1. Chronic Renal Diseases: Pathological aspects
Dr Rodney Itaki
Division of Pathology, SMHS, UPNG
Anatomical Pathology Discipline.

2. Gross anatomy
Ref: Goggle Images

3. Microanatomy
Robins Pathological Basis of Diseases, 6th Ed. Figure 21.1

4. Glomeruli - Ultra filtration

5. Glomeruli & Renal Capsule

6. Blood Supply

7. Juxtaglomerular Apparatus
+low BP & Ischaemia
+Low NaCl

8. Renin-Angiotensin-Aldosterone System
Ref:

10. Chronic Renal Disease
Definition: Chronic renal disease (CRD) is a pathophysiologic process with multiple etiologies, resulting in the inexorable attrition of nephron number and function, and frequently leading to end-stage renal disease (ESRD).
Irreversible deterioration in renal function (C.R.W.Edwards et al, 1998, pg.631)
Ref: Harrison 15th Ed.

11. Azotemia There is azotemia in chronic renal failure.
Azotemia is the biochemical state in which there is an elevation of:
Blood urea nitrogen (BUN) and
Creatinine levels when there is a decreased glomerular filtration rate (GFR).
Persistent azotemia gives rise to signs, symptoms and biochemical abnormalities, which is referred to as uremia.

12. Types of azotemia Type Feature Pre-renal azotemia
Due to hypoperfusion of kidneys.
For e.g. in congestive heart failure, shock, hemorrhage, and dehydration.
Post-renal azotemia
Due to any obstruction to the urinary flow below the level of kidneys.
[Note azotemia is not specific for chronic renal failure.]

13. Uremia
Definition:
Uremia is the clinical and laboratory syndrome, reflecting dysfunction of all organ systems as a result of untreated or under-treated acute or chronic renal failure. (CD-ROM 15th Harrison)

14. Pathogenesis
Due to disturbances in water, electrolytes & acid-base balance.
Accumulation of substances such as phosphate, parathyroid hormone, urea, creatinine, guanidine, phenols,& idoles.

15. Fig: Pathophysiologic pathway of chronic renal failure.
©2003 American Medical Association. All rights reserved.
on July 17, Downloaded from

16. Figure 1. Sympathetic over-activity and disease progression in chronic renal failure

17. Pathophsiology of Chronic Renal Failure
Diminished renal reserve
2. Renal insufficiency
3. Renal failure
4. End-stage renal disease (Chronic Renal Failure)

18. End Stage Renal Disease (ESRD)
In ESRD there is a degree of irreversible damage to the kidney and its function.
The patient usually becomes dependent on renal replacement therapy (dialysis or transplantation) in order to avoid life-threatening uremia.

19. Gross Morphology

20. Microscopic Morphology
Tubular atrophy
Interstitial fibrosis
Enlarged & hypertrophic tubules
Thickened basement membrane

21. Clinical Features of Uraemia
Anaemia
Metabolic bone diseases(renal osteodystrophy)
Neuropathy
Myopathy
Endocrine abnormalities
Hypertension & atherosclerosis
Acidosis
Susceptibility to infection

22. Signs & Symptoms of Uraemia
Vague-ill health
Generalized weakness & lack of energy
Breathlessness on exertion
Anorexia
Nausea & vomiting particularly in mornings
Disordered intestinal motility
Headaches
Visual disturbances
Pruritis
Pallor
Pigmentations
Loss of libido

23. Laboratory Investigation
Aim - Diagnosis and disease monitoring
FBC - anaemia
UEC – electrolyte imbalances, urea and nitrogen abnormalities
Renal biopsy
Others – Ca, phosphate, EPO, etc.
Genetic & immunological studies - transplant

24. Chronic Renal Diseases - Causes
The causes of chronic renal failure can be due to any disease process affecting the following structures:
Glomeruli (glomerulonephritis)
Tubules (reflex nephropathy)
Interstitium (pyelonephritis, reflux nephropathy)
Blood vessels (Hypertension)

25. Glomerular Diseases
Types:
Immune or
Non-immune mediated injury

26. Immune mediated Glomerular Diseases
Immune mechanism can be of antibody-associated injury. Two forms are known:
Immune response resulting in injury due to deposition of soluble circulating antigen-antibody complexes in the glomeruli. Referred to as Circulating Immune complex injury.
Immune response resulting injury due to antibodies reacting in situ within the glomerulus. Referred to as Cell Mediated Injury.
Others may be due to cytotoxic antibodies directed against the glomerular cells.

27. Non-immune Mediated Glomerular Diseases
1. Metabolic glomerular injury.
Diabetic nephropathy: the glomerular lesion is glomerulosclerosis whereby there is thickening of the glomeular basement membrane.
2. Hemodynamic glomerular injury.
This is due to the high intra-glomerular pressure caused by systemic hypertension or local change in glomerular hemodynamics (glomerular hypertension).
3. Toxic glomerulopathies.
The toxic verotoxic from the E.Coli is directly toxic to renal endothelium and induces hemolytic-uremic syndrome in patients with infective diarrhea caused by E.Coli.Verotoxic interacts with specific cell membrane receptor inducing thrombotic microangiopathy.

28. Non-immune Mediated Glomerular Diseases
4. Deposition disease.
There is deposition of abnormal proteins in the glomeruli inducing inflammatory reaction or glomerulosclerosis. For e.g. amyloidosis, cryoglobulins, light and heavy chain deposition disease.
5. Infectious glomerulopathies.
Infectious microorganisms can cause injury by:
Direct infection of renal cell
Elaboration of nephrotoxic e.g. E.Coli
Intraglomerular deposition of immune complexes e.g. post-infectious glomerulonephritis.
Providing chronic stimulus for amyloidosis.
6. Inherited glomerular diseases.
A common e.g. is:
Alport’s disease: Transmitted, as X-linked dominant trait. There is mutation in COL4A5 gene that encodes -5 chain of type IV collagen located on X-chromosome. The glomerular basement membrane (GBM) is affected.

29. The determinants of the severity of glomerular damage are
The nature of primary insult and secondary mediator system that evoke it.
The site of injury within the glomerulus.
The speed of onset, extend and intensity of disease.

30. Common Chronic Renal Failure Causes
Non-Immune Mediated - Diabetic Nephropathy
Immune Mediated – Glomerulonephritis
Blood vessel - Hypertension
Interstitial injury & Tubules - Reflux nephropathy in children
Interstitial, tubules & Glomerular - Polycystic kidney disease
Interstitial & tubules - Kidney infections & obstructions
Source: Wendy DeMartino, MD, Teaching Slides. Downloaded via Goggle Search.

31. Diabetic Nephropathy
Ref: Robins Pathological Basis of Diseases, 6th E. Table 20.1

32. Diabetic Nephropathy Capillary BM thickening.
Diffuse glomerulosclerosis.
Nodular glomerulosclerosis.
Ref:

33. Basement membrane Thickening
Thickened BM
Ref:

34. Amyloidosis Amyloid deposits
Deposition of abnormal protein in the glomerulus & blood vessel wall
Amyloid deposits

35. Amyloidosis
Congo red stain. Examined under polarization microscopy. “Apple-green” birefringence.
Ref:

36. Glomerulonephritis
Ref: Robins Pathological Basis of Diseases, 6th Ed. Table 21.3

37. Glomerulonephritis
Ref. Robins Pathological Basis of Diseases, 6th Ed. Figure 21.29

38. Histological Types of GN
Post-streptococcal GN
Rapidly Progressive Glomerulonephritis
Membranous GN
Focal glomerulosclerosis
Membranoproliferative GN

39. Post-streptococcal GN
Normal glomerulus
Acute proliferate GN
Hypercellularity due to intercapillary leucocytes & proliferation of glomerular cells
Ref: Robins Pathological Basis of Diseases, 6th Ed. Fig 21.16

40. Rapidly Progressive (Crescentic) GN
Ref:

41. Crescent GN Collapsed glomerular tufts
Mass of crescent shaped proliferating cells & leucocytes
Ref: Robins Pathological Basis of Diseases, 6th Ed. Fig 21.17

42. Membranous GN
Diffuse thickening of capillary wall without increase in number of cells
Diagrammatic representation
Ref: Robins Pathological basis of Diseases, 6th Ed. Fig

43. Minimal Change Disease (Lipoid Nephrosis)
Visceral epithelial cells show uniform and diffuse effacement of foot process
Thin BN. No proliferation

44. Minimal Change Disease
Normal glomerular tuft. No hypercellularity. Thin BM.
Ref:

45. Focal Glomerular Sclerosis
Sclerotic segment shows deposition of hyaline masses
Lipid in sclerotic area (small vacuoles)
Foam cells
Ref:

46. Membranoproliferative GN
Differentiation based on electron microscopy
Ref: Robins Pathological Basis of Diseases, 6th Ed. Fig 21.24

47. Membranoproliferative GN
Thickened in BM
Proliferation of mesangial cells (glomerular cells)
Leukocyte infiltration
Ref: Robins Pathological Basis of Diseases, 6th Ed. Fig 21.23

48. IgA Nephropathy (Berger Disease)
IgA deposited within mesangium increasing its cellularity
Immunofluorescence demonstrating positivity with antibody to IgA.
Ref:

49. Focal Proliferative & Necrotising GN (Focal GN)
Main differential diagnosis for Focal glomerulosclerosis as histological features very similar.
Main lesions are predominantly proliferative.
Focal necrosis & fibrin deposition often occur within lesions.
Occur as part of a systemic disease (e.g. SLE), component of known glomerular disease (e.g. IgA nephropathy) or primary (cause unknown).

50. Blood Vessel Injury - Hypertension
Atherosclerosis:
Multifactorial
The vascular injury is due to cholesterol- containing micro-emboli (atheroemboli) dislodged from atheromatous plaque in larger arteries. The micro-emboli occlude the small vessels in the kidney.
Direct injury to blood vessel wall.
It may result in renal artery stenosis and ischemic renal diseases.

51. Pathogenesis Of Disease Involving Blood Vessels
Hypertension:
The persistent exposure of renal circulation to intraluminal hypertension results in hyaline arteriosclerosis of the afferent arterioles and finally loss of function (nephrosclerosis). That is,
Benign arteriolar nephrosclerosis: found in patients who are hypertensive for sometime with BP > 150/90 mmHg. Hypertension has not progressed to malignant form.
Malignant arteriolar nephrosclerosis: found in patients who have long-standing benign hypertension and not known hypertensive. There is sudden elevation in BP (diastolic  130mmHg). There is accompanied papilledema, cardiac decompensation, CNS involvement, and progressive renal deterioration.

52. Hypertension – Renal Changes
Hyperplastic arteriolitis (onion-skin lesion)
Fibrinoid necrosis of afferent arteriole.
Robins Pathological Basis of Diseases, 6th Ed. Figure 21.20

53. Others Reflux nephropathy – renal scaring and loss of glomeruli.
Polycystic kidney diseases – multiple dilated cysts. Genetic.
Kidney infections & obstructions – acute to chronic inflammation. Renal scaring and loss of glomeruli.
Focal GN/Focal proliferative & nectrotising GN. Main differential diagnosis of Focal sclerosis GN.

54. Complications Endocrine abnormalities Muscle dysfunction
Anemia
Bone disease
Skin disease
Gastrointestinal complications
Metabolic abnormalities
Endocrine abnormalities
Muscle dysfunction
Nervous complications
Cardiovascular

55. Prognosis Poor Treatment can only slow progression
Renal transplant offers true cure (but has its own complications).

56. END
Main reference: Robins Pathological Basis of Diseases, 6th Ed. Chapter on Kidney & Endocrine diseases.