Kidney nontumor

Tubulointerstitial disease

Drug and toxin related tubulointerstitial injury

Calcineurin Inhibitor toxicity



Topic Completed: 7 January 2013

Minor changes: 12 November 2020

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PubMed Search: Cyclosporin A toxicity [title]

Nikhil Sangle, M.D.
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Cite this page: Sangle N. Calcineurin Inhibitor toxicity. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/kidneycyclosporinA.html. Accessed December 8th, 2021.
Definition / general
  • Anticalcineurins (cyclosporine A and tacrolimus) were discovered in late 70's; constitute a basic component of all immunosuppressive protocols to control transplant rejection for solid organ graft recipients
  • Nephrotoxicity is major concern (Clin J Am Soc Nephrol 2009;4:481)
  • Nephrotoxic, hepatotoxic and neurotoxic
  • Also causes gingival hyperplasia, hypertrichosis and lymphoma
  • Nephrotoxicity is dose related, occurs in 3%
  • Tacrolimus: immunosuppressive drug used frequently in renal transplants, effect may be mediated by binding to FKBP12, a cytosolic protein; FKBP12/FK506 binds to and inactivates calcineurin (a serine / threonine phosphatase), which inhibits calcium and calmodulin dependent B and T cell responses by blocking NFAT-mediated transcription
Clinical features
  • Systemic levels of tacrolimus, if kept within a relatively narrow target window, may not be associated with nephrotoxicity (Transplant Proc 2009;41:3393)
  • The presence of rejection does not rule out Tacrolimus or Cyclosporine toxicity
  • Red cell exchange transfusion may be useful for severe toxicity (Pediatr Nephrol 2011;26:2245)
  • Although mechanism of action is similar to cyclosporine A, mechanisms causing nephrotoxicity may differ (J Proteomics 2011;75:677)
  • Treatment: reduce dosage
Functional toxicity
  • Mild decrease in renal function and increase in serum creatinine, hypertension in 50%, reversible if dosage lowered and no morphologic changes in kidney
  • Toxicity due to alteration in intrarenal hemodynamics (vasoconstrictive phenomenon)
Acute tubular toxicity
  • Similar to functional toxicity but more severe
  • Microscopic changes include vacuoles in proximal tubules (due to dilated endoplasmic reticulum with giant mitochondria, large lysosomes) and microcalcifications
  • Also arteriolar smooth muscle cell degeneration, endothelial cell swelling, intimal thickening, variable hyaline or mucoid deposits which narrow lumen
  • Dose dependent and reversible
Thrombotic microangiopathy
  • Resembles hemolytic uremic syndrome
  • Occurs days to weeks after transplantation
  • Glomeruli and vessels show thrombotic microangiopathy with platelet and fibrin thrombi and minimal inflammatory infiltrate
  • Poor prognosis
  • In one study, most common cause was antibody mediated rejection, not cyclosporine toxicity (Am J Transplant 2010;10:1804)
Chronic toxicity
  • Hypertension and slow progression to renal failure
  • Arterioles show nodular or diffuse hyalinosis of vessel walls or mucoid thickening of intima, leading to luminal narrowing
  • Also diffuse interstitial fibrosis and tubular atrophy
  • Early glomerular changes are aggregates of platelets and fibrin
  • Late changes are focal and segmental glomerulosclerosis or global scarring
  • Changes are irreversible
Microscopic (histologic) description
  • Toxicity (in 1%) of tacrolimus is similar to cyclosporin A at level of renal vascular endothelium, leading to fibrin thrombi in glomerular capillaries and afferent arterioles (Am J Surg Pathol 1996;20:306, Am J Surg Pathol 1993;17:60)
  • May also cause arteriolar hyalinosis and splitting / reduplication of glomerular basement membrane
Microscopic (histologic) images

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Various images

Allograft treated with cyclosporine A

Classic features of
calcineurin inhibitor
toxicity (cyclosporine
and tacrolimus)
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