pathology glomerulonephritis

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

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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



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


Kidney Enlarged

Petechial Haemorrhage

Acute PSGN - IF

Diffuse Involvement

Glomerular Enlarged, Edematous

↑ Cellularity

Normal Glomerulus


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



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



pathology glomerulonephritis

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