation:
Nephrotic syndrome
Slowly progressive chronic kidney injury
Rapidly progressive (crescentic) glomerulonephritis
Immunoglobulin A Nephropathy
Histopathology
Light microscopy (LM): mesangial expansion and hypercellularity, may be segmental and global glomerulosclerosis, endocapillary hypercellularity, crescents
Immunoglobulin A Nephropathy
Histopathology
Immunofluorescent microscopy (IF): mesangial deposits of IgA, dominant or codominant with IgG or IgM ± C3. Staining of anything other than IgA is equal to or less intense than IgA.
Immunoglobulin A Nephropathy
Histopathology
“MEST” Oxford Classification for IgAN:
Mesangial proliferation (>50% glomeruli = M1)
Endocapillary proliferation: most active lesion which suggests best indication for therapy (>1 occluded glomerular capillary = E1)
Segmental sclerosis (>1 segment of sclerosis = S1)
Tubular atrophy and interstitial fibrosis (T0 = 0% to 25%, T1 = 26% to 50%, T2 > 50%)
“M1,” “S1,” “T1,” and T2 are associated with worse prognosis and are additive
Immunoglobulin A Nephropathy
Prognostic Indicators
NOTE: Well-established presenting factors indicating worse prognosis for IgAN: proteinuria ≥ 1 g/d, hypertension (DBP ≥ 95 mm Hg) or normotensive on antihypertensive therapy, SCr ≥ 1.5 mg/dL, kidney biopsy with greater degree of tubular atrophy and interstitial fibrosis.
Immunoglobulin A Nephropathy
Prognostic Indicators
Novel markers using available techniques/samples: clinical risk score based on (presenting GFR, hemoglobin, albumin, and systolic blood pressure) genetic risk score, glomerular density measurement (number of nonsclerotic glomeruli per biopsied cortical area)
Immunoglobulin A Nephropathy
Prognostic Indicators
Emerging tests: Gd-IgA1 levels, antiglycan autoantibodies, markers of oxidative stress or fibroblast, urine and serum proteomics, gene expression analyses
Immunoglobulin A Nephropathy
Management
All patients:
BP control < 130/80 mm Hg; consider <125/75 mm Hg if presenting proteinuria > 1 g/d
Immunoglobulin A Nephropathy
Management
All patients:
ACEI or ARB is “recommended” if proteinuria > 1 g/d, otherwise ACEI/ARB is “suggested.”
Immunoglobulin A Nephropathy
Management
All patients:
Aldosterone blockers may also be considered for antiproteinuric and antifibrotic effects.
Low-sodium diet
Consider tonsillectomy if recurrent tonsillitis
Immunoglobulin A Nephropathy
Management
All patients:
Use of fish oil is suggested in patients with proteinuria > 1 g/d despite 3 to 6 m of optimized ACEI/ARB and blood pressure control. Note that the benefit of fish oil is marginal on proteinuria. However, the use of ACEI has been shown to enhance the effect of fish oil.
Immunoglobulin A Nephropathy
Management
Mild disease: normal GFR, proteinuria < 500 mg/d; benign histology (noncrescentic), normotensive: observation
Immunoglobulin A Nephropathy
Management
Moderate or severe disease: proteinuria > 1 g/d or ≥0.5 to 1 g/d with clinical or histologic features suggesting risk of progression (mesangial hypercellularity, endocapillary proliferation, segmental sclerosis):
Glucocorticoids × 6 months (if GFR > 50 mL/min/1.73 m2): two suggested regimens
Intravenous bolus of 1 g methylprednisolone × 3 days at months 1, 3, and 5, followed by oral prednisone at 0.5 mg/kg on alternate days × 6 months
Oral prednisone at 0.8 to 1.0 mg/kg/d × 2 months then reduced by 0.2 mg/kg/d per month for the next 4 months.
Immunoglobulin A Nephropathy
Management
Moderate or severe disease: proteinuria > 1 g/d or ≥0.5 to 1 g/d with clinical or histologic features suggesting risk of progression (mesangial hypercellularity, endocapillary proliferation, segmental sclerosis):
Consider cytotoxics (poor data on preferred agent: KDIGO suggests cyclophosphamide (CYC) based on one low-quality study; mycophenolate mofetil (MMF) not suggested due to conflicting data and possible risk for delayed pneumonia)
Immunoglobulin A Nephropathy
Management
End-stage or advanced disease: GFR < 30 mL/min/1.73 m2, biopsy with severe global glomerulosclerosis and tubular atrophy, interstitial fibrosis: immunosuppressive therapy is not recommended.
Immunoglobulin A Nephropathy
Management
Crescentic IgAN: rapidly progressive glomerulonephritis, >30% to 50% cellular or fibrocellular crescents on biopsy: pulse followed by high dose oral glucocorticoids; consider adding CYC.
Immunoglobulin A Nephropathy
Management
AKI associated with macroscopic hematuria in IgAN: repeat kidney biopsy if there is no improvement after 5 days from onset to rule out crescentic IgAN.
