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

Tags:
Jul 9, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Calcineurin Inhibitor Toxicity

Full access? Get Clinical Tree
Get Clinical Tree app for offline access