**3. Pharmacodynamics and nonimmune toxicity of the calcineurin inhibitors**

In the classification of immunosuppressants, small molecules are included (from which the immunophilin-binding drugs are derived, such as CNIs, mechanism target of rapamycin (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 between the desired immunosuppressant effect and the unwanted toxicity.

**1. Introduction**

354 Organ Donation and Transplantation - Current Status and Future Challenges

**kidney transplantation**

**inhibitors**

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].

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

the long term, evoking enthusiasm for strategies to minimize the side effects of CNIs.

**3. Pharmacodynamics and nonimmune toxicity of the calcineurin** 

In the classification of immunosuppressants, small molecules are included (from which the immunophilin-binding drugs are derived, such as CNIs, mechanism target of rapamycin

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 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, hemolytic uremic syndrome, and NODAT [40].

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 reduction in order to achieve a therapeutic concentration. Similarly, it has been identified that the CYP3A4 \* 22 variant reduces the enzymatic activity of CYP3A4, associated with a lower dose requirement. On the other hand, there are ethnic considerations that participate in allelic variability since Caucasian patients are commonly carriers of the CYP3A5 \* 3 allele [46].

**Immunosuppressor Used dose in renal** 

Tacrolimus 0.1–0.15 mg/kg/day

Cyclosporine 5–8 mg/kg/day

Mycophenolate mofetil 2 g/day orally divided

Prednisone 0.5–1 mg/kg, orally

Alemtuzumab 30 mg/kg

Bortezomib 1.3 mg/m2

Belatacept 10 mg/kg

in two doses

divided in two doses with a taper of 5–10 mg/day indefinitely

intravenously unique pre-transplant induction dose

intravenously on day 1, 4, 8 and 11 for two

intravenously on posttransplant days 1, 5, 14 and then every 4 weeks indefinitely

cycles

**transplant**

divided in two doses

divided in two doses

**Adverse reactions Minimization strategy**

Immunosuppressive Minimization Strategies in Kidney Transplantation

Dose reduction; with lower nephrotoxicity without a higher

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

357

Dose reduction; improves the glomerular filtration rate and graft survival when compared to

Dose reduction not less than 1.5 g/day can decrease the gastrointestinal, hematological and infectious adverse reactions without an acute rejection rate

Steroid withdrawal; better graft survival, lower risk of mortality, decrease in graft dysfunction with an improved metabolic and hemodynamic profile, although with contradictory results that may involve higher acute rejection rates proved by biopsy without affecting the long-term

Used as pre-transplant induction therapy allowing early steroid taper, CNI decrease or change to mTOR with a reduction in AR episodes in the first posttransplant year, without differences in graft survival in patients with low immunological risk and conventional therapy.

Used as desensitization therapy, severe humoral rejection treatment, allowing an immunosuppression restart at an adjusted dose, being considered an immunosuppression minimization strategy.

Adjuvant treatment with MMF and prednisone maintains a CNIfree immunosuppression with an increase in acute rejection in the first 6 months (posttransplant) but better long-term renal graft function compared with CsA.

acute rejection rate.

mTOR inhibitor.

increase.

graft survival.

Nephrotoxicity, tremor, headache, dizziness, gingival hyperplasia, hypertension, carbohydrate intolerance, increased risk of infections and

Nephrotoxicity, hypertension, hyperlipidemia, gingival hyperplasia, hirsutism, lymphoproliferative disorders associated to EBV, Kaposi sarcoma, TMA, HUS.

Gastrointestinal: abdominal pain, nausea, vomits, diarrhea. Hematological: anemia, leukopenia, thrombocytopenia, increased risk of infections (especially viral), neoplasms.

Susceptibility to infections, obesity, osteonecrosis (avascular necrosis), hyperglycemia, hypertension, dyslipidemia, peptic ulcer, cushinoid features, long-term myopathy, osteoporosis, atherosclerosis, skin atrophy,

Predisposition to severe infections (bacterial, viral, fungal) and increased risk of

cataracts.

neoplasms.

Peripheral sensory neuropathies.

Hematologic: anemia, leukopenia, thrombocytopenia Nausea, diarrhea, weakness.

Greater predisposition to lymphoproliferative disorders not associated to EBV, herpes virus and tuberculosis

infections.

neoplasms.
