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Pathology & Pathophysiology of Glomerulonephritis

Kidneys Histological Diagnosis

Normal Glomerulus
Functions
Remove wastes from body
Regulate electrolytes
Regulate blood pressure
Stimulate RBC production
GBM
Ultrafiltration barrier, 310-380nm
Mesangial cells
Regulate Blood flow in glomerulus
Phagocytic activity
Epithelial cell (Epc)
Glomerular permeability
Acute glomerulonephritis Chronic glomerulone phritis
Acute diffuse proliferative GN
Rapidly progressive GN
(Crescentic GN )
Mesangial proliferative GN
Focal Segmental GN
Minimal change GN
Membranous GN
Mechanisms of Glomerular Injury
Depositions of Preforme d Immu ne Comple x
Formations of Immune Comple x In Situ
Compliment activation
Nephrotoxic Antibody to GBM (Glomerular Basement Membrane)
Antigens
Endogenous Exogenous
SLE Nephritis Poststreptococcal nephritis
Hepatitis B (HbsAg) Infection
Treponema pallidum
Plasmodium falci parum
Variations
Same cause may give spectrum of change in glomeruli
Same cause may give different effect on different people
Same cause may give no effect on some people
Different organisms may give same changes in glomeruli

Antigen cause Renal Damage

Antigen-Antibody complexes are formed in circulation
Clinical manifestation (Glomerular disease) Trapped in glomeruli
Nephritic syndrome (not a disease) Binds complements (most cases)
Nephrotic syndrome (not a disease) Get deposited – Mesangium, Subendothelial, Subepithelial
Rapidly progressive renal failure Stimulate Acute Inflammatory reaction
Chronic renal failure Lead to Glomerular Cell Proliferation

Syndromes Causes of Antigen-Antibody trapped in Glomeruli

Nephritic Nephrotic Charge of immune complex
Hematuria Massive Proteinuria > 3.5G /day Haemodynamic factors (glomerulus)
Azotemia (↑BUN) Hypoalbuminaemia Permeability of endothelial cells
Proteinuria (plasma albumin <3g/dL)
Oliguria Generalised Edema Immune Mediated Injury
Edema Hyperlipidaemia Non-I nflammatory Inflammatory
Hypertension

Clinical outcome (Glomerular disease)

Proteinuria
Disturbance of Sieving (filter) function
Ultrafiltrate contains large molecules
Oliguria
↓ GFR
Edema, Hypertension
Disturbance in Electrolyte regulation
Hematuria
Inability to keep RBC in capillary lumen
Chronic Renal Failure
Chronic ↓ in GFR

Terminology of Glomerular Lesions


Kidney Reaction to Injury
1. Proliferation of cells of Glomerulus
Mesangial cells (macrophages of kidney)
(normally ↓ than 3-4)
Endothelial cells – capillary lumen ↓
Epithelial cells – crescent formation
(when severe, Bowman’s space ↓)
(usually stimulated by Fibrin)
Caused by
Inflammatory process – SLE, Post-streptococcal
Infective process – Viruses, Fungus, Parasites
4. ↑ Mesangial Matrix
Due to deposition of IgG, Compleme nts
Immune Mechanism of Glomerular Injury
In Situ Immune Complex Deposition
Fixed Intrinsic Tissue Antigen
(eg. Anti GBM Nephritis)
Outcomes of Glomerulonephritis
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2. Infiltration by Inflammatory cells 3. Capillary Basement Membrane Thickening
Neutrophils – activate inflammatory mediators Deposition of immu ne complexes (eg. Complements)
Lymphocytes • Deposition can be subepithelial, subendothelial,
Macrophages mesangial, intramembranous
• Rate of migration determined by immune
complex size, charge
Alteration of BM thickness capillary permeability
(Blood & Protein leaks)
Caused by
Inflammatory process – SLE, Paraneoplastic
Infection – Bacterial, Viral, Parasitic pathogens
5. Epithelial foot process fusion 6. Hyalinisation & Sclerosis 7. End stage disease
Results when leakage of protein from Accumulation/ precipitation of
glomerular capillary extracellular material (protein)
Planted Antigens Circulating Immune Complex Deposition
(Type III Hypersensitivity)
Exogenous Endogenous Antigen-Antibody Complexes
Drugs
Infectious agents
Interrelationship of Pathologic & Clinical Manifestations of Glomerular Injury
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Nephritic Syndrome Nephrotic Syndrome

Clinical Clinical
Hematuria Massive Proteinuria > 3.5G /day
Azotemia - ↑ BUN (Blood Urea Nitrogen) Hypoalbuminaemia (plasma albumin < 3g/dL)
Proteinuria Generalised Edema
Oliguria Hyperlipidaemia
Edema
Hypertension Pathophysiol ogy
Heavy Proteinuria
Causes of Acute Glomerulonephritis (AGN) Damage to Filtration barrier of Glomerulus (GBM)
Bacterial – Acute Post-Streptococcal GN (APSGN) Excessive Permeability of plasma proteins
Group A β Haemolytic Streptococci Proteinuria (Normal < 150mg/day)
Pharyngitis Impetigo (Skin Infection) Selective Non-Selective
Serotypes 1, 2, 4, 12 Serotypes 47, 49, 57 Leak from ↓ molecular weight Leak from ↑ molecular weight
8-30 days to develop APSGN 14-21 days to develop APSGN protein protein
Non-Ba cterial – Virus, Fungus, Parasites Albumin IgM
2° to Systemic Disease Transferrin IgG
SLE Hypoalbuminaemia
HSP Depletion of plasma proteins (mainly albumin)
Infective Endocarditis Edema
Rapidly Progressive GN (Crescentic GN) Reversed A:G Ratio (Liver compensates but not success ful)
↓ Albumin, ↓ Colloid OncoƟc Pressure of Blood
Acute Poststreptococcal GN (Diffuse Proliferative GN) Stimulated ADH
Childhood (common ) Hyperlipidaemia (VLDL, LDL)
Age ↑ Lipoprotein synthesis, ↓ Catabolism by Liver
Peak at 7 y/o HDL lost in urine
Uncommon < 3 y/o, Infections
Uncommon > 21 y/o ↓ Body Proteins (Immu noglobulins/ Complement )
Male ↑ Thrombotic, Embolic phenomenon
Infection (skin/ throat) precedes 1-8 weeks before Renal symptoms Loss of Anticoagulants – Antithrombin III, Antiplasmin
Immune complexes formed in Glomerular Filtration Membrane between
Antigen (in organism) Histology/ Urine Examination
Antibody (host)
Activate Complement
Acute Proliferative GN (any cause) can progress to
Rapidly Progressive GN (Crescentic GN)

Nephrotic Syndrome
Children Adult
Kidney Enlarged Acute PSGN - IF Minimal change GN (65%) Membranous GN (40%)
Petechial Haemorrhage Membranous GN (5%) Diabetes Glomerulosclerosis
Membrano-proliferative GN Amyloidosis
SLE

Minimal Change GN Membranous GN

Epidemiology Epidemiology
Young children < 6 y/o Common in Adults
Male ↑ Characteristics
Diffuse Involvement Normal Glomerulus Children (80%) Electron-Dense Immu ne Deposits
Glomerular Enlarged, Edematous Adults (20-30%) along epithelial side of GBM
↑ Cellularity (subepithelium)
Proteinuria Selective 2° Causes
Rapidly Progressive GN (Crescentic GN) (↓ Molecular Weight)(eg. Albumin) Diabetes, SLE, Amyloidosis,
URTI preceeds Infections (Malaria, HBV), Malignancy
History of Pathogenesis
Allergies Chronic Antigen-Antibody disease
HLR-DR/2 (Japanese) HLR-DR/3 (European)
Recent Immu nization
Complete remission common Imbalance T-Helper/ T-Suppressor
(after Steroid course) Circulating Immune complexes
Intrinsic Tissue Antigen

Abnormal Normal
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Investigations Approach to Proteinuria

Urine Investigating the Cause
Inflammatory cells Throat swab
Protein Blood culture
Casts ANA
RBC Compliment levels
Blood Anti GBM Antibody
BUN
Serum Creatinine
Renal Biopsy

Urinalysis
Colour, Clarity, pH, Specific Gravity
Protein, Glucose, Reducing Substances, Ketone s, Bilirubin, Urobilinogen
RBC, WBC
Nonrenal Epithelial cells, Hyaline casts, Granular casts, Waxy casts
Bacteria, Mucous, Amorphous Urates
Approach to Haematuria

Urinary RBCs Urinary Leukocytes

Infection/ In flammation
Casts
Protein based cylindrical molds of renal tubule
Form in Distal Tubules & Collecting Ducts
Result of Damage to Renal Tubule
Predisposi ng Factor
Dehydration
Acidic Urine

Red Cell Cast

Associated with White Blood Cell Cast
Glomerulonephritis, Vasculitis Glomerulonephritis
Exclude extra-renal causes of bleeding

Hyaline Cast Granular Cast

Can be found in Nor mal individuals Usually Pathologic (but non-speci fic)
Granules are from
Degeneration of Cellular Casts