Early Era (1954–1962)

The first human-to-human kidney transplantation was performed by Russian surgeon Yu Yu Voronoy in 1933 across major blood group mismatch, and it resulted in prompt allograft failure. Interest in organ transplantation remained, but it was largely done experimentally among animals until 1954, when the first successful kidney transplantation between identical twins was performed by Joseph Murray. This event heralded intensified interest in the technical and immunobiological aspects of organ transplantation, along with efforts to prevent allograft rejection. Immunosuppressive agents were very limited during this era, primarily comprising corticosteroids and total body irradiation. In the absence of effective immunosuppression, immunological matching between donors and recipients played a central role in transplantation, with most transplants occurring between identical twins and siblings. Consequently, this era was characterized by high rejection rates and dismal 1-year graft survival rates of less than 10%.

The Azathioprine Era (1962–1980)

First synthesized in 1957 as a chemotherapeutic agent, azathioprine (AZA) was found to suppress antibody formation in rabbits exposed to antigens and to extend canine allograft survival. The use of AZA in human kidney transplantation was slow to catch on because initial experience with AZA monotherapy was associated with poor outcomes. However, the discovery that combining AZA with prednisone resulted in improved 1-year graft survival (of up to 70%) made this combination the standard immunosuppressive therapy of this era, and ushered in the concept of maintenance chemical immunosuppression.

The Cyclosporine Era (1980s–1990s)

After the initial isolation of calcineurin inhibitors (CNIs) in 1976, cyclosporine soon became the next therapeutic tool to advance the immunosuppression arsenal ^. The addition of cyclosporine to combination prednisone and AZA therapy decreased 1-year rejection rates to <50% and improved graft survival rates to >85%.

The Contemporary Era (1990s–Present)

The contemporary era of transplantation began with the discovery that tacrolimus, another CNI, was more efficacious than cyclosporine at clinically relevant dosing, resulting in its approval for organ transplantation in 1994. The approval of mycophenolate mofetil (MMF) shortly thereafter, followed by interleukin (IL)‐2 receptor blockers (basiliximab and daclizumab) and then rabbit antithymocyte globulin (rATG) around the millennium, catalyzed the emergence of a variety of new treatment combinations. Now entering the third decade since these contemporary agents were introduced into the clinical arena, they remain the gold standard against which all subsequent comparator immunosuppressive drugs in development have failed to show equivalent, let alone superior, effectiveness. Transplant recipients enjoy significantly lower 1-year rejection rates of 10% to 15% and 1-year graft survival in excess of 95%. As discussed later, challenges in the contemporary era include combating chronic rejection, minimizing side effects of current therapy, and improving long-term graft and patient outcomes.

Immunological Risk

In the 2009 Kidney Disease Improving Global Outcomes (KDIGO) transplant guidelines, potential recipients are stratified into “high” or “low” immunological risk depending on their risk for rejection. Patients who are younger, have anti-human leukocyte antigen (HLA) antibodies, or, are of African descent are considered high risk for rejection, whereas patients who are older, nonsensitized, of Asian or non-African ancestry, or have received closely HLA-matched kidneys are considered low risk. KDIGO recommends that high-risk patients receive more intensified immunosuppression than would otherwise be administered to low-risk recipients. Although this immunological risk stratification may be broadly applicable, an optimal risk-stratified treatment regimen has not been established because of the lack of standardization with calculated panel reactive antibodies (CPRAs), degree of HLA-mismatch, or demographic factors in immunosuppression studies.

Medical Risk

Patients’ medical history, as well as their functional and nutritional status must also be considered in the dosing and choice of immunosuppressants. For example, belatacept use in patients who are Epstein-Barr virus (EBV) seronegative is contraindicated because of the risk for posttransplant lymphoproliferative disease (PTLD). Some transplant professionals consider minimizing or avoiding tacrolimus in elderly recipients because of the potential risk for increased neurotoxicity, or consider a steroid-sparing regimen in patients with bipolar disorder because of risk for exacerbation.

Overall Efficacy

An evidence-based approach of overall efficacy using high-quality studies and randomized trials (whenever possible) should guide immunosuppression management. In transplant recipients, efficacy of therapy should translate into lower rates of rejection and improved graft and patient survival. As we review contemporary therapies and landmark trials that led to current standards, it should be kept in mind that although registries offer the benefit of generalizations from large patient cohorts, they usually are limited by incomplete information related to indication for use/nonuse of certain agents, dose adjustment or drug concentrations/exposures, and inadequate information on specific complications. On the other hand, although prospective randomized trials eliminate these shortcomings, many of these trials are constrained by small cohorts in single centers.

Lymphocyte-Depleting Agents

Lymphocyte-depleting therapies lead to durable T-cell depletion that typically takes several months to repopulate to preadministration levels. This section is limited to the two lymphocyte-depleting agents that remain in use in the United States: rATG and alemtuzumab. rATG (trade name Thymoglobulin) is a polyclonal antibody preparation made by immunization of rabbits with human lymphoid tissue. It targets multiple pathways in T-cell activation and results in T-cell lysis (see Fig. 38.1 ). Initially developed decades ago to treat rejection, but only approved by the US Food and Drug Administration (FDA) in 2017 specifically to prevent rejection, rATG has been the most widely used induction agent in the United States for many years. It usually is given at a dose of 1 to 1.5 mg/kg for a total of three to five doses. The major early side effect is serum sickness, an infrequent occurrence because of concomitant administration of high-dose steroids. Other side effects include constitutional symptoms such as fever, chills or arthralgias, hematological side effects such as leukopenia, thrombocytopenia and clotting of dialysis accesses, and a propensity for certain infections and malignancies. Alemtuzumab (trade name Campath 1H), initially developed to treat chronic lymphocytic leukemia, also has been used for induction therapy, although it is not FDA-approved for this latter indication. It is a recombinant DNA-derived humanized monoclonal antibody (mAb) against cell surface glycoprotein CD52 in T and B cells, and results in profound and prolonged depletion of peripheral and central lymphoid cells (see Fig. 38.1 ). It usually is given as a single intraoperative dose, allowing ease of administration and shorter hospital stay. Side effects include infusion reactions such as fever, chills, nausea, and rash. Profound lymphocyte depletion also can lead to serious infections.

Interleukin-2 Receptor Blockers

Basiliximab (brand name Simulect) is currently the only nonlymphocyte-depleting agent used in kidney transplantation. It is a chimeric monoclonal anti-CD25 antibody that targets CD25 on the IL-2 receptor, effectively preventing delivery of signal 3 need for T-cell activation (see Fig. 38.1 ). It is given in two 20-mg doses, usually given 4 days apart. It has few side effects, but because it prevents T-cell proliferation rather than causing depletion, it is considered less potent than rATG or alemtuzumab. Daclizumab is another humanized anti-CD25 antibody that, although no longer available for use, is of historical interest as it was used in some of the pivotal trials.

Landmark Trials With Induction Therapy

Most induction trials have been limited by being underpowered, with wide variation regarding accompanying maintenance therapies used, short follow-up, and primary endpoints largely focused on reduced acute rejection rates. In this section, we review the most pertinent studies.

The superiority of rATG over IL-2 receptor blockade in immunologically high-risk recipients has been demonstrated in two randomized controlled trials (RCTs), showing a reduction in incidence and severity of rejection, as well as improved 5-year outcomes in this population.

Compared with alemtuzumab, outcomes for basiliximab-treated patients appear to be mixed. In a prospective single-center study, where maintenance immunosuppression differed in each arm, rates of acute rejection were similar but chronic allograft injury and death-censored graft loss was higher in alemtuzumab-treated recipients. In another prospective, single-center study, where uniform prednisone-sparing maintenance regimen was used, acute rejection occurred earlier after basiliximab than alemtuzumab induction (51 ± 83 vs. 148 ± 82 days), but 12-month rejection rates and survival outcomes were similar. A third study, the 3C study, a prospective randomized trial, compared alemtuzumab with prednisone-free, tacrolimus-mycophenolic acid (MPA) maintenance against basiliximab-tacrolimus-mycophenolic acid-prednisone therapy, and found lower rates of acute rejection by 6 months in the alemtuzumab group.

Alemtuzumab also was compared with basiliximab in low immunological risk patients and to rATG in high-risk recipients in a prospective randomized trial in which all patients received maintenance therapy with tacrolimus-MMF after early prednisone withdrawal. At 3 years posttransplant, alemtuzumab was superior to basiliximab in preventing rejection in low-risk patients (10% vs. 22%; P = 0.003), whereas alemtuzumab and rATG fared similarly in high-risk recipients (18% vs. 15%). Adverse reactions were similar in all treatment groups.

Several retrospective analyses have compared alemtuzumab with rATG, with results generally favoring the latter induction agent. In one study of deceased donor kidney recipients, patient survival and adjusted allograft survival were inferior in alemtuzumab-treated patients. A registry analysis examined outcomes in lower immunological-risk live kidney recipients, stratified by use or nonuse of steroids together with tacrolimus-MPA maintenance immunosuppression. Among recipients on steroid-free regimens, acute rejection was lower with rATG (odds ratio [OR], 0.73; 95% confidence interval [CI], 0.59 to 0.90) and alemtuzumab (OR, 0.53; 95% CI, 0.42 to 0.67) than IL-2 receptor blocker; however, there was an increased risk for allograft failure with alemtuzumab (hazard ratio [HR], 1.27; 95% CI, 1.03 to 1.56) but not rATG compared with IL-2 blocker. Among those on a steroid-containing regimen, rATG use was associated with lower rejection rates than IL-2 receptor antibodies (OR, 0.78; P = 0.001), although this did not translate into a graft survival advantage.

In a more recent study where Organ Procurement and Transplantation Network data were linked with Medicare claims, outcomes were compared after 1:1 matching of recipient pairs of alemtuzumab versus rATG and rATG versus basiliximab. Compared with recipients treated with rATG, the risk for death or allograft failure was increased by 18% with alemtuzumab and 8% with basiliximab.

In summary, most studies show that compared with lymphocyte-depleting agents, basiliximab may have a better safety profile comparable to placebo, although in high-risk recipients, it is associated with higher rates of rejection and donor-specific antibody formation. KDIGO transplant guidelines recommend basiliximab induction in low immunological risk recipients and lymphocyte-depleting therapies in high immunological risk recipients. We generally endorse KDIGO recommendations, although favor rATG over alemtuzumab as the lymphocyte-depleting therapy of choice based on the data just described.

Corticosteroids

Corticosteroids have been used since the early days of organ transplantation and remain a basic component of many immunosuppression protocols. Corticosteroids act by blocking T-cell derived and APC-derived cytokine and cytokine expression via different mechanisms. After passive diffusion across the cell membrane, steroids bind to intracellular glucocorticoid receptors forming complexes that then translocate into the nucleus. These complexes interact with glucocorticoid-responsive elements, resulting in altered transcription of various cytokines (see Fig. 38.1 ). By affecting posttranslational events, steroids also inhibit secretion of inflammatory cytokines. High-dose steroids are typically administered intravenously in the perioperative period as part of the induction regimen, followed by oral dose tapering. Although some centers completely eliminate maintenance prednisone using an avoidance or early posttransplant withdrawal approach (steroid-sparing regimens), most continue low-dose maintenance prednisone (e.g., tapered to 5 mg/day by 1 to 2 months posttransplant). High-dose corticosteroid therapy is associated with several adverse effects such as growth retardation in children, glucose intolerance and diabetes, osteoporosis, avascular necrosis, dyslipidemia, hypertension, impaired wound healing, skin fragility, and cataracts.

Calcineurin Inhibitors

CNIs have dramatically affected allograft outcomes. The two CNIs used in transplant are cyclosporine and tacrolimus, with tacrolimus considered more potent at clinically relevant dosing. Calcineurin dephosphorylates transcription factors, including nuclear factor of activated T cells, which can then translocate into the nucleus and induce gene transcription (see Fig. 38.1 ). Cyclosporine and tacrolimus bind to cyclophilin and FK-binding protein, respectively, forming active complexes that inhibit calcineurin release and thereby block subsequent T-cell activation. Cyclosporine and tacrolimus have similar side-effect profiles with few differences detailed in Table 38.1 . Both undergo gut and hepatic metabolism via cytochrome P450 enzymes. Because several drugs commonly used in transplantation (e.g., macrolides, azoles, dihydropyridine calcium channel blockers, amiodarone, and HIV medications) are metabolized by this enzyme system, mindfulness for drug–drug interactions is required in patients receiving CNIs.

Historically, CNIs were manufactured as twice-daily formulations. Two tacrolimus formulations that require only once-daily dosing have recently been approved in several countries. Tacrolimus-ER (brand name Astagraf XL in the United States, Advagraf in Europe) and LCP-tacrolimus (brand name Envarsus XR), demonstrated to be noninferior to twice-daily tacrolimus in conversion and de novo RCTs, offer the potential of improved patient adherence. Pharmacokinetic differences between the once- and twice-daily formulations often impact the total daily tacrolimus dose requirement for patients. When switching between formulations, we recommend monitoring through tacrolimus levels at 1 and 3 weeks postconversion and dose titration as indicated.

Mycophenolic Acid

MPA is a noncompetitive inhibitor of the rate-limiting enzyme inosine monophosphate dehydrogenase in the de novo purine biosynthesis pathway (see Fig. 38.1 ). Because lymphocytes cannot efficiently use the salvage pathway and are highly dependent on the de novo pathway of purine synthesis, MPA effectively inhibits the proliferation of T and B lymphocytes. MPA is poorly absorbed after oral administration and is therefore formulated as a prodrug to improve drug bioavailability, as either MMF (brand name CellCept) or mycophenolate sodium (MPS, brand name Myfortic). MMF, a semisynthetic derivative of MPA produced by the fungus Penicillium, was first approved by the FDA in 1995 for use in kidney transplantation, whereas MPS was approved about a decade later. After oral administration, MMF is rapidly and completely converted to MPA in the stomach; this process is delayed with MPS, occurring more distally in the gastrointestinal tract. Although not bioequivalent, MMF and MPS have been demonstrated to have very similar efficacy and safety profiles. Common side effects include nausea, vomiting, and diarrhea, occasional severe esophagitis and gastritis, oral ulcers and leukopenia.

Azathioprine

AZA is a purine analog that inhibits the de novo purine synthesis pathway through suppression of the enzyme glutamine phosphoribosyl pyrophosphate aminotransferase (see Fig. 38.1 ). Purine nucleotides form key elements of DNA and RNA; inhibition of purine synthesis therefore affects DNA synthesis required for cell proliferation, and RNA transcription required for protein synthesis. In addition, purines are needed for the glycosylation of adhesion molecules and the activation of lymphocytes and macrophages. AZA usually is given at a maintenance dose of 1 to 2 mg/kg daily as a single oral dose, with dose adjusted to white blood cell count >3500 cells/mm . Side effects of AZA include bone marrow suppression (usually reversed by decreasing the dose), hepatitis, pancreatitis, and hair loss. It is metabolized in the liver to 6-mercaptopurine, which is subsequently converted to inactive 6-thiouric acid by xanthine oxidase. Because of this, simultaneous administration with a xanthine oxidase inhibitor such as allopurinol can lead to significantly high levels of AZA and profound and long-lasting neutropenia; therefore AZA dose should be reduced when combined with allopurinol or the combination avoided if possible.

mTOR Inhibitors

The mTOR inhibitors form complexes with the FK-binding protein that subsequently bind to mTOR, causing dephosphorylation and inactivation of p70S6 kinase. By inhibiting G1 to S phase of the cell cycle, this effectively blocks cytokine-driven T-cell proliferation. The two mTOR inhibitors used in clinical transplantation are sirolimus and everolimus. Side effects in the early posttransplant period include delayed graft function, poor wound healing, and lymphoceles, whereas longer-term side effects include severe edema, proteinuria, hyperlipidemia, thrombocytopenia, leukopenia, and anemia.

Belatacept

Belatacept is a fusion protein that binds to CD80/CD86 on APCs, thereby effectively blocking the costimulatory signal required for T-cell activation (see Fig. 38.1 ). The most important reported side effects are increased risk for central nervous system PTLD and progressive multifocal leukoencephalopathy (PML), especially in EBV-seronegative recipients. As a result, belatacept is now contraindicated in patients whose EBV serostatus is unknown or negative.

Combination Therapies and Trials That Led to Current Standards

Because the combination of AZA with prednisone was shown to be safer and more efficacious than either agent alone more than 5 decades ago, clinical trials have focused on using combination therapies with each new agent that came along for several reasons. First, since T-cell activation is complex, combination therapies provide the opportunity to simultaneously target multiple steps involved in the process of activation and thereby circumvent potentially redundant pathways. Furthermore, combination therapies can bring about a state of adequate overall immunosuppression at submaximal doses of individual agents, therefore minimizing drug-specific toxicities that might occur with use of individual therapies at higher doses.

Most centers currently use a multidrug maintenance regimen comprising one agent from each column in Table 38.2 , although use of prednisone is quite variable. As a result of RCTs demonstrating lower rates of rejection and better allograft and patient survival compared with cyclosporine, tacrolimus has been the predominant CNI since the turn of the century. MPA-based therapies are typically used in conjunction with tacrolimus based on comparative trials demonstrating less acute rejection than AZA. According to US Registry data, regimens comprising tacrolimus-MPA (with or without prednisone) were used in 93% of all de novo kidney transplants in 2015, thereby constituting the contemporary gold standard against which both existing and investigational therapies are tested.

TABLE 38.2

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