Glomerulonephritis / Vasculitis
Dr Catherine Wall
AMNCH
2009
Glomerular Filtration
Afferent arteriole
Efferent arteriole
Glomerulus
Angiotensin II - efferent
arteriolar vasoconstriction
Filtrate
Filtration Barrier
BLOOD
endothelium
Sub-endothelial space
Type IV collagen
GBM
Sub-epithelial space
epithelium
URINE
Normal Urine Protein
• Upto 150mg / 24 hours in adults
– 300mg in children / adolescents
– Generally
50% filtered
Albumin / Immunoglobulin
Light chains / B2M
50% secreted
Tamm Horsfall protein (TALH)
• Transiently increased
– Fever / heavy exercise / infection / CCF / orthostatic
Proteinuria
• Glomerular
– Heavy proteinuria highly suggestive glomerular lesion
– Typically nephrotic range
– ‘High Selectivity’ – implies mainly albumin – gen MCD
• Tubular
– Typically 1-2g of protein (sub nephrotic)
– Usually due to failure to reabsorb small molecular
weight proteins e.g. B2 Microglobulin
• Overflow
– Haemoglobin / myoglobin
– Light chains – myeloma – not detected by Dipstix
Detecting Proteinuria
• Urine dipstick
– Primarily detects albumin > 300-500mg / day
– Will not detect
Light chains (BJP)
Microalbuminuria
• Quantitation
– 24 hour urine
inaccurate / incomplete collection
poor patient compliance
– Protein / creatinine ratio (PCR) – general clinic
– Diabetics
ACR / Micral stix
Protein creatinine ratio
• Spot urine protein:creatinine ratio works
well (especially if morning urine) - no
need for 24 hour collections
Protein/creatinine mg/mmol
g/24 hours
<20
<0.15
120
1
400
3.5
1200
10
(for SI units: just divide by ~100 !)
Microalbuminuria
• Protein excretion above normal but below the
threshold of “Standard Dipstick”
– Albuminuria normally <20mg/24 hrs (15 µg/min);
– Microalbuminuria = 30-300mg/24 hrs (20-200
µg/min)
• Albumin-to-creatinine ratio
– microalbuminuria = 2.5 - 3.5 mg alb/mmol creatinine
• Risk factor in Diabetic Nephropathy
• High incidence of false positives
Microalbuminuria
Early marker of Diabetic Nephropathy
Usually develops within 10 years of onset of DM
• Duration of disease before onset of Microalbuminuria
correlates with risk of progression to nephropathy
– Microalbuminuria < 10 years - Most progress
– Microalbuminuria > 10 years 30 -50 % progress
Outcome much better than original studies –
?effect of active Rx
Diabetic nephropathy
Stage
GFR
24 hr
albumin
Description
Urine dip Micral
I Normal
N  inc
< 30
Normal
Negative Negative
30 - 300
Microalbuminuria
Negative Positive
II Incipient Inc  N
III Overt
N  dec
> 300
Macroalbuminuria Positive
Positive
IV
ESRD
> 3000
Nephrotic
Positive
Positive
Dipstick Urinalysis – Haematuria
• Dipstick urinalysis detects Haem protein
– either red blood cells or Hb or myoglobin)
– Highly sensitive but many false positive tests
– Confirm with urine microscopy.
– Transient haematuria is relatively common in
young subjects and is not indicative of
disease.
Negative tests reliably excludes abnormal
haematuria
Discoloration of urine
•
•
•
•
•
•
Rifampicin
Beetroot
Rhabdo
Black
Red / brown
Blue
orange
red
smoky brown
alkaptonuria
co-danthramer
methylene blue / amitrip
Urine Microscopy
•
•
•
•
•
•
•
•
Hyaline casts
Fine granular casts
Coarse granular casts
Muddy brown casts
White cell casts
Red cell casts
Crystals
Oval fat bodies
normal
normal
proteinuria
ATN
AIN / pyelo
vasculitis / crescentic GN
nephrotic syndrome
Autosomal Dominant
Polycystic Kidney Disease
• 2 Types
PKD 1
85%
PKD 2
15%
• 25% spontaneous mutations
• Prevalence
• Sex
Chr 16
Chr 4
1 : 500 - 1 : 1000 (Europe)
8 - 10% of dialysis patients
Males = Females
• Clinical onset Typically 20’s - 50’s
Polycystic Kidneys
Pathophysiology
• Disease begins in utero
• Cysts can arise anywhere along the nephron
– only 1 - 5% of nephrons are involved
• Intervening areas show nephrosclerosis and
chronic interstitial nephritis
• Typically 1-2 g proteinuria only (tubular)
Clinical Features / Associations
• Abdo pain / macro haem / cyst infection / stone /
rupture
• No inc risk of RCC in cysts
• Cysts –
– pancreas (<10%) – no panc failure
– liver (50-90% - F>>M) – no liver failure
•
•
•
•
Cardiac – MVP / AI / hypertension
Diverticular disease
Polycythaemia / anaemia
Berry aneurysms – 5%
Renal failure
“50% by age 70”
• Progresses to ESRF in about 10yrs once
serum creatinine rises above normal
• Rate of progression of CRF usually similar in
families
Progression is faster with
- PKD1:
Median age of ESRF = 56 years
- PKD2:
Median age of ESRF = 68 years
- high BP
- gross haematuria
- proteinuria
- pregnancy
- male sex
- larger kidneys
Subarachnoid Haemorrhage
Risks & Prevalence overestimated
• Berry aneurysms
– 4% young adults rising to 10% in elderly
– 65% risk of rupture
• Tend to cluster in families
• Prevalence in asymptomatic patients is felt to be
lower
• Role of screening controversial
Risk of hypertensive stroke or intracerebral haemorrage is
still 10x higher than risk of subarachnoid
GENETICS
2 genes involved
PKD 1
• Short arm of chr 16
• Encodes polycystin 1
- ? adhesion
PKD 2
• Long arm of chr 4
• Encodes polycystin 2 ? cation channel
DIAGNOSIS
Ultrasound
• Very sensitive and specific
–
–
–
–
Especially in Patient > 30 years of age
Detects cysts as small as 1 - 1.5 cm
Increased false negatives in young patients
multiple cysts in both kidneys which are large
• CT (with contrast )
• More sensitive than USS
– Detects cysts of 0.5cm
– Definitive radiological test
• Genetic screening – not available
CT Scan APKD
Glomerular Disease
Primary
Secondary
Minimal change
Membranous GN
FSGS
Mesangioproliferative GN
IgA
Renal limited crescentic GN
Metabolic
DM HbS
Immunologic SLE
MCGN
Crescentic GN
HSP
Drugs
NSAIDS etc
Infections
Paraproteins / Neoplasia
Alports
Pregnancy related
Major Clinical Syndromes of
Glomerular Disease
•
•
•
•
•
Nephrotic Syndrome
Nephritic syndrome
Rapidly Progressive Glomerulonephritis
Chronic Glomerulonephritis
Persistent urinary abnormalities with no
symptoms
Dept. of Renal Medicine, St.
James's Hospital.
Nephrotic Syndrome
•
•
•
•
•
•
Proteinuria
> 3.5g in 24 hours
Hypoalbuminaemia < 30g/dL
Oedema
Hyperlipidaemia / lipiduria
Hypercoagulable state
Hypogammaglobulinaemia
• Loss of Vit D BG / Vit D – osteomalacia
• Loss of EPO / transferrin – anaemia
• Loss of TBG – low T4 but N TSH ie euthyroid
Investigations – Nephrotic Syndrome
• Biochem / Haem / endocrine
• Urine
• Immunology
• Radiology
Case 1
• 47 year old male with DM2 for 7 years on oral
hypoglycaemics, he has no retinopathy. BP is
125/75mmHg. He has severe rheumatoid
arthritis for over 25 years. He developes ankle
swelling and is found to have 4+ protein on dip
–
–
–
–
Creatinine 98umol/l (eGFR 79mls/min)
HbA1C 6.4%
Alb
22mg/dl
Chol 8.9
Urine protein 8g / 24hrs
Case 1
• What renal condition is present?
• What other information would you like?
• Suggest potential likely causes based on the
history
• What investigations would you perform?
Case 1
• You discover that he has taken gold and penicillamine in
the past as DMA. He takes NSAIDS daily.
• Suggest alternate diagnoses?
• His renal US is normal. He admits to weight loss and a
non-productive cough for over 6 months. He is a lifelong
smoker. CXR identifies a suspicious lesion.
• How will you investigate this man further ?
Case 2
• A 34 year old woman presents with weight loss,
intermittent fevers and joint pains for 6 months.
On examination her BP is 158/95mmHg, she
has swollen joints and a L pleural rub.
–
–
–
–
Urea 18
Creatinine 259
Albumin 16
ESR 108
Glucose 4.8
Urine 3+ blood and protein
PCR 1080
– Urine microscopy
red cell and granular casts
Case 2
• Suggest appropriate initial investigations.
• Suggest a unifying diagnosis
Case 2
• She is ANA and dsDNA strongly positive. Her
complements are reduced and she is anticardiolipin Ab
positive – what is the diagnosis?
• Her creatinine rises to 450umol/l overnight and she
developes severe L loin pain and frank haematuria,
suggest a differential and relevant investigations.
Classes of Lupus Nephritis
•
•
•
•
•
•
Class I
Class II
Class III
Class IV
Class V
Class VI
normal
mesangial
focal proliferative GN
diffuse proliferative GN
membranous
sclerotic
• Hallmark
full house immunology
Nephrotic Syndrome due to Primary
Glomerular Disease
Minimal change
Membranous
Mesangiocapillary
FSGS
Proliferative
< 15 yr
80%
1%
8%
7%
4%
> 15 yr
28%
25%
12%
15%
20%
Minimal Change Disease
• Presentation
– Nephrotic syndrome (selective proteinuria)
– Acute renal failure (typically ATN)
• Treatment
(frequently relapses)
– Steroids
– Cyclophosphamide/chlorambucil
– Cyclosporin A
– Levamisole
I
T
G
Membranous GN
• Idiopathic
•
•
•
•
•
•
M < F, 5th decade onwards
Neoplasia
bowel / breast / bronchus
Infection
Hep B / C / syphilis
Drugs
Penicillamine
SLE
Type V lupus nephritis
Disease of ‘thirds’
Rx – controversial
• Subepithelial deposits with spikes
Membranous nephropathy
• 1/3 remit spontaneously
• 1/3 progress to ESRF
• 1/3 no change
Granular C3 and
IgG on basement
membrane
Focal Segmental Glomerulosclerosis
• Presents with nephrotic syndrome in 75%
• Secondary FSGS consequent on glomerular
scarring
– IgA Nephritis
– Sickle cell disease
Post vasculitis
Alport’s disease
reflux
• Histology - focal & segmental sclerosis, no ICS
• Can recur in renal Tx - 23% ~ graft loss 10%
Focal Segmental Glomerulosclerosis
• Collapsing Variant
– Explosive onset NS with renal failure
• Causes
–
–
–
–
–
HIVAN – Tx HAART / ACEi
Pamidronate
Heroin
Idiopathic
Parvovirus B19
MesangioCapillary GN -MCGN
(Membranoproliferative GN)
• Presentation - Nephrotic (50%) - Nephritic (25%)
• Histologically Type 1 - Subendothelial deposits
Type 2 - Dense deposit disease
• Associated with low complement levels
– C3 nephritic factor
– Partial lipodystrophy
• No treatment shown to be effective
– 50 % ESRF at 10 years
– Can recur in renal Tx - 25% ~ graft loss 10%
Acute Poststreptococcal Glomerulonephritis
• Principally a disease of children (M>F)
• Characteristic 10 day latent period between sore
throat and renal disease
• Urine
- ‘Smoky Brown’ haematuria
- oliguria, ARF
• Dx – rising ASO titre, low C3
– throat culture - streptococcal A
– renal biopsy – subendo deposits, proliferative lesion
Dept. of Renal Medicine, St.
James's Hospital.
IgA Nephropathy
• Synonym - Berger's Disease
– Commonest primary glomerulonephritis
– Increased incidence in the Far East
• Unknown aetiology
– IgA dysregulation / Viral aetiology
– IC disease – mesangial C3 / IgA on biopsy
– 50% have raised IgA
• HSP – IgA + vasculitic rash buttocks etc
IgA Nephropathy
• Associations
– Cirrhosis
– Dermatitis herpetiformis / Gluten enteropathy
– Mycosis fungoides
• Presentation / Outcome
–
–
–
–
Microscopic / macro haematuria (synpharyngitic)
Proteinuria / NS
RPGN with crescents
20% ESRF at 20 years
• Treatment
– Controversial. Some patients may benefit from
steroids, fish oils or MMF.
Vasculitis
Determinants of Clinical Manifestations
• Target organ involved
• Size of blood vessel involved
• Pathobiology of inflammatory process of
involved vasculature
Sequelae of Vasculitis
• Vasculitis is a primary inflammatory process of
vasculature
• Stenosis / occlusion of involved vessels
resulting in organ ischaemia or infarction
• Necrosis of vessel walls
– Aneurysmal dilatation and / or thrombosis
– Causing organ ischaemia / infarction / haemorrhage
Crescentic Glomerulonephritis
Crescentic GN
• Immune complex mediated
– Widespread immune deposits eg SLE / MPGN
• Linear Ig deposition
– Typical of anti-GBM disease
• Pauci-immune
– Absence of immune deposits
– Classical for ANCA assoc vasculitis
Pauci-immune Crescentic GN
Anti-GBM mediated Crescentic GN
Immune Complex mediated Crescentic GN
Wegener’s Granulomatosis
• Necrotising vasculitis of arterioles / capillaries
/ post capillary venules
– Associated with ANCA antibodies
– Characterised by non-caseating granulomata on
biopsy
• Triad of clinical manifestations
– Upper respiratory tract involvement
– Lower respiratory tract involvement
– Crescentic GN
Wegener’s Granulomatosis – ENT Disease
•
•
•
•
•
•
•
Chronic sinusitis
Chronic otitis
Epistaxis
Nasal crusting
Destruction nasal cartilage – saddle nose
Hoarseness
Tracheal stenosis
Wegener’s Granulomatosis – ENT Disease
Wegener’s Granulomatosis – Lung Involvement
Wegener’s Granulomatosis – Skin Involvement
Wegener’s Granulomatosis –
Mononeuritis Multiplex
ANCA positive vasculitis
Wegener’s, microscopic
polyarteritis, Churg-Strauss
syndrome, renal limited
Rapidly progressive ARF
Haemoptysis,
Anti-MPO/anti PR3 antibodies
Emerging Role of ANCA
• ANCA background
– Identified in 1980s, marker of disease
– Useful for confirming diagnosis, predicting
relapse, reposnse to therapy etc
– Autoantibodies directed against neutrophil
cytoplasmic antigens
• C-ANCA
• P-ANCA
antigen Proteinase 3
antigen usually MPO
P-ANCA
C-ANCA
Antigen:
Antigen:
Myeloperoxidase
Proteinase-3
Are ANCA Pathogenic?
• Compelling in vivo evidence emerging
• Murine models
– Transfer of anti-MPO causes pauci-immune vasculitis
– Transfer of anti-PR3 causes skin inflammation at site
of TNFa administration
• WKY rat immunised with human MPO (Little et al)
– Developes anti-MPO antibodies
– Developes crescentic GN and lung vasculitis
– Neutrophils show enhanced adhesion / transmigration
on intravital microscopy of mesenteric venules
Treatment of Wegener’s Granulomatosis
• Immunosuppression
– Methylprednisolone / steroids
– Cyclophosphamide
– MMF or AZA maintenance (relapse+++)
• Plasma Exchange
– Pulmonary haemorrhage
– Severe renal failure
Goodpasture’s
• Mediated by anti GBM antibody directed
against basement membrane of kidney / alveolus
• Goodpasture’s Disease
– Crescentic GN
• Goodpasture’s Syndrome
– Crescentic GN
– Alveolar haemorrhage
Goodpasture’s
• Exceedingly rare
– 1 case per million per annum
• Male preponderance
– Young males / 2nd peak in 5-6th decade
– Smokers / exposure to hydrocarbons
• Uniformly fatal without treatment
– No recurrence following recovery
• Ab directed against alpha III chain of Type IV
Collagen (Alport’s Ag)
Goodpastures
Anti-GBM disease
Treatment
Steroids
Plasma exchange
Cyclophosphamide
Case 1
• A 40-year-old garage mechanic presents with a 3month history of generalised malaise, decreased
appetite, fever, cough, intermittent haemoptysis and
increasing shortness of breath. He is a life long nonsmoker.
• What other history would you like to obtain from
this gentleman?
• What is your differential based on the history?
Relevant History
Weight loss / other constitutional symptoms
Nature of haemoptysis: streaky / clots / amount
Quantify SOB / diurnal variation etc
Wheeze / hoarseness / CP (inc pleuritic) / epistaxis
PND / orthopnea / ankle swelling
Haematuria / altered urine output / uraemic symptoms
Skin rashes / joint problems / neuro
Family history: thrombophilia / autoimmune disease / TB
Social history: occupational exposure / foreign travel /
hobbies
Physical Findings
Exam:
Pale, unwell looking, sats 93% RA,
BP 160/95, RR 30, pulse 110
CVS normal
RESP coarse creps both lung bases
Mild pedal oedema
Skin / joints normal
Urinalysis:
Proteinuria 3+ Blood 3+
Urine microscopy:
Dysmorphic red cells
Red cell casts
Results 1
FBC
Coag
Bio
Hb
8.7 g/dl
WCC
10.5 x 109 /l
Plt
350
MCV / film normal
normal
Urea
22 mmol/l
HCO3
18 mmol/l
Creatinine
450 umol/l
Albumin
29 mg/dl
K
5.3 mmol/l
Ca (corr)
1.98 mmol/l
Na
138 mmol/l
PO4
2.01 mmol/l
What initial investigations would you
perform?
Results 2
ABG’s
pH
7.33
PO2
9.5 kPa
PCO2
3.3 kPa
HCO3
19 mmol/l
Sats
94%
Sputum culture: Negative including Zn / TBC
Sputum cytology: Negative for malignant cells
CXR:
diffuse bilateral alveolar shadowing
What is Your Differential Now?
What is Your Differential Now?
Wegener’s granulomatosis
Microscopic polyangiitis
Churge-Strauss syndrome
Goodpasture’s syndrome
What Other Investigations Will You Order?
What Other Investigations Will You Order?
Immunology
ANA / RF / Cryoglobulins negative
C3 / C4 normal
SPEP / UPEP normal
ANCA negative
Anti-GBM 93% (highly positive)
PFTs
FEV1
FVC
TLC
KCO
Actual
2.6
2.9
5.1
2.8
Renal US
Predicted
3.0
4.2
6.5
2.2
• What is the likely diagnosis?
• How might you treat this patient?
• What is his prognosis?