C3 Dominant Glomerulopathy

Slide 1 · C3-Dominant

Glomerulopathy

Complement dysregulation • glomerular morphology • clinicopathologic diagnosis

Dense deposit disease | C3 glomerulonephritis

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain how alternative-pathway dysregulation produces C3-dominant glomerular deposits.

Distinguish dense deposit disease from C3 glomerulonephritis by ultrastructure.

Integrate light microscopy, immunofluorescence, electron microscopy and clinical context.

Recognize key diagnostic pitfalls and implications for prognosis and transplantation.

Slide 3 · MPGN is a pattern of injury, not one etiology

Morphologic designation

Glomerular cell proliferation with capillary-wall remodeling.

Basement-membrane duplication produces double contours.

Mechanistic diagnosis

Immune complex–mediated disease and complement-mediated C3G can share this appearance.

Deposits and pathway of injury determine classification.

Slide 4 · The MPGN pattern remodels capillary walls

Capillary lumen / endothelium

Subendothelial region

GBM (lamina densa)

Subepithelial region

Podocyte side

Double contours indicate GBM remodeling

Simplified cross-section — not an electron micrograph

Mesangial interposition and new basement-membrane material can create double contours.

Slide 5 · Two pathogenetic pathways behind MPGN

Feature

Immune complex–mediated MPGN

C3-dominant glomerulopathy

Primary driver

Immunoglobulin-containing immune complexes

Alternative complement-pathway dysregulation

Glomerular IF

IgG and C3; C1q/C4 often present

C3-dominant; IgG usually absent

Characteristic EM

Discrete subendothelial deposits

DDD ribbon or C3GN cloudy deposits

Slide 6 · Historical types do not equal modern mechanisms

Older classification

Type I MPGN: Often immune complex–mediated.

Type II MPGN: Now termed dense deposit disease.

Mechanism-led classification

C3G encompasses dense deposit disease and C3 glomerulonephritis.

Morphologic MPGN is not obligatory in C3G.

Slide 7 · C3G encompasses two major deposit patterns

Dense deposit disease (DDD)

Formerly type II MPGN.

Extremely electron-dense intramembranous ribbonlike deposits.

C3 glomerulonephritis (C3GN)

Ill-defined or cloudy electron-dense deposits.

Deposits may occupy several glomerular compartments.

Slide 8 · The unifying mechanism is alternative-pathway excess

Mechanistic / diagnostic sequence

Genetic or acquired disturbance

Prolonged alternative pathway activity

C3 consumption / deposition

Glomerular injury

Distinct etiologies converge on the same complement-driven lesion.

Slide 9 · Why C3 deposition can occur without IgG

The alternative pathway can activate complement without immunoglobulin-containing immune complexes.

C3-containing products accumulate in glomeruli.

IgG is usually absent or much weaker than C3 on immunofluorescence.

Predominance of C3 is therefore pathogenetically informative.

Slide 10 · Alternative-pathway activation: The components

Core cascade relevant to glomerular C3 deposition

C3

C3b

C3b + factor B

C3bBb

C3 activation

Factor D cleaves B

Convertase identity

C3bBb is the alternative-pathway C3 convertase.

This enzyme generates additional C3b.

Mechanistic consequence

More active convertase amplifies C3 activation.

Poor control promotes glomerular complement deposition.

Slide 11 · Stimuli that initiate alternative-pathway activation

Bacterial polysaccharides

A non-antibody microbial activator named.

Endotoxin

A microbial trigger of the complement cascade.

IgA aggregates

An additional triggering stimulus.

Slide 12 · C3 activation generates C3b

C3 is central to alternative-pathway activation.

Activation yields C3b, which participates in convertase assembly.

Excessive cleavage leads to increased downstream complement activity.

C3

C3b

Activation

Glomerular C3 deposition

Slide 13 · Factor B enters the convertase assembly pathway

Mechanistic / diagnostic sequence

C3 activation

C3b formation

Factor B association

C3b–factor B complex

Factor B is a core alternative-pathway component.

Slide 14 · Factor D supports generation of the convertase

Mechanistic / diagnostic sequence

C3b + factor B

Factor D acts on B

Bb remains associated with C3b

C3bBb forms

The active C3 convertase comprises C3bBb.

Slide 15 · C3bBb is the alternative-pathway C3 convertase

Assembly of the enzyme that cleaves additional C3

C3

C3b

C3b + factor B

C3bBb

C3 activation

Factor D cleaves B

Convertase identity

C3bBb is the alternative-pathway C3 convertase.

This enzyme generates additional C3b.

Mechanistic consequence

More active convertase amplifies C3 activation.

Poor control promotes glomerular complement deposition.

Slide 16 · C3 amplification creates positive feedback

Persistent C3 convertase activity multiplies C3b production

C3bBb

C3 convertase

C3

More C3b

Positive feedback: New C3b sustains more convertase assembly

Slide 17 · Normal C3bBb is intrinsically labile

Normal behavior

C3bBb does not remain indefinitely active.

Its limited stability constrains complement amplification.

Disease-state implication

Stabilization or impaired inactivation allows continued C3 cleavage.

Persistent activation drives complement consumption.

Slide 18 · Properdin stabilizes C3 convertase

Properdin is a physiologic alternative-pathway component.

It prolongs the activity of C3bBb.

This positive influence contrasts with regulatory inactivation by factor H and factor I.

C3bBb

Stabilized

Persistent cleavage of C3

Slide 19 · Factor H and factor I restrain complement activity

Normal inhibition counterbalances convertase stabilization

C3bBb

Properdin

C3NeF autoantibody

Factor H / factor I

Stabilization

Stabilization

Inactivation

Disease results when activation persists despite normal restraining mechanisms.

Slide 20 · C3 nephritic factor sustains C3bBb

C3 nephritic factor (C3NeF) is an acquired autoantibody.

It binds and stabilizes the C3bBb convertase.

Protection from inactivation permits persistent C3 activation and C3 depletion.

C3bBb

Stabilized

Persistent cleavage of C3

Slide 21 · C3NeF mimics a convertase-stabilizing action

Mechanistic / diagnostic sequence

Circulating C3NeF

Binding to C3bBb

Resistance to inactivation

Persistent C3 consumption

C3NeF in acquired C3GN.

Slide 22 · Inherited complement abnormalities also cause C3G

Genetic variants in alternative-pathway components or regulators may produce disease.

Factor H is one example cited.

Genetic forms may present in children and younger adults.

C3bBb

Stabilized

Persistent cleavage of C3

Slide 23 · Acquired and inherited routes converge

Different initiating lesions share an excessive complement-activation endpoint

Genetic regulator defect

C3NeF autoantibody

Persistent C3bBb

C3 consumption +

Glomerular C3 deposition

Two initiating pathways converge on excessive alternative-pathway activation.

Slide 24 · The complement profile reflects pathway consumption

Typically decreased

Serum C3.

Factor B and properdin may be reduced through alternative-pathway activity.

Relatively preserved

Early classical pathway components such as C1 and C4.

An alternative-pathway pattern is suggested by low C3 with preserved C4.

Slide 25 · C3 and C4 help localize the activated pathway

Serologic observation

Mechanistic interpretation

Low C3

Supports complement activation / consumption

Normal C4 and early classical components

Compatible with preferential alternative-pathway involvement

Low factor B or properdin

Further supports alternative-pathway activity

A normal serum complement test

Cannot by itself exclude tissue-defined C3G

Slide 26 · Complement dysregulation becomes glomerular injury

The pathogenic sequence connects a circulating process with a tissue lesion

Genetic regulator defect

C3NeF autoantibody

Persistent C3bBb

C3 consumption +

Glomerular C3 deposition

Two initiating pathways converge on excessive alternative-pathway activation.

Slide 27 · Pathologic confirmation needs three modalities

Light microscopy

Defines the glomerular injury pattern and severity.

Immunofluorescence

Establishes dominance of C3 over routine immune reactants.

Electron microscopy

Localizes and characterizes deposits; Distinguishes DDD from C3GN.

Slide 28 · C3G displays diverse light-microscopic patterns

Mesangial proliferative

Mesangial cells and matrix predominate.

Inflammatory / endocapillary

Infiltrating leukocytes and increased glomerular cellularity.

Crescentic / MPGN-like

Crescents or double-contour capillary walls may occur.

Slide 29 · Mesangial proliferation is common in C3G

Many C3G biopsies are predominantly mesangial proliferative.

This differs from the assumption that every case must show classic MPGN.

Cellular and matrix expansion are patterns of injury, not proof of a specific complement defect.

Remodeled glomerular loops

Schematic — not a clinical or histologic specimen

Slide 30 · An inflammatory pattern can obscure the cause

Some glomeruli are hypercellular with inflammatory leukocytes.

Endocapillary inflammation may accompany complement deposition.

Immunofluorescence and EM remain necessary for mechanistic classification.

Remodeled glomerular loops

Schematic — not a clinical or histologic specimen

Slide 31 · Crescents signal a severe injury pattern

What is observed

C3G may show focally crescentic lesions.

Crescents indicate major glomerular capillary-wall injury.

Why it matters

A crescentic pattern raises concern for rapidly progressive clinical dysfunction.

The presence of crescents does not specify the deposit etiology.

Slide 32 · A classic MPGN pattern may also occur in C3G

Capillary lumen / endothelium

Subendothelial region

GBM (lamina densa)

Subepithelial region

Podocyte side

Double contours indicate GBM remodeling

Simplified cross-section — not an electron micrograph

MPGN remodeling and alternative-pathway disease are compatible.

Slide 33 · Double contours reflect GBM remodeling

Mechanistic / diagnostic sequence

Subendothelial-region injury

Interposition of cellular elements

New basement-membrane formation

Split / double-contour GBM

These changes can occur in immune complex MPGN and complement-driven lesions.

Slide 34 · Light microscopy cannot separate DDD from C3GN

LM can establish

Mesangial, endocapillary, crescentic or MPGN pattern.

Severity of glomerular cell response.

LM cannot reliably establish

The characteristic ultrastructural nature of deposits.

DDD versus C3GN without electron microscopy.

Slide 35 · Immunofluorescence identifies dominant C3

C3 signal is stronger than routine immune reactants.

The dominant component is complement, not deposited IgG.

C3-dominant staining directs attention to alternative-pathway dysregulation.

C3-dominant glomerular signal

Schematic — not a clinical or histologic specimen

Slide 36 · C3 dominance is a semiquantitative IF concept

Source / convention

Description

Robbins, 11th edition

C3 is typically much stronger than other routine reactants.

Consensus reporting convention

At least two IF intensity grades above any other immune reactant (0–3+ scale).

Interpretation

Do not equate this semiquantitative comparison with a literal biochemical concentration ratio.

Slide 37 · Immunoglobulin staining is usually absent

Expected C3G profile

Intense glomerular C3.

IgG generally absent or weak description.

Interpretation caveat

Some C3G biopsies can contain weaker immunoglobulin staining.

Absolute Ig negativity is not the defining requirement.

Slide 38 · Dense deposit disease has a distinctive IF distribution

C3 may outline capillary walls in irregular granular or linear foci.

C3 signal adjacent to, rather than within, the most electron-dense material.

Correlate the IF compartment with EM rather than expecting exact spatial identity.

C3-dominant glomerular signal

Schematic — not a clinical or histologic specimen

Slide 39 · C3 and properdin deposition support the mechanism

C3 and properdin within glomeruli.

These are products or components of the alternative pathway.

The deposited complement pattern links pathway dysregulation to the renal lesion.

C3-dominant glomerular signal

Schematic — not a clinical or histologic specimen

Slide 40 · Classical-pathway components are usually inconspicuous

Analyte

Typical pattern

Implication

Glomerular C3

Dominant signal

Complement-mediated injury

Glomerular IgG

Usually absent

Against conventional immune-complex dominance

C1q / C4

Generally absent in deposits

Classical-pathway activation less prominent

Slide 41 · Masked monoclonal immunoglobulin is a pitfall

Why caution is needed

Circulating paraproteins can accompany alternative complement activation.

Some deposits may be hidden on routine IF techniques.

What the pathologist must exclude

Masked monoclonal immunoglobulin deposits.

A paraprotein-related lesion that changes the final clinicopathologic diagnosis.

Slide 42 · EM requires precise compartment recognition

Capillary lumen / endothelium

Subendothelial region

GBM (lamina densa)

Subepithelial region

Podocyte side

Simplified cross-section — not an electron micrograph

Distinguish mesangial, subendothelial, intramembranous and subepithelial locations.

Slide 43 · Dense deposit disease: The hallmark is a ribbon

Capillary lumen / endothelium

Subendothelial region

GBM (lamina densa)

Subepithelial region

Podocyte side

Continuous intensely dense intramembranous ribbon

Simplified cross-section — not an electron micrograph

DDD shows homogeneous, extremely electron-dense material in the GBM.

Slide 44 · DDD deposits are intramembranous, not merely external

Anatomic location

The characteristic dense material lies within the lamina densa.

On EM it appears as a continuous or ribbonlike dense band.

Differential significance

This differs from discrete subendothelial immune-complex deposits.

The intramembranous ribbon strongly favors DDD.

Slide 45 · The biochemical nature of dense deposits is unresolved

Established morphology

Extremely electron-dense, homogeneous ribbonlike material.

The hallmark remains ultrastructural rather than molecular.

Source nuance

The precise composition as unknown.

Apolipoprotein E enrichment has been reported in dense deposits; This is not a substitute for EM diagnosis.

Slide 46 · C3GN shows less defined electron-dense deposits

Capillary lumen / endothelium

Subendothelial region

GBM (lamina densa)

Subepithelial region

Podocyte side

Indistinct deposits in variable locations

Simplified cross-section — not an electron micrograph

Cloudy, ill-defined deposits contrast with the dense ribbons of DDD.

Slide 47 · C3GN deposits occupy multiple compartments

Mesangium

Glomerular mesangial deposits may be present.

Capillary wall

Subendothelial and intramembranous deposits can occur.

Variable pattern

No defining continuous, extremely dense lamina-densa ribbon.

Slide 48 · Subepithelial humps occur in both C3G forms

Capillary lumen / endothelium

Subendothelial region

GBM (lamina densa)

Subepithelial region

Podocyte side

Subepithelial hump

Simplified cross-section — not an electron micrograph

Both DDD and C3GN may show subepithelial hump-shaped deposits.

Slide 49 · DDD versus C3GN: The decisive EM features

Feature

Dense deposit disease

C3 glomerulonephritis

Deposit texture

Homogeneous, exceptionally dense

Ill-defined, cloudy

Dominant location

Intramembranous lamina densa

Mesangial / intramembranous / subendothelial

Subepithelial humps

May occur

May occur

Light microscopy

Several proliferative patterns

Several proliferative patterns

Slide 50 · Immune-complex MPGN differs on IF and EM

Diagnostic axis

Immune complex MPGN

C3G

Mechanism

Immune complexes activate complement

Alternative-pathway dysregulation

IF

IgG + C3; C1q/C4 may be seen

Dominant C3; IgG usually weak/absent

EM

Discrete subendothelial deposits

DDD ribbon / cloudy C3GN deposits

LM

Can show GBM duplication

Can also show GBM duplication

Slide 51 · A practical biopsy interpretation pathway

Mechanistic / diagnostic sequence

Identify glomerular lesion on LM

Evaluate C3 / Ig dominance on IF

Characterize deposits by EM

Correlate with clinical/complement workup

Exclude masked monoclonal immunoglobulin when the phenotype suggests paraprotein-associated disease.

Slide 52 · Clinically, C3G bridges nephritic and nephrotic syndromes

Nephritic features

Hematuria and inflammatory glomerular injury.

Can coexist with substantial proteinuria.

Nephrotic features

Heavy proteinuria from filtration-barrier damage.

Patients may have a mixed nephritic–nephrotic phenotype.

Slide 53 · Dense deposit disease tends to present earlier

Children and young adults.

Clinical presentation may be nephritic, nephrotic, or mixed.

Age is a useful clue but is not itself diagnostic.

C3

C3b

Activation

Glomerular C3 deposition

Slide 54 · C3GN occurs across a broader age range

Early-onset / genetic forms

Genetic complement-regulator abnormalities may present in children or younger adults.

Factor H-related mechanisms are a textbook example.

Acquired forms

Age may reflect an associated disease.

Lymphoproliferative disorders are particularly relevant in older adults.

Slide 55 · Hematuria represents the nephritic dimension

Mechanistic / diagnostic sequence

Inflammatory glomerular injury

Capillary barrier disruption

Erythrocytes enter the urine

Clinical hematuria

Nephritic features arise from glomerular inflammation and capillary-wall injury.

Slide 56 · Proteinuria represents the nephrotic dimension

Mechanistic / diagnostic sequence

Complement-mediated glomerular injury

Filtration barrier dysfunction

Increased urinary protein loss

Nephrotic presentation

Marked proteinuria may coexist with active inflammatory changes.

Slide 57 · A single biopsy can show mixed injury

Cell proliferation

Mesangial or endocapillary hypercellularity.

Capillary-wall remodeling

GBM double contours when MPGN-like.

Complement deposits

C3 dominance on IF with EM-defined dense material.

Slide 58 · The prognosis can be unfavorable

Natural history

Substantial progression to end-stage kidney disease.

More than one-half progress to ESRD in the cited textbook overview.

Meaning for assessment

Morphologic activity and chronic damage are clinically consequential.

The patient needs longitudinal renal evaluation beyond the initial biopsy.

Slide 59 · Dense deposit disease frequently recurs after grafting

Textbook observation

Transplant recurrence in DDD at rates up to 90%.

The systemic complement abnormality can persist after renal replacement.

Pathogenetic lesson

Replacing the kidney does not automatically correct an upstream alternative-pathway defect.

Allograft pathology must be interpreted in clinical context.

Slide 60 · Teaching case: C3-dominant nephritis in a child

A child has hematuria, proteinuria, depressed serum C3, preserved C4, and a biopsy with dominant glomerular C3 staining.

Which pathway is implicated most directly?

A. Classical pathway only

B. Alternative complement pathway

C. A podocyte-only lesion

D. A primary IgG immune-complex process

Slide 61 · Teaching case: Interpret the complement findings

Best interpretation

Alternative-pathway dysregulation is strongly supported.

Low C3 with preserved C4 fits pathway consumption.

What biopsy data complete the workup?

LM identifies the injury pattern.

EM separates DDD from C3GN and assesses deposit distribution.

Slide 62 · Teaching case: An older adult with paraprotein

An older adult has an MPGN-like lesion, strongly dominant C3 staining and a circulating monoclonal protein.

Which issue requires particular exclusion?

A. Masked monoclonal immunoglobulin deposits

B. Foot-process effacement alone

C. An isolated podocyte structural mutation

D. A primary inherited collagen IV lesion

Slide 63 · Teaching case: A diagnostic pitfall resolved

Why this matters

Paraproteins may alter complement regulation.

Masked monoclonal deposits can change mechanistic classification.

The correct interpretation

Do not stop at a C3-dominant IF pattern alone.

Investigate paraprotein-related renal pathology with appropriate laboratory and pathology correlation.

Slide 64 · Morphology plus mechanism determines the diagnosis

Domain

The finding that matters

Pathogenesis

Abnormal alternative complement-pathway activity

LM

Variable injury pattern: Mesangial / inflammatory / crescentic / MPGN

IF

Dominant C3 staining; Assess immunoglobulins and C1q

EM

DDD ribbon vs C3GN cloudy deposits

Clinical

Hematuria, proteinuria, complement profile and associated conditions

Slide 65 · Test yourself: Classify the ultrastructure

Biopsy A

Intensely electron-dense homogeneous ribbon transforming lamina densa.

C3 is dominant on IF.

Biopsy B

Ill-defined mesangial and subendothelial deposits.

C3 is dominant on IF.

Slide 66 · EM classification: A is DDD, B is C3GN

Teaching biopsy

Subclassification

Decisive evidence

Biopsy A

Dense deposit disease

Ribbonlike extremely dense intramembranous deposits

Biopsy B

C3 glomerulonephritis

Cloudy, ill-defined mesangial / capillary-wall deposits

Slide 67 · C3G: Mechanism, tissue, clinic

Mechanistic / diagnostic sequence

Alternative-pathway dysregulation

C3 convertase persistence

Dominant glomerular C3 deposits

Nephritic / nephrotic renal disease

EM morphology separates dense deposit disease from C3 glomerulonephritis.

Slide 68 · References and source distinctions

Primary textbook

Robbins, Cotran & Kumar: Pathologic Basis of Disease. 11th ed. (2026). Chapter 20: The Kidney.

Supplementary diagnostic convention

Pickering MC, et al. C3 glomerulopathy: consensus report. Kidney International (2013).

All glomerular wall / immunofluorescence illustrations are original editable schematics, not patient images.