L76: Diseases Of Kidneys 1

Question 1

Diagnosis of renal disease

Answer 1

1. Clinical history + manifestation
2. Biopsy
   - light microscopy
   - electron microscopy
   - immunofluorescence study

Both = Clinical-pathological diagnosis

Question 2

Classification of renal disease

Answer 2

• Nephrotic / Nephritic
• Primary / Systemic / Hereditary
• Acute / Chronic / Endstage

Question 3

Nephrotic syndrome

Answer 3

• Proteinuria >3.5g/day
• Low serum albumin (hypoalbuminemia)
• Generalised oedema
• Hyperlipidaemia (compensate for loss of protein)

Affect GLOMERULUS:

1. Membranous nephropathy
2. Minimal change disease
3. Focal segmental glomerulosclerosis
4. Membranoproliferative glomerulonephritis
5. Amyloidosis

Complications:

1. Hypercoagulability (thromboembolism)
2. Hyperlipidaemia
3. Serum binding protein reduction (warfarin level)
4. Infection (loss of IgG, complement)
5. Renal failure

Question 4

Nephritic syndrome

Answer 4

• Acute onset with gross / microscopic haematuria with red cell casts
• ↓ GFR
• Mild to moderate proteinuria
• Hypertension

Affect GLOMERULUS
1. Acute Post-streptococcal glomerulonephritis
2. Rapidly progressive glomerulonephritis
—> Type I (Anti-GBM antibody): Goodpasture syndrome
—> Type II (Immune complex): Acute post-streptococcal GN
—> Type III (Pauci-immune): ANCA-associated vasculitis
3. IgA nephropathy

Question 5

Acute kidney injury

Answer 5

• Rapid decline in GFR (hours/days) —> reflected by urea and creatinine in blood
• Oliguria / Anuria

Affect GLOMERULUS, INTERSTITIUM, TUBULES / BLOOD VESSELS

Question 6

Chronic kidney injury

Answer 6

• Persistent decline in GFR (<60 for at least 3 months) (stage 3)

Affect GLOMERULUS, INTERSTITIUM, TUBULES / BLOOD VESSELS
- if presumed glomerular nature —> Chronic glomerulonephritis

Question 7

End stage renal disease

Answer 7

• GFR <5% of normal
• Irreversible
• Require renal replacement:
  1. Haemodialysis
  2. Peritoneal dialysis
  3. Kidney transplantation

Question 8

Poor kidney function (Azotemia, Uraemia)

Answer 8

Azotemia:
Biochemical abnormality —> ↑ blood urea + creatinine —> related to ↓ GFR

Uraemia:
Toxic condition: retention of waste product in bloodstream (urea in blood)

Question 9

Glomerular disease

Answer 9

1. Primary glomerulonephritis
   - Membranous nephropathy
   - Minimal change
   - Focal segmental glomerulosclerosis (FSGS)
   - IgA nephropathy
   - Membranoproliferative glomerulonephritis (MPGN)
   - Acute post-infectious glomerulonephritis
2. Systemic disease with glomerular involvement
   - Goodpasture syndrome (Anti-GBM antibody mediated)
   - Amyloidosis
3. Hereditary disorder
   - Alport syndrome

Question 10

Pathogenesis of glomerulonephritis

Answer 10

1. Immune mechanism (Ag-Ab reaction)
   - antibodies react in glomerulus (Membranous, within podocyte processes)
   - Ag/Ab complex deposition (IgA, within subendothelial layer above GBM)
   - antibodies directed against GBM (Goodpasture, within GBM)
   - cell-mediated, alternative complement pathway activation
2. Metabolic alterations of GBM (Diabetes)
3. Genetic defect of GBM synthesis and cellular protein (Alport syndrome)

Question 11

Effects of glomerulonephritis

Answer 11

1. ↓ glomerular blood flow —> uraemia
2. ↓ glomerular filtration rate —> uraemia
3. Leakage of protein —> proteinuria / nephrotic syndrome
4. Leakage of blood cells —> microscopic / gross haematuria
5. Irreversible damage —> chronic renal failure —> end stage renal failure

Question 12

Membranous nephropathy (MGN)

Answer 12

• Immune complex (IgG) in between podocyte and GBM
  —> spikes stick out from GBM
  —> subepithelial (sub-podocyte) electron dense deposits
• 30-50 years
• Primary cause: M-type phospholipase A2 receptor (PLA2R) on podocyte
• Secondary cause:
  —> Hepatitis B/C
  —> Maliganancy
  —> SLE
  —> drugs (NSAIDs)
  —> Sarcoidosis

Treatment:

• Steroid
• Underlying cause

Outcome:

• 60% persistent proteinuria
• 10% renal failure in 10 years

Question 13

Membranoproliferative glomerulonephritis (MPGN)

Answer 13

- Immune complex (IgG) deposition
—> thickened capillary wall
—> markedly increased cell number
—> GBM splitting: caused by new GBM growing beneath as a result of IC deposition
- Nephrotic syndrome
- Haematuria

• MPGN: Pattern of injury
  —> Idiopathic MPGN (children and young adults)
  —> Secondary MPGN (Hep B, C, lymphoid malignancy)
  —> C3 GN
  —> Dense deposit disease

Treatment:

• Underlying cause
• **- steroid, immunosuppressant NOT helpful
• Drugs targeting complement pathway for C3 GN

Outcome:
- 50% chronic renal failure within 10 years

Question 14

Minimal change disease

Answer 14

• NOT immune complex
• Podocyte problem —> loss of protein filter function of GBM
  —> light microscopy: normal glomerulus in light microscopy
  —> immunofluorescence: nothing
  —> electron microscopy (ONLY DIAGNOSIS): diffuse loss of podocyte processes (loss of ion charges to repel protein)
• 90% in children
• unknown cause
• drugs (NSAIDs), lymphoma, infection associated

Treatment:

• Steroid (good response)
• Excellent long term prognosis

Question 15

Focal Segmental Glomerulosclerosis (FSGS)

Answer 15

• Focal: <50% of total glomeruli affected
• Segmental: part of one glomeruli
• Glomerulosclerosis:
  —> Acellular, amorphous material replacing glomerular capillary (from plasma protein, collagen, GBM materials)
  —> presentation similar to minimal change disease
• Primary cause: Idiopathic
• Secondary cause: HIV, diabetes etc.

Treatment:

• NO treatment
• NO response to steroid

Outcome:

• likely progress to chronic renal failure
• recurrence 25-50% after transplant

Question 16

Acute post-infectious glomerulonephritis

Answer 16

• Nephritic syndrome —> haematuria
• Immune complex (IgG)
  —> LM: hypercellular glomeruli with neutrophils
  —> IF: spotty immune deposits
  —> EM: electron dense deposit, subepithelial humps
• preceded by Group A streptococcal pharyngitis/skin infection 1-4 weeks before
• can occur in other infection
• most frequently in children

Treatment:
- 95% recover with conservative therapy

Question 17

Rapid progressive glomerulonephritis

Answer 17

• Nephritic syndrome
• Acute renal failure
• Severe glomerular injury
• multiple possible causes
  —> Type I (Anti-GBM antibody): Goodpasture syndrome
  —> Type II (Immune complex): Acute post-streptococcal GN
  —> Type III (Pauci-immune): ANCA-associated vasculitis

Question 18

Goodpasture syndrome

Answer 18

• Anti-GBM antibody mediated GN (within GBM)
  —> “Tsunami” of Autoantibody against NC1-terminal of α3 chain of collagen type IV
  —> formation unknown
  —> cross react with pulmonary alveolar BM —> pulmonary haemorrhage —> massive haemoptysis —> death
  LM:
• broken GBM, fibrin deposition (due to leakage of fibrin and clotting factors)
• cellular crescent: proliferation of parietal epithelium of Bowman’s capsule
  IF: linear staining pattern for IgG
  EM: NO deposit due to very small antibodies
• Medical emergency

Treatment:

• Plasmapheresis
• HIGH dose steroid and cyclophosphamide

Outcome:
- many require renal replacement therapy

Question 19

IgA nephropathy

Answer 19

• Immune complex (IgA) deposition WITHIN MESANGIAL
  —> microscopic / gross haematuria
  —> proteinuria
  —> acute/chronic renal failure
  —> LM: Mesangial proliferation with increase in cells and matrix (pinkish)
  —> IF: Dominant/ co-dominant deposit for IgA
  —> EM: Mesangial electron dense deposits
• MOST common GN worldwide
• wide range of age

Treatment:
- Steroid (for significant proteinuria / rapidly progressive renal injury)

Outcome:

• slow progression to chronic renal failure in 15-40% in 20years
• CAN recur after transplant