**4. Minimization strategies of immunosuppression with calcineurin inhibitors**

Given the nonimmunological toxic effects of CNI, two general strategies to reduce CNI are proposed: *de novo* minimization, where maintenance immunosuppression with CNI is sought immediately after transplantation at low doses subsequent to a powerful induction; and the second strategy, selective minimization, in which a class of immunosuppressants is avoided, showing a reduction of the undesired effects related to the drug. The Symphony study evaluated 1645 patients divided into four groups: (1) Standard dose of CsA, mycophenolate mofetil (MMF), and prednisone (PDN); (2) Low dose of CsA with induction therapy with daclizumab; (3) Low dose of TAC with induction with daclizumab; (4) Low dose of sirolimus (SRL) with induction with daclizumab. The primary aim was to reduce the nephrotoxicity using a low dose of CNI and SRL and to secondarily reduce the side effects, at the same time as maintaining the efficacy in terms of avoiding acute rejection, improving the overall survival of the patient and the graft. Their results at 1 and 3 years showed a better glomerular filtration rate (GFR) and graft survival in the group with low dose of TAC, as well as a low AR rate, compared with the SRL group [42, 48].

On the other hand, avoiding CNIs is the complete omission of these drugs from the maintenance immunosuppression regimen, while minimization schemes use reduced doses of CNI in order to avoid their nephrotoxicity [49]. Larso et al., compared regimens without CNI (SRL, MMF and PDN) and with CNI (TAC, MMF and PDN), in RT recipients, with similar results at 12 months in patient survival (98% SRL, 96% TAC, p = 0.42) and graft survival (94% SRL, 92% TAC, p = 0.95), as well as in the incidence of AR between both groups [50]. The regimens without CNI were also evaluated in the ORION51 study, which compared the efficacy of three schemes; (1) SRL + TAC with discontinuation of CNI at 13 weeks; (2) SRL + MMF; and (3) TAC + MMF. The SRL + MMF group presented more AR events (32.8%) compared to SRL + TAC (17.4%) and TAC + MMF (12.3%); however, the graft and patient survival were similar and there was the presence of hyperlipidemia in the group treated with SRL and NODAT in the group with TAC (**Table 1**) [51].

The BENEFIT study [52] compared two regimens (an intensive and a less intensive dose) with betalacept (selective T cell co-stimulation blocker) *versus* CsA in patients with living donor RT with standard criteria; finding better renal function with belatacept regimens (GFR of 65, 63, and 50 ml/min, respectively) but with a lower AR rate with CsA (22, 17 and 7%, respectively).

On the other hand, Weir et al. [53], who evaluated the efficacy and safety of the combination of MMF and SRL *versus* MMF and a CNI (TAC or CsA) at 24 months, found that the GFR was higher in the MMF/SRL regimen, with a similar AR rate in both groups.

Finally, a meta-analysis and systematic reviews related to these strategies have recently been published, with the aim of preventing nephrotoxicity and graft loss by a nonimmune character.


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].

Given the nonimmunological toxic effects of CNI, two general strategies to reduce CNI are proposed: *de novo* minimization, where maintenance immunosuppression with CNI is sought immediately after transplantation at low doses subsequent to a powerful induction; and the second strategy, selective minimization, in which a class of immunosuppressants is avoided, showing a reduction of the undesired effects related to the drug. The Symphony study evaluated 1645 patients divided into four groups: (1) Standard dose of CsA, mycophenolate mofetil (MMF), and prednisone (PDN); (2) Low dose of CsA with induction therapy with daclizumab; (3) Low dose of TAC with induction with daclizumab; (4) Low dose of sirolimus (SRL) with induction with daclizumab. The primary aim was to reduce the nephrotoxicity using a low dose of CNI and SRL and to secondarily reduce the side effects, at the same time as maintaining the efficacy in terms of avoiding acute rejection, improving the overall survival of the patient and the graft. Their results at 1 and 3 years showed a better glomerular filtration rate (GFR) and graft survival in the group

**4. Minimization strategies of immunosuppression with calcineurin** 

356 Organ Donation and Transplantation - Current Status and Future Challenges

with low dose of TAC, as well as a low AR rate, compared with the SRL group [42, 48].

NODAT in the group with TAC (**Table 1**) [51].

On the other hand, avoiding CNIs is the complete omission of these drugs from the maintenance immunosuppression regimen, while minimization schemes use reduced doses of CNI in order to avoid their nephrotoxicity [49]. Larso et al., compared regimens without CNI (SRL, MMF and PDN) and with CNI (TAC, MMF and PDN), in RT recipients, with similar results at 12 months in patient survival (98% SRL, 96% TAC, p = 0.42) and graft survival (94% SRL, 92% TAC, p = 0.95), as well as in the incidence of AR between both groups [50]. The regimens without CNI were also evaluated in the ORION51 study, which compared the efficacy of three schemes; (1) SRL + TAC with discontinuation of CNI at 13 weeks; (2) SRL + MMF; and (3) TAC + MMF. The SRL + MMF group presented more AR events (32.8%) compared to SRL + TAC (17.4%) and TAC + MMF (12.3%); however, the graft and patient survival were similar and there was the presence of hyperlipidemia in the group treated with SRL and

The BENEFIT study [52] compared two regimens (an intensive and a less intensive dose) with betalacept (selective T cell co-stimulation blocker) *versus* CsA in patients with living donor RT with standard criteria; finding better renal function with belatacept regimens (GFR of 65, 63, and 50 ml/min, respectively) but with a lower AR rate with CsA (22, 17 and 7%, respectively). On the other hand, Weir et al. [53], who evaluated the efficacy and safety of the combination of MMF and SRL *versus* MMF and a CNI (TAC or CsA) at 24 months, found that the GFR was

Finally, a meta-analysis and systematic reviews related to these strategies have recently been published, with the aim of preventing nephrotoxicity and graft loss by a nonimmune

higher in the MMF/SRL regimen, with a similar AR rate in both groups.

**inhibitors**

character.


groups with and without corticosteroids. Lopez Soler et al. [59], similarly reported in a cohort undergoing ESW with a 10-year follow-up that showed better graft survival (p = 0.023), lower

Immunosuppressive Minimization Strategies in Kidney Transplantation

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359

Similar to minimization of the CNI, numerous meta-analyses have been published regarding a population undergoing ESW, both in the adult and pediatric populations, concluding, in some, a higher rate of AR, especially of mild characteristics, without greater impact in the function or graft survival, and with satisfactory results in the metabolic and hemodynamic

Knight et al. [19], evaluated a meta-analysis of 34 clinical trials with 5637 patients in regimens that included withdrawal or nonuse of steroids at any time of the transplantation, and found that the withdrawal of steroids was associated with a higher incidence of AR (RR 1.56; 95% CI 1.31–1.87), but with a lower incidence of hypertension (RR 0.64; 95% CI 0.50–0.83), diabetes (RR 0.90; 95% CI 0.85–0.94), and hypercholesterolemia (RR0.96; 95% CI 0.67–0.87); concluding that AR had no impact on function or survival of the grafts because it was considered mild. Zhang et al. [60], in a meta-analysis of 13 clinical trials in 3520 patients with ESW after transplantation found a higher incidence of AR; but when the trials that used TAC were exclusively analyzed, the statistical significance was lost and only remained in those that used CsA. Studies that involve corticosteroid withdrawal associated with TAC in the immunosuppression regimen, document the development of borderline changes in AR, especially in the early stage of transplantation, without impact on function or survival of the graft [23, 62].

The current use of immunosuppression induction with anti-DC25 antibodies (basiliximab) or lymphocyte depletion (thymoglobulin) combined with MMF and TAC has favored that the minimization or elimination of the use of posttransplant steroids be safe with cell type AR rates comparable to those that maintain the use of the posttransplant steroid [16, 17, 20–27,

The good results from minimization or suspension of some immunosuppressants are encouraging because one of the main associated causes with poor long-term kidney graft survival is directly or indirectly related to the side effects of immunosuppressants that cause long-term

Experience with this intervention in our transplant center has shown satisfactory short-term (12 months) results with similar AR rates in immunosuppression with and without steroids, with lower glucose levels, lipids, and better blood pressure parameters, which leads to less use of antihypertensive and lipid-lowering drugs in the group without steroids [17, 23]. Nonetheless, despite the acceptable results found with these strategies the community dedicated to transplantation is concerned about what happens with these long-term immunosuppression strategies, especially since presently one of the main causes of graft loss is the

chronic antibody-mediated rejection mainly associated to sub-immunosuppression.

Nonetheless, the sub-immunosuppression generated by minimization strategies or suspension of an immunosuppressant in the posttransplant context causes uncertainty regarding the formation of antihuman leukocyte antigen (HLA) antibodies [donor-specific antibodies

complications and even a higher cardiovascular mortality [4, 11, 43, 68–71].

29–31, 58, 60, 63–67].

profile, reducing cardiovascular morbidity and mortality (**Table 1**) [19, 20, 60, 61].

risk of mortality (0.23, p ≤ 0.011), and less graft failure (0.57, p = 0.026).

TMA, thrombotic microangiopathy; EBV, Epstein-Barr Virus; HUS, hemolytic uremic syndrome; mTOR, mechanistic target of rapamycin; CNI, calcineurin inhibitors; CsA, cyclosporine [50, 51, 53, 60, 61, 95, 97, 100, 101, 103].

**Table 1.** Immunosuppression in renal transplant, adverse reactions and minimization strategies.

Sawinski et al. [54], evaluated 88 clinical trials regarding CNI reduction strategies associated with MMF or imTOR in a meta-analysis (minimization of the CNI without suspending it, conversion to another immunosuppressant "imTOR," and withdrawal of the CNI in the posttransplant period or never used in the RT); finding the best results with the strategies in which the CNI was minimized, especially in the first 6 months without stopping it, with a lower incidence of AR (RR 0.80, 95% CI 0.68–0.95), graft loss (RR 0.71 95% CI 0.56–0.9), and better graft function and no differences in mortality (RR 0.87, 95% CI 0.66–1.15), compared to standard regimens with CNI. Nevertheless, it is important to mention that the majority of studies were based on CsA induction with basiliximab, thus more research is needed to determine the role with other immunosuppressants (TAC and thymoglobulin) and their doses, with the aforementioned strategies. Finally, a systematic review of 83 studies that included a total of 16,156 patients with a removing sample (RR 2.54; CI 95%: 1.56–4.12) or an avoiding sample (RR 2.16; CI 95%: 0.85–5.49) of CNI from the immunosuppression maintenance regimen, was associated to AR without a difference in graft loss (RR 0.96; CI 95%: 0.79–1.16), and with a lower incidence of hypertension in the CNI-abstained groups (RR 0.82, CI 95%: 0.71–0.95) [55].
