Kidney nontumor / medical renal
Tubulointerstitial disease
Drug and toxin related tubulointerstitial injury
Calcineurin Inhibitor toxicity
Author: Nikhil Sangle, M.D.
Last author update: 7 January 2013
Last staff update: 18 October 2023
Copyright: 2002-2024, PathologyOutlines.com, Inc.
PubMed Search: Cyclosporin A toxicity
Table of Contents
Definition / general | Clinical features | Functional toxicity | Acute tubular toxicity | Thrombotic microangiopathy | Chronic toxicity | Microscopic (histologic) description | Microscopic (histologic) imagesCite this page: Sangle N. Calcineurin Inhibitor toxicity. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/kidneycyclosporinA.html. Accessed April 19th, 2024.
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
Images hosted on other servers:
Various images
Allograft treated with cyclosporine A
Classic features of
calcineurin inhibitor
toxicity (cyclosporine
and tacrolimus)
