**2. Minimizing immunosuppression with calcineurin inhibitors in kidney transplantation**

The introduction of CNI has achieved exceptional short-term results in recent years in the field of allograft transplants, especially by reducing the rate of AR episodes, reaching, in the last 20 years, an overall graft survival of more than 90% in the first year [39]. However, the attention now focuses on the search for better long-term outcomes with strategies that sustain a low AR rate along with a decrease in the side effects of immunosuppression. The immunosuppressants have three effects: the therapeutic effect (rejection of suppression), unwanted consequences related to immunosuppression (infections, neoplasms, metabolic and hemodynamic disorders), and the nonimmune toxicity to tissues [40]. The nonimmune toxicity is immunosuppressive agent-specific and is related to the mechanism of action of the drug, since they target-specific molecules with certain functions in nonimmune tissues, conditioning progressive tissue damage, and gradual kidney graft failure. This, coupled with the death of the patient with a functional graft, encourages the new concept of focusing on nonimmune factors that intervene in the long term, evoking enthusiasm for strategies to minimize the side effects of CNIs.
