217 A.B. Fogo et al., Fundamentals of Renal Pathology, DOI 10.1007/978-3-642-39080-7_21, © Springer-Verlag Berlin Heidelberg 2014 Calcineurin Inhibitor Toxicity (CIT) Introduction/Clinical Setting Cyclosporin A (CsA) and tacrolimus have greatly improved graft survival since their introduction in the 1980 and 1990s, respectively. While the drugs are structur- ally unrelated, their mechanism of immunosuppression is remarkably similar. The dramatic immunosuppressive and nephrotoxic effects of CsA and tacrolimus are largely explained by their calcineurin inhibition. The pathology of CsA and tacroli- mus toxicity is pathologically indistinguishable. Pathologic Findings There are three pathologic forms of toxicity: acute nephrotoxicity, chronic nephro- toxicity, and thrombotic microangiopathy (hemolytic-uremic syndrome). Each can also arise in native kidneys in patients on CsA or tacrolimus for other reasons. Acute Tubulopathy The biopsy features of acute toxicity range from no morphologic abnormality to acute tubular injury or marked tubular vacuolization and vascular smooth muscle apoptosis (Fig. 21.1). The proximal tubules show loss of brush borders and isomet- ric clear vacuolization (deﬁned as cells ﬁlled with uniformly sized vacuoles). The vacuoles, much smaller than the nucleus, contain clear aqueous ﬂuid rather than lipid and are indistinguishable from those caused by osmotic diuretics. Immunoﬂuorescence microscopy is negative. By electron microscopy, the vacuoles are dilated endoplasmic reticulum and appear empty [1]. These lesions are reversible with decreased dosage. 21 Calcineurin Inhibitor Toxicity, Polyomavirus, and Recurrent Disease