Immunosuppression

Overview

Immunosuppression after solid organ transplantation is complex. Over the past 50 years, the medical community has witnessed great advances in the care of patients receiving organ transplants. Improved therapeutic strategies have been associated with better patient and graft survival rates; however, the adverse effects associated with these agents and the risks of long-term immunosuppression present a number of challenges for the clinician. With all the successes of immunosuppressive therapies come the obligations to tailor treatments to meet the individual patient's characteristics and to balance the risks and benefits of these medications.

The image below depicts the points of action of immunosuppressive drugs.

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Simplified diagram illustrating the points of action of immunosuppressive drugs. Corticosteroids inhibit production of interleukin-1. Macrolides (ie, ....

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History

The ability to prolong life by transplanting organs had long been a dream of medical practitioners. Early efforts at transplantation were unsuccessful because of inadequacies in surgical technique and lack of fundamental knowledge of the immune system.

Skin and eyes were among the first successful transplants. However, the more complex organs posed countless problems. The kidney was the first such organ to be successfully transplanted. Surgical techniques progressed with the unsuccessful attempt at transplanting a cadaveric kidney in 1933. Initial attempts at immunosuppression were with total body radiation, but all the patients died. Steroids alone were then used, also without success.

With the development of 6-mercaptopurine (Purinethol), followed by azathioprine (Imuran) in the early 1960s, pharmacological immunosuppression became the standard of care. In the early 1960s, 2 major breakthroughs finally addressed the rejection problem. Beginning in 1962, it became possible to closely match donor and recipient tissue. After the first initially successful series of transplantations performed between 1962 and 1964, the combination of azathioprine and steroids came into widespread use and became part of the primary immunosuppressive regimen for the next 20 years. The first human pancreas transplantation was performed in 1966.

As knowledge of the immune system evolved, therapy targeted to specific immunoregulatory sites became possible. The first polyclonal antilymphocyte globulin was used in 1967 and spawned the development of other polyclonal and monoclonal antibodies. Introduced in the 1980s, cyclosporine (Sandimmune and, later, Neoral), a calcineurin inhibitor, was used in combination with azathioprine and steroids and was credited with a dramatic improvement in graft survival. Cyclosporine greatly improved the outcome of such transplants. The first successful heart-lung transplant was carried out in 1981.

The next advance came in 1994 with the introduction of mycophenolate mofetil (CellCept). After tacrolimus (another calcineurin inhibitor) became available in 1994, debate followed regarding which calcineurin inhibitor was superior. Tacrolimus has gradually supplanted cyclosporine in many centers. In contrast, mycophenolate mofetil rapidly replaced azathioprine almost universally. To expand the armamentarium further, sirolimus (Rapamune), a macrolide antibiotic, was developed and released.

While the short-term outcomes provided with these medications have continued to improve, the consequences of their administration have become the subject of intense scrutiny as comorbid conditions, drug toxicities, and adverse effects keenly affect both patient and graft survival.

• References

Drugs

Immunosuppressive drugs can be classified as induction therapies, maintenance therapies and antirejection therapies. Maintenance immunosuppressive therapies include small molecule drugs (calcineurin inhibitors and antiproliferatives), fusion proteins and glucorticorticoids. There is also special agents include intravenous immunoglobulin, rituximab, leflunomide, eculizimab and bortezomib. Induction immunosuppressive agents consist of depleting and non-depleting protein drugs (polyclonal and monoclonal antibodies).

Table. Classification of Immunosuppressive Therapies Used in Organ Transplantation

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See Table

A study by Molnar et al compared the clinical efficacy and bioequivalence of generic immunosuppressive drugs in patients with solid organ transplant. The study did not find high quality data showing bioequivalence and clinical efficacy of generic immunosuppressive drugs.^{[1, 2]}

Corticosteroids

Corticosteroids are used for induction and maintenance immunosuppression, as well as for acute rejection. These agents prevent production of cytokines and vasoactive substances, including interleukin (IL)–1, IL-2, IL-6, tumor necrosis factor-α, chemokines, prostaglandins, major histocompatibility class II, and proteases. Corticosteroids act as agonists of glucocorticoid receptors but, at higher doses, have receptor-independent effects.

Glucocorticoid receptors are in cytoplasm in an inactive complex with heat shock proteins. The binding of corticosteroids to the glucocorticoid receptors dissociates heat shock protein from the glucocorticoid receptor. Formed active corticosteroid–glucocorticoid receptor complex migrates to the nucleus and dimerizes on palindromic DNA sequences in many genes. The binding of glucocorticoid receptors in the promoter region of the target genes can lead to either induction or suppression of gene transcripts.

The most common corticosteroids used in transplantation are oral prednisolone and intravenous methylprednisolone. These agents are metabolized by the liver and excreted by the kidneys as inactive metabolites. Drug interactions with P450 inhibitors and inducers are common.

Adverse effects of corticosteroids include cushingoid features, osteoporosis, avascular necrosis, cataracts, glucose intolerance, infections, hyperlipidemia, hypertension, peptic ulcer disease, pancreatitis, bowel perforation, weight gain, psychiatric disturbances, and growth restriction. Orofacial clefts and fetal adrenal suppression with corticosteroids have been reported in pregnancy.

Small-molecule drugs

Calcineurin inhibitors

Cyclosporine

Cyclosporine has been a keystone of immunosuppression in transplantation for 4 decades. This agent is used for induction and maintenance immunosuppression. It is a polypeptide of 11 amino acids of fungal origin and a prodrug that binds to cyclophilin; complex inhibits calcineurin phosphatase and T-cell activation by dephosphorylation of inactive nuclear factor of activated T cells (NF-AT). Therefore, it prevents the production of IL-2 via calcineurin inhibition.

Cyclosporin trough level or checking levels 2 hours after administration is required. Multiple drug interactions are possible, primarily with agents affecting the cytochrome P-450 system.

Adverse effects of cyclosporin include nephrotoxicity (immediate, secondary to renal ischemia; 2-3 weeks after transplantation, secondary to renal vasoconstriction; and chronic, secondary to interstitial nephritis). Other adverse effects include hyperkalemia, hypomagnesemia, nausea, vomiting, diarrhea, hypertrichosis, hirsutism, gingival hyperplasia, skin changes, hyperlipidemia, glucose intolerance, infection, malignancy, hyperuricemia, and hemolytic uremic syndrome. Hypertrichosis and hirsutism can be alleviated by switching from cyclosporine to tacrolimus.

The adverse consequences (eg, hypertension, renal impairment) of long-term cyclosporine use for solid organ transplant rejection have prompted exploration of various treatment regimens.

Tacrolimus

Tacrolimus is a macrolide antibiotic and is active against helper T cells, preventing the production of IL-2 via calcineurin inhibition (binds to tacrolimus-binding protein instead of cyclophilin protein). The tacrolimus:FKBP12 active complex inhibits calcineurin with greater potency than the corresponding cyclosporine complex. This agent is used for maintenance immunosuppression and for rescue therapy in patients with refractory rejection under cyclosporine-based therapy.

Multiple drug interactions are possible, primarily with agents affecting the cytochrome P-450 system. One study evaluated the long-term safety and efficacy of tacrolimus in orthotopic liver transplantation (OLT). The study reviewed 1000 primary OLTs performed between August 1989 and December 1992 and maintained with tacrolimus-based immunosuppression therapy. After 17- to 20-year follow-up, the results found patient survival rates at 35.8% and graft survival rates at 32.6%, with significantly better survival among children. Graft loss was attributed to age-related complications, recurrence of primary disease, and malignancy; rarely was graft loss related to immunologic reasons. The data conclude that tacrolimus is a potent immunosuppressive agent in OLT.

Adverse effects are similar to those of cyclosporine but with a lower incidence of hypertension, hyperlipidemia, skin changes, hirsutism, and gum hyperplasia and a higher incidence of new-onset diabetes mellitus after transplantation (NODAT) and neurotoxicity. Although tacrolimus causes less cosmetic effects than cyclosporine, it can cause reversible alopecia.

Mammalian target of rapamycin (mTOR) inhibitors

Sirolimus, also called rapamycin, is a macrolide product of a soil fungus found on Easter Island. This agent is used for maintenance immunosuppression and chronic rejection. Everolimus is a rapamycin analog with a similar mechanism of action and adverse effect profile.

The mode of action of sirolimus is to bind the cytosolic protein-FKBP12 in a way similar to tacrolimus. Unlike the tacrolimus-FKBP12 complex, which inhibits calcineurin, the sirolimus-FKBP12 complex inhibits the mTOR pathway by directly binding the mTOR Complex1 (mTORC1). This complex inhibits signal 3 by stopping translation of the RNA and preventing the progression from G1 phase to the S phase of DNA synthesis. It also inhibits IL-2– and IL–4-dependent proliferation of T and B cells.

Similarly, sirolimus inhibits proliferation of nonimmune cells and the pathways that could be involved in oncogenesis. The antiproliferative effects of sirolimus may have a role in treating cancer. Sirolimus was shown to inhibit the progression of dermal Kaposi sarcoma in patients with renal transplants. Sirolimus-based regimens have been associated with a reduced incidence of posttransplantation malignant neoplasms. It has been reported that a cyclosporine a–free immunosuppressant regimen based on sirolimus reduced aortic stiffness, plasma endothelin-1, and oxidative stress in renal transplant recipients enrolled in the CONCEPT trial.

Multiple drug interactions are possible, especially because of the extremely long half-life. Concomitant use with strong CYP3A4/P-gp inducers or strong CYP3A4/P-gp inhibitors decreases or increases sirolimus concentrations. When mTOR inhibitors are used simultaneously with cyclosporine, maximum concentration of the drug (Cmax) and area-under-the-curve (AUC) for both the compounds are increased. Thus, it is recommended that cyclosporine and mTOR inhibitors to be administered 4 hours apart.

Adverse effects associated with mTOR inhibitors are hyperlipidemia, thrombocytopenia, anemia, pneumonitis, oral ulcers, and diarrhea. Low testosterone levels may cause infertility. These agents can also cause poor wound healing and dehiscence formation of lymphoceles. When used combination with calcineurin inhibitors, sirolimus potentiates calcineurin nephrotoxicity. Sirolimus is associated with worsening of proteinuria. It may also cause delayed recovery from acute tubular necrosis.

Although successful pregnancies with sirolimus have been reported, it is not routinely used in pregnancy.

Finally, thrombotic angiopathy cases have been reported with sirolimus. Avoidance of calcineurin may be considered in patients with a primary etiology of atypical hemolytic uremic syndrome or other forms of thrombotic angiopathy, and use of sirolimus may "decrease" the incidence of hemolytic uremic syndrome recurrence.

Inhibitors of nucleotide synthesis (purine synthesis [IMDH] inhibitors)

Mycophenolate acid

Mycophenolate acid inhibits the enzyme inosine monophosphate dehydrogenase (IMDH; required for guanosine synthesis) and impairs B- and T-cell proliferation, sparing other rapidly dividing cells (because of the presence of guanosine salvage pathways in other cells). This agent is used for maintenance immunosuppression and chronic rejection.

Adverse effects include nausea, vomiting, diarrhea, leukopenia, anemia, and thrombocytopenia.

In current practice, tacrolimus and mycophenolate mofetil are considered more efficient than cyclosporine A and mycophenolate mofetil, but recent studies have challenged this assumption. With antithymocyte globulins and steroids, clinically suspected acute rejections did not differ between cyclosporine A//azathioprine and tacrolimus/mycophenolate mofetil arms. Cyclosporine A/azathioprine allowed a low acute rejection rate, but tacrolimus/mycophenolate mofetil seemed to be a better regimen regarding severe secondary outcomes.

Among a cohort of patients being followed long term, mycophenolate mofetil appeared to be highly efficient for preventing both allograft rejection episodes and the development of coronary artery stenoses early after heart transplantation. Mycophenolate mofetil also significantly improved the survival of heart transplant recipients compared with azathioprine, despite a greater incidence of infections linked to mycophenolate mofetil therapy.

A study from the National Adult Solitary Renal Transplant Recipients database from 1998 to 2006 evaluated patient death and graft loss, complications, and renal function. One-year acute rejection rates were reduced for patients on mycophenolate mofetil versus azathioprine (10% vs 13%, P< .01); there were no statistically significant differences for malignancies, renal function, or BK virus infection at 1 year. The primary findings suggested that the association of mycophenolate mofetil with improved outcomes may not be apparent in patients also receiving tacrolimus.

Outcomes after lung transplantation did not meaningfully vary between those assigned to cyclophosphamide/mycophenolate mofetil compared with tacrolimus/azathioprine combined with IL-2 inhibitor induction therapy.

A retrospective study has shown that mycophenolate mofetil rescue therapy improves the long-term kidney graft survival compared with azathioprine despite high early rejection rates, and it avoids the negative impact of acute rejections on graft survival.

In a study done in cadaveric kidney transplantation, patients treated with mycophenolate mofetil have increased risk for the development of CMV disease. However, the disease course was less severe and was less frequently accompanied with deterioration of renal function in comparison to the azathioprine group.

The mycophenolate, steroid-sparing, multicenter, prospective, randomized, parallel-group trial compared acute rejections and adverse events in recipients of cadaver kidney transplants. The study concluded that in recipients of cadaver kidney transplants given cyclosporin microemulsion, mycophenolate mofetil offers no advantages over azathioprine in preventing acute rejections and is about 15 times more expensive.

Trough levels and AUC values are increased with concurrent administration of tacrolimus.

Enteric-coated mycophenolate sodium (EC-MPS)

EC-MPS is introduced with fewer reports of gastrointestinal adverse effects. Acute noninfectious diarrhea after simultaneous pancreas and kidney transplantation is related to the duration of diabetes and to prescription of mycophenolate mofetil, a prodrug of mycophenolate acid. Preferential use of EC-MPS is associated with a lower necessity of dose reduction and less severe episodes of acute diarrhea compared with mycophenolate mofetil, although dose reduction is equally associated with acute episodes of kidney rejection.

Clinical trials, including the Myfortic Prospective Multicenter Study (myPROMS), have begun to demonstrate similar clinical outcomes (eg, rejection rates) between the 2 drugs.

Mizoribine

Mizoribine has been demonstrated to inhibit T-lymphocyte proliferation by depleting these cells of guanine ribonucleotides as a consequence of inhibiting the enzyme IMDH. Inhibition of guanine ribonucleotide biosynthesis appears to be a novel and perhaps more selective mechanism of inhibiting T-cell proliferative responses after T-cell activation. Its use has not been approved in North America. It has been used widely in Japan.

Multicenter, randomized clinical trials revealed that the efficacy and safety of mizoribine were similar and statistically not inferior to mycophenolate mofetil in combination therapy with tacrolimus. The uric acid level was significantly elevated in the mizoribine group (P = .002). Case reports describe acute kidney injury due to uric acid nephropathy.

Leflunomide

Leflunomide is a synthetic isoxazole-derivative drug that possesses both immunosuppressive and antiviral properties. It has been used off-label in the setting of resistant CMV infection or BK virus nephropathy, or in renal transplant recipients with chronic allograft dysfunction.

A prospective randomized trial is needed for its use in transplantation. Its careful usage under close monitoring may provide to eradicate BK virus or CMV infection. Its current use as a first-line agent instead of mycophenolate mofetil or sirolimus cannot be recommended.

Adverse effects such as hepatotoxicity and hemolytic anemia cannot be overlooked.

Azathioprine

Azathioprine was the first immunosuppressive agent used in organ transplantation and provided a share of the 1988 Nobel Prize to its developers. It is an antimetabolite prodrug that converts 6-mercaptopurine to tissue inhibitor of metalloproteinase, which is converted to thioguanine nucleotides that interfere with DNA synthesis. Other possible mechanism includes converting co-stimulation into an apoptotic signal. It is used for maintenance immunosuppression; however, it became a second-line drug after cyclosporine was introduced.

Adverse effects of azathioprine include leukopenia, thrombocytopenia, and liver toxicity. Myelosuppression becomes a serious problem when used with allopurinol. The dose of azathioprine should be decreased when administered with allopurinol and when withdrawing steroids. Complete blood cell counts and pancreatic and liver enzyme levels must be monitored. Myelosuppression can improve with drug discontinuation. Azathioprine is compatible with cyclosporine and tacrolimus. Azathioprine use in transplantation has been widely replaced by mycophenolate mofetil in North America.

Results from a study on the conversion from mycophenolate mofetil to azathioprine in high-risk renal allograft recipients on cyclosporine-based immunosuppression suggest that selective conversion from mycophenolate mofetil to azathioprine after 1 year is safe, even in high-risk kidney transplants. Normal serum creatinine and absence of proteinuria are good screening parameters to identify patients at low risk for acute rejection following such conversion.

Cost comparison suggests azathioprine to be 6-10 times cheaper than mycophenolate mofetil. In tacrolimus-based immunosuppression, azathioprine may be as good as mycophenolate mofetil as a maintenance immunosuppressive drug in living-donor kidney transplantation.

The 3-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in heart transplant patients revealed no significant differences between treatments in quantitative coronary angiographic measurements of transplant coronary vasculopathy. Congestive heart failure, atrial arrhythmia, and leukopenia were more common in the azathioprine group, whereas diarrhea, esophagitis, herpes simplex infection, herpes zoster infection, and CMV infection were more common in mycophenolate mofetil–treated patients.

Consideration is increasing on whether mycophenolate acid provides survival benefits comparable to azathioprine after renal transplantation. The type of antimetabolite, azathioprine or mycophenolate acid, was not independently associated with any safety or efficacy outcome 5 years after transplantation, suggesting that azathioprine is still a viable option for low-risk kidney transplantation recipients receiving tacrolimus and steroids.

Biologic agents

Biologic agents are polyclonal and monoclonal antibodies and are frequently used in transplantation for induction immunosuppression or treatment of rejection. The 3 antibodies used for induction therapy are the lymphocyte-depleting agents: (1) antithymocyte globulin, (2) alemtuzumab, and (3) basiliximab, which is nondepleting. Historically, immunosuppressant selection was based solely on efficacy for the prevention of rejection. In the current era of transplantation, it is now common practice in the transplant community to select induction therapy based on risk-benefit considerations for each patient.

Polyclonal antilymphocyte antibodies were first successfully used in the 1970s in organ transplantation; however, 10 years later, monoclonal antibodies emerged as a new class of immunosuppressive agents in transplantation, with the potential to target highly specific immune cells responsible for acute rejection. Some have proved their efficacy, such as monoclonal antibodies recognizing CD3- and CD25-positive T cells, and have been extensively studied in clinical trials. Others, such as monoclonal antibodies against CD52 and CD20, are still under investigation; finally, the next challenge is, based on improved understanding of the mechanisms of immune recognition and allograft rejection, to use these monoclonal antibodies either alone or in combination with standard immunosuppressive regimens to control the allogenic response to reach antigen-specific tolerance desired in solid-organ transplantation.

Polyclonal antibodies (antithymocyte globulins)

Antithymocyte globulins have been used commonly for induction immunosuppression and treatment of acute rejection in solid organ transplantation. These agents are derived by injecting animals (rabbit or horse) with human lymphoid cells, then harvesting and purifying the resultant antibody. Polyclonal antibodies induce the complement lysis of lymphocytes and uptake of lymphocytes by the reticuloendothelial system and mask the lymphoid cell-surface receptors. Preparations include horse antithymocyte globulin (Atgam) and rabbit antithymocyte globulin (Thymoglobulin, ATG). Although ATG is the favored agent, equine preparations have historically been used.

Most regimens involve 5-7 days of intravenous administration of thymoglobulin for induction immunosuppression or treatment of corticosteroid-resistant rejection or antibody-mediated rejection.

Thymoglobulin is a polyclonal antibody that has been used in the field of transplantation over the last 4 decades. Thymoglobulin's lack of nephrotoxic properties (unlike calcineurin inhibitors) may potentiate it to be a beneficial induction therapy during the early days following transplantation. In conjunction with inhibitors of terminal complement activation, it has been shown to be beneficial in cross-match–positive transplantation.

Thymoglobulin possibly provides better protection against acute rejection and improves patient and graft survival but may result in more CMV infection and posttransplantation malignancy. Thymoglobulin causes leukocyte depletion with a greater delay to recover. Of special importance is adding antiviral therapy to the treatment regimen of patients who receive antithymocyte globulins as induction therapy.

As polyclonal agents are xenogenic proteins, adverse effects include fever and chills. Other adverse effects are thrombocytopenia, leukopenia, hemolysis, respiratory distress, serum sickness, and anaphylaxis. Thymoglobulin rarely causes adult respiratory distress syndrome. Some adverse effects are ameliorated with steroids, acetaminophen, and diphenhydramine. A high average dose of antithymocyte immunoglobulin has been associated with an increased risk of non-Hodgkin lymphoma.

Thymoglobulin administration is associated with coagulopathy. Using an international normalized ratio screening protocol and an aggressive transfusion protocol, bleeding complications associated with coagulopathy can be avoided in this higher-risk group.

Murine monoclonal anti-CD3 antibody (muromonab-CD3)

Muromonab-CD3 (OKT3) is a murine monoclonal antibody of immunoglobulin 2A clones to the CD3 portion of the T-cell receptor. It blocks T-cell function and has limited reactions with other tissues or cells. This agent is used for induction and acute rejection (primary treatment or steroid-resistant). Soon after muromonab-CD3 administration, T cells disappear from the circulation as a result of opsonization and subsequent removal by the reticuloendothelial system.

Adverse effects include cytokine release syndrome (ie, fever, dyspnea, wheezes, headache, hypotension) and pulmonary edema. Avoiding administration in hypervolemic patients is especially important, although pulmonary edema can occur in euvolemic patients. This therapy requires premedication with steroids (first 2 doses only), acetaminophen, and diphenhydramine to avoid cytokine release syndrome. Its effects of therapy can be monitored by using a CD3 antigen assay.

Muromonab-CD3 is immunogenic in humans, and approximately 50% of patients make antibodies to it after a course of treatment, decreasing the efficacy of subsequent courses.

Post transplantation lymphoproliferative disorders have been reported after muromonab-CD3 administration.

Humanized monoclonal anti-CD52 antibody (alemtuzumab)

Alemtuzumab (Campath-1H), a humanized monoclonal antibody directed against CD52, is a lymphocyte-depleting agent currently being evaluated as an induction agent in solid organ transplantation. Alemtuzumab has been used in off-label studies of solid organ transplantation. CD52, a 25- to 29-kd membrane protein and is on all B and T cells and most macrophages and natural killer cells. Alemtuzumab has powerful depletional properties and a favorable cost profile compared with other induction agents. Treatment results are a rapid and effective depletion of lymphoid cells that may take several months to return to pretransplantation levels.

Alemtuzumab induction and tacrolimus monotherapy was analyzed in 42 pediatric consecutive living-donor kidney transplantations. No patients had antibody-mediated rejection. Tacrolimus monotherapy was attempted in 16 (38%) and was successful in 12 (26%) patients. All patients were steroid free. There was no tissue invasive CMV disease or infection, no BK/polyoma viral nephropathy, and no posttransplantation proliferative disease. This study revealed the 4-year safety and efficacy of this approach in pediatric recipients.

Alemtuzumab induction was found to be safe in deceased donor kidney transplantation, with satisfactory patient and graft survivals at 1 year. Alemtuzumab induction was found to be safe even for recipients of extended criteria donor renal transplantation. Serious adverse events were absent; there was no hyperlipidemia or new-onset diabetes. There was no acute rejection. The 3 (27%) recipients with infectious complications experienced pericardial tuberculosis, urinary tract infection, or invasive pulmonary aspergillosis. Two (18%) cases of posttransplantation lymphoproliferative disease were diagnosed in this study during the follow-up. Overall, patient and graft survival rates were both 91%.

Alemtuzumab induction and tacrolimus monotherapy in 200 living donor solitary kidney transplantations with 3 years of follow-up revealed the actuarial 1-, 2-, and 3-year patient and graft survivals were 99%, 98%, 96.4% and 90.8%, 93.3%, 86.3%, respectively. Fifty (25%) recipients had a total of 89 episodes of acute cellular rejection. About 88.7% of acute cellular rejection episodes were Banff 1, and of those, 82% were steroid sensitive. Nine (4.5%) recipients had antibody-mediated rejection. About 76.5% were weaned but only 46% are currently on spaced-dose (qod or less) tacrolimus monotherapy, and 94.4% remained steroid-free from the time of transplantation. Infectious complications were uncommon.

National registry data indicate a trend towards the incorporation of lymphocyte-depletion antibody-induction therapy into immunosuppressive regimens for solid organ transplantation. In general, alemtuzumab is well tolerated and substantially reduces the risk of acute rejection in the first 6 months posttransplantation in nonsensitized recipients. There is little evidence to support the notion that it uniquely promotes tolerance, and growing evidence suggests it is ineffective in the setting of allosensitization. Alemtuzumab-treated patients clearly remain dependent on maintenance immunosuppression. Long-term outcome data are required to determine the magnitude and type of maintenance therapy that makes best use of alemtuzumab's depletional effects.

The use of alemtuzumab as induction immunosuppression for renal transplantation introduces the possibility of long-term tacrolimus monotherapy, avoiding maintenance with both corticosteroids and mycophenolate mofetil. Renal transplantation with alemtuzumab induction followed by tacrolimus monotherapy leads to good graft and patient outcomes, with no major differences detected compared with basiliximab induction and tacrolimus/mycophenolate mofetil maintenance at 1 year. It was shown that alemtuzumab induction is associated with delayed inflammation at 4 and 12 months, but this inflammation did not appear to negatively impact the glomerular filtration rate or graft survival.

Adverse effects of alemtuzumab include mild cytokine-release syndrome, neutropenia, anemia, idiosyncratic pancytopenia, autoimmune disorders (eg, hemolytic anemia), thrombocytopenia, and thyroid disease. Further controlled trials are needed to establish safety and efficacy. The risk of immunodeficiency-related malignancies was evaluated in a retrospective study including 1350 kidney transplant recipients (between 2001 and 2009). The study concluded that with the exception of nonmelanoma skin cancer and after excluding cancers occurring within 60 days posttransplantation, alemtuzumab induction was not associated with increased cancer incidence post kidney transplantation when compared with no induction therapy and was associated with lower cancer incidence compared with thymoglobulin.

Monoclonal anti-CD25 antibody

Basiliximab (Simulect) and daclizumab (Zenapax) are chimeric and humanized antimonoclonal antibodies that target the IL-2 receptor (CD25). Clinically, both agents are very similar, and both are used for induction. These agents bind to the IL-2 receptor α-chain (CD25 antigen) on activated T cells, depleting them and inhibiting IL-2–induced T-cell activation. Daclizumab was withdrawn from the United States market because of diminished use and emergence of other effective therapies.

These agents have a very low prevalence of adverse effects, although hypersensitivity reactions have been reported with basiliximab, albeit rarely. Induction treatment with basiliximab requires 2 doses, and no monitoring is required. Induction with daclizumab requires 5 doses but 2 may suffice; no monitoring is required.

Anti-CD20 antibodies

Rituximab (anti-CD20 monoclonal antibody) eliminates most B cells and is approved for treating refractory non-Hodgkin B-cell lymphomas, including some posttransplantation lymphoproliferative disease in organ transplant recipients. Rituximab is used off-label in combination with maintenance immunosuppressive drugs, plasmapheresis, and intravenous immune globulin to suppress deleterious alloantibody responses in transplant recipients. Although plasma cells are usually CD20 negative, many are short-lived and require replacement from CD20-positive precursors. Thus, depletion of CD20-positive cells does reduce some antibody responses. CD20-positive B cells can act as secondary antigen-presenting cells, which raises the possibility that rituximab can ameliorate T-cell responses.

Off-label applications for rituximab include treatment of antibody-mediated rejection and possibly severe T-cell–mediated rejection and suppression of preformed alloantibody before transplantation. Again, controlled trials are needed.

Antibody-mediated rejection is a major cause of late kidney transplant failure. Although plasmapheresis is effective in removing alloantibodies (donor-specific antibodies) from the circulation, rebound synthesis of alloantibodies can occur.

Splenectomy is used in desensitization protocols for ABO-incompatible transplants and for antibody-mediated rejection refractory to conventional treatment. Also used are agents targeted for plasma cells, B cells, and the complement cascade, which are bortezomib, rituximab, and eculizumab, respectively.

LEA29Y

LEA29Y is a second-generation cytotoxic-T-lymphocyte–associated antigen 4 (CTLA-4) immune globulin that is a fusion protein combining CTLA-4 (which engages CD80 and CD86) with the Fc portion of immunoglobulin G. The LEA29Y trial introduces the concept of long-term use of nondepleting protein immunosuppressive agents to reduce reliance on toxic small-molecule immunosuppressive drugs.

• References

Therapeutic Management

Phases

Immunosuppressive treatment of the transplantation patient begins with the induction phase, perioperatively and immediately after transplantation. Maintenance therapy then continues for the life of the allograft. Induction and maintenance strategies use different medicines at specific doses or at doses adjusted to achieve target therapeutic levels to give the transplantation patient the best hope for long-term graft survival.

Maintenance immunosuppression is the key to prevention of acute and chronic rejections throughout the life of the graft.

Primary Immunosuppressive Agents

Calcineurin inhibitors

These agents combine with binding proteins to inhibit calcineurin activity. This works to inhibit IL-2, which is a critical link in the proliferation of helper T cells. Calcineurin normally exerts phosphatase activity on the nuclear factor of activated T cells. This factor then migrates to the nucleus to start IL-2 transcription. Studies have shown that cyclosporine and tacrolimus were associated with similar rates of graft survival, but several studies showed lower rates of rejection episodes with tacrolimus.^{[3, 4]}

Recent United Network for Organ Sharing data revealed that more than 50% of patients with new transplants are started on tacrolimus (80% with liver and pancreas transplants, 65% with kidney transplants, < 50% with heart and lung transplants). Although little information compares the long-term graft survival in patients treated with cyclosporine versus patients treated with tacrolimus, recent data demonstrated a less rapid decline in glomerular filtration rate (GFR) in patients receiving tacrolimus compared with patients receiving cyclosporine (Neoral). Whether this translates into improved graft survival has yet to be proven.^[5]

Levels of both cyclosporine and tacrolimus must be carefully monitored. Trough levels seem to correlate well with drug exposure in patients receiving tacrolimus. Initially, levels can be kept in the range of 10-20 ng/mL, but, after 3 months, levels are kept lower (5-10 ng/mL) to reduce the risk of nephrotoxicity. Controversy continues about the best method of monitoring cyclosporine levels. Trough levels have been used for some time; however, current data suggest that levels 2 hours after a dose (C2 monitoring) may be more reflective of drug exposure, particularly with the microemulsion formulation (Neoral).

One investigation studied living donor transplants, comparing cyclosporine and mycophenolate mofetil to tacrolimus and mycophenolate mofetil. The 2-year graft survival rate favored the cyclosporine arm, but the actual graft survival rate difference was only 2.1%. The Collaborative Transplant Study reported a 3-year graft survival rate of more than 80%, including both cyclosporine-based and tacrolimus-based regimens.^[6]

Adjuvant agents

These agents are usually combined with a calcineurin inhibitor and include steroids, azathioprine, mycophenolate mofetil, and sirolimus. Currently, most protocols use a calcineurin inhibitor and steroids with or without mycophenolate mofetil. The use of adjuvant agents allows clinicians to achieve adequate immunosuppression while decreasing the dose and toxicity of individual agents.

Mycophenolate mofetil in kidney transplant recipients has assumed an important role in immunosuppression after several clinical trials have shown a markedly decreased prevalence of acute cellular rejection compared with azathioprine and a reduction in 1-year treatment failures. Ongoing long-term studies suggest mycophenolate mofetil also reduces the prevalence of chronic rejection.^{[3, 7]}

Sirolimus has shown great promise for its potential to combat acute cellular rejection and to provide rescue immunosuppression. Current work shows that sirolimus causes a significant decrease in acute rejection and improvement in patient and graft survival compared with azathioprine. The combination of sirolimus and mycophenolate mofetil is currently undergoing investigation.^[7] A single-center trial of cyclosporine, sirolimus, and prednisone in living, related renal transplant patients demonstrated a reduced rate of acute rejection compared with historical data. Rates of acute rejection were reported at 7.5%, with a 12% rate in African American patients.^[8]

The 2 types of induction strategies used to avoid early acute rejection are (1) antibody-based therapy and (2) aggressive early immunosuppression.

• Antibody-based therapy: This therapy uses monoclonal (eg, muromonab-CD3) or polyclonal antibodies or anti-CD25 antibodies (eg, basiliximab, daclizumab) and is administered in the early posttransplant period (up to 8 wk). Antibody-based therapy allows for avoidance or dose reduction of calcineurin inhibitors, possibly reducing the risk of nephrotoxicity. All agents are effective for preventing acute rejections, although the anti-CD25 antibodies may require concurrent administration of calcineurin inhibitors. The adverse effect profile of the polyclonal and monoclonal antibodies limits their use in some patients. Patients at highest risk of rejection may receive rabbit antithymocyte globulin (Thymoglobulin).
• Aggressive early immunosuppression: This therapy uses maintenance drugs at higher doses to achieve the strongest immunosuppressive effect soon after transplantation. Approximately 50% of patients do not receive antibody therapy at the time of transplantation. The highest doses of calcineurin inhibitors place patients at increased risk of nephrotoxicity and may not be the best strategy for patients at the highest risk for rejection.

Rejection

Acute

The 3 agents used to treat acute rejection are (1) steroids, (2) antithymocyte globulin, and (3) muromonab-CD3.

• Steroids: These agents are the mainstay of therapy for acute rejection episodes, preventing release of IL-1 by macrophages and blocking synthesis of IL-2 by helper T cells. Steroids also have anti-inflammatory properties. The typical dosage is 3-5 mg/kg/d for 3-5 days, which is then tapered to a maintenance dose. Steroids reverse 60-75% of rejection episodes.
• Antithymocyte globulin: This agent binds all circulating T and B lymphocytes, which are then lysed or phagocytosed by the reticuloendothelial system. Antithymocyte globulin has efficacy similar to that of muromonab-CD3. It is reserved for steroid-resistant acute rejection secondary to cost, toxicity, and the development of drug antibodies.
• Muromonab-CD3: This agent displaces the T3 molecule from antigen receptors, captures all mature T cells, and prevents alloantigen recognition. The reversal rate of first acute rejection episodes is 94%. Muromonab-CD3 is sometimes used as the first-line agent for severe vascular rejections. The development of human antimurine antibodies allows for the reappearance of CD3 T cells, which may decrease the efficacy of muromonab-CD3 and necessitate higher doses (increasing risk of infection). A second course of muromonab-CD3 may be given for recurrent rejection, although repeat treatment may be associated with complications from the development of antimouse antibodies. The success rate in recurrent episodes is approximately 40-50%.

Chronic

Unless inadequate immunosuppression is the cause of rejection, changes in immunosuppressive therapy are generally not effective in reversing chronic rejection. The addition of sirolimus to mycophenolate mofetil is currently being studied to determine efficacy.^[7] Long-term data on transplanted patients treated with sirolimus demonstrated a chronic rejection rate of 14%, which is much lower than rates traditionally reported in cyclosporine-based regimens.^[9]

Control of blood pressure, treatment of hyperlipidemia, and management of diabetes are the current mainstays of treatment for graft preservation.

• References

Clinical Questions

Steroid versus steroid-free protocols

The known toxicity of long-term steroid exposure has prompted the development of steroid-free immunosuppressive regimens. Benefits of the withdrawal or avoidance of steroids include normal growth in children, improved lipid profiles, improved blood pressures, better glycemic control, and lower risk of bone disease.

The development of cyclosporine prompted attempts to develop steroid-free protocols. Initially, patients were doing well with cyclosporine monotherapy. Over time, 50% of these patients required steroids, usually for acute rejection. More recently, a follow-up study of 100 patients in Denmark who underwent transplantation on steroid-free protocols showed a 1-year graft survival rate of 97% and a 4-year rate of 82%. Strong randomized studies are undoubtedly needed to prove both efficacy and safety of these protocols.^[10]

Steroid withdrawal has been used as a strategy to avoid adverse steroid effects in transplantation patients. Recent data show the risk of rejection is higher in patients withdrawn from steroids on a cyclosporine-based protocol. After tacrolimus became available, protocols with this drug showed that withdrawal of steroids after 6 months was successful 80% of the time. More recently, studies involving rapid steroid withdrawal (over 1-2 wk) in patients taking tacrolimus show similar graft survival rates compared with patients withdrawn after 3-6 months.

In African American patients, the risk of acute rejection is high; therefore, steroid-tapering regimens are prohibited. The use of sirolimus with tacrolimus followed by a steroid taper at 3 months has resulted in acceptable rejection rates in African Americans in one early study.^[11] The role of sirolimus and mycophenolate mofetil in steroid-free protocols has yet to be definitively determined, although the future looks promising for greater use of steroid-free protocols.

Calcineurin inhibitor-free protocols

Because of the risk of both acute and chronic nephrotoxicity attributed to calcineurin inhibitors, the development of protocols free of these agents is desirable.^[12] The use of sirolimus, mycophenolate mofetil, and anti-CD25 antibodies has been studied to determine whether graft survival and acute rejection rates can be maintained at the present rates in the absence of a calcineurin inhibitor.

The withdrawal of cyclosporine has been investigated in several trials. While the long-term graft survival rates were similar in patients withdrawing from cyclosporine compared with those maintained on it, the incidence of acute rejection in the withdrawal group was higher. The addition of sirolimus has been used in these withdrawal protocols, with a suggestion of improved renal function at 2-year follow-up. Higher rates of acute rejection were again noted in the withdrawal group.

Many other protocols that minimize exposure to calcineurin inhibitors have been studied. Promising protocols include sirolimus, mycophenolate mofetil, and steroids or the combination of anti-CD25 antibodies, sirolimus, mycophenolate mofetil, and steroids. One study has shown that belatacept plus mycophenolate mofetil or belatacept plus sirolimus provide primary immunosuppression with acceptable rates of acute rejection, improved renal function compared to a TAC-based regimen, and may avoid the need for calcineurin inhibitors and corticosteroids.^[13] These protocols have shown acceptable graft survival rates and acute rejection rates, although the studies are small and further research is warranted. In short, multiple regimens have been shown to be effective.

Length of treatment

Although induction of tolerance may allow withdrawal of immunosuppression in the future, at this time, immunosuppressive medications appear to be necessary for the life of the transplanted organ. Episodes of acute cellular rejection have occurred after the cessation of medication even 20 years after transplantation. For patients with stable graft function, individual components of the treatment regimen may be gradually diminished or completely discontinued; however, in most patients, some degree of immunosuppression must be continued. Some patients with severe resistant infections or malignancy related to immunosuppressants require the discontinuation of these medicines.

Pregnancy

Current data suggest that protocols involving cyclosporine, azathioprine, and steroids are associated with low rates of birth defects, although patients are treated with high-risk pregnancy strategies. However, also note that children born to parents with previous transplants are often small for gestational age. Preliminary data also suggest the safety of tacrolimus. Mycophenolate mofetil animal data and some early human studies show adverse effects on fetal development. Presently, few data exist regarding sirolimus and pregnancy.

Infection and malignancy issues

An increasingly recognized problem associated with immunosuppression is BK virus nephropathy. This virus, a member of the human papovavirus family, lives in the human genitourinary tract and replicates in some patients who are immunosuppressed, leading to allograft dysfunction. While antiviral agents such as cidofovir and leflunomide are active against the BK virus, the mainstay of therapy is a reduction in immunosuppression. In one study of 178 pancreas-kidney transplant recipients, the incidence of BK virus nephropathy was found to be low (1.1%), and no evidence of pancreatic allograft dysfunction was evident. Concurrent renal allograft rejection was treated with pulse steroid therapy and a reduction in immunosuppression, and, in one patient, the use of leflunomide, meaningful, though not complete, recovery of renal function was realized.^[14] The risk of acute allograft rejection with this reduction in dose is being studied.^[15]

The results of one study found that a combination of monthly screening for polyoma BK virus nephropathy (PVN) using PCR and a modest decrease in immunotherapy is a safe and effective in preventing PVN and may significantly decrease cytomegalovirus and Epstein-Barr virus in renal transplant patients.^[16]

The results of another study found that monthly nucleic acid testing during the first 6 months post renal allograft and immediate reduction of immunosuppression is effective in preventing BK polyomavirus virus nephropathy (BKVN) in viremic patients.^[17]

Opportunistic infections remain an important risk to the immunocompromised patient despite the use of prophylactic measures. Exposure to viruses such as Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus, and human papillomavirus place the donor at risk for infection and, potentially, later malignancy.

The incidence of CMV has been reduced with the use of antiviral prophylaxis in the first 3 months posttransplant; preemptive monitoring and initiation of treatment in the case of significant viremia after discontinuation of prophylaxis remains to be proven as a strategy for reducing the risk of late-onset CMV disease.^[18] The cause of death of approximately 27% of patients who die with a functioning graft is related to infectious or malignant complications.^[19] This highlights the question of the appropriate amount of immunosuppression required to balance the aspects of graft function with complications related to therapy.

Posttransplant lymphoproliferative disease (PTLD) is a growing concern in the transplant population. Most of these are of B-cell origin and linked to EBV infections. Patients present with constitutional symptoms such as night sweats, fevers, and weight loss. An acute rise in creatinine levels, similar to acute allograft rejection, may also be seen. Risk factors for PTLD include primary EBV infection;^[20] the use of cyclosporine, tacrolimus, and MMF; and an exposure to antithymocyte globulin (ATG) or OKT3. Treatment options include reduction or discontinuation of immunosuppression with an increase in prednisone to reduce rejection risk.^[20] Further studies involving the efficacy of sirolimus and rituximab are needed to determine their specific role.

• References

Author

Bethany Pellegrino, MD, Assistant Professor of Medicine, Section of Nephrology, West Virginia University Hospitals

Disclosure: Nothing to disclose.

Coauthor(s)

Rebecca J Schmidt, DO, FACP, FASN, Assistant Dean for Outreach and Community Engagement, Professor of Medicine, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine

Disclosure: Nothing to disclose.

Songul Onder, MD, Assistant Professor of Medicine, Section of Nephrology, West Virginia University School of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Debra L Sudan, MD, Professor of Surgery, Chief, Abdominal Transplant Surgery, Vice Chair of Clinical Operations, Department of Surgery, Duke University School of Medicine

Disclosure: Nothing to disclose.

Chief Editor

Mary C Mancini, MD, PhD, MMM, Surgeon-in-Chief and Director of Cardiothoracic Surgery, Christus Highland

Disclosure: Nothing to disclose.

Additional Contributors

Ron Shapiro, MD, Professor of Surgery, Robert J Corry Chair in Transplantation Surgery, Associate Clinical Director, Thomas E Starzl Transplantation Institute, University of Pittsburgh Medical Center

Disclosure: Nothing to disclose.

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