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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 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 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
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 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 • 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
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 • 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) • 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
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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 • 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%
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.