Delayed graft function

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Delayed graft function

• Kim Solez, M.D.

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Key Points - Delayed Graft Function

• The Pathologic Differential of DGF
• What Are We Missing in Traditional Approaches?
• Pathophysiology of Known Processes
• Speculation on Unknown Processes
• Therapeutic Directions and the Future!

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The Pathologic Differential of DGF

• Acute tubular necrosis
• Acute rejection (cell mediated)
• Antibody-mediated rejection
• Cortical necrosis/infarction (rare)
• Endothelial denudation ?due to brain trauma
  (rare)
• Acute cyclosporine or tacrolimus toxicity (rare)
• Thrombotic microangiopathy - OKT3, CMV etc.
• Drug-induced interstitial nephritis (rare)

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What Are We Missing From The Traditional Approach?

• Important determinants of graft outcome such as
  donor age, female donor to male recipient,
  storage solution, and brain death do not have a
  known morphologic counterpart.
• P16, telomere length, Y chromosome, in situ DNA
  nick-end labeling (TUNEL), and other apoptosis
  assessments may be necessary.
• Cold ischemia could have manifestations beyond
  acute tubular necrosis.
• Fibrogenic effects of delayed graft function
  effects. Sirius Red quantitation of fibrosis by
  morphometry.

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Pathophysiology of Known Processes

• Acute tubular necrosis
• Tubular obstruction
• Backleak of filtrate
• Afferent arteriolar vasoconstriction
• Decreased ultrafiltation coefficient
• Medullary congestion, blood flow abnormalities
• Leukocytes in vasa recta, inflammatory mediators

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Pathophysiology of Known Processes - cont.

• Acute tubular necrosis - pharmacologic reversal
• Atrial natriuretic peptide/urodilatin/thyroxine/
  IGF1 work in animals
• Failed in native kidney ATN in human clinical
  trials
• Registry being established to readdress this
• Agents might work in transplant ATN?

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Pathophysiology of Known Processes cont.

• Acute tubular necrosis in transplanted kidney -
  different from in the native kidney
• Fewer tubular casts
• Occasional complete cross section necrosis
• Less tubular dedifferention and regeneration
• More calcium oxalate crystals
• More microcalfication (?cyclosporine)
• More isometric vacuolization (?cyclosporine)

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Pathophysiology of Known Processes cont.

• Acute rejection during delayed graft function
• A. Cell mediated rejection
• 1. Tubulitis
• 2. Intimal arteritis
• B. Late appearing antibody-mediated rejection
• 1. Polymorphs in peritubular capillaries
• 2. Mononuclear cells in glomeruli (glomerulitis)
• 3. Vasculitis, capillary/arteriolar thrombosis
• 4. Persisting ATN-like tubular injury

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Unknown Processes

• 1. Senescence
• 2. Vascular wear and tear - atherosclerosis
• 3. Brain death effects (catecholamines?)
• 4. Warm ischemia - anastomosis time effects
• 5. Cold ischemia effects
• 6. Genetics - race, sex effects
• 7. Slope vs. Intercept effects - Chr.
  rejection
• 8. Others

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Future Directions

• New investigative/diagnostic/therapeutic/practice
  approaches
• 1. New indications for and examination
  modalities employed in transplant biopsies.
• 2. New donor criteria.
• 3. Standardized assessment of donor biopsies.
• 4. Pharmacologic reversal of transplant ATN.

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Contact Kim.Solez_at_UAlberta.CAhttp//www.cybernep
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