**8.1. Alemtuzumab**

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

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

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

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 recircula-

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

greater gastrointestinal disorders in patients with MMF doses of 2000 and >2000 mg.

and no conclusive results have been established [85].

362 Organ Donation and Transplantation - Current Status and Future Challenges

it jeopardizes the survival of the graft.

tion, and the concentration before the dose (C 0) [89].

New strategies in the minimization of immunosuppression involve the use of alemtuzumab (humanized monoclonal antibody that targets CD52 on lymphocytes) used as a reduction strategy in doses of CNI and immunosuppression without steroids [93, 94].

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

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].

The therapeutic effect of alemtuzumab is not different from the immunological induction with thymoglobulin in the areas of AR incidence, delayed graft function, CMV infection, development of NODAT, and use of granulocyte colony stimulant [98].

new drugs have failed in the course of transplantation, including janus kinase inhibitors (tofacitinib), sphingosine-1-phosphate receptor modulator (FTY720, fingolimod), protein kinase C inhibitor (sotrastaurin, AEB), inhibitors of adhesion anti-LFA-1 molecules (efalizumab), anti-ICAM-1, and the first generation of anti-CD40-ligand. Most of the current treatments, still in research and focused on the immunology of the transplant, are biological or cell-based treatments. The blocking of co-stimulation with the purpose to prevent T cell activation remains a point of interest. The ASKP1240, an anti-CD40 monoclonal antibody, has recently been tested in immunosuppression minimization regimens based on CNI dose reduction or suspension, compared to a control group based on standard dose TAC, finding higher AR and infection rates in the group treated with anti-CD40, so the future of this drug remains uncertain. More recently, CFZ533, a fully humanized monoclonal antibody has shown efficacy in primates, and clinical research is being initiated in

Immunosuppressive Minimization Strategies in Kidney Transplantation

http://dx.doi.org/10.5772/intechopen.77292

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Belimumab (human monoclonal antibody that inhibits B cell activating factor), approved for treatment in systemic lupus erythematosus (SLE), is in use in early-stage clinical studies for the prevention of antibody-mediated RA, as well as in patients sensitized with low titers of

Cellular therapies represent an innovative therapeutic objective for the maintenance of longterm renal graft, and thus avoidance of adverse reactions related to the maintenance of immunosuppression. The premise of cell therapy is the induction of donor-specific nonresponse in

A single center study evaluated the autologous use of mesenchymal progenitor cells instead of the antibody-based induction with schemes based on low and high doses of CNI, comparing induction with basiliximab and standard maintenance with MMF-CNI. The induction of autologous mesenchymal progenitor cells resulted in a lower AR rate, a decrease in opportunistic infections, and better renal graft function 1 year after transplantation, concluding with

Another study was carried out in hematopoietic progenitor cells transplant with HLA concordant kidney donors in adjunct with total lymphoid radiation and thymoglobulin, which resulted in persistent mixed chimerism with stable renal graft function and removal of all

The most recently used strategies include the use of a product based on hematopoietic stem cells "facilitating cells" co-administered with nonmyeloablative reconditioning in living donor kidney graft recipients, reaching, in five out of eight patients, a satisfactory donorchimerism with successful immunosuppression maintenance withdrawal without evidence

The results of the previous studies, although very encouraging, should be validated in larger multi-centric controlled and randomized studies, from the safety-efficacy and cost–benefit

points of view, compared with conventional immunosuppression therapy.

the context of operational tolerance or mixed chimerism (**Table 1**) [100].

conventional immunosuppressive maintenance [102].

of AR or graft-versus-host disease [104].

immunosuppressants in 50% of the patients (**Table 1**) [103].

humans (**Table 1**) [101].

anti-donor-specific antibodies.

**8.4. Belimumab**
