Pathology & Pathophysiology of Glomerulonephritis
Kidneys
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
Clinical manifestation (Glomerular disease)
Nephritic syndrome (not a disease)
Nephrotic syndrome (not a disease)
Rapidly progressive renal failure
Chronic renal failure
Syndromes
Nephritic Nephrotic
Hematuria Massive Proteinuria > 3.5G /day
Azotemia (↑BUN) Hypoalbuminaemia
(plasma albumin <3g/dL) Proteinuria
Oliguria Generalised Edema
Edema Hyperlipidaemia
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
Histological Diagnosis
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 Immune 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
Trapped in glomeruli
Binds complements (most cases)
Get deposited – Mesangium, Subendothelial, Subepithelial
Stimulate Acute Inflammatory reaction
Lead to Glomerular Cell Proliferation
Causes of Antigen-Antibody trapped in Glomeruli
Charge of immune complex
Haemodynamic factors (glomerulus)
Permeability of endothelial cells
Immune Mediated Injury
Non-Inflammatory Inflammatory
jslum.com | Medicine
Kidney Reaction to Injury
1. Proliferation of cells of Glomerulus 2. Infiltration by Inflammatory cells 3. Capillary Basement Membrane Thickening
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)
Neutrophils – activate inflammatory mediators
Lymphocytes
Macrophages
Deposition of immune complexes (eg. Complements)
• Deposition can be subepithelial, subendothelial,
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, Post-streptococcal
Infective process – Viruses, Fungus, Parasites
Caused by
Inflammatory process – SLE, Paraneoplastic
Infection – Bacterial, Viral, Parasitic pathogens
4. ↑ Mesangial Matrix 5. Epithelial foot process fusion 6. Hyalinisation & Sclerosis 7. End stage disease
Due to deposition of IgG, Compleme nts Results when leakage of protein from
glomerular capillary
Accumulation/ precipitation of
extracellular material (protein)
Immune Mechanism of Glomerular Injury
In Situ Immune Complex Deposition Planted Antigens Circulating Immune Complex Deposition
(Type III Hypersensitivity)
Fixed Intrinsic Tissue Antigen
(eg. Anti GBM Nephritis)
Exogenous Endogenous
Drugs
Infectious agents
Antigen-Antibody Complexes
Outcomes of Glomerulonephritis
Interrelationship of Pathologic & Clinical Manifestations of Glomerular Injury
jslum.com | Medicine
Nephritic Syndrome
Clinical
Hematuria
Azotemia - ↑ BUN (Blood Urea Nitrogen)
Proteinuria
Oliguria
Edema
Hypertension
Causes of Acute Glomerulonephritis (AGN)
Bacterial – Acute Post-Streptococcal GN (APSGN) Group A β Haemolytic Streptococci
Pharyngitis Impetigo (Skin Infection)
Serotypes 1, 2, 4, 12 Serotypes 47, 49, 57
8-30 days to develop APSGN 14-21 days to develop APSGN
Non-Ba cterial – Virus, Fungus, Parasites
2° to Systemic Disease
SLE
HSP
Infective Endocarditis
Rapidly Progressive GN (Crescentic GN)
Acute Poststreptococcal GN (Diffuse Proliferative GN)
Childhood (common)
Age
Peak at 7 y/o
Uncommon < 3 y/o,
Uncommon > 21 y/o
Male ↑
Infection (skin/ throat) precedes 1-8 weeks before Renal symptoms
Immune complexes formed in Glomerular Filtration Membrane between
Antigen (in organism)
Antibody (host)
Activate Complement
Acute Proliferative GN (any cause) can progress to
Rapidly Progressive GN (Crescentic GN)
Kidney Enlarged
Petechial Haemorrhage
Acute PSGN - IF
Diffuse Involvement
Glomerular Enlarged, Edematous
↑ Cellularity
Normal Glomerulus
Rapidly Progressive GN (Crescentic GN)
Nephrotic Syndrome
Clinical
Massive Proteinuria > 3.5G /day
Hypoalbuminaemia (plasma albumin < 3g/dL)
Generalised Edema
Hyperlipidaemia
Pathophysiol ogy
Heavy Proteinuria
Damage to Filtration barrier of Glomerulus (GBM)
Excessive Permeability of plasma proteins
Proteinuria (Normal < 150mg/day)
Selective Non-Selective
Leak from ↓ molecular weight
protein
Leak from ↑ molecular weight
protein
Albumin IgM
Transferrin IgG
Hypoalbuminaemia
Depletion of plasma proteins (mainly albumin)
Edema
Reversed A:G Ratio (Liver compensates but not success ful)
↓ Albumin, ↓ Colloid OncoFc Pressure of Blood
Stimulated ADH
Hyperlipidaemia (VLDL, LDL) ↑ Lipoprotein synthesis, ↓ Catabolism by Liver
HDL lost in urine
Infections
↓ Body Proteins (Immunoglobulins/ Complement )
Thrombotic, Embolic phenomenon
Loss of Anticoagulants – Antithrombin III, Antiplasmin
Histology/ Urine Examination
Nephrotic Syndrome
Children Adult
Minimal change GN (65%) Membranous GN (40%)
Membranous GN (5%) Diabetes Glomerulosclerosis
Membrano-proliferative GN Amyloidosis
SLE
Minimal Change GN Membranous GN
Epidemiology
Young children < 6 y/o
Male ↑
Children (80%)
Adults (20-30%)
Epidemiology
Common in Adults
Characteristics
Electron-Dense Immune Deposits
along epithelial side of GBM
(subepithelium)
Proteinuria Selective
(↓ Molecular Weight)(eg. Albumin)
2° Causes
Diabetes, SLE, Amyloidosis,
Infections (Malaria, HBV), Malignancy URTI preceeds
History of
Allergies
Recent Immunization
Pathogenesis
Chronic Antigen-Antibody disease HLR-DR/2 (Japanese) HLR-DR/3 (European)
Imbalance T-Helper/ T-Suppressor
Circulating Immune complexes
Intrinsic Tissue Antigen
Complete remission common
(after Steroid course)
Abnormal Normal
jslum.com | Medicine
Investigations
Urine
Inflammatory cells
Protein
Casts
RBC
Investigating the Cause
Throat swab
Blood culture
ANA
Compliment levels
Anti GBM Antibody
Blood
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
Urinary RBCs
Urinary Leukocytes
Infection/ Inflammation
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
Glomerulonephritis, Vasculitis
Exclude extra-renal causes of bleeding
White Blood Cell Cast Glomerulonephritis
Hyaline Cast Can be found in Nor mal individuals
Granular Cast
Usually Pathologic (but non-speci fic)
Granules are from
Degeneration of Cellular Casts
Approach to Proteinuria
Approach to Haematuria
jslum.com | Medicine