1. PATHOLOGY Chronic Renal Failure 2015

2. Objectives  Recognize the clinical pathological correlation of biological progression and gross and microscopic features of Polycystic disease.  List the commonest disease processes leading to obstruction or reflux and describe the gross features of these diseases and their complications.  Describe the gross and microscopic features of renal vascular disease (hypertension, atherosclerosis).  Recognize the general principles of a chronic immune complex mediated glomerulonephritis as illustrated by Systemic Lupus Erythematosis (SLE).  Recognize the features of segmental fibrosis in glomeruli that occur as a result of increased single nephron perfusion in remaining nephrons in states of chronic loss of total nephron number.

3. Pathology of Chronic Renal Disease *Progressive loss renal function * Associated with compensatory hyperfiltration *Over time hyperfiltration causes further damage (maladaptive) *With progressive damage the original etiology can be obscured by non specific scarring

4. Review of pathology of common causes of Chronic renal failure  Pre:(chronic hypoperfusion/ Ischemic  Post: obstruction/ backpresssure  Renal: hereditary,chronic glomerulonephritis, metabolic abnormalities, tubulointerstitial diseases

5. Review of pathology of common causes of Chronic renal failure  Congenital / hereditary (10%)  Obstructive/ chronic pyelonephritis/ other tubulointerstitial diseases (10%)  Diabetes (30%)  Hypertension/ vascular (25%)  Glomerulonephritis (15-20%)

6. CASE #1 Adult Polycystic Disease Example of Hereditary disease leading to CRF  52 year old man  Presented at 35 years of age with flank pain and gross hematuria  Kidneys enlarged by palpation bilaterally  Also hypertensive  Mother died of an intracerebral hemorrhage  Mother had kidney disease of uncertain type  Prior to death the patient was dialysis dependent then received a renal transplant  He died of infectious complications at 52 years old  Kidneys are from autopsy

7. Adult Polycystic disease Overview  Relatively common (4-10% CRF)  Autosomal dominant  PKD 1 and 2 most common  PKD1 on chromosome 16 represents 85% abnormal protein polycystin 1  Protein thought to be important for cell interaction and tubular growth and differentiation  There is active secretion into the cysts  PKD2 usually less severe  Individual cases can be unpredictable as to age of CRF  Other abnormalities Cysts of liver spleen pancreas. Mitral valve prolapse, intracranial berry aneurysm, hypertension, diverticulosis

9. Normal kidney

10. Bilaterally enlarged kidneys distorted by numerous cysts

11. Cut surface shows cysts leaving little residual kidney Some cysts show hemorrhage within them

12. Histological section and corresponding schematic

13. Cysts can occur at various levels Pressure results in atrophy of adjacent tissue

14. Screening  Ultrasound need to have cysts big enough  No need to diagnose early as no treatment  unless decision re having children or donating a kidney from transplant  Genetic screening available but cannot predict severity or age of onset

15. Child, MVA victim with early changes of Adult Polycystic Kidney Disease

16. Ultrasound

17. MRI Liver Cystic kidney cysts

18. CASE #2 Obstruction with hydronephrosis  44 year old woman with past history of Invasive carcinoma of cervix  Rx with radiotherapy  Prior to death developed progressive renal failure

19. tumour

20. Hydroureter and hydronephrosis

21. Normal Hydronephrosis

22. Features: - Interstitial fibrosis -Atrophic and dilated tubules -Secondary effects on glomeruli

24. End Stage Hydronephrosis Progression to end stage

25. Histology of end stage kidney is similar no matter initial cause. Fibrosis, atrophy and non specific inflammation Often with thickened arteries. Dilated tubules may look thyroidized Clues may still be seen focally or on gross

26. Other causes of mechanical obstruction - calculi - tumours - congenital - inflammation

27. Renal Calculi

28. Renal calculi in ureter

30. primary Tumour within ureter with obstruction

33. Posterior urethral web

34. Retroperitoneal fibrosis

35. ill defined inflammation and fibrosis

36. Case #3 Pseudo obstructive/ non mechanical Complications of obstruction  Patient with history of Multiple sclerosis  As a sequela developed a neurogenic bladder (did not contract and empty properly)  Complicated by numerous episodes of infection.

37. Scarring Chronic pyelonephritis

38. Renal pelvis Cortical abcesses Infected medulla with linear streaks Infection can be a complication of obstruction

39. Acute inflammatory cells in tubules

40. Collecting ducts White blood cell cast Interstitial inflammation Repeated episodes of acute inflammation can result in chronic inflammation fibrosis and loss of function

41. End result is Chronic Pyelonephritis With deep scars “U” shaped involving cortex and medulla

44. Deep “U “ shaped scar involving cortex down to renal pelvis

45. Chronic active inflammation extending to and involving calyceal transitional mucosa

46. Scar with Hyalinized scarred glomeruli and atrophic tubules “so called Thyroidization”

47. Ureteropelvic junction “stricture ””

49. #4 Vascular causes of Chronic renal failure: Arteriosclerosis due to atherosclerosis and arteriolar changes in hypertension As arteries and arterioles become narrow decreased blood delivery results in ischemic changes  Glomeruli Ischemic change with wrinkling shrinkage and fibrosis  Tubules - atrophic  Interstitium Fibrosis and non specific chronic inflammation

50. Arterio and arteriolar Nephrosclerosis Gross -Small kidney Arteriosclerotic scarring with cortical scars small and large but shallower than those of pyelonephritis

52. Microscopy of arteriosclerotic scar Fibrosis of interstitium and glomeruli with associated vessel changes

53. Arteriosclerotic scarring with non specific interstitial inflammation Marked arteriosclerosis with vessel lumen narrowed Periglomerular fibrosis

54. Vascular changes can also result in acute renal failure especially in those already compromised

55. 1. Cholesterol emboli Embolic atherosclerotic plaque dislodged from Aorta Risk factors include surgery on atherosclerotic aorta or arteriography Can result in showers of emboli that can lodge in small vessels of kidney and result in acute decrease in renal function in kidneys already borderline in function

56. 2. Hypertensive effects can become accelerated (malignant) usually on top of preexisting benign hypertension (1-5% of hypertensive patients)  Interlobular arteries and arterioles similar to those in retina can show vessel wall damage that is necrotizing (fibrinoid necrosis) especially at branches & as enters glomerulus  There can also be a proliferation of intimal myofibroblasts with narrowed lumen (onion skin)  This can result in rapid obstruction or narrowing of blood flow to glomeruli and an ACUTE decrease in renal function

57. Gross changes are so called flea bitten kidney with small hemorrhages

58. onion skin" change caused by lamellation mucoid change with swelling of the intimal layer.

59. Fibrinoid necrosis vessel wall damage with fibrinoid eosinophilic material (and red cells) moving into damaged vessel wall.

60. Onion skinning Fibrinoid necrosis vessel wall damage with fibrin (and red cells) moving into damaged vessel wall.

61. Case #5 Glomerulonephritis progressing to chronic phase  30 year old woman with SLE  Presented with a diffuse proliferative Glomerulonephritris associated with nephritic picture and decreased serum complement  Over three years some exacerbations of disease  Now in chronic renal failure with GFR about 30% normal and has a normochromic normocytic anemia

62. Compare to normal http ://www.uptodate.com/contents/image.do?imageKey=NEPH%252F14385

63. Diffuse proliferative glomerulonephritis

65. Proliferation and “Wire Loops ”

66. Small crescent

67. Effective capillary lumen is narrowed by proliferation of cells and deposit of immune complexes and reaction to them

68. Immunofluorescence was positive for IgG, IgA, IGM, C3

69. Multiple deposition sites for Immune complexes seen on EM

70. SLE IV wireloop Large subendothelial deposits There are subepithelial ones also There is an occluding thrombus like structure in lumen Immune complexes fix complement and damage proceeds

71. S00-12090 With continuing damage areas of scarring develop highlighted by this stain which shows collagen in blue-green

72. Interstitial inflammation can also occur with tubular damage fibrosis and tubular atrophy

73. Gross fearures of chronic glomerulonephritis are not specific