Glomerulonephritis vasculitis
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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

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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

Type IV collagen

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 urineinaccurate / incomplete collection

      poor patient compliance

    • Protein / creatinine ratio (PCR) – general clinic

    • DiabeticsACR / 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

1201

4003.5

120010

(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


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

  • Rifampicinorange

  • Beetrootred

  • Rhabdosmoky brown

  • Black alkaptonuria

  • Red / brownco-danthramer

  • Bluemethylene blue / amitrip


Urine Microscopy

  • Hyaline castsnormal

  • Fine granular castsnormal

  • Coarse granular castsproteinuria

  • Muddy brown castsATN

  • White cell castsAIN / pyelo

  • Red cell castsvasculitis / crescentic GN

  • Crystals

  • Oval fat bodiesnephrotic syndrome


Autosomal Dominant Polycystic Kidney Disease

  • 2 TypesPKD 185% Chr 16PKD 2 15%Chr 4

  • 25% spontaneous mutations

  • Prevalence 1 : 500 - 1 : 1000 (Europe)

    8 - 10% of dialysis patients

  • SexMales = 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


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

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


Primary

Minimal change

Membranous GN

FSGS

Mesangioproliferative GN

IgA

Renal limited crescentic GN

Secondary

MetabolicDM HbS

ImmunologicSLE

MCGN

Crescentic GN

HSP

DrugsNSAIDS etc

Infections

Paraproteins / Neoplasia

Alports

Pregnancy related

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

  • 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)

    • HbA1C6.4%

    • Alb 22mg/dlChol 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 18Glucose 4.8

    • Creatinine 259Urine 3+ blood and protein

    • Albumin 16PCR 1080

    • ESR 108

    • 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 Inormal

  • Class IImesangial

  • Class IIIfocal proliferative GN

  • Class IVdiffuse proliferative GN

  • Class Vmembranous

  • Class VIsclerotic

  • Hallmarkfull house immunology


Nephrotic Syndrome due to Primary Glomerular Disease

< 15 yr> 15 yr

Minimal change80%28%

Membranous1%25%

Mesangiocapillary8%12%

FSGS7%15%

Proliferative4%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

  • IdiopathicM < F, 5th decade onwards

  • Neoplasiabowel / breast / bronchus

  • InfectionHep B / C / syphilis

  • DrugsPenicillamine

  • SLEType 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 NephritisPost vasculitisreflux

    • Sickle cell diseaseAlport’s disease

  • 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 depositsType 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 antigen Proteinase 3

      • P-ANCAantigen usually MPO


P-ANCA

Antigen:

Myeloperoxidase

C-ANCA

Antigen:

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

  • 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

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 Hb 8.7 g/dl

WCC10.5 x 109 /l

Plt350

MCV / film normal

Coagnormal

BioUrea22 mmol/lHCO318 mmol/l

Creatinine450 umol/l

Albumin29 mg/dl

K5.3 mmol/l

Ca (corr)1.98 mmol/l

Na138 mmol/l

PO4 2.01 mmol/l


What initial investigations would you perform?


Results 2

ABG’spH7.33

PO29.5 kPa

PCO23.3 kPa

HCO319 mmol/l

Sats94%

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?

ImmunologyANA / RF / Cryoglobulins negative

C3 / C4 normal

SPEP / UPEP normal

ANCA negative

Anti-GBM 93% (highly positive)

PFTsActualPredicted

FEV12.63.0

FVC2.94.2

TLC5.16.5

KCO2.82.2

Renal US


  • What is the likely diagnosis?

  • How might you treat this patient?

  • What is his prognosis?


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