Other Glomerular Diseases

Slide 1 · Other Glomerular Diseases

IgA nephropathy • Alport spectrum disorders

Morphology | Pathogenesis | Clinicopathologic diagnosis

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Distinguish immune-complex glomerular injury from inherited basement-membrane disease.

Explain the multistep pathogenesis and mesangial morphology of IgA nephropathy.

Interpret IgA immunofluorescence and electron-microscopy patterns.

Relate type IV collagen defects to Alport renal and extrarenal manifestations.

Use integrated clinical, family-history, LM, IF, and EM findings in differential diagnosis.

Slide 3 · Two pathways to glomerular hematuria

Feature

IgA nephropathy

Alport spectrum disorders

Primary mechanism

Aberrantly glycosylated IgA1; immune complexes

Inherited defects of type IV collagen

Main initial site

Mesangial immune deposits

Glomerular basement membrane network

Defining evidence

Mesangial IgA on IF

Collagen-IV–associated ultrastructural/genetic findings

Shared manifestations

Hematuria; variable proteinuria

Hematuria; later proteinuria

Slide 4 · Glomerular compartments relevant to diagnosis

Capillary loops

Mesangial region

Conceptual schematic — not a histologic specimen

What each modality resolves

LM: Proliferation and scarring

IF: Immunoglobulin identity and location

EM: Electron-dense deposits or GBM defects

Slide 5 · Clinical phenotype directs the tissue question

Hematuria

Macroscopic or microscopic

Proteinuria / renal dysfunction

Variable severity and time course

Tissue findings

LM + IF + EM

Etiologic interpretation

Immune deposition vs structural collagen defect

The same urinary phenotype may reflect very different mechanisms.

Slide 6 · Core mechanisms are not interchangeable

IgA nephropathy

Alport disorders

Abnormal IgA1 and immune complexes

Mesangial deposition and activation

IF identifies mesangial IgA

Inherited collagen-IV defects

Basement-membrane instability

EM / collagen staining / genetics assist

Slide 7 · IgA nephropathy: Defining features

Prominent IgA deposits in the glomerular mesangium are required for diagnosis.

Recurrent hematuria is characteristic; Proteinuria is often mild.

It is as the most common glomerulonephritis worldwide.

Severe podocyte injury may occasionally produce nephrotic syndrome.

Crescentic glomerulonephritis is an uncommon presentation.

Slide 8 · Mesangial localization is the central clue

Capillary loops

Mesangial IgA deposits

Conceptual schematic — not a histologic specimen

Source-defined hallmark

IgA deposits in mesangial regions

Possible associated C3 staining

LM alone may underestimate disease

Slide 9 · Normal IgA handling provides mechanistic context

IgA is the principal immunoglobulin in mucosal secretions.

Circulating IgA is mainly monomeric and relatively low in concentration.

Polymeric IgA is normally catabolized in the liver.

In IgA nephropathy, circulating polymeric IgA increases, but increased production alone does not explain injury.

Slide 10 · Abnormal IgA1 hinge-region glycosylation

Normal IgA1

Galactose-bearing O-glycans

Galactose-deficient IgA1

Reduced galactose-bearing O-glycans

Simplified native vector model of IgA1 hinge-region O-glycosylation; Not molecular scale

Slide 11 · IgA nephropathy: The proposed multihit sequence

Aberrant IgA1

Galactose-deficient O-linked glycans

Anti-IgA response

IgG autoantibodies may recognize abnormal IgA1

Immune complexes

Circulating or in situ complexes

Mesangial injury

Cell activation, complement, matrix and inflammation

Robbins frames this sequence as the favored model, not as a fully resolved initiating cause.

Slide 12 · A glycosylation defect is not simply IgA overproduction

Glomerular deposits contain predominantly polymeric IgA with abnormal glycans.

A key proposed defect concerns galactose-bearing O-linked glycans on the IgA1 hinge region.

The defect may be hereditary or acquired.

Abnormally glycosylated IgA provides a substrate for mesangial deposition and autoantibody recognition.

Slide 13 · Autoantibodies amplify the initial IgA abnormality

IgG autoantibodies may target structurally abnormal IgA1.

IgG–IgA interactions can generate circulating immune complexes.

The model explains why elevated IgA production alone is insufficient.

The source also allows mesangial deposition of abnormal IgA before local complex formation.

Slide 14 · Two routes to mesangial immune complexes

Circulating deposition

In situ formation

Aberrant IgA1 reacts with IgG

Preformed complexes circulate

Complexes become trapped in mesangium

Aberrant IgA1 deposits first

Antibody then binds deposited IgA1

Complex forms within mesangium

Slide 15 · Complement involvement in IgA nephropathy

Typical IgA-nephropathy IF

IgA: Mesangial dominant deposition

C3 and properdin: Often present

IgG or IgM: May be weaker

Usually absent or not prominent

C1q: Usually absent

C4: Usually absent

Supports alternative-pathway involvement

Slide 16 · Deposits translate into mesangial injury

Mesangial deposits

IgA-containing immune complexes

Cell activation

Mesangial proliferation and mediators

Matrix expansion

Extracellular matrix deposition

Glomerular injury

Leukocyte recruitment; Altered capillary function

A mesangial deposit is a stimulus for cellular and matrix responses, not merely a passive stain.

Slide 17 · Inflammatory amplification affects lesion severity

Activated mesangial cells release cytokines and growth factors.

These mediators further stimulate mesangial cells and recruit inflammatory cells.

Leukocytes contribute to injury but also aid clearance of immune complexes.

The balance between injury and repair helps explain heterogeneous biopsy patterns.

Slide 18 · Genetic susceptibility modifies risk

Familial occurrence and affected HLA-identical siblings support inherited susceptibility.

Associations have been reported with certain HLA and complement genotypes.

Genome-wide studies implicate MHC class II loci.

Genetic susceptibility does not identify a single obligatory initiating antigen.

Slide 19 · Mucosal exposures may influence abnormal IgA production

Respiratory and gastrointestinal exposure to environmental agents may increase abnormal IgA synthesis.

Viruses, bacteria, and dietary antigens have been implicated.

The precise initiating antigen remains unknown in the source account.

This context helps explain hematuria episodes temporally related to infection.

Slide 20 · Secondary IgA deposition: Relevant systemic settings

Clinical context

Source-supported rationale

Chronic liver disease

Defective hepatobiliary clearance of IgA complexes

Celiac disease

Increased frequency with altered intestinal mucosal barrier

Other intestinal disorders

Secondary IgA nephropathy may occur

Staphylococcal infection

Infection-associated IgA deposition may occur

Slide 21 · Primary and secondary IgA disease

Primary renal disease

Secondary IgA disease

Often an isolated glomerular process

Recurrent hematuria is frequent

Mesangial IgA remains the defining tissue feature

Associated with liver/intestinal disorders or infection

Systemic context can influence interpretation

IgA deposits alone do not establish primary disease

Slide 22 · Light microscopy: Wide morphologic spectrum

Observed pattern

Potential interpretation

Normal-appearing glomeruli

LM may fail to reveal the immune-deposition process

Mesangial expansion

More cells, matrix, deposits, or combinations

Endocapillary proliferation

Inflammatory/proliferative activity

Focal or segmental proliferation

Involves only some glomeruli or tuft segments

Crescentic lesion

Rare severe proliferative injury

Slide 23 · Mesangial expansion: More than one substrate

Capillary loops

Mesangial IgA deposits

Conceptual schematic — not a histologic specimen

Mesangial widening arises from

Increased mesangial-cell number

Extracellular matrix accumulation

Immune deposits or mixed causes

Slide 24 · Endocapillary and segmental activity

Endocapillary proliferation may accompany mesangial changes.

Focal proliferative lesions involve only some glomeruli.

Segmental disease may affect part of the tuft rather than its entirety.

The number of intracapillary leukocytes varies from case to case.

Slide 25 · Crescents identify an unusually severe phenotype

Crescentic glomerulonephritis is uncommon in ordinary IgA nephropathy.

Its appearance correlates with a rapidly progressive nephritic presentation in some patients.

Severity cannot be inferred from mesangial IgA staining alone.

Interpret crescents together with the entire injury pattern and clinical trajectory.

Slide 26 · Proliferative injury can leave a sclerotic residue

Focal injury

Localized active tuft lesion

Healing response

Resolution with structural repair

Segmental scarring

Secondary focal segmental sclerosis

Functional loss

Reduced functional glomerular reserve

Current biopsy activity and chronic scarring provide different kinds of information.

Slide 27 · Immunofluorescence establishes the diagnosis

Mesangial IgA deposition is characteristic and is required for the diagnosis.

C3 and properdin are frequently detected together with IgA.

IgG or IgM can be present in lower abundance.

Early complement components are usually absent.

Slide 28 · IgA immunofluorescence: Interpret the full panel

Target

Typical biopsy observation

Inference

IgA

Prominent mesangial staining

Defining immune deposit

C3 / properdin

Often present

Alternative-pathway involvement

IgG / IgM

May be present in lesser amounts

Mixed immune-component deposition

C1q / C4

Usually absent

Early complement pathway not typically prominent

Slide 29 · Electron microscopy confirms deposit localization

Electron-dense immune deposits are predominantly mesangial.

Capillary-wall deposits can occur but are usually sparse.

Electron microscopy complements rather than replaces IF identification of IgA.

LM and EM heterogeneity should be reconciled with the immune staining pattern.

Slide 30 · Three microscopy modalities answer different questions

Light microscopy

Normal → proliferative

Mesangial / endocapillary

Rare crescents

Immunofluorescence

Mesangial IgA

Often C3, properdin

Early complement usually absent

Electron microscopy

Electron-dense deposits

Predominantly mesangial

Sparse capillary deposits

Slide 31 · IgA diagnostic synthesis

Clinical phenotype

Hematuria ± proteinuria

Renal biopsy LM

Activity, matrix, sclerosis

IgA-predominant IF

Specific mesangial immunoglobulin

Deposit distribution

Mesangial electron densities

Biopsy findings are interpreted with secondary causes and clinical context in mind.

Slide 32 · Clinical expression ranges from silent to severe

Some patients have microscopic hematuria detected incidentally.

Others experience episodic gross hematuria after mucosal infection.

Proteinuria ranges from mild to nephrotic-range in severe podocyte injury.

A small minority present with acute nephritic or rapidly progressive disease.

Slide 33 · Recurrent hematuria can follow a relapsing course

Mucosal infection

Respiratory infection often precedes episode

Macroscopic hematuria

Visible blood may last several days

Resolution

Hematuria subsides between attacks

Recurrence

Episodes may recur after months

Conceptual time course without quantitative incidence or fixed individual timing

Slide 34 · Microscopic hematuria is a frequent presentation

Microscopic hematuria alone in about 30%–40% of patients.

Proteinuria may be present or absent in this group.

Detection depends on urinalysis rather than visible change in urine.

An initially mild presentation does not eliminate the need to assess longitudinal renal risk.

Slide 35 · Nephritic and nephrotic expressions are distinct

Acute nephritic syndrome in approximately 5%–10% of cases.

Rapidly progressive glomerulonephritis may occur in a subgroup with severe injury.

The nephrotic syndrome is less common and may reflect extensive podocyte damage.

The clinical syndrome and biopsy lesion should be described separately.

Slide 36 · Age and episodic symptoms provide diagnostic context

IgA nephropathy can affect any age group.

Older children and young adults are most commonly affected.

Gross hematuria may follow respiratory, gastrointestinal, or urinary tract infection.

Visible hematuria usually resolves over several days and may recur months later.

Slide 37 · Why prognosis is heterogeneous

Relatively preserved course

Progressive course

Many patients maintain stable renal function for decades

Hematuria may recur without immediate failure

Clinical follow-up distinguishes the trajectory

Sustained proteinuria and hypertension increase concern

Glomerulosclerosis indicates established structural injury

Progression may be prolonged rather than abrupt

Slide 38 · Long-term renal outcomes cohort

Chronic renal failure in 15%–40% of patients over about 20 years.

This is a historical textbook estimate rather than a personalized prediction.

Many patients maintain normal renal function for decades.

The observed course reflects marked heterogeneity in activity and chronic injury.

Slide 39 · Markers of greater progression risk

Feature

Clinicopathologic rationale

Older age at onset

Textbook-associated adverse course

Heavy proteinuria

More severe glomerular barrier injury

Hypertension

Concomitant clinical injury burden

More glomerulosclerosis

Established irreversible structural damage

Slide 40 · IgA deposits can recur after renal transplantation

IgA deposition in transplanted kidneys is frequent in the source account.

A recurrent deposit is not automatically equivalent to clinically progressive dysfunction.

That approximately 15% of patients with recurrent IgA deposits follow a similarly progressive course.

Histologic recurrence and clinically important recurrence should be distinguished.

Slide 41 · IgA nephropathy versus systemic IgA vasculitis

Feature

IgA nephropathy

IgA vasculitis (Henoch–Schönlein)

Distribution

Typically isolated renal disease

Skin, gastrointestinal tract, joints, kidneys

Renal deposits

Mesangial IgA

Often analogous mesangial IgA

Clinical clue

Episodic hematuria

Purpura with systemic manifestations

Mechanistic overlap

IgA-driven immune processes

Overlapping IgA-driven immune processes

Slide 42 · Apply the IgA pathway to a clinical vignette

Fictional teaching vignette

An older child has brief recurrent gross hematuria after respiratory illness.

Urinalysis also detects mild proteinuria.

Biopsy IF is dominated by mesangial IgA.

Questions

Which compartment is involved?

Which antibody class is essential to the diagnosis?

Why may LM show varied degrees of proliferation?

Teaching vignette — constructed for learning, not a real patient case

Slide 43 · Interpret the IgA vignette

Fictional teaching vignette

Recurrent post-infectious hematuria is compatible with the clinical pattern.

Mesangial IgA provides the decisive immunopathologic clue.

Activity and scar burden must still be documented.

Interpretation

Mesangium is the main deposit compartment.

IgA immunofluorescence is defining.

Mesangial activation, immune deposits, matrix and leukocytes vary.

Teaching vignette — constructed for learning, not a real patient case

Slide 44 · Alport spectrum: A structural glomerular disorder

Alport disorders are familial nephropathies associated with basement-membrane component mutations.

Classic severe Alport syndrome reflects defective type IV collagen assembly.

Hematuria is the common initial renal manifestation.

The full phenotype may combine progressive kidney injury, sensorineural hearing loss, and ocular changes.

Slide 45 · The glomerular collagen IV network requires α3, α4 and α5

α3 chain

α4 chain

α5 chain

Collagen IV α3–α4–α5 network

Variant affecting one essential chain → defective network assembly

Slide 46 · A defective chain compromises network assembly

Intact collagen IV network

Disordered network

Conceptual collagen-IV network topology; Not an image of glomerular basement membrane

Slide 47 · Collagen-IV mutations produce multisystem effects

The α3–α4–α5 collagen IV network is central to glomerular basement-membrane function.

Collagen IV also supports specialized basement membranes in the inner ear and eye.

Missense, splice-site, insertion and deletion variants are described.

The inheritance pattern depends on which collagen-IV gene is affected.

Slide 48 · Inheritance patterns in the Alport spectrum

Mode

Typical implications

X-linked

Majority of classic cases in Robbins; often severe disease in affected males

Autosomal recessive

Both sexes can manifest the full syndrome

Autosomal dominant / heterozygous

Often milder hematuria spectrum; progression remains possible

Slide 49 · X-linked Alport disease is frequently more severe in males

The textbook attributes approximately 85% of cases to X-linked inheritance.

Affected males often manifest the complete renal and extrarenal syndrome.

Heterozygous females commonly present with hematuria, but require surveillance.

Phenotype varies with the pathogenic variant; Not every carrier remains clinically mild.

Slide 50 · Penetrance and renal risk require contextual interpretation

Complete penetrance for classic X-linked Alport syndrome.

It reports that about 90% of affected males develop end-stage renal disease by age 40.

These figures describe the textbook’s reported cohorts and are not individualized predictions.

Less severe phenotypes occur within the broader collagen-IV disease spectrum.

Slide 51 · Early light microscopy may be deceptively normal

Glomeruli may appear normal by light microscopy early in Alport disease.

Early urinary blood loss reflects a molecular structural defect rather than required immune deposits.

Light microscopy becomes more abnormal as chronic scarring develops.

An unremarkable LM sample does not exclude inherited collagen-IV disease.

Slide 52 · Alternating GBM thinning and thickening

Thin segment

Thickened segment

Irregular alternation of attenuated and expanded GBM regions

Conceptual basement-membrane schematic — not an electron micrograph

Slide 53 · Lamina-densa splitting creates a basket-weave pattern

Central splitting / lamellation

Single dense layer

Reconverging layers

Layer separation produces the characteristic basket-weave description

Conceptual basement-membrane schematic — not an electron micrograph

Slide 54 · Electron microscopy provides structural evidence

Fully developed disease may show irregular GBM thickening alternating with attenuation.

Splitting and lamellation of the lamina densa can create a basket-weave appearance.

Similar basement-membrane alterations may occur in tubules.

These features are most informative within the clinical and familial context.

Slide 55 · Late Alport lesions evolve toward chronic scarring

Focal segmental glomerulosclerosis can occur as disease progresses.

Global glomerulosclerosis reflects more extensive permanent injury.

Tubular atrophy, interstitial fibrosis and vascular sclerosis may accompany late disease.

Underlying basement-membrane instability may increase podocyte vulnerability.

Slide 56 · Collagen IV staining complements morphology

Tissue/target

Textbook observation

Interpretive role

Glomerular / tubular BM

Classic X-linked disease may lack α3, α4, α5 staining

Supports disturbed collagen-IV network

Skin biopsy

Loss of α5 staining may be seen

Ancillary evidence in classic X-linked disease

Electron microscopy

Thinning, thickening, lamellation

Structural evidence of glomerular BM disorder

Slide 57 · The classic Alport phenotype spans three organ systems

Kidney

Hematuria → proteinuria → declining function

Inner ear

Sensorineural hearing loss

Eye

Lens, cataract and corneal abnormalities

One inherited basement-membrane network can affect multiple organs.

Slide 58 · Sensorineural hearing loss may be clinically subtle

Cochlear basement-membrane dysfunction produces sensorineural hearing deficits.

Auditory involvement can be mild or initially overlooked.

Sensitive auditory testing may be required.

Hearing impairment provides an important extrarenal clue to renal hematuria.

Slide 59 · Ocular lesions broaden the diagnostic phenotype

Lens dislocation and posterior cataracts.

Corneal dystrophy is another reported manifestation.

Eye findings reflect the role of collagen IV in ocular basement membranes.

Their coexistence with hematuria and hearing loss strengthens clinical suspicion.

Slide 60 · Alport renal presentation can evolve over years

Hematuria

Often earliest clinical finding

Proteinuria

May arise after years

GBM remodelling

Thinning, thickening and lamellation

Chronic kidney injury

Sclerosis, fibrosis and declining function

Conceptual progression; Timing and penetrance vary across variants

Slide 61 · Typical ages and chronology in classic disease

Urinary hematuria is often first detected between ages 5 and 20 years.

Proteinuria may arise later in the disease course.

Overt male renal failure between approximately ages 20 and 50 years.

A later-onset, milder course is possible within the spectrum.

Slide 62 · COL4A5 variant type can influence severity

The source associates large deletions affecting COL4A5 with earlier end-stage kidney disease in X-linked cases.

Type IV collagen assembly is impaired by different pathogenic variant classes.

Genotype–phenotype correlations vary and must not replace phenotype assessment.

Genetic findings support inheritance counseling and longitudinal follow-up.

Slide 63 · Mild Alport variants and thin GBM findings

Domain

Source-supported features

Clinical

Familial hematuria; sometimes mild or moderate proteinuria

Ultrastructure

Diffuse or segmental GBM attenuation; focal lack of lamina densa

Genetic background

Often heterozygous type IV collagen-related variants

Long-term outcome

May remain stable or develop renal decline and FSGS

Slide 64 · Basement-membrane thickness in the source text

Condition

Illustrative adult GBM width

Thin basement-membrane phenotype

Approximately 150–225 nm

Healthy adult reference in Robbins

Approximately 300–400 nm

Textbook ranges require careful EM processing and laboratory interpretation.

Slide 65 · A disease spectrum requires family-based interpretation

Milder heterozygous X-linked and autosomal variants may share clinical features with severe Alport syndrome.

Some relatives with apparently isolated familial hematuria may have severe disease.

Thin basement-membrane nephropathy overlaps genetically with collagen-IV disorders.

Genetic counseling and sustained clinical follow-up are important across the spectrum.

Slide 66 · IgA nephropathy versus Alport spectrum

Dimension

IgA nephropathy

Alport spectrum

Fundamental defect

Immune-complex deposition

Inherited collagen-IV network defect

Initial anatomic focus

Mesangium

GBM

IF

Mesangial IgA

Collagen-IV staining may be abnormal

EM

Mesangial electron-dense deposits

GBM thinning, thickening, lamellation

Extrarenal clues

Mucosal illness; secondary settings

Hearing loss; ocular anomalies; family history

Slide 67 · Diagnostic reasoning for persistent hematuria

Clinical pattern

Recurrent infection-linked? Progressive familial?

Family / systemic clues

IgA-associated disease vs hearing/ocular findings

Biopsy interpretation

Mesangial IgA deposits vs altered GBM ultrastructure

Etiologic conclusion

Integrate IF, EM and hereditary context

No single routine light-microscopic pattern distinguishes every patient.

Slide 68 · Compare two hematuria presentations

Fictional teaching vignette

Case A: Recurrent hematuria after respiratory illnesses; Mesangial IgA staining.

Case B: Familial hematuria with hearing impairment; EM reveals lamellated GBM.

Interpretation

Case A: IgA nephropathy is favored.

Case B: Alport-spectrum disease is favored.

Which test establishes each mechanism?

Teaching vignette — constructed for learning, not a real patient case

Slide 69 · Synthesis: Link mechanism to diagnostic observation

Disease group

Causal lesion

Best differentiating clue

IgA nephropathy

Aberrant IgA1 → immune complexes → mesangial activation

Mesangial IgA by immunofluorescence

Alport spectrum

Type IV collagen defect → GBM network instability

GBM ultrastructure, collagen-IV studies and family/genetic context

Both

Variable glomerular barrier injury and hematuria

Clinical phenotype alone may overlap

Slide 70 · Clinical reasoning check

Which source-supported lesion explains mesangial IgA with recurrent gross hematuria?

Why is isolated hematuria compatible with early Alport disease despite normal LM?

Which biopsy modality directly demonstrates lamina-densa lamellation?

Which Alport-associated extrarenal findings should be actively sought?

Why must secondary contexts be considered before labeling IgA nephropathy primary?

Slide 71 · Answers: Core discriminating principles

IgA immune-complex deposition and mesangial activation.

The primary collagen-IV structural defect can precede light-microscopic scarring.

Electron microscopy identifies GBM thickness changes and lamellation.

Sensorineural hearing abnormalities and characteristic ocular changes.

Liver, intestinal, and infection-associated conditions may cause secondary IgA deposition.

Slide 72 · Primary reading

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th edition (2026).

Renal chapter: glomerular diseases; IgA nephropathy and Alport spectrum disorders.

Core diagnostic framework: clinical findings together with LM, IF, EM and genetic/family context.

Schematic drawings in this lecture are conceptual, editable and not patient images.