Understanding Glomerulonephritis: (Part 1 – Pathophysiology and mechanisms)

 The kidney is not merely a blood-cleaning organ — it’s a precisely engineered filtration system, packed into a space smaller than your fist. At the heart of this system lies the glomerulus, a tight ball of capillaries ensconced within Bowman’s capsule, where blood meets filter.

When this filter becomes inflamed — a condition called glomerulonephritis (GN) — its normally selective barrier becomes leaky, irritable, and dysfunctional. Blood cells and proteins that should stay in the bloodstream escape into the urine. Waste products that should be cleared begin to build up.

 

In this post, we’ll explore what glomerulonephritis actually is, how it disrupts the kidney’s filtration barrier, and why understanding its immune mechanisms matters — especially before diving into clinical patterns.

🧭 Coming Up after this in Part 2, we’ll explore how these injuries translate into clinical syndromes — particularly the classic nephritic vs nephrotic divide — and walk through real-world cases to bring the concepts to life.

Glomerulonephritis (GN) refers to a group of kidney disorders characterized by inflammation of the glomeruli — the microscopic filters in the nephron responsible for removing waste and excess fluid from the blood. This inflammation disrupts the filtration barrier, leading to leakage of protein and/or blood into the urine.

Why It Matters

GN is a key cause of chronic kidney disease and can present acutely or insidiously. It represents a point where immunology, microbiology, and physiology collide — a systemic story told through the microscope and the dipstick. Whether it’s a ten-year-old boy with cola-coloured urine after a sore throat, or a young woman with lupus and frothy urine, recognising patterns of GN helps anchor everything. Understanding its underlying mechanisms lays the groundwork for interpreting urinalysis, managing renal syndromes, and appreciating systemic diseases with renal involvement.

🔬 Pathophysiology of glomerulonephritis: The “how” behind the haematuria

At its core, glomerulonephritis is an immune-mediated injury to the glomerular capillary wall — the filtration barrier. This barrier consists of: 

1. Fenestrated endothelium – allows plasma through but blocks blood cells. 
2. Glomerular basement membrane (GBM) – a dense protein meshwork that selectively filters based on size and charge. 
3. Podocytes with slit diaphragms – wrap around the capillaries, offering the final gatekeeper function.

Any immune-mediated damage to these structures disrupts selective permeability, allowing red cells and/or proteins to leak into the urine, setting the stage for either nephritic (inflammatory, haematuric) or nephrotic (leaky, proteinuric) patterns — a dichotomy we’ll discuss in Part 2.

🔬 Mechanisms of injury: Not all inflammation is the same

Glomerulonephritis can arise from multiple immune processes. Think of them as different routes to the same destination — structural damage to the glomerulus:

• Immune complex–deposition (e.g. post-streptococcal GN, lupus nephritis): circulating antigen–antibody complexes deposit in the glomerulus, activating complement and recruiting inflammatory cells.
• Anti-GBM–mediated (e.g. Goodpasture’s): antibodies target intrinsic glomerular structures, leading to direct tissue attack.
• Pauci-immune (e.g. ANCA vasculitis): no immune complexes, but activated neutrophils wreak havoc on the glomerular capillaries.

Each process leaves a molecular fingerprint — from complement consumption in PSGN to the eerie immunofluorescent silence of ANCA vasculitis.

🧩 Types of Glomerulonephritis: Classifying the Chaos

Glomerulonephritis can wear many faces. Classifying it helps us make sense of its tempo, pathology, and potential reversibility — all key clues for clinical reasoning.

⏱ Temporal Patterns: How Fast is the Injury Unfolding?

Acute GN

• Sudden, often dramatic onset. Commonly post-infectious.
• Example: Post-streptococcal GN (PSGN)
• ⮞ Typically presents with haematuria, oedema, and hypertension in children.

Chronic GN

• Insidious progression over months to years.
• Example: Chronic IgA nephropathy
• ⮞ May silently smoulder until proteinuria or declining renal function is detected.

Rapidly Progressive GN (RPGN)

• A medical emergency. Crescents on biopsy reflect severe glomerular injury and capillary rupture.
• Example: Goodpasture’s, ANCA-associated vasculitis
• ⮞ Think: “rapid decline in renal function over days to weeks.”

🔬 Histological Patterns: What Does the Glomerulus Look Like?

Proliferative GN

• Hallmark: increased cellularity — either from infiltrating leukocytes, proliferating mesangial cells, or both.
• Examples: IgA nephropathy, PSGN, lupus nephritis (Class III/IV)
• ⮞ Inflammation compromises capillary lumens, leading to haematuria and reduced filtration.

Non-proliferative GN

• Hallmark: normal or minimal hypercellularity, but significant changes to basement membrane or podocytes.
• Examples: Minimal change disease, membranous nephropathy
• ⮞ Here, barrier structure is altered — especially the slit diaphragm — leading to heavy proteinuria and nephrotic features without much inflammation

💡 Teaching Pearl

Proliferative → think inflammation and nephritic features.
Non-proliferative → think leakiness and nephrotic features.

Now let's talk about a few key conditions

🦠 Post-Streptococcal glomerulonephritis (PSGN) 

Trigger: A group A Streptococcus (GAS) infection, like strep throat or skin infections, can trigger an immune response.

Timeline: GN usually develops 1–3 weeks after the infection has resolved — a key clue in history-taking.

🔄 What happens?

1. Strep antigens (e.g. nephritogenic exotoxins) circulate. The body produces antibodies to fight off the infection and the bacterial antigens form immune complexes with host antibodies.
2. These complexes deposit in the glomerular basement membrane and mesangium.
3. Complement is activated (especially C3), leading to:

• Recruitment of neutrophils and monocytes
• Release of proteases and reactive oxygen species
• Inflammation and capillary wall damage

The “why” in PSGN lies in the immune system’s response to streptococcal antigens — particularly nephritogenic strains of Streptococcus pyogenes.

• Molecular mimicry is one proposed mechanism: Some streptococcal antigens share structural similarities with proteins found in the glomeruli. Antibodies generated against streptococcal antigens (like streptococcal pyrogenic exotoxin B or nephritis-associated plasmin receptor) may cross-react with glomerular proteins, mistaking self for non-self.
• These antibodies form immune complexes either in circulation or directly in the glomerulus (in situ), triggering complement activation and inflammatory damage in the glomerulus.
• Some streptococcal proteins, like the streptococcal inhibitor of complement, may also interfere with normal immune regulation, amplifying injury.
• This is a classic Type III hypersensitivity reaction — immune complex–mediated tissue injury.

🧪 Key findings

• Low serum C3 (returns to normal in 6–8 weeks)
• “Lumpy-bumpy” immune complex deposits on immunofluorescence
• Hypercellular glomeruli on light microscopy (due to neutrophil influx)
• Red cell casts and proteinuria on urinalysis

🧠 Clinical analogy

Think of the glomerulus as a coffee filter. In PSGN, immune complexes clog and inflame the filter, causing it to leak both blood and protein — but not in the massive quantities seen in nephrotic syndrome.

📦 Pathophysiology Spotlight: Post-Streptococcal Glomerulonephritis (PSGN)

Type: Immune complex–mediated GN (Type III hypersensitivity)
Trigger: Nephritogenic Group A Streptococcus

Mechanism:

• Streptococcal antigens form immune complexes with antibodies
• Complexes deposit in glomeruli
• Complement activation → neutrophil recruitment → inflammation

Why? Molecular mimicry and excessive immune activation

Histology Tip: “Lumpy-bumpy” granular deposits, hypercellular glomeruli
Clinical Clue: Haematuria 1–3 weeks post-pharyngitis or impetigo

Reminder - this is the same Group A Streptococcus that can cause scarlet fever, rheumatic fever, rheumatic heart disease and neurological disorders - all because of its immunological effects !!!

🫁Goodpasture's syndrome

In Goodpasture’s syndrome, the immune system produces autoantibodies against the α3 chain of type IV collagen, a structural protein found in the basement membranes of certain organs. What’s fascinating is that this specific collagen isoform is highly expressed in both the glomerular basement membrane (GBM) of the kidneys and the alveolar basement membrane in the lungs — but not in most other tissues.

So, the reason both organs are affected is anatomical and molecular: they share a target antigen! 

Here’s how it plays out:

• In the kidneys, direct antibody binding to the GBM leads to complement activation, inflammation, and rapidly progressive glomerulonephritis (type II hypersensitivity)
• In the lungs, the same antibodies bind to the alveolar basement membrane, causing pulmonary haemorrhage — especially in the setting of increased capillary permeability (e.g. from smoking or infection).

This dual involvement gives rise to the classic “pulmonary-renal syndrome”.

Interestingly, environmental exposures like smoking, hydrocarbon inhalation, or respiratory infections may increase alveolar permeability, making the lungs more vulnerable to antibody attack — which is why some patients present with haemoptysis before renal symptoms.

🧪 Key findings

• Anti-GBM antibodies positive in serum
• Linear IgG deposition along the GBM on immunofluorescence
• Crescentic glomerulonephritis on light microscopy (indicative of rapidly progressive GN)
• Haematuria and red cell casts on urinalysis
• Pulmonary infiltrates or haemoptysis if alveolar involvement
• Normal complement levels (helps distinguish from immune complex GN)

🧠 Clinical analogy

Imagine the glomerular basement membrane as a smooth wall. In Goodpasture’s, the immune system fires antibodies like paintballs directly at the wall — coating it in a linear pattern and punching holes through it. The result? Blood leaks out, fast. And if the same wall lines your alveoli, you might cough up blood before your kidneys even complain.

📦 Pathophysiology Spotlight: Goodpasture’s Syndrome

Type: Anti-GBM–mediated GN (Type II hypersensitivity)
Trigger: Autoantibodies against α3(IV) collagen

Mechanism:

• Direct antibody binding to GBM and alveolar basement membrane
• Complement activation and tissue injury

Why? Loss of tolerance to normally hidden antigen (may be unmasked by infection or smoking)

Histology Tip: Linear IgG deposition on immunofluorescence
Clinical Clue: Pulmonary hemorrhage + GN = “pulmonary-renal syndrome”

🧪Autoimmune glomerulonephritis 

Autoimmune GN arises when the immune system targets self-antigens in the kidney. 🔍 Three Major Immunopathological Patterns

Anti-GBM–mediated disease – Type II hypersensitivity

• Autoantibodies directly bind to GBM antigens (e.g. Goodpasture’s).
• Characteristic linear IgG deposition.
• Often presents with pulmonary hemorrhage + GN (hence “pulmonary-renal syndrome”).

Immune complex–mediated GN – Type III hypersensitivity

• Circulating or in situ immune complexes deposit in the glomerulus (e.g. lupus nephritis).
• Can present with nephritic or nephrotic features, depending on the class.
• Granular “lumpy-bumpy” immunofluorescence with full-house staining (IgG, IgA, IgM, C3, C1q) is characteristic in lupus.

Pauci-immune GN – ANCA-associated vasculitis

• Minimal or no immune complex deposition.
• Injury is mediated by neutrophil activation via ANCAs (e.g. granulomatosis with polyangiitis, microscopic polyangiitis leading to capillaritis and crescent formation.).

Each reflects a different immune mechanism: direct autoantibodies, immune complex deposition, or cell-mediated inflammation

In autoimmune GN, the immune system fails to distinguish self from non-self, leading to loss of tolerance and direct attack on glomerular components.

🧬 Anti-GBM Disease (Goodpasture’s Syndrome) while I described this one separately because its so interesting, it is a subset of autoimmune disease

• Autoantibodies target the α3 chain of type IV collagen in the GBM — a normally hidden antigen.
• This may be unmasked by environmental triggers (e.g. smoking, infections), leading to loss of central or peripheral tolerance.
• The result is Type II hypersensitivity: direct antibody-mediated cytotoxicity.

🧬 Lupus Nephritis

• Driven by defective clearance of apoptotic cells, leading to persistent exposure of nuclear antigens.
• This chronic antigenic stimulation promotes autoantibody production (e.g. anti-dsDNA), forming immune complexes that deposit in glomeruli.
• The immune system’s failure to regulate autoreactive B and T cells underpins the   pathology — a breakdown in immune tolerance checkpoints.

🧬 ANCA-Associated Vasculitis

• ANCAs activate neutrophils, which damage small vessels including glomerular capillaries.
• The exact trigger is unclear, but epigenetic changes, infections, and genetic susceptibility may all contribute to loss of tolerance to neutrophil antigens (like proteinase 3 or myeloperoxidase).

📦 Pathophysiology Spotlight: Lupus Nephritis

Type: Immune complex–mediated GN (Type III hypersensitivity)

Mechanism:

• Autoantibodies (especially anti-dsDNA) bind nuclear antigens → form circulating immune complexes
• Complexes deposit in glomeruli (mesangial, subendothelial, or subepithelial)
• Activate complement (↓C3, ↓C4) → inflammation, endothelial injury, and glomerular damage

Why? Impaired clearance of apoptotic cells and loss of immune tolerance → persistent autoantigen exposure and B/T cell dysregulation

Histology Tip: “Full house” immunofluorescence (IgG, IgA, IgM, C3, C1q); class-dependent features (e.g. wire loops in Class IV)
Clinical Clue: Proteinuria and hematuria in a patient with SLE features (malar rash, photosensitivity, arthritis, cytopenias)

🧭 Bridging to Clinical Patterns:

Understanding GN’s classifications — whether by timeline or histological pattern — gives us the anatomical and microscopic vocabulary. But to bring this to life clinically, we need to ask: How does this look in a patient? What does it sound like in the history? How does it behave on a dipstick or in a blood test?

This is where the concepts of nephritic and nephrotic syndromes become powerful tools. They distil histopathology into recognisable, pattern-based presentations — helping you move from the microscope to the medical record with confidence.

So in Part 2, we’ll dive into:

• The pathophysiology behind nephritic and nephrotic syndromes
• How to distinguish them at the bedside
• Common conditions associated with each
• And real-world case vignettes to strengthen your diagnostic reasoning

Think of it as translating glomerular damage into a clinical dialect — one that helps you recognise urgency, guide investigations, and direct treatment.