Kidney transplantation in children: Immunosuppression

INTRODUCTION — The major advance allowing prolonged allograft survival in pediatric kidney transplantation has been the use of immunosuppressive drugs that downregulate the immune response. Although data from adult kidney transplantation trials are used to help guide management decisions in pediatric patients, immunosuppression must often be modified because of the unique clinical effects of some of these agents in children, including their impact on growth and development.

An overview of immunosuppression regimens used in children undergoing kidney transplantation will be reviewed here. Additional issues concerning transplantation in children, as well as detailed discussions of immunosuppressive issues in kidney transplantation common to both children and adults, are presented separately.(See "Kidney transplantation in children: General principles" and "Kidney transplantation in children: Outcomes" and "Kidney transplantation in adults: Maintenance immunosuppressive therapy" and "Kidney transplantation in adults: Induction immunosuppressive therapy".)

GOAL AND COMPONENTS OF IMMUNOSUPPRESSIVE THERAPY

Goal — The goal of immunosuppression is to prevent allograft rejection while minimizing drug side effects such as infection, nephrotoxicity, malignancy, and adverse cosmetic effects.

Immunosuppressive drug regimens are modified as the risk of acute rejection and allograft loss varies to optimize allograft and patient survival and reduce drug adverse effects.

Components — Immunosuppressive regimens for children who undergo kidney transplantation are divided into three categories based on the risk of acute rejection:

●Induction therapy – Induction therapy is used at the time of kidney transplant to reduce the risk of allograft rejection. Most induction strategies mitigate T cell activation and use either interleukin 2 (IL-2) receptor antagonists or T cell-depleting agents in combination with conventional agents. Risk of acute rejection is lower when induction therapy precedes the start of maintenance immunosuppressive therapy.

●Maintenance therapy – Maintenance therapy is typically started following induction therapy in the first days following transplantation. The intensity of maintenance immunosuppressive therapy is typically reduced after the perioperative period as the risk of acute rejection decreases.

●Acute rejection therapy – Immunosuppressive therapy is increased to treat acute rejection.

Patient risk stratification — Immunosuppression strategies vary based on a patient's underlying immunologic risk for acute rejection and graft loss. In general, more intensive immunosuppression, particularly T cell-depleting induction therapy, is selected for patients who are at greater risk for allograft rejection (defined as high risk). Risk factors for acute rejection include one or more of the following (see "Kidney transplantation in adults: Induction immunosuppressive therapy", section on 'Assessment of immunologic risk'):

●One or more human leukocyte antigen mismatches (see "Kidney transplantation in adults: HLA matching and outcomes")

●Panel reactive antibody greater than 0 percent (sensitization)

●Presence of a donor-specific antibody

●Blood group incompatibility

●Retransplant

●Delayed onset of graft function

●Cold ischemia time greater than 24 hours

●In the United States, Black individuals [1]

OUR APPROACH — The optimal immunosuppressive regimen for children who undergo kidney transplantation remains unclear, and there are a wide range of approaches using multiple immunosuppressive agents. Many pediatric transplant centers rely on patient risk stratification to choose induction therapy and then titrate maintenance therapy to avoid excessive immunosuppression. For acute rejection, specific allograft pathologic changes guide the selection of more intensive immunosuppression.

Our immunosuppressive regimen, which minimizes glucocorticoids, consists of induction therapy that uses a biologic agent (rabbit antithymocyte globulin [rATG]-thymoglobulin) with methylprednisolone, as well as maintenance combination immunosuppression therapy with a calcineurin inhibitor (CNI; tacrolimus) and an antimetabolite (mycophenolate mofetil [MMF]) [2,3].

●Induction therapy – At our center, we administer rATG-thymoglobulin rather than antithymocyte globulin (ATGAM), alemtuzumab, or interleukin 2 (IL-2) receptor antibodies (eg, basiliximab). (See 'Data comparing different agents' below.) [4,5].

Intraoperative – For all patients, the first dose of rATG-thymoglobulin is provided intraoperatively at an intravenous (IV) dose of 1.5 mg/kg, preceded with administration of IV methylprednisolone given at a dose of 10 mg/kg (maximum dose of 1 g) [4,5].

Postoperative – Further postoperative induction therapy is based on patient risk stratification:

•Low-risk profile (first transplant, zero donor-specific antibody, no risk of recurrent disease)

-rATG-thymoglobulin – rATG-thymoglobulin is administered for an additional two doses (three total doses of thymoglobulin, with a cumulative dose of 4.5 mg/kg).

-Glucocorticoid minimization – No further glucocorticoid is administered.

•High-risk profile (risk factors for acute rejection, as discussed above (see 'Patient risk stratification' above))

-rATG-thymoglobulin – rATG-thymoglobulin is administered for an additional four doses (five total doses of thymoglobulin, with a cumulative dose of 7.5mg/kg).

-Glucocorticoid therapy – On postoperative day 1, IV methylprednisolone (dose 10 mg/kg, maximum dose 1 g) or oral prednisone (dose of 1 mg/kg given twice a day, maximum dose 40 mg) is administered. Prednisone is then provided or continued and gradually tapered to 0.1 mg/kg daily by six months post-transplant.

●Maintenance immunosuppression – At our center, maintenance immunosuppression includes enteral MMF and tacrolimus. (See 'Maintenance immunosuppressive agents' below.)

•MMF is started in the operating room at a daily dose of 1200 mg/m² and quickly reduced to 900 mg/m²/day until postoperative day 14, when the dose is further decreased to 600 mg/m²/day. Dosing is modified to target mycophenolic acid levels (MPA) trough levels between 2 and 4 mcg/mL and are reduced further if there is evidence of bone marrow suppression (ie, leukopenia). Enteric-coated mycophenolate sodium (EC-MPS) is used in cases of gastrointestinal intolerance to MMF. 'Preferred antimetabolite agent: Mycophenolate' below

•Tacrolimus – Initial administration and dosing of enteral tacrolimus is based on donor source.

-Living donor recipients – Tacrolimus therapy is started on preoperative day 2 at a dose of 0.025 mg/kg/dose given twice a day. On postoperative day 1, the dose is increased to 0.15 mg/kg/day, divided twice a day (0.075 mg/kg per dose). Of note, other centers do not start tacrolimus prior to transplantation but begin therapy post-transplantation, similar to the protocol we use for deceased donor recipients.

-Deceased donor recipients – On postoperative day 1, tacrolimus is provided at a daily dose of 0.15 mg/kg/day, divided twice a day (0.075 mg/kg per dose).

The dose is adjusted to obtain a 12-hour trough blood level of 10 to 15 ng/mL during the first month post-transplantation. The target trough level is lowered progressively over time. For patients who are rejection free at one-year post-transplant, the trough level is maintained at 3 to 5 ng/mL. (See 'Calcineurin inhibitors' below.)

Immunosuppression is decreased if there are signs or symptoms of excessive immunosuppression (eg, leucopenia or problematic viral or other infections) or increased if the patient develops acute rejection or subclinical rejection based on surveillance biopsies.

We do not routinely use a mammalian (mechanistic) target of rapamycin (mTOR) inhibitor as part of an initial maintenance immunosuppression regimen. Initial use of mTOR is avoided due to effects on wound healing. Subsequent use of mTOR as maintenance immunosuppression is uncommon; however, we use an mTOR inhibitor as an alternative agent in patients who cannot continue taking a CNI due to toxicity, who develop a new cancer after transplantation, or who are noncompliant with therapy.

●Acute rejection therapy – Acute rejection is diagnosed by biopsy with staging based on Banff criteria for acute cell-mediated and/or antibody-mediated rejection (ABMR) (table 1). While empiric therapy with glucocorticoids may be indicated if a biopsy cannot be performed in a timely manner, it is discouraged to avoid unnecessary glucocorticoid exposure.

Our treatment approach for acute rejection depends on the specific pathologic changes found in the allograft, as follows:

•Acute T cell-mediated rejection (TCMR). (See 'Acute T cell-mediated rejection' below.)

-Banff grade I – A three-day course of IV methylprednisolone (10 mg/kg/day, maximum dose 1 g) is administered, followed by prednisone 1 mg/kg (maximum dose 40 mg) twice a day for three days, followed by a two-week oral taper back to the prerejection dose. Other centers also administer rATG-thymoglobulin (dose 1.5 mg/kg) for three days for Banff grade 1B rejection.

-Banff grade II or higher or glucocorticoid-resistant rejection – rATG-thymoglobulin (dose 1.5 mg/kg) is administered for 5 to 10 days, in addition to the glucocorticoid regimen used in Banff grade I. The number of doses depends on the severity of TCMR and initial response to therapy. (See 'Response to therapy' below.)

•Antibody-mediated acute rejection – A three- to five-day course of plasma exchange is administered, followed by a single dose of intravenous immune globulin (IVIG; 2 g/kg). Rituximab (375 mg/m²) is then also given weekly for up to four doses. The number of doses depends on the severity of rejection and initial response to therapy. (See 'Antibody-mediated rejection' below and 'Response to therapy' below.)

INDUCTION IMMUNOSUPPRESSIVE AGENTS — Induction therapy is used to prevent T cell activation and is administered during the perioperative period, when the risk of acute rejection is highest. It generally includes the use of antibodies directed against T cell antigens, in combination with the initiation of maintenance immunosuppression using nonbiologic agents.

In adults, a large number of controlled randomized trials and meta-analyses indicate that induction therapy consisting of biologic antibodies plus conventional immunosuppressive therapy (eg, glucocorticoids, antimetabolites, and/or calcineurin inhibitor [CNI]) is superior to conventional agent therapy alone in reducing kidney allograft rejection and failure. In children, data are limited on the optimal induction therapy that prevents allograft rejection and failure while minimizing serious adverse effects (eg, infections and malignancies). As a result, the optimal induction therapy agent for children remains unclear and the choice often depends on center preference.

Antibody induction therapy — Antibody induction agents include specific antilymphocyte or interleukin 2 (IL-2) receptor antibodies (ie, antagonist) that target T cells.

The efficacy of antibody induction therapy is supported by a meta-analysis of randomized trials demonstrating that it reduces kidney allograft rejection and allograft failure compared with conventional (ie, nonbiologic) immunosuppressive therapy alone [6]. While these clinical trials enrolled mostly adult patients, several trials included patients as young as 10 years old. In addition, three pediatric trials evaluated antibody induction therapy (OKT3 in one trial, basiliximab in two trials), but they were underpowered to detect a difference in allograft outcomes [7-9]. Retrospective studies in pediatric kidney transplant recipients suggest that prophylactic anti-T cell antibody therapy added to conventional immunosuppressive therapy has a beneficial effect on allograft survival [10].

Data supporting antibody induction therapy in adult kidney transplant recipients are discussed in greater detail separately. (See "Kidney transplantation in adults: Induction immunosuppressive therapy", section on 'Indications for induction therapy'.)

Choice of agent — There are fewer data guiding antibody induction agent selection in children receiving a kidney transplant, and induction regimens tend to be center- or patient-specific.

In our center, we suggest rabbit antithymocyte globulin (rATG)-thymoglobulin rather than other antibody therapy in most patients, but we adjust the number of doses based on patient risk, whereas other centers may use an IL-2 receptor antagonist for induction in a low-risk recipient but use antilymphocyte antibody therapy in a highly sensitized patient or a patient who had a previous failed transplant. (See 'Our approach' above and 'Data comparing different agents' below.)

Antibody therapy includes:

●Antilymphocyte antibodies – Antilymphocyte antibodies to T cells block lymphocyte functions by the direct killing of bound T lymphocytes. These agents are used to reverse and prevent acute rejection episodes [11].

•Polyclonal preparations consist of antisera raised in animals (eg, horse, rabbit) immunized with human lymphocytes, thymocytes, or lymphoblasts. They contain a wide variety of antibodies directed against many hematopoietic antigens, including cluster determinant (CD) 2, CD3, CD4, CD8, CD18, and human leukocyte antigen molecules. The two available polyclonal lymphocyte-depleting antibodies are antithymocyte globulin (ATGAM), a polyclonal horse-derived antilymphocyte globulin, and rATG-thymoglobulin (Thymoglobulin), a polyclonal rabbit-derived antilymphocyte globulin.

•Monoclonal antibodies include OKT3 (Muronab-CD3, Orthoclone), which is no longer used, because there is no clear benefit of OKT3 compared with other antilymphocyte antibody preparations and it has significant adverse effects [9,12-14], and alemtuzumab, a humanized anti-CD52 antibody [15-22], used as induction in some pediatric kidney transplant centers. (See "Kidney transplantation in adults: Induction immunosuppressive therapy", section on 'Alemtuzumab'.)

●IL-2 receptor antagonists – Full T cell activation leads to the calcineurin-mediated stimulation of the transcription, translation, and secretion of IL-2, which induces T cell proliferation. Thus, abrogation of IL-2 activity via the administration of anti-IL-2 receptor antibodies would be an attractive potential therapeutic option for the prevention of acute rejection. The only IL-2 receptor antibody available is basiliximab (Simulect), a chimeric human/mouse monoclonal antibody to the alpha chain of the IL-2 receptor.

Data comparing different agents — Although evidence that compares different antibody induction therapy is limited, we use rATG-thymoglobulin for all pediatric kidney transplant recipients based on data from adult and pediatric studies, as follows:

●Lower rates of acute rejection with rATG-thymoglobulin compared with other antibody therapy:

•rATG-thymoglobulin versus ATGAM – In a single-center historic cohort study of pediatric kidney transplant recipients, rATG was associated with a lower acute rejection rates compared with ATGAM [4]. A clinical trial in adults also demonstrated lower acute rejection rates and improved allograft survival in patients who received rATG-thymoglobulin compared with those treated with ATGAM.

•rATG-thymoglobulin versus IL-2 receptor antibodies (basiliximab)

-In adult trials, for patients with a high risk of rejection, rATG-thymoglobulin was more effective compared with basiliximab in preventing acute rejection and, at five-year follow-up, graft loss and mortality. (See "Kidney transplantation in adults: Induction immunosuppressive therapy", section on 'Patients at high risk of rejection'.)

-Indirect pediatric data from two large randomized clinical trials reported that the addition of basiliximab to conventional nonantibody induction therapy (eg, standard-dose cyclosporine, glucocorticoids, and mycophenolate mofetil [MMF] [8] or standard-dose tacrolimus, glucocorticoids, and azathioprine [7,23]) did not improve clinical outcome in children who underwent kidney transplantation.

•Scientific Registry of Transplant Recipients data regarding induction therapy – Analyses of data on all pediatric kidney transplants in the United States between 2000 and 2018 compared induction with alemtuzumab, ATGAM, and IL-2RA agents with primary outcomes of graft and patient survival and risk of rejection at six months.

-For children undergoing living donor transplant, long-term graft or patient survival were not affected by the choice of induction agent (alemtuzumab n = 289, anti-thymocyte n = 1197, and IL-2RA n = 1625) [24]. However, children receiving alemtuzumab induction did have higher acute rejection rates in the first year after transplant and children receiving ATGAM had a higher risk of post-transplant lymphoproliferative disease [24].

-For children undergoing deceased donor transplant who received maintenance immunosuppression of tacrolimus and mycophenolate, the choice of induction therapy (alemtuzumab n = 320, r-ATG n = 2091, and IL-2RA n = 2165) did not affect the risk of rejection at 6 or 12 months and did not affect graft and patient survival rates [25].

●rATG-thymoglobulin and glucocorticoid minimization; no effect on rate of acute rejection – In two observational pediatric studies, rATG-thymoglobulin induction with glucocorticoid minimization resulted in rejection rates comparable with historic glucocorticoid-based therapy [2,3]. In a third study, thymoglobulin induction and glucocorticoid minimization resulted in stable graft function, favorable linear growth, and no significant infectious complications [5].

Nonbiologic agents — Nonbiologic agents are generally started at maintenance doses in combination with antibody induction therapy at the time of transplantation. These include antimetabolites (mycophenolate and, less frequently, azathioprine) and CNIs (tacrolimus and, less frequently, cyclosporine) [12]. Glucocorticoid therapy was commonly used in the past for maintenance immunosuppression in pediatric kidney transplant recipients but is now infrequently used due to significant adverse effects. (See 'Maintenance immunosuppressive agents' below.)

MAINTENANCE IMMUNOSUPPRESSIVE AGENTS

General principles

Glucocorticoid-sparing regimen — Glucocorticoids were the mainstay of immunosuppressive therapy in the early days of pediatric kidney transplantation. However, the development of newer immunosuppressive agents has greatly reduced the need for glucocorticoid therapy in children undergoing kidney transplantation, thereby avoiding the significant side effects of glucocorticoid therapy. In our center, glucocorticoids are used in low-risk patients only in the setting of premedication for rabbit antithymocyte globulin (rATG)-thymoglobulin during induction therapy. For high-risk patients, glucocorticoids are used in the perioperative period (first six months following transplantation). (See 'Our approach' above.)

Glucocorticoids have multiple side effects in children, including growth impairment, susceptibility to infections, Cushingoid appearance, acne, hypertension, aseptic bone necrosis, cataracts, hyperglycemia, poor wound healing, and psychological effects. The negative impact that glucocorticoids have on appearance may play a role in poor adherence, especially in the body image-conscious adolescent [26].

Based on the available data, the approach of using a glucocorticoid-sparing protocol in pediatric kidney transplant does not appear to increase the risk of rejection or worsen graft survival [27-32]. However, the optimal approach remains uncertain as other centers continue to use glucocorticoid therapy through the first year following kidney transplantation.

There are concerns that glucocorticoid withdrawal may be associated with an increased risk of graft loss due to recurrent disease; however, one study reported no difference in graft survival due to recurrent disease in children (4 to 18 years of age) treated with a rapid prednisone-discontinuation protocol compared with historical controls who received glucocorticoid therapy [32]. Nevertheless, more data are needed to ensure that there is not an untoward increased risk of recurrent disease with glucocorticoid withdrawal. In particular, the effect of glucocorticoid withdrawal on recurrence may vary depending on the primary disease.

Combination therapy — Maintenance immunosuppression regimens generally consist of a combination of agents with different mechanisms of action, such as antimetabolites (eg, mycophenolate or, less frequently, azathioprine) and calcineurin inhibitors (CNIs; eg, tacrolimus or, less frequently, cyclosporine) [12]. Combination therapy provides a synergistic immunosuppressive effect while minimizing the side effects of each individual agent. In our center, a double-agent regimen that includes mycophenolate and tacrolimus is used for maintenance immunosuppression. (See 'Preferred antimetabolite agent: Mycophenolate' below.)

Transplant expertise — Drug therapy should be managed by a transplant specialist with expertise in balancing the maintenance of excellent allograft function and survival and minimization of the adverse effects of therapy, monitoring therapeutic drug dosing and potential drug interactions (table 2).

In addition, extended follow-up is needed to determine whether there are increases in the incidence of post-transplant lymphoproliferative disease and accelerated chronic allograft nephropathy, particularly with the advent of glucocorticoid-sparing regimens.

Preferred antimetabolite agent: Mycophenolate — Antimetabolic agents interfere with the synthesis of nucleic acids and inhibit the proliferation of both T and B lymphocytes. Although more expensive, mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS) is the preferred antimetabolite over azathioprine because of the reduction of acute rejection and fewer side effects (eg, bone marrow toxicity). In the United States, azathioprine is used less often in maintenance therapy for pediatric kidney transplant patients [12], although it has a role when there is severe gastrointestinal toxicity related to MMF or EC-MPS or in cases where once-daily dosing of immunosuppression is desirable due to adherence issues. In our center, MMF is used in combination with tacrolimus as maintenance immunosuppression.

This approach is supported by the following:

●Efficacy of mycophenolate versus azathioprine

•Observational data in children report that MMF in combination with cyclosporine and glucocorticoid therapy had better allograft survival compared with historical controls treated with azathioprine [33,34].

•In a multicenter study of children treated with MMF, cyclosporine, and glucocorticoids, the three-year patient and allograft survival rates were 98 and 95 percent, respectively [35].

•In addition, data from adult trials have shown that MMF compared with azathioprine is associated with lower rates of acute rejection and, possibly, improved graft survival. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy", section on 'Mycophenolate'.)

●Adverse effects – MMF was developed as a replacement for azathioprine for maintenance immunosuppression and as rescue therapy in patients with rejection episodes refractory to OKT3 [36-38]. It has less bone marrow toxicity compared with azathioprine. Although leukopenia is the most serious adverse effect of azathioprine, pancreatitis, hepatoxicity, neoplasia, and, most notably, skin cancer are rare but serious adverse events. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases" and "Kidney transplantation in adults: Maintenance immunosuppressive therapy", section on 'Mycophenolate'.)

Mycophenolate: Dosing, monitoring, and target levels — In our center, enteral MMF is started at a daily dose of 1200 mg/m², then decreased to 900 mg/m²/day until postoperative day 14, when the dose is further decreased to 600 mg/m²/day. We monitor mycophenolic acid levels (MPA) levels using a trough level 12 hours after administration, with targeted levels between 2 and 4 mcg/mL. MPA monitoring avoids both underdosing, which prevents rejection [39-42], and overdosing, which increases the risk of adverse reactions [39,41-43]. In addition, we use monitoring levels as a measure of adherence to the immunosuppression plan.

Mycophenolate: Adverse effects — Side effects of MMF are dose related. They include diarrhea, vomiting, leukopenia, anemia, and infectious complications. Compared with adults and older children, there is a higher incidence of adverse effects with MMF observed in children below the age of six years that may result in drug discontinuation [44-46]. Kidney transplantation in adults: Maintenance immunosuppressive therapy, section on 'Mycophenolate'

EC-MPS, an enteric-coated formulation of mycophenolate, was developed to try to improve the upper gastrointestinal tolerability of mycophenolate. Some adult studies and small pediatric case series reported that EC-MPS produced fewer gastrointestinal side effects [47,48]. However, EC-MPS cannot be crushed or made into a suspension, forcing practitioners to only use this in patients who can swallow pills whole. In addition, data on target MPA predose levels or algorithms for the calculation of MPA-AUC_0-12 values generated from MMF-treated patients cannot be applied to patients treated with EC-MPS, because the slow-release galenics of this preparation lead to a more variable pharmacokinetic profile.

Calcineurin inhibitors — CNIs have been mainstays of immunosuppression for pediatric transplantation for the past several decades and likely account for the continuing improvement in graft survival rates [49-51]. CNIs selectively inhibit calcineurin, thereby impairing the transcription of interleukin 2 (IL-2) and several other cytokines in T cells. By inhibiting cytokine gene transcription, CNIs suppress T cell and T cell-dependent B cell activation.

Although the choice between the two CNIs, tacrolimus and cyclosporine, is based on center preference, tacrolimus is our preferred agent because of the increase in adverse cosmetic effects associated with cyclosporine and the decreased rate of acute rejection seen with tacrolimus [12]. Kidney transplantation in adults: Maintenance immunosuppressive therapy, section on 'Calcineurin inhibitors'

Comparison between tacrolimus and cyclosporine — Tacrolimus is the preferred CNI over cyclosporine because data suggest that tacrolimus is associated with lower rate of acute rejection and better graft survival and lower risk of cosmetic adverse effects.

●Efficacy – The efficacy of tacrolimus relative to cyclosporine in pediatric kidney transplant recipients is supported by observational data and a single randomized trial, suggesting that tacrolimus reduces the rate of acute rejection and may improve graft survival [52-55].

In an open multicenter trial of 196 pediatric kidney transplant recipients, acute rejection rates at one-year follow-up were lower in the tacrolimus group compared with the cyclosporine group (37 versus 59 percent) and graft survival at four-year follow-up was improved in the tacrolimus versus cyclosporine group (86 versus 69 percent) [55]. Patient survival was similar at four-year follow-up (94 versus 92 percent).

The efficacy of tacrolimus relative to cyclosporine is also supported by randomized trials in adult kidney transplant recipients. These data are discussed separately and are based on trials that reported a lower incidence of acute rejection and comparable or superior graft survival with tacrolimus compared with cyclosporine. Kidney transplantation in adults: Maintenance immunosuppressive therapy, section on 'Calcineurin inhibitors'

●Adverse effects – The toxicity profiles of tacrolimus and cyclosporine are similar. Side effects of both CNIs include nephrotoxicity, hypertension, diabetes mellitus (which is more common with tacrolimus), neurotoxicity, hyperkalemia, hypomagnesemia, dyslipidemia, and increased susceptibility to serious infection and risk of malignancy. However, gingival hyperplasia and hirsutism are seen with cyclosporine therapy but not with tacrolimus. The adverse cosmetic effects of cyclosporine may contribute to nonadherence to medications, especially in adolescent patients [56]. (See "Pharmacology of cyclosporine and tacrolimus", section on 'Side effects'.)

Dosing and drug target level

Tacrolimus

●Dosing – The initial oral or nasogastric dose for tacrolimus is 0.2 to 0.3 mg/kg/day administered in two divided doses [57]. In some cases, tacrolimus is initially administered intravenously (IV) at a dose of 0.05 to 0.1 mg/kg over 24 hours and switched to oral medication within two to three days post-transplant. Dosing is adjusted based on maintaining target levels.

●Drug target level – Target levels for tacrolimus are generally higher in the early post-transplant period and then are reduced. Target levels vary by center and specific protocol used. In our center, target trough whole blood levels are:

•10 to 15 ng/mL during the first month

•5 to 10 ng/mL for subsequent months

•If patients are rejection free at one-year post-transplant, our target trough whole blood levels are further reduced to a range between 3 and 5 ng/mL

Cyclosporine

●Dosing – Cyclosporine doses are higher than those prescribed in adults because the drug appears to have a more rapid metabolism in children [58]. The recommended starting oral dose of cyclosporine is age dependent:

•Children younger than six years – The starting dose is 500 mg/m²/day divided every eight hours.

•Children older than six years, for patients on combination therapy with glucocorticoids and/or purine synthesis inhibitors – The starting dose is between 12 and 15 mg/kg/day divided every 12 hours.

Three to six months post-transplant, dosing is reduced to 4 to 6 mg/kg/day and is adjusted based on trough drug levels.

●Drug target level – Target trough whole blood levels are:

•150 and 300 mcg/L for the first three to six months post-transplant

•75 to 125 mcg/L for subsequent months

Drug interactions with calcineurin inhibitors — An important consideration for patients who receive CNIs is that several drugs may interfere with CNI metabolism. A brief review of the drugs is presented elsewhere, and additional information on drug interactions can be found in the drug interactions program provided by UpToDate. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy", section on 'Drug interactions'.)

Modification of maintenance therapy — Maintenance immunosuppression may be modified in the following settings:

●ABO-incompatible transplant – Cases of successful ABO-incompatible kidney transplants using desensitization strategies in children have been reported, similar to those reported in adults [59,60]. Desensitization protocols are used to lower the immunogenicity of the incompatibility and involve a combination of rituximab, plasmapheresis, and intravenous immune globulin (IVIG) to deplete B cell and reduce circulating anti-A/B antibody. (See "Kidney transplantation in adults: ABO-incompatible transplantation".)

●Intolerance or toxicity of CNIs – For patients who are unable to tolerate CNIs due to nephrotoxicity or other adverse effects, alternative immunosuppression regimens include use of mammalian (mechanistic) target of rapamycin (mTOR) inhibitors (everolimus or sirolimus) [61,62]. (See "Pharmacology of mammalian (mechanistic) target of rapamycin (mTOR) inhibitors" and "Kidney transplantation in adults: Maintenance immunosuppressive therapy", section on 'Calcineurin inhibitor-related toxicity'.)

ACUTE REJECTION IMMUNOSUPPRESSION — There have been no controlled trials of treatment of acute organ transplant rejection in children. The two principal histologic forms of acute rejection include acute T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) and are treated with different regimens. Management of these two conditions in children are based on adult data.

Acute T cell-mediated rejection — TCMR is caused by T cells that react to donor histocompatibility antigens present within tubules, interstitium, vessels, and glomeruli of the allograft. The histologic changes noted on kidney biopsy that occur with acute TCMR include interstitial infiltration with mononuclear cells and, occasionally, eosinophils and disruption of the tubular basement membranes by the infiltrating cells (ie, tubulitis) (picture 1). (See "Kidney transplantation in adults: Clinical features and diagnosis of acute kidney allograft rejection", section on 'Acute T cell-mediated (cellular) rejection'.)

Management is guided predominately by the Banff histologic classification of acute TCMR (table 1), based on data from adult studies (see "Kidney transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection"). The Banff grades are as follows:

●Borderline – Mild interstitial inflammation (<25 percent of nonsclerotic cortical parenchyma; i0 or i1) plus any tubulitis (t1, t2, or t3) or significant interstitial inflammation (>25 percent of nonsclerotic cortical parenchyma; i2 or i3) plus foci of mild tubulitis (t1).

●Type IA – Significant interstitial inflammation (>25 percent of nonsclerotic cortical parenchyma; i2 or i3) and foci of moderate tubulitis (t2).

●Type IB – Significant interstitial inflammation (>25 percent of nonsclerotic cortical parenchyma; i2 or i3) and foci of severe tubulitis (t3).

●Type IIA – Mild-to-moderate intimal arteritis (v1) with or without interstitial inflammation and tubulitis.

●Type IIB – Severe intimal arteritis comprising >25 percent of the luminal area (v2) with or without interstitial inflammation and tubulitis.

●Type III – Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic inflammation.

In our center, therapy for acute TCMR is guided by the Banff histologic grade, as follows:

●In patients with Banff grade I, pulse high-dose glucocorticoids (30 mg/kg, maximum dose 1 g) are provided for three days, followed by a course of oral prednisone starting at 1 mg/kg (maximum dose 40 mg) administered twice a day for three days that is then tapered to the prerejection dose over two weeks. Some centers also administer rabbit antithymocyte globulin (rATG)-thymoglobulin for patients with Banff grade IB during the three-day intravenous (IV) steroid pulse.

●In patients with Banff grade II or III, rATG-thymoglobulin is administered for 5 to 10 days depending on the severity of rejection, in addition to the glucocorticoid regimen used in Banff grade I.

Antibody-mediated rejection — ABMR is thought to be caused by the binding of circulating antibodies to donor alloantigens on graft endothelial cells, which results in inflammation, cell damage, and, ultimately, graft dysfunction. Such antigens most commonly include human leukocyte antigen class I and class II antigens and, in recipients of ABO-incompatible transplants, ABO blood group antigens; other nonmajor histocompatibility complex alloantigens on the endothelium may also be targeted. (See "Kidney transplantation in adults: Clinical features and diagnosis of acute kidney allograft rejection", section on 'Active antibody-mediated rejection'.)

ABMR is treated with a combination of immunosuppressive agents with a goal of removing existing donor-specific antibodies and eradicating the clonal population of B cells or plasma cells that is responsible for their production. Therapeutic interventions include plasma exchange, high-dose intravenous immune globulin (IVIG), rituximab (anti-CD20 agent), and pulse IV methylprednisolone.

In our center, a three- to five-day course of plasma exchange is administered, followed by a single dose of IVIG (2 g/kg) and rituximab (375 mg/m²) weekly for four doses. The number of doses depends on the severity of ABMR and response to therapy.

Response to therapy — After the initiation of antirejection therapy, the plasma creatinine concentration may continue to increase for three to four days. However, if therapy reverses rejection, creatinine levels should decrease after one week. The rejection episode may be completely reversible, with the creatinine level returning to levels similar to those observed prior to the rejection episode. In approximately 40 percent of cases, the serum creatinine remains elevated above baseline, which can be due to either chronic damage or ongoing rejection [63].

A rejection episode may be considered glucocorticoid resistant if no improvement is observed in the plasma creatinine 7 to 10 days after initiation of glucocorticoid pulse therapy. Glucocorticoid-resistant, severe, or recurrent episodes are treated with lymphocyte-depleting antibodies (eg, rATG-thymoglobulin).

Reevaluation of maintenance immunosuppression is warranted following a rejection episode. One may consider switching immunosuppressive agents. For example, adjustments may include changing to an alternative calcineurin inhibitor (CNI) or from an antimetabolite (ie, mycophenolate mofetil [MMF] or azathioprine) to mammalian (mechanistic) target of rapamycin (mTOR) inhibitor (eg, sirolimus) to take advantage of the synergism between sirolimus and the CNIs as well as considering glucocorticoid therapy. In addition, assessment of the patient's adherence to the medication regimen is always important.

SUMMARY AND RECOMMENDATIONS

●Goal – The goal of immunosuppression in pediatric kidney transplant recipients is to provide an immunosuppressive regimen that optimizes patient survival and allograft survival by preventing acute rejection, while minimizing toxicities such as infection, nephrotoxicity, malignancy, and adverse cosmetic effects. (See 'Goal' above.)

●Components – Immunosuppressive therapy is divided into three components. (See 'Goal and components of immunosuppressive therapy' above.)

•Induction therapy – Induction therapy provides the highest degree of immunosuppression and is administered during the perioperative period, when the risk of acute rejection is highest.

•Maintenance therapy – The intensify of maintenance immunosuppressive therapy is less as the risk of acute rejection decreases after the perioperative period. Maintenance therapy is typically started at the time of transplantation.

•Acute rejection therapy – Immunosuppressive therapy is increased to treat acute rejection.

●Patient risk stratification – More intensive immunosuppression (eg, induction therapy) is selected for patients who are at greater risk for allograft rejection (defined as high risk). Risk factors include:

•One or more human leukocyte antigen mismatches (see "Kidney transplantation in adults: HLA matching and outcomes")

•Panel reactive antibody greater than 0 percent (sensitization)

•Presence of a donor-specific antibody

•Blood group incompatibility

•Retransplant

•Delayed onset of graft function

•Cold ischemia time greater than 24 hours

•In the United States, Black individuals

●Induction immunosuppression – For pediatric kidney transplant recipients, we recommend that antibody induction therapy be used in conjunction with conventional immunosuppression (Grade 1B). This is based on data from clinical trials (largely in high-risk adult kidney transplantation recipients) showing that antibody induction therapy improves allograft survival and reduces the risk of acute rejection. Observational studies in pediatric kidney transplant recipients suggest that antibody induction therapy likely has similar benefits in this population. (See 'Antibody induction therapy' above and "Kidney transplantation in adults: Induction immunosuppressive therapy", section on 'Indications for induction therapy'.)

For most pediatric kidney transplant recipients, we suggest rabbit antithymocyte globulin (rATG)-thymoglobulin as the preferred agent for induction therapy rather than antithymocyte globulin (ATGAM) or interleukin-2 (IL-2) receptor antibodies (eg, basiliximab) (Grade 2C). In observational pediatric studies and clinical trials in adults, rATG-thymoglobulin was associated with lower rates of acute rejection and adverse effects compared with ATGAM or basiliximab. (See 'Choice of agent' above and "Kidney transplantation in adults: Induction immunosuppressive therapy", section on 'rATG-Thymoglobulin'.)

In our center, an initial intravenous (IV) dose of rATG-immunoglobulin (1.5 mg/kg) is administered intraoperatively. Additional doses are administered postoperatively, and the number of doses depends on the patient's risk for acute rejection. (See 'Data comparing different agents' above and 'Our approach' above and 'Patient risk stratification' above.)

●Maintenance immunosuppression – All children who receive a kidney transplantation require maintenance immunosuppression. Maintenance immunosuppression regimens generally consist of a combination of agents with different mechanisms of action such as antimetabolites (eg, mycophenolate mofetil [MMF] or, less frequently, azathioprine) and calcineurin inhibitors (CNIs; eg, tacrolimus or, less frequently, cyclosporine). Combination therapy provides a synergistic immunosuppressive effect while minimizing the side effects of each individual agent. (See 'Maintenance immunosuppressive agents' above.)

•For most pediatric transplant recipients, we suggest a glucocorticoid-sparing maintenance regimen (Grade 2C). This minimizes the considerable adverse effects associated with long-term glucocorticoid therapy. The available data suggest that a glucocorticoid-sparing regimen does not affect the risk of acute rejection and graft loss. (See 'Glucocorticoid-sparing regimen' above.)

•For most pediatric kidney transplant recipients, we suggest a maintenance regimen consisting of MMF plus tacrolimus rather than other agents (eg, azathioprine or cyclosporine) (Grade 2C). Compared with azathioprine, MMF is better tolerated and may be associated with lower acute rejection rates. Compared with cyclosporine, tacrolimus is generally better tolerated (in particular, it avoids the adverse cosmetic effects of cyclosporine, which may contribute to nonadherence) and it may be associated with lower acute rejection rates. (See 'Preferred antimetabolite agent: Mycophenolate' above and 'Calcineurin inhibitors' above and 'Modification of maintenance therapy' above.)

-MMF – Enteral MMF is started at a daily dose of 1200 mg/m², and then it is decreased to 900 mg/m²/day until postoperative day 14, when the dose is decreased to 600 mg/m²/day and modified based on targeted mycophenolic acid levels (MPA) trough levels between 2 and 4 mcg/mL. (See 'Our approach' above and 'Mycophenolate: Dosing, monitoring, and target levels' above.)

-Tacrolimus – Enteral tacrolimus is started on postoperative day 1 for deceased donor recipients and preoperatively for living donor recipients. The starting dose is 0.075 mg/kg administered as two divided oral doses. This is a lower dose than used in other centers because its administration overlaps with that of rATG-thymoglobulin for two days. The dose is adjusted to obtain a 12-hour trough blood level of 10 to 15 ng/mL during the first month post-transplantation. The target trough level is lowered progressively over time. For patients who are rejection free at one-year post-transplant, the trough level is maintained at 3 to 5 ng/mL. (See 'Our approach' above and 'Tacrolimus' above.)

●Acute rejection immunosuppression – Immunosuppression for acute rejection, defined as an acute deterioration in allograft function, is based on the specific histology findings observed on kidney biopsy (see 'Acute rejection immunosuppression' above):

•For children with acute T cell-mediated rejection (TCMR), management is guided by the Banff histologic classification of acute TCMR. As the severity of TCMR increases, more intensive immunosuppression is administered. (See 'Acute T cell-mediated rejection' above.)

-For patients with Banff grade I TCMR, we suggest administering pulse high-dose glucocorticoids (Grade 2C). In our center, a three-day course of IV methylprednisolone (30 mg/kg/day, maximum dose 1 g) is administered, followed by prednisone 1 mg/kg (maximum dose 40 mg) twice a day for three days, followed by a two-week oral taper back to the prerejection dose.

-For patients with Banff grades II or III, we suggest treatment with rATG-thymoglobulin (1.5 mg/kg), in addition to the glucocorticoid regimen used in Banff grade I (Grade 2C).

•For children with antibody-mediated acute rejection, we suggest combined treatment with plasma exchange plus intravenous immune globulin (IVIG) and rituximab (Grade 2C). In our center, a typical regimen consists of a three-day course of plasma exchange, followed by a single dose of IVIG (2 g/kg) and rituximab (375 mg/m²) weekly for four doses. (See 'Antibody-mediated rejection' above.)