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Primer: histopathology of calcineurin-inhibitor toxicity in renal allografts

Abstract

Calcineurin inhibitors (ciclosporin and tacrolimus) can cause acute and chronic nephrotoxicity. The serum levels of these drugs do not correlate well with the extent of renal damage caused, and the clinical manifestation is nonspecific. Renal biopsy is a reliable tool with which to diagnose calcineurin-inhibitor-induced nephrotoxicity. Ciclosporin and tacrolimus produce identical lesions, which are focal in nature and can be overlooked, necessitating the evaluation of serial tissue sections. Acute toxicity is characterized histologically by necrosis and early hyalinosis of individual smooth muscle cells in the afferent arterioles, and/or isometric vacuolation of the proximal straight tubules; thrombotic microangiopathy is a rare manifestation. In chronic toxicity, the damaged media smooth muscle cells in afferent arterioles are replaced by beaded medial hyaline deposits that bulge into the adventitia; the interstitium displays striped fibrosis and tubular atrophy. As maintenance doses of calcineurin inhibitors in renal transplant recipients have been lowered during the past decade, the incidence of acute toxicity has decreased markedly. Chronic toxicity, however, is still prevalent, and causes chronic allograft damage.

Key Points

  • Immunosuppressants of the calcineurin inhibitor (CNI) class (tacrolimus and ciclosporin) can have acute and chronic deleterious effects on transplanted kidneys

  • Renal biopsy and microscopy of serial tissue sections provide information that is essential to diagnosis of CNI-induced nephrotoxicity

  • Histological features of acute CNI-induced nephrotoxicity include early-stage hyalinization and dropout of individual myocytes in afferent arterioles, and isometric vacuolation of proximal straight tubules

  • Histological features of chronic CNI-induced nephrotoxicity include replacement of myocytes in afferent arterioles with beads of hyaline that bulge into the adventitia, striped interstitial fibrosis and tubular atrophy

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Figure 1: Acute calcineurin-inhibitor-induced nephrotoxicity.
Figure 2: Ciclosporin-induced thrombotic microangiopathy.
Figure 3: Chronic calcineurin-inhibitor-induced nephrotoxicity.
Figure 4: Hyaline arteriolopathy on electron microscopy.
Figure 5: Interstitial fibrosis and tubular atrophy in a band-like pattern indicative of chronic calcineurin-inhibitor-induced nephrotoxicity (area between the arrows).

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Acknowledgements

The nephropathological activities of B Ivanyi are supported by the Hungarian Scientific Research Fund (OTKA) via grant T-038271.

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Correspondence to Bela Ivanyi.

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Liptak, P., Ivanyi, B. Primer: histopathology of calcineurin-inhibitor toxicity in renal allografts. Nat Rev Nephrol 2, 398–404 (2006). https://doi.org/10.1038/ncpneph0225

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