|Year : 2015 | Volume
| Issue : 2 | Page : 272-281
Recent advances in immunosuppression for kidney transplantation
Ahmed R El Arbagy, Mahmoud A Kora, Hany S El Barbary, Noha Shawky
Department of Internal Medicine, Faculty of Medicine, Menoufiya University, Menoufiya, Egypt
|Date of Submission||07-Nov-2014|
|Date of Acceptance||28-Nov-2014|
|Date of Web Publication||31-Aug-2015|
Internal Medicine Department, Faculty of Medicine, Menoufia University, Shebin Al-Kom, Menoufia
Source of Support: None, Conflict of Interest: None
To perform a systematic review on the recent advances in immunosuppression for kidney transplantation and how these recent strategies over the past decades have led to significant improvements in the field of renal transplantation.
MEDLINE, EMBASE, and Cochrane databases were searched. The search was performed on 1 November 2013 and included articles published ahead of print, with no language restrictions.
The initial search presented 500 articles, of which 20 fulfilled the inclusion criteria. The articles studied whether transplantation is the ideal treatment for kidney failure, presenting details on graft immunology and the mechanism of action of immunosuppressants, with a focus on novel mechanisms.
Because of heterogeneity in the postoperative follow-up periods and outcome measures reported, it was not possible to pool the data and carry out a meta-analysis. Comparisons were performed by a structured review.
Excellent outcomes have been achieved in the field of renal transplantation. A significant reduction in acute rejection has been achieved at many renal transplant centers using currently available immunosuppressives, consisting of an induction agent, a calcineurin inhibitor, and an antiproliferative agent with or without a corticosteroid. Despite improvements with these regimens, chronic allograft injury and adverse events still persist. The perfect immunosuppressive regimen would limit or eliminate calcineurin inhibitors and/or corticosteroid toxicity while resulting in enhanced allograft outcomes. The aim of this review is to consolidate the published evidence of the effectiveness and safety of investigational immunosuppressive agents in renal transplant recipients.
Keywords: immunosuppression, investigational agents, renal/kidney transplant
|How to cite this article:|
El Arbagy AR, Kora MA, El Barbary HS, Shawky N. Recent advances in immunosuppression for kidney transplantation. Menoufia Med J 2015;28:272-81
|How to cite this URL:|
El Arbagy AR, Kora MA, El Barbary HS, Shawky N. Recent advances in immunosuppression for kidney transplantation. Menoufia Med J [serial online] 2015 [cited 2020 May 31];28:272-81. Available from: http://www.mmj.eg.net/text.asp?2015/28/2/272/163862
| Introduction|| |
Kidney disease is defined as end stage when a patient's glomerular filtration rate has decreased to less than 15 ml/min/1.73 m 2 . Mortality associated with end-stage kidney disease (ESKD) is high. The incidence of end-stage renal disease (ESRD) is estimated to be about 100 patients/million populations. Diabetes and chronic glomerulonephritis are the leading causes of ESRD, followed by hypertension and renal stone disease  .
Renal transplantation has become the treatment of choice for most patients with ESRD. Kidney transplantation is a procedure that involves placement of a healthy kidney from another individual into the body of a patient with renal failure  . The patient with renal failure may receive a kidney from a member of their family. This kind of donor is called a living-related donor. A patient may receive a kidney from an individual who has recently died. This type of donor is called a cadaver donor. Sometimes, a spouse or a very close friend may donate a kidney. This kind of donor is called a living-unrelated donor  .
The immune response to a transplant involves both innate immunity and the adaptive (or acquired) immune response. The basis of the latter response is the ability to recognize certain proteins as foreign or non-self. Allograft rejection is dependent on recipient T lymphocytes responding to highly polymorphic class I and class II cell surface molecules encoded by the major histocompatibility complex (MHC) genes (the HLA system in humans), and may be avoided by matching donor and recipient MHC (HLA) molecules. Incompatibility between the donor graft and recipient for antigens encoded by genes of MHC is the most important cause of rapid graft rejection. Long-term (20 years after transplant) graft survival correlates with the level of HLA mismatch  .
Advances in immunosuppressive strategies over the past decades have led to significant improvements in the field of renal transplantation. The objective of immunosuppression in kidney transplantation is to prevent and treat acute rejection and avoid chronic graft damage, thus minimizing the adverse effects of immunosuppressants. The introduction of cyclosporine, tacrolimus, and mycophenolate mofetil (MMF) reduced rates of acute rejection and improved short-term and midterm graft survival. However, the decrease in acute rejection rates has not been associated with increased long-term graft survival. As such, strategies that can increase long-term graft survival and patient survival are still being sought  .
Also, the primary interest in developing new immunosuppressants no longer involves simply improving short-term results but also improving the safety profile, preserving kidney function, and improving cardiovascular and metabolic profiles. Furthermore, the tolerability and adverse effects of immunosuppressants are just as important as their efficacy, above all when taking into account that kidney transplant recipients are growing older, with associated cardiovascular comorbidities  .
| End-stage kidney disease and kidney transplantation|| |
Chronic kidney disease (CKD), also known as chronic renal insufficiency, progressive kidney disease, or nephropathy, is defined as the presence of kidney damage or decreased glomerular filtration rate for 3 months or more. Generally, CKD is a progressive decrease in kidney function (decrease in the number of functioning nephrons) that occurs over a period of several months to years. The decrease in kidney function in CKD is often irreversible. Therefore, measures to treat CKD are aimed at slowing the progression to end-stage kidney disease  .
Incidence of end-stage renal disease
The incidence of ESRD is estimated to be 100 patients/million populations. During the last 5 years, the incidence of diabetes mellitus as a cause of ESRD has increased and now diabetes and chronic glomerulonephritis are the leading causes of ESRD, followed by hypertension and renal stone disease  .
The stages of chronic kidney disease
The National Kidney Foundation developed a classification system for CKD. The staging system defines the stages of CKD on the basis of glomerular filtration rate (GFR) levels but also accounts for evidence of kidney damage in the absence of changes in GFR, as in stage 1 CKD. The severity of CKD is described by five stages: First stage: CKD1 - GFR above 90 ml/min/1.73m 2 with evidence of kidney damage, second stage CKD2 (mild) - GFR of 60-89 ml/min/1.73 m 2 with evidence of kidney damage, third stage CKD3 (moderate) - GFR of 30-59 ml/min/1.73m 2 , fourth stage CKD4 (severe) - GFR of 15-29 ml/min/1.73m 2 , and fifth stage CKD5 kidney failure - GFR less than 15 ml/min/1.73 m 2 .
Some people add CKD5D for those stage 5 patients requiring dialysis; many patients in CKD5 are not yet on dialysis.
Clinical presentation of chronic kidney disease
General: the development of CKD is usually subtle in onset, often with no noticeable symptoms.
Stages 1 and 2 CKD may generally be asymptomatic.
Stages 3 and 4 CKD may be associated with minimal symptoms.
Stage 5 CKD is associated with pruritus, dyspepsia, nausea, vomiting, constipation, muscle pain, fatigue, and bleeding abnormalities  .
Cardiovascular: worsening hypertension, edema, dyslipidemia, left ventricular hypertrophy, electrocardiographic changes, and chronic heart failure.
Neuropsychiatric: depression, anxiety, impaired mental cognition.
Gastrointestinal: gastroesophageal reflux disease, gastrointestinal bleeding, and abdominal distention.
Genitourinary: changes in urine volume and consistency and foaming of urine  .
| Kidney transplantation|| |
Kidney transplantation is a procedure that involves the placement of a healthy kidney from another individual into the body of a patient with renal failure. Usually, the failed kidneys are left in place, but are sometimes removed. The transplanted kidneys take over the work of two failed kidneys and an individual no longer requires dialysis  .
During a transplant, the surgeon places the new kidney in the lower abdomen and connects the artery and vein of the new kidney with the artery and vein of the patient who is undergoing transplantation  .
The renal failure patient may receive a kidney from a member of their family. This kind of donor is called a living-related donor. A patient may receive a kidney from an individual who has died recently. This type of donor is called a cadaver donor. Sometimes, a spouse or a very close friend may donate a kidney. This kind of donor is called a living-unrelated donor  .
The time it takes to obtain a kidney varies. There are not enough cadaver donors for every patient who requires a transplant. Because of this, the patient must be placed on a waiting list to receive a cadaver donor kidney. However, if a patient's relative gives him/her a kidney, the transplant operation can be performed sooner [Figure 1]  .
| Transplant operation|| |
The renal allograft is placed extraperitoneally in the right or the left iliac fossa (see [Figure 2]. Vascular anastomoses are present between the donor renal vessels and usually the external iliac vessels of the recipient. Urinary reconstruction is almost always through ureteroneocystostomy (donor ureter to recipient bladder), although sometimes, other types of reconstruction may be chosen. Initial function is enhanced by short cold ischemic times, short re-warm (anastomosis) times, and intravascular volume repletion  .
|Figure 2: The three-signal model of T-cell activation. HLA, human leukocyte antigens; IL, interleukin; MHC, major histocompatibility complex; mTOR, mechanistic target of rapamycin; NFAT, nuclear factor of activated T cells; TCR, T-cell receptors.|
Click here to view
Complications in the early postoperative phase
Major complications that can occur in the early postoperative phase include the following: delayed graft function, infection, and graft rejection.
Graft rejection episodes occur in less than 20% of low-risk transplant recipients within the first 26 weeks after transplantation. It is important to keep in mind most rejection episodes are reversible. There are usually no symptoms of rejection. The diagnosis of rejection is usually made on the basis of an increase in serum creatinine  .
Pathophysiology of graft rejection
When a foreign organ, such as a kidney, is transplanted into a nonidentical individual of the same species, the organ is called an allograft. The immune response from the recipient to the allograft is termed an alloimmune response, which is initiated by T-cell recognition of alloantigens (commonly known as allorecognition). Allorecognition is the first step of a series of complex events that leads to T-cell activation, antibody production, and allograft rejection  .
Three-signal model of T-cell activation
T-cell activation is the key process of allograft rejection. T-cells recognize alloantigen through T-cell receptors (TCR). The initiation of intracellular signaling requires additional peptides known as CD3 complex, and the antigen-specific signal (signal 1) is transduced through the TCR-CD3 complex  . Two signals are needed for complete T-cell activation [Figure 2]  .
The second costimulatory signal depends on the receptor ligand interactions between T-cells and APCs (signal 2). Numerous costimulatory pathways have been described and blockage of these pathways can lead to antigen-specific inactivation or the death of T-cells. The best-studied ones are the CD28-B7 and CD154-CD40 pathways.
This unique interaction leads to the clinical development of a fusion protein CTLA-4-Ig (belatacept) as a novel immunosuppressive medication  . CD154-CD40 blockages have also been shown to prevent allograft rejection in animal models, including anti-CD154 antibody and molecules that target CD40  .
The combination of signal 1 and 2 activates three downstream signal transduction pathways: the calcium calcineurin pathway, the RAS-mitogen activated protein kinase pathway, and the IKK-nuclear factor kB (NF-kB) pathway. These three pathways further activate transcription factors including the NK of activated T cells, activated protein-1, and NF-kB, respectively. Several new molecules and cytokines including CD25, CD154, interleukin (IL)-2, and IL-15 are subsequently expressed  .
IL-2 and IL-15 deliver growth signals (signal 3) through the mammalian target of the rapamycin pathway and the phosphoinositide-3-kinase pathway, which subsequently trigger the T-cell cycle and proliferation [Figure 2]. The fully activated T-cells undergo clonal expansion and produce a large number of cytokines and effector T-cells, which eventually produce CD8+ T-cell mediated cytotoxicity, boost macrophage-induced delayed-type hypersensitivity response (by CD4+Th1), and aid B cells with antibody production (by CD4+Th2). A subset of activated T-cells becomes the alloantigen-specific memory T-cells  .
Immunosuppression can be achieved by depleting lymphocytes, diverting lymphocyte traffic, or blocking lymphocyte response pathways. Immunosuppressive drugs exert three effects: the therapeutic effect (suppressing rejection), undesired consequences of immunodeficiency (infection or cancer), and nonimmune toxicity to other tissues. Immunodeficiency leads to characteristic infections and cancers, such as post-transplantation lymphoproliferative disease, which are related more to the intensity of immunosuppression than to the specific agent used .
Classification of immunosuppressive drugs
Immunosuppressive drugs include small-molecule drugs, depleting and nondepleting protein drugs (polyclonal and monoclonal antibodies), fusion proteins, intravenous immune globulin, and glucocorticoids Table 1.
Most small-molecule immunosuppressive agents are derived from microbial products and target proteins that have been highly conserved in evolution. Small-molecule immunosuppressive drugs at clinically tolerated concentrations probably do not saturate their targets. For example, cyclosporine acts by inhibiting calcineurin, but only partially inhibits calcineurin as used clinically. Without target saturation, the effects of the drug are proportional to the concentration of the drug, which makes dosing and monitoring critical  .
Depleting protein immunosuppressive agents are antibodies that destroy T cells, B cells, or both. T-cell depletion is often accompanied by the release of cytokines, which produces severe systemic symptoms, especially after the first dose. The use of depleting antibodies reduces early rejection but increases the risks of infection and post-transplantation lymphoproliferative disease and can be followed by late rejection as the immune system recovers  .
Recovery from immune depletion takes months to years and may never be complete in older adults. The depletion of antibody-producing cells is better tolerated than T-cell depletion, because it is not usually accompanied by cytokine release and immunoglobulin levels are usually maintained. However, depletion of antibody-producing cells is incomplete because many plasma cells are resistant to the available antibodies that target B cells, such as anti-CD20 antibody  .
Nondepleting protein drugs are monoclonal antibodies or fusion proteins that reduce responsiveness without compromising lymphocyte populations. They typically target a semiredundant mechanism such as CD25, which explains their limited efficacy but the absence of immunodeficiency complications. These drugs have low nonimmune toxicity because they target proteins that are expressed only in immune cells and trigger little release of cytokines .
Immunosuppression protocols for kidney transplantation
Currently available immunosuppressive agents can be classified into three categories: induction agents, maintenance therapy, and treatment for rejection.
Induction agents are typically polyclonal antibodies (antithymocyte globulins) and IL-2 receptor antagonists (basiliximab).
The four drug classes that comprise maintenance regimens include calcineurin inhibitors (cyclosporine and tacrolimus), mammalian target of rapamycin (mTOR) inhibitors (sirolimus and everolimus), antiproliferative agents (azathioprine and mycophenolic acid), and corticosteroids  .
| Induction agents|| |
Induction therapy is primarily used to avoid early acute rejection, which is historically known to predict subsequent graft loss. Drugs that are used for induction therapy include basiliximab and antithymocyte globulin.
Basiliximab (Simulect; Novartis)
Basiliximab is an IL-2 receptor antagonist that is the only food and drug administration (FDA)-approved induction agent in renal transplantation. Dosed at 20 mg and administered at the time of and 4 days following transplantation, basiliximab has few adverse reactions or drug interactions  .
Basiliximab has been shown to lead to a statistically significant reduction in the incidence of acute rejection in three clinical trials, two of which used a maintenance regimen of cyclosporine and corticosteroids without an antimetabolite. The third trial included azathioprine in the maintenance regimen and yielded a 20.8% rejection rate in the basiliximab arm compared with 34.9% in the placebo arm  .
Rabbit antithymocyte globulin (Thymoglobulin; Genzyme)
They are antibodies derived from rabbit sources that are commonly used induction agents, although they are approved for corticosteroid-resistant rejection. These antibodies are FDA approved for the treatment of acute rejection at a dose of 1.5 mg/kg for 7-14 days on the basis of the results of a multicenter, double-blind randomized trial.
Although rabbit antithymocyte globulin is not currently FDA approved as induction therapy for kidney transplantation, it is the most commonly administered agent for this purpose. Reported induction doses range from 1 to 6 mg/kg/dose over 1-10 days with a more typical regimen of 1.5 mg/kg for 3-5 days. Common adverse events include cytokine release syndrome, leucopenia, and thrombocytopenia  .
| Maintenance therapy|| |
Over the last two decades, calcineurin inhibitors have been used extensively in post-transplant immunosuppressive regimens and have gained a vital place in today's solid organ post-transplant care for the prevention of acute rejection and prolonging patient and graft survival. Cyclosporine (Neoral; Novartis) and tacrolimus (Prograf; Astellas) are calcineurin inhibitors that primarily suppress the activation of T lymphocytes by inhibiting the production of cytokines, specifically IL-2)  .
Several landmark trials have compared the calcineurin inhibitors available. The first two multicenter studies have compared tacrolimus with microemulsion cyclosporine using a combination of calcineurin inhibitors, azathioprine, and corticosteroids; they showed a significant decrease in acute rejection with tacrolimus, but there was no difference in patient or graft survival after transplantation  .
The next study randomized first deceased donor recipients to one of three immunosuppressive regimens (all included corticosteroids):
Acute rejection rates were similar in each group (≤20%), but the incidence of corticosteroid-resistant rejection was lower in the tacrolimus arms.
- Tacrolimus with azathioprine.
- Tacrolimus with MMF.
- Microemulsion cyclosporine and MMF.
A 3-year follow-up found no statistically significant difference in renal function, patient or overall graft survival, but improved graft survival in recipients with delayed graft function in the tacrolimus arms.
In agreement with these data, a meta-analysis reported that for every 100 patients treated with tacrolimus rather than cyclosporine for the first year, acute rejection would be prevented in 12 patients, graft failure would be prevented in two patients, but five patients would develop new-onset diabetes after transplantation (NODAT)  .
Over the last two decades, there have been significant improvements in transplantation, in large part because of the decreased incidence of acute rejection with the use of calcineurin inhibitors. This success has come at the expense of associated adverse side effects, including metabolic side effects that are risk factors for cardiovascular disease and cerebrovascular disease. Long-term use of these drugs has been associated with the development of chronic allograft nephropathy. New immunosuppressive agents that eliminate these issues are needed  .
Mammalian target of rapamycin inhibitors
Although calcineurin inhibitors have significantly reduced acute rejection rates, they are direct nephrotoxins and show several other side-effects. Calcineurin-sparing regimens are an attractive immunosuppressive option that may minimize the risk of long-term graft loss while maintaining low rates of acute rejection. A potential alternative to the calcineurin inhibitor-based regimens are mTOR inhibitors  .
Two agents, sirolimus and everolimus, have been developed and FDA approved with the hopes of achieving this goal.
Sirolimus is dosed orally once daily. Dose adjustments are based on target trough levels of 5-15 ng/ml. Sirolimus may play a favorable role in calcineurin inhibitor-free maintenance therapy, but caution is warranted as nephrotoxicity and rejection are still concerns. Several investigators have conducted trials with mTOR inhibitors in the hope of developing calcineurin-sparing regimens  .
Everolimus (Zortress; Novartis) is a sirolimus derivative with a much shorter half-life that recently received FDA approval for renal transplantation.
Everolimus, initially dosed at 0.75 mg orally twice daily, followed by routine serum drug concentration monitoring, has an adverse events profile similar to sirolimus. The efficacy of everolimus 1.5 versus 3 mg/day with steroids and low-exposure cyclosporine without induction (n = 237) or with induction (basiliximab, n = 256) has been studied. In this study, the use of an induction agent eliminated the need for high-dose everolimus  .
Six-month biopsy-proven acute rejection occurred in 25.0 and 15.2% of patients (P = 0.073) in the 1.5 and 3 mg/day groups without induction, and 13.7 and 15.1% of patients in the study groups with induction (P = 0.859). Calculated glomerular filtration rates (62-67 ml/min) and adverse events were similar in all arms  .
Antiproliferative agents are usually considered the 'third agent' in triple immunosuppressive regimens, exerting additive effects, but less essential than the calcineurin inhibitor or the corticosteroid component. Azathioprine and mycophenolic acid are the commonly used agents in this category. Currently, there are two forms of mycophenolic acid available on the market: MMF (CellCept; Roche Laboratories) and mycophenolate sodium (EC-MPS, Myfortic; Novartis Pharmaceuticals)  .
Treatment of antibody-mediated rejection
Antibody-mediated rejection is an important cause of acute and chronic graft failure. Acute and chronic antibody-mediated rejections are difficult to treat, because they are typically less responsive to conventional antirejection therapy. Treatment regimens for humoral rejection may include one or more of the following: plasmapheresis, intravenous immunoglobulin, and rituximab  .
A recent meta-analysis of over 10 000 citations on the treatment of antibody-mediated rejection concluded that data describing these treatments are of low or very low quality. The first, prospective, randomized study comparing these strategies (plasmapheresis/ IVIG/rituximab vs. IVIG alone) showed improved graft survival in the combination group. Little guidance has been provided by the KDIGO Clinical Practice Guidelines; they suggest the treatment of antibody-mediated acute rejection with one or more of the following alternatives with or without corticosteroids: plasma exchange; intravenous immunoglobulin; anti-CD20 antibody; and lymphocyte-depleting antibody (Grade 2C Recommendation)  .
| Discussion|| |
The objective of immunosuppression in kidney transplantation is to prevent and treat acute rejection and avoid chronic graft damage, thus minimizing the adverse effects of immunosuppressants. The introduction of cyclosporine, tacrolimus, and MMF reduced rates of acute rejection and improved short-term and midterm graft survival, as reported by data from the Organ Procurement and Transplantation Network (OPTN) and the Scientific Registry of Transplant Recipients (SRTR) in the USA, and the Grupo Español para el Estudio de laNefropatía CrÓnica del Trasplante (Spanish Chronic Allograft Nephropathy Study Group)  . However, the decrease in acute rejection rates has not been associated with increased long-term graft survival. Results from the OPTN/SRTR 2009 report showed no significant differences over time. As such, strategies are still being sought that can increase long-term graft survival and patient survival Table 3  .
The primary interest in developing new immunosuppressants no longer involves simply improving short-term results but also improving the safety profile, reducing nephrotoxicity, and improving cardiovascular and metabolic profiles. Furthermore, the tolerability and adverse effects of immunosuppressants are just as important as their efficacy, above all when taking into account that kidney transplant recipients are growing older, with associated cardiovascular comorbidities 
Novel immunosuppressive agents
Alternatives to currently available calcineurin inhibitors.
Belatacept a second-generation costimulation blocker that received FDA approval for use in kidney transplantation in June 2011. It is a selective T-cell blocker. It is a human fusion protein that combines a modified extracellular portion of cytotoxic T-cell antigen 4 (CTLA-4) and the fragment crystallizable region of human IgG1 (Fc region)  .
It blocks the costimulatory signal by binding to APC CD80 and CD86 antigens, thus inhibiting the complete activation of T cells and promoting anergy and apoptosis. This drug is derived from abatacept, a fusion protein that is effective in autoimmune disorders such as rheumatoid arthritis. The belatacept molecule includes two replaced amino acids that confer a greater binding ability to CD80 and CD86, greater binding strength to T cells, and greater efficacy in prophylaxis against rejection  .
Belatacept is the first drug in a new class of immunosuppressants. The data from clinical trials comparing belatacept with cyclosporine suggest that they have similar efficacy, but belatacept preserves renal graft structure and function, and is associated with lower rates of chronic allograft nephropathy.
In long-term treatment regimens, renal function remained stable, which contrasts with the annual decrease of 1-3 ml/min/m 2 that is usually observed with calcineurin inhibitors at stable doses, and is consistent with first-year results  .
The recommended initial dose is 10 mg/kg on days 1 (before the intervention), 5, 14, and 28, and after weeks 8 and 12 following the transplantation. In the maintenance phase, the recommended dose is 5 mg/kg every 4 weeks (3 days), starting at the end of the 16th week following the transplant  .
Belatacept yields a more favorable cardiovascular and metabolic profile than calcineurin inhibitors. According to the results from a systematic review of randomized and controlled studies, patients treated with belatacept had a 69% lower probability of death compared with those treated with tacrolimus. Cardiovascular disease is the most common cause of death in patients with kidney transplants and functioning graft.
In clinical trials such as BENEFIT and BENEFIT-EXT, the incidence of NODAT with belatacept has been lower than that in patients treated with calcineurin inhibitors, and belatacept has shown a better cardiovascular and metabolic profile than currently used immunosuppressants  .
A novel calcineurin inhibitor, voclosporin (ISA 247; Isotechnika Pharma Inc.) is being investigated in solid organ transplant, uveitis, and psoriasis. Animal studies have shown that voclosporin, a cyclosporine analog, had a higher affinity and greater in-vivo potency  .
PROMISE, a phase 2b trial of low-risk renal transplant recipients with immediate allograft function (n = 334) compared low (0.4 mg/kg), medium (0.6 mg/kg), and high (0.8 mg/kg) doses of voclosporin with tacrolimus (0.05 mg/kg), in combination with a standard immunosuppressive regimen (anti-CD25 antibody, MMF, and corticosteroids). Rejection rates were noninferior to tacrolimus (11, 9, 2, and 6%, respectively) and renal function was clinically similar (69-72 ml/min) at 6 months after transplantation  .
The incidence of NODAT was significantly lower in the low-dose voclosporin group (1.6 vs. 16.4% tacrolimus), but not in the medium-dose (5.7%) and high-dose (17.7%) arms. The major limitation of this trial was that only low-risk patients were studied. Low-dose to medium-dose voclosporin may provide adequate immunosuppression with a lower incidence of NODAT. A large, phase 3 (n = 598) trial is planned for 2013.
Recently, pharmacokinetic data of voclosporin were presented at the American Transplant Congress. Researchers have learned that voclosporin should be administered on an empty stomach and that dosage adjustment may be needed in patients with severe renal failure (<30 ml/min) and mild to moderate hepatic impairment. Optimal trough concentrations should be targeted between 35 and 60 ng/ml  .
Prolonged release tacrolimus
Prolonged release tacrolimus (Astragraf XL; Astellas) has been approved for use in various European countries, Canada, and the USA (in July 2013). The expectation is that dosing of the products once daily, rather than twice daily, will improve adherence in transplant recipients. Large, randomized, phase 3 studies have compared prolonged-release tacrolimus with tacrolimus, with similar efficacy and safety outcomes  .
Of note, tacrolimus levels in patients may be slightly lower with prolonged-release tacrolimus compared with twice-daily tacrolimus, although serum creatinine, creatinine clearance, and estimated glomerular filtration rate were very similar. Prolonged-release tacrolimus has a noninferior efficacy profile compared with convenient daily dosing, which is expected to improve patient compliance. The cost of the drug may influence the widespread use of this product as generic tacrolimus formulations are now available Table 2  Table 4, Table 5.
Anti-CD40 monoclonal antibody
A fully human anti-CD40 monoclonal antibody, ASKP1240, has shown promise in phase 1 studies. The first human, phase 1 study of healthy individuals (n = 12) showed that the antibody was safe and well tolerated  . Subsequently, a phase 1b trial, conducted in de-novo kidney transplant recipients who received a single intravenous dose of 50 mg (n = 10), 100 mg (n = 9), 200 mg (n = 10), 500 mg (n = 9) or placebo (n = 8), with no induction and standard maintenance immunosuppression according to the protocol of each center  .
ASKP1240 showed nonlinear pharmacokinetics and was well tolerated at all doses. Acute rejection occurred in three patients in the 50 mg arm, three patients in the 500 mg arm, and one patient in the placebo arm. The incidence of infection was not dose dependent. A phase 2 trial will compare the efficacy of ASKP1240 with avoidance of calcineurin (basiliximab induction, ASKP1240, MMF, and steroids) with the standard of care immunosuppressive regimen (basiliximab induction+tacrolimus+MMF+steroids). In addition, the study will compare the efficacy of calcineurin inhibitor minimization-MMF avoidance (basiliximab induction, ASKP1240, tacrolimus, and steroids) with the standard of care immunosuppressive regimen  .
Treatment of antibody-mediated rejection
Two investigational treatments for antibody-mediated rejection include bortezomib and eculizumab.
Bortezomib has been used for the treatment of acute antibody-mediated rejection, although it is approved for multiple myeloma in the USA (2010). One case series of 52 transplant patients treated for antibody-mediated rejection or desensitization reported bortezomib-associated toxicity to be low, most commonly reported as manageable anemia or peripheral neuropathy. Dosing of bortezomib is 1.3 mg/m 2 on days 1, 4, 8, and 11. No adjustments are necessary for renal impairment, but the dosage should be reduced by one-half for moderate to severe hepatic impairment  .
Few comparative trials have been conducted. One German, historical control study of 10 bortezomib-treated patients (four doses of 1.3 mg/m 2 ) versus nine rituximab-treated patients (one fixed dose of 500 mg) with antibody-mediated rejection showed improved survival in the bortezomib-treated group with an 18 months graft survival of 60 versus 11% in the rituximab group. All patients received plasmapheresis and intravenous immune globulin (30 g). Randomized trials are required to determine the influence of bortezomib on antibody removal  .
Eculizumab is a humanized monoclonal IgG antibody that binds to complement protein C5 and blocks the activation of the terminal complement. Eculizumab has also been successful in reducing antibodies in a highly sensitized patient with positive cross-matches before live donor transplant and in the prevention of antibody-mediated rejection in a case series of patients with donor-specific antibodies and positive flow cytometry cross-matches (n = 4)  .
In a larger case-control study, patients with donor-specific antibodies who received pretransplant plasmapheresis and post-transplant eculizumab were compared with historical controls. At a median follow-up of 12 months for the eculizumab group, antibody-mediated rejection occurred in 7.7% of patients (2/26) in the eculizumab group compared with 41% of individuals (21/51) in the control group (P < 0.01). One-year protocol biopsy indicated transplant glomerulopathy in 6.7% (1/15) of eculizumab-treated recipients and in 35.7% (15/42) of control patients (P = 0.044).
Eculizumab 600 mg weekly for six doses with plasmapheresis has also been successful in reversing refractory, early (mean time 6.5 days), acute antibody-mediated rejection in four transplant recipients  .
| Conclusion|| |
Renal transplantation has become the treatment of choice for most patients with ESRD. The immune response to a transplant involves both innate immunity and the adaptive (or acquired) immune response. Incompatibility between the donor graft and the recipient is the most important cause of rapid graft rejection. The alloimmune response is initiated by T-cell recognition of alloantigens through direct or indirect pathways.
Three signal models have been established during T-cell activation, which subsequently produces various effector T-cells and antibody production. Sensitive cross-match is performed routinely before kidney transplant to detect any significant DSA so that hyperacute rejection can be eliminated.
The past decade has witnessed significant improvements in the immunosuppressive armamentarium. Evidenced based medicine has provided valuable information on the management of post-transplant immunosuppression in the three categories of induction, maintenance, and treatment of rejection. The FDA indications are listed in Table 6. Two drug classes are used for 'induction': polyclonal antibodies (antithymocyte globulins) and IL-2 receptor antagonist (basiliximab). Basiliximab may be preferred in low-risk patients and rabbit antithymocyte globulin in high-risk patients. Recently, alemtuzumab has shown promise in low-risk patients. Future research is with alefacept is warranted.
'Maintenance' immunosuppressives consist of calcineurin inhibitors, mTOR inhibitors, antimetabolites, and corticosteroids. Today, tacrolimus is the most commonly used calcineurin inhibitor. Prolonged-release tacrolimus allows once daily dosing of this product and this may hopefully simplify a complex post-transplant immunosuppressive regimen. At this point in the clinical trials, voclosporin, a cyclosporine analog, has not shown superior efficacy outcomes, but perhaps improvement in the safety profile (namely new-onset diabetes after transplant) will ensure its place in transplant immunotherapy.
Although calcineurin inhibitors have significantly reduced acute rejection rates, they are direct nephrotoxins and chronic allograft nephrotoxicity still persists. A potential alternative to the calcineurin inhibitor-based regimens are mTOR inhibitors, sirolimus, and everolimus.
The de novo use of mTOR inhibitors, although promising, has been associated with many adverse effects and it appears that the mTOR conversion is only successful in a subgroup of patients. Whether calcineurin inhibitor-free/sparing regimens using mTOR-I maintenance therapy is efficacious in the long term remains unknown. Currently, there are three antimetabolites on the market: azathioprine, MMF, and mycophenolate sodium. It is still unclear whether enteric coated mycophenolate sodium has a gastrointestinal side effect benefit over MMF. These perceived benefits should be weighed with the cost savings benefit associated with generic MMF.
Three maintenance agents with novel mechanisms of action that should be studied include sotrastaurin, a protein kinase C inhibitor; belatacept, a recently approved costimulation blocker; and tolfacitinib, a JAK3 inhibitor.
Belatacept, the first immunosuppressive to show a renal benefit over a calcineurin inhibitor-based regimen, may prove beneficial to the immunosuppressive maintenance regimens.
Treatment regimens for humoral rejection may include one or more of the following: plasmapheresis, intravenous immunoglobulin, and rituximab. Investigations of bortezomib and eculizumab have been hindered by small, nonrandomized trials. Although results are encouraging, larger studies and long-term follow-up are needed.
While awaiting further advancements in the immunosuppressive armamentarium, we should be able to improve the functional life of most renal allografts by tailoring our available agents for induction and maintenance therapy. The information obtained through further study in these complex regimens should provide innovative strategies and new immunosuppressive agents that will serve to extend the functional life of allografts without toxicity or infection [Figure 1].
| Acknowledgements|| |
Conflicts of interest
| References|| |
EM Bolton, JA Bradley. Essential immunology for surgeons. Transpl Immunol 2011; 3
M Ahmad, F Saeed, Mehjabeen, N Jahan. Renal failure: its treatment in current systems of medicines. Kidney Transpl 2013; 15
O Bestard, JM Campistol, JM Morales, A Sánchez-Fructuoso, M Cabello, V Cabello, et al.
Advances in immunosuppression for kidney transplantation: new strategies for preserving kidney function and reducing cardiovascular risk. Nefrologia 2012; 32
Schold JD, Srinivas TR, Braun WE, Shoskes DA, Nurko S, Poggio ED. The relative risk of overall graft loss and acute rejection among African American renal transplant recipients is attenuated with advancing age. Clin Transplant 2011; 25
Global Dialysis Market Report. 2011 Edition - New Report by Koncept Analytics; Global Dialysis Market Report.
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009; 9
Danovitch GM. Handbook of kidney transplantation. 4th ed. Philadelphia: Lippincott Williams and Wilkins; 2005. 23-71.
Stegall MD, Diwan T, Raghavaiah S. Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients. Am J Transplant. 2011; 11
Klein C, Brennan DC. HLA and ABO sensitization and desensitization in renal transplantation. 2013
Durrbach A, Francois H, Jacquet A, Beaudreuil S, Charpentier B. Co-signals in organ transplantation. Curr Opin Organ Transplant 2010; 15
Kalluri HV, Hardinger KL. Current state of renal transplant imunosuppression present and future. World J Transplant 2012; 2
Schena FP, Pascoe MD, Alberu J, del Carmen Rial M, Oberbauer R, Brennan DC, et al.
Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal allograft recipients: 24-month efficacy and safety results from the CONVERT trial. Transplantation 2009; 87
Douthat WG, Garay G, de Arteaga J, Fernández Martín JL, Cannata Andía JB, Massari PU. [Biochemical and histological spectrum of renal osteodystrophy in Argentina]. Nefrologia 2003; 23
Copley JB, Wüthrich RP. Therapeutic management of postkidney transplant hyperparathyroidism. Clin Transplant 2011; 25
Hougardy JM, Broeders N, Kianda M, Massart A, Madhou P, Le Moine A, et al.
Conversion from Prograf to Advagraf among kidney transplant recipients results in sustained decrease in tacrolimus exposure. Transplantation 2011; 91
Silva HT, Yang HC, Abouljoud M, Kuo PC, Wisemandle K, Bhattacharya P, et al.
First MR. One-year results with extended-release tacrolimus/MMF, tacrolimus/MMF and cyclosporine/MMF in de novo kidney transplant recipients. Am J Transplant 2007; 7
Vitko S, Tedesco H, Eris J, Pascual J, Whelchel J, Magee JC, et al.
Everolimus with optimized cyclosporine dosing in renal transplant recipients: 6-month safety and efficacy results of two randomized studies. Am J Transplant 2004; 4
Weir MR, Mulgaonkar S, Chan L, Shidban H, Waid TH,Preston D, et al.
Mycophenolate mofetilbased immunosuppression with sirolimus in renal transplantation: a randomized controlled Spare-the-Nephron trial. Kidney Int 2011; 79
Roberts DM, Jiang SH, Chadban SJ. The treatment of acute antibody-mediated rejection in kidney transplant recipients - a systematic review. Transplantation 2012; 94
Vanrenterghem Y, Bresnahan B, Campistol J, Durrbach A,Grinyó J, Neumayer HH, et al.
Belatacept based regimens are associated with improved cardiovascular and metabolic risk factors compared with cyclosporine in kidney transplant recipients (BENEFIT and BENEFIT-EXT studies). Transplantation 2011; 91
Vincenti F, Blancho G, Durrbach A, Friend P, Grinyó J, Halloran PF, et al.
Five-year safety and efficacy of belatacept in renal transplantation. J Am Soc Nephrol 2010; 21
Kuglstatter A, Mueller F, Kusznir E, Gsell B, Stihle M, Thoma R, et al.
Structural basis for the cyclophilin A binding affinity and immunosuppressive potency of E-ISA247 (voclosporin). Acta Crystallogr D Biol Crystallogr 2011; 67
KL Hardinger, DC Brennan. Novel immunosuppressive agents in kidney transplantation. World J Transplant 2013; 3
Kitada H, Okabe Y, Nishiki T, Miura Y, Kurihara K, Terasaka S, et al.
One-year follow-up of treatment with once-daily tacrolimus in de novo renal transplant. Exp Clin Transplant 2012; 10
Watanabe M, Yamashita K, Suzuki T, Kamachi H, Kuraya D, Koshizuka Y, et al.
ASKP1240, a fully human anti-CD40 monoclonal antibody, prolongs pancreatic islet allograft survival in nonhuman primates. Am J Transplant 2013; 13
Rostaing L, Neumayer HH, Reyes-Acevedo R, Bresnahan B, Florman S, Vitko S, et al.
Belatacept-versus cyclosporine-based immunosuppression in renal transplant recipients with pre-existing diabetes. Clin J Am Soc Nephrol 2011; 6
J Vella, DC Brennan, AM Sheridan. Investigational immunosuppressive drugs and approaches in clinical kidney transplantation. 2014.
Cohney SJ, Hughes P, Rosemary M, Walker RG, Cantwell L, Vanhardeveld E, et al.
C5 inhibition with eculizumab to prevent antibody mediated rejection (AbMR) in patients with donor specific anti-HLA antibody (DSAb) and a positive cross match [abstr]. Am J Transplant 2011; 11
[Figure 1], [Figure 2]