**6. Antihuman leukocyte antigen antibodies in kidney recipients with steroid withdrawal**

One of the leading causes of long-term graft loss is interstitial fibrosis and tubular atrophy (IFTA) and the appearance of DSA posttransplant, which seems to play an important role in graft dysfunction.

The B lymphocyte antibody suppression combined with the use of steroids has created the idea that avoiding or removing these drugs in the posttransplant period may induce the appearance of antibodies. Unfortunately, there is not sufficient evidence to uphold that the withdrawal of steroids contributes to the increase in production of antibodies or if it is associated to a higher rejection rate and chronic graft dysfunction, that being with steroids in the immunosuppression regimen. Delgado et al. [73], in a retrospective study of 43 kidney recipients during posttransplant antibody monitoring, showed that patients with steroid withdrawal did not develop DSA compared to the steroid maintained group posttransplantation. Drugs such as MMF and thymoglobulin, in addition to interacting with T lymphocytes, inhibit the formation of B lymphocyte antibodies, so it is possible that the immunosuppression regimens that use these drugs provide greater safety even when steroids are avoided or suspended after the transplantation. Furthermore, the avoidance or withdrawal of steroids may enhance the myelosuppressive effect of MMF, since steroids induce greater activity of the hepatic enzyme uridine diphosphateglucoronosyltransferase that degrades MMF [76]. In addition, steroids induce the cytochrome P450 isoenzyme 34ª responsible for the metabolism of TAC, and so avoiding these drugs would favor the increase of TAC serum levels, thereby increasing their immunosuppressive effect [77]. These possible mechanisms suggest that the appearance of DSA induced by the suspension of steroids after transplantation could be no different than in the immunosuppression schemes maintained by these drugs.

In a clinical trial recently performed at our center with living donor kidney transplant recipients who underwent protocolized biopsies every 3 months, it was found that the presence of AR was no different between patients who had an early steroid removal compared to those in which the drugs were sustained. However, the suspension of steroids has generated uncertainty about the risk of developing DSA posttransplant, over the course of time. Due to this 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 immunosuppression maintenance regimen based on MMF and TAC.

(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].

360 Organ Donation and Transplantation - Current Status and Future Challenges

**with steroid withdrawal**

graft dysfunction.

maintained by these drugs.

**6. Antihuman leukocyte antigen antibodies in kidney recipients** 

One of the leading causes of long-term graft loss is interstitial fibrosis and tubular atrophy (IFTA) and the appearance of DSA posttransplant, which seems to play an important role in

The B lymphocyte antibody suppression combined with the use of steroids has created the idea that avoiding or removing these drugs in the posttransplant period may induce the appearance of antibodies. Unfortunately, there is not sufficient evidence to uphold that the withdrawal of steroids contributes to the increase in production of antibodies or if it is associated to a higher rejection rate and chronic graft dysfunction, that being with steroids in the immunosuppression regimen. Delgado et al. [73], in a retrospective study of 43 kidney recipients during posttransplant antibody monitoring, showed that patients with steroid withdrawal did not develop DSA compared to the steroid maintained group posttransplantation. Drugs such as MMF and thymoglobulin, in addition to interacting with T lymphocytes, inhibit the formation of B lymphocyte antibodies, so it is possible that the immunosuppression regimens that use these drugs provide greater safety even when steroids are avoided or suspended after the transplantation. Furthermore, the avoidance or withdrawal of steroids may enhance the myelosuppressive effect of MMF, since steroids induce greater activity of the hepatic enzyme uridine diphosphateglucoronosyltransferase that degrades MMF [76]. In addition, steroids induce the cytochrome P450 isoenzyme 34ª responsible for the metabolism of TAC, and so avoiding these drugs would favor the increase of TAC serum levels, thereby increasing their immunosuppressive effect [77]. These possible mechanisms suggest that the appearance of DSA induced by the suspension of steroids after transplantation could be no different than in the immunosuppression schemes

In a clinical trial recently performed at our center with living donor kidney transplant recipients who underwent protocolized biopsies every 3 months, it was found that the presence of AR was no different between patients who had an early steroid removal compared to those in which the drugs were sustained. However, the suspension of steroids has generated uncertainty about the risk of developing DSA posttransplant, over the course of time. Due to this 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 risk of activating the immune system [17, 23].
