Glomerular Pathology

Question 1

Define nephrotic syndrome

Answer 1

• Nephrotic syndrome - when glomerulus leaks proteins into the nephron
• Greater than 3.5g of protein loss in 24 hours

Question 2

Where is the likely site of injury for nephrotic syndrome

Answer 2

Podocytes

Question 3

What are features of nephrotic syndrome

Answer 3

• Most of the protein lost is albumin - proteinuria
• Leads to decreased oncotic pressure causing oedema
• Also present with high cholesterol levels - as protein acts as a carrier of cholesterol
• Non-proliferative - number of cells generally unchanged in inflammation
• Hallmarks - proteinuria, hypoalbuminaemia, oedema, hyperlipidaemia, lipiduria

Question 4

What are some primary and secondary causes of nephrotic syndrome

Answer 4

• Common primary causes - disease of the kidney
  
  • Minimal change glomerulonephritis
  • Focal segmental glomerulosclerosis (FSGS)
  • Membranous glomerulonephritis
• Common secondary causes
  - Diabetes mellitus

Question 5

State the age groups common for each nephrotic syndrome

Answer 5

• Minimal change GN - common in children and adolescence
• Focal segmental glomerulosclerosis - common in adults
• Membranous GN - common in adults

Question 6

Describe the pathogenesis of minimal change glomerulonephritis

Answer 6

• Type IV collagen in the basement membrane seen as normal
• Problem with the podocytes, where foot processes are lost
• Loss of negative charge repelling proteins, allowing albumin to pass
• No immune complex deposition

Question 7

Describe the pathogenesis of focal segmental glomerulosclerosis

Answer 7

• Circulating factor damaging podocytes
  
  • Can be due to infection, drugs, disease such as diabetes, HIV, lupus
• Proteins not only travel into the nephron, but also become trapped between the glomerulus and capsule
• Build up leads to development of sclerosis
• Progressive to renal failure

Question 8

Describe the pathogenesis of membranous glomerulonephritis

Answer 8

• Since immune complex cannot be directly filtered, either antigens are presented on the GBM that causes antibodies to bind (autoimmune)
  
  • Or antigens in blood is filtered by glomerulus to GBM and antibodies follow leading to autoimmune attack
  • Immune complexes consist of an antigen and an antibody
• Immune complex activated releases substances that damage the endothelial layer of the glomerulus
  
  • Activate complement system and recruits inflammatory cells
• Basement membrane becomes leaky, leading to protein filtering through

Question 9

Describe the features of nephritic syndrome

Answer 9

• Blood in urine - haematuria
• Proteinuria may also be present causing oedema
• Disruption of the endothelium results in inflammatory response and damage to glomerulus
• Commonly leads to acute renal failure and patients are hypertensive
• Proliferative - increased number of cells in the glomerulus
• Presentation triad - haematuria, reduced urine production, hypertensive

Question 10

Describe the management of nephrotic syndrome

Answer 10

• Oedema - diuretics given IV
  
  • Salt and fluid restriction
• ACE-inhibitor - antiproteinuric
• Hypercholesterolaemia - reduce levels to prevent atheroma
• Treat underlying condition - eg. Steroids for minimal change glomerulonephritis
  - Focal segmental glomerulosclerosis does not respond to steroids - fibroids irreversible

Question 11

Describe the features of IgA nephropathy

Answer 11

• Commonest type of glomerulonephritis
• Classically present with visible/invisible (picked up in urine dipstick) haematuria
• Becomes more symptomatic after mucosal infections
  
  • Body produces more IgA to fight infection
  • IgA deposits in urine and increases haematuria
• Proteinuria may or may not be present
• Likely to progress to renal failure
• No effective treatment

Question 12

Describe the pathogenesis of IgA nephropathy

Answer 12

• Auto-antibodies bind to abnormal IgA1
• Deposition of circulating IgA containing immune complexes in the glomerulus
• No semi-permeable membrane in mesangium allows immune complexes to freely deposit
• Inflammation occurs where cytokines and macrophages are recruited
  
  • Causes proliferation of cells or high matrix quantity in mesangium
• Damage to blood vessels causes blood vessels to escape into the nephron

Question 13

Describe the pathogenesis of rapidly progressive GN

Answer 13

• Cell-mediated immunity and macrophage inflammation cause GBM to break
• Allows red blood cells to escape into the nephron and further inflammation to occur
• Epithelial cell proliferation leads to thick crescent moon shape of epithelial cells, which can undergo sclerosis (scarring)

Question 14

Describe Alport’s syndrome and its pathogenesis

Answer 14

• X-linked inherited condition
• Abnormal type IV collagen which forms the glomerular basement membrane
• Associated with deafness - collagen IV important in the ear
• Pathogenesis
  
  • Abnormal type IV collagen overtime causes GBM to become thin and porous
  • Allows red blood cells to pass into filtrate
  • Excessive protein loss leading to proteinuria and sclerosis
• Progresses to renal failure

Question 15

Describe the features of Goodpasture syndrome

Answer 15

• Affects lungs and kidneys
• Relatively uncommon but rapidly progressive glomerulonephritis
• Acute onset of severe nephritic syndrome - haematuria, hypertension as well as haemoptysis
• Classically describe association with pulmonary haemorrhage (smokers)
• IgG antibodies directed against the glomerular basement membrane and triggering an inflammatory reaction
• Treatable by immunosuppression and plasmaphoresis (filter out immune complexes) if caught early

Question 16

Describe association with anti-neutrophil cytoplasmic antibody (ANCA)

Answer 16

• Antibody abnormally activates neutrophils which act on blood vessels
• Neutrophils punch holes through glomerular basement membrane, causing haematuria
• No immune deposits in kidney

Question 17

Explain systemic lupus erythematosus and its effect on the kidney

Answer 17

• Damage to cell DNA causes apoptosis (auto-immune)
• Immune cells attack DNA and proteins from nucleus (nuclear antigens)
• Antibodies produced against nuclear antigens which clump together into an immune complex and build up in places around the body
• Damages blood vessels in the kidney, leading to haematuria
• Also leads to proteinuria causing nephrotic syndrome

Question 18

Describe the pathogenesis of diabetes nephropathy

Answer 18

1. Hyperfiltration/capillary hypertension
   
   • In diabetes, there is upregulation of SGLT2 receptors which increases glucose and salt reabsorption
   • This decreases the amount of NaCl that reaches the macula densa cells (kidney thinks GFR is low)
   • Release of prostaglandins which dilate the afferent arteriole
   • Causes glomerular hypertension and increased GFR
2. Glomerular basement membrane thickening
   
   • High intraglomerular pressure pushes more molecules through, including albumin
   • Thickened GBM increases pore size - allows protein to pass through
   • Damage to podocytes causes widened filtration slits
   • First signs of diabetes is microalbuminuria
3. Mesangial expansion
   
   • In response to high glomerular pressure, mesangial cells secrete more matrix to help support the structures
   • Can also form Kimmelstiel-Wilson nodules, which are depositions of protein
   • Gradually, mesangial cells and matrix can consume the glomerulus and shutting off filtration (fibrosis/sclerosis)
4. Podocyte injury
5. Glomerular sclerosis/arteriosclerosis

Question 19

Describe the changes in GFR that occur across diabetes nephropathy

Answer 19

• Hyperfiltration and hypertrophy causes increased GFR
• Overt proteinuria
  
  • Falling GFR due to sclerosis of glomerulus

Question 20

Describe the risk factors of diabetes nephropathy

Answer 20

• Genetic susceptibility
• Race
• Hypertension
• Hyperglycaemia
• High level of hyperfiltration
• Increasing age
• Duration of diabetes
• Smoking

Question 21

How can diabetes nephropathy be prevented

Answer 21

• Tight blood glucose control
  
  • Multiple injections or insulin pump
  • Can reverse initial hyperfiltration and delay microalbuminuria
  • However doesn’t slow GFR loss once overt proteinuria develops
• Tight blood pressure control

Question 22

Describe how ACE inhibitors can help against diabetes nephropathy

Answer 22

• Inhibition of RAAS - help control systemic blood pressure
• Angtiotensin II leads to:
  
  • Increased glomerular permeability to proteins
  • Mesangial cell proliferation
  • Increased mesangial matrix
  • Efferent glomerular constriction - increased glomerular pressure
• A RAAS blockade such as ACE inhibitor will reduce glomerular hyperfiltration
  
  • Reduce proteinuria and slow progression of diabetic nephropathy as decreases glomerular permeability to proteins
  • Decreasing mesangial cell and matrix spreads slows down progression of fibrosis

Question 23

Describe how renal artery stenosis differs from diabetes nephropathy

Answer 23

• Hypertension often more acute and refractory to treatment
• Decline in GFR often more rapid, irreversible compared to diabetes nephropathy
• Evidence of atherosclerosis elsewhere
• Acute worsening with ACE inhibitor