Glomerulonephritis / Vasculitis Dr Catherine Wall AMNCH 2009.
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Transcript of Glomerulonephritis / Vasculitis Dr Catherine Wall AMNCH 2009.
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Glomerulonephritis / Vasculitis
Dr Catherine Wall
AMNCH
2009
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Glomerular Filtration
Afferent arteriole Efferent arteriole
Glomerulus
Angiotensin II - efferent arteriolar vasoconstriction
Filtrate
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Filtration Barrier
endothelium
GBM
epithelium
Type IV collagen
BLOOD
URINE
Sub-endothelial space
Sub-epithelial space
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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
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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
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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
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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 !)
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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
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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
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Diabetic nephropathy
Stage GFR 24 hr albumin
Description Urine dip Micral
I Normal N inc < 30 Normal Negative Negative
II Incipient Inc N 30 - 300 Microalbuminuria Negative Positive
III Overt N dec > 300 Macroalbuminuria Positive Positive
IV ESRD > 3000 Nephrotic Positive Positive
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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
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Discoloration of urine
• Rifampicin orange
• Beetroot red
• Rhabdo smoky brown
• Black alkaptonuria
• Red / brown co-danthramer
• Blue methylene blue / amitrip
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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
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Autosomal Dominant Polycystic Kidney Disease
• 2 Types PKD 1 85% Chr 16PKD 2 15% Chr 4
• 25% spontaneous mutations
• Prevalence 1 : 500 - 1 : 1000 (Europe)
8 - 10% of dialysis patients• Sex Males = Females
• Clinical onset Typically 20’s - 50’s
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Polycystic Kidneys
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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)
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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%
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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
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Subarachnoid HaemorrhageRisks & 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
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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
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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
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CT Scan APKD
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Glomerular Disease
Primary
Minimal changeMembranous GNFSGSMesangioproliferative GNIgARenal limited crescentic GN
Secondary
Metabolic DM HbSImmunologic SLE
MCGNCrescentic
GNHSP
Drugs NSAIDS etcInfectionsParaproteins / NeoplasiaAlportsPregnancy related
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Dept. of Renal Medicine, St. James's Hospital.
Major Clinical Syndromes of Glomerular Disease
• Nephrotic Syndrome
• Nephritic syndrome
• Rapidly Progressive Glomerulonephritis
• Chronic Glomerulonephritis
• Persistent urinary abnormalities with no symptoms
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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
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Investigations – Nephrotic Syndrome
• Biochem / Haem / endocrine
• Urine
• Immunology
• Radiology
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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
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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?
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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 ?
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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
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Case 2• Suggest appropriate initial investigations.
• Suggest a unifying diagnosis
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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.
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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
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Nephrotic Syndrome due to Primary Glomerular Disease
< 15 yr > 15 yr
Minimal change 80% 28%
Membranous 1% 25%
Mesangiocapillary 8% 12%
FSGS 7% 15%
Proliferative 4% 20%
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Minimal Change Disease
• Presentation– Nephrotic syndrome (selective proteinuria)– Acute renal failure (typically ATN)
• Treatment (frequently relapses)– Steroids– Cyclophosphamide/chlorambucil– Cyclosporin A– Levamisole
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T
G
I
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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
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Membranous nephropathy
• 1/3 remit spontaneously• 1/3 progress to ESRF• 1/3 no change
Granular C3 and IgG on basement
membrane
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Focal Segmental Glomerulosclerosis
• Presents with nephrotic syndrome in 75%• Secondary FSGS consequent on glomerular
scarring– IgA Nephritis Post vasculitis reflux – Sickle cell disease Alport’s disease
• Histology - focal & segmental sclerosis, no ICS
• Can recur in renal Tx - 23% ~ graft loss 10%
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Focal Segmental Glomerulosclerosis
• Collapsing Variant– Explosive onset NS with renal failure
• Causes– HIVAN – Tx HAART / ACEi– Pamidronate– Heroin– Idiopathic– Parvovirus B19
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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%
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Dept. of Renal Medicine, St. James's Hospital.
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
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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
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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.
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Vasculitis
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Determinants of Clinical Manifestations
• Target organ involved
• Size of blood vessel involved
• Pathobiology of inflammatory process of involved vasculature
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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
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Crescentic Glomerulonephritis
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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
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Pauci-immune Crescentic GN
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Anti-GBM mediated Crescentic GN
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Immune Complex mediated Crescentic GN
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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
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Wegener’s Granulomatosis – ENT Disease
• Chronic sinusitis
• Chronic otitis
• Epistaxis
• Nasal crusting
• Destruction nasal cartilage – saddle nose
• Hoarseness
• Tracheal stenosis
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Wegener’s Granulomatosis – ENT Disease
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Wegener’s Granulomatosis – Lung Involvement
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Wegener’s Granulomatosis – Skin Involvement
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Wegener’s Granulomatosis – Mononeuritis Multiplex
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ANCA positive vasculitis
Wegener’s, microscopic polyarteritis, Churg-Strauss syndrome, renal limited
Rapidly progressive ARF
Haemoptysis,
Anti-MPO/anti PR3 antibodies
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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
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P-ANCA
Antigen:
Myeloperoxidase
C-ANCA
Antigen:
Proteinase-3
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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
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Treatment of Wegener’s Granulomatosis
• Immunosuppression– Methylprednisolone / steroids– Cyclophosphamide – MMF or AZA maintenance (relapse+++)
• Plasma Exchange– Pulmonary haemorrhage– Severe renal failure
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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
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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)
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Goodpastures
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Anti-GBM disease
Treatment
Steroids
Plasma exchange
Cyclophosphamide
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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?
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Relevant HistoryWeight 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
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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
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Results 1
FBC Hb 8.7 g/dlWCC 10.5 x 109 /lPlt 350MCV / film normal
Coag normalBio Urea 22 mmol/l
HCO3 18 mmol/lCreatinine 450 umol/lAlbumin 29 mg/dlK 5.3 mmol/lCa (corr) 1.98 mmol/lNa 138 mmol/lPO4 2.01 mmol/l
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What initial investigations would you perform?
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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
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What is Your Differential Now?
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What is Your Differential Now?
Wegener’s granulomatosis
Microscopic polyangiitis
Churge-Strauss syndrome
Goodpasture’s syndrome
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What Other Investigations Will You Order?
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What Other Investigations Will You Order?
Immunology ANA / RF / Cryoglobulins negativeC3 / C4 normalSPEP / UPEP normalANCA negativeAnti-GBM 93% (highly positive)
PFTs Actual PredictedFEV1 2.6 3.0FVC 2.9 4.2TLC 5.1 6.5KCO 2.8 2.2
Renal US
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• What is the likely diagnosis?
• How might you treat this patient?
• What is his prognosis?