Contemporary immunosuppression in renal transplantation (original) (raw)

Evolution of Immunosuppressive Agents in Renal Transplantation: An Updated Review

Suppression of allograft rejection is the central issue in renal transplantation (RT). Thus, development of immunosuppressive agents is the key for successful allograft function. Immunosuppression agents in RT have evolved over the last six decades beginning with total lymphoid irradiation to the currently available immunosuppressive strategies, which have significantly reduced the incidence of acute rejection episodes and improved short-term graft and patient outcomes. However their use is associated with long-term graft dysfunction, hypertension, hyperlipidaemia, diabetes mellitus, infections and malignancies. Chronic antibody-mediated rejection and chronic allograft dysfunction still remain the major problems, often leading to graft loss and shortened long-term graft survival.

New developments in immunosuppressive therapy in renal transplantation

Expert Opinion on Biological Therapy, 2002

The introduction of new immunosuppressive agents and protocols has improved outcomes for renal transplant recipients by decreasing the risk of rejection and by increasing the function and lifespan of the allograft. This article reviews the major changes in the combinations of therapies used: calcineurin inhibitors, target of rapamycin inhibitors, mycophenolate mofetil, non-depleting monoclonal versus depleting monoclonal and polyclonal antibodies for induction and increasing emphasis on protocols for reduction or avoidance of steroids and calcineurin inhibitors. The new agents with novel immunological targets such as anti-CD40 ligand, LEA29Y, FTY720, anti-CD20 (rituximab, Rituxan™, Mabthera™) and anti-CH52 (alemtuzumab, Campath™), which are under development but have yet to survive the rigors of clinical trials are also discussed. In the presence of low early rejection rates, immunosuppressive therapy is setting new goals such as better graft function (glomerular filtration rates), reduction in adverse effects such as hypertension, hyperlipidaemia and drug toxicity and, above all, the prevention of late graft deterioration.

Advances in immunosuppression for renal transplantation

Nature Reviews Nephrology, 2010

| The development of immunosuppressants with minimal adverse and nephrotoxic effects is important to improve outcomes, such as acute and chronic antibody-mediated rejection, after organ transplantation. In addition, the application of expanded criteria for donors and transplantation in immunized patients necessitates the development of new therapies. Drug development over the past 10 years has generally been disappointing, but several new promising compounds have been or are being developed to prevent acute and chronic transplant rejection. In this Review, we report on several compounds that have been developed to remove allogenic T cells and/or to inhibit T-cell activation. We also discuss compounds that interfere with antibody-mediated rejection.

Immunosuppressive Drugs in Renal Transplantation

Drugs, 1992

Currently, expected IO-year first graft survival rates for kidneys from HLA-identical sibling, I-haplotype-matched relative, and cadaver donors are 74, 51, and 40%, respectively. Histocompatibility, immunological conditioning with blood products, and immunosuppression with glucocorticoids, azathioprine, cyclosporin, and the antithymocyte (antilymphocyte) antibody preparations have been significant factors in the gradual improvement of kidney graft survival rates. Nearly all immunosuppression regimens are cyclosporin-based, Antithymocyte antibody induction therapy with delayed administration of cyclosporin is widely practised to avoid cyclosporin nephrotoxicity while the kidney graft is recovering from preservation injury. Late cyclosporin withdrawal results in inferior cadaver kidney transplant survival rates. Rejection crises usually respond to high dose glucocorticoid therapy. Glucocorticoid-resistant rejection usually responds to treatment with antithymocyte antibody. FK-506 is a promising new immunosuppressant that has properties similar to cyclosporin. Prophylaxis against viral, bacterial and fungal infections is necessary to reduce the morbidity of immunosuppression. The incidence of malignant conditions associated with viral infections is significantly increased with immunosuppression.

Immunosuppression in Kidney Transplantation

OBM Transplantation

Immunosuppressive therapy in renal transplantation is divided into two phases as induction and maintenance therapy. Induction therapy is an intense immunosuppressive therapy administered at the time of kidney transplantation to reduce the risk of acute allograft rejection. In general, induction immunosuppressive strategies utilized by kidney transplant centers fall in one of the two categories. One approach relies upon high doses of conventional immunosuppressive agents, while the other uses antibodies directed against Tcell antigens with lower doses of conventional agents. Maintenance immunosuppressive therapy is administered to almost all kidney transplant recipients to help prevent acute rejection and the loss of renal allograft. Although an adequate level of immunosuppression is required to dampen the immune response, the level of chronic immunosuppression is decreased over time (as the risk of acute rejection decreases) to help lower the overall risk of infection and malignancy; these risks directly correlate with the degree of overall immunosuppression. However, the optimal maintenance immunosuppressive therapy in kidney transplantation is not established. The major immunosuppressive agents that are available in various combination regimens are glucocorticoids (primarilyoral prednisone), azathioprine, mycophenolate mofetil (MMF), enteric-coated mycophenolate sodium (EC-MPS), cyclosporine (unmodified or modified [micro emulsion] form), tacrolimus, everolimus, rapamycin (sirolimus), and belatacept.

Immunosuppressive Minimization Strategies in Kidney Transplantation

Organ Donation and Transplantation - Current Status and Future Challenges, 2018

The long-term graft survival in renal transplantation results is still controversial, the toxicity and adverse reactions of the immunosuppressive drugs are implicated, as well as cellular and humoral antigen-specific immune mechanisms; therefore, different strategies for adapting immunosuppression are used to reduce the complications associated with the use of these drugs. Calcineurin inhibitors (CNI) require an adequate dose-dependent concentration leading to the appearance of drug-related adverse reactions. The variability in the required dose of CNI leads to minimization strategies that do not result in a higher acute rejection (AR) incidence when compared to other immunosuppressive agents. Early steroid withdrawal is another strategy, although with an increase in AR, but without an impact on the function and survival of the renal graft. The reduction of mycophenolate mofetil to 1.5 g/day seems to be a therapeutic option, decreasing the infectious, hematological and gastrointestinal adverse reactions. Finally, alemtuzumab, bortezomib, belatacept and cellular therapies are in the search for the new treatments, whose premise is the induction of donor-specific nonresponse in the context of operational tolerance or mixed chimerism. The use of adapted and adequate immunosuppression has led to variable results and some are very encouraging; however, they must be validated with experimental studies.

Targets of new immunosuppressants in renal transplantation

Kidney International Supplements, 2011

Although current immunosuppression is highly effective in avoiding acute rejection, it is associated with nephrotoxicity, cardiovascular morbidity, infection, and cancer. Thus, new drugs dealing with new mechanisms, as well as minimizing comorbidities, are warranted in renal transplantation. Few novel drugs are currently under investigation in Phase I, II, or III clinical trials. Belatacept is a humanized antibody that inhibits T-cell co-stimulation and has shown encouraging results in Phase II and III trials. Moreover, two new small molecules are under clinical development: AEB071 or sotrastaurin (a protein kinase C inhibitor) and CP-690550 or tasocitinib (a Janus kinase inhibitor). Refinement in selecting the best combinations for the new and current immunosuppressive agents is probably the main challenge for the next few years.

Renal allograft immunosuppression

Transplant International, 1990

We have investigated the impact of triple drug immunosuppression on the occurrence of early inflammatory episodes, as detected by fine needle aspiration biopsy, and of episodes of clinical rejection during the immediate postoperative period. The prospective component of this study includes 128 consecutive first cadaveric renal transplant recipients receiving triple drug treatment consisting of azathioprine (Aza), cyclosporin (CyA) and methylprednisolone (MP). For controls we have used three historical groups: one immunosuppressed with Aza and MP (group A), another with CyA monotherapy (group B), and the third with CyA together with MP (group C) in equivalent drug dosages. On the average, 0.8 episodes of inflammation per patient were recorded during the immediate postoperative period of 30 days with triple drug treatment. This was significantly less than the 1.3 episodes in patients receiving Aza and MP (P < 0.01), the 1.7 episodes in patients on CyA monotherapy (P < 0.001), or the 1.6 episodes in patients receiving CyA together with MP (P < 0.001). Although the first episode of inflammation commenced concurrently in each group and the peak intensity of inflammation was the same, the mean duration of inflammation was significantly shorter -2.7 daysunder triple drug treatment than the 7.8-11.7 days for controls (P < 0.001). The frequency of rejection episodes under triple treatment was also significantly lower -0.2 per patient -than the 0.8 per patient in controls (P < 0.001). The first rejection episode occurred later in the triple drug treatment group -on the average, on day 15.2 -than in the historical controls (on days 7.7-11.7). There was, however, no difference in the duration of rejection. There were no differences in patient survival between the four groups. Graft survivalwas 97% at 10 weeks for triple drug-treated recipients and 79%, 68%, and 87% for first grafts in groups A, B, and C, respectively. Disregarding a minor demographic bias for the triple drugtreated group with respect to preformed antibodies and preoperative dialysis treatment, the study suggests that Offprint requests to." H. Isoniemi the triple drug protocol, in the short run, is superior to any conceivable double drug combination or CyA monotherapy.

[Immunosuppression after renal transplantation]

Nefrología : publicación oficial de la Sociedad Española Nefrologia, 2000

Immunosuppression (IS) is administered to kidney transplant recipients to prevent rejection episodes and loss of the renal allograft. Most centers rely on a triple IS after induction with either interleukin-2 receptor antibodies or antithymocyte globulin. The most frequently used substances for maintenance IS are glucocorticoids, antimetabolites, mTOR inhibitors (mTORi), calcineurin inhibitors (CNI) and the costimulation blocker belatacept. Guidelines recommend a triple combination consisting of CNIs, antimetabolites and corticosteroids for the majority of patients. The long-term risk for malignancy in general is increased in solid organ recipients compared to the general population. Modification of IS may result in reduced risk for nonmelanoma skin cancers but results in higher graft rejection rates and in the case of mTORi, deaths. In the case of posttransplantation lymphoproliferative disorders (PTLD) treatment options are reduction of IS, rituximab, chemotherapy, radiation therapy or a combination of these. The optimal protocol has not yet been established and depends on patient age and status, tumor load, laboratory findings, organ functions (heart, kidney, liver) and PTLD subtype. Posttransplantation diabetes mellitus is a frequent complication after kidney transplantation. Tacrolimus more than cyclosporine A, sirolimus and corticosteroids are considered to be diabetogenic; however, tacrolimus remains the first choice as the mainstay of IS. In general, the IS regimen should be tailored for optimal kidney allograft survival rather than better diabetic