5 General Pathology Review & Introduction to Renal Pathology

Question 1

Homeostasis & the normal response of cells to physiologic stress

Answer 1

• Homeostasis
  
  • Normal physiologic balance in the body
• Normal response of cells to physiologic stress
  
  • Adapt
    
    • Hypertrophy (ex. muscles of body builders)
    • Atrophy (ex. leg muscles after paralysis
  • Necrosis
    
    • Cell death

Question 2

Causes of cell injury & cell death

• Causes
• Reversible vs. irreversible cell injury
• Cell injury
• Necrotic cells

Answer 2

• Causes
  
  • Oxygen deprivation
  • Ischemia
  • Physical agents (ex. radiation)
  • Chemical agents
  • Infections
  • Immunologic reactions
  • Genetic derangements
  • Nutritional imbalances
• Reversible vs. irreversible cell injury
  
  • Reversible
    
    • Seen w/ EM but not microscope
    • Cellular swelling
    • Hydropic changes
  • Irreversible damage
    
    • Seen w/ EM & microscope
    • Coagulation of cytoplasmic proteins
    • Nuclear degeneration
• Cell injury
  
  • Cell membranes are made of lipids
  • Influx of Ca –> decreased ATP, decreased phospholipids, disrupted proteins, & chromatin damage
  • Free radicals –> disrupted cell membranes, ribosome leakage, mitochondria problems, & lysosome rupture
  • Cell damage –> lubbimg membranes, swelling, & chromatin clumping
    
    • Normal cell –> recovery
    • Further injury –> more damage, more leakage, lysosome rupture –> digest cell contents
• Necrotic cells
  
  • Eosinophilic due to increased binding of eosin (dye) to natured proteins (eosinophilia)
    
    • Increased red/pink cells from denatured proteins
  • Cytoplasm: glassy, homogeneous, & vacuolated (moth-eaten, due to digestion by lysosomal enzymes)
  • Focal, dystrophic calcification (low pH, high cytosolic Ca)

Question 3

Different types of cell death

• Necrosis
• Other types

Answer 3

• Necrosis
  
  • Coagulative
  • Liquefactive
  • Caseous
• Other types
  
  • Autolysis
  • Apoptosis

Question 4

Coagulative necrosis

Answer 4

• Retains structure, loses function
• Result of denaturing cellular proteins (coagulation)
  
  • Intracellular acidosis & Ca denatures cellular structural proteins & proteolytic enzymes –> blocks proteolysis
• Basic outline of cells is preserved w/ nuclear degeneration
• Occurs in hypoxia (decreased oxygen) & ischemia (decreased blood flow –> decreased oxygen)
• Histology
  
  • Normal: lots of nuclei
  • Necrosis: destroyed nuclei, only see contours of cells
    
    • Glomeruli maintain structure longer than tubular epithelial cells

Question 5

Liquefactive necrosis

Answer 5

• Cells burst from fluid, lose structure
• Seen in bacterial & fungal infections
• Accumulation of inflammatory cells bring lytic enzymes (abscess)
  
  • –> complete digestion of dead cells
    
    • Via spillage of active lysosomal enzymes in injured cells or via inflammatory cells
  • –> liquid viscous mass (pus)
• Histology
  
  • Top: abscess
    
    • Purple = nuclei of inflammatory cells release enzymes & cause necrosis
  • Bottom: lot of inflammatory cells & necrotic debris

Question 6

Caseous necrosis

Answer 6

• White & cheesy
• Fragmented cells w/ coagulative necrosis & amorphous granular debris
• Seen w/ mycobacterial infections or TB
• Histology
  
  • Left: lung
    
    • Inflammatory cells on the outside
    • Homogenous stuff in the middle
    • Giant cells around it
  • Right
    
    • Looks like curd
    • Lots of proteins
    • Can barely make out the outline of any cells

Question 7

Inflammation

• General
• Cellular response
• Acute vs. chronic inflammation
• When inflammation can be harmful
• Repair

Answer 7

• General
  
  • Essential for the body to defend itself against harmful agents (ex. bacterial infections)
  • Destroys injurious agents, dilutes injurious agents, & walls off the process
    
    • –> healing & reconstruction of the damaged tissues
• Cellular response
  
  • Cells respond to chemotactic agents by exiting the blood stream into affected tissues & performing specific functions
• Acute vs. chronic inflammation
  
  • Acute
    
    • Short lived (minutes to a few days)
    • Hallmark cell: neutrophil or granulocyte
  • Chronic
    
    • Longer duration
    • Hallmark cells: mononuclear lymphocytes, plasma cells, macrophages, & eosinophils
• W/o inflammation
  
  • Infections go unchecked –> wounds never heal –> injured organs remain permanent sores
• When inflammation can be harmful
  
  • Hypersensitivity rxns to insect bites or drugs
  • Rheumatoid arthritis when inflammation destroys joints
  • Atherosclerosis –> atheromas + decreased blood flow to organs
  • Glomerulonephritis –> renal failure
• Repair
  
  • Resolution: regeneration of native parenchyma (ex. liver)
  • Organization: filling the defect w/ fibroblastic tissues or scar (ex. heart or muscles)
  • Most common: combination of both (ex. kidneys)

Question 8

Inflammatory cells

• In blood
  
  • Polymorphonuclear leukocytes (neutrophils)
  • Leukocytes
  • Platelets
  • Monocytes
  • Eosinophils
  • Basophils
• In connective tissue
  
  • Fibroblasts
  • Macrophages
  • Macrophages & giant cells
  • Plasma cells
  • Mast cells
  • Proteoglycans, elastic fibers, & collagen fibers

Answer 8

• In blood
  
  • Polymorphonuclear leukocytes (neutrophils)
    
    • Small
    • Multi-lobed nucleus never looks the same
    • Inflammatory granules
  • Leukocytes
    
    • Thin rim of cytoplasm
    • Perfectly round nucleus
  • Platelets
  • Monocytes
    
    • Phagocytic
    • –> macrophages when in connective tissue
  • Eosinophils
    
    • Bright red granules
    • Response to IgE mediated reactions or parasitic infections
  • Basophils
    
    • Larger granules
    • Darker blue
• In connective tissue
  
  • Fibroblasts
    
    • Deposit collagen for repair
    • Chemotactic properties call in inflammatory cells
  • Macrophages
    
    • First cousin of monocytes
    • “Pac man,” clean debris
  • Macrophages & giant cells
    
    • See granulomas
    • Engulf specific types of bacteria (ex. TB, leprosy, syphilis) or foreign bodies (ex. foreign body granulomas)
  • Plasma cells
    
    • Larger
    • Halo, clock face, eccentric nucleus (on one side of the cell)
    • Shouldn’t be seen in the blood
    • Make immunoglobulins
    • First cousin of B lymphocytes
  • Mast cells
    
    • Release histamine to bring in fluid
    • Role in bee stings, etc.
  • Proteoglycans, elastic fibers, & collagen fibers
    
    • Repair

Question 9

Granulomatous inflammation

Answer 9

• aka type IV hypersensitivity rxn
• Activated macrophages & multinucleate giant cells
• Seen in…
  
  • TB
  • Sarcoidosis
  • Leprosy
  • Syphilis
  • Wegener’s granulomatosis
  • Foreign body rxn

Question 10

Renal pathology statistics

Answer 10

• 20% of women get UTIs
  
  • Complications: acute & chronci pyelonephritis
• 1% of ppl get renal stones
  
  • Complications: hydronephrosis, hydroureter
• Dialysis & renal transplants keep pts alive
• Many deaths related to renal diseases are in young pts

Question 11

Gross pathology of the kidney

• Normal kidney
• Composition
• Blood vessels –> ureter
• Embryology: successive pairs

Answer 11

• Normal kidney
  
  • Weight: 150 grams
  • Length: 12-15 cm
• Composition
  
  • Cortex: 1.2-1.5 cm thick
  • Medulla: 12 pyramids + base at the corticomedullary junction
• Blood vessels –> ureter
  
  • Blood vessels
  • –> 12 minor calyces
  • –> 2-3 major calyces
  • –> funnel shaped renal pelvis
  • –> ureter
• Embryology: successive pairs
  
  • Pronephros
  • Mesonephros
  • Metanephros

Question 12

Kidney problems

• Congenital anomalies
  
  • Agenesis
  • Hypoplasia
  • Ectopic Kidneys
  • Horseshoe kidney
• Cystic diseases
  
  • Congenital
    
    • Cystic renal dysplasia
    • Polycystic kidney disease
    • Medullary cystic disease
  • Acquired
  • Localized

Answer 12

• Congenital anomalies
  
  • Agenesis: absence of kidneys
  • Hypoplasia: small & ill-formed kidneys
  • Ectopic kidneys: in the wrong place
  • Horseshoe kidney: 2 kidneys don’t separate & are joined at the lower poles
• Cystic diseases
  
  • Congenital
    
    • Cystic renal dysplasia: numerous small cysts in the kidneys, presents at a young age
    • Polycystic kidney disease: AR in childhood, AD in young adults
    • Medullary cystic disease: cysts mostly affect distal tubules in the medulla
  • Acquired
    
    • Associated w/ long-term renal dialysis
  • Localized
    
    • Simple
    • Vary in size
    • Commonly seen as incidental findings at resection or autopsy
    • Mostly asymptomatic

Question 13

Renal biopsy

• Purpose
• Types
  
  • Closed core needle biopsy
  • Open biopsy
• After biopsy
• 3 portions
  
  • Largest
  • Small
  • Smallest

Answer 13

• Purpose
  
  • Provide sufficient accurate info on which to base the right diagnosis, approach to treatment, & prognosis
• Types
  
  • Closed core needle biopsy
    
    • Obtaiend by a tru-cut needle under ultrasound guidance & local anesthesia
  • Open biopsy
    
    • Perfomred in the OR under general anesthesia
• After biopsy
  
  • Renal tissue is immediately submitted to pathology in normal saline for processing under a scanning microscope to ensure there’s enough cortical tissue & _>_10-12 glomeruli
  • Complete study: light microscopy, special stains, IF microscopy, & EM
• 3 portions
  
  • Largest: fixed in Bouin’s fixative for 2 hours, washed, processed, & cut at 2-3 microns for light microscopy
  • Small: immediately frozen in OCT & cut at 5 micron thickness to be stained for Igs & studied under IF microscopy
  • Smallest: cubed at 1mm & fixed in 2% glutaraldehyde sol’n, embedded in hard resin, cut, & examined under EM

Question 14

Light microscopy: stains

• H&E
• Methamine silver
• Periodic acid schiff (PAS)
• Trichrome
• Congo-red

Answer 14

• H&E
  
  • Basic morphology
• Methamine silver
  
  • Black
  • Basement membrane morphology (thickness, splitting, & spikes)
• Periodic acid schiff (PAS)
  
  • Fuscia red
  • Basement membranes, deposits, & glycogen
• Trichrome
  
  • Blue or green in a red background
  • Amt of fibrosis, chronicity of renal damage
• Congo-red
  
  • Pink w/ apple-green birefringence under polarized light
  • Amyloidosis

Question 15

Light microscopy: glomeruli

• Cellularity
• ECM
• Peripheral capillary basement membrane
• Bowman’s space
• Image: normocellular
• Image: hypercellular
• Image: mesangial sclerosis

Answer 15

• Cellularity
  
  • Number of cells within mesangial areas, endothelial (intraglomerular vs. extraglomerular)
• ECM
  
  • Sclerosis, increased mesangial sustance, fibrosis, amyloidosis, etc.
• Peripheral capillary basement membrane
  
  • Thickening, wrinkling, splitting, etc.
• Bowman’s space
  
  • Normal or filled w/ hemorrhage, epithelial cells, proteinaceous substances, fat droplets, etc.
• Image: normocellular
  
  • Tubules come togehter like a jigsaw puzzle
  • Can’t see any interstitium
• Image: hypercellular
  
  • Too many crowded cells
  • Increased cellularity –> not enough blood goes to the tubules –> tubules don’t look good
• Image: mesangial sclerosis
  
  • Diabetic kidney
  • Fibrotic nodules
  • Accentuated blood vessels & basement membranes

Question 16

Light microscopy: tubules

• Normal
• Pathologic tubules
• Pathologic tubular basement membranes
• Pathologic lumen can be filled w/…
• Image: normal
• Image: blood
• Image: luminal casts (hyaline)
• Image: adenoma
• Image: tubular necrosis
• Image: tubular atrophy

Answer 16

• Normal
  
  • Close together w/ little interstitial tissue
  • Open & empty lumen
• Pathologic tubules
  
  • Necrotic (ex. acute tubular necrosis)
  • Degenerative (ex. atherosclerosis)
  • Dilated (ex. compensatory mech for lost adjacent tubules)
• Pathologic tubular basement membranes
  
  • Thickened w/ amyloid deposits
  • Interrupted in severe injury
  • Wrinkled when tubular cells are necrotic
• Pathologic lumen can be filled w/…
  
  • Proteinaceous material (ex. protein-losing syndromes)
  • Inflammatory cells (ex. pyelonephritis)
  • Blood (ex. glomerulonephritis)
  • Tubular casts
• Image: normal
  
  • Tubules fit like a jigsaw puzzle around glomeruli
  • Tubules have enough nuclei around them & have a pearl color
• Image: blood
  
  • Very bad to see RBCs in lumen
• Image: luminal casts (hyaline)
  
  • Full of thick protein spilling –> renal failure
• Image: adenoma
  
  • Abnormal proliferation or tubular epithelial cells
• Image: tubular necrosis
  
  • Coagulative necrosis
  • See some outline of cells close to the membrane that will end up in the urine as casts
• Image: tubular atrophy
  
  • Right: tubules look nice, fit together, & don’t have space in b/n
  • Left: tubules are smaller, have thickened basement membranes due to cell loss, & expanded interstitium

Question 17

Light microscopy: interstitium

• Normal
• Pathologic
• Image: interstitial fibrosis
• Image: interstitial inflammation

Answer 17

• Normal
  
  • Framework that holds glomerular, tubular, & vascular structures together
  • Barely seen b/n tubules
• Pathologic
  
  • Expand (ex. tubular atrophy)
  • Edema or inflammatory infiltrate (ex. pyelonephritis)
  • Fibrosis (ex. long standing chronic renal failure)
• Image: interstitial fibrosis
  
  • Bad b/c see a lot of green interstitium b/n tubules
• Image: interstitial inflammation
  
  • Red: eosinophils
  • Blue: plasma cells
  • See few tubules w/ many inflammatory cells

Question 18

Light microscopy: blood vessels

• Cellular changes
• AffA & EffA
• Interstitial arteries & arterioles
• Image: normal
• Image: mild intimal thickening
• Image: severe fibroelastic intimal thickening / duplication of internal elastic lamina

Answer 18

• Cellular changes
  
  • Intima, media, or adventitia
• AffA & EffA
  
  • Thickness, fibrin, degeneration, etc.
• Interstitial arteries & arterioles
  
  • Thickness, elastic lamina duplicaiton, inflammatoyr infiltrate, abnormal findings, etc.
• Image: normal
  
  • Thin wall
  • Open lumen w/ RBCs & WBCs
• Image: mild intimal thickening
  
  • Thickened intima
• Image: severe fibroelastic intimal thickening / duplication of internal elastic lamina
  
  • Huge blood vessel w/ many elastic lamina
  • Intimal thickening or severe HTN

Question 19

Immunofluorescence microscopy

• Detects…
• Procedure
• Types of deposits
• Locations

Answer 19

• Detects…
  
  • Cellular changes in intima, media, adventitia, etc.
  • Ig, fibrin, or complement deposition within kidneys
• Procedure
  
  • Multiple frozen sections are cut
  • Sections are stained by direct IF for…
    
    • Igs (IgG, IgM, IgA, Kappa & Lambda light chains)
    • Complements (C1q, C3, & C4)
    • Fibrinogen, transferrin, albumin, & alpha-2-macroglobulin
  • Positive & negative controls accompany studies
• Types of deposits
  
  • Glomerular
  • Mesangial
  • Combined
• Locations
  
  • Glomeruli
    
    • Linear vs. granular
      
      • Linear
        
        • Ex. antiglomerular BM antibody (anti-GBM)
        • Looks like cigarette smoke
        • Follows capillary walls
      • Granular
        
        • Ex. lupus
        • Little dots all over the place
        • Mesangial + capillaries
    • Subepithelial, subendothelial, or intramembranous
  • Tubules
    
    • BM, epithelial cells
  • Interstitium
  • Blood vessels (ex. thrombotic diseases)

Question 20

Electron microscopy

• Procedure: thick sections
• Procedure: thin sections
• Normal
• Pathologic
• Image: normal
• Image: thick BM + electron dense deposits

Answer 20

• Procedure: thick sections
  
  • Glutaraldehyde-fixed portion of cortex is embedded in plastic renin
  • Cut into 1-2 micron sections
  • Examined for the presence of glomeruli & tubules
• Procedure: thin sections
  
  • Cut & stained for EM exam to detect abnormalities
• Normal
  
  • Glomerular capillaries are patent
  • BMs are thin & intact
  • Epithelial cells show intact, sharp foot processes
• Pathologic
  
  • Glomeruli have thick or interrupted capillary BMs & occasional deposits in subepithelial or subendothelial regions
  • Epithelial cells may lose foot processes
  • Mesangial cells may be increased in number & matrix deposition
    
    • Increased, duplicated, thinned, interrupted
  • Electron-dense deposits can be seen in mesangial areas
  • Bowman’s space may have crescents or abnormal fat or proteinaceous droplets
• Image: normal
  
  • In the glomerular capillary
    
    • Inside: blood
    • Outside: urine
  • See podocytes sticking off the outside
  • See fenestration on the inside
  • Filtratoin occurs in the BM
• Image: thick BM + electron dense deposits
  
  • Thick, irregular, & filled w/ electron dense deposits

Question 21

Glossary of descriptive terms

• Diffuse
• Focal
• Segmental
• Global
• Sclerosis
• Hyalinosis
• Necrosis

Answer 21

• Diffuse
  
  • All (>50%) of glomeruli are involved in the disease
• Focal
  
  • Some (<50%) of glomeruli are involved in the disease
• Segmental
  
  • Portion of teh glomerulus shows pathologic changes
• Global
  
  • Entire glomerulus shows pathologic changes
• Sclerosis
  
  • Fibrosis
  • Increased matrix (mesangial, in the vascular wall, increased fibrosis, etc.)
  • Loss of structure –> homogenous fibrosis, collagen deposition, etc.
• Hyalinosis
  
  • Degeneration
  • Proteinaceous serum insudate (either glomerulus or arterioles)
• Necrosis
  
  • Cell death