3. Glomerular Disease Flashcards
What is Glomerular Disease?
Characterised Anatomically by Inflammatory Alterations to the Glomeruli
Glomerular Disease typically presents as one of 5 clinical syndromes. What are these syndromes?
Asymptomatic Haematuria +/- Proteinuria
Nephritic Syndrome
Acute Renal Failure / Nephritic Syndrome
Nephrotic Syndrome
A mix of Nephritic/Nephrotic Syndrome
Which form of glomerulonephritis typically presents as symptomatic haematuria +/- proteinuria
IgA Nephropathy
Clinical Presentation of IgA Nephropathy
Presents as recurrent episodes of haematuria, which typically begin hours-days after an Upper Respiratory Tract Infection (less commonly after UTI or GIT infection)
What are associations/predispositions to developing IgA Nephropathy?
Who does it typically affect?
Coeliacs Disease
Liver Disease (especially if there is impaired clearance of IgA complexes)
Older children and young adults
IgA Nephropathy prognosis
Usually good
But because it is rather common it accounts for a lot of ESRF
25% will go on to ESRF
Mechanism of injury of IgA Nephropathy
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
Microscopic Feautures of IgA Nephropathy
Accumulation of IgA in Mesangium of every glomerulus
Focal and segmented Mesangial proliferation
Endocapillary proliferation
Segmental Glomerulosclerosis
Which forms of glomerular disease typically present as Nephritic Syndrome?
- Acute Proliferative Glomerulonephritis (post-streptococcal)
- Non-streptococcal post-infectious Acute Glomerulonephritis
What is Nephritic Syndrome?
A syndrome with different possible causes characterised by a key set of symptoms/signs
Primarily:
1. Haematuria (glomerular)
Secondary Features:
- Variable Proteinura (less than nephrotic syndrome)
- Hypertension (probably due to H2O and Na retention and stimulation of RAS)
+/- Reduced GFR
+/- Oliguria
+/- Oedema
How do you know if haematuria is glomerular in origin?
The RBCs will be pleomorphic
Formation of RBC Casts
(non-glomerular haematuria are uniform in appearance)
Urine must be examined fresh: <1hr
What is Acute Proliferative Post-Streptococcal Glomerulonephritis?
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)
What will laboratory investigations reveal, if there is Acute Post-streptococcal Glomerulonephritis?
- Increasing ASO titre (antibody produced in response to a haemolytic toxin - streptolysin O - oroduced by most strains of Strep A, C and G)
- Low C3 due to compliment being consumed
- Presence of likely pathogen in microbial culture
- Urine sediment may reveal granular or cellular (either epithelial, red or white cells) casts
Aetiology/Mechanism of Injury of Acute Post-Streptococcal Glomerulonephritis
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
Microscopic Features of Acute Post-Streptococcal Glomerulonephritis
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)
Prognosis of Acute Post-streptococcal Glomerulonephritis
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….
What is Non-Streptococcal Postinfectious Glomerulonephritis?
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
What are the Microscopic Features of Non-Streptococcal Glomerulonephritis?
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
Treatment and prognosis for Non-streptococcal Glomerulonephritis?
“Supportive”
What is the major cause of a presentation of Acute Renal Failure / Nephritic Syndrome
Rapidly Progressive (Crescentic) Glomerulonephritis
What is Rapidly Progressing (Crescentic) Glomerulonephritis?
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%)
Describe Type I Crescentic Glomerulonephritis: Anti-glomerular basement membrane disease
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
Describe Type II Crescentic Glomerulonephritis: Immune Complex Disease
Includes Post-Infectious Glomerulonephritis (post-strep and non-strep), SLE, IgA Nephropathy
Immune complexes trigger inflammatory response, in the glomerulus - often affecting mesangial cells
Describe Type III Crescentic Glomerulonephritis: Pauci-Immune Disease
Mediated by Anti-neutrophil cytoplasmic antibodies
Can be idiopathic or associated with systemic vasculitis
What is Crescentic Formation?
Non-specific marker of severe glomerular injury - involves compression of the glomerulus
What are the general microscopic features of Crescentic Glomerulonephritis?
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
Treatment and Prognosis of Crescentic Glomerulonephritis
Immunosuppressives: steroids, cytotoxics etc depending on the Type
There is Rapidly Declining Renal Function - Aggressive Disease
HTN is variable
Rapid intervention is important
What are the clinical features of Nephrotic Syndrome?
What is a cardinal sign that may be picked up from lab investigations?
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:
- Hypoalbuminaemia
- Clinical Oedema
- Hyperlipidaemia (high lipids) and Lipiduria (commonly mixed - high cholesterol and TG)
+/- Hypertension, Haematuria and Renal Impairment
Hyaline Casts (proteinaceous) in urine**
Which Glomerular Diseases/Pathologies Typically Present with Nephrotic Syndrome?
- Minimal Change Syndrome
- Membranous Glomerulonephritis
- Focal and Segmental Glomerulosclerosis
- Membranoproliferative Glomerulonephritis
- Diabetic Nephropathy
- Hypertensive Nephropathy
What is Minimal Change Disease?
What treatment is used?
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
Minimal Change Disease Mechanism of Injury
Associations with other conditions?
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
Microscopic Appearance of Minimal Change Disease?
(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
Treatment and Prognosis of Minimal Change Disease?
(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
What is Membranous Glomerulonephrosis?
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
What are some of the causes of Secondary Membranous Glomerulonephritis?
(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
Mechanisms of Injury in Primary (idiopathic) Membranous Glomerulonephritis
(nephrotic syndrome)
Thought to be an Autoimmune Condition
Associated with susceptibility genes
and Caused by an unknown renal auto-antigen
Leading to Immune Complexes
Mechanisms of Injury in Secondary Membranous Glomerulonephritis
(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
Microscopic features of Membranous Glomerulonephritis
LM, IF and EM
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
Treatment and Prognosis of Membranous Glomerulonephritis
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
What is Focal and Segmental Glomerulosclerosis?
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
Mechanism of damage in Focal Segmental Glomerulonephrosis
Variety of mechanisms…
- Idiopathic: 10% children and 35% adults nephrotic syndrome
- Associated with other diseases: HIV, heroin, severe obesity, sickle cell
- Adaptive Forms
- 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
Microscopic Appearance of Focal and Segmental Glomerulonephrosis
(LM, IF, EM)
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
Treatment and Prognosis of Focal and Segmental Glomerulonephrosis
NO specific treatment at present.
Control HTN > Inhibit RAS
Idiopathic form: 50% progress to ESRF in 10 years, and 20% have an accelerated form
What Glomerular Disease is characterised by both Nephrotic OR Nephritic syndrome?
Membranoproliferative Glomerulonephrosis
What is Membranoproliferative Glomerulonephrosis?
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
Mechanism of Injury in Membranoproliferative Glomerulonephrosis
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
Prognosis of Membranoproliferatie GN?
50% develop chronic renal failure in 10 year.
No proven treatment.
Few remissions, slowly and relentlessly progressive disease
