徐芳英 ( xfy@zju )

1. Diseases of the Kidney 徐芳英 (xfy@zju.edu.cn)

2. Kidney Functions Excretion of the waste products of metabolism Regulation of body’s water and salt Maintenance of appropriate acid balance of plasma Secretion of a variety of hormones and autacoids: Erythropoietin Renin Prostaglandins

3. Nephron Renal Corpuscle Glomerulus Renal Capsule (Bowman’s Capsule） Bowman’s Space Juxtaglomerular apparatus Renal Tubule

4. Schematic representation of a glomerular lobe

5. Mesangium A supporting structure in the center of the lobe Consisting of mesangial cells & mesangial matrix Functions: Being contractile Being phagocytic Being capable of proliferation Synthesize both matrix & collagen Secreting a number of biologically active mediators

6. Filtering membrane consisting of A thin layer of fenestrated endothelial cells A glomerular basement membrane (GBM) The visceral epithelial cells (podocyte) Filtering depended on Volume Charge

7. Bowman’s capsule & Bowman’s space Bowman’s capsule: Visceral epithelium Parietal epithelium Bowman’s space (the urinary space) A cavity in which plasma filtrate first collects

8. Disorders of the Kidney Congenital – Malformations, ectopic, cysts, dysplasia. Acquired – Glomerular diseases – Tubulointerstitial diseases – Renal calculi – Neoplasms – carcinoma

9. Glomerular Diseases (Glomerulonephritis,GN) Primary Glomerular Diseases Secondary to Systemic Diseases Hereditary Disorders

10. Primary GN Acute diffuse proliferative glomerulonephritis Rapidly progressive (crescentic) glomerulonephritis Membranous glomerulopathy Minimal change disease Focal segmental glomerulosclerosis Membranoproliferative glomerulonephritis Mesangioproliferative glomerulonephritis IgA nephropathy Chronic glomerulonephritis

11. Secondary GN Systemic lupus erythematosus Diabetes mellitus Amyloidosis Goodpasture syndrome Microscopic polyarteritis/polyangiitis Wegener granulomatosis Henoch-Schönlein purpura Bacterial endocarditis Hereditary Disorders Alport syndrome Thin basement membrane disease Fabry disease

12. Pathogenesis of Glomerular Injury Immune Mechanisms Antibody-Mediated Injury In Situ Immune Complex Circulating Immune Complex Deposition Cell-mediated Immune Injury Activation of Alternative Complement Pathway

14. Antibody-mediated glomerular injury can result either from the deposition of circulating immune complexes (A) or, more commonly, from in situ formation of complexes exemplified by anti-GBM disease (B) or Heymann nephritis (C)

15. Two patterns of deposition of immune complexes as seen by immunofluorescence microscopy: granular, characteristic of circulating immune complex nephritis and linear, characteristic of in situ immune complex nephritis

16. 肾小球损伤的机制 • 抗体介导的免疫损伤：主要通过补体和白细胞介导的途径发挥作用 • 大多数抗体介导的肾炎由循环免疫复合物沉积引起，免疫荧光呈颗粒状 • 抗GBM成分的自身抗体可引起抗GBM性肾炎，免疫荧光呈线性分布 • 抗体可与植入肾小球的抗原发生反应，形成原位免疫复合物，免疫荧光呈颗粒状

17. Basic Histologic Alteration 肾活检： 1.光镜 特殊染色： 过碘酸-Schiff（PAS）染色：糖原和糖蛋白染成红色，可显示基膜和系膜基质 过碘酸六胺银（PASM)染色：基膜、系膜基质及IV型胶原显黑色，可更好地显示基膜等结构 Masson三色染色：基膜和胶原显蓝色或绿色，免疫复合物、血浆和纤维素显红色，可显示特殊蛋白性物质、胶原纤维等 Fibrin染色：显示血栓和纤维素样坏死 2.免疫荧光：显示免疫球蛋白和补体成分沉积 3.透射电镜：超微结构改变和免疫复合物沉积状况及部位

18. Basic Histologic Alteration • Hypercellularity:系膜细胞和内皮细胞、炎症细胞、壁层上皮细胞 • Basement Membrane Thickening and Rupture • Inflammatory Exudate and Necrosis：中性粒细胞和纤维素渗出，纤维素样坏死，血栓形成 • Hyalinization and Sclerosis： • 玻璃样变：均质的嗜酸性物质沉积，成分为沉积的血浆蛋白、增厚的基膜和增多的系膜基质 • 硬化：系膜区和（或）毛细血管袢细胞外胶原数量增多 • 肾小管和间质的改变： 肾小管上皮细胞变性，管腔内出现管型、萎缩和消失 • 间质充血、水肿和炎细胞浸润、纤维化

19. Clinical Manifestations Features Syndromes Nephritic syndrome Hematuria Proteinuria Edema Hypertension Azotemia Rapid progressive nephritic syndrome Oliguria Anuria Azotemia Renal function failure Nephrotic syndrome Proteinuria Edema Hyperlipidemia Hypoproteinemia Asymptomatic hematuria or proteinuria Chronic nephritic syndrome Polyuria Nocturia Isosthenuria Anemia Hypertension Azotemia Uremia

20. Major Primary GN Acute proliferative GN Rapidly Progressive GN Membranous Nephropathy Minimal-change GN Membranoproliferative GN IgA Nephropathy Chronic GN

21. Acute Proliferative GN

22. Acute Proliferative GN Postinfectious GN : Poststreptococcal GN Nonstreptococcal GN Appears usually 1-4 weeks after a group A β-hemolytic streptococcal pharyngeal or skin infection Occurs most frequently in children 6-10 years old Characterized histologically by diffuse proliferation of glomerular cells (endothelial cells and Mesangial cells)with infiltration of leukocytes Caused by deposition of immune complexes:Inciting Ag may be exogenous or endogenous

23. Morphology Enlarged kidneys slightly with scattered petechial hemorrhages 大红肾 蚤咬肾

24. Hypercellularity: proliferation of Mesangial cells Endothelial cells Enlarged glomeruli-diffuse Infiltrated by WBC’s (neutrophils and monocytes) Compression of glomerular capillary lumina

26. Granular deposits of IgG, IgM & C3 in the mesangium & along the GBM Electron dense deposits – subepithelial “humps”

27. Clinical Manifestation • Acute Nephritic Syndrome 血尿：30%肉眼血尿，红细胞管型 水肿：肾小球滤过率降低，水、钠潴留 高血压：轻-中度，水、钠潴留，血容量增加 • > 95% of children completely recover 30-50% of adults suffer progressive renal disease

28. Rapidly Progressive GN

29. Crescentic GN • Characterized clinically by rapid & progressive loss of renal function with severe oliguria • Death from renal failure within weeks to months if untreated • Is a syndrome associated with severe glomerular injury and does not denote a specific etiologic form of glomerulonephritis

30. Type I RPGN (Anti-GBM Antibody) • Idiopathic • Goodpasture syndrome (肺出血-肾炎综合征） Type II RPGN (Immune Complex) • Idiopathic • Postinfectious • Systemic lupus erythematosus • Henoch-Schönlein purpura (IgA) • Others Type III RPGN (Pauci-Immune) • ANCA associated • Idiopathic • Wegener granulomatosis • Microscopic polyarteritis

31. Morphology The kidneys are enlarged and pale, often with petechial hemorrhages on the cortical surfaces

32. Morphology • Crescent formation by proliferation of parietal cells and infiltration of WBC’s & fibrin • deposition in Bowman’s space • EM reveals focal disruptions in the GBM

33. cellular crescent fibrous crescent fibrinoid necrosis in the wall of capillary

34. Clinical Manifestation • acute nephritic syndrome occasionally, nephrotic Syndrome • ANCA, anti-GBM & antinuclear Ab’s are helpful in diagnosis • Poor prognosis • steroids, cytotoxic drugs & longterm dialysis or renal transplantation

35. 肾病综合征相关肾炎 肾小球毛细血管壁损伤 蛋白尿（≥ 3.5 g/day） 选择性蛋白尿（主要为低分子量的白蛋白和转铁蛋白） 非选择性蛋白尿（严重时大分子量蛋白也滤过） 低蛋白血症（< 3 g/dl） 血浆胶体渗透压降低 刺激肝脏合成脂蛋白 脂质颗粒运送障碍 外周脂蛋白分解障碍 血容量下降，醛固酮和抗利尿激素分泌增加，水钠潴留 高脂血症 水肿 脂尿

36. Membranous Nephropathy

37. Membranous Nephropathy • Main cause of nephrotic syndrome in adults • Characterized by diffuse thickening of the GBM & the accumulation of electron-dense immunoglobulin-containing deposits

38. Primary membranous GN (85% of cases) • Secondary membranous GN Drugs (e.g., penicillamine, NSAIDs) Malignancies (esp. carcinoma of lung & colon, melanoma) SLE Infections (e.g. hepatitis B & C, syphilis) Hashimoto thyroiditis

39. Primary membranous GN is caused by autoantibodies directed against an Ag on the visceral epithelial cells • Secondary membranous GN is caused by deposition of immune complexes

40. 大白肾

41. Diffuse thickening of glomerular capillary wall Spikes can be seen by silver stains

42. Granular deposits of Ig’s & complements

43. Subepithelial deposits

44. Important to rule out secondary causes proteinuria is nonselective & does not usually respond well to corticosteroids • Course is variable but generally indolent • Only ~ 10% die or progress to CRF within 10 years

45. IgA Nephropathy

46. Berger Disease • Characterized by presence of prominent deposits of IgA in the mesangium • Most common type of GN worldwide • Affects children & young adults • Present with hematuria often after a respiratory infection

47. Abnormality of immune regulation ⇒ mucosal IgA synthesis in response to respiratory or GI exposure to environmental antigens • IgA & IgA immune complexes are entrapped in the mesangium ⇒ activation of alternative complement pathway ⇒ glomerular injury

48. Considerable variation on LM: glomeruli may appear normal, may exhibit mesangioproliferative GN, focal proliferative GN or rarely crescentic GN Mesangial cellularity and matrix increased, and there was a thickening of the glomerular basement membrane

49. Mesangial deposition of IgA, often with C3 & properdin

50. Affects children & young adults • Slow progression to CRF in 15-40% of cases in 20 years • IgA deposits recur in 20-60% of allografts