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Glomerulonephritis / Vasculitis

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... Disease 2 Types PKD 1 85% Chr 16 PKD 2 15% Chr 4 25% spontaneous mutations Prevalence 1 : 500 - 1 : 1000 (Europe) 8 - 10% of ... – PowerPoint PPT presentation

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Title: Glomerulonephritis / Vasculitis


1
Glomerulonephritis / Vasculitis
  • Dr Catherine Wall
  • AMNCH
  • 2009

2
Glomerular Filtration
Afferent arteriole
Efferent arteriole
Glomerulus
Angiotensin II - efferent arteriolar
vasoconstriction
Filtrate
3
Filtration Barrier
BLOOD
endothelium
Sub-endothelial space
GBM
Type IV collagen
Sub-epithelial space
epithelium
URINE
4
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

5
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

6
Detecting Proteinuria
  • Urine dipstick
  • Primarily detects albumin gt 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

7
Protein creatinine ratio
  • Spot urine proteincreatinine ratio works well
    (especially if morning urine) - no need for 24
    hour collections

Protein/creatinine mg/mmol g/24
hours lt20 lt0.15 120 1 400 3.5 1200
10 (for SI units just divide by 100 !)
8
Microalbuminuria
  • Protein excretion above normal but below the
    threshold of Standard Dipstick
  • Albuminuria normally lt20mg/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

9
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 lt 10 years - Most progress
  • Microalbuminuria gt 10 years 30 -50 progress
  • Outcome much better than original studies
  • ?effect of active Rx

10
Diabetic nephropathy
Stage GFR 24 hr albumin Description Urine dip Micral
I Normal N ? inc lt 30 Normal Negative Negative
II Incipient Inc ? N 30 - 300 Microalbuminuria Negative Positive
III Overt N ? dec gt 300 Macroalbuminuria Positive Positive
IV ESRD gt 3000 Nephrotic Positive Positive
11
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

12
Discoloration of urine
  • Rifampicin orange
  • Beetroot red
  • Rhabdo smoky brown
  • Black alkaptonuria
  • Red / brown co-danthramer
  • Blue methylene blue / amitrip

13
Urine Microscopy
  • Hyaline casts normal
  • Fine granular casts normal
  • Coarse granular casts proteinuria
  • Muddy brown casts ATN
  • White cell casts AIN / pyelo
  • Red cell casts vasculitis / crescentic GN
  • Crystals
  • Oval fat bodies nephrotic syndrome

14
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15
Autosomal Dominant Polycystic Kidney Disease
  • 2 Types PKD 1 85 Chr 16 PKD 2 15 Chr 4
  • 25 spontaneous mutations
  • Prevalence 1 500 - 1 1000 (Europe)
  • 8 - 10 of dialysis patients
  • Sex Males Females
  • Clinical onset Typically 20s - 50s

16
Polycystic Kidneys
17
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)

18
Clinical Features / Associations
  • Abdo pain / macro haem / cyst infection / stone /
    rupture
  • No inc risk of RCC in cysts
  • Cysts
  • pancreas (lt10) no panc failure
  • liver (50-90 - FgtgtM) no liver failure
  • Cardiac MVP / AI / hypertension
  • Diverticular disease
  • Polycythaemia / anaemia
  • Berry aneurysms 5

19
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

20
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

21
GENETICS 2 genes involved
  • PKD 2
  • Long arm of chr 4
  • Encodes polycystin 2 - ? cation channel
  • PKD 1
  • Short arm of chr 16
  • Encodes polycystin 1 - ? adhesion

22
DIAGNOSIS
  • Ultrasound
  • Very sensitive and specific
  • Especially in Patient gt 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

23
CT Scan APKD
24
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25
Glomerular Disease
  • Primary
  • Minimal change
  • Membranous GN
  • FSGS
  • Mesangioproliferative GN
  • IgA
  • Renal limited crescentic GN
  • Secondary
  • Metabolic DM HbS
  • Immunologic SLE
  • MCGN
  • Crescentic GN
  • HSP
  • Drugs NSAIDS etc
  • Infections
  • Paraproteins / Neoplasia
  • Alports
  • Pregnancy related

26
Major Clinical Syndromes of Glomerular Disease
  • Nephrotic Syndrome
  • Nephritic syndrome
  • Rapidly Progressive Glomerulonephritis
  • Chronic Glomerulonephritis
  • Persistent urinary abnormalities with no symptoms

27
Nephrotic Syndrome
  • Proteinuria gt 3.5g in 24 hours
  • Hypoalbuminaemia lt 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

28
Investigations Nephrotic Syndrome
  • Biochem / Haem / endocrine
  • Urine
  • Immunology
  • Radiology

29
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

30
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?

31
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 ?

32
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 Glucose 4.8
  • Creatinine 259 Urine 3 blood and protein
  • Albumin 16 PCR 1080
  • ESR 108
  • Urine microscopy red cell and granular casts

33
Case 2
  • Suggest appropriate initial investigations.
  • Suggest a unifying diagnosis

34
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.

35
Classes of Lupus Nephritis
  • Class I normal
  • Class II mesangial
  • Class III focal proliferative GN
  • Class IV diffuse proliferative GN
  • Class V membranous
  • Class VI sclerotic
  • Hallmark full house immunology

36
Nephrotic Syndrome due to Primary Glomerular
Disease
  • lt 15 yr gt 15 yr
  • Minimal change 80 28
  • Membranous 1 25
  • Mesangiocapillary 8 12
  • FSGS 7 15
  • Proliferative 4 20

37
Minimal Change Disease
  • Presentation
  • Nephrotic syndrome (selective proteinuria)
  • Acute renal failure (typically ATN)
  • Treatment (frequently relapses)
  • Steroids
  • Cyclophosphamide/chlorambucil
  • Cyclosporin A
  • Levamisole

38
I
T
G
39
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40
Membranous GN
  • Idiopathic M lt 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

41
Membranous nephropathy
  • 1/3 remit spontaneously
  • 1/3 progress to ESRF
  • 1/3 no change

Granular C3 and IgG on basement membrane
42
Focal Segmental Glomerulosclerosis
  • Presents with nephrotic syndrome in 75
  • Secondary FSGS consequent on glomerular scarring
  • IgA Nephritis Post vasculitis reflux
  • Sickle cell disease Alports disease
  • Histology - focal segmental sclerosis, no ICS
  • Can recur in renal Tx - 23 graft loss 10

43
Focal Segmental Glomerulosclerosis
  • Collapsing Variant
  • Explosive onset NS with renal failure
  • Causes
  • HIVAN Tx HAART / ACEi
  • Pamidronate
  • Heroin
  • Idiopathic
  • Parvovirus B19

44
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

45
Acute Poststreptococcal Glomerulonephritis
  • Principally a disease of children (MgtF)
  • 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

46
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

47
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.

48
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49
Vasculitis
50
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51
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52
Determinants of Clinical Manifestations
  • Target organ involved
  • Size of blood vessel involved
  • Pathobiology of inflammatory process of involved
    vasculature

53
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

54
Crescentic Glomerulonephritis
55
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

56
Pauci-immune Crescentic GN
57
Anti-GBM mediated Crescentic GN
58
Immune Complex mediated Crescentic GN
59
Wegeners 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

60
Wegeners Granulomatosis ENT Disease
  • Chronic sinusitis
  • Chronic otitis
  • Epistaxis
  • Nasal crusting
  • Destruction nasal cartilage saddle nose
  • Hoarseness
  • Tracheal stenosis

61
Wegeners Granulomatosis ENT Disease
62
Wegeners Granulomatosis Lung Involvement
63
Wegeners Granulomatosis Skin Involvement
64
Wegeners Granulomatosis Mononeuritis Multiplex
65
ANCA positive vasculitis Wegeners, microscopic
polyarteritis, Churg-Strauss syndrome, renal
limited Rapidly progressive ARF Haemoptysis,
Anti-MPO/anti PR3 antibodies
66
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 antigen Proteinase 3
  • P-ANCA antigen usually MPO

67
P-ANCA Antigen Myeloperoxidase
C-ANCA Antigen Proteinase-3
68
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

69
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70
Treatment of Wegeners Granulomatosis
  • Immunosuppression
  • Methylprednisolone / steroids
  • Cyclophosphamide
  • MMF or AZA maintenance (relapse)
  • Plasma Exchange
  • Pulmonary haemorrhage
  • Severe renal failure

71
Goodpastures
  • Mediated by anti GBM antibody directed against
    basement membrane of kidney / alveolus
  • Goodpastures Disease
  • Crescentic GN
  • Goodpastures Syndrome
  • Crescentic GN
  • Alveolar haemorrhage

72
Goodpastures
  • 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 (Alports Ag)

73
Goodpastures
74
Anti-GBM disease Treatment Steroids Plasma
exchange Cyclophosphamide
75
Case 1
  • A 40-year-old garage mechanic presents with a
    3-month history of generalised malaise, decreased
    appetite, fever, cough, intermittent haemoptysis
    and increasing shortness of breath. He is a life
    long non-smoker.
  • What other history would you like to obtain from
    this gentleman?
  • What is your differential based on the history?

76
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

77
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78
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

79
Results 1
  • FBC Hb 8.7 g/dl
  • WCC 10.5 x 109 /l
  • Plt 350
  • MCV / film normal
  • Coag normal
  • Bio 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

80
What initial investigations would you perform?
81
Results 2
  • ABGs 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

82
What is Your Differential Now?
83
What is Your Differential Now?
  • Wegeners granulomatosis
  • Microscopic polyangiitis
  • Churge-Strauss syndrome
  • Goodpastures syndrome

84
What Other Investigations Will You Order?
85
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 Actual Predicted
  • FEV1 2.6 3.0
  • FVC 2.9 4.2
  • TLC 5.1 6.5
  • KCO 2.8 2.2
  • Renal US

86
  • What is the likely diagnosis?
  • How might you treat this patient?
  • What is his prognosis?
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