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肾病综合征 Nephrotic Syndrome

肾病综合征 Nephrotic Syndrome. 武汉大学第一临床学院 刘红燕. Definition. Nephrotic syndrome (NS) is defined by the presence of following: Heavy proteinuria (>3.5g/d) Hypoalbuminemia (serum albumin <30g/L) Peripheral edema Hyperlipidemia / hypercholesterolemia. Major causes of NS (primary or idiopathic).

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肾病综合征 Nephrotic Syndrome

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  1. 肾病综合征Nephrotic Syndrome 武汉大学第一临床学院 刘红燕

  2. Definition Nephrotic syndrome (NS) is defined by the presence of following: • Heavy proteinuria (>3.5g/d) • Hypoalbuminemia (serum albumin <30g/L) • Peripheral edema • Hyperlipidemia / hypercholesterolemia

  3. Major causes of NS (primary or idiopathic) • Minimal change disease (微小病变型） • Mesangial proliferative glomerulonephritis （系膜增生性肾小球肾炎） • Focal segmental glomerulonephritis （局灶节段硬化性肾小球肾炎） • Membranous glomerulonephritis （膜性肾病） • Membranoproliferative glomerulonephritis （膜增殖性肾小球肾炎/系膜毛细血管性肾小球肾炎）

  4. Major causes of NS (secondary or systemic) • Antoimmune: systemic lupus erythematosus (SLE) • Endocrine: diabetic nephropathy • Infections: Hepatitis B, C, HIV • Allergenic: Henoch-Schonlen purpura • Neoplastic: Hodgkin’s and non-Hodgkin’s lymphomas, multiple myeloma • Others: Amyloidosis, Hereditary nephritis, medications

  5. Pathophysiology • Heavy protinuria • Hypoalbuminemia • Edema • Hyperlipidemia

  6. Heavy proteinuria • Damage to the charge-selective barrier of GMB →ultrafiltration of negatively charged albumin • Damage to the size-selective barrier of GMB →passsage of lager molecular proteins • Protein filtration > reabsorption capacity of tubules • Heperperfusion/Hyperfiltration factors (hypertension, protein-rich diet) →proteinuria increase

  7. Consequence of urinary loss of plasma proteins • Serum protein ↓or hypoalbuminemia • IgG/Complement ↓→infection • Coagulation component alternation (anticoagulants ↓)→thrombosis • Hormone-binding proteins ↓/metal-binding proteins ↓→endocrine or metabolic abnormalities • Lager proteins may increase

  8. Hypoalbuminemia • Urinary loss • albumin catabolism ↑ by tubules • Malnutrition due to GI changes

  9. Edema • Reduced plasma oncotic pressure (colloid osmotic pressure) • Hypovolemia →renin-angiotensin-aldosteron ↑ ; Sympathetic nervouse and vasopression systems ↑ • Primary renal Na+ retension (non-plasma Hormone effects on the kidney)

  10. Hyperlipidemia • One of the sentinel features of NS with numerous alterations in lipids profiles (hypercholesterolemia, hypertriglyceridemia, LDL and VLDL ↑) • Overproduction by the liver of lipoproteins • Decreased catabolism of lipoproteins and triglyceride

  11. Minimal changes nephropathy(MCD, 微小病变型肾病） Overview and Terminology • First described in 1913 by Monk as “lipoid nephrosis” • other terms “nil disease” and “idiopathic nephrotic syndrome”

  12. Pathogenesis • Unclear • Most likely a consequence of T cell abnormalities (glomerular permembility factor) • Other potential mechanisms (circulating immune complexes)

  13. Histopathology Light microscope (LM) • Lack alteration in glomerular structure • Some lipid droplets in tubule cells Immunoflurescent microscopy( IM) • No change Electron microscopy (EM) • Fusion of epithelial foot processes

  14. Clinical presentation • Most common in children; accouting for 10%-15% of NS in adults with male predominance • Typical feature of NS • Uncommon with nephritic features (hematuria, hypertension) • Renal function (normal or dereasesd transiterily)

  15. Diagonosis • Children and prealdolescent children presenting with NS will have MCD (about 80%-85%) • Children with NS sensitive to steroid treatment • Secondary MCD kept in mind when adult or old patients presents with MCD • Renal biopsy

  16. Treatment (1) Corticosteroid therapy • Exquisitely sensitive • Dose of prednisone • Caution with the side-effects of steroid

  17. Dose of prednisone • Initial (full) • Tapering(slowly) • Maintainece (longer) Children • 2mg/kg/d<60mg/d×8-12w • 10%reduction/1-2w • Effetively minimal dose(10mg/d)×6-12m Adult • 1 mg/kg/d×8-12w • 10%reduction/1-2w • Effetively minimal dose(10mg/d)×6-12m

  18. Treatment (2) Cytotoxic therapy • For patients with more relapses, steroid-dependant or steroid-resistant • Cyclophosphamide 2mg.kg-1.d-1; total dose 6-8g; side-effects • Chlorambucil (苯丁酸氮芥） 0.1-0.2mg/kg/d for 8 weeks

  19. Treatment(3) Cyclosporine • Selectively inhibits Th, Tc • As the second line medication to treat patients with steroid-resistant, frequently relapsing/steroid-dependent MCD • 5 mg .kg-1.d-1 for 8-12 weeks, then tapering • Side effects

  20. Treatment (4) • Other medications: MMF • General therapy • Symptomatic treatment • Chinese medicine

  21. Mesangial proliferative glomerulonephritis(MsPGN, 系膜增生性肾小球肾炎）

  22. Overview and Terminology • MsPGN is a morphlogic entity and characterized by glomerular mesangial hypercellularity • This morphologic definition includes many well-characterized GNs (IgA nephropathy, Henoch-Schonlein purpura nephritis, lupus nephritis and others) • When these well-defined entities are diagnosed and excluded, the resuliting are known as MsPGN or non-IgA MsPGN

  23. Pathogenesis • Unclear • Possibly due to immune complex depositon and complement fixation • Altered mesangial function may play an active role

  24. Clinic presentation • More in adolescents and young adults, more male patients • 50% of patients with a pre-episode of upper respiratory tract infection • 70% of patients with hematuria • Some patients with mild hypertension, azotemia • Accounting for 20-25% of renal biopsed patients and 30% of primary NS

  25. Histopathology • LM Varying degrees of mesangial hypercellularity with an increase in mesangial matrix • IM IgG, IgM, C3deposition in mesangial region and/or in capillary wall in granular pattern • EM Elctron-dense deposits in the mesangium

  26. Differential diagnosis • Clinical presentation • Renal biopsy • Exclusion of the secondary GN and other primary glomerulopathies (IgA nephropathy)

  27. Treatment • Therapy for MsPGN not-defined • Efficacy of steroid or cytotoxic therapy depends on the degree of pathologic injury • Other medications (ACEI /ARB /Chinese medicine)

  28. Membranous Nephropathy(MN, 膜性肾病） Overview and Terminology • Most common pattern of idiopathic NS in adults, less common than MCD in children • 15-25% of MN adult patients with no associated systemic illnesses • Up to 30% of MN patients with associated systemic illnesses(SLE,HBV,tumors)

  29. Pathogenesis • Immune complex formation in situ at the subepithelial capillary wall • Deposition of circulating immune complexes • Complement activation →proteinuria

  30. Clinical presentation • Heavy proteinuria in more than 80% of patients with full expression of NS • 30% of patients with microscopic hematuria • More male patients and more severe • 80%-90% of patients old than 30 years at diagnosis • The older the patients, the greater possibility of malignancy • Most common pattern of NS associated with venous thromboses

  31. Histopathology Usually classified as four stages LM: capillary walls thickened with subepithelial projections (Spikes) IM: strong granular capillary wall staining for IgG, C3 EM: subepithelial electron-dense deposits all along the capillary walls

  32. Diagnosis(1) • Based on histological findings in patients whose history, physical examination and appropriated laboratory tests exclue the likelihood of a secondary cause

  33. Diagnosis(2) Following lab tests negtive or normal • Antinuclear Ab • Anti-DNA Ab • Rheumatoid factor • Glycosylated HB • Hepatitis Ag or Ab • Carcinoembryonic Ag • cryoglobulins

  34. Treatment (1) Treatment of idiopathic MN remains controversial and should be individualized Steroids+Cytotoxic (ponticelli protocol)

  35. Ponticelli protocol • Months 2, 4, 6 chlorambucil 0.2mg/kg/d • Months 1, 3, 5 methylprednisone 1.0 iv qd×3d • then methylprednisone 0.4mg/kg/d×27d

  36. Treatment (2) • Immune inhibition agents(MMF,骁悉） • ACEI/ARB • Other therapies (anticoagulation)

  37. Focal segmental glomerulosclerosis(FSGS, 局灶节段性肾小球硬化）

  38. Terminology Focal vs diffuse • Some glomeruli involved (focal) • All glomoruli involved (diffuse) Segmental vs global (dealing with individual glomerulus) • Only part of the glomerulus involved (segmental) • Whole golmerulus involved (global)

  39. Overview • Accounting for less than 15% of cases of idiopathic NS in children, but more in adults • Hematuria,hypertension and GFR↓often found in patients at presentation

  40. Pathogenesis • Loss of renal mass( compensatory theory) • GEC injury • RAS activation • Cytokine overproduction(TGF-β）

  41. Clinical presentaion • Most patients with idiopathic FSGS present with asymptomatic proteinuria or full NS • Detection of asympotomatic cases occurs often at physicals • Patients with NS present with edema

  42. Histopathology • LM: focal segmental distribution of sclerosis (mesangial matrix ↑,capillary lumen obliteration, adhesion to Bowman’s capsule) • IM: IgM and C3 deposition in focal areas(团块状沉积） • EM: some or extensive effacement of foot process

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