IgA Nephropathy

Slide 1 · IgA Nephropathy

Immune pathogenesis · glomerular morphology · clinical correlation

Renal pathology teaching lecture

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Recognize the clinicopathologic definition of IgA nephropathy

Trace the multi-hit mechanism from altered IgA1 to mesangial injury

Interpret light microscopy, immunofluorescence, and electron microscopy

Relate morphology to hematuria, proteinuria, and renal outcomes

Slide 3 · Defining lesion: Mesangial IgA deposition

Pathologic identity

Prominent IgA deposits in the glomerular mesangial region are essential to its diagnosis.

Clinical expression

Recurrent hematuria is characteristic; Proteinuria is often mild.

Slide 4 · Why IgA nephropathy is a glomerulonephritis

Immune process

Deposited IgA or IgA-containing immune complexes initiate local injury.

Mesangial response

Mesangial cells proliferate and synthesize extracellular matrix.

Functional disturbance

Glomerular inflammation produces hematuria; Barrier injury may cause proteinuria.

Slide 5 · Three biopsy modalities answer different questions

Method

Principal question

Expected clue

Light microscopy

What is the injury pattern?

Mesangial expansion ± proliferation

Immunofluorescence

Which immunoreactant deposits?

Dominant mesangial IgA

Electron microscopy

Where are the dense deposits?

Predominantly mesangial

Slide 6 · IgA nephropathy in epidemiologic context

It as the most common glomerulonephritis worldwide

It may occur at any age, particularly older children and young adults

Clinical presentation and long-term prognosis vary substantially

Slide 7 · The cardinal presentation is hematuria

Macroscopic hematuria

Visible blood in urine may appear after a respiratory, gastrointestinal, or urinary infection.

Microscopic hematuria

Urine sediment abnormalities may be the only initial clue, sometimes with proteinuria.

Slide 8 · Infection-associated hematuria is often recurrent

Mucosal illness

Respiratory illness is the common clinical antecedent.

Hematuria

A macroscopic episode may last several days.

Intermission

Visible blood subsides.

Recurrence

Episodes may recur months later.

Slide 9 · The infection association does not identify a single agent

Respiratory and gastrointestinal exposure may stimulate production of abnormal IgA

Viruses, bacteria, and food proteins have all been implicated

The specific initiating antigen or antigens remain unknown

Slide 10 · Microscopic hematuria may be the only clue

Isolated or predominant microscopic hematuria in 30%–40%

Proteinuria may accompany microscopic hematuria

A relatively silent clinical presentation does not establish a specific biopsy pattern

Slide 11 · Proteinuria reflects variable barrier injury

Typical proteinuria

Usually mild in IgA nephropathy.

Marked proteinuria

Can accompany more extensive glomerular injury and worsens prognostic assessment.

Slide 12 · Nephrotic syndrome is not the dominant phenotype

The nephrotic syndrome may occasionally arise

Robbins relates such cases to widespread podocyte injury

Podocyte injury adds a filtration-barrier component to mesangial disease

Slide 13 · A minority present with acute nephritic syndrome

Acute nephritic presentation

5%–10% of patients with an acute nephritic syndrome.

Rapidly progressive presentation

Some severe cases show crescentic glomerulonephritis and an aggressive course.

Slide 14 · Primary and secondary contexts must be separated

Usually renal-limited

Primary IgA nephropathy is typically an isolated kidney disease.

Potentially associated disease

Mesangial IgA deposits also occur in systemic conditions or secondary renal involvement.

Slide 15 · Recognized secondary clinical associations

Liver disease

Impaired hepatobiliary clearance of IgA-containing complexes.

Gluten enteropathy

Altered intestinal mucosal integrity in celiac disease.

Staphylococcal infection

An infectious setting can be accompanied by secondary IgA-dominant glomerular injury.

Slide 16 · IgA links mucosal immunity with renal deposition

Mucosal antigen exposure

IgA response

Abnormal circulating IgA

Mesangial deposition

Schematic — proposed link

Slide 17 · Normal plasma IgA exists mainly as monomers

Mucosal IgA

IgA is the principal immunoglobulin in mucosal secretions.

Circulating IgA

Serum IgA is normally present mainly as monomers; Polymeric forms are cleared, including by the liver.

Slide 18 · Polymeric IgA is increased but is insufficient alone

Patients may have increased circulating polymeric IgA

Polymeric IgA abundance by itself does not explain disease

The molecular quality of IgA1 is central to the proposed pathogenesis

Slide 19 · The IgA1 hinge region is a vulnerable target

IgA1 architecture

O-linked glycans are attached to the hinge region of IgA1.

Abnormal IgA1

Defective assembly or attachment of galactose-containing glycans changes the molecule recognized by the immune system.

Slide 20 · Abnormal O-glycosylation is a central hit

Altered glycosylation

Galactose-deficient IgA1

Immune recognition

Glomerular deposition

Conceptual pathogenesis

Slide 21 · A multi-hit pathogenesis integrates several events

1

Production of galactose-deficient IgA1

2

Immune recognition of the altered IgA1 molecule

3

Formation or local assembly of immune complexes

4

Mesangial cell activation and glomerular injury

Slide 22 · IgG autoantibodies recognize abnormal IgA1

Antigen

An abnormally glycosylated IgA1 molecule may become an autoimmune target.

Antibody response

IgG antibodies may bind altered IgA1 and create circulating immune complexes.

Slide 23 · Immune complexes can form along two routes

Circulating route

IgG antibodies bind abnormal IgA1 before glomerular deposition.

In situ route

Abnormal IgA1 deposits first; Immune complexes then form within the mesangial compartment.

Slide 24 · The mesangium is the dominant deposition site

Mesangial immune deposits

Central supporting region of the glomerular capillary tuft

Schematic — not a specimen

Slide 25 · IgA deposits stimulate mesangial activation

IgA-containing deposits

Mesangial cell activation

Cell proliferation

Expanded mesangial compartment

Native conceptual diagram

Slide 26 · Mesangial matrix increases with inflammation

Cellular component

Activated mesangial cells proliferate and increase cellularity.

Matrix component

The same activated cells generate additional extracellular matrix.

Slide 27 · Cytokines and growth factors amplify the response

Mesangial stimulation

Secreted mediators

Further mesangial activation

Glomerular injury

Autocrine and paracrine effects

Slide 28 · Inflammatory cells add to glomerular injury

Recruitment

Mesangial mediators may recruit inflammatory leukocytes into glomeruli.

Consequences

Leukocytes contribute to injury as well as clearance and repair of immune complexes.

Slide 29 · Immune complex handling is both injurious and reparative

Potential harm

Complement and inflammatory cells can amplify tissue damage.

Potential resolution

Opsonization and immune-complex removal contribute to repair.

Slide 30 · Alternative complement pathway is implicated

Deposited IgA complexes

Alternative pathway activation

C3-associated deposits

Inflammatory consequences

Complement pathway simplified

Slide 31 · Complement staining is a mechanistic clue

Deposit

Robbins description

Interpretive role

IgA

Prominent mesangial staining

Defines deposited immunoglobulin

C3 / properdin

Frequently accompany IgA

Consistent with complement activation

C1q / C4

Usually absent

Early classical components not typical

IgG / IgM

May occur in lesser amounts

Ancillary deposits

Slide 32 · Inherited susceptibility modifies disease risk

Familial clustering and concordance in HLA-identical siblings are reported

Some HLA and complement-related genotypes are associated with disease

Genome-wide association studies implicate MHC class II regions

Slide 33 · Environmental exposure acts on a susceptible host

Genetic susceptibility

Mucosal immune stimulus

Abnormal IgA1 response

Mesangial inflammation

Risk and response are not a deterministic sequence

Slide 34 · The multi-hit model connects blood to biopsy

1

Mucosal immune stimulation in a susceptible host

2

Circulating polymeric, aberrantly glycosylated IgA1

3

IgG autoantibodies / IgA-containing complexes

4

Mesangial deposition, complement and cell activation

5

Proliferation, matrix expansion, inflammatory injury

Slide 35 · Clinical and tissue findings need integration

Urine

Gross or microscopic hematuria; Often mild proteinuria.

Light microscopy

Variable mesangial and proliferative patterns.

Immunopathology

Mesangial IgA deposition anchors diagnosis.

Slide 36 · Light microscopy shows a wide spectrum

Minimal change

Glomeruli may appear nearly normal.

Proliferative

Mesangial or endocapillary cell increases.

Severe active

Focal lesions or rare crescents.

Chronic injury

Secondary segmental or global sclerosis.

Slide 37 · Normal-looking glomeruli do not exclude IgA disease

IgA nephropathy may have few changes by light microscopy

A visually subtle biopsy can still show prominent IgA on immunofluorescence

Diagnostic correlation across light microscopy, IF, and EM is essential

Slide 38 · Mesangial hypercellularity is a common active pattern

Expanded mesangium

Central supporting region of the glomerular capillary tuft

Schematic — not a specimen

Slide 39 · Expanded mesangium has several contributors

Cells

Proliferation increases mesangial cell number.

Matrix

Extracellular matrix accumulation enlarges the compartment.

Deposits

Immune material may also contribute to widening.

Slide 40 · Endocapillary proliferation changes capillary patency

Tissue finding

Cells within glomerular capillary spaces increase and may be accompanied by leukocytes.

Functional meaning

Inflammatory crowding can reduce filtration surface and contribute to nephritic manifestations.

Slide 41 · Focal and segmental proliferation is possible

Focal

Only some glomeruli are affected by proliferative lesions.

Segmental

Within an affected glomerulus, only part of the tuft may show injury.

Slide 42 · Crescentic IgA nephropathy is a severe pattern

Morphology

Crescents may occur, although overt crescentic GN is uncommon in this source.

Clinical correlation

The severest presentations can include a rapidly progressive nephritic course.

Slide 43 · Healing may leave focal segmental glomerulosclerosis

Focal proliferative injury

Repair / remodeling

Segmental tuft scar

Chronic filtration loss

Chronic sequelae

Slide 44 · Immunofluorescence demonstrates mesangial IgA

Illustrative mesangial IgA distribution

IgA localization is mesangial

C3 and properdin often accompany IgA

Early classical components usually absent

Schematic — not a specimen

Slide 45 · IgA staining must be interpreted with co-deposits

IgA

Mesangial pattern is diagnostic in the appropriate clinical setting.

C3 / properdin

Common accompanying immune reactants.

IgG / IgM

May be present but are usually less prominent.

Slide 46 · Electron microscopy localizes immune deposits

Capillary lumina

Mesangial region

Electron-dense immune deposits

Predominantly mesangial; Capillary-wall deposits usually sparse when present

Schematic — not a specimen

Slide 47 · Capillary-wall deposits are usually sparse

Electron-dense deposits predominate in the mesangium

Additional capillary-wall deposits, when present, are usually sparse

The dominant mesangial location helps connect pathogenesis with immunofluorescence

Slide 48 · The three modalities provide convergent evidence

Finding

Light microscopy

IF / EM corroboration

Mesangial expansion

More cells and / or matrix

Mesangial deposits on IF / EM

Endocapillary activity

Capillary crowding ± leukocytes

IgA immune deposits establish type

Segmental scarring

Chronic focal segmental sclerosis

IgA may remain detectable

Crescents

Severe extracapillary injury

Biopsy still requires immune typing

Slide 49 · How morphology links to clinical phenotype

Pathologic process

Expected consequence

Mesangial + glomerular inflammation

Erythrocyte leakage → hematuria

Podocyte / barrier injury

Increased albumin passage → proteinuria

Active severe proliferation

Acute nephritic or rapidly progressive syndrome

Glomerular scarring

Loss of functioning filtration units

Slide 50 · Biopsy IgA and circulating IgA are different measures

Circulating IgA

Elevated polymeric IgA may occur but is not sufficient for disease.

Deposited IgA

Glomerular IgA deposits are required to establish the biopsy diagnosis.

Slide 51 · Henoch–Schönlein purpura has overlapping renal disease

IgA nephropathy

Usually an isolated renal process with mesangial IgA.

Henoch–Schönlein purpura

A systemic disorder of children may show a similar IgA-associated renal lesion.

Slide 52 · Secondary IgA deposition requires clinical context

Liver disease

Consider defective IgA complex clearance.

Intestinal disease

Consider celiac disease and mucosal defects.

Staphylococcal infection

Consider an infection-associated immune process.

Slide 53 · IgA nephropathy versus Alport-spectrum disease

Distinguishing feature

IgA nephropathy

Alport spectrum

Dominant mechanism

Mesangial immune deposits

Type IV collagen defect

IF pattern

Mesangial IgA

IgA deposition not defining

Ultrastructure

Mesangial electron-dense deposits

Irregular GBM thinning / splitting

Clinical clues

Recurrent hematuria after infection

Familial hematuria ± hearing / eye findings

Slide 54 · The subsequent course is highly variable

Stable course

Some patients retain renal function for decades.

Recurrent activity

Hematuria episodes may recur repeatedly.

Progressive course

A subset develops chronic renal impairment.

Slide 55 · Long-term progression is a substantive risk

Chronic renal failure in 15%–40% over 20 years

Risk is not uniform across patients

Clinical and biopsy predictors help identify those more likely to progress

Slide 56 · Clinical predictors of progression

At presentation

Older age at onset is associated with increased risk.

During follow-up

Heavy proteinuria and hypertension are unfavorable.

At biopsy

Greater glomerulosclerosis suggests chronic injury and risk.

Slide 57 · Biopsy scarring has prognostic meaning

Active lesion

Mesangial or endocapillary proliferation reflects inflammation at biopsy.

Chronic lesion

Glomerulosclerosis indicates accumulated irreversible injury and is linked to worse prognosis.

Slide 58 · IgA deposits often recur after transplantation

Pathologic recurrence

IgA deposits frequently reappear in renal allografts.

Clinical evolution

Similar slow progression in about 15% of those with recurrent IgA deposits.

Slide 59 · Diagnostic reasoning begins with the phenotype

1

Recognize recurrent gross or persistent microscopic hematuria

2

Assess concomitant proteinuria and kidney dysfunction

3

Consider systemic and secondary IgA-associated conditions

4

Use biopsy morphology together with IgA immunofluorescence

Slide 60 · Case study: Recurrent visible hematuria

Illustrative vignette

A young adult reports repeated short episodes of visible hematuria following respiratory illnesses. Between episodes, urine appearance normalizes.

Question

Which renal immune-deposit pattern would strongly support IgA nephropathy?

Slide 61 · Case discussion: Hematuria after mucosal illness

Central clue

Recurrent gross hematuria after respiratory infections is a recognized presentation.

Pathologic answer

Mesangial IgA deposition by immunofluorescence; EM typically shows mesangial electron-dense deposits.

Slide 62 · Case study: Silent urine abnormalities

Illustrative vignette

Routine testing reveals persistent microscopic hematuria and mild proteinuria without a history of visible blood in the urine.

Question

Can IgA nephropathy be present if the light microscopic biopsy appearance is subtle?

Slide 63 · Case discussion: IF resolves subtle light microscopy

Interpretation

Yes. Some IgA nephropathy biopsies appear normal or nearly normal under light microscopy.

Diagnostic test

IgA staining in the glomerular mesangium is needed for diagnosis.

Slide 64 · Case study: Rapidly declining kidney function

Illustrative vignette

A person with hematuria develops rapidly worsening renal function and a biopsy containing crescents.

Question

Does the presence of crescents exclude IgA nephropathy?

Slide 65 · Case discussion: Severe active IgA disease

Interpretation

No. Crescentic glomerulonephritis is an uncommon but recognized IgA-associated pattern.

Required correlation

The biopsy still needs immunopathologic confirmation and clinical evaluation.

Slide 66 · Integrated synthesis: Molecule to clinical outcome

Altered IgA1 + immune complexes

Mesangial activation / complement

Inflammation and matrix expansion

Hematuria ± proteinuria ± scarring

Schematic integration

Slide 67 · Core distinctions for pathology practice

Light microscopy provides injury pattern; Immunofluorescence demonstrates the defining IgA deposits

Most deposits are mesangial; C3 often accompanies them without typical C1q / C4

Clinical behavior spans recurrent hematuria to progressive chronic renal failure

Age, heavy proteinuria, hypertension, and sclerosis inform prognosis

Slide 68 · References and source boundaries

Robbins, Cotran & Kumar: Pathologic Basis of Disease

11th edition (2026) · Chapter 20, The Kidney · pp. 836–837

Substantive section: “Other Glomerular Diseases” → “IgA Nephropathy”

Original native diagrams are conceptual schematics, not patient specimens.

No external treatment guideline, grading system, or uncited clinical image is included.