Calcineurin Inhibitor Toxicity

Calcineurin Inhibitor Toxicity
Shane M. Meehan, MBBCh
Key Facts
Terminology
  • Kidney dysfunction attributable to injury from calcineurin inhibitor immunosuppressive therapy
Etiology/Pathogenesis
  • Transplanted and native kidneys affected by CIT
  • CIT is dose related
  • Functional CIT: Reversible acute renal dysfunction associated with afferent arteriolar vasoconstriction
  • Structural CIT: Tubular and vascular CIT
Clinical Issues
  • Acute or chronic elevation of serum creatinine
  • Elevated blood or serum levels of CI
  • Correlation of structural tissue injury and blood levels is not strong
Microscopic Pathology
  • Tubular toxicity: Acute tubular injury with focal isometric vacuolization of proximal tubular segments
  • Acute arteriolopathy: Smooth muscle loss and expansion of intima and media by loose matrix
  • Thrombotic microangiopathy (TMA)
  • Chronic arteriolopathy: Nodular medial hyalinization
Diagnostic Checklist
  • Exposure to CI is a sine qua non for diagnosis
  • Absence of pathologic lesions in kidney biopsy does not exclude CIT
  • Observation of combined tubulopathy and vasculopathy increases diagnostic certainty
Isometric vacuolization of straight segments of the proximal tubules image with acute tubular injury image is shown in a kidney transplant with CI toxicity.
Focal tubular isometric vacuolization image is evident in a renal transplant biopsy with tacrolimus toxicity. The affected tubules have thickened basement membranes, a nonspecific finding.
TERMINOLOGY
Abbreviations
  • Calcineurin inhibitor toxicity (CIT)
Synonyms
  • Cyclosporine toxicity, cyclosporine A (CsA) toxicity, tacrolimus toxicity, FK506 toxicity
Definitions
  • Acute or chronic kidney dysfunction attributable to direct injury from calcineurin inhibitor drugs
ETIOLOGY/PATHOGENESIS
Types of CIT
  • Functional CIT: Reversible acute renal dysfunction associated with afferent arteriolar vasoconstriction
  • Structural CIT: Characterized by cellular injury and matrix remodeling
    • Tubular CIT: Acute tubular injury with vacuolization of epithelium
    • Vascular CIT: Direct toxic injury to endothelium of arterioles and glomeruli, as well as to smooth muscle of arterioles
      • May manifest as thrombotic microangiopathy or chronic hyaline arteriolopathy
  • Tubular and vascular toxicity typically coexist
  • Native and transplanted kidneys are affected by CIT; histologic manifestations are similar
Mechanisms
  • Histologic lesions are dose related
    • Acute CIT with markedly elevated blood levels of CI
    • Chronic CIT with long-term exposure to CI
  • May also be dose-independent susceptibility factors
  • CsA and tacrolimus bind intracellular receptors called immunophilins
    • Immunophilin/CI complexes bind, inhibit calcineurin
    • Calcineurin is T-cell activator via nuclear factors of activated T cells (NFAT)
    • NFAT activate transcription of inflammatory mediators like interleukin-2, interferon γ, and tumor necrosis factor α
  • Immunosuppressive potency and renal toxicity of CI are pharmacologically inseparable
  • Nephrotoxic effects of CsA & tacrolimus are identical
  • CIT affects endothelium, vascular smooth muscle, and tubular epithelium
    • Endothelium: Increased thromboxane A2, endothelin-1, superoxide and peroxynitrite, decreased prostaglandin and prostacyclin, apoptosis, necrosis
    • Smooth muscle: Vacuolization, necrosis, apoptosis, hyalinization
    • Tubular epithelium: Vacuolization, megamitochondria, calcification, necrosis
CLINICAL ISSUES
Epidemiology
  • Incidence
    • In kidney transplants
      • Thrombotic microangiopathy (TMA) attributable to CI toxicity in 2-5%
      • Chronic CIT in 60-70% at 2 years and > 90% at 10 years
Presentation
  • Acute or chronic elevation of serum creatinine
    • CIT may arise at any time after initiation of therapy
  • Elevated trough blood levels of CI may confirm diagnosis, but correlation of structural tissue injury and blood level is not strong
  • TMA may be localized to kidney (40%) or may be systemic
Treatment
  • Dose reduction or cessation of CI therapy
Prognosis
  • Acute CIT is typically reversible and associated with resolution of histologic changes
  • Chronic CIT is less likely to be reversible; however, resolution of arteriolopathy has been observed with cessation of CI
MICROSCOPIC PATHOLOGY
Histologic Features
  • Functional CIT
    • No morphologic tissue injury by definition
  • Acute tubular CIT
    • Focal proximal tubular epithelial isometric vacuolization affecting straight more than convoluted segments
    • Vacuolar changes may be accompanied by acute tubular injury
    • Proximal tubules may have large eosinophilic cytoplasmic granules corresponding to megamitochondria (CsA toxicity) or lysosomes (tacrolimus toxicity)
    • Tubular calcium phosphate deposition
  • Chronic tubular CIT
    • Cortical tubular atrophy and interstitial fibrosis in a striped pattern (striped fibrosis)
      • Characterized by radial fibrosis affecting cortex with intervening nonscarred parenchyma
      • May arise as result of chronic ischemia from arteriolopathy in addition to direct tubular toxicity
  • Tubular CIT is typically accompanied by vascular CIT, which may be very focal
  • Vascular CIT
    • Vasculopathies of CIT tend to be focal and mainly affect arterioles
    • Acute CIT has spectrum of severity from acute arteriolopathy to TMA
    • Chronic CIT is characterized by hyalinization of arterioles
    • Acute and chronic vasculopathy may be evident in same biopsy
    • Acute arteriolopathy
      • Loss of definition of smooth muscle cells
      • Myocyte cytoplasmic vacuolization and dropout from necrosis or apoptosis
      • Medial swelling and thickening with separation of myocytes
      • Clear or basophilic medial or intimal loose matrix accumulation
      • Intimal or medial platelet insudates may be identifiable by immunohistochemistry for CD61
    • Thrombotic microangiopathy (TMA)
      • Arteriolar thrombi
      • Arteriolar intimal and medial fibrinoid exudate with erythrocytolysis
      • Obliterative arteriolopathy: Stenosis, intimal and medial interstitial swelling, and hypercellularity (“onion skinning”)
      • Arteries may have intimal myxoid thickening in TMA
    • Chronic arteriolopathy
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Jul 9, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Calcineurin Inhibitor Toxicity

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