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GLOMERULOPATHY clinical categories

GLOMERULOPATHY clinical categories. Acute nephritic syndrome : haematuria, red blood cell casts, proteinuria, oliguria, hypertension, edema, circulatory congestion

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GLOMERULOPATHY clinical categories

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  1. GLOMERULOPATHYclinical categories • Acute nephritic syndrome: haematuria, red blood cell casts, proteinuria, oliguria, hypertension, edema, circulatory congestion • Rapidly progressive nephritic syndrome: relentlessly progressive glomerulonephritis resulting in ESRF within weeks • Recurrent gross haematuria

  2. GLOMERULOPATHYclinical categories • Asymptomatic glomerulopathy: proteinuria, haematuria, or both – without clinical symptoms • Chronic nephritic (glomerular) syndrome: glomerular disease that progress in chronic renal failure • Nephrotic syndrome

  3. GLOMERULOPATHYstructural characteristics • Acute damage (diffuse or segmental): - proliferation of epithelial, endothelial and mesangial cells; - exudation of polymorphonuclear leukocytes in the glomerulus; - necrosis of glomerular capillaries

  4. GLOMERULOPATHYstructural characteristics • Chronic damage: - proliferation of cellular elements (epithelium, endothelium, mesangium); - membranous involvement with thickening of glomerular basement membrane (GBM); - sclerosis of the glomerulus; - tubular atrophy, nephrosclerosis, interstitial scarring (in ESRF)

  5. GLOMERULOPATHYpathogenesis • Immunologic reactions • Vascular diseases • Abnormalities in coagulation • Metabolic defects • Hereditary factors • Unknown factors

  6. GLOMERULOPATHYimmunologic mechanism • Circulating immune complex– mediated disease • Antitissue antibody– mediated disease • Cell- mediated disease • Disease associated with activation of alternative complement pathway

  7. Physiology of protein excretion • Protein filtration through the glomerulus is dependent on the protein size, shape and electrical charge

  8. Physiology of protein excretion • Protein charge • At physiological pH, most proteins are negatively charged • Since the basement membranes are also negatively charged, most proteins are retained

  9. Physiology of protein excretion • Protein size • Proteins greater than 40kDa are almost completely retained • Thus, only small proteins, e.g. retinol-binding protein, ß2microglobulin, passes into the ultrafiltrate

  10. Physiology of protein excretion • However, most of the filtered proteins are reabsorbed by the proximal tubules. • Consequently, very little plasma protein appears in the urine • Normally < 150mg/24hours

  11. “Physiological” proteinuria • In some non-pathological situations, a higher than normal urine protein level is found: • A concentrated spot urine • Exercise • Orthostatic proteinuria • Contamination e.g. from vagina

  12. Classification • Tubular proteinuria • Tubular dysfunction • Overflow proteinuria • Glomerular proteinuria • Selective proteinuria • Non-selective proteinuria • microalbuminuria

  13. Tubular proteinuria • This occurs when glomerular function is intact, but protein is lost to the urine either because of: • Tubular dysfunction • Overflow

  14. Tubular proteinuria • Tubular dysfunction • The tubules are damaged and cannot function properly • Therefore, the small MW proteins that are normally filtered are not reabsorbed by the tubules • The small MW proteins include: retinol-binding protein, ß2 microglobulin, lysozyme, light chains, haemoglobin, myoglobin

  15. Tubular proteinuria • Tubular dysfunction • Pyelonephritis • Acute tubular necrosis • Papillary necrosis e.g. analgesic nephropathy • Heavy metal poisoning • SLE • Fanconi’s syndrome

  16. Tubular proteinuria • Overflow proteinuria • Occurs when the concentration of one of the small MW proteins is so high that the filtered load exceeds the tubular reabsorptive capacity • Thus, the excess filtered load appears in the urine

  17. Tubular proteinuria • Overflow proteinuria • Bence Jones proteinuria • Myoglobinuria • Haemoglobinuria

  18. Glomerular proteinuria • When there is glomerular dysfunction, proteins > 40kDa can escape into the urine • The most common form of proteinuria

  19. Glomerular proteinuria • Causes • Glomerulonephritis • Diabetes mellitus • Multiple myeloma • Amyloidosis • SLE • Pre-eclampsia • Penicillamine, gold

  20. Definitions • Proteinuria • Urine protein excretion > 150mg/day • Microalbuminuria • Urine [albumin] > 30mg/day but not detectable by urine dipstick • Nephrotic syndrome • Urine protein excretion > 3.5g/day (with hypoalbuminaemia, oedema and hyperlipidaemia)

  21. Nephrotic Syndrome (NS) • Is not a disease but a group of signs and symptoms seen in patients with heavy proteinuria • presents with oedema • proteinuria usually > 3.5g / 24hrs (>0.05g / kg / 24hrs in children) • serum albumin < 30g/l • other features: hyperlipidaemia, and hypercoaguable state

  22. NS pathophysiology • proteinuria:due to an increase in glomerular permeability • hypoalbuminuria:occurs when liver synthesis cannot keep up with urine losses • oedema mechanism is complex and still in dispute: primary salt and water retention associated with reduced renal function as well as reduced plasma oncotic pressure are primary factors (overfill and underfill) • hyperlipidaemia:increased liver synthesis • hypercoagulation:increased fibrinogen and loss of antithrombin III

  23. Clinical Features in NS - Thrombosis • Serious risk of thrombosis • Increased fibrinogen concentration • Antithrombin III concentration reduced • NS patients resistant to heparin • Platelets hyperaggregable • Increased blood viscosity

  24. NS - laboratory Features • Hct may be elevated • Hyponatremia is common • Plasma creatinine is elevated in 33% of patients

  25. NS laboratory- Plasma Protein • Albumin • Hypoalbuminemia due to loss via the kidney • Urinary excretion • Proximal tubular cells catabolism • Immunoglobulins • IgG levels reduced • IgM levels elevated • IgM-IgG-Switching

  26. NS laboratory- Hyperlipidemia • Increased synthesis of cholesterol, triglycerides and lipoproteins • Decreased catabolism of lipoproteins • Decreased activity of lipoprotein lipase • Decreased LDL receptor activity • Increased urinary loss of HDL • Lp(a) levels are elevated

  27. Primary glomerular diseases commonly causing the nephrotic syndrome • minimal change disease • focal and segmental glomerulosclerosis • membranous glomerulonephritis • proliferative glomerulonephritis (various histology and less common cause) • membranoproliferative (mesangiocapillary) • focal proliferative • diffuse proliferative • mesangial proliferative

  28. Other causes of the nephrotic syndrome 1 • Systemic diseases • diabetes mellitus • amyloidosis • SLE and other connective tissue diseases • HIV/AIDS • nephrotoxins • nsaids • mercury poisoning • penicillamine • gold salts

  29. Other causes of the nephrotic syndrome 2 • Allergies • bee sting • pollens • poison ivy • Circulatory effects • congestive cardiac failure • constrictive pericarditis • renal vein thrombosis (cause or result?) • Neoplastic • leukaemia • solid tumours

  30. NS epidemiology

  31. NS treatment- Diet • Low protein • Decreases albuminuria • Malnutrition • Salt restriction (Na+< 60 mmol/24 hrs) • During edema • Calorie control • Steroids

  32. NS treatment • water restriction • diuretics (if not volume depleted) • reduced protein diet (controversial) • treat infections • prophylaxis for thrombosis • specific therapy • corticosteroids • immunosuppression

  33. NS treatment- Albumin • Controversial • Indication- Hypovolemia • Abdominal pain • Hypotension • Oliguria • Renal insufficiency

  34. NS complications • Mortality • 1940’s- 40% 1 year mortality • Now 1-2% • Main cause of death • Infection • Thrombosis

  35. Corticosteroids Initiation in NS • High dose steroids • 2 mg/kg/day (max 80 mg) • 60 mg/m2 (max 80 mg) • 3 accepted protocols • 80% respond within 2 weeks

  36. Steroid Toxicity • Cushingoid habitus • Obesity • Striae • Hirsutism • Acne • Growth failure • Avascular necrosis • Osteoporosis

  37. Steroid Toxicity • Peptic ulceration • Pancreatitis • Posterior lens opacities • Myopathy • Increased ICP • Susceptibility to infection

  38. Options for Alternative Therapy in NS • Alkylating Agents • Nitrogen mustard • Cyclophosphamide • Chlorambucil • Levamisole • Cyclosporine

  39. Indications for Alternative Therapy in NS • Relapse on Prednisone Dosage >0.5 mg/kg/alt day plus: • Severe steroid side effects • High risk of toxicity- diabetes • Unusually severe relapses • Relapses on Prednisone Dosage >1.0 mg/kg/alt day

  40. Acute Nephritic Syndrome • Syndrome characterised in typical cases by: • haematuria • oliguria • oedema • hypertension • reduced GFR • proteinuria • fluid overload

  41. Clinical Features of the Acute Nephritic Syndrome • haematuria is usually macroscopic with pink or brown urine (like coca cola) • oliguria may be overlooked or absent in milder cases • oedema is usually mild and is often just peri-orbital- weight gain may be detected • hypertension common and associated with raised urea and creatinine • proteinuria is variable but usually less than in the nephrotic syndrome

  42. Etiology of the Nephritic Syndrome • Most common cause is acute post infectious glomerulonephritis • group A beta haemolytic streptococci of certain serotypes important in NZ • IgA disease and Henoch-Schonlein purpura, crescentic glomerulonephritis and SLE can also present in this way

  43. Complications of the Nephritic Syndrome • Hypertensive encephalopathy (seizures, coma) • Heart Failure (pulmonary oedema) • Uraemia requiring dialysis

  44. Acute poststreptococcal GN • Archetype of acute nephritic syndrome • Proliferative character • Only certain varietes of beta-hemolytic streptococci (nephritogenic strains) induce abnormalities in kidneys • Production of nonspecific evidence of streptococcal exposure (elevated antistreptolisin titers) • Antibody production and immune complexes

  45. Acute poststreptococcal GN • Kidneys are enlarged, edematosus, pale • Electron-dense deposits on the epithelial side of GBM • Reduced GFR • Elevation of urea and creatinine is characteristic • Urine: reduced in volume, concentrated, reddish brown; contains as much as 2 to 4 mg/day of protein

  46. Acute poststreptococcal GN • More common in males than females and most frequent between the ages of 3 and 7 years • Classically, 10 days after sore throat • Acute nephritic syndrome • Gross hematuria and fever • Worse prognosis in adults

  47. Definition of glomerulonephritis Glomerulonephritides are supposedly immunologically mediated glomerular diseases, often, but not always, inflammatory in nature

  48. Glomerular inflammation • Exsudation of neutrophils and/or macrophages 2. Proliferation of mesangial and/or endothelial cells

  49. Ultrastructural changes in non-proliferative vs. proliferative glomerulonephritides

  50. Mechanisms of glomerular damage

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