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Glomerulonephritis / Vasculitis

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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  1. Glomerulonephritis / Vasculitis Dr Catherine Wall AMNCH 2009

  2. Glomerular Filtration Afferent arteriole Efferent arteriole Glomerulus Angiotensin II - efferent arteriolar vasoconstriction Filtrate

  3. Filtration Barrier BLOOD endothelium Sub-endothelial space GBM Type IV collagen Sub-epithelial space epithelium URINE

  4. 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

  5. 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

  6. 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

  7. 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 !)

  8. 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

  9. 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

  10. Diabetic nephropathy

  11. 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

  12. Discoloration of urine • Rifampicin orange • Beetroot red • Rhabdo smoky brown • Black alkaptonuria • Red / brown co-danthramer • Blue methylene blue / amitrip

  13. 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

  14. 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

  15. Polycystic Kidneys

  16. 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)

  17. 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%

  18. 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

  19. 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

  20. 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

  21. 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

  22. CT Scan APKD

  23. 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

  24. 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.

  25. 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

  26. Investigations – Nephrotic Syndrome • Biochem / Haem / endocrine • Urine • Immunology • Radiology

  27. 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

  28. 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?

  29. 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 ?

  30. 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

  31. Case 2 • Suggest appropriate initial investigations. • Suggest a unifying diagnosis

  32. 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.

  33. 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

  34. 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%

  35. Minimal Change Disease • Presentation • Nephrotic syndrome (selective proteinuria) • Acute renal failure (typically ATN) • Treatment (frequently relapses) • Steroids • Cyclophosphamide/chlorambucil • Cyclosporin A • Levamisole

  36. I T G

  37. 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

  38. Membranous nephropathy • 1/3 remit spontaneously • 1/3 progress to ESRF • 1/3 no change Granular C3 and IgG on basement membrane

  39. 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%

  40. Focal Segmental Glomerulosclerosis • Collapsing Variant • Explosive onset NS with renal failure • Causes • HIVAN – Tx HAART / ACEi • Pamidronate • Heroin • Idiopathic • Parvovirus B19

  41. 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%

  42. 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.

  43. 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

  44. 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.

  45. Vasculitis

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