**5. Strategies for removing steroids from immunosuppression in kidney transplantation**

Another tempting strategy for reduction of posttransplant immunosuppression is to withdraw or avoid the use of corticosteroids because of the numerous side effects, with the purpose of improving quality of life and reducing cardiovascular mortality.

This intervention has increased from 5 to 35% since the year 2000 until today, in RT recipients in the USA. Historically, the removal of steroids has been associated with the risk of precipitating AR [56, 57]; however, long-term safety in terms of patient and graft survival has been satisfactory with early steroid withdrawal (ESW); as Rizzaari shows [58] in a 10 year followup of 1241 RT recipients with graft survival, showing similar death in living donor RT recipients with maintained with steroids (79 *vs.* 73%) and with even an better survival in deceased donor RT (80 *vs.* 67%) with a report in their survival analyses free of AR, similar between the 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 risk of mortality (0.23, p ≤ 0.011), and less graft failure (0.57, p = 0.026).

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

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.

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].

TMA, thrombotic microangiopathy; EBV, Epstein-Barr Virus; HUS, hemolytic uremic syndrome; mTOR, mechanistic

infections.

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.

Infusion related (bradycardia, myalgias, rash, urticarial, hypotension), depression, insomnia, nausea, diarrhea, bronchitis, pharyngitis, increased risk of viral

**Adverse reactions Minimization strategy**

strategy.

Is in experimental phase, it can induce immunologic tolerance or mixed chimerism as an immunosuppression reduction

**5. Strategies for removing steroids from immunosuppression in** 

pose of improving quality of life and reducing cardiovascular mortality.

Another tempting strategy for reduction of posttransplant immunosuppression is to withdraw or avoid the use of corticosteroids because of the numerous side effects, with the pur-

This intervention has increased from 5 to 35% since the year 2000 until today, in RT recipients in the USA. Historically, the removal of steroids has been associated with the risk of precipitating AR [56, 57]; however, long-term safety in terms of patient and graft survival has been satisfactory with early steroid withdrawal (ESW); as Rizzaari shows [58] in a 10 year followup of 1241 RT recipients with graft survival, showing similar death in living donor RT recipients with maintained with steroids (79 *vs.* 73%) and with even an better survival in deceased donor RT (80 *vs.* 67%) with a report in their survival analyses free of AR, similar between the

**kidney transplantation**

**Immunosuppressor Used dose in renal** 

Belimumab Initial dose:120 mg

**transplant**

intravenously, then 400 mg IV every 2 weeks indefinitely

358 Organ Donation and Transplantation - Current Status and Future Challenges

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, 29–31, 58, 60, 63–67].

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

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 (DSA) or nondonor-specific antibodies (NDSA)] over time, with an increased risk of antibody-mediated AR and graft loss. Some studies show results in the incidence of DSA with immunosuppression regimens considered less potent, which could cause the appearance of humoral AR and long-term graft loss [33–37]. Kreijveld et al. [72] showed that the reduction or removal of TAC from immunosuppression in the posttransplant period does not generate antibodies and does not even predict the development of AR. As for steroids, the mechanism of suppression of antibodies by the B lymphocyte with the use of these drugs has created the idea that avoiding or removing steroids in the posttransplant period favors the appearance of antibodies against the major histocompatibility complex (MHC) and against other renal donor antigens. Even so, information related to the formation of DSA with the minimization or suspension of steroids posttransplantation is scarce [73–75].

concern, our team recently conducted a prospective cohort of 77 patients with low immunological risk (data not yet published) where findings revealed that the presence of cellular AR was a predictor for the formation of DSA against class II antigens, coinciding with the results of other authors [78]. There is currently little scientific evidence in which the absence of steroids in the posttransplant period may generate a greater presence of posttransplant DSA. Delgado et al. [73], observed that in a retrospective study of 43 kidney recipients during posttransplant antibody monitoring, patients with steroid suspension did not develop DSA compared to the group with maintained steroids. On the other hand, de Kort et al. [79] recently showed that in a population with steroids suspended using lymphocyte-depleting immunosuppressive induction (alentuzumab) and monotherapy with TAC, there was an increased risk for the development of DSA from an early posttransplant stage. Our study (data not yet published) also showed a higher incidence of DSA in patients with immunosuppression therapy without steroids appearing from a very early stage of the transplantation (<12 months). Unlike the study by de Kort et al. [79], 97% of our population undergoing steroid withdrawal used nonlymphocyte-depleting antibodies (basiliximab) with a double

Immunosuppressive Minimization Strategies in Kidney Transplantation

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

361

The immunoglobulin subclasses (IgG1/IgG3) capable of binding and activating the classical complement pathway (C1q) can predict the presence of antibody-mediated AR even with phenotypes of more severe damage (extensive microvascular inflammation and increased C4d deposition) and risk of kidney graft loss [80–83]. Undoubtedly, the measurement of antibody subclasses in patients subjected to a sub-immunosuppression state with minimization schemes or suspension of immunosuppression should be considered in order to discern whether the presence of these antibodies, according to the ability to fix complement, can generate chronic damage and lower the survival of the grafts. Finally, the benefits obtained from the nonsteroid schemes in the posttransplant stages in the lipid, metabolic, and blood pressure profiles, in our previously reported experience, should be considered for its possible

immunosuppression maintenance regimen based on MMF and TAC.

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

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 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

risk of activating the immune system [17, 23].

the dose of MMF has not been established [84].

**transplantation**

azathioprine (AZA).
