Monday, January 18, 2016

Renal pathology

Renal Pathology

nephritic syndrome II

Anti-GBM GN - Clinical Features (II)
• Can present as:
– pure glomerulonephritis
– GN with pulmonary hemorrhage (more 
often young men)

= Goodpasture syndrome

Anti-GBM GN - Pathogenesis
• Immune-mediated
• Pts make auto-antibodies against alpha 3 
chain of collagen IV


• Auto-antibodies bind to glomerular GBM 
and incite inflammation


• Pts have anti-GBM auto-antibodies in serum 
– inc. anti-GBM antibody titer in serum



Anti-GBM GN - Light Microscopy
• Damage to glomerular capillary walls
– leak of fibrin into Bowman’s space
• Typically crescent formation
– proliferation of Bowman’s capsule epithelial cells
• Red cell casts in interstitial tubules

Anti-GBM GN - IF and EM
• By immunofluorescence
– LINEAR deposits of IgG and C3 along glomerular basement membrane - only GN with linear staining
• By electron microscopy
– wrinkling of glomerular basement membrane
– focal breaks in glomerular basement membrane
– no deposits

Pauci-Immune GN - (=ANCA Disease)
ANCA = Anti-Neutrophil Cytoplasmic Antibodies
Clinical
• Acute renal failure - medical emergency:
– oliguria, hematuria, red cell casts, Inc. creatinine
• More common in adults, also occurs in children

Pauci-immune GN – Pathogenesis I
• Caused by circulating auto-antibodies
• Auto-antibodies are called “Anti-Neutrophil Cytoplasmic Antibodies” (=ANCA)
• ANCAs bind to proteins in cytoplasm of neutrophils
• ANCAs activate neutrophils
• Activated neutrophils incite inflammation in glomeruli

Pauci-immune GN - Pathologic Features
• Light microscopy:
– Crescentic GN
• Immunofluorescence:
– NO GLOMERULAR STAINING (or slight non-specific staining)
– That’s why it’s called PAUCI-immune GN


pau·ci·ty  

Noun
The presence of something only in small or insufficient quantities or amounts; scarcity.
Synonyms
scarcity - shortage - dearth - lack - want - deficiency
Lupus Nephritis - secondary disease to LE - most danderous aspect of LE
Lupus Erythematosus – Definition
• Auto-immune disease
• More common in females than males (10:1)
• Affects multiple organ systems → multi-system disease
• Clinical presentation highly variable

• Glomerulonephritis WHO class I – VI
• Caused by immune deposits:
– IgG, IgA, IgM, C3, C1q  all stain = only in Lupus  "Full House"

Lupus – Criteria defined by American College of Rheumatology
Criterion Definition -  need 3 of the following
1. Malar rash - erythema over malar excrescences
2. Discoid rash - skin rash
3. Photosensitivity - skin rash after UV exposure
4. Oral ulcers - usually painless
5. Arthritis - joint tenderness, swelling, effusion
6. Serositis - pleual effusion, pericardial effusion
7. Renal disorder - Proteinuria or glomerulonephritis
8. Neurologic disorder - Seizures or psychosis
9. Hematologic disorder - anemia, leukopenia, thrombocytopenia
10. Immunologic disorder - anti-ds DNA, anti Sm, antiphospholipid auto-antibodies
11. Antinuclear antibodies - positive ANA auto-antibodies


Alport Syndrome and Thin GBM Disease


• Hereditary nephritis = group of familial diseases
– Alport sydrome
– Thin basement membrane disease (=benign familial hematuria)
• Thin basement membrane disease:
– asymptomatic hematuria (miscrocopic)
– familial, but fairly common
– diffuse thinning of GBM
– prognosis excellent



• Cause:
– X-linked inheritance most common 
– mutation in gene for alpha 5 chain of collagen IV
• Pathogenesis:
– abnormal assembly of collagen IV
– altered structure and functions of GBM and other basement membranes

Clinical features:
– nephritis
– nerve deafness
– eye abnormalities (lens dislocation, corneal dystrophy)
– express full syndrome
– are carriers
• Renal abnormalities:
– hematuria (micro- or macroscopic)
– proteinuria
– renal failure in adult 




Tubulo-Interstitial Diseases
more common than glomerular diseases


  • Anatomy of normal nephron
    • each normal kidney has 800,000 -1,200,000 nephrons
  • Acute tubular necrosis
    • Definition:
      • – damage to tubular epithelial cells and necrosis
      • → acute loss of renal function (renal failure)
      • – is clinico-pathologic entity
    • Causes:
      • – ischemia (typically pre-renal) = first affects tubules
      • – toxic (intra-renal)
      • – acute tubulo-interstitial nephritis (intra-renal)
      • – urinary obstruction (post-renal)
  • Ischemia:
    • sudden drop in blood pressure (pre-renal)
      • shock (severe blood loss, burns, sepsis, acute heart failure, dehydration, prolonged diarrhea)
        • → decrease in circulating blood volume
        • → hypo-perfusion of kidneys 
        • → renal tubules oxygen-deprived
        • → necrosis of tubular epithelial cells
  • Vasculitis:
    • vascular inflammation → narrowing of renal 
    • vessels → hypo-perfusion of kidneys → → → 
  • Ischemia:
    • – tubular cell injury
      • → detachment
      • → tubular obstruction
      • → impaired urine flow in tubules
      • → increased intra-tubular pressure
      • → decreased GFR
      • → tubulo-glomerular feedback (renin-angiotensin, dec. NO, dec. prostaglandin I2)
      • → constriction of afferent arteriole supplying the nephron
      • → acute renal failure
  • Toxic:
    • drugs (e.g. antibiotics)
    • radio-contrast dyes
    • poisons (e.g. mercury, organic solvents)
    • myoglobin (released from muscles in crush injury)
    • hemoglobin (hemolysis e.g. due to transfusion reaction)
  • Acute tubulo-interstitial nephritis
    • Definition:
      • acute inflammation of tubules and interstitium - nl glomerulus
    • Two main causes:
      • Infection (typically ascending!)
      • drugs - esp. antibiotics, diuretics, NSAIDS
      • others (see Robbins p. 996, Table 20-9)
    • Clinical features:
      • begins 15 days after exposure
      • fever, blood eosinophilia, rash
      • hematuria, mild proteinuria, leukocyturia with eosinophils
      • inc. serum creatinine or acute renal failure
    • Pathogenesis: abnormal immune reaction
    • Typically: acute hypersensitivity immune reaction
      • IgE-mediated hypersensitivity (type I hypersensitivity reaction)
      • drug binds to proteins in tubular cells and becomes immunogenic (i.e. functions as a hapten)
      • idiosyncratic, i.e. NOT dose-related
    • When granulomas present (less common):
      • – delayed-type hypersensitivity (type IV hypersensitivity reaction)
  • Acute pyelonephritis
    • Very common:
      • – one of the most common kidney diseases !!!
    • Cause: bacterial infection
      • ascending from urethra and bladder, typically from pt’s own fecal flora
      • Gram-negative bacilli:
        • E. coli, Proteus, Klebsiella, Streptococcus faecalis
      • hematogeneous via bloodstream (less common)
    • Factors that promote infection and inflammation:
      • obstruction: stones, tumors, enlarged prostate, pregnancy
      • bladder dysfunction (e.g. spinal cord injury, diabetes)
      • vesico-ureteral reflux - due to incompetent vesicoureteral valve
    • Complications:
      • papillary necrosis, typically in diabetics
        • areas of gray-white necrosis in tips of renal papillae
      • pyelonephrosis
        • pus fills renal pelvis, calyces, ureter
      • peri-nephric abscess
        • inflammation spreads into retro-peritoneal soft tissue
      • sepsis → septic shock → potentially life-threatening!!!
      • Evolution into chronic inflammation with scarring
        • Chronic Pyelonephritis
          • polar scars with blunted calices
          • tubular atrophy, chronic lymphocytic infiltrate, interstitial fibrosis
  • Chronic pyelonephritis

  • Urinary tract obstruction (hydonephrosis, obstructive uropathy)
    • • Urinary tract obstruction:
      • caused by stones, tumors, enlarged prostate, others
      • → dilatation of ureter, renal pelvis, renal calices
      • → atrophy of renal cortex
      • → hydronephrosis
  • Myeloma cast nephropathy (myeloma kidney)
    • Multiple myeloma = malignant proliferation of 
    • plasma cells in bone marrow
    • Typically associated with Bence-Jones proteins in 
    • urine
      • = immunoglobulin light chains produced by malignant plasma cells
      • – appear in the urine
      • – can combine with Tamm-Horsfall protein 
      • → form casts that obstruct tubular lumina
      • – cast in tubules cause obstruction and inflammation
      • → cast nephropathy
      • Sir Henry Bence Jones in 1848:
        • – observed peculiar thermoreactivity of urine from multiple myeloma patient
        • – urine becomes turbid only between 40 C and 60 C
      • Bence-Jones proteins are monoclonal immunoglobulin light chains
      • monoclonal protein increased in serum (Mprotein, M-component, or myeloma protein)

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