EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Every graft counts because there remains a disparity between the demand and supply of organs; in addition, the 10-year kidney graft survival rate remains low (<60%).¹ There is also a global difference in organ acceptance preferences; for example, France uses more marginal organs from patients with disease (higher kidney donor profile index) than the United States, with still reasonable results.

The 3 most important causes of graft loss in pediatric and adolescent patients are noncompliance (nonadherence), disease recurrence, and subclinical rejection. The incidence of pediatric graft failure due to nonadherence has been reported to range between 10% and 1%, although rates of 5% to 50% have also been reported.^2,3

A meta-analysis on medical regimen adherence in pediatric solid-organ transplant recipients found that nonadherence to clinic appointments and tests was prevalent at 12.9 cases per 100 patients per year (PPY), followed by nonadherence to immunosuppression at 6 cases/100 PPY.⁴ Poorer adherence was associated with a worse psychological status and family dysfunction. Educational and counseling programs can improve medical regimen adherence, which has the potential to improve graft survival.

According to Sellares and colleagues,⁵ causes of graft failure as shown in histological evaluations and biopsies were antibody-mediated rejection (ABMR) in 50% of cases, with 47% of these due to nonadherence.

Disease recurrence is the third cause of graft loss after graft rejection and death with functioning graft. Among pediatric patients, recurrence of primary disease is responsible for renal allograft failure in 5% to 15% of cases.⁴ In the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) database,⁶ the overall graft failure rate due to recurrent disease was shown to be about 7%. Among glomerular diseases that may recur in the graft, the most frequent is focal segmental glomerular sclerosis (FSGS).

Steroid-resistant idiopathic nephrotic syndrome due to primary FSGS accounts for 10% of cases of end-stage renal disease in childhood.^7,8 The overall risk of recurrence of nephrotic syndrome after transplant is estimated to be about 30%.7 Focal segmental glomerular sclerosis is the most frequent cause of graft loss due to recurrent disease, with the risk of recurrence of FSGS greater in children than in adults. For example, recurrence in a previous study occurred in 8 of 16 children compared with 3 of 27 adults. Another study reported an even higher recurrence rate in pediatric versus adult patients (86% vs 3%).^7,8

Table 1 presents some biomarkers for recurrence. Subclinical rejection could be detected by molecular biomarkers rather than with protocol biopsies. The ALLOSURE test (using donor-derived cell-free DNA) is one of the markers under investigation.

Immunosuppression options to avoid nonadherence and rejection
Induction remains an important aspect in transplant treatment protocols. Induction protocols lead to decreased rejection rate, decreased graft loss, and lower delayed graft function. Other benefits of induction therapies are to facilitate withdrawing steroids and minimizing calcineurin inhibitors in high-risk transplant patients, possibly as a step in the direction of tolerance. In the HARMONY study, rapid steroid withdrawal was safe with unchanged excellent survival and biopsy-proven acute rejection rates.⁹ In this respect, rabbit antithymocyte globulin was not superior to basiliximab.

Conversion strategies from classic tacrolimus to long-acting preparations could help, as was shown in the Adhere Study with long-acting tacrolimus (ADVAGRAF) plus a mechanistic target of rapamycin (mTOR; sirolimus).¹⁰ In the large de novo interventional phase 4 TRANSFORM study, a shift from calcineurin inhibitors (CNIs) to mTOR inhibitors was conducted in >2000 kidney transplant patients recruited across 195 sites in 42 countries.¹¹ The study met its primary endpoint at month 12, showing that the incidence of treated biopsy-proven acute rejections was similar across the 2 treatment groups; the proportion of patients with continuous measure of graft function (estimated glomerular filtration rate of <50 mL/min) was also similar. The study also met its key secondary endpoint for noninferiority of the composite endpoint of treated biopsy-proven acute rejection, graft loss, and death. An everolimus-based regimen, combined with reduced CNI dose, also significantly reduced viral infections, such as cytomegalovirus.

A late shift to mTOR inhibitors was investigated in the APOLLO trial.¹² This open-label, 12-month, prospective, randomized, parallel-group study was conducted at 11 transplant centers, with patients switched from CNI therapy to everolimus or continue current CNI treatment. Both patient groups received mycophenolic acid and steroids if administered at study entry. There was no increase in rejection or graft loss.¹² In addition, investigators suggested that costimulation blockade with intermittent injections could replace CNIs, especially for indications for belatacept, including thrombotic microangiopathy,¹³ FSGS recurrence, and low levels of donor-specific antibodies (DSAs).¹⁴

New drugs in the pipeline
Ideal characteristics of future immunosuppressives should include at least comparable results to current immunosuppressives, short-term and long-term benefits, better compliance, better glomerular filtration rate, less chronic allograft nephropathy, less cardiovascular risk, less risk of diabetes, less infection, less malignancy, studied in pediatric and adolescent age groups, and less expensive.

Different strategies to control acute ABMR include removing antibodies (intravenous immunoglobulin, plasmapheresis with TheraSorb), removing mature and emerging cells (anti-CD20; rituximab, obinutuzumab), removing antibody-producing plasma cells (bortezomib), blocking B-cell survival, differentiation (atacicept and belimumab), blocking the effects of antibodies (C5 inhibitors; eculizumab), removing memory B cells (CD27 blockade), and promoting regulatory B cells.¹⁵

In costimulation blockade, selective blockade of CD28 allows CTLA4 and PD-L1 to bind to CD80/86 and activate the inhibitory pathways, resulting in an enhanced immunosuppressive effect on T cells. In contrast to belatacept, anti-CD28 antibodies may have less of an adverse impact on T-regulatory cells (Tregs). Two investigational drugs have been tested: lulizumab (Bristol-Myers Squibb; anti-CD28 domain antibody) and FR104 monoclonal antibody fragment (Effimmune). Use of the CD40 pathway resulted in the anti-CD154 antibody (the ligand for CD40, expressed on platelets) causing unexpected thromboembolic events. The other side of that receptor-ligand pair is also potentially interesting, with groups pursuing anti-CD40 monoclonal antibodies. Astellas, Bristol-Myers Squibb, and Novartis have anti-CD40 antibodies in development to block the CD40/CD154 pathway. From Astellas, ASKP1240 is furthest in development in humans; it is a fully humanized immunoglobulin G4 antibody to CD40 but is not effective in CNI-free immunosuppression. From Novartis, CFZ533 is planned to enter a phase 2 trial. In vivo, CFZ533 blocks primary and recall T-cell-dependent antibody responses in nonhuman primates and abrogates germinal formation without depleting peripheral blood B cells.

The 26S proteasome inhibitor bortezomib was not successful in patients with late ABMR.¹⁶ Bortezomib has been used for desensitization, the treatment of acute ABMR, and in experimental protocols of transplant tolerance. It has been shown to significantly reduce anti-HLA antibody levels. The main toxicity of bortezomib is neurologic, with de novo or worsened peripheral neuropathy being common. Hematologic and gastrointestinal toxicity can occur. The second-generation proteasome inhibitor carfilzomib (Kyprolis) irreversibly binds to and inhibits the chymotrypsin-like activity of the 20S proteasome. An advantage of carfilzomib over bortezomib is the reduced risk of neuropathy. A phase 1 clinical trial of carfilzomib as part of a desensitization strategy in kidney transplant candidates is currently under way.^15,17

The immunoglobulin G (IgG)-degrading endopeptidase of Streptococcus pyogenes cleaves the pool of intact IgG and may effectively counteract IgG-mediated graft injury. Hydrolysis of IgG yields soluble F(ab¢)2 and Fc fragments that persist for a couple of days. Whether and in what way these fragments might exert modulatory effects on innate or adaptive immunity remains to be established. In addition, this endopeptidase may also cleave the IgG-type B-cell receptor and thus compromise memory B-cell activation and potentially counteract allograft rejection.

Obinutuzumab, also known as afutuzumab until 2009, is a fully humanized monoclonal antibody to CD20 on mature B cells that is currently approved by the Food and Drug Administration for the treatment of chronic lymphocytic leukemia in combination with chlorambucil.18 Recent data15 documented its safety for the desensitization of candidates for renal transplant.

Belimumab (Benlysta) is a humanized monoclonal antibody that specifically inhibits the B-cell-activating factor BAFF. It has been approved for the treatment of systemic lupus and may be useful for B-cell depletion and to decrease antibody production. New antibodies at week 24 postoperative were reduced by this drug.¹⁹

Atacicept is a fusion protein formed from the transmembrane activator and CAML (calcium-modulator and cyclophilin-ligand)-interactor (TACI) and the extracellular domain of one of the receptors for BAFF. It binds BAFF and APRIL (a proliferation-inducing ligand), which also promotes B-cell and plasma cell survival. Atacicept may be useful in sensitized patients with established plasma cells.

Eculizumab (Soliris) is a monoclonal antibody to the complement protein C5, which blocks C5 cleavage and halts the formation of the membrane attack complex. It is approved for the treatment of paroxysmal nocturnal hemoglobinuria. It is emerging as a novel therapy for the treatment of acute ABMR due to its ability to arrest complement-mediated injury. This creates a window of opportunity for other therapies to clear DSA.

Complement 1 esterase inhibitor (CINRYZE) C1?INH, when added to intravenous immunoglobulin, has been shown to be safe and may improve allograft function in kidney transplant recipients with nonresponsive acute ABMR.²⁰

Other new agents include interleukin 6 (IL-6) inhibitors; IL-6 drives B-cell activation and differentiation to antibody-producing plasma cells and IL-6 inhibitors have been used extensively to control the cytokine storm in COVID-19 treatment over the past 2 years. Tocilizumab (Actemra) and clazakizumab (Vitaeris) have been studied, with monthly tocilizumab injections showing good graft survival at 6 years compared with standard of care, with DSA decreasing beginning at 24 months.²¹ The IMAGINE study is a global, double-blind, placebo-controlled, phase 3 trial on clazakizumab in chronic ABMR to evaluate its role in prevention of graft loss.²²

Janus kinases are important cytoplasmic tyrosine kinases involved in cell signaling. Tofacitinib (CP-690550) inhibits JAK3, which is expressed on natural killer cells, activated T cells, B cells, and myeloid cells. In clinical trials, it was noninferior to tacrolimus in terms of rejection rate and graft survival.²³ It also showed a lower rate of hyperglycemia but a trend toward more infections, including cytomegalovirus and polyomavirus.

Cell therapy is another possible option. The “One Study” aimed to produce distinct populations of hematopoietic regulatory cells and comparatively test their safety and promise in minimizing immunosuppressives in European and US centers in living donor kidney transplant recipients (planned number of patients was 60, with 8-12 patients per center). The primary endpoint was biopsy-proven rejection. In the UK ONE Study trial, safety and feasibility of Treg therapy in renal tranplantation was investigated. The Tregs were expanded by stimulation with CD3/CD28 beads plus interleukin 2 in the presence of rapamycin, which was administered 5 days posttransplant, along with steroids for 3 months, mycophenolate mofetil for 9 to 12 months, and tacrolimus. So far, 11 patients have been included, with median follow-up of 10 months. The results showed no cell infusion-related adverse events and no biopsy-proven rejection. All patients had stable transplant function with median serum creatinine level of 128 (90-176).²³

Late allograft failure remains a leading problem in kidney transplantation. Adherence to medications and compliance remain important issues underlying rejection, especially in adolescent patients. Although early ABMR responds to treatment, late presentation and chronic ABMR are harder to treat. Shifting to other immunosuppressive protocols could help until new immunosuppressives become available.

Volume: 20 Issue: 5 May 2022 - Supplement - 3

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