Deciphering calcineurin inhibitor nephrotoxicity: a pharmacological approach

The calcineurin inhibitors ciclosporin and tacrolimus are used to prevent acute rejection of solid organs after transplantation. Their use can lead to chronic renal damage characterized by progressive and irreversible deterioration of renal function associated with interstitial fibrosis, tubular atrophy, arteriolar hyalinosis and glomerulosclerosis. Many approaches to better understand the mechanisms of this toxicity are in use. The aim of these approaches is to find biomarkers of early kidney injury and potential therapeutic targets. Despite these efforts, the biological processes leading to calcineurin inhibitor nephrotoxicity remain poorly understood. Furthermore, the diagnosis of chronic renal damage remains inaccurate without definitive diagnostic tools, no effective prevention exists and a therapy to treat the damage has yet to be developed. In this article, theories of pharmacodynamics, pharmacokinetics, therapeutic drug monitoring and pharmacogenetics are synthesized in ways that may improve the understanding of mechanisms leading to calcineurin inhibitor toxicity. The importance of global approaches such as toxicogenomics is emphasized to characterize early cellular responses implicated in calcineurin inhibitor nephrotoxicity.