3. Glomerular Disease

Question 1

What is Glomerular Disease?

Answer 1

Characterised Anatomically by Inflammatory Alterations to the Glomeruli

Question 2

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

Answer 2

Asymptomatic Haematuria +/- Proteinuria

Nephritic Syndrome

Acute Renal Failure / Nephritic Syndrome

Nephrotic Syndrome

A mix of Nephritic/Nephrotic Syndrome

Question 3

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

Answer 3

IgA Nephropathy

Question 4

Clinical Presentation of IgA Nephropathy

Answer 4

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

Question 5

What are associations/predispositions to developing IgA Nephropathy?

Who does it typically affect?

Answer 5

Coeliacs Disease

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

Older children and young adults

Question 6

IgA Nephropathy prognosis

Answer 6

Usually good

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

25% will go on to ESRF

Question 7

Mechanism of injury of IgA Nephropathy

Answer 7

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

Question 8

Microscopic Feautures of IgA Nephropathy

Answer 8

Accumulation of IgA in Mesangium of every glomerulus

Focal and segmented Mesangial proliferation

Endocapillary proliferation

Segmental Glomerulosclerosis

Question 9

Which forms of glomerular disease typically present as Nephritic Syndrome?

Answer 9

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

Question 10

What is Nephritic Syndrome?

Answer 10

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

Primarily:
1. Haematuria (glomerular)

Secondary Features:

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

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

Question 11

How do you know if haematuria is glomerular in origin?

Answer 11

The RBCs will be pleomorphic

Formation of RBC Casts

(non-glomerular haematuria are uniform in appearance)

Urine must be examined fresh: <1hr

Question 12

What is Acute Proliferative Post-Streptococcal Glomerulonephritis?

Answer 12

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)

Question 13

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

Answer 13

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

Question 14

Aetiology/Mechanism of Injury of Acute Post-Streptococcal Glomerulonephritis

Answer 14

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

Question 15

Microscopic Features of Acute Post-Streptococcal Glomerulonephritis

Answer 15

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)

Question 16

Prognosis of Acute Post-streptococcal Glomerulonephritis

Answer 16

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….

Question 17

What is Non-Streptococcal Postinfectious Glomerulonephritis?

Answer 17

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

Question 18

What are the Microscopic Features of Non-Streptococcal Glomerulonephritis?

Answer 18

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

Question 19

Treatment and prognosis for Non-streptococcal Glomerulonephritis?

Answer 19

“Supportive”

Question 20

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

Answer 20

Rapidly Progressive (Crescentic) Glomerulonephritis

Question 21

What is Rapidly Progressing (Crescentic) Glomerulonephritis?

Answer 21

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%)

Question 22

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

Answer 22

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

Question 23

Describe Type II Crescentic Glomerulonephritis: Immune Complex Disease

Answer 23

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

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

Question 24

Describe Type III Crescentic Glomerulonephritis: Pauci-Immune Disease

Answer 24

Mediated by Anti-neutrophil cytoplasmic antibodies

Can be idiopathic or associated with systemic vasculitis

Question 25

What is Crescentic Formation?

Answer 25

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

Question 26

What are the general microscopic features of Crescentic Glomerulonephritis?

Answer 26

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

Question 27

Treatment and Prognosis of Crescentic Glomerulonephritis

Answer 27

Immunosuppressives: steroids, cytotoxics etc depending on the Type There is Rapidly Declining Renal Function - Aggressive Disease HTN is variable Rapid intervention is important

Question 28

What are the clinical features of Nephrotic Syndrome? What is a cardinal sign that may be picked up from lab investigations?

Answer 28

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: 2. Hypoalbuminaemia 3. Clinical Oedema 4. Hyperlipidaemia (high lipids) and Lipiduria (commonly mixed - high cholesterol and TG) +/- Hypertension, Haematuria and Renal Impairment Hyaline Casts (proteinaceous) in urine****

Question 29

Which Glomerular Diseases/Pathologies Typically Present with Nephrotic Syndrome?

Answer 29

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

Question 30

What is Minimal Change Disease? What treatment is used?

Answer 30

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

Question 31

Minimal Change Disease Mechanism of Injury Associations with other conditions?

Answer 31

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

Question 32

Microscopic Appearance of Minimal Change Disease?

Answer 32

(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

Question 33

Treatment and Prognosis of Minimal Change Disease?

Answer 33

(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

Question 34

What is Membranous Glomerulonephrosis?

Answer 34

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

Question 35

What are some of the causes of Secondary Membranous Glomerulonephritis?

Answer 35

(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

Question 36

Mechanisms of Injury in Primary (idiopathic) Membranous Glomerulonephritis

Answer 36

(nephrotic syndrome) Thought to be an Autoimmune Condition Associated with susceptibility genes and Caused by an unknown renal auto-antigen Leading to Immune Complexes

Question 37

Mechanisms of Injury in Secondary Membranous Glomerulonephritis

Answer 37

(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

Question 38

Microscopic features of Membranous Glomerulonephritis | LM, IF and EM

Answer 38

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

Question 39

Treatment and Prognosis of Membranous Glomerulonephritis

Answer 39

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

Question 40

What is Focal and Segmental Glomerulosclerosis?

Answer 40

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

Question 41

Mechanism of damage in Focal Segmental Glomerulonephrosis

Answer 41

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

Question 42

Microscopic Appearance of Focal and Segmental Glomerulonephrosis (LM, IF, EM)

Answer 42

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

Question 43

Treatment and Prognosis of Focal and Segmental Glomerulonephrosis

Answer 43

NO specific treatment at present. Control HTN > Inhibit RAS Idiopathic form: 50% progress to ESRF in 10 years, and 20% have an accelerated form

Question 44

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

Answer 44

Membranoproliferative Glomerulonephrosis

Question 45

What is Membranoproliferative Glomerulonephrosis?

Answer 45

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

Question 46

Mechanism of Injury in Membranoproliferative Glomerulonephrosis

Answer 46

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

Question 47

Prognosis of Membranoproliferatie GN?

Answer 47

50% develop chronic renal failure in 10 year. No proven treatment. Few remissions, slowly and relentlessly progressive disease