New Immunosuppressants in Pediatric Kidney Transplantation: What's in the Pipeline for Kids?

ABSTRACT

The 1‐ and 5‐year patient and graft survival rates of pediatric kidney transplant recipients have improved considerably in recent years. Regardless of early success, kidney transplantation is challenged by suboptimal long‐term allograft and patient survival. Many kidney transplants are lost due to immune (rejection) and nonimmune allograft injuries, and patient survival is limited from cardiovascular disease, infection, and malignancy. Many of these co‐morbidities are due to side effects of the currently available immunosuppressive drugs, especially calcineurin inhibitors and glucocorticoids, which are associated with long‐term toxicity. Hence, there is an urgent need to develop new, more specific and less toxic immunosuppressive drugs. Unfortunately, there have also been no new drug approvals for adult kidney transplant recipients since belatacept in 2012, leaving the immunosuppressive drug armamentarium unchanged for more than 20 years. As a consequence of the lack of innovation in adult kidney transplant recipients, the pipeline of novel immunosuppressive agents for pediatric solid organ transplant recipients is also limited. The most promising agent in the near future, at least for adolescent patients, appears to be belatacept, despite its many limitations. In this review article, we report on three areas that appear to be the most relevant topics at this time: (i) extended‐release tacrolimus, (ii) costimulation blockade with belatacept, and (iii) treatment of antibody‐mediated rejection. Improved synergies between the pharmaceutical industry and the transplant community are needed to achieve the ultimate goal of improving long‐term outcomes in pediatric kidney transplantation.

1. Introduction

According to data from the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS), the 5‐year patient survival rate for living and deceased kidney donors is currently 89% and 85% respectively [1]. The most common causes of death are infections (27.9%), cardiopulmonary complications (14.5%), malignancy (11.3%), and dialysis‐related complications (3%). Almost half of the patients who died (48%) had a functioning graft [1]. The survival rate of transplants has also improved considerably in recent years, especially in deceased donor kidney transplants. According to the data of the Collaborative Transplant Study, a 5‐year transplant survival rate of 84% after living donation and 76% after deceased donation can currently be expected for pediatric patients in Europe, North America and Australia (Figure 1). Regardless of early success, kidney transplantation is challenged by suboptimal long‐term allograft and patient survival. Many kidney transplants are lost due to immune (rejection) and nonimmune allograft injuries, and patient survival is limited from cardiovascular disease, infection, and malignancy. Many of these co‐morbidities are due to side effects of the currently available immunosuppressive drugs, especially calcineurin inhibitors and glucocorticoids, which are associated with long‐term toxicity. Hence, there is an urgent need to develop new, more specific and less toxic immunosuppressive drugs. Unfortunately, the pipeline of novel immunosuppressive drugs for adult and pediatric kidney transplant recipients is rather limited. ClinicalTrials.gov currently lists only 8 trials of immunosuppressants in pediatric kidney transplant recipients, 7 of which are investigator‐initiated and only 1 of which is an industry‐sponsored trial (for the approval of belatacept), and only 5 of these 8 trials are currently recruiting (Table 1). In this review article on new immunosuppressants in pediatric kidney transplantation, we report on three areas that appear to be the most relevant topics at this time: (i) extended‐release tacrolimus, (ii) costimulation blockade with belatacept, and (iii) treatment of antibody‐mediated rejection. This review article focuses on pediatric kidney transplant recipients, but many aspects can be applied on pediatric recipients of other solid organ transplants such as liver and heart.

FIGURE 1.

Five‐year kidney transplant survival in pediatric patients in Europe, North America and Australia after deceased (DecDon) or living donation (Liv‐Don), stratified by the periods 2000–2009 and 2010–2019. (With kind permission of the “Collaborative Transplant Study,” Priv.‐Doz. Dr. Tran, Heidelberg).

TABLE 1.

Current trials of immunosuppressants in pediatric kidney transplant recipients listed on the website ClinicalTrials.gov.

Type and title of study (according to ClinialTrials.gov)	NCT number	Study population	Sponsor	Geographical region	Study status
Maintenance immunosuppressive therapy
Once daily dosing to improve medication adherence and patient satisfaction in kidney transplant recipients (OnceDaily) (Advagraf) a	NCT02426502	12 years and older (+ adults)	IIT	Canada	Active, not recruiting
Pharmacokinetics, effectiveness and tolerability of prolonged‐release tacrolimus after pediatric kidney transplantation (Pro‐Tac) (Envarsus XR)	NCT06057545	8–18 years	IIT	Germany	Recruiting
Envarsus XR in adolescent renal transplant recipients	NCT03266393	13–20 years	IIT	USA	Active, not recruiting
Advancing transplantation outcomes in children (ADVANTage) (belatacept)	NCT06055608	13–20 years	IIT	USA, Canada	Recruiting
A study to evaluate the benefits and risks of conversion of existing adolescent kidney transplant recipients aged 12 to < 18 Years to a Belatacept‐based immunosuppressive regimen as compared to continuation of a calcineurin inhibitor‐based regimen, and their adherence to immunosuppressive medications	NCT04877288	12–17 years	Industry b	USA, Europe, UK	Recruiting
Cell therapy for induction of tolerance
Early trial of allogeneic hematopoietic stem cell transplantation for patients who will receive a kidney transplant from the same donor	NCT05508009	1–30 years	IIT	USA	Recruiting
Treatment of antibody‐mediated rejection
Transplant antibody‐mediated rejection: guiding effective treatments (TAR:GET‐1) (standard of care‐treatment vs. standard of care‐treatment + rituximab, outcome measure: 4 year allograft survival)	NCT03994783	5 years and older (+ adults)	IIT	UK	Active, not recruiting
Comparison between bortezomib and rituximab plus plasmapheresis in AMR	NCT03737136	Children and adults	IIT	Iran	Recruiting

Abbreviations: AMR, antibody mediated rejection; IIT, investigator initiated trial.

^a “Astagraf XL” in USA.

^b Bristol‐Myers Squibb.

2. Individual Immunosuppressive Drugs and Their Sites of Action in the Three‐Signal Model

Current immunosuppressive and immunomodulatory drugs can be pharmacologically categorized on the basis of their mechanism of action. The three‐signal model of T‐cell activation and proliferation is helpful in understanding the molecular mechanisms and site of action of various immunosuppressive drugs [2]. Signal 1 features antigen‐presenting cells (APCs; macrophages and dendritic cells) presenting the foreign antigen to the T lymphocyte, activating the T‐cell receptor (TCR), which further relays the signal through the transduction apparatus known as the CD3 complex. Signal 2 is a nonantigen‐specific costimulatory signal which occurs as a result of binding of the B7 molecule on the APC to CD28 on the T cell. Both signal 1 and signal 2 activate signal transduction pathways: the calcium–calcineurin pathway, mitogen‐activated protein (MAP) pathway, and the nuclear factor‐κB (NF‐κB) pathway. This, in turn, leads to increased expression of interleukin (IL)‐2, which through its receptor (IL‐2R) activates the cell cycle (signal 3). Signal 3 activation requires the enzyme target of rapamycin for translation of messenger RNA (mRNA) and cell proliferation. Thus, various drugs act on different cellular signals and achieve immunosuppression by a number of mechanisms: depleting lymphocytes, diverting lymphocyte traffic, or blocking lymphocyte response pathways. Figure 2 depicts a schematic representation of the three‐signal model along with the site of action of current immunosuppressive drugs.

FIGURE 2.

Individual immunosuppressive drugs and sites of action in the three‐signal model. MPA denotes mycophenolic acid. Modified according to (ref. [2]).

3. Extended‐Release Tacrolimus

The calcineurin inhibitor (CNI) tacrolimus is considered to be the backbone of maintenance immunosuppressive therapy in solid organ transplantation. Tacrolimus is currently available in three oral formulations: immediate‐release capsules (IR‐Tac) twice daily, extended‐release capsules (ER‐Tac, Astagraf XL; Northbrook, IL: Astellas Pharma US Inc.; named Advagraf outside the US) once daily, and as extended‐release, melt‐dose tablets (LCP‐Tac, Envarsus XR; Cary, NC: Veloxis USA Inc.). LCP‐Tac is the latest formulation available with improved bioavailability and lower maximum concentrations compared to IR‐Tac. While ER‐Tac inhibits the release of Tac by slowing the diffusion rate of Tac, LCP‐Tac improves absorption throughout the gastrointestinal tract due to a more distally directed distribution of tacrolimus [3]. The advantages of LCP‐Tac are its improved bioavailability, less fluctuation in tacrolimus blood concentrations between peak and trough levels during a dosing interval, a delayed time to reach maximum blood concentrations and lower maximum tacrolimus blood concentrations with the potential for improved side effects [4, 5]. In addition, LCP‐Tac has shown the potential for improved medication adherence compared to the IR formulation in adult transplant recipients [6]. In adult kidney transplant recipients, LCP‐Tac has been shown to be non‐inferior to IR‐Tac with respect to the primary efficacy endpoints of death, graft failure and acute rejection. In addition, several studies have demonstrated comparable renal function (eGFR) of the kidney graft in patients treated with LCP‐Tac and IR‐Tac [6, 7]. The safety results were also similar in both groups [8]. Experience with liver transplantation in adults has shown that switching from IR‐Tac to LCP‐Tac leads to improved renal function and stable liver graft function [9]. The literature on heart transplants in adults also describes low rejection rates and a better side effect profile when switching to LCP‐Tac [10, 11].

There are no large prospective studies evaluating the use of LCP‐Tac in pediatric organ transplant patients, and the few studies that do exist are small and address safe use in kidney transplant recipients, dosing conversion in adolescent and young adult transplant recipients with abdominal grafts, and the pharmacokinetic profile of LCP‐Tac in adolescent and young adult renal and liver transplant recipients [12, 13]. Huang and colleagues investigated de novo and conversion use of LCP‐Tac in pediatric abdominal transplant recipients and showed that therapeutic trough concentrations can be achieved with lower doses (0.1 mg/kg) than in adults (0.14 mg/kg) and that there are no changes in rejection rates despite differences in pharmacokinetics in pediatric patients [14]. There are currently no published reports on the use of LCP‐Tac in pediatric heart transplant recipients. In addition, data evaluating clinical outcomes such as graft function, survival and drug concentration variability in pediatric, adolescent and young adult transplant recipients are lacking.

On the website of clinicaltrials.gov, there are currently three studies listed with extended‐release tacrolimus in pediatric kidney transplant recipients (Table 1). The study NCT02426502 evaluates the feasibility and safety of transitioning kidney transplant recipients to a once‐daily treatment regimen including Advagraf, once daily MPA and once daily anti‐hypertensive medication to enhance medication adherence and patient satisfaction. It focuses primarily on safety and feasibility and secondarily on adherence and satisfaction. The study NCT06057545 evaluates the pharmacokinetics, effectiveness and tolerability of once‐daily and prolonged release tacrolimus (Envarsus) in pediatric kidney transplant recipients, comparing it to the conventional twice‐daily immediate‐release tacrolimus (Prograf). The study NCT03266393 evaluates the safety and efficacy of switching adolescent kidney transplant recipients from twice‐daily tacrolimus to once‐daily extended‐release tacrolimus (Envarsus XR). It aims to examine safety, medication adherence and patient reported outcomes.

4. Costimulatory Blockade With BELATACEPT

Costimulation is required for the regulation of an effective alloimmune response (Figure 2). The costimulatory pathway is not addressed by conventional immunosuppressive therapy. Biological agents that can interfere with the costimulatory pathway may allow a more precise targeting of the immune response without causing non‐immune side effects. Belatacept, a fusion protein composed of a crystallizable fragment (Fc) of immunoglobulin (Ig) G1 and the extracellular domain of cytotoxic T‐lymphocyte protein 4 (CTLA4), is the only costimulation blockade therapy currently available for the prevention of rejection after kidney transplantation [15, 16]. Belatacept is well tolerated and its use is associated with improved allograft function compared with CNI in certain subgroups of kidney transplant recipients [17, 18]. However, due to the high risk of acute rejections, belatacept may not be the hoped‐for turning point [19].

Belatacept interferes with the CD28‐CD80/CD86 signaling pathway. The costimulatory molecule CD28 is a surface receptor that is constitutively expressed on T cells (Figure 3). The inhibitory receptor CTLA4 is localized in intracellular vesicles in resting T cells and is expressed on the cell surface 48–72 h after T cell activation. CTLA4 binds to CD80 and CD86 with a higher affinity than CD28 [20]. Therefore, the binding of CTLA4 to CD80/CD86 attenuates T cell activation [21]. At birth, almost all human T cells express CD28 [22]. Aging, continuous antigenic stimulation (e.g., by kidney failure, human immunodeficiency virus infection and autoimmune disease) and cytomegalovirus infection result in loss of CD28 expression by T cells [22, 23, 24]. These CD28 effector memory T cells have reduced costimulatory requirements and limited proliferative capacity, but are highly proinflammatory [22, 25]. These cells rapidly secrete effector cytokines (i.e., tumor necrosis factor alpha and interferon gamma) upon restimulation.

FIGURE 3.

Belatacept: A second generation CTLA4‐Ig fusion protein selectively blocks CD28‐CD80/86 pathway for T‐cell activation.

In 2011, belatacept was approved by the European Medicines Agency and the US Food and Drug Administration as a treatment for the prevention of acute rejection based on the results of two large randomized, controlled, multicenter phase III studies: the Belatacept Evaluation of Nephroprotection and Efficacy as First‐line Immunosuppression (BENEFIT) study (with standard criteria donors) and the BENEFIT‐EXT study (expanded criteria donors) [16, 26, 27]. In these studies, 1264 kidney transplant recipients were treated with either cyclosporine or belatacept as first‐line therapy in combination with mycophenolic acid and glucocorticoids. The main results of the BENEFIT and BENEFIT‐EXT studies were that the 1‐year survival of patients treated with belatacept and the survival of allografts were comparable to those of patients treated with cyclosporine [26, 27]. Although the incidence of acute T‐cell‐mediated rejection was increased in patients treated with belatacept, renal function was better in these patients compared to those treated with cyclosporine. In addition, the use of belatacept was associated with an increased risk of lymphoproliferative disorders after transplantation, especially in Epstein–Barr virus seronegative kidney transplant recipients [26, 27, 28].

In 2016, the 7‐year follow‐up results of the BENEFIT and BENEFIT‐EXT studies were published. In these studies, the risks of death and graft loss in patients with kidney transplantation who were treated with belatacept were similar to those in patients treated with cyclosporine [17, 18]. Although the risk of acute T cell‐mediated rejection was higher in patients treated with belatacept compared to those treated with cyclosporine, their renal function was better after 7 years. One explanation for the better renal function could be that belatacept is associated with less interstitial inflammation and tubular atrophy compared to CNI. Vitalone et al. compared the 1‐year protocol biopsies of KTRs treated with belatacept or cyclosporine [29] and found that the biopsies of patients treated with belatacept had less interstitial inflammation, interstitial fibrosis and tubular atrophy, and gene expression analysis revealed lower expression of genes involved in fibrosis and tubulointerstitial damage than in the biopsies of patients treated with cyclosporine [29]. In another study, 10‐year protocol biopsies from 23 clinically stable kidney transplant recipients treated with belatacept and 10 kidney transplant recipients treated with CNI (seven on cyclosporine and three on tacrolimus) were analyzed [30]. In biopsies of patients treated with belatacept, there was less interstitial inflammation and tubular atrophy, and less hyalinosis.

The 7‐year follow‐up studies also showed that the formation of new donor‐specific anti‐HLA antibodies (DSAs) in patients treated with belatacept compared to those treated with cyclosporine was significantly lower [17, 18]. A possible explanation for this observation could be that the costimulatory blockade with belatacept leads to a more effective prevention of DSA formation by B cells and that the drug adherence in patients treated with belatacept is better due to the intravenous administration. The occurrence of post‐transplant diabetes mellitus, arterial hypertension, and dyslipidemia was not discussed in the long‐term follow‐up studies on belatacept. In summary, these long‐term results show that belatacept therapy is a safe therapy for kidney transplant recipients and is associated with better renal function and a lower incidence of de novo DSA. Whether long‐term belatacept therapy leads to a better metabolic profile than CNI therapy is not known [17, 18, 28].

Although the use of belatacept is associated with a risk of acute T cell‐mediated rejection, it has been shown to be a good alternative in kidney transplant recipients with a contraindication to CNIs. Several studies have reported successful conversion to belatacept in kidney transplant recipients with CNI‐induced nephrotoxicity, impaired allograft function, delayed graft function, CNI‐mediated thrombotic microangiopathy or atypical hemolytic‐uremic syndrome (for review see ref. [31]). In addition, kidney transplant recipients with poorly controlled diabetes mellitus during CNI therapy have benefited from belatacept [32, 33]. Since belatacept must be administered intravenously, it has the potential advantage of offering better compliance, for example in young transplant recipients [34].

Several approaches to switching to belatacept have been investigated, including early or late switching [35, 36, 37, 38], belatacept in combination with a short course of tacrolimus [39], and non‐invasive screening for acute rejection after switching to detect acute rejection at an early stage [40]. A phase 3b randomized controlled trial [41] randomized stable adult kidney transplant recipients 6–60 months post‐transplant to either continue CNI‐based immunosuppression (with 90% of these patients treated with tacrolimus) or switch to belatacept. While 24‐month graft survival was identical in both groups, eGFR was significantly higher in the belatacept group (55.5 vs. 48.5 mL/min per 1.73 m²) and the rate of de novo DSAs (1% vs. 7%) was lower, albeit at the expense of a higher incidence of biopsy‐proven acute cellular rejection (8% vs. 4%).

By far the most common indication for belatacept conversion rescue therapy is allograft dysfunction caused by either CNI toxicity, interstitial fibrosis/tubular atrophy, or the development of de novo DSAs (for review see ref. [42]). The vast majority of these studies found that belatacept conversion rescue therapy stabilized eGFR in this patient population with allograft dysfunction. A recently published retrospective cohort study of 139 renal transplant recipients with chronic vascular lesions (Banff cv score > 2) and impaired graft function (eGFR < 40 mL/min per 1.73 m²) confirmed these earlier findings and showed that switching to belatacept was associated with a significant improvement in graft survival (at 3 years 84% vs. 65.1% in the control group, p < 0.001), with less de novo DSA formation and no increase in the rate of biopsy‐proven acute cellular rejection [43]. However, the role of belatacept conversion in this patient group requires further investigation, as a recent retrospective study of 48 patients with chronic antibody‐mediated rejection failed to show any improvement in mean eGFR or de novo DSA incidence in patients converted to belatacept compared with patients who remained immunosuppressed with tacrolimus, MMF, and prednisone [44]. Future studies may help to identify patients who will benefit most from belatacept conversion salvage therapy, depending on the etiology of the disease and the pre‐existing degree of renal allograft dysfunction and damage. At least one study suggesting that patients with higher proteinuria at the time of conversion are less likely to benefit from belatacept treatment supports the possibility that certain cases of allograft damage are irreversible and no longer amenable to belatacept treatment.

The most recent study of belatacept‐based CNI‐ and glucocorticoid‐sparing immunosuppression was a multicenter phase 2 trial comparing rabbit antithymocyte globulin (rATG) induction with rapidly tapered steroid induction (discontinued on postoperative Day 7). The trial compared kidney transplant recipients receiving belatacept and daily everolimus with a control group treated with conventional tacrolimus and MMF. This study showed similar biopsy‐proven rejection rates at 6 months (7.7% vs. 9.4%) and 24 months (16.0% vs. 15.2%) in the belatacept plus everolimus and tacrolimus plus MMF groups. However, no benefit in 24‐month mean unadjusted eGFR was observed between these regimens (71.8 vs. 68.7 mL/min per 1.73 m²) [45]. Although the results are promising due to the similar rejection rates between the groups, the lack of improvement in renal function with the combination of belatacept with depleting induction and the use of an mTOR inhibitor may limit enthusiasm for this therapy.

4.1. Belatacept in Pediatrics

Although currently only approved for adult kidney transplant recipients, case series show that there is potential to expand the clinical indications of belatacept in transplantation. Several centers have published case reports on the use of belatacept in adolescent pediatric kidney transplant recipients [34, 46, 47, 48]. Belatacept offers several unique benefits in this patient population. First, the benefits of belatacept on long‐term eGFR may be even higher in pediatric patients due to the longer period of time they would otherwise be treated with potentially nephrotoxic CNIs. Second, adherence to immunosuppressive therapy in adolescence and young adults is notoriously challenging, and a drug such as belatacept, which requires a monitored monthly infusion, may offer distinct advantages over CNIs that require daily administration. However, the requirement that belatacept recipients be EBV seropositive to reduce the risk of post‐transplant lymphoproliferative disease may limit the use of belatacept in younger children, as only 54% of children between the ages of 6 and 8 years are estimated to be EBV‐seropositive, compared to 83% of adolescents aged 18–19 years [49]. A phase 3b prospective, open‐label, multicenter, randomized trial for the approval of belatacept in children and adolescents is currently being conducted in Europe and North America (Table 1). This study evaluates the benefits and risks of conversion of adolescent kidney allograft recipients aged 12–17.9 years to a belatacept‐based immunosuppressive regimen as compared to continuation of a CNI‐based regimen, and their adherence to immunosuppressive medications. This study will enroll approximately 102 adolescent kidney allograft recipients who are at least 6 months post‐transplant. Participants must meet the following key inclusion criteria: (i) Male and females between 12 and < 18 years of age; (ii) documented EBV seropositivity prior to transplant and randomization; (iii) receiving a stable regimen of a CNI with a mycophenolate with or without concomitant glucocorticoids for > 1 month prior to randomization; (iv) stable renal function 12 weeks prior to screening based upon investigator assessment and protocol‐defined criteria for eGFR and proteinuria, (v) no treatment for biopsy‐proven acute rejection of any degree of severity within 6 months prior to enrollment, (vi) no history of acute antibody‐mediated rejection or Banff Grade IIA or higher acute cellular rejection with the current transplant.

Another trial on belatacept, the investigator‐initiated ADVANtage (Advancing Transplant Outcomes in Children) trial, is currently being performed in the United States [50] (Table 1). This trial is based on the concept that successful preservation of long‐term allograft function requires an immunosuppressive regimen that targets donor‐specific alloantibody (DSA) production and promotes immunomodulation while preserving pathogen‐specific immunity. The investigators propose that pediatric recipients require precision tools to monitor, identify and prevent silent subclinical intragraft inflammation/rejection, which is common at early times in the post‐transplant period. Based on a recent pilot study using de novo belatacept therapy in combination with an mTOR inhibitor (mTORi) in pediatric recipients, the investigators will test the hypothesis that early introduction of a belatacept/sirolimus maintenance immunosuppressive regimen is safe and efficacious in children to augment immunoregulation, prevent DSA production and enhance long‐term allograft function. EBV seropositive primary renal transplant recipients, aged between 6 and 21 years, from 20 experienced pediatric clinical centers will be randomized to receive induction therapy with anti‐thymocyte globulin and either belatacept therapy in combination with sirolimus or remain on standard immunosuppression therapy using tacrolimus and mycophenolate mofetil. Primary endpoint analysis includes de novo DSA development after 12 months and assessment of allograft function after 24 months of follow‐up. Associated studies include surveillance monitoring of the alloimmune response, the use of a novel automated point‐of‐care urine biomarker assay, and in‐depth mechanistic studies on the cellular basis for pathogen‐specific immunity and evaluation of functional antibody responses to vaccine. Extensive mechanistic studies will also be performed to assess the impact of de novo introduction of belatacept/mTORi on cellular and humoral alloimmunity and the further development of urinary biomarkers to differentiate subclinical rejection from infection.

5. Novel Agents for Selective COSTIMULATION Blockade

Concerns about increased short‐term acute cellular rejection risks have limited the application of belatacept. Numerous third generation costimulation blockade drugs are currently in clinical development in the hope of addressing these concerns. Many of these new agents provide selective costimulation blockade by antagonizing the CD28‐CD80/86 interaction while leaving inhibitory signaling mediated by the interaction of CTLA‐4 with CD80/86 unaffected, unlike belatacept, which blocks both the activating and inhibitory pathways [51]. FR104 is a novel antagonistic pegylated anti‐CD28 Fab antibody fragment that selectively blocks the CD28‐CD80/86 interaction. Its efficacy has been demonstrated in non‐human primate kidney transplant models [52], and it is currently in phase 1/2 trials in adult kidney transplant patients at the University Hospital of Nantes in France (ClinicalTrials.gov CT04837092). Lulizumab, a pegylated domain antibody against human CD28, has also been shown to be effective in preclinical transplant models in non‐human primates [53, 54] and has successfully undergone initial pharmacokinetic and pharmacodynamic analysis as well as safety profile analysis in humans [55]. Whether selective CD28 blockade improves the efficacy of current costimulation blockade with belatacept remains to be determined in human transplant recipients. In addition to the CD28‐CD80/86 costimulatory pathway, other therapeutics targeting the CD40‐CD154 costimulatory pathway are also in preclinical studies and have shown particular promise as cornerstones of immunosuppression in several preclinical xenotransplantation models [56] (ClinicalTrials.gov NCT05027906). The most notable of these studies is a phase 2a study investigating dual costimulation blockade with dazodalibep (Fc‐silenced CD40L protein antagonist, VIB4920 or HZN4920) and belatacept with thymoglobulin induction (NCT04046549).

New, more selective induction therapies could also improve the clinical efficacy of belatacept‐based immunosuppression and limit the development of rejection resistant to costimulatory blockade. One promising candidate is siplizumab, a humanized monoclonal anti‐CD2 drug that has been shown to increase alloreactive regulatory T cells and simultaneously deplete effector memory T cells [57], which are thought to be the main mediators of rejection resistant to costimulatory blockade [58]. Combination therapy of siplizumab with belatacept or abatacept largely inhibited alloreactivity of human T cells [59] and was shown to be safe in initial phase 1 dosing studies in kidney transplant recipients [60]. Future studies combining induction therapy with siplizumab with maintenance of costimulatory blockade maintenance therapy are underway and may provide a promising approach to achieve de novo CNI‐free immunosuppression with improved acute rejection rates (ClinicalTrials.gov NCT05669001).

6. Treatment of Antibody‐Mediated Rejection

Long‐term graft survival is variable and dependent on multiple risk factors. In children and adults, antibody‐mediated rejection (AMR) is recognized as one of the leading causes of kidney allograft failure. Over the past 25 years, the pivotal causative role of donor‐specific HLA antibodies (HLA‐DSA) in ABMR and premature allograft failure has been established [61, 62, 63]. Risk factors for AMR include pre‐formed HLA‐DSA due to previous immunization events such as previous transplants, blood transfusions, or pregnancy in female recipients, a high degree of HLA mismatch, especially against HLA class II antigens such as HLA‐DR and HLA‐DQ, and under‐immunosuppression, either due to non‐adherence to immunosuppressive medications or physician‐initiated tapering of immunosuppressive medications due to side effects or recurrent infections [61, 64, 65]. While some of these risk factors also apply to the pediatric patient population, there are pediatric‐specific risk factors such as immunologic naivety to transplant‐relevant viral infections in young children and poor adherence to immunosuppressive medications in adolescents [66, 67, 68]. Recently, we published the first multicenter study in pediatric kidney transplant recipients on the incidence, risk factors, management strategies, and graft survival probability of AMR [69]. We observed a cumulative incidence of acute AMR of 10% and of chronic active AMR of 5.9% at 5 years posttransplant. Using a multivariable Cox regression model with time‐varying covariates adjusted for center effect, we found that immunologic risk factors for graft dysfunction were AMR and T cell‐mediated rejection (TCMR). While several treatment options are available for the treatment of TCMR, such as steroid pulse therapy, anti‐thymocyte globulin, and optimization of immunosuppressive therapy with calcineurin inhibitors, there are no agents approved by the FDA or EMA for the treatment of AMR. In particular, chronic active AMR has an unfavorable prognosis, as demonstrated by our analysis using the semi‐Markov multistate model. The graft survival probability for patients with chronic active AMR was remarkably lower than for patients with acute AMR (Figure 4). These data show that AMR remains a difficult to treat complication, with nearly 25% of patients having lost their graft within 1 year of diagnosis of acute AMR, and nearly 50% of patients lost their graft within 1 year of diagnosis of chronic AMR.

FIGURE 4.

Allograft survival probability of acute antibody‐mediated rejection (AMR) (n = 30, red line) and chronic active AMR (n = 16, blue line); patients with mixed AMR and TCMR (n = 13) were assigned to the AMR category determined by the histologic lesions, in this analysis always the acute AMR category. Analysis was performed using a semi‐Markov multi‐state model. Follow‐up time is taken from the time of the event (clock reset model). The gray line indicates patients without AMR. Modified according to (ref. [69]).

There are currently no approved therapies for the treatment of antibody‐mediated rejection [70]. To date, clinical trials of the CD20 antibody rituximab, the proteasome inhibitor bortezomib, imlifidase, or complement inhibitors have not shown efficacy [71, 72, 73, 74, 75]. A recent phase 3 trial of an interleukin‐6 (IL‐6) antibody, clazakizumab, was stopped early due to lack of efficacy [76, 77], despite earlier studies evaluating IL‐6 antagonism showing encouraging results [78, 79]. One uncontrolled pediatric study reported the experience with monthly tocilizumab, an anti‐interleukin‐6‐receptor antibody, in 25 pediatric kidney transplant recipients with AMR, refractory to IVIg/Rituximab [80]. From January 2013 to June 2019, a median (IQR) of 12 doses of tocilizumab were given per patient. Serial assessments of renal function, biopsy findings, and HLA‐DSA and relative intensity score were performed. At median follow‐up of 15.8 months post‐tocilizumab initiation, renal function was stable except for 1 allograft loss. There was no significant decrease in the immunodominant HLA‐DSA or relative intensity score. Follow‐up biopsies showed reduction in peritubular capillaritis and C4d scoring. The most frequent adverse events were cytopenias. The authors concluded that tocilizumab in pediatric patients with refractory AMR was well tolerated and appeared to stabilize renal function. The utility of tocilizumab in the treatment of AMR in this population should be further explored. However, in another study of 6 pediatric kidney transplant recipients with biopsy‐proven chronic active antibody‐mediated rejection resistant to standard treatments, rescue therapy with Tocilizumab did not appear to be effective in modifying the natural history of chronic active antibody‐mediated rejection [81]. Thus, there is an unmet therapeutic need for the treatment of antibody‐mediated rejection. Recently, an exploratory phase 2, randomized, double‐blind, placebo‐controlled trial to evaluate the safety, side‐effect profile, and efficacy of felzartamab in the treatment of antibody‐mediated rejection that has occurred at least 180 days after kidney transplantation was published [82]. Felzartamab is an investigational, fully human IgG1 monoclonal CD38 antibody that depletes target cells through antibody‐dependent cellular cytotoxicity and phagocytosis [83, 84]. CD38 is a transmembrane glycoprotein that is expressed by immune and hematopoietic cells, particularly plasma cells and natural killer (NK) cells [85]. Depletion of malignant plasma cells with CD38 monoclonal antibodies has been approved for the treatment of multiple myeloma [86, 87, 88]. CD38 has emerged as a promising therapeutic target in antibody‐mediated rejection, given the potential for its use as a target for the depletion of the plasma cells that produce donor‐specific antibodies and NK cells, which are presumed to be critical for microvascular inflammation [89, 90, 91]. In this trial, resolution of morphologic antibody‐mediated rejection at study Week 24 was more frequent with felzartamab (in 9 of 11 patients [82%]) than with placebo (in 2 of 10 patients [20%]) (Figure 5). The median microvascular inflammation score was lower in the felzartamab group than in the placebo group (0 vs. 2.5). Also lower was a molecular score reflecting the probability of antibody‐mediated rejection (0.17 vs. 0.77) and the level of donor‐derived cell‐free DNA (0.31% vs. 0.82%). At Week 52, the recurrence of morphologic AMR activity was reported in three of nine patients who had a response to felzartamab, with an increase in molecular activity and biomarker levels toward baseline levels. Mild or moderate infusion reactions occurred in eight patients in the felzartamab group. Serious adverse events occurred in one patient in the felzartamab group and in four patients in the placebo group. The results of this trial suggest that felzartamab may have the potential to effectively and safely reverse ongoing AMR, which underscores the potential of felzartamab as a therapeutic option warranting further investigation in the context of late or even early rejection after organ transplantation.

FIGURE 5.

Key efficacy outcomes of a phase 2 trial exploring the CD38 antibody felzartamab in late antibody‐mediated rejection (AMR) [80]. Shown are (panel A) Sankey plots illustrating the dynamics of morphologic AMR activity in the felzartamab and placebo arms across biopsy samples obtained at baseline, Week 24, and Week 52. Panel B illustrates the evolution of a Molecular Microscope Diagnostic system (MMDx) score reflecting AMR activity (AMRProb). Changes in donor‐derived cell‐free DNA (dd‐cfDNA) fractions reflecting graft injury are shown in panel C.

On the website of clinicaltrials.gov, there are currently two studies listed for the treatment of AMR in pediatric kidney transplant recipients (Table 1). The study NCT03994783 evaluates whether adding rituximab to the standard treatment of acute AMR improves graft function and survival. Standard of care treatment includes intravenous methylprednisolone, intravenous immunoglobulins and/or plasma exchange. The study NCT03737136 compares bortezomib with rituximab plus plasmapheresis plus intravenous immunoglobulins for treating chronic active AMR. The primary outcome measure is graft survival. For adult kidney transplant recipients, the clinicaltrials.gov website lists four trials for the treatment of AMR: bortezomib (NCT02201576), completed, unpublished, ineffective; fostamatinib (NCT03991780), a spleen tyrosine kinase inhibitor licensed for the treatment of chronic immune thrombocytopenia, recruiting; tocilizumab (NCT04561986), a recombinant humanized anti‐IL‐6 receptor monoclonal antibody which has a main use in the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis and polyarticular juvenile idiopathic arthritis, recruiting; and BIVV020 (NCT05156710), an investigational monoclonal antibody that targets complement C1s, recruiting.

7. Conclusions

The optimal posttransplant immunosuppressive regimen is unknown. The goal remains to find the best combination of immunosuppressive agents that will optimize patient and graft survival by preventing acute and chronic rejection while limiting drug toxicities. Much additional work is needed to define optimal immunosuppressive regimens in pediatric renal transplant patients, particularly with regard to newer and evolving regimens. The safety and efficacy of these protocols need to be established, with particular emphasis on long‐term graft survival and PTLD. Although data from adult kidney transplantation trials are used to guide management decisions in pediatric patients, immunosuppressive therapy in pediatric kidney transplant recipients often needs to be modified because of the unique dosing requirements and clinical effects of these agents in children, including their impact on growth and development. Unfortunately, there have also been no new drug approvals for adult kidney transplant recipients since belatacept in 2012, leaving the immunosuppressive drug armamentarium unchanged for more than 20 years [92]. This has been attributed to the acceptance of current results as adequate in a risk averse field with considerable regulatory oversight, the lack of consistent industry commitment due to low return on investment compared to the larger autoimmune and cancer markets, and importantly, the lack of change in primary endpoints for new drug trials [93]. As a consequence of the lack of innovation in adult kidney transplant recipients, the pipeline of novel immunosuppressive agents for pediatric solid organ transplant recipients is also limited. The most promising agent in the near future, at least for adolescent patients, appears to be belatacept, despite its many limitations. The experience with belatacept has revealed strategies to safely integrate belatacept into the immunosuppressive regimen while reducing the short‐term risk of acute cellular rejection by tacrolimus therapy for a limited period of time after transplantation. Improved synergies between the pharmaceutical industry and the transplant community are needed to achieve the ultimate goal of improving long‐term outcomes in pediatric kidney transplantation.

Data Availability Statement

The authors have nothing to report.