Nephrology Hypertension

Kidney Transplantation: Transplant Immunology and Use of Immunosuppression

Does this patient have too much or too little immunosuppression?

Choosing the proper immunosuppression for a patient involves balancing the risk of immunologic graft injury against the risks of infection and malignancy. This requires an understanding of basic immunology, the mechanism of action and side effects of immunosuppressive medications, and a thorough immunologic risk assessment. Immunological risk is estimated from the patient’s medical history, immunogenetic testing, characteristics of the donor organ (living versus deceased donor), and time elapsed since transplant. Various combinations of immunosuppressants are chosen to target low and higher risk patients.

Immune system: Concepts and Components

The human immune system is composed of the innate and adaptive components. The innate immune system is composed of macrophages, neutrophils and natural killer (NK) cells as well as nonpolymorphic proteins, such as complement and cytokines, which respond to generic antigens. The cardinal features of the adaptive immune response are specificity to antigenic diversity, memory, and tolerance to self. It is composed of cellular (T cells) and humoral (B cells/ antibodies) components. Though both responses (innate and adaptive) are important in transplantation, the majority of treatment modalities in transplantation are directed against the adaptive immune response.

  • T cells: T cells are derived in the thymus during embryogenesis and early childhood. CD8 T cells bind to class I MHC molecules and generally mediate cytotoxicity. CD4 T cells bind to class II MHC molecules, secrete cytokines to amplify inflammation, and provide help to induce cytotoxic T cells and antibody-producing B cells.

  • B cells: B-cell receptors, generally a form of IgM antibody, bind to foreign proteins. Antigen is taken up by receptor-mediated endocytosis, digested, and presented to T cells in the context of class II MHC. CD4 T cells bind B cells, and via transmission of costimulatory signals (CD40 is an important example) induce B-cell differentiation into antibody-secreting plasma cells or into long-living memory B cells.

The immune response induced by a transplanted organ

The host immune system is able to distinguish self from non-self by recognizing foreign HLA molecules (allorecognition) then mounting a highly specific immune response to donor cells in the transplanted organ.

HLA antigens: Grafts transplanted from one member of a species to a different non-identical member of that same species (eg, one human to another) are termed allografts. In this situation, the two individuals differ at MHC loci (also known as human leukocyte antigen [HLA] loci) and/or differ at minor histocompatibility (mH) antigens. HLA antigens can be divided into class I and class II. Class I antigens (HLA A, B and C) are present on all nucleated cells while class II antigens (HLA DR, DQ and DP) are found on antigen presenting cells and can be upregulated on vascular endothelium after ischemia reperfusion injury.

Each person inherits two sets of HLA antigens, one from each parent, which are co-dominantly expressed. The HLA antigens are both polygenic and polymorphic making it extremely unlikely that two unrelated individuals have the same HLA antigen combination. Even when limited to HLA A, B and DR there are over 100 distinct antigens. This diversity protects us from pathogens but provides a large number of immune targets after organ transplantation. HLA frequencies depend on ethnicity. For example, A2 is found in approximately 50% of all ethnic populations while HLA-B54 is found almost exclusively in patients of Japanese heritage.

Cellular alloimmunity: Cell-mediated alloimmunity is initiated by antigen-specific T cells that, in concert with other cellular components, result in cytolytic and cytokine-induced damage of a transplanted organ. Initial antigen recognition predominantly occurs in secondary lymphoid organs where recipient T cells interact with antigens derived from the donor. The primed T cells then migrate back to the graft where they re-encounter antigens and mediate their effector functions.

T cells recognize MHC:peptide complexes through heterodimeric T-cell receptors (TCRs) expressed on their cell surface. In the normal host, T cells are "trained" to recognize foreign peptides expressed in the context of self-MHC molecules and are tolerant to self antigens. T cells also recognize foreign MHC:peptide complexes. This is now known to occur through two distinct but not necessarily mutually exclusive pathways – the direct and the indirect allorecognition pathways. Direct allorecognition of intact surface MHC:peptide molecules expressed on donor cells is a process unique to transplantation.

  • Direct pathway: Donor dendritic “passenger" cells migrate out of the transplanted graft and into the hosts lymphoid tissue. In the lymphoid tissue T cells recognize the foreign MHC:peptide complex and are activated.

  • Indirect pathway: Host dendritic cells migrate to the transplanted graft, acquire foreign peptides, and present them to CD4 T cells in host lymphoid tissue. This pathway is thought to be important in late transplant chronic rejection.

T-cell activation: Three signals are required to activate a T cell.

  1. T cell receptor ligation: T cell receptor CD3 complex along with T cell surface molecules CD4 or CD8 interact with its counterpart MCH molecule and antigenic peptide.

  2. Co-stimulation: Positive co-stimulation is required for T cell activation. There are numerous positive and negative co-stimulatory pathways. The best known positive co-stimulatory pathway is the interaction between CD28 on the T cell and B7 found on antigen presenting cells. The combination of T cell receptor ligation and co-stimulation result in T cell activation and production of various cytokines and growth factors including IL-2.

  3. IL-2/ CD25: Activation of the T cell receptor and positive co-stimulation results in the production of the potent T cell growth factor IL-2 and upregulation of the activated IL-2 receptor, CD25. IL-2 works in an autocrine and paracrine manner on the CD25 receptor to induce lymphocyte proliferation.

Rejection - the effector phase of the immune response: The effector phase of the immune response exhibits memory and escalating response to foreign antigen. It requires secondary lymphoid organs (where antigen presentation takes place) as well as both the innate and adaptive immune system.

  • Innate immune response: Inflammation from ischemia reperfusion injury in the allograft leads to the migration of NK cells, macrophages and neutrophiles to the allograft resulting in injury.

  • Adaptive immune response: CD4 T cells are primed against donor antigens and release cytokines which direct an immune response in the allograft. This results in CD8 T cells, macrophages and NK cells migrating to the graft and causing cell damage and apoptosis. Cytotoxic CD8 T cells kill their targets in an antigen specific method through direct cell-cell contact in one of two mechanisms. The first is by secreting proteins granzyme and perforin which result in cell lysis. The second mechanism is by activation of the Fas/ Fas ligand pathway. Fas ligand in the T cell binds to Fas on the graft cell inducing apoptosis. At the same time CD4 T cells activate B cells via the CD40/CD40 ligand pathway which help B cells transform into antibody producing plasma cells that cause complement mediated damage to the graft cells.

  • The type and grade of rejection can be defined by the Banff criteria. The Banff criteria are an attempt to standardize rejection criteria in order to facilitate therapeutic studies across various centers. Rejections may be humoral, cellular or a combination of both.

    • Humoral rejection: Requires evidence of circulating antibody, either by assay or C4D (a complement split product) detection on biopsy tissue, histological evidence of tissue injury and allograft dysfunction.

    • Cellular rejection: Appears as lymphocytic interstitial inflammation and lymphocytic cells infiltrating the tubular basement membrane (tubulitis) of varying degrees along with allograft dysfunction.

Immunosuppressant medications

Induction agents: Used to decrease the risk of rejection early post transplant when it is the highest. These agents can be classified as depleting or non-depleting agents.

  • Depleting agents

    • Polyclonal agents/antithymocyte globulin: The most commonly used anti-thymocyte globulin is procured from rabbits (Thymoglobulin®). It is used as an induction agent or to treat severe rejection and results in a profound lymphopenia. Thymoglobulin® decreases the risk of acute cellular rejection however, increases the risk for infections and malignancy. Side effects include infusion reactions (fever, rigors, dyspnea), leucopenia, thrombocytopenia and rarely serum sickness. Methylprednisone, tylenol and benedryl should be prescribed to reduce infusion reactions. It is usually dosed 1.5 - 2mg/kg/day as an IV infusion over 4-6 hours. The total dose of thymoglobulin® is 6-10 mg/kg for induction and 8-12 mg/kg to treat rejection

    • Alemtuzumab (Campath 1H®) - Alemtuzumab is a monoclonal anti-CD52 antibody found on T-cells, B cells, monocytes, macrophages and eosinophils. Mechanism of action includes antibody-dependent cellular toxicity (ADCC), complement dependent cytotoxicity (CDC) and apoptosis all of which result in profound lymphopenia. Its use is associated with an increased frequency of infections. However, recent publication from the INTACT study group revealed similar incidence of infections when compared to rabbit-antithymocyte globulin when used in a steroid withdrawal protocol. Infusion reactions include, fever, rigors hypotension and dyspnea which can be minimized with pre-medication. Alemtuzumab can be given IV or SQ over 2 hours for a total dose of 30-40 mg.

    • Rituximab - Rituximab is an anti-CD20 monoclonal antibody approved for use in CLL. It results in profound depletion of B cells. It has been associated with progressive multifocal leukoencephalopathy (PML) in patients with Lupus and increases the risk for severe infections in transplant recipients when given with thymoglobulin. It is used in patients with pre-transplant donor specific antibodies, in desensitization protocols, to treat post transplant lymphoproliferative disease (PTLD) or as a treatment for antibody mediated rejection. Potential infusion reactions include hypotension, fever, tachycardia and arthralgias.

  • Non-depleting agents

    • Anti-CD25 antibodies: Basiliximab is a humanized murine antibody with low immunogenicity which causes reversible blockade of CD25. As an induction agent it reduces the risk of rejection especially in low to moderate risk individuals. It is almost devoid of side effects and is given as a dose of 20 mg on days 0 and 4 post transplantation.

    • Intravenous Immunoglobulin (IVIg): Pooled human blood product use to "neutralize" pre-existing anti-donor antibodies. IVIg has many immunomodulatory activities including decreasing antibody production, anti-idiotypic antibodies, and neutralizing complement. Side effects include clotting and headache. It is sometimes used as an induction agent for patients with a positive crossmatch and/or those with donor specific preformed HLA antibodies.

Calcineurin inhibitors (CNIs), cyclosporine and tacrolimus: Cyclosporine binds cyclophilin and tacrolimus binds FK binding protein. The resulting complex binds with calcineurin which does not permit dephosphorylation of NFAT preventing it from entering the nucleus. This in turn impairs expression of several cytokine genes that promote T-cell activation and proliferation especially IL-2, IL-4, IFN-gamma, TNF-alpha. Therapeutic levels of cyclosporine and tacrolimus reduce calcineurin activity by about 50%. CNI are not myelosuppressive. Cyclosporine and tacrolimus are also available as generic formulation.

  • Are all formulations of CNI the same?

    • The different formulations of cyclosporine have different bioavailability and therefore should not be interchanged. Lipid emulsified formulations (Neoral, Gengraf) have been developed improving adsorption and leading to more predictable bioavailability.

  • How are cyclosporine and tacrolimus different?

    • Tacrolimus is a more potent immunosuppressive and has a slightly different adverse effect profile when compared to cyclosporine (see Table 1).

  • Nephrotoxicity: Nephrotoxicity can be divided into acute hemodynamic decrease in glomerular filtration rate (GFR) from vasoconstriction on the efferent and afferent glomerular arterioles and chronic renal insufficiency seen with long term use of CNI’s. The acute form of CNI toxicity is related to the CNI level and reversible with dose reduction. Chronic CNI toxicity is manifested by "striped" fibrosis and eccentric hylanosis of arterioles. This is best demonstrated in non-renal solid organ recipients maintained on CNI where the incidence of CKD IV ranges between 7 to 21% at 5 years post transplantation. The exact mechanism of chronic CNI toxicity is incompletely understood but may be related to chronic ischemic nephropathy. Another rare form of CNI nephrotoxicity is thrombotic microangiopathy.

  • What drug/food interactions do I need to be aware of when using the calcineurin inhibitors?

    • Many drugs and foods can either increase or decrease the metabolism of calcineurin inhibitors. In addition diarrhea has been shown to increase the trough values of tacrolimus which is thought to be mediated by loss of P- glycoprotein, an enzyme which metabolizes tacrolimus, on the gut mucosa.

    • Common interactions that increase the levels of CNI's (see Table 2) and decrease the level of CNI's (Table 3).

  • Other drug interactions

    • Combination of CNIs and HMG CoA reductase inhibitors (statins) increase the risk for rhabdomyolysis. Generally only 50% of maximal recommended dose of statin should be used. Simvastatin is contraindicated in patients on CNIs.

    • Sirolomus increases total drug exposure (AUC) of CNI's without raising trough levels.

  • Dosing: Both the therapeutic efficacy and toxicity of tacrolimus and cyclosporine vary based on drug exposure. Twelve-hour trough levels correlated to drug exposure and are important monitoring parameters. Two-hour cyclosporine peak levels may correlate better with drug toxicity and exposure (area under the curve (AUC)). Genetic factors play a role in CNI metabolism and there is considerable inter-patient variability of trough levels obtained with a given dose. Children and African Americans are often rapid metabolizers of tacrolimus and may require TID dosing or adjuvant medications to boost the trough level.

    • Tacrolimus: The initial oral dose of tacrolimus varies from 0.15 to 0.3mg/kg/day divided in two doses. The first 3 months' trough levels should be between 7 to 15 ng/ml then 5 to 10 months 3 to 12 then 3 to 8 thereafter.

    • Cyclosporine: The initial oral dose is 6 to 10 mg/kg/day divided into two doses, then maintained based on trough levels.

      • Trough levels: Suggested levels are 200 - 350 ng/ml for the first 3 months, 100 - 250 ng/ml from 3 to 12 months then 50 -150 thereafter.

    • Intravenous dosing: Both cyclosporine and tacrolimus can be administered IV. The intravenous dose should be given as 1/3rd the total daily oral dose infused over 24 hours.

    • What if I am unable to obtain the target trough despite very high doses of tacrolimus?

      • These patients should take tacrolimus on an empty stomach to improve absorption. In addition patients may require additional medications used to boost the tacrolimus level (ex. diltiazem or ketoconazole) or require TID dosing. It is important to realize that TID dosing results in 8 hour troughs which may not correlate as well as 12 hour troughs with drug toxicity.

Table 1.

Adverse effects of tacrolimus versus cyclosporine
Adverse Effect Comments
Nephrotoxicity Seen with rental trasnplantation and non-renal solid organ transplant recipients
Cardiovascular Hypertension Hypercholesterolemia Tacrolimus-treated patients may require fewer antihypertensive agents and less lipid lowering agents.
Glucose intolerance Tacrolimus is more pancreas islet toxic and results in more post transplant diabetes.
Neurotoxicity Tremor Headache Insomnia Parasthesia Seen more often with tacrolimus and generally improves with dose reduction.
PRES (posterior reversible encephalopathy sydrome) Clinical/radiographic syndrome of headache, confusion, visual changes, and seizures, with radiographic evidence of posterior cerebral white matter swelling. Reported more often with cyclosporin.
Cosmetic Gingival hypertrophy Hirsutism Alopecia Gingival hypertrophy and hirsutism are associated with cyclosporine.Steroid use may exagerate hirsutism and calcium channel blockers can exacerbate gingival hypertrophy.Alopecia may occur with tacrolimus
Malignancy Incidence appears to be a function of overall amount and duration of immunosuppression rather than from any specific agent

Table 2.

Interactions that increase CNI level
Non-Dihydropyridine calcium channel blockers Diltiazem
Verapamil
Antibiotics Erythromycin
Clarithromycin
Antifungal agents Voriconazole (requires 1/3 dose reduction of CNI)
Itraconazole
Clotrimazole
Cardiovascular drugs Amiodarone
Ranolazine
Antiviral agents Protease inhibitors (extreme effect sometimes requiring weekly dosing of tacrolimus)
Foods Grapefruit and grapefruit juice

Table 3.

Interactions that decrease CNI level
Antibiotics Rifampin
Rifabutin (less so than rifampin)
Terbinafine
IV trimethoprim
IV sulfadimidine
Imipenim
Anticonvulsants Barbituates
Phenytoin
Carbamazepine
Ticlopidine
Octreotide
Nefazodone
Herbal medications St. John's Wart

Mammalian Target of Rapamycin (mTOR) inhibitors

  • Sirolimus (rapamycin) -. MTOR inhibitors bind FK binding protein which then binds to the target of rapamycin (TOR). Inhibiting mTOR prevents signal transduction through several growth factor receptors such as IL-2 thereby inhibiting cell-cycle progression and immune activation. As a class mTOR tend to be less immunosuppressive than the CNI's but stronger than other anti-proliferative agents. In addition, many cell lines depend upon the MTOR pathway for proliferation leading to numerous side effects which often limit the use of this drug but have a benefit in certain malignancies such as skin cancer, Kaposi's sarcoma and renal cell carcinoma.

    • Side effects related to inhibiting MTOR: apthous ulcers, GI toxicity, mucositis, leukopenia, thrombocytopenia, poor wound healing, lymphoceles. These effects are typically dose dependent.

    • Other side effects: severe hyperlipidemia, non infectious idiopathic pneumonia (BOOP), severe hyperlipidemia (esp. triglycerides), anemia, thrombocytopenia, myelosuppression.

    • Nephrotoxicity: Sirolimus has been found to induce or worsen pre-existing proteinuria possibly be affecting podocytes in the glomerulus. It may also lead to hypokalemia and magnesium wasting. In addition, combining sirolimus with CNI's increases total drug exposure resulting potentiating CNI toxicity. Sirolimus has also been shown to result in thrombotic microangiopathy.

    • Dosing: Sirolimus has a half-life of 62 hours which allows once daily dosing. It is usually started at a loading dose of 2-10mgs then continued at 2-5mg/day. Similar to the CNI's trough levels correlate to therapeutic activity and toxicity. Sirolimus should be administered 4 hours after the morning CNI dose to reduce nephrotoxicity. Target trough levels vary depending on other agents it is being used with and will be discussed in the immunosuppressive protocols section.

      • Combined with CNI's: Sirolimus should be administered 4 hours after the morning CNI dose to reduce nephrotoxicity. Target troughs are 5-10 ng/ml with CsA levels of 50 to 100 ng/ml and tacrolimus levels of 3-6 ng/ml.

      • Combined with MMF: The optimal trough ranges from 5 to 25 ng/ml depending on when it is used. When used in CNI conversion strategies target trough ranges from 5 to 12 ng/ml. Optimal timing and dosing will be discussed in the immunosuppressive protocols section.

  • Everolimus: Same mechanism of action as sirolimus but it has a shorter half life of 23 hrs which requires twice a day dosing. It is approved for treating renal cell carcinoma, and for kidney transplant recipients in the United States when combined with basiliximab induction, cyclosporine and corticosteroids. Side effects are similar to sirolimus.

    • Dosing: Everolimus dosing is recommended at 0.75 mg BID then adjusted by trough. Target troughs are similar to sirolimus (see immunosuppressive protocols).

Glucocorticoids: Their mechanism of action involves binding to DNA regulatory sequences called glucocorticoid-responsive elements. These elements include sequences in the promoter regions of several cytokine genes and effects are exerted on many cell types. At high doses (pulse steroids) they are directly lympholytic and at low maintenance doses their immunosuppressive mechanism is probably nonspecific and anti-inflammatory.

  • Side effects: Glucocorticoids have been long known to have many side effects. Immediate effects include psychosis, myopathy and hyperglycemia while side effects related to cumulative and long term dosing include diabetes, weight gain, hyperlipidemia, hypertension, osteopenia, and avascular necrosis among others.

  • Dosing: Glucocorticoids are given at doses of 250 - 1000 mgs for the first few days post transplant then usually tapered to 5mgs per day by 3 months. Rapid steroid withdrawal dosing involves high doses that are tapered off in 3 to 7 days.

Antimetabolites

  • Azathioprine: This pro-drug of 6-mercaptopurine is one of the earliest used immunosuppressive agents in transplantation. It has been largely replaced by mycophenolate mofetil (see below). It works by inhibiting the formation of phosphoribosyl pyrophosphate which is needed in purine synthesis, thereby preventing cell proliferation.

    • Side effects: The most serious side effect is myelosuppression leading to leukopenia, anemia and thrombocytopenia. It also may lead to cholestatic hepatotoxicity. As azathioprine is degraded by xanthine oxidase it should never be used with an inhibitor of xanthine oxidase - allopuriol or febuxostat (Uloric).

    • Dosing: The typical dose is 1 - 2 mg/kg per day when combined with a CNI. The dose should be reduced if WBC count is less than 3,000.

  • Mycophenolate Mofetil (MMF) and enteric-coated Mycophenolate sodium (Myfortic®): MMF is a prodrug of mycophenolic acid which inhibits IMPDH - an enzyme needed for de novo purine synthesis. Purine synthesis can occur by two pathways, the de novo and salvage pathway in most cells, except in lymphocytes. It results in impairment of both T and B cell proliferation, inhibits generation of cytotoxic T cells, decreases adhesion molecule function and decreases antibody production. Myfortic® is enteric coated MPA which results in delayed release of MPA at the level of the small bowel in an attempt to decrease gastrointestinal symptoms. It should be avoided in patients with known gastroparesis.

    • Side effects: The most common side effect of MPA is GI toxicity manifested by nausea, bloating and or diarrhea. Rarely it may lead to mouth and colon ulceration necessitating cessation of the medication. It is also myelosuppressive leading to leukopenia, anemia and thrombocytopenia. The side effect profile of Myfortic tends to be similar to MMF.

    • Dosing: 1gm of MMF is equivalent to 720 mg of Myfortic®. MPA exposure is reduced with CsA but not with tacrolimus therefore patients on tacrolimus may require less MMF. The dose should be reduced if WBC count is less than 3,000.

Co-stimulation blockade

  • Belatacept: Belatacept is a selective co-stimulation blocker (given IV), which binds surface costimulatory ligands (CD80 and CD86) of antigen-presenting cells. It inhibits T-cell activation, promoting anergy and apoptosis. Studies using it de novo as well as converting from CNI based to belatacept based immunosuppression have revealed a higher incidence of rejection compared with CNI’s when combined with MMF and prednisone; however better GFR. The major concern with Belatacept is an increased risk for post transplant lymphoproliferative disease and the lack of long term data. It is contraindicated in EBV seronegative patients or patients with unknown EBV serostatus as they have a higher risk of PTLD.

    • Belatacept is administered IV over 30 minutes and the recommended dosing is 10 mg/kg on the day of transplantation then on day 5, then at the end of weeks 2, 4, 8, and 12. After week 16 it is recommended that the maintenance dose be 5 mg/kg every 4 weeks. When converting from CNI to to belatacept the studied dose is 5mg/kg IV on day 1, 15, 29, 43, 57 then every 28 days thereafter.

Immunologic risk assessment

  • Recipient Age: Younger recipients are in general at higher risk for immunologic injury than the elderly.

  • Recipient Ethnicity: African Americans have been reported to a higher incidence of rejection episodes and overall graft loss despite correction for socio-economic status.

  • Recipient with HIV infection: Patients with HIV tend to be at a higher risk for rejections and graft loss compared to age matched controls.

  • Degree of HLA matching: The degree of HLA matching impacts the expected risk of rejection and graft survival in kidney transplantation. Historically the most important HLA antigens have been HLA A, B, and DR. A perfect match using only these antigens would be referred to a 0 antigen missmatch or a "6" antigen match. This is in contrast to an HLA identical transplant where all HLA antigens, including Cw, DQ and DP, are the same (sibling). With deceased donors greater HLA mismatches clearly increase the risk for graft loss. Zero antigen mismatch kidney recipients have a graft half life of 16 years whereas 5 to 6 antigen mismatch recipients have a graft half life of about 10 years. With living donor transplantation an HLA identical kidney transplant carries the lowest risk of rejection and best graft survival (half life 26 years) whereas smaller degrees of HLA mismatch do not seem to matter (half life 15-18 years).

  • Panel reactive antibody (PRA): PRA is an approximation of preformed HLA antibodies the recipient has against the donor pool. Patients with a higher PRA are sensitized and carry a higher risk for chronic rejection and graft loss even in the absence of anti-donor specific antibodies. This was best seen in the Collaborative study where outcome of 4048 HLA identical transplants were stratified by recipient PRA. Patients with a zero PRA had a 10 year graft survival of 72%, 1-50% PRA of 63% and patients with a PRA of greater than 50% had a graft survival of 56%. This suggests that non-HLA or minor HLA antibodies play a role in long-term allograft survival.

  • Pre-formed donor specific antibodies (DSA): The different methods to determine DSA will be described below ("What tests to perform" section). in general, the more sensitized the recipient is against donor HLA molecules the higher the risk for rejection and subsequent graft failure.

  • Donor organ (deceased versus living donor): Deceased organ source carries both a higher risk for rejection and graft loss as compared with living donation transplantation. This is thought to occur due to ischemia reperfusion injury and the detrimental effects of brain death. Patients with delayed graft function are at a higher risk for rejection and graft loss than those with immediate function.

  • Time on dialysis: Pre-emptive living donor transplants carry the lowest rate of rejection and the best organ survival. Time on dialysis has been shown to have a dose related effect on allograft outcome in deceased donor organ transplantation.

  • Time elapsed since transplant: The highest risk for rejection is within the first year post transplant. It is believed that there is some degree of graft “accommodation” that occurs as time passes after transplantation therefore reducing the requirement for aggressive immunosuppression.

Immunosuppressive protocols

Most protocols consist of induction therapy then maintenance immunosuppression with a CNI (tacrolimus or cyclosporine), an anti-proliferative agent (MMF or azathioprine) with or without maintenance prednisone. Protocols using sirolimus include combining it with an anti-proliferative agent and prednisone or combining it with a CNI and prednisone. Finally the recent FDA approval of belatacept introduces a novel protocol of belatacept combined with MMF and prednisone.

What is the most commonly prescribed immunosuppression?

Induction therapy

  • Based on data collected and analyzed up to 2008 by the Scientific Registry for Transplant Recipients (SRTR), 82% of patients received induction therapy. Thymoglobulin was used most commonly (44%) followed by anti-CD25 (28%) then alemtuzumab in 10% of cases.

Maintenance Immunosuppression

  • The ELITE-Symphony study demonstrated maintenance with low-dose tacrolimus (target trough 3 to 7 ng/ml) to have lower rejection rates and best graft survival as compared to low dose cyclosporine (target trough 50 to 100 ng/ml), standard dose cyclosporine (target trough 150-300 ng/ml first 3 months then 100-200 ng/ml thereafter) and sirolimus (target trough 4 to 8 ng/ml) when accompanied by MMF and prednisone. The results of this study have popularized low dose tacrolimus with MMF and prednisone as is seen by the vast majority of patients on this protocol.

  • In 2008 the most commonly prescribed immunosuppressive regime at discharge after transplantation was the combination of tacrolimus, MMF/MPA, and steroids (54% of patients) followed by Tacrolimus, MMF/MPA (28%), and cyclosporine, MMF/MPA (4.5%).

  • Sixty-six percent of patients were discharged on steroids, 88% of patients were discharged on tacrolimus, 7% of patients on cyclosporine, 74% on MMF, 19% on Myfortic, and 4% on sirolimus.

When and what to use as an induction agent?

  • Induction therapy is given to reduce the risk of acute rejection and to allow drug minimization. Data from the Thymoglobulin Induction Study Group revealed a lower risk of rejection as compared to anti-CD25 in deceased donor organs at high risk for acute rejection, although at a higher cost of malignancies and infections. Alemtuzumab is also a potent induction agent used in minimization protocols, which was recently shown (INTACT study group) to reduce the risk of rejection in low risk patients when compared to basiliximab and had a similar rate of rejection, although more late rejection, in high risk patients when compared to Thymoglobulin®.

  • The choice of the induction agent should be based on immunologic and infectious risks. Low risk patients may benefit from basiliximab where higher risk may benefit from Thymoglobulin® or alemtuzumab. An alternate approach to the low risk patient is induction with antithymocyte globulin or alemtuzumab and minimize immunosuppression post transplantation. Patients on steroid withdrawal protocols receive an induction agent at the time of transplantation.

What is the optimal dose of dose of CNI?

  • Target CNI troughs can be adapted from the ELITE Symphony trial when combined with MMF and prednisone (tacrolimus 3-7 ng/ml, cyclosporine 50 to 100 ng/ml) in low risk patients. In general, the target troughs should be decreased with time post transplant and high risk patients (repeat transplant, donor specific antibody present) may require higher troughs (see dosing guidelines under immunosuppressive medications).

Which CNI should I use?

  • Trials comparing tacrolimus to cyclosporine have revealed decreased rejection rates in the tacrolimus arm. However, the majority of these trials compared Sandimmune (not a microemulsification of cyclosporin) to tacrolimus. Even better matched studies reveal advantages of tacrolimus in higher risk patients such as those with delayed graft function and African Americans. The enhanced immunosuppression of tacrolimus may be related to higher drug exposure to MMF as compared to CsA. If patients do not tolerate or cannot afford tacrolimus, cyclosporine remains a good alternative.

Which antiproliferative agent should I use?

  • The addition of sirolimus to a CNI is nephrotoxic and suggested in patients who do not tolerate other antimetabolites and are at high risk of rejection on CNI monotherapy.

    MMF has been shown to decrease the risk of rejection compared to azathioprine, and tends to be less myelosuppressive and hepatotoxic. Azathioprine is an acceptable alternative to MMF especially in patients who cannot afford MMF or do not tolerate it due to GI toxicity.

What is the optimal dose of MMF/MPA?

  • In most studies patients are started on the equivalent of 1gm of MMF twice a day (360mg Myfortic is equivalent to 500 mg of MMF). In patients discharged off of steroids absorption of MMF is improved and these patients may be candidates for maintenance with a lower dose of MMF. Stable low to moderate risk patients who received induction and tacrolimus can often be safely lowered to 500mgs BID of MMF in 6 months to 1 year post transplant.

What is the best protocol for higher risk patients?

  • High risk patients benefit from induction therapy, of which the most potent is rabbit antithymocyte globulin or alemtuzumab. In addition those with donor specific antibodies may require IVIg, rituximab, and occasionally plasma exchange (depending on the strenght of antibody). The protocol with the best data for reduction in acute rejection is tacrolimus, MMF/ MPA and corticosteroids.

What is the best protocol for low risk patients?

  • Monozygotic HLA- identical transplant: These patients do not need induction or long term immunosuppression. Most patients can be given an antimetabolite and prednisone with or without low dose CNI which can be withdrawn within 3 months post transplant.

  • HLA identical transplant (not from monozygotic twin): One approach to immunosuppression is no induction, or induction with basiliximab along with low dose tacrolimus and MMF 500 mgs BID. Alternative approaches include maintenance immunosuppression with only MMF and prednisone or MMF monotherapy. A prospective study treated twenty HLA-identical transplant recipients with MMF, tacrolimus and sirolimus which were tapered off by one year post transplant, leaving patients on MMF monotherapy (at a dose of 1000 mg BID). At a median follow up of 633 days there was 100% graft survival and no rejection episodes. This approach has the benefit of avoiding long term CNI toxicity.

  • Zero antigen mismatch deceased donor transplant: We suggest induction with basiliximab and maintenance with tacrolimus and MMF 500 milligrams twice a day.

It is important to realize that there is no clear evidence to support steroid withdrawal over standard steroids or basiliximab over antilymphocyte globulin. Deciding on immunosuppression should be based on risk of rejection versus infection and malignancy.

When is rapid steroid withdrawal a good option?

  • Rapid steroid withdrawal (usually within 4-7 days after transplantation) is a reasonable option in low to moderate risk patients. Steroid withdrawal has shown good 5 year graft survival albeit with a slightly higher rate of acute rejection. The use of rabbit antithymoglobulin and alemtuzumab has resulted in lower rejection rates then anti-CD25. Prospective studies show small benefits with RSW protocols including a reduction of insulin requiring diabetes, a small decrease in weight gain and reduced incidence of bone disease (combined endpoint of AVN plus fractures) in patients maintained off of steroids.

Is it possible to withdraw steroids after 3 to 6 months post transplant?

  • Studies of steroid late withdrawal have revealed an elevated risk of rejection and graft failure. This was largely reported in the era of cyclosporine, and data with modern immunosuppression (antithymocyte globulin induction with tacrolimus and MMF) is lacking. In patients with significant steroid toxicity it is reasonable to slowly withdraw steroids when patient receive tacrolimus and MMF.

If my patient has a rejection episode should I resume chronic steroids?

  • It is not necessary to resume steroids after one low to moderate rejection episode.

When are the mTOR inhibitors a good drug to use?

  • Studies reveal inconsistent results when using sirolimus as the initial immunosuppressive agent as compared to CNI’s. Several single center studies reveal comparable patient and graft survival in patients on sirolimus and MMF compared to CNI’s. However, a multicenter trial has been halted due to higher than expected rejection rates in patients receiving sirolimus and MMF. In addition, the randomized multicenter ELITE-Symphony study revealed the worst rejection rate and graft survival in patients treated with low-dose sirolimus (target trough 4 to 8 ng/ml) combined with MMF and corticosteroids compared to CNI’s with MMF and prednisone. Finally SRTR analysis of transplants between 2000 and 2005 reveal the lowest 5 year survival in patients on sirolimus/ MMF compared to CNI’s and MMF.

  • Poor wound healing and lymphoceles also complicate the de novo use of mTOR inhibitors. Due to conflicting data and post operative complications mTOR inhibitors are usually not used as a de novo immunosuppressive agent.

  • The combination of an mTOR inhibitor and CNI is more immunosuppressive than sirolimus and MMF but infrequently used due to enhanced nephrotoxicity. This combination may be an acceptable treatment option in a high risk individual that does not tolerate other antimetabolites.

  • Specific cohorts who benefit from conversion are patients who do not tolerate CNI side effects, have significant CNI toxicity on biopsy or malignancy (Kaposi’s sarcoma or skin cancer).

  • Conversion from CNI to mTOR inhibitor is discussed below.

Is it ok to change to generic formulations of CNI’s and MMF?

  • Generic medications are the same medication as the brand drug, but may differ in bioavailability (80% and 125% of that of the brand medication). Therefore close monitoring of therapeutic drug levels and renal function should be performed when converting.

When should I convert from a CNI to mTOR inhibitor?

Converting CNI to an mTOR inhibitor has been proposed as a method to reduce long-term nephrotoxicity of CNI’s while avoiding the immediate post op period, where outcomes are inferior with mTOR inhibitors. The large multicenter CONVERT trial found conversion to sirolimus at 6 to 12 months post transplant to be detrimental in patients with proteinuria and/or GFR < 40 ml/min. In addition there was a higher discontinuation rate in the sirolimus group.

More recent data from two multicenter trials converting CNI to sirolimus and everolimus in low risk patients prior to 6 months post transplant revealed comparable GFR in the mTOR group with a similar rejection rates. Target mTOR troughs in these studies were 5 to 10 ng/ml for sirolimus and 6 to 10 ng/ml for everolimus. Taken together conversion seems to be a reasonable approach in treating low risk patients with preserved GFR and no proteinurea, in addition to patients with histologic evidence of CNI toxicity or malignancy (Kaposi's sarcoma, skin cancer).

What tests to perform?

The ability to assess the degree of immunosuppression is limited. However, pre-transplant testing can be very informative on post transplant immunologic risk. Immune assays are currently being validated to determine net immunosuppression.

Pre-transplant immunologenetic testing

HLA: HLA analysis is currently being performed by DNA based methods (sequence specific primer PCR (SSP), sequence specific oligonucleotide probes (SSOP). Currently tested class I HLA alleles include A, B and sometimes Cw. Tested class II loci include DR, DQ and sometimes DP. The degree of HLA matching impacts the risk of rejection and graft survival in kidney transplantation.

Detection of HLA antibodies, panel reactive antibody (PRA) and donor specific antibodies (DSA): PRA is an approximation of preformed HLA antibodies the recipient has against the donor pool. Donor specific antibodies (DSA) are antibodies against donor HLA antigens. Various methods are available to determine both PRA and DSA.

  • CDC crossmatch: Donor lymphocytes are mixed with recipient sera, exogenous complement and a vital dye. If greater than 10% of the donor cells are killed then the crossmatch is positive. Positive T-cell crossmatch implies cytotoxic antibody against donor class I antigens while a positive B-cell crossmatch implies cytotoxic antibodies against either class I antigens, class II antigens or surface Fc receptors found on the B cell membrane. Positive T – cell crossmatch is a contraindication to transplantation because of the very high risk for hyperacute rejection. Positive CDC B cell crossmatch is less specific however, does indicate a higher risk of rejection when DSA is confirmed by other methods. CDC crossmatch is repeated after heating serum or adding dithiothreitol (DTT) which removes IgM antibodies. IgM antibodies are usually auto-antibodies and are not detrimental to the transplanted organ. Anti-human globulin (AHG) is now usually being added before complement to increase the sensitivity of the crossmatch.

  • CDC PRA: To Recipient sera is added to a panel of 30 to 60 cells representing most antigens encountered in the general population. Similar to CDC crossmatch, complement and vital dye is added. The amount of dead cells are quantified and PRA is calculated. For example, if 15 of 30 wells contain dead cells the PRA is 50% implying that the patient has antibodies against 50% of the population. PRA greater than 80% is considered highly sensitized. Sensitized individuals experience greater time waiting for a compatible donor and are at higher risk for rejection and graft failure.

  • Flow crossmatch: Donor lymphocytes are incubated with patient sera and stained with fluorescence-labeled anti-IgG then run through a flow cytometer. Positive flow crossmatch implies recipient anti-HLA antibodies binding to donor lymphocytes (T or B cells depending on the type of lymphocytes chosen). It is more sensitive than the CDC crossmatch but less specific for predicting rejection. T crossmatch confers a high risk for rejection while B is less specific.

  • Solid phase assays: Either antigen coated trays (ELISA) or antigen coated synthetic microbeads are used to determine specific HLA antibodies. Elisa is about 10% more sensitive in determining HLA antibody than AHG CDC methods and microbead technology is about 10% more sensitive than ELISA.

    • ELISA method: Recipient sera are added to pre-specified antigen coated trays which can be used to determine the presence of specific HLA antibodies.

    • Synthetic microbeads with recombinant HLA molecules: Recombinant HLA molecules are combined to synthetic beads that display a unique fluorescent pattern (Luminex platform). Depending on the platform, there may be multiple HLA antigens on one bead or a specific HLA antigen on each bead. Recipient sera are added along with fluorescence-labeled anti-IgG then run through either a traditional flow cytometer or on the Luminex platform. The result will be an estimation of HLA antibodies the patient has against the donor pool or, in the case of single antigen beads, specific HLA antibodies in the patients’ serum. Though initially developed as a qualitative test, single antigen bead results are given as a “mean fluorescent intensity (MFI)” which is being used in a semiquantitative manner to determine antibody strength.

Important labs in the post transplant period

CBC with differential: Leucopenia may result from immunosuppressants as well as viral infections (ex. CMV) and malignancy. Commonly attributed medications are anti-thymocyte globulin, alemtuzumab, MMF, azathioprine, pepcid and valgancyclovir. In general CNIs are not myelosuppressive. Total white blood cell count under 3,000 should result in a dose reduction of MMF and azathioprine.

BK virus PCR: BK virus is a prion virus, related to JC virus, known to cause nephropathy in kidney transplant patients. It can be measured in the blood by PCR, which correlates with BK nephropathy, or in the urine which is more sensitive but less specific in predicting nephropathy. BK viremia is a disease of over-immunosuppression and is treated mainly by reducing immunosuppression.

Histolopathology

Allograft biopsy: Biopsy is used to detect rejection episodes and polyomavirus nephropathy. High risk patients may benefit from protocol biopsies to screen for subclinical rejection or features of chronic rejection. Chronic rejection appears as double contouring of the glomerular basement membrane similar in appearance to MPGN. The pathologic term to describe chronic rejection is transplant glomerulopathy. It is often due to HLA antibodies and usually demonstrates positive C4D (complement split product released during classic cascade activation) staining.

Controversies in diagnostic testing

Monitoring donor specific antibodies (DSA): Donor specific antibodies may be present before transplantation (as in sensitized patients) or may arise de novo in the post transplant period. There are many methods to monitor though due to limited donor cells, is often performed by solid phase assay (Luminex). Most studies have shown persistence or a rise in pre-existing DSA, and de novo DSA, to be detrimental to allograft survival as they probably signify low grade chronic antibody mediated rejection. However, it unknown if increased immunosuppression reduces the appearance of HLA antibodies or if increasing immunosuppression after the appearance of de novo HLA antibodies improves graft survival.

Cylex ImmunKnowAssay®: This assay is FDA approved and commercially available. Recipient T cells are stimulated with a T cell mitogen, PHA. The amount of ATP produced from the T cell is quantified and is proportional to T-cell reactivity. Low ATP production has been associated with opportunistic infections, however no prospective data exists on changing immunosuppression based solely on this assay.

Virtual Crossmatch and calculated PRA (cPRA)

By knowing specific HLA antibodies present in a patient's serum and a donor's HLA type, we can anticipate positive crossmatches and calculate a PRA value. For example is a patient has a strong antibody to HLA A2 we can infer that a crossmatch with a donor expressing HLA A2 would be positive. We can then avoid crossmatching the patient with any donors with HLA A2, which is considered a virtual crossmatch. Since HLA A2 is present in 47% of the donor pool we would be removing 47% of available donors for this patient. Therefore the cPRA would be 47%. cPRA has been implemented by UNOS as a means for reducing time and resources spent on crossmatching sensitized patients.

How should patients with too much or too little immunosuppression be managed?

Too much immunosuppression: Patients on triple therapy should have prednisone tapered to 5 mg, and may benefit from reducing the dose of the antimetabolite or target CNI trough. Replacing CNI with an mTOR inhibitor may be beneficial in certain patients. In general, late steroid withdrawal is not recommended but may be attempted in patients with significant steroid related morbidity.

Too little immunosuppression: Potential approach in increasing immunosuppression include increase target CNI trough, change from cyclosporine to tacrolimus, increase anti-metabolite dose, or resume steroids in patients on steroid free protocols.

What happens to patients with too much or too little immunosuppression?

Unfortunately it is often difficult to ascertain whether an individual patient has the ideal amount of immunosuppression.

  • Acute rejection episodes: Patients under-immunosuppressed may demonstrate multiple episodes of acute rejection which is one of the strongest predictors of chronic allograft nephropathy (now known as interstitial fibrosis and tubular atrophy (IF/TA). Early low grade rejection episodes which are treated may not affect long term outcome whereas late or aggressive rejection episodes lead to premature allograft failure.

  • Chronic rejection: Patients under-immunosuppressed may demonstrate pathologic changes consistent with transplant glomerulopathy. Transplant glomerulopathy is often mediated by the humeral immune system but cases without apparent humoral rejection have been described.

  • De novo HLA antibodies: See controversies in diagnostic testing

  • Infections: Over-immunosuppressed patients are often characterized by recurrent infections not explained by anatomic abnormalities. In addition patients with opportunistic infections > 6 months post transplant suggest over-immunosuppression. (Example. Late onset PCP pneumonia).

  • Polyomavirus: BK virus present in the blood and especially on pathologic examination is a marker for over-immunosuppression and should be treated with a reduction in immunosuppression.

How to utilize team care?

Taking care of the transplant patients can be difficult and involves participation of a multidisciplinary team.

  • The transplant center: Transplant centers include physicians and supportive caregivers who deal with the complexities of transplantation on a daily basis and possess a wealth of information in taking care of transplant recipients. In addition they may hold valuable information about the patients immunologic risk, anatomic details of their transplant, induction therapy and rationale for current immunosuppression.

  • Transplant pharmacists: Pharmacists play a substantial role in the multidisciplinary team and can provide valuable information in managing the complexities of dosing immunosuppression and the various drug- drug interactions.

  • The HLA laboratory: The HLA lab is the source of immunologic testing for the transplant center. They hold valuable information of the patients PRA, crossmatch and degree of HLA matching which will impact the decision on how much immunosuppression a patient will require.

  • Other important team members that may be involved in taking care of the transplant patient include dieticians, social workers, nurse coordinators, transplant surgeons and transplant nephrologists.

Are there clinical practice guidelines to inform decision making?

Guidelines

KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 9(Suppl 3):S1, 2009

The 2009 Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guidelines on the monitoring, management, and treatment of kidney transplant recipients offer guidelines in immunosuppressive management as well as other transplant related complications.

Limitations

Guidelines are based on data accumulated until 2009. Our recomendations often, but not always, corresponds with these guidelines.

What is the evidence?

Racusen, L.C., Solez, K., Colvin, R.B., Bonsib, S.M., Castro, M.C., Cavallo, T., Croker, B.P., Demetris, A.J., Drachenberg, C.B., Fogo, A.B., Furness, P., Gaber, L.W., Gibson, I.W., Glotz, D., Goldberg, J.C., Grande, J., Halloran, P.F., Hansen, H.E., Hartley, B., Hayry, P.J., Hill, C.M., Hoffman, E.O., Hunsicker, L.G., Lindblad, A.S., Yamaguchi, Y.. "The Banff 97 working classification of renal allograft pathology". Kidney Int.. vol. 55. 1999. pp. 713-23.

(This landmark article describes the creation of the Banff 97 classification for diagnosis of renal allograft pathology. The Banff criteria, now further modified, have allowed for standardization of renal allograft pathology which is used to guide therapy and to establish an objective end point for clinical trials.)

Delves, P.J., Roitt, I.M.. "The immune system. First of two parts". N Engl J Med.. vol. 343. 2000. pp. 37-49.

(This paper provides an essential understanding of all the major aspects of the immune system. It represents the first of two parts.)

Delves, P.J., Roitt, I.M.. "The immune system. Second of two parts". N Engl J Med.. vol. 343. 2000. pp. 108-17.

(This paper provides an essential understanding of all the major aspects of the immune system. It represents the second of two parts.)

Hariharan, S., Johnson, C.P., Bresnahan, B.A., Taranto, S.E., McIntosh, M.J., Stablein, D.. "Improved graft survival after renal transplantation in the United States, 1988 to 1996". N Engl J Med.. vol. 342. 2000. pp. 605-12.

(In this study, the authors analyze graft survival for 93,934 renal transplantations performed in the United States between 1988 and 1996. They demonstrate a substantial increase in short-term and long-term survival of kidney grafts from 1988 to 1996, as well as provide graft half lives for both living and deceased donor transplants.)

Klein, J., Sato, A.. "The HLA system. First of two parts". N Engl J Med.. vol. 343. 2000. pp. 702-9.

(This paper provides an essential understanding of all the major aspects of the HLA system. It represents the first of two parts.)

Klein, J., Sato, A.. "The HLA system. Second of two parts". N Engl J Med.. vol. 343. 2000. pp. 782-6.

(This paper provides an essential understanding of all the major aspects of the HLA system. It represents the second of two parts.)

Mange, K.C., Joffe, M.M., Feldman, H.I.. "Effect of the use or nonuse of long-term dialysis on the subsequent survival of renal transplants from living donors". N Engl J Med.. vol. 344. 2001. pp. 726-31.

(In this study, the authors evaluated the effect of long term dialysis on the subsequent survival of kidney transplants from living donors. After adjusting for confounding variables, pre-emptive transplantation was associated with a reduction of 52 percent in the rate of allograft failure during the first year after trans- plantation (P=0.002), a reduction of 82 percent during the second year (P=0.001), and a reduction of 86 percent during subsequent years (P=0.001).)

Cecka, J.M.. "The UNOS Renal Transplant Registry". Clin Transpl. 2002. pp. 1-20.

(This publication presents the overall one- and projected 10-year graft survival rates for deceased donor and living donor transplants based upon data reported to the UNOS Renal Transplant Registry between 1998-2001. The data is then further analyzed into cohorts of patients with repeat transplants, those who received expanded criteria donor kidneys, and within differing degree's of HLA matching.)

Goggins, W.C., Pascual, M.A., Powelson, J.A., Magee, C., Tolkoff-Rubin, N., Farrell, M.L., Ko, D.S., Williams, W.W., Chandraker, A., Delmonico, F.L., Auchincloss, H., Cosimi, A.B.. "A prospective, randomized, clinical trial of intraoperative versus postoperative Thymoglobulin in adult cadaveric renal transplant recipients". Transplantation.. vol. 76. 2003. pp. 798-802.

(This prospective randomized study compared the effect of intra-operative Thymoglobulin (before reperfusion of transplant) to postoperative Thymoglobulin administration on the incidence of delayed graft function. Intra-operative Thymoglobulin resulted in a lower incidence of delayed graft function and a lower mean serum creatinine on post operative days 10 and 14.)

Le Bas-Bernardet, S., Hourmant, M., Valentin, N., Paitier, C., Giral-Classe, M., Curry, S., Follea, G., Soulillou, J.P., Bignon, J.D.. "Identification of the antibodies involved in B-cell crossmatch positivity in renal transplantation". Transplantation.. vol. 75. 2003. pp. 477-82.

(In this study, the authors selected a retrospective cohort of patients transplanted with a positive B-cell CDC crossmatch and attempted to identify the antibody which lead to the positive result using a variety of assays. They found that 16% were due to auto-antibodies, 23% were due to HLA antibodies against class II antigens, and in 61% of cases the causative antibody was not identified. Compared to those patients with a negative B cell CDC crossmatch, graft survival in the positive B cell CDC crossmatch was worse if the positive crossmatch was attributable to class II HLA antibodies.)

Jordan, S.C., Tyan, D., Stablein, D., McIntosh, M., Rose, S., Vo, A., Toyoda, M., Davis, C., Shapiro, R., Adey, D., Milliner, D., Graff, R., Steiner, R., Ciancio, G., Sahney, S., Light, J.. "Evaluation of intravenous immunoglobulin as an agent to lower allosensitization and improve transplantation in highly sensitized adult patients with end-stage renal disease: report of the NIH IG02 trial". J Am Soc Nephrol.. vol. 15. 2004. pp. 3256-62.

(This landmark paper was a multicenter placebo controlled prospective randomized controlled trial evaluating both the effect of high dose intravenous immunoglobulin (IVIg) in lowering panel reactive antibody (PRA) in sensitized patients, and transplantation rate. The authors found that IVIg resulted in a temporary reduction of PRA but significantly improved transplantation rate compared to patients who received placebo.)

Ciancio, G., Miller, J., Gonwa, T.A.. "Review of major clinical trials with mycophenolate mofetil in renal transplantation". Transplantation. vol. 80. 2005. pp. S191-200.

(In this paper, the authors review the three major trials that lead to the approval of mycophenolate mofetil in kidney transplantation, including long-term follow-up data.)

Martins, P.N., Pratschke, J., Pascher, A., Fritsche, L., Frei, U., Neuhaus, P., Tullius, S.G.. "Age and immune response in organ transplantation". Transplantation.. vol. 79. 2005. pp. 127-32.

(In this paper the authors review papers that address the effect of both donor and recipient age on the incidence of rejection, graft survival and patient survival. In addition to clinical outcome data they review the science behind how age affects immunity.)

Lorber, M.I., Mulgaonkar, S., Butt, K.M., Elkhammas, E., Mendez, R., Rajagopalan, P.R., Kahan, B., Sollinger, H., Li, Y., Cretin, N., Tedesco, H.. "Everolimus versus mycophenolate mofetil in the prevention of rejection in de novo renal transplant recipients: a 3-year randomized, multicenter, phase III study". Transplantation.. vol. 80. 2005. pp. 244-52.

(This was a large randomized 3 year study evaluating two different doses of everolimus, 1.5 mgs and 3mgs per day, with cyclosporine and prednisone versus mycophenolate mofetil (MMF)with cyclosporine and prednisone. Importantly the protocol was amended after 1.5 years to target lower cyclosporine troughs and to measure everolimus troughs due to enhanced nephrotoxicity seen in this and other trials. At the conclusion of the study, everolimus was found to be as efficacious as MMF, although the side-effect profile featured increased adverse events.)

Brennan, D.C., Daller, J.A., Lake, K.D., Cibrik, D., Del Castillo, D.. "Rabbit antithymocyte globulin versus basiliximab in renal transplantation". N Engl J Med.. vol. 355. 2006. pp. 1967-77.

(This prospective, randomized international study compared rabbit anti-thymocyte globulin induction to basiliximab induction. The primary composite endpoint of biopsy proven acute rejection, delayed graft function, graft survival and patient survival at 12 months was similar in both groups. Rejection rates were significantly lower in the rabbit anti-thymocyte globulin group. The incidence of adverse events was similar in both groups.)

Ekberg, H., Tedesco-Silva, H., Demirbas, A., Vitko, S., Nashan, B., Gurkan, A., Margreiter, R., Hugo, C., Grinyo, J.M., Frei, U., Vanrenterghem, Y., Daloze, P., Halloran, P.F.. "Reduced exposure to calcineurin inhibitors in renal transplantation". N Engl J Med.. vol. 357. 2007. pp. 2562-75.

(The Efficacy Limiting Toxicity Elimination (ELITE)-Symphony study was initiated to assess whether a mycophenolate mofetil–based regimen would allow lower doses of adjunct immunosuppressive agents (e.g., cyclosporine, tacrolimus, and sirolimus) while maintaining an acceptable rate of acute rejection with less adverse effects. In this prospective multicenter randomized trial, four arms were compared: low dose tacrolimus, low dose sirolimus, standard dose cyclosporine, and low dose cyclosporine with basiliximab induction, MMF and prednisone. The tacrolimus group had the highest mean cGFR, lowest incidence of rejection, and best allograft survival at 12 months. Serious adverse events were the highest in the low dose sirolimus group.)

Woodle, E.S., First, M.R., Pirsch, J., Shihab, F., Gaber, A.O., Van Veldhuisen, P.. "A prospective, randomized, double-blind, placebo-controlled multicenter trial comparing early (7 day) corticosteroid cessation versus long-term, low-dose corticosteroid therapy". Ann Surg.. vol. 248. 2008. pp. 564-77.

(In this study, 5-year results from the first randomized, double-blind, placebo-controlled trial comparing early corticosteroid withdrawal to steroid maintainence. The authors found no differences in the proportion of patients experiencing: the primary end point (composite of death, graft loss, or moderate/severe acute rejection), patient death, death-censored graft loss, or moderate/severe acute rejection. Kaplan Meier analysis revealed higher biopsy confirmed acute rejection in the early corticosteroid withdrawal group. Corticosteroid withdrawal favored lower triglycerides, less weight gain, and similar new onset diabetes, but were less likely to require insulin.)

Hardinger, K.L., Brennan, D.C., Schnitzler, M.A.. "Rabbit antithymocyte globulin is more beneficial in standard kidney than in extended donor recipients". Transplantation.. vol. 87. 2009. pp. 1372-6.

(This study reanalyzed the data from a randomized international trial comparing the safety and efficacy of antithymocyte globulin and basiliximab in 278 deceased donor renal transplant recipients considered to be at high risk for acute rejection or delayed graft function. Here they specifically aimed to identify if antithymocyte globulin was more beneficial in patients receiving expanded criteria donors (those age > 60 or 50-60 with a history of HTN and renal insufficiency due to data limitations) compared to standard criteria donors or hypertensive donors. The authors found fewer antithymocyte globulin treated patients who received SCD donors who had an acute rejection and the combined triple primary endpoint of acute rejection, graft loss or death.)

Schena, F.P., Pascoe, M.D., Alberu, J., del Carmen Rial, M., Oberbauer, R., Brennan, D.C., Campistol, J.M., Racusen, L., Polinsky, M.S., Goldberg-Alberts, R., Li, H., Scarola, J., Neylan, J.F.. "Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal allograft recipients: 24-month efficacy and safety results from the CONVERT trial". Transplantation.. vol. 87. 2009. pp. 233-42.

(In this randomized multicenter trial 830 renal allograft recipients between 6 to 120 months posttransplant receiving cyclosporine or tacrolimus, were randomly assigned to continue the calcineurin inhibitor (CNI) (n=275) or convert from CNI to sirolimus (n=555). Enrollment of patients with a GFR between 20 to 40 mL/min was halted by the Drug Safety Monitoring Board when, during a protocol-specified review of data, the primary safety endpoint of acute rejection, graft loss, or death was found to be higher in the conversion group. Intent to treat analysis in patients with GFR > 40 revealed no difference in renal function at 12 and 24 months of follow up. However, the authors identified a subgroup of patients who remained on sirolimus, with a GFR > 40 mL/min and with a urine protein creatinine ratio less than or equal to 0.11, that displayed superior renal function than those maintained on CNI. Malignancy rates were lower in the sirolimus group and conversion was associated with an increase in proteinuria.)

Tait, B.D., Hudson, F., Cantwell, L., Brewin, G., Holdsworth, R., Bennett, G., Jose, M.. "Review article: Luminex technology for HLA antibody detection in organ transplantation". Nephrology (Carlton).. vol. 14. 2009. pp. 247-54.

(Here the authors provide an excellent review of Luminex technology and compare it to other methods of assessing HLA antibodies.)

Tinckam, K.. "Histocompatibility methods". Transplant Rev (Orlando).. vol. 23. 2009. pp. 80-93.

(This paper provides an excellent clinical review of histocompatibility testing, including methods of HLA typing, and HLA antibody assessment.)

Walker, J.K., Alloway, R.R., Roy-Chaudhury, P., Mogilishetty, G., Cardi, M.A., Weimert, N.A., Rike, A.H., First, M.R., Woodle, E.S.. "A prospective trial of a steroid-free/calcineurin inhibitor minimization regimen in human leukocyte antigen (HLA)-identical live donor renal transplantation". Transplantation.. vol. 87. 2009. pp. 408-14.

(This unique study identified HLA-identical live donor transplant recipients, known to be at very low risk for rejection, and prospectively enrolled them in a steroid-free and calcineurin inhibitor minimization regime to optimize long term graft survival and side effect profile. Twenty HLA-identical LD recipients were treated with mycophenolate mofetil (MMF) (2 g/day), tacrolimus (target trough 4-8 ng/mL), sirolimus (target trough 6-10 ng/mL), and no pre- or postoperative steroids. If patients had no rejection episodes, tacrolimus was discontinued at post-transplant day 120 and sirolimus at 1 year, leaving patients on MMF monotherapy. Tacrolimus was successfully withdrawn in 94% of patients (16/17) with 4 months of follow up. At a median of 571 days of follow up, death censored graft survival was 100%, and there were no cases of acute cellular rejection.)

"KDIGO clinical practice guideline for the care of kidney transplant recipients". Am J Transplant. vol. 9. 2009. pp. S1.

(The 2009 Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guidelines on the monitoring, management, and treatment of kidney transplant recipients offer guidelines in immunosuppressive management as well as other transplant related complications.)

Durrbach, A., Pestana, J.M., Pearson, T., Vincenti, F., Garcia, V.D., Campistol, J., Rial Mdel, C., Florman, S., Block, A., Di Russo, G., Xing, J., Garg, P., Grinyo, J.. "A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study)". Am J Transplant.. vol. 10. 2010. pp. 547-57.

(The BENEFIT-EXT study compared two different doses of belatacept, a selective co-stimulation blocker, to cyclosporine based immunosuppression in de novo renal transplant recipients who received extended criteria kidney donors. The co-primary end- points at 12 months were composite patient/graft survival and a composite renal impairment endpoint. Patient/ graft survival was similar in both groups however fewer patients in the belatacept group reached the renal impairment endpoint. Estimated GFR was better in the belatacept group. Rejection rates were similar among the groups although patients on belatacept had more severe rejections. More cases of central nervous system post transplant lymphoproliferative disease occurred in the belatacept group.)

Pascual, J., Galeano, C., Royuela, A., Zamora, J.. "A systematic review on steroid withdrawal between 3 and 6 months after kidney transplantation". Transplantation.. vol. 90. 2010. pp. 343-9.

(In this paper the authors performed a meta-analysis of randomized trials where steroids were withdrawn 3-6 months after transplant in patients receiving a calcineurin inhibitor and mycophenolate mofetil. They included 9 trials (1820 patients) with the longest follow up of 3 years. They found that biopsy proven rejection episodes were higher in steroid withdrawal patients on cyclosporine, but not if they were on tacrolimus. Serum cholesterol level was lower after steroid withdrawal but there was no difference in blood pressure, serum triglycerides, new-onset diabetes mellitus, infections, or malignancies.)

Vincenti, F., Blancho, G., Durrbach, A., Friend, P., Grinyo, J., Halloran, P.F., Klempnauer, J., Lang, P., Larsen, C.P., Muhlbacher, F., Nashan, B., Soulillou, J.P., Vanrenterghem, Y., Wekerle, T., Agarwal, M., Gujrathi, S., Shen, J., Shi, R., Townsend, R., Charpentier, B.. "Five-year safety and efficacy of belatacept in renal transplantation". J Am Soc Nephrol. vol. 21. 2010. pp. 1587-96.

(This trial represents the extension of a phase II trial comparing 2 dosing regimes of de novo belatacept use to cyclosporine maintenance therapy. It represents the longest experience on belatacept safety and efficacy to date. Of 102 and 26 patients on belatacept and cyclosporine who completed the initial trial, 78 and 16 completed the long term extension period. Patients on belatacept had stable GFR over the five years of follow up, stable pharmacokinetics and a good safety profile. Three cases (2.1%) of post transplant lymphoproliferative disease occurred in the belatacept group from the time of transplant. Rejection was more common in the belatacept group although the episodes did not lead to graft loss.)

Vincenti, F, Charpentier, B, Vanrenterghem, Y, Rostaing, L, Bresnahan, B, Darji, P, Massari, P, Mondragon-Ramirez, Agarwal, M., Di Russo, G., Lin, C.S., Garg, P., Larsen, C.P.. "A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study)". Am J Transplant. vol. 10. 2010. pp. 535-46.

(The BENEFIT study compared two different doses of belatacept, a selective co-stimulation blocker, to cyclosporine based immunosuppression in de novo renal transplant recipients who received either a living donor or a standard criteria deceased donor transplant. The co-primary end- points at 12 months were composite patient/graft survival, a composite renal impairment endpoint and the incidence of acute rejection. Patient/ graft survival was similar in both groups however fewer patients in the belatacept group reached the renal impairment endpoint. Patients on belatacept had a higher incidence and intensity of acute rejection. More cases of post transplant lymphoproliferative disease occurred in the belatacept group.)

Weir, MR., Mulgaonkar, S, Chan, L, Shidban H Waid, Preston, D., Kalil, RN, Pearson, TC. "Mycophenolate mofetil-based immunosuppression with sirolimus in renal transplantation: a randomized, controlled Spare-the-Nephron trial". Kidney Int. vol. 79. 2011. pp. 897-907.

(In the Spare-the-Nephron trial patients maintained on a calcineurin inhibitor and mycophenolate mofetil were randomized to continue their current therapy (n=151), or be converted from calcineurin inhibitor to sirolimus (n=148) at 30 to 180 days post-transplantation. At 12 months, patients receiving MMF/ SRL had a significantly greater mean improvement in measured GFR than did the MMF/CNI group (primary endpoint), although at 24 months this change was not significant. There were fewer deaths in the MMF/sirolimus group, and a trend towards fewer late acute rejection episodes (>12 months post randomization) and graft loss. There was a greater degree of proteinuria and hyperlipidemia in the MMF/sirolimus group.)

Rostaing, L, Massari, P, Garcia, VD, Mancilla-Urrea, E., Nainan, G., del Carmen Rial, M., Steinberg, S., Vincenti, F., Shi, R., Di Russo, G., Thomas, D., Grinyo, J.. "Switching from calcineurin inhibitor-based regimens to a belatacept-based regimen in renal transplant recipients: a randomized phase II study". Clin J Am Soc Nephrol. vol. 6. 2011. pp. 430-9.

(In this study kidney transplant recipients were converted 1:1 from a calcineurin inhibitor-based regimen (cyclosporine or tacrolimus) to a belatacept- based regimen between 6 and 36 months post transplant. Patients randomized to belatacept (n=84) had a greater improvement in cGFR at 12 months post conversion compared to those who remained on CNI (n=89). Both groups had similar adverse events although rejection was more common in the belatacept group (7% belatacept vs. no patients in CNI group). There were no cases of post-transplant lymphoproliferative disease in either group.)

Budde, K., Becker, T., Arns, W., Sommerer, C., Reinke, P., Eisenberger, U., Kramer, S., Fischer, W., Gschaidmeier, H., Pietruck, F. "Everolimus-based, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an open-label, randomised, controlled trial". Lancet. vol. 377. 2011. pp. 837-47.

(Better known as the Zeus trial, this study evaluated the effects of converting from cyclosporine based immunosuppression to everolimus, an mTOR inhibitor, based immunosuppression along with basiliximab induction, mycophenolate mofetil and prednisone maintenance at 4.5 months post transplant. Immunologic high risk individuals were excluded. The authors concluded that patients converted to everolimus had a higher eGFR at 12 months post transplant although they also had a higher incidence of biopsy proven acute rejection after randomization.)

Kimball, PM, Baker, MA, Wagner, MB, King, A. "Surveillance of alloantibodies after transplantation identifies the risk of chronic rejection". Kidney Int. vol. 79. 2011. pp. 1131-7.

(In this study the authors prospectively monitored donor specific antibody levels in patients transplanted with a positive flow cytometry crossmatch. They identified two groups, patients in which donor specific antibodies declined and those which demonstrated persistence of antibody. At 3 years of follow up patients who lost their donor specific antibodies had equivalent graft survival (95%) to those transplanted with a negative crossmatch while those who had persistence of donor specific antibody had a much lower graft survival (67%) primarily due to chronic rejection.)

Hanaway, M.J., Woodle, ES, Mulgaonkar, S, Peddi, VR, Kaufman, DB, First, MR, Croy, R, Holman, J. "Alemtuzumab induction in renal transplantation". N Engl J Med. vol. 364. 2011. pp. 1909-19.

(This was a prospective multicenter study comparing the effect of three induction agents, alemtuzumab, basiliximab, and rabbit anti-thymocyte globulin in facilitating steroid free immunosuppression in kidney transplant recipients. The authors found that alemtuzumab induction led to the lowest incidence of biopsy proven rejection in low risk individuals and an equivalent risk of rejection when compared to rabbit anti-thymocyte globulin in high risk individuals. Kidney graft survival was similar in all groups.)
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