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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. GBM.

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Glomerulonephritis vasculitis

Glomerulonephritis / Vasculitis

Dr Catherine Wall

AMNCH

2009


Glomerular filtration
Glomerular Filtration

Afferent arteriole

Efferent arteriole

Glomerulus

Angiotensin II - efferent arteriolar vasoconstriction

Filtrate


Filtration barrier
Filtration Barrier

BLOOD

endothelium

Sub-endothelial space

GBM

Type IV collagen

Sub-epithelial space

epithelium

URINE


Normal urine protein
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
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
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
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
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
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



Dipstick urinalysis haematuria
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
Discoloration of urine

  • Rifampicin orange

  • Beetroot red

  • Rhabdo smoky brown

  • Black alkaptonuria

  • Red / brown co-danthramer

  • Blue methylene blue / amitrip


Urine microscopy
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


Autosomal dominant polycystic kidney disease
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 20’s - 50’s



Pathophysiology
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
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
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
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

GENETICS 2 genes involved


Diagnosis
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



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

Glomerular Disease


Major clinical syndromes of glomerular disease
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
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
Investigations – Nephrotic Syndrome

  • Biochem / Haem / endocrine

  • Urine

  • Immunology

  • Radiology


Case 1
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 11
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 12
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
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


Case 21
Case 2

  • Suggest appropriate initial investigations.

  • Suggest a unifying diagnosis


Case 22
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
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


Nephrotic syndrome due to primary glomerular disease
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%


Minimal change disease
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
Membranous GN

  • Idiopathic M < F, 5th decade onwards

  • Neoplasiabowel / 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
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
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%


Focal segmental glomerulosclerosis1
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
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
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
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 nephropathy1
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.



Determinants of clinical manifestations
Determinants of Clinical Manifestations

  • Target organ involved

  • Size of blood vessel involved

  • Pathobiology of inflammatory process of involved vasculature


Sequelae of vasculitis
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 gn
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





Wegener s granulomatosis
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
Wegener’s Granulomatosis – ENT Disease

  • Chronic sinusitis

  • Chronic otitis

  • Epistaxis

  • Nasal crusting

  • Destruction nasal cartilage – saddle nose

  • Hoarseness

  • Tracheal stenosis





Wegener s granulomatosis mononeuritis multiplex
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
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


P-ANCA

Antigen:

Myeloperoxidase

C-ANCA

Antigen:

Proteinase-3


Are anca pathogenic
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
Treatment of Wegener’s Granulomatosis

  • Immunosuppression

    • Methylprednisolone / steroids

    • Cyclophosphamide

    • MMF or AZA maintenance (relapse+++)

  • Plasma Exchange

    • Pulmonary haemorrhage

    • Severe renal failure


Goodpasture s
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 s1
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)



Anti-GBM disease

Treatment

Steroids

Plasma exchange

Cyclophosphamide


Case 13
Case 1

  • A40-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?


Relevant 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
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
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



Results 2
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 now1
What is Your Differential Now?

Wegener’s granulomatosis

Microscopic polyangiitis

Churge-Strauss syndrome

Goodpasture’s syndrome



What other investigations will you order1
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



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