**7. Minimization strategies of mycophenolate mofetil in renal transplantation**

Mycophenolate mofetil (MMF) has been established as the leading immunosuppressive regimen in most clinical trials and in almost 100% of the renal transplant centers in the world. With the initial use of CsA a daily dose of MMF was established at 2000 mg, while now, since the immunosuppressant regimen has changed to TAC significantly improving graft survival, the dose of MMF has not been established [84].

The MMF is an antiproliferative drug that requires de-esterification in gastrointestinal tissue for its absorption, thus releasing mycophenolic acid (MPA) that is freely absorbed and needs a pH > 5.5 to facilitate absorption in the small intestine. The most common use of MMF is still the prevention of AR in renal, pulmonary, cardiac, and hepatic organs, in adjunct with other immunosuppressive agents, which has shown to reduce AR by 20–40% in RT compared with azathioprine (AZA).

CsA and TAC have a different influence on enterohepatic circulation and the metabolism of MPA. The TAC increases serum levels of MMF and therefore exposure of the metabolite in the blood circulation in patients undergoing this immunosuppression regimen when compared to CsA, while the decrease in MMF dosage combined with TAC has not yet been well studied and no conclusive results have been established [85].

obtained by the EMIT method are typically higher than those of HPLC. The overestimation of the MPA concentration by the use of EMIT is approximately 24–35%. The degree of overestimation varies depending on the patients' characteristics, the time elapsed since the transplantation, and time of the blood sampling. However, in pediatric RT recipients the EMIT assay showed a diagnostic efficacy comparable to HPLC to assess the risk of AR, leaving EMIT as an acceptable monitoring tool for MPA. Therefore, either HPLC or EMIT can be used, although HPLC is a more specific analytical tool for the accurate assessment of MPA and metabolites [90, 91].

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This clinical data supports the need for therapeutic monitoring of MPA. However, this could result in higher costs and time since the precise measurement of MPA AUC 0–12 h requires multiple blood samples during the dosing interval, which can be expensive and clinically

It is well established that in RT recipients, MMF reduces the risk of AR and improves graft survival; nonetheless, the side effects that include diarrhea in up to 37.3%, hematological alterations (leukopenia, anemia, thrombocytopenia), and an increase in the incidence of infections in 23–25% during the first year of transplantation, make it necessary to reduce the dose of MMF. Such side effects can be avoided by individualizing immunosuppression in patients, and other studies have demonstrated that the minimization strategies of immunosuppression must be adjusted according to the race, gender, and anthropometric characteristics at each

**8. New strategies for minimization of immunosuppressive therapy** 

strategy in doses of CNI and immunosuppression without steroids [93, 94].

New strategies in the minimization of immunosuppression involve the use of alemtuzumab (humanized monoclonal antibody that targets CD52 on lymphocytes) used as a reduction

Chan et al. [95], reported in 82 patients treated with alemtuzumab (TAC as monotherapy) *versus* 42 patients with daclizumab, TAC, and MMF; all with ESR, with results of a low AR incidence at 6 months posttransplant, and without differences in the survival of the graft or in its function, confirming the minimization of immunosuppression as a therapeutic strategy

In 3-year posttransplant follow-up studies, alemtuzumab combined with ESR has shown reduction in AR episodes in patients with low immunological risk compared to basiliximabbased induction, while the presentation of AR was similar in those patients with high immunological risk in whom immunosuppressive induction was compared with thymoglobulin. The main advantage of the use of alemtuzumab as a strategy to reduce immunosuppression is found in the availability to reduce the used dosage of CNI and the subsequent conversion to maintenance immunosuppression based on imTOR, whose main objective is to avoid chronic

nephrotoxicity and improve graft survival and long-term function (**Table 1**) [96, 97].

impractical [91].

transplant center [92].

**8.1. Alemtuzumab**

with this drug (**Table 1**).

**in kidney transplantation**

Clinical trials have tried to establish the MMF dosage. Doria et al. [86], included 901 patients with *de novo* RT, assigning three study groups with a MMF dose of <2000, =2000, and >2000 mg with thymoglobulin and an alemtuzumab-based induction, and no significant differences were found at 1 year follow-up regarding AR and graft loss; but they did find an increase, though not significant, in hematological complications related to leukopenia, anemia, and greater gastrointestinal disorders in patients with MMF doses of 2000 and >2000 mg.

These side effects have also motivated the establishment of adjusted dosing for certain populations. There are several controversies about whether reducing MMF dose modifies graft survival. Ji et al. [87], evaluated 128 patients with a low immunological risk at 12 months of follow-up, using immunological induction with basiliximab, methylprednisolone bolus (MPD) and TAC with a dosage of 0.1 mg/kg/day divided into two doses, PDN at 1 mg/kg/day at dose reduction, and MMF in different doses: = 500, <1500, and >1500 mg; finding, in the low dosage groups (=500 and <1500 mg), an increased number of cases of AR, renal graft dysfunction, and C4d deposition in follow-up biopsies, while the conventional dose group of MMF ≥ 1500 mg did not present any representative difference. Therefore, it is suggested that the dose should be individualized to the demographic characteristics of each population, under an integral evaluation of weight and height, and likewise that immunosuppression should not be reduced to doses less than 1 g of MMF per day nor suspension of the antimetabolite, since it jeopardizes the survival of the graft.

The side effects of MMF are divided into those due to gastrointestinal disease where diarrhea is the main manifestation with a frequency of up to 40–50% and in severe cases has been attributed as a cause of histologically inflammatory colitis type lesions similar to Crohn's disease.

Within the hematological side effects attributed to the drug there is leukopenia with or without neutropenia that can be potentiated by the use of other, concomitant drugs (Valganciclovir, trimethoprim with sulfamethoxazole, etc.) during the early period of RT. Other attributable side effects are hypogammaglobulinemia and severe anemia, especially in the first posttransplant months. The MMF has been associated with pneumonia due to pneumocystitis jirovecci, cytomegalovirus (CMV) disease, reactivation of Chagas disease, infection with Epstein-Barr virus (EBV), and risk of malignancy. On the other hand, patients with solid organ transplantation with hepatitis C seem to have better long-term outcomes with MMF therapy [88]. There is a strong association between the concentration of MPA, the pharmacological effects, and inter-individual variability between the MPA within the area under the curve (MPA AUC) estimated as the concentration of MMF after systemic elimination, enterohepatic recirculation, and the concentration before the dose (C 0) [89].

Two analysis tools have been used for the measurement of MPA plasma levels: high performance liquid chromatography (HPLC) and enzyme multiplied immunoassay technique (EMIT). The EMIT is less specific in the measurement of MPA than HPLC: the concentrations of MPA that are obtained by the EMIT method are typically higher than those of HPLC. The overestimation of the MPA concentration by the use of EMIT is approximately 24–35%. The degree of overestimation varies depending on the patients' characteristics, the time elapsed since the transplantation, and time of the blood sampling. However, in pediatric RT recipients the EMIT assay showed a diagnostic efficacy comparable to HPLC to assess the risk of AR, leaving EMIT as an acceptable monitoring tool for MPA. Therefore, either HPLC or EMIT can be used, although HPLC is a more specific analytical tool for the accurate assessment of MPA and metabolites [90, 91].

This clinical data supports the need for therapeutic monitoring of MPA. However, this could result in higher costs and time since the precise measurement of MPA AUC 0–12 h requires multiple blood samples during the dosing interval, which can be expensive and clinically impractical [91].

It is well established that in RT recipients, MMF reduces the risk of AR and improves graft survival; nonetheless, the side effects that include diarrhea in up to 37.3%, hematological alterations (leukopenia, anemia, thrombocytopenia), and an increase in the incidence of infections in 23–25% during the first year of transplantation, make it necessary to reduce the dose of MMF. Such side effects can be avoided by individualizing immunosuppression in patients, and other studies have demonstrated that the minimization strategies of immunosuppression must be adjusted according to the race, gender, and anthropometric characteristics at each transplant center [92].
