Management of the Kidney Transplant Patient
Clarice E. Carthon
Timothy A. Horwedel
General Principles
Immunosuppression is used for induction at the time of transplant to promote graft acceptance, to prevent rejection (maintenance), and for the treatment of acute rejection (AR).
Adverse effects of immunosuppression are both immune-mediated (e.g., increased risk of infection and malignancy) and nonimmune effects.
Immunosuppressive protocols tend to be center and organ specific, but can be individualized based on immunologic or side-effect profile.
At present, the most commonly used regimens for recipients in the United States consist of induction with a T-cell–depleting agent (antithymocyte globulin or alemtuzumab) and maintenance immunosuppressive with a combination of tacrolimus, mycophenolate, and prednisone.
Induction and Rejection—Antibody Therapies
Antibody therapies have many applications in transplant medicine, including induction, treatment of acute cellular- and antibody-mediated rejection, and treatment of select recurrent diseases (Table 28-1).
Polyclonal
Antithymocyte globulin is produced by injecting human thymocytes into animals and collecting sera containing cytotoxic antibodies against a variety of T-cell markers.
The available preparations are horse antithymocyte globulin (ATGAM) and rabbit antithymocyte globulin (Thymoglobulin). They cause T-lymphocyte depletion and are used for induction as well as for treatment of rejection.
Common side effects include fever, chills, arthralgias, and myelosuppression. Serum sickness and anaphylaxis (rare) can also occur.
Monoclonal
Alemtuzumab is a humanized monoclonal antibody against CD52, approved for use in chronic lymphocytic leukemia (CLL). It causes rapid and profound B- and T-cell depletion and is used off-label in transplantation, desensitization protocols, and induction.
Basiliximab is a humanized monoclonal antibody inhibiting the alpha subunit of the interleukin-2 receptor (CD25), thereby inhibiting IL-2 activation of T cells. Basiliximab is used for induction only. There are few side effects, although rare cases of anaphylaxis have been reported.
Rituximab is a monoclonal antibody directed against CD20 on B lymphocytes, causing rapid and sustained B-cell depletion. It is used in transplantation for desensitization and ABO- and HLA-incompatible kidney transplant protocols, treatment of acute antibody-mediated rejection, certain recurrent diseases (e.g., membranous nephropathy and focal segmental glomerulosclerosis), and for CD20+ post-transplant lymphoproliferative disorders (PTLDs).
TABLE 28-1 ANTIBODY THERAPIES | ||||||||||||||||||||||||||||||||||||||||
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Maintenance Immunosuppression
Available immunosuppressive agents for maintenance immunosuppression include glucocorticoids, calcineurin inhibitors (CNIs), costimulation inhibitors, antimetabolites, and mammalian target of rapamycin inhibitors (mTORi) (Fig. 28-1).
Owing to the different mechanisms of action, along with the renal and nonrenal toxicities of each drug, combination therapy is used to achieve the desired immunosuppressive effect while minimizing other side effects (Fig. 28-2).
Glucocorticoid (Prednisone, Prednisolone)
Glucocorticoids are anti-inflammatory agents, which inhibit cytokine and chemokine production, and induce lymphopenia.
Adverse side effects include development of post-transplant diabetes mellitus (PTDM), bone disease, poor wound healing, infections, cataracts, bruising, dyslipidemia, psychopathologic effects, and steroid myopathy.
Maintenance dose is usually 5 mg of prednisone by day 30 post-transplant.
Steroid-free or minimization protocols are offered at select centers but higher rejection rates and lack of long-term data limit general acceptance of steroid withdrawal.
The so-called stress dose increases in steroids are generally not needed for routine surgery or illness and may only increase risk of infection, poor wound healing, or hyperglycemia.
Calcineurin Inhibitors
Cyclosporine and tacrolimus are the two types of CNIs.
By inhibiting calcineurin, they prevent cytokine gene expression and subsequent T-cell activation (Fig. 28-1).
Cyclosporine and tacrolimus have similar side effects, including renal vasoconstriction, development of chronic interstitial fibrosis, hypertension, hyperkalemia, hypomagnesemia, hyperuricemia, and risk of drug-induced thrombotic microangiopathy.
Hirsutism, hyperlipidemia, hypertension, and gingival hyperplasia are associated with cyclosporine.
Tacrolimus is more neurotoxic and diabetogenic than cyclosporine.
FIGURE 28-1. Antigen-Presenting Cells of Host or Donor Origin With T cell. Signal 1 (recognition): Antigen-presenting cells trigger T-cell receptors (TCRs). This activates several signals including the calcium–calcineurin pathway. This activates transcription factor nuclear factor of activated T cells (NFAT). Signal 2 (costimulation): CD80 and CD86 on the antigen-presenting cell engage CD28 on the T cell. Signal 3: Interleukin-2 delivers growth signals through the phosphoinositide-3-kinase (PI3K) pathway and the mechanistic target of rapamycin (mTOR) pathway, which initiates the cell cycle.
FIGURE 28-2. Rationale for individualizing immunosuppression medication.
Cyclosporine formulations include Sandimmune (dependent on bile for absorption), microemulsion formula (Neoral), and generic (Gengraf).
Formulations are not interchangeable; if changes are made, then close monitoring of drug levels is needed, with dose adjustments carried out as necessary.
Typical starting dose is 6 to 8 mg/kg/day divided twice daily, tapered to achieve long-term maintenance troughs of 75 to 200 ng/mL or peaks of 400 to 600 ng/mL.
Tacrolimus formulations include Prograf (available in generic formulation) dosed twice daily as well as Astagraf XL and Envarsus XR dosed once daily.
As with cyclosporine, a change of formulation necessitates monitoring of drug levels and allograft function.
Typical Prograf starting dose is 0.15 to 0.3 mg/kg/day divided twice daily, tapered to achieve maintenance trough levels of 3 to 10 ng/mL.
For conversion from Prograf (immediate release) to Astagraf XL, initiate treatment in a 1:1 ratio using total daily dose once daily.
For conversion from Prograf (immediate release) to Envarsus XR, initiate treatment with 70% to 80% of total daily dose once daily.1
Intravenous administration of CNIs is almost never indicated, as tacrolimus is readily absorbed and can be given via a nasogastric tube or sublingually.
For patients on cyclosporine, temporary conversion to tacrolimus is preferable to intravenous administration.
Conversion from oral to sublingual should be done at a 50% dose reduction in patients with stable tacrolimus levels that are at goal.
Costimulation Inhibitors
Belatacept is a fusion protein, which acts as a selective T-cell costimulation blocker by binding CD80 and CD86 receptors on antigen-presenting cells (APCs), blocking the required CD28-mediated interaction between APCs and T cells needed to activate T lymphocyte.
Use only in adult Epstein–Barr virus (EBV) seropositive kidney transplant patients due to the increased risk of PTLD in EBV-seronegative patients receiving belatacept.2
Belatacept is dosed as an initial phase and maintenance phase.
Initial phase: 10 mg/kg on day 1 and day 5, followed by 10 mg/kg at the end of week 2, week 4, and week 12 following transplant.3
Maintenance phase: 5 mg/kg every 4 weeks beginning at the end of week 16.
Side effects include viral infections and PTLD.Related posts:
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