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**CAM202 RENAL Pathology > 3. Glomerular Disease > Flashcards

3. Glomerular Disease Flashcards

1
Q

What is Glomerular Disease?

A

Characterised Anatomically by Inflammatory Alterations to the Glomeruli

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2
Q

Glomerular Disease typically presents as one of 5 clinical syndromes. What are these syndromes?

A

Asymptomatic Haematuria +/- Proteinuria

Nephritic Syndrome

Acute Renal Failure / Nephritic Syndrome

Nephrotic Syndrome

A mix of Nephritic/Nephrotic Syndrome

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3
Q

Which form of glomerulonephritis typically presents as symptomatic haematuria +/- proteinuria

A

IgA Nephropathy

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4
Q

Clinical Presentation of IgA Nephropathy

A

Presents as recurrent episodes of haematuria, which typically begin hours-days after an Upper Respiratory Tract Infection (less commonly after UTI or GIT infection)

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5
Q

What are associations/predispositions to developing IgA Nephropathy?

Who does it typically affect?

A

Coeliacs Disease

Liver Disease (especially if there is impaired clearance of IgA complexes)

Older children and young adults

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6
Q

IgA Nephropathy prognosis

A

Usually good

But because it is rather common it accounts for a lot of ESRF

25% will go on to ESRF

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7
Q

Mechanism of injury of IgA Nephropathy

A

Largely unknown

Thought that repeated exposure to environmental antigens results in higher systemic IgA1 subclass

Accumulation of IgA in glomeruli

IgA is abnormally glycosylated and Interacts with mesangial cells and activates alternative complement pathway

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8
Q

Microscopic Feautures of IgA Nephropathy

A

Accumulation of IgA in Mesangium of every glomerulus

Focal and segmented Mesangial proliferation

Endocapillary proliferation

Segmental Glomerulosclerosis

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9
Q

Which forms of glomerular disease typically present as Nephritic Syndrome?

A
  1. Acute Proliferative Glomerulonephritis (post-streptococcal)
  2. Non-streptococcal post-infectious Acute Glomerulonephritis
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10
Q

What is Nephritic Syndrome?

A

A syndrome with different possible causes characterised by a key set of symptoms/signs

Primarily:
1. Haematuria (glomerular)

Secondary Features:

  1. Variable Proteinura (less than nephrotic syndrome)
  2. Hypertension (probably due to H2O and Na retention and stimulation of RAS)

+/- Reduced GFR
+/- Oliguria
+/- Oedema

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11
Q

How do you know if haematuria is glomerular in origin?

A

The RBCs will be pleomorphic

Formation of RBC Casts

(non-glomerular haematuria are uniform in appearance)

Urine must be examined fresh: <1hr

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12
Q

What is Acute Proliferative Post-Streptococcal Glomerulonephritis?

A

Symptoms of Acute Nephritis occurs after infection with Streptococcus (Group A Beta-haemolytic streptococcus, or S. pyogenes) - usually of the throat or skin

Nephritis occurs 7-12 days after a throat infection, and 3 weeks after a skin infection

Typically occurs in children 6-10 years, but can occur in adolescents and adults (eg. if immunosuppressed, elderly)

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13
Q

What will laboratory investigations reveal, if there is Acute Post-streptococcal Glomerulonephritis?

A
  1. Increasing ASO titre (antibody produced in response to a haemolytic toxin - streptolysin O - oroduced by most strains of Strep A, C and G)
  2. Low C3 due to compliment being consumed
  3. Presence of likely pathogen in microbial culture
  4. Urine sediment may reveal granular or cellular (either epithelial, red or white cells) casts
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14
Q

Aetiology/Mechanism of Injury of Acute Post-Streptococcal Glomerulonephritis

A

Caused by infection with certain types of Group A Beta haemolytic streptococci, or S. pyogenes.

The latent period (7-12 days for throat, 3 weeks for skin) is the time taken for production of antibodies and formation of immune complexes

Immune Complexes are Deposited in the Mesangium

(or it may be an antigen in the glomerular basement membrane - exact antigen unknown)

Causes Inflammation

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15
Q

Microscopic Features of Acute Post-Streptococcal Glomerulonephritis

A

Diffuse Hypercellularity with Inflammation

Diffuse - involves most glomeruli

Hypercellularity - See enlarged hypercellular glomeruli

Hypercellularity is caused by inflammatory cell infiltrate and proliferation of Endothelial and Mesangial Cells.

Swelling of these cells also occurs

Results in obliteration of the Glomerular Capillary Lumens

RBC Casts often seen in the tubules

In severe cases there may be Crescent Formation (compression of the GBM)

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16
Q

Prognosis of Acute Post-streptococcal Glomerulonephritis

A

90% Recover

1% Acute Renal Failure

5-10% slowly progress into Chronic Renal Failure (takes decades)

Recovery may be incomplete in adults

Chronic Renal Impaiement may occur with repeated episodes

*Acute Poststreptococcal Glomerulonephritis is thought to be a common cause of ESRF amongst Aboriginal Australians

Approach = support renal function, and use Abx if persisting infection, control any HTN, wait….

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17
Q

What is Non-Streptococcal Postinfectious Glomerulonephritis?

A

Similar form of Glomerulonephritis to Acute Post-Streptococcal Glomerulonephritis

But occurs in association with other bacterial, viral and parasitic infections

Bacteria: staph, endocarditis, pneumococcal oneumonia, meningococcal septicaemia

Viral: HPV, HCV, Mumps, HIV

Parasitic: Malaria, Taxoplasmosis

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18
Q

What are the Microscopic Features of Non-Streptococcal Glomerulonephritis?

A

Diffuse Hypercellularity: Affecting most glomeruli, immune cell infiltrate and proliferation (and swelling) of endothelial and mesangial cells

obliteration of glomerular capillaries

RBC Casts in tubules

Severe cases may show crescent formation

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19
Q

Treatment and prognosis for Non-streptococcal Glomerulonephritis?

A

“Supportive”

20
Q

What is the major cause of a presentation of Acute Renal Failure / Nephritic Syndrome

A

Rapidly Progressive (Crescentic) Glomerulonephritis

21
Q

What is Rapidly Progressing (Crescentic) Glomerulonephritis?

A

Syndrome associated with severe immune-mediated glomerular injury

Can lead to Acute Renal Failure

Divided into 3 groups based on immunologic findings:

Type I = Anti-Glomerular Basement Membrane Disease (20%)

Type II = Immune-complex Mediated Disease (25%)

Type III = Pauci Immune Disease (55%)

22
Q

Describe Type I Crescentic Glomerulonephritis: Anti-glomerular basement membrane disease

A

Antibodies against glomerular basement membrane - against Type IV collagen antigen

There are linear deposits of IgG and sometimes C3

*Some of these patients also have anti-pulmonary aveolar basement membrane antibodies > can result in pulmonary haemorrhage > Goodpasture Syndrome

23
Q

Describe Type II Crescentic Glomerulonephritis: Immune Complex Disease

A

Includes Post-Infectious Glomerulonephritis (post-strep and non-strep), SLE, IgA Nephropathy

Immune complexes trigger inflammatory response, in the glomerulus - often affecting mesangial cells

24
Q

Describe Type III Crescentic Glomerulonephritis: Pauci-Immune Disease

A

Mediated by Anti-neutrophil cytoplasmic antibodies

Can be idiopathic or associated with systemic vasculitis

25
Q

What is Crescentic Formation?

A

Non-specific marker of severe glomerular injury - involves compression of the glomerulus

26
Q

What are the general microscopic features of Crescentic Glomerulonephritis?

A

Crescent Formation (compression of glomerulus)

Crescents form in most glomeruli

Crescents formed by proliferation of parietal epithelial cells lining the bowman’s capsule, and in part by infiltration of monocytes and macrophages

Fibrin strands lie between the cellular layers of the crescents

27
Q

Treatment and Prognosis of Crescentic Glomerulonephritis

A

Immunosuppressives: steroids, cytotoxics etc depending on the Type

There is Rapidly Declining Renal Function - Aggressive Disease

HTN is variable

Rapid intervention is important

28
Q

What are the clinical features of Nephrotic Syndrome?

What is a cardinal sign that may be picked up from lab investigations?

A

Nephrotic Syndrome can be caused be a variety of pathologies and is classified by a specific group of signs/symptoms

Primarily:
1. MARKED Proteinuria >3.5g/24hrs

Secondarily:

  1. Hypoalbuminaemia
  2. Clinical Oedema
  3. Hyperlipidaemia (high lipids) and Lipiduria (commonly mixed - high cholesterol and TG)

+/- Hypertension, Haematuria and Renal Impairment

Hyaline Casts (proteinaceous) in urine**

29
Q

Which Glomerular Diseases/Pathologies Typically Present with Nephrotic Syndrome?

A
  1. Minimal Change Syndrome
  2. Membranous Glomerulonephritis
  3. Focal and Segmental Glomerulosclerosis
  4. Membranoproliferative Glomerulonephritis
  5. Diabetic Nephropathy
  6. Hypertensive Nephropathy
30
Q

What is Minimal Change Disease?

What treatment is used?

A

Relative Benign Glomerulonephritis

It is the MOST FREQUENT cause of nephrotic syndrome (with only normal or near normal GFR, no HTN and no haematuria) in CHILDREN

Less Common in Adults

Peak Incidence at 2-6 yo

Disease sometimes follows a respiratory tract infection or immunization

Associate with highly selective proteinuria: mainly low molecular-weight proteins (albumin) rather than other larger molecular weight proteins. This implies less severe membrane damage

Dramatic response to CORTICOSTEROIDS

31
Q

Minimal Change Disease Mechanism of Injury

Associations with other conditions?

A

Likely to involve some immune dysfunction

Results in the elaboration of cytokines that damage the visceral epithelial cells (podocytes) - i.e. loss of pedicles of podocytes

May be associated with Atopic conditions - HLA haplotypes, hodgkin disease

32
Q

Microscopic Appearance of Minimal Change Disease?

A

(type of nephrotic syndrome)

No abnormal changes on LM or IF

Under EM there is diffuse loss of podocyte pedicles, which allows leakage of low MW proteins from glomerular capillaries

Also microvillous formation within the urinary space

33
Q

Treatment and Prognosis of Minimal Change Disease?

A

(type of nephrotic syndrome)

Usually Steroids. Low salt and at least a normal protein diet.

Prognosis ultimately excellent

85-90% of cases respond to steroids

Immunosuppression used in resistant or unresponsive disease

Relapse is frequent

10% is steroid dependent or unresponsive

Biopsies are generally done in adults to exclude other diseases

Sometimes biopsy children with unusual clinical course

34
Q

What is Membranous Glomerulonephrosis?

A

A type of Nephrotic Syndrome

Common cause of nephrotic syndrome in adults - accounts for 30% of adult nephrotic syndromes

Peak age 30-50 years

Often have mild microscopic haematuria

Two Types: Primary (idiopathic) = 85%; and Secondary (due to another underlying disease/condition - needs to be investigated)

NEITHER TYPE IS RESPONSIVE TO CORTICOSTEROIDS

35
Q

What are some of the causes of Secondary Membranous Glomerulonephritis?

A

(nephrotic syndrome)

Drugs: Penicillins, NSAIDS, Captopril, Gold

Underlying Malignant Tumors

Autoimmune conditions

Systemic Lupus Erythemus

Various infections: HPV, HBV, Syphillus

**Thus, important to look for potential secondary causes of membranous GN

36
Q

Mechanisms of Injury in Primary (idiopathic) Membranous Glomerulonephritis

A

(nephrotic syndrome)

Thought to be an Autoimmune Condition

Associated with susceptibility genes

and Caused by an unknown renal auto-antigen

Leading to Immune Complexes

37
Q

Mechanisms of Injury in Secondary Membranous Glomerulonephritis

A

(nephrotic syndrome)

Immune complexes*

Complement causes damage to glomerular basement membrane

Complement also activates Glomerular Epithelial cells (podocytes) and Mesangial Cells

There is also Protease and Oxidant Production causing injury and protein leakage

38
Q

Microscopic features of Membranous Glomerulonephritis

LM, IF and EM

A

Under LM: Normal or diffuse thickening of the glomerular basement membrane

IF: Shows immunoglobulins and complement

EM: Thickening of the basement membrane caused by large deposits between the basement membrane and podocytes. Effaced pedicles of podocytes. Basement membrane is laid down between the deposits, appearing as irregular spikes protruding from the glomerular basement membrane

Advanced Lesions: Membrane thickening can lead to occlusion of glomerular capillaries. This can lead to Sclerosis of the Mesangium and potentially whole-glomeruli sclerosis

39
Q

Treatment and Prognosis of Membranous Glomerulonephritis

A

Treat the cause if possible (i.e. if secondary MGM and the cause is treatable)

There is debate over who to treat

Trial steroids - not usually responsive
Then try immunosuppressants

Also, prophylactic anti-coagulation therapy to prevent thromboembolic disease in those with low serum albumin (i.e. immunologic thromboemboli)

50% of patients progress to ESRF in 10-20 years.

30% spontaneous remission in young women

40
Q

What is Focal and Segmental Glomerulosclerosis?

A

Type of Nephrotic Syndrome
Common cause of nephrotic syndrome in ADULTS

Progressive renal damage (that in many cases is idiopathic) involving sclerosis of some glomeruli (focal) and only parts of the each glomerulus affected (segmented)

Diffuse effacement of podocyte pedicles results in haemodynamic changes: haematuria, rnon-selective proteinuria

Clinical Presentation: Haematuria, non-specific proteinuria, decreased GFR and HTN

Generally has poor response to corticosteroids

41
Q

Mechanism of damage in Focal Segmental Glomerulonephrosis

A

Variety of mechanisms…

  1. Idiopathic: 10% children and 35% adults nephrotic syndrome
  2. Associated with other diseases: HIV, heroin, severe obesity, sickle cell
  3. Adaptive Forms
  4. Inherited Forms

Endothelial or Podocyte Injury > Increased glomerular capillary permeability and proteinuria > Proteins accumulate in Mesangium > This causes Glomerular Hypertrophy and haemodynamic changes (i.e. glomerular HTN).

There is then proliferation of Mesangial cells > Infiltration of macrophages > Increased ECM production > Segmental and then global sclerosis of the glomerulus

42
Q

Microscopic Appearance of Focal and Segmental Glomerulonephrosis

(LM, IF, EM)

A

LM: Sclerosis of some glomeruli, and only parts of those glomeruli. Podocyte and Endothelial cell injury.

IF: Non specific trapping of IgM and C3

EM: Diffuse loss of podocyte pedicles

43
Q

Treatment and Prognosis of Focal and Segmental Glomerulonephrosis

A

NO specific treatment at present.

Control HTN > Inhibit RAS

Idiopathic form: 50% progress to ESRF in 10 years, and 20% have an accelerated form

44
Q

What Glomerular Disease is characterised by both Nephrotic OR Nephritic syndrome?

A

Membranoproliferative Glomerulonephrosis

45
Q

What is Membranoproliferative Glomerulonephrosis?

A

Characterised by both nephrotic and nephritic syndrome

Primary Type: Accounts for 10-20% of nephrotic syndrome in children and young adults with a nephritic component (i.e. nephrosis with haematuria)

Secondary Type: Occurs with complex immune disorders: SLE, HBV, HCV, Malignancy, Alpha 1 Anti-Trypsin Deficiency

46
Q

Mechanism of Injury in Membranoproliferative Glomerulonephrosis

A

There are 2 primary subtypes, the clinical significance of which are unknown

Type 1 - most cases: immune complement in glomerulus > activation of comlement alternative and classical pathways > circulating immune complexes >

Type 2 - Dense deposit disease, suggestive of activation of alternative complement pathway

47
Q

Prognosis of Membranoproliferatie GN?

A

50% develop chronic renal failure in 10 year.

No proven treatment.

Few remissions, slowly and relentlessly progressive disease

**CAM202 RENAL Pathology (3 decks)

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