Glomerulonephritis / Vasculitis

Dr Catherine Wall

AMNCH

2009

Glomerular Filtration

Afferent arteriole Efferent arteriole

Glomerulus

Angiotensin II - efferent arteriolar vasoconstriction

Filtrate

Filtration Barrier

endothelium

GBM

epithelium

Type IV collagen

BLOOD

URINE

Sub-endothelial space

Sub-epithelial space

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

II Incipient Inc N 30 - 300 Microalbuminuria Negative Positive

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 orange

• Beetroot red

• Rhabdo smoky brown

• Black alkaptonuria

• Red / brown co-danthramer

• Blue methylene blue / amitrip

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

• 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

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 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

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

Minimal changeMembranous GNFSGSMesangioproliferative GNIgARenal limited crescentic GN

Secondary

Metabolic DM HbSImmunologic SLE

MCGNCrescentic

GNHSP

Drugs NSAIDS etcInfectionsParaproteins / NeoplasiaAlportsPregnancy related

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

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 Glucose 4.8– Creatinine 259 Urine 3+ blood and protein– Albumin 16 PCR 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 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

< 15 yr > 15 yr

Minimal change 80% 28%

Membranous 1% 25%

Mesangiocapillary 8% 12%

FSGS 7% 15%

Proliferative 4% 20%

Minimal Change Disease

• Presentation– Nephrotic syndrome (selective proteinuria)– Acute renal failure (typically ATN)

• Treatment (frequently relapses)– Steroids– Cyclophosphamide/chlorambucil– Cyclosporin A– Levamisole

T

G

I

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 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 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%

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

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-ANCA antigen 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

• 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?

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

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/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

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 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

• What is the likely diagnosis?

• How might you treat this patient?

• What is his prognosis?