**1. Introduction**

Renal transplantation (RT) is currently considered the best therapeutic option for renal replacement therapy in patients with end-stage renal disease (ESRD), with controversial results related to long-term graft survival [1–3]. Several factors can contribute to loss of the renal graft over time, which may be nonimmunological in nature, such as chronic nephrotoxicity due to drugs used for transplantation maintenance [particularly calcineurin inhibitors (CNI) tacrolimus (TAC) and cyclosporin] or for the side effects of immunosuppression when corticosteroids are involved, such as: infections, neoplasms, dyslipidemia, hypertension, cardiovascular disease, and newonset diabetes mellitus (NODAT) that can lead to high mortality in patients with a functional graft [4–6]. Other conditions that induce long-term graft loss are the antigen-specific humoral and cellular immune mechanisms that contribute to an increase in the number and severity of episodes of acute rejection (AR), inducing chronic alloimmune damage [5–14]. These damage mechanisms raise the awareness that there must be a balance in posttransplantation immunosuppression; however, the new and powerful immunosuppressive drugs used today, and the alarming loss of kidney grafts, particularly due to the side effects of immunosuppression, have motivated transplant centers globally to try to minimize, suspend, or change the immunosuppressive maintenance drugs to try and further reduce the complications associated to them [15–39].

(mTOR) inhibitor (imTOR), nucleotide blocking agents, and antimetabolites); the proteindepleting and nonlymphocyte-depleting agents (monoclonal and polyclonal antibodies), the intravenous immunoglobulin, and corticosteroids [40]. The effects of CNI are proportional to the serum concentration levels, since this depends on the saturation dose of its targets [40], which makes the dosage and the control of serum levels important in maintaining the balance

Immunosuppressive Minimization Strategies in Kidney Transplantation

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

355

Cyclosporin A (CsA) is a fungal origin polypeptide (derived from *Tolypocladium inflatum),* composed of 11 amino acids, with a molecular weight of 1203 Da, which interacts by binding to its cytoplasmic receptor (cyclophilin); a protein from the family of immunophilins, forming a complex that binds to the calcineurin, inhibiting its normal phosphatase action on regulatory nuclear proteins (nuclear factor -KB and activator protein 1), preventing the cytokine production (IL-2), and eventually the T lymphocyte activation [41]. The adverse reactions to CsA, related to the serum concentration of the drug, include: nephrotoxicity, hypertension, hyperlipidemia, gingival hyperplasia, hirsutism, and tremor [42]; and, less frequently, hemo-

In 2004, a longitudinal cohort where 888 renal biopsies were collected from 99 patients who were in immunosuppressive treatment with CsA for 10 years after renal transplantation, was evaluated; finding arteriolar hyalinosis as the most sensitive marker for nephrotoxicity due to CsA [43]. Another CNI introduced in the mid-1990s, that was initially called FK506 and is currently known as TAC, is a macrolide isolated from the fungi *Streptomyces tsukubaensis* that possesses suppressive effects similar to CsA (cell-mediated and humoral immune responses) [41]. The TAC binds to a protein called FKBP12 (binding protein of FK506–12) and a complex that inhibits the phosphatase activity of calcineurin, preventing the activation of the T cell, and selectively affecting the transcription of IL-2 and other cytokines. The adverse reactions are similar to those of CsA but with less incidence of hypertension, hyperlipidemia, hirsutism, and gingival hyperplasia; however, the incidence of NODAT and nephrotoxicity is higher [44].

The mechanism through which nephrotoxicity occurs is explained by the endothelial dysfunction associated with reduced production of local vasodilators (nitric oxide and prostaglandins) and increased production of vasoconstrictors (endothelin and thromboxane) [45].

The determination of the serum levels of the CNI is part of the management of immunosuppression in transplant recipients, due to the variability between patients (and the intra-patient variability). The inter-individual variability with TAC is explained by polymorphisms in genes that encode transporter proteins and enzymes that metabolize the drug. The TAC is metabolized in the intestine, liver, and kidney by cytochrome P450 (CYP) 3A4 and 3A5. Interindividual differences in CYP3A activity are the most important determinants of variability in TAC metabolism. Polymorphisms in the CYP3A5 gene explain 40–50% of the variability in the TAC dose requirement to maintain adequate serum levels: the most studied one is the single nucleotide polymorphism CYP3A5\*3. This allele causes a reduced enzymatic activity associating with the need to reduce the administered dose of TAC. On the other hand, when CYP3A5 is expressed, a dose of about 50% higher is required [46, 47]. To a lesser extent, the CYP3A4 genotype with impact on the determination of doses in transplant patients receiving TAC has also been identified. Individuals carrying the CYP3A4 \* 1B allele reported up to a 35% dose

between the desired immunosuppressant effect and the unwanted toxicity.

lytic uremic syndrome, and NODAT [40].
