Immunoglobulin A Nephropathy

Question 1

Immunoglobulin A Nephropathy

Answer 1

Background
Most common glomerulonephropathy (GN) worldwide

Highest incidence among Eastern Asians, common in Native Americans, and very low incidence in African Americans

Question 2

Immunoglobulin A Nephropathy

Answer 2

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.

Question 3

Immunoglobulin A Nephropathy

Answer 3

Despite being slowly progressive, IgAN comprises 10% to 20% of ESRD due to high prevalence.

Question 4

Immunoglobulin A Nephropathy

Answer 4

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).

Question 5

Immunoglobulin A Nephropathy

Answer 5

Antibodies directed against the underglycosylated hinge region of Gd-IgA1 are produced, likely driven by molecular mimicry.

Question 6

Immunoglobulin A Nephropathy

Answer 6

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).

Question 7

Immunoglobulin A Nephropathy

Answer 7

Deposited IC activate complement cascade (C3) and induce mesangial cell proliferation, matrix deposition, and activation, all leading to irreversible kidney damage.

Question 8

Immunoglobulin A Nephropathy

Answer 8

Common Associations/Etiologies

IgAN may occur as a primary or secondary glomerulonephritis.

Question 9

Immunoglobulin A Nephropathy

Primary isolated IgAN:

Answer 9

May occur at any age, but typically in older patients

Kidney involvement only

IgA rheumatoid factor may be positive in 30% of affected patients.

Question 10

Immunoglobulin A Nephropathy

Primary systemic Henoch–Schonlein purpura (HSP):

Answer 10

Typically occurs in first decade of life, but may occur at any age

Question 11

Immunoglobulin A Nephropathy

Primary systemic Henoch–Schonlein purpura (HSP):

Answer 11

Systemic manifestations: palpable purpura affecting extensor surfaces (>90%), abdominal pain +/− (bloody) diarrhea (50%), arthritis, positive IgA rheumatoid factor (50% to 60%), IgA ANCA titers

Question 12

Immunoglobulin A Nephropathy

Secondary causes generally involve organs that produce or clear IgA, conditions that stimulate IgA production, or autoimmune diseases:

Answer 12

Skin: dermatitis herpetiformis, psoriasis, psoriatic arthritis

Question 13

Immunoglobulin A Nephropathy

Secondary causes generally involve organs that produce or clear IgA, conditions that stimulate IgA production, or autoimmune diseases:

Answer 13

Liver: alcoholism, primary biliary cirrhosis, cirrhosis; hepatitis B, chronic schistosomiasis. Cirrhotic liver has reduced capacity to metabolize/clear IgA.

Question 14

Immunoglobulin A Nephropathy

Secondary causes generally involve organs that produce or clear IgA, conditions that stimulate IgA production, or autoimmune diseases:

Answer 14

Gastrointestinal tract: inflammatory bowel disease, celiac disease, ulcerative colitis, Crohn’s

Question 15

Immunoglobulin A Nephropathy

Secondary causes generally involve organs that produce or clear IgA, conditions that stimulate IgA production, or autoimmune diseases:

Answer 15

Pulmonary: sarcoidosis, idiopathic hemosiderosis, cystic fibrosis, bronchiiiolitis obliterans, ANCA disease involving upper respiratory tract.

Question 16

Immunoglobulin A Nephropathy

Secondary causes generally involve organs that produce or clear IgA, conditions that stimulate IgA production, or autoimmune diseases:

Answer 16

Neoplasia: lung, larynx, pancreas, mycosis fungoides

Infection: HIV, leprosy

Question 17

Immunoglobulin A Nephropathy

Secondary causes generally involve organs that produce or clear IgA, conditions that stimulate IgA production, or autoimmune diseases:

Answer 17

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

Question 18

Immunoglobulin A Nephropathy

Clinical Manifestations

IgAN may present with various patterns of clinical presentation:

Answer 18

Episodic macroscopic “gross” hematuria:

More common in children

Question 19

Immunoglobulin A Nephropathy

Clinical Manifestations

IgAN may present with various patterns of clinical presentation:

Answer 19

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

Question 20

Immunoglobulin A Nephropathy

Clinical Manifestations

IgAN may present with various patterns of clinical presentation:

Answer 20

Prolonged remission of clinical signs is common.

Asymptomatic (incidental finding) hematuria and proteinuria:

Question 21

Immunoglobulin A Nephropathy

Clinical Manifestations

IgAN may present with various patterns of clinical presentation:

Answer 21

More common in adults

Hypertension and impaired kidney function may be present at diagnosis.

Question 22

Immunoglobulin A Nephropathy

Clinical Manifestations

IgAN may present with various patterns of clinical presentation:

Answer 22

Remission is uncommon.

Gross hematuria with concurrent AKI

Question 23

Immunoglobulin A Nephropathy

Clinical Manifestations

IgAN may present with various patterns of clinical presentation:

Answer 23

Nephrotic syndrome

Slowly progressive chronic kidney injury

Rapidly progressive (crescentic) glomerulonephritis

Question 24

Immunoglobulin A Nephropathy

Histopathology

Answer 24

Light microscopy (LM): mesangial expansion and hypercellularity, may be segmental and global glomerulosclerosis, endocapillary hypercellularity, crescents

Question 25

Immunoglobulin A Nephropathy

Histopathology

Answer 25

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.

Question 26

Immunoglobulin A Nephropathy

Histopathology

Answer 26

“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

Question 27

Immunoglobulin A Nephropathy

Prognostic Indicators

Answer 27

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.

Question 28

Immunoglobulin A Nephropathy

Prognostic Indicators

Answer 28

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)

Question 29

Immunoglobulin A Nephropathy

Prognostic Indicators

Answer 29

Emerging tests: Gd-IgA1 levels, antiglycan autoantibodies, markers of oxidative stress or fibroblast, urine and serum proteomics, gene expression analyses

Question 30

Immunoglobulin A Nephropathy

Management

All patients:

Answer 30

BP control < 130/80 mm Hg; consider <125/75 mm Hg if presenting proteinuria > 1 g/d

Question 31

Immunoglobulin A Nephropathy

Management

All patients:

Answer 31

ACEI or ARB is “recommended” if proteinuria > 1 g/d, otherwise ACEI/ARB is “suggested.”

Question 32

Immunoglobulin A Nephropathy

Management

All patients:

Answer 32

Aldosterone blockers may also be considered for antiproteinuric and antifibrotic effects.

Low-sodium diet

Consider tonsillectomy if recurrent tonsillitis

Question 33

Immunoglobulin A Nephropathy

Management

All patients:

Answer 33

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.

Question 34

Immunoglobulin A Nephropathy

Management

Answer 34

Mild disease: normal GFR, proteinuria < 500 mg/d; benign histology (noncrescentic), normotensive: observation

Question 35

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):

Answer 35

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.

Question 36

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):

Answer 36

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)

Question 37

Immunoglobulin A Nephropathy

Management

Answer 37

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.

Question 38

Immunoglobulin A Nephropathy

Management

Answer 38

Crescentic IgAN: rapidly progressive glomerulonephritis, >30% to 50% cellular or fibrocellular crescents on biopsy: pulse followed by high dose oral glucocorticoids; consider adding CYC.

Question 39

Immunoglobulin A Nephropathy

Management

Answer 39

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.