Abstract
The biologics used in transplantation clinical practice include several monoclonal and polyclonal antibodies aimed at specific cellular receptors. The effect of their mechanisms of action includes depleting or blocking specific cell subpopulations, complement system, or removing circulating preformed antibodies and blocking their production. They are used in induction, desensitization ABO-incompatible renal transplantation, rescue therapy of steroid-resistant acute rejection, treatment of posttransplant recurrence of primary disease such as nephrotic syndrome or atypical hemolytic–uremic syndrome, and in late humoral rejection. There are various indications for the use of biologic agents before and early or late after renal transplantation in both high- and low-risk recipients. In the latter situation, the biologics-based induction is used to further minimize immunosuppression maintenance. The targets of several biologic agents are present across a variety of cells, and manipulation of the immune system with biologics may be associated with significant risk of acute and late-onset adverse events; therefore, clinical risk-versus-benefit ratio must be carefully balanced in every case. Several trials on novel biologics are reported in adults but not in the pediatric population.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Biologic agents used in renal transplantation include several drugs of different mechanisms of action, given intravenously, aimed at blocking or depleting specific cell subpopulations or blocking circulating alloantibody responses or the complement system. From a clinical standpoint, they are used in induction, desensitization procedures in hyperimmunized patients, ABO-incompatible renal transplantation, treatment of steroid-resistant and/or humoral rejection, and therapy for recurrence of specific primary renal disease, such as nephrotic syndrome (NS) or atypical hemolytic uremic syndrome (aHUS) (Fig. 1). They are used before and early or late after renal transplantation in both high- and low-risk recipients (Fig. 2). Several biologic agents are used in clinical practice in pediatric renal transplantation; however, the majority is used off-label, and their dose range and optimal number of doses are not clearly defined. This review summarizes data on experience, efficacy, and safety of biologics used in renal transplantation in children and on emerging new agents, used only in adult practice or clinical trials, that have not yet been verified in the pediatric setting. Drugs used in children include monoclonal antibodies (MAb) daclizumab, basiliximab, and alemtuzumab; polyclonal antibodies thymoglobulin or ATGAM [lymphocyte immune globulin, antithymocyte globulin (equine) sterile solution], specific MAb such as rituximab and eculizumab; and human immunoglobulin preparations [intravenous immunoglobulins (IVIG)]. Targets for and mechanisms of action of these agents are presented in Table 1. Indications, duration of action, and specific monitoring are presented in Table 2 [1–3, 11–19, 21–23, 25–28, 39, 42–47, 49, 53, 56, 57, 62–64]. A variety of new drugs were investigated in several clinical trials that recruited adult renal graft recipients [3, 4]. These new molecules were used to desensitize high-risk patients, in induction protocols, and to treat humoral rejection. Emerging new drugs and their specific targets in the immune system are listed in Table 3 [4]; clinical experience from clinical trials in adult patients is summarized in Table 4 [4–10], and evidence-based (EB) clinical experience in the pediatric population is presented in Table 5 [11–19, 21–23, 25–28, 33, 39, 42–47, 49, 53, 56, 57, 62–64].
Biologics in induction
Induction is the most common indication to use biologic agents in pediatric renal graft recipients. It is used for two reasons: (1) to enhance the strength of initial triple immunosuppression in patients with high immunological risk [sensitized, retransplanted, poor human leukocyte antigen (HLA) matching or marginal donor transplant] or (2) to introduce minimization protocol aimed at reducing exposure to steroids or calcineurin inhibitors (CNI), or both. In the second indication, MAbs were used in patients with low immunological risk and polyclonal Ab in patients with low and high immunological risk.
MAb used in pediatric transplantation include anti-CD25 (IL-2Rα) inhibitors daclizumab and basiliximab and anti-CD52-depleting Ab alemtuzumab used off label. The duration of effect (for two doses of basiliximab) expressed as receptor saturation was present at about 5 weeks with no mycophenolate mofetil (MMF) and about 10 weeks with concomitant MMF therapy [11]. In the Stanford steroid avoidance trial, the trough concentration of daclizumab was monitored by sequential sandwich enzyme-linked immunosorbent assay (ELISA); however, routinely, no specific monitoring is used in practice [12]. Comprehensive information on efficacy and safety of anti-CD25 inhibitors basiliximab and daclizumab, including in renal-graft recipients of different ages, comes from a Cochrane database large systematic review involving 71 adult and pediatric trials and 10,520 participants. Use of both daclizumab and basiliximab given in induction decreased the risk of acute rejection in the first year after transplantation by 25 % [relative risk (RR) 0.75], as well as incidence of 1-year graft loss by 25 % [13]. Two pediatric randomized controlled trials (RCTs) proved that adding anti-CD25 Ab basiliximab to triple-maintenance protocol tacrolimus/azathioprine/prednisolone (TAC/AZA/Pred) or cyclosporin A/MMF/Pred (CsA/MMF/Pred) in patients of low to moderate immunological risk is not justified, as the incidence of rejection and patient and graft survival was no different in children with or without induction [14, 15]. Monoclonal induction was also used in a majority of pediatric clinical trials on steroid minimization. The Stanford complete steroid avoidance study was based on an extended daclizumab induction (overall nine doses) [12]. Only two daclizumab doses of 1 mg/kg were used in the TWIST trial, and steroids were stopped at day 5 after surgery [16]. It should be noted that daclizumab is no longer manufactured, and two doses of basiliximab were used in further pediatric trials on steroid withdrawal [17–19]. Early and long-term results of all these and other trials have shown that in pediatric patients with low to moderate immunological risk, monoclonal induction with anti-CD25 Ab with combination TAC/MMF therapy was sufficient to allow early steroid withdrawal, resulting in all expected clinical benefits, including better growth, with no detrimental effect on long-term patient/graft survival and renal function [20]. Basiliximab was also used in the innovative protocol, which aimed to double the minimization of immunosuppression (CNI plus steroids). With monoclonal induction and use of everolimus, reduced exposure to cyclosporine was possible; in further follow-up, with a normal renal biopsy, the late (> 6 months after transplantation) steroid withdrawal was also possible. This protocol was very effective in patients at low immunological risk, with no rejection within 1 year and with 100 % patient and graft survival in the 3-year follow-up [21]. The ongoing multicenter CRADLE RCT aims at verifying the efficacy and safety of a similar protocol but with Csa replaced by TAC, especially in the subgroup of patients given basiliximab, as monoclonal induction with basiliximab is not mandatory in this trial and depends on the individual decisions of each center (www.clinicaltrials.gov/ct2/show/NCT01544491).
Induction with basiliximab and the then new drug belatacept, administered IV every 2 weeks then repeated infusions every 4 weeks, was used for prophylaxis of acute rejection in adult patients after renal transplantation, randomized to three arms, including two with different dosages of belatacept and one with CsA, all combined with MMF and steroids. At 1 year, both belatacept arms showed no inferiority to the CsA arm in terms of graft and patient survival, with better renal function in belatacept arms. An important clinical benefit was better metabolic profile in belatacept-treated patients; however, there was a safety concern related to high posttransplant lymphoproliferative disease (PTLD) rate in Epstein-Barr virus (EBV)-seronegative patients [5]. Another option of monoclonal antibody induction was the use of alemtuzumab, primarily in children, by Pittsburgh group, who used the single dose of 0.4–0.5 mg/kg, followed by TAC monotherapy and early steroid withdrawal (at 1–5 days after transplantation). Using this approach and long-lasting depletion of target cells, maintenance immunosuppression was limited to TAC monotherapy [22, 23].
An innovative protocol of alemtuzumab induction (30 mg/dose) with monthly belatacept IV (10 mg/kg/dose) and daily sirolimus given after renal transplantation to avoid calcineurin and steroid exposure in 20 adult renal transplant recipients was recently reported. There was no acute rejection or de novo donor-specific antibody (DSA) production within the first year. Ten patients remained on belatacept as the single immunosuppressive drug [24].
Polyclonal induction
In a retrospective single-center study, 198 children and adolescents were given polyclonal combined with triple-maintenance regimen. Significantly fewer episodes of acute rejection were seen in patients treated with thymoglobulin (33 % vs 50 %, p = 0.02) [25]. Overall, 37 adolescents (mean age 15.2 ± 2.8 years) were treated with the induction protocol, including five to seven fixed doses of 1.5 mg/kg thymoglobulin combined with TAC/MMF/Pred; there was an 8.1 % incidence of acute rejection within 1 year and 91.9 % graft and 100 % patient survival [26]. Six fixed doses of 1.5 mg/kg thymoglobulin induction were used by the Stanford group in an early steroid withdrawal protocol in 13 children with high immunological risk, with no further rejection episode within 1-year follow-up, normal picture biopsies performed every 3 months up to 1 year after transplantation, and no de novo DSA [27]. Overall, five to seven doses of 1.5 mg/kg thymoglobulin were given to 21 pediatric patients undergoing an early steroid minimization protocol compared with six to 15 doses given as steroid maintenance (retrospective control group). With steroid withdrawal on day 6, the incidence of acute rejection was 23 % and graft survival 90 % at 1 year, which was no different than in controls [28].
The optimal number of thymoglobulin doses (days of treatment) in induction protocols is not defined. The attempt to keep optimal balance between efficacy and safety is the basis of using short (<3 doses) or longer (up to 10 doses) induction and adjusting the dose to trough CD3 (target 50–100/mm3) or WBC count (target > 3000/mm3) versus a fixed dose of 1.5 mg/kg [29, 30]. The median cumulative dose in adult renal graft recipients in TAILOR registry data was 5 mg/kg per treatment (1.56-15.00); 46.6 % of patients (overall n = 2,322) received between 1.5 and 5 mg/kg, 35.4 % from 5 to 7 mg/kg, and 18 % from 7 to 15 mg/kg per treatment. Up to 64.6 % of patients tolerated the full intended induction dose [31]. The US Organ Procurement and Transplantation Network (OPTN) database stratified the incidence of based on depleting and nondepleting agents: lymphocyte-depleting Ab were used in 47.5 % and IL-2R antibodies in 43 % of 1,276 children treated with steroid minimization protocols and induction between 2002 and 2009 [32].
Summarizing: induction with biologic agents, such as anti- IL2 Ab (basiliximab) or polyclonal Ab, after verification in clinical trials and reports, has entered routine practice in selected patients with clear clinical indications.
Biologics in desensitization of HLA-incompatible renal-graft recipients
In patients awaiting renal transplantation, reducing the titer of pre-formed anti-HLA antibodies by using plasmapheresis (PF), IVIG administration alone, combined with PF, or rituximab was reported in several adult studies and a few pediatric case reports [33–35]. The most common protocol used in adult patients in the USA was based on a combination of IVIG and PF (82 %), and preoperative rituximab was used in more than half of reporting centers [36]. The combination of IVIG and rituximab was used by Jordan’s group to reduce the titer of pre-formed anti-HLA antibodies in highly sensitized patients awaiting renal transplantation [37]. The authors described the protocol based on administration of 2 g/kg IVIG on the days 0 and 30, combined with rituximab (375 mg/m2) given on days 7 and 22 (after first dose if IVIG). This protocol caused significant reduction of mean panel-reactive antibody (PRA) level from 77 ± 19 % to 44 ± 30 % (p < 0.0001) after second infusion of IVIG and shortened the waiting time to successful transplantation from 144 ± 89 months to 5 ± 6 months. Regardless of the encouraging short-term results, the long–term efficacy of the desensitization protocol was questioned in adult patients in a retrospective comparative cohort study. The 1- and 5-year graft survival rate was significantly inferior in patients who underwent the desensitization protocol based on a course of PF combined with IVIG and then depletional induction (89.9 vs 97.6 % and 69.4 vs 80.6 %, respectively). The overall risk of graft loss was significantly higher in desensitized patients [hazard ratio (HR) 2.6; p = 0.04)] but with no detrimental effect on patient survival [38].
Biologics in ABO-incompatible renal transplantation
Other specific desensitization protocol was used by Tyden et al. in living- donor ABO-incompatible pediatric transplantation. The pretransplant protocol included a single dose of 375 mg/m2 rituximab given 4 weeks before scheduled immunoadsorption, triple immunosuppression, four sessions of antigen-specific immunoadsorption, followed by 0.5 g/kg IVIG preoperatively and continuation of immunoadsorption after surgery. Five-year patients survival rate was 98 % and graft survival rate 97 % [39], which are obviously not inferior to outcomes in ABO-compatible transplantation. Eculizumab was used to enhance the desensitization protocol (PF followed by polyclonal induction) in adult patients undergoing living-donor renal transplantation against positive cross match in terms of preventing antibody-mediated rejection (AMR). Overall, 26 patients received preemptively 1,200 mg of eculizumab immediately before transplantation, then 600 mg on day 1, then four times weekly. Further dosing was adjusted to the presence of DSA. The incidence of antibody-mediated rejection (AMR) was 7.7 % vs 41.2 % in the control group (p = 0.0031) [40]. Bortezomib (4 x 1.3 g/m2) was given pre-emptively (early posttransplant) to remove de novo DSA (before expected further humoral rejection occurs). In a series of 26 patients, bortezomib combined with steroids was given within a mean of 30 days after DSA appearance (n = 26), with PF and rituximab (n = 9), with PF only (n = 5), or with IVIG (n = 1). There was significant reduction in DSA level at 1 year (p = 0.002), correlated with better allograft function at a mean of 25.8 months of follow-up [41].
Summarizing: Desensitization of HLA-incompatible patients with biologic agents (or combination of biologics with plasma exchange) allows further renal transplantation and may shorten the waiting time for transplant. However, these patients still present a high risk of rejection and inferior long-term graft survival. This will be very important in pediatric renal-graft recipients, who have a long life expectancy on renal replacement therapy. A specific desensitization protocol, as described by Tyden et al., allows successful ABO-incompatible renal transplantation with excellent long-term outcome.
Biologics in recurrence of primary disease after renal transplantation
Eculizumab has been used in prophylaxis and treatment of posttransplant recurrence of aHUS. The report by the French Group for Atypical HUS assessed 22 pediatric cases in their retrospective multicenter study. Thirteen patients were treated due to recurrence, and nine received pre-emptive eculizumab as prophylaxis. Single and multiple doses were given is cases presenting several CFH, CFI, and C3 gene mutations. Some patients were resistant to PF (n = 10), and some were PF dependent (n = 2). In some cases, the picture of renal biopsy included signs of acute rejection. All but one patient from the prophylaxis group remained recurrence free at a mean 14.5-month follow-up. In all 13 patients with recurrence, the hematological features of aHUS rapidly returned to normal following eculizumab administration, whereas mean creatinine concentration dropped from a mean of 295 ± 171 to 135 ± 69 μmol/L (p = 0.002) within 3 subsequent months. Patients with delayed introduction of eculizumab treatment (>28 days after diagnosis) had lower functional benefit than patients treated earlier after aHUS onset [42]. Rituximab was used to treat recurrence of severe NS in a series of children after renal transplantation. One to four doses (of 375 mg/m2) were given, and complete or partial response was observed in six of seven patients [43]. Variable response to one to four doses of rituximab was reported in series of eight patients; complete response was seen in two and partial in four. In some cases, there was a correlation between CD19 depletion and clinical response and between CD19 recovery and relapses; in others, there was no association between CD19 count and clinical course of NS [44]. The efficacy of rituximab (four doses) in a girl with Finnish-type congenital NS and clinical “recurrence” due to anti-nephrin Ab production was reported. Remission was sustained during the 5-year follow-up [45].
Summarizing: recurrence of severe primary renal diseases has become potentially treatable with currently available biologic agents (rituximab and eculizumab); however, important limitations remain, including overall efficacy and safety for rituximab and enormous financial cost for eculizumab in prolonged prophylaxis.
Biologics in rejection therapy
Acute rejection
Acute rejection is associated with allograft infiltration by several cell types, including T and B cells, macrophages, and NK cells. Polyclonal Ab therapy is commonly used in steroid-resistant cases. The significant presence of B cells in biopsy-proven infiltrate may suggest that rituximab might be useful. The Stanford group conducted a randomized trial comparing 4 weekly doses of rituximab (375 mg/m2) versus thymoglobulin (6 x 1.5 mg/kg) in 20 pediatric renal recipients with late acute rejection (mean time from transplantation to rejection 34 and 21.36 months) in two arms of ten patients each. All patients were pretreated with methylprednisolone (MP). . In six patients in the rituximab group and two from the control group, humoral component of rejection was confirmed by CD4 presence. The presence of CD20 cells in graft infiltrates was confirmed in all patients. Results confirmed the efficacy of rituximab therapy in CD20-positive acute rejection [46]. Limited efficacy of single-dose (0.3 mg/kg) alemtuzumab in rescue treatment of late acute cellular rejection was reported in three children at high immunological risk, with recurrent episodes of rejection and poor previous response to other therapies (including steroids and polyclonal Ab) [47]. More successful treatment was described in 15 adult patients. The use of multiple doses (4–10 days, dose 6–10 mg/kg) showed no increase in malignancy or cytomegalovirus (CMV) infection over 10 years of follow-up despite, high doses used in this study [48]. Whether or not this difference in efficacy was related to the use of single versus multiple doses, rejection type, or patient specificity is not clear. Three successful pediatric cases of ABR were reported with the use of MP, 2 g/kg IVIG, a single dose of rituximab (375 mg/m2), and course of plasma exchange (up to ten procedures) [49]. The protocol proposed by Jordan et al., based on clinical experience, distinguished patients with less and more pronounced pathologic features of ABR. Those with a milder clinical picture received a combination of three MP pulses, initial dose of 2 g/kg IVIG given between first and second pulses, and a single dose of rituximab (375 mg/m2) on day 2, followed by two consecutive MP pulses. The second (and last) dose of 2 g/kg IVIG was given between 30 and 60 days of treatment. More severe cases, with signs of thrombotic microangiopathy in biopsy, were treated with a series of PF, followed by single doses of IVIG (2 g/kg) and a single dose of rituximab (375 mg/m2) [50]. Bortezomib, in a retrospective comparison with rituximab, was reported in ten adult patients treated also with MP, PF (six sessions), and IVIG (30 g/treatment) [51]. The efficacy of bortezomib was lower in cases of late AMR, i.e., occurring > 6 months after transplantation. Delay in diagnosis and difference in characteristics of cells producing DSA in late-onset AMR (long-lived plasma-cell population) is proposed as an explanation of a worse response [52]. Eculizumab was successfully used in a hyperimmunized 17-year-old patient with PF resistant of acute humoral rejection, developing in the second graft, after a desensitization protocol based on combined PF, IVIG, and rituximab. The patient was treated with MP, repeated PF, and IVIG; however, DSA and ongoing rejection persisted, proven in repeated biopsy, despite 45 sessions of PF and absence of CD19 cells. Four doses of eculizumab (600 mg) were given, and remission was present at the third biopsy. Eculizumab was then continued on a monthly basis (eight doses) due to increasing DSA titer, which appeared after PF was stopped. Two years after therapy, the patient was stable, with creatinine concentration of 1.2 mg/dl and DQ DSA of mean fluorescent intensity (MFI) 5,000 [53]. Similar reports were published regarding eculizumab efficacy in highly sensitized adults patients developing acute humoral rejection despite pretransplant (PF/IVIG/rituximab) desensitization and use of polyclonal induction; one to five doses of eculizumab were used in rescue therapy [54, 55].
Chronic humoral rejection
The protocol described by Jordan et al. in patients with chronic antibody-mediated rejection as a result of the presence of de novo DSA had three options: IVIG alone, IVIG plus rituximab, and combination of plasmapheresis with lower dose of IVIG (1 g/kg) with or without rituximab [50]. The combination of IVIG (4 × 1 g/kg) and a single dose of rituximab (375 mg/m2) given 1 week after last IVIG dose was reported as a therapeutic tool for chronic humoral rejection in six children: four responded to antirejection therapy and showed increased glomerular filtration rate (GFR) within 12 months: significantly at 6 months by 21 ml/min/1.73 m2 (p < 0.05) and then not significantly at 12 months by 19 ml/min/1.73 m2 (p = 0.063) [56]. The same protocol (four doses of IVIG 1 g/kg plus a single dose of 375 mg/m2 rituximab) was used in a prospective study recruiting 20 children with Banff diagnostic criteria of Ab-mediated rejection together with CD20-positive infiltrates (12 (60 %) patients). The response rate was 70 % (14 patients) [57]. Bortezomib (4 × 1.3 g/m2) was used in adult patients with humoral rejection as a single rescue agent or in combination with IVIG or PF [58].
Summarizing: Availability of biologic agents increases the range of therapeutic tools in resistant, acute, and humoral chronic allograft rejection. However, selecting the potentially most effective treatment protocol requires very detailed diagnosis based on close DSA monitoring and interpretation of results and relevant pathomorphologic evaluation, including the phenotype of infiltrating cells (T or B). There remains a need for further clinical investigation in this area.
Safety concerns with biologic agents in clinical practice
Biologic agents used in renal transplantation are highly potent immunosuppressants, interfering with normal immune response and therefore increasing the risk of specific complications. Their safety profile is variable and might be dose dependent and related to cumulative side effects of certain drugs combinations. The safety profile of commonly used biologics is summarized in Table 6 [59–66].
Posttransplant lymphoproliferative disease
The risk of posttransplant lymphoproliferative disease (PTLD) in pediatric renal graft recipients is higher than in adults mainly due to higher incidence of EBV seronegativity in the first decade of life, and depletional induction is regarded as an additional risk factor. The incidence of PTLD was significantly higher in children < 10 years of age treated with polyclonal Ab [59, 60]. Analysis of PTLD risk relation used various antibodies in 59,560 kidney recipients [data from the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS)], including 3,105 children, showed that only polyclonal induction was associated with significant risk (RR 1.63, p = 0.0025 vs no induction). Additional factors included age <18 years (RR 3.67; p < 0.0001), seronegative EBV (RR 5.225; p < 0.0001), CMV (RR 2.036; p < 0.0001) status, and—interestingly— the use of sirolimus in maintenance immunosuppression (RR 2.047; p < 0.0001) [61]. A more recent report provides data on a higher risk of PTLD in patients receiving alemtuzumab for induction [62]. Pretransplant EBV seronegative status was also a risk factor of PTLD in children given nondepletional induction with basiliximab combined with sirolimus, tacrolimus, or cyclosporine, and steroids. Up to 6.9 % of patients developed PTLD. This was mainly seen in young EBV-naïve children receiving an EBV-seropositive renal allograft [18]. Of note is the specific relation of the new drug belatacept to PTLD (in adult patients): in EBV-seronegative cases, treatment was associated with a high incidence of PTLD, affecting in particular the central nervous system [5]. As the incidence of EBV-seronegative status is much higher in the first decade of life [59], the safety of further use of belatacept in pediatric patients is questionable.
Infections
As reported by North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS), induction is associated with significant higher risk of infection [odds ratio (OR) 1.45; p < 0.001), especially in terms of viral etiology (OR 1.47; p = 0.003) and in young children < 2 years of age, including the risk of BK–JC polyoma-virus (JVC)-related nephritis. The incidence of hospitalization within 2 years of follow-up (after induction) due to viral infections was about 30 % and bacterial infections about 28.4 % [63, 64]. Specific vaccination is mandatory with the use of eculizumab to prevent meningitis [42]. The association between treatment with rituximab JVC and, in consequence, development of progressive multifocal leukoencephalopathy (PML) was reported mainly in bone marrow transplant patients. The relevant report described 5.5 % incidence of JVC replication in adult solid-organ recipients (in the majority renal transplant patients) treated with rituximab, suggesting the need for close monitoring [65].
Rituximab-specific serious adverse event: rituximab-associated lung injury
Rituximab-associated lung injury was reported in patients treated with anti-CD20 Ab. This life-threatening syndrome may include interstitial pneumonitis, alveolar–interstitial pneumonia, and rapidly progressing pulmonary fibrosis. The need for mechanical ventilation is a predictor of poor prognosis [66].
Summarizing: Use of biologic agents is associated with risk of several general or drug-specific adverse events; therefore, the risk/potential clinical benefit ratio must be carefully balanced. EBV-seronegative status, the most common in children < 10 years of age, is a specific problem in the pediatric population and may limit or increase the risk of biologic agent use.
Key points regarding the use of biologics in rejection therapy are:
-
Biologics are used in transplantation to remove circulating antibodies and block their production, to reduce further exposure to toxic maintenance immunosuppressives, to treat recurrence of specific primary disease, and to treat severe rejection.
-
Depending on indication, biologics may be used before and early and late after renal transplantation.
-
Clinically additive mechanisms of action promote a combination of these drugs in specific clinical situations, such as desensitization or humoral rejection.
-
Biologic targeting of receptors on different cells may enhance the risk of serious adverse events, despite specific prophylactic measures.
Research points in biologics use in rejection therapy are:
-
Optimal treatment protocol for chronic humoral rejection should be established in controlled trials.
-
Optimal combinations of biologic agents (and/or extracorporeal procedures) aimed to reduce circulating DSA level for prophylaxis of humoral rejection need to be established in sensitized candidates for transplantation and active post-transplant de novo DSA producers Optimal treatment of primary disease recurrence after transplantation, including rituximab for NS and eculizumab for aHUS, should be verified in controlled trials.
References
Halloran PF (2004) Immunosuppressive drugs for kidney transplantation. N Eng J Med 351:2715–2729
Shehata N, Palda V, Meyer RM, Blydt-Hansen TD, Campbell P, Cardella C, Martin S, Nickerson P, Peltekian K, Ross H, Waddell TK, West L, Anderson D, Freedman J, Hume H (2010) The use of immunoglobulin therapy for patients undergoing solid organ transplantation: an evidence-based practice guideline. Transfusion Med Rev 24(1):S7–S27
De Serres SA, Yeung M, Mfarrej B (2011) Najafian N (2011) Effect of biologic agents on regulatory T cells. Transplant Rev 25:110–116
Hardinger K, Brennan D (2013) Novel immunosuppressive drugs in kidney transplantation. World J Transplant 3(4):68–77
Vincenti F, Charpentier B, Vanrenterghem Y, Rostaing L, Bresnahan B, Darji P, Massari P, Mondragon-Ramirez GA, Agarwal M, Di Russo G, Lin CS, Garg P, Larsen CP (2010) A phase III study of Belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT Study). Am J Transplant 10:535–546
Vincenti F, Blancho G, Durrbach A, Friend P, Grinyo J, Halloran PF, Klempnauer J, Lang P, Larsen CP, Mühlbacher F, Nashan B, Soulillou JP, Vanrenterghem Y, Wekerle T, Agarwal M, Gujrathi S, Shen J, Shi R, Townsend R, Charpentier B (2010) Five-Year Safety and Efficacy of Belatacept in Renal Transplantation. J Am Soc Nephrol 21:1587–1596
Busque S, Leventhal J, Brennan D, Steinberg S, Klintmalm G, Shah T, Mulgaonkar S, Bromberg JS, Vincenti F, Hariharan S, Slakey D, Peddi VR, Fisher RA, Lawendy N, Wang C, Chan G (2009) Calcineurin-inhibitor-free immunosuppression based on the JAK inhibitor CP-690,550: a pilot study in de-novo kidney allograft recipients. Am J Transplant 9:1936–1945
Vincenti F, Yang H, Klintmalm G, Steinberg S, Wang L, Zhang W, Conkle A, Blahunka P, First R, Holman J (2013) Clinical outcomes in phase 1b, randomized double-blind, parallel, placebo-controlled, single-dose study of ASKP1240 in de novo kidney transplantation. Am J Transplant 13: S5, abstr 181
Trivedi H, Terasaki P, Feroz A, Everly MJ, Vanikar AV, Shankar V, Trivedi VB, Kaneku H, Idica AK, Modi PR, Khemchandani SI, Dave SD (2009) Abrogation of anti-HLA antibodies via proteasome inhibition. Transplantation 87:1555–1556
Walsh R, Everly J, Brailey P, Rike AH, Arend LJ, Mogilishetty G, Govil A, Roy-Chaudhury P, Alloway RR, Woodle ES (2010) Proteasome-inhibitor based primary therapy for antibody-mediated renal allograft rejection. Transplantation 89:277–284
Höcker B, Kovarik J, Daniel V, Opelz G, Fehrenbach H, Holder M, Hoppe B, Hoyer P, Jungraithmayr TC, Köpf-Shakib S, Laube GF, Müller-Wiefel DE, Offner G, Plank C, Schröder M, Weber LT, Zimmerhackl LB, Tönshoff B (2008) Pharmacokinetics and immunodynamics of basiilximab in pediatric renal transplant recipients on mycophenolate mofetil comedication. Transplantation 86:1234–1240
Sarwal MM, Vidhun JR, Alexander SR, Satterwhite T, Millan M, Salvatierra O Jr (2003) Continued superior outcomes with modification and lengthened follow-up of a steroid-avoidance pilot with extended daclizumab induction in pediatric renal transplantation. Transplantation 76(9):1331–1339
Webster AC1, Ruster LP, McGee R, Matheson SL, Higgins GY, Willis NS, Chapman JR, Craig JC (2010) Interleukin 2 receptor antagonists for kidney transplant recipients. Cochrane Database Syst Rev 1:CD003897
Grenda R, Watson A, Vondrak K, Webb NJ, Beattie J, Fitzpatrick M, Saleem MA, Trompeter R, Milford DV, Moghal NE, Hughes D, Perner F, Friman S, Van Damme-Lombaerts R, Janssen F (2006) A prospective, randomized, multicenter trial of tacrolimus-based therapy with or without basiliximab in pediatric renal transplantation. Am J Transplant 6:1666–1672
Offner G, Tönshoff B, Hoecker B, Krauss M, Bulla M, Cochat P, Fehrenbach H, Fischer W, Foulard M, Hoppe B, Hoyer PF, Jungraithmayr TC, Klaus G, Latta K, Leichter H, Mihatsch MJ, Misselwitz J, Montoya C, Müller-Wiefel DE, Neuhaus TJ, Pape L, Querfeld U, Plank C, Schwarke D, Wygoda S, Zimmerhackl LB (2008) Efficacy and safety of basiliximab in pediatric renal transplant patients receiving cyclosporine, mycophenolate mofetil, and steroids. Transplantation 86(9):1241–1248
Grenda R, Watson A, Trompeter R, Tönshoff B, Jaray J, Fitzpatrick M, Murer L, Vondrak K, Maxwell H, van Damme-Lombaerts R, Loirat C, Mor E, Cochat P, Milford DV, Brown M, Webb NJ (2010) A Randomized Trial to Assess the Impact of Early Steroid Withdrawal on Growth in Pediatric Renal Transplantation: The TWIST Study. Am J Transplant 10:828–836
Delucchi A, Valenzuela M, Lillo A, Lillo AM, Guerrero JL, Cano F, Azocar M, Zambrano P, Salas P, Pinto V, Ferrario M, Rodríguez J, Cavada G (2011) Early steroid withdrawal in pediatric renal transplant: five years of follow-up. Pediatr Nephrol 26(12):2235–2244
Benfield MR, Bartosh S, Ikle D, Warshaw B, Bridges N, Morrison Y, Harmon W (2010) A randomized double-blind, placebo controlled trial of steroid withdrawal after pediatric renal transplantation. Am J Transplant 10:81–88
Montini G, Murer L, Ghio L, Pietrobon B, Ginevri F, Ferraresso M, Cardillo M, Scalamogna M, Perfumo F, Edefonti A, Zanon GF, Zacchello G (2005) One-year results of basiliximab induction and tacrolimus associated with sequential steroid and MMF treatment in pediatric kidney transplant recipients. Transplant Int 18:36–42
Grenda R (2013) Steroid withdrawal in renal transplantation. Pediatr Nephrol 28(11):2107–2112
Pape L, Lehner F, Blume C, Ahlenstiel T (2011) Pediatric kidney transplantation by de novo therapy with everolimus, low-dose cyclosporine A and steroid elimination: 3-year data. Transplantation 92(6):658–662
Shapiro E, Ellis D, Tan HP, Moritz ML, Basu A, Vats AN, Khan AS, Gray EA, Zeevi A, McFeaters C, James G, Jo Grosso M, Marcos A, Starzl TE (2006) Antilimphoid antibody preconditioning and tacrolimus monotherapy for pediatric kidney transplantation. J Pediatr 148(6):813–818
Tan HP, Donaldson J, Ellis D, Moritz ML, Basu A, Morgan C, Vats AN, Erkan E, Shapiro R (2008) Pediatric living donor kidney transplantation under alemtuzumab pretreatment and tacrolimus monotherapy: 4 years experience. Transplantation 86(12):1725–1731
Kirk A, Guasch A, Xu H, Cheeseman J, Mead SI, Ghali A, Mehta AK, Wu D, Gebel H, Bray R, Horan J, Kean LS, Larsen CP, Pearson TC (2014) Renal transplantation using belatacept without maintenance steroids or calcineurin inhibitors. Am J Transplant 14(5):1142–1151
Khositseth S, Matas A, Cook M, Bilingham K, Chavers B (2005) Thymoglobulin versus ATGAM induction therapy in pediatric kidney transplantation recipients: a single center report. Transplantation 79:958–963
Schwartz J, Ishitani M, Weckwerth J, Morgenstern B, Milliner D, Stegall MD (2007) Decreased incidence of acute rejection in adolescent kidney transplant recipients using antithymocyte induction and triple immunosuppression. Transplantation 84:715–717
Li L, Chaudhuri A, Chen A, Zhao X, Bezchinsky M, Concepcion W, Salvatierra O Jr, Sarwal MM (2010) Efficacy and safety of thymoglobulin induction as an alternative approach for steroid-free maintenance immunosuppression in pediatric renal transplantation. Transplantation 90:1516–1520
Chavers BM, Chang C, Gillingham KJ, Matas A (2009) Pediatric kidney transplantation using a novel protocol of rapid (6-day) discontinuation of prednisolone: 2-year results. Transplantation 88(2):237–241
Mourad G, Morelon E, Noël C, Glotz D, Lebranchu Y (2012) The role of Thymoglobulin induction in kidney transplantation: an update. Clin Transplant 26:E450–E464
Peddi VR, Bryant M, Roy-Chaudry P, Woddle ES, First MR (2002) Safety, efficacy and cost-analysis of Thymoglobuline induction therapy with intermittent dosing based on CD3+ lymphocyte counts in kidney and kidney-pancreas transplant recipients. Transplantation 73:1514–1508
Gaber OA, Matas AJ, Henry ML, Brennan DC, Stevens RB, Kapur S, Ilsley JN, Kistler KD (2012) Cosimi AB: on behalf of the Thymoglobulin Antibody Immunosuppression in Living Donor Recipients Investigators (2012) Antithymocyte Globulin Induction in Living Donor Renal Transplant Recipients: Final Report of the TAILOR Registry. Transplantation 94:331–337
Nehus E, Goebel J, Abraham E (2012) Outcomes of steroid avoidance protocols in pediatric kidney transplant recipients. Am J Transplant 12(12):3441–3448
Nair V, Sawinski D, Akalin E, Friedlander R, Ebcioglu Z, Sehgal V, Dinavahi R, Khaim R, Ames S, Lerner S, Murphy B, Bromberg JS, Heeger PS (2012) Schröppel B (2012) Effect of high-dose intravenous immunoglobulin on anti-HLA antibodies in sensitized kidney transplant candidates. Clin Transplant 26(3):E261–E268
Valentini RP, Nehlsen-Cannarella SL, Gruber SA, Mattoo TK, West MS, Lang C, Imam AA (2007) Intravenous immunoglobulin, HLA allele typing and HLA Matchmaker facilitate successful transplantation in highly sensitized pediatric renal allograft recipients. Pediatr Transplant 11(1):77–81
Lobashevsky A, Higgins N, Rosner K, Mujtaba MA, Goggins WC, Taber TE (2013) Analysis of anti-HLA antibodies in sensitized kidney transplant candidates subjected to desensitization with intravenous immunoglobulin and rituximAb Transplantation 96:182–190
Garonzik Wang J, Montgomery R, Kucirka L, Berger JC, Warren DS, Segev DL (2011) Incompatible live-donor kidney transplantation in United States: results of national survey. Clin J Am Soc Nephrol 6:2041–2046
Vo A, Lukovsky M, Toyoda M, Wang J, Reinsmoen NL, Lai CH, Peng A, Villicana R, Jordan SC (2008) Rituximab and intravenous immune globulin for desensitization during renal transplantation. N Eng J Med 359:242–251
Hariran A, Nogueira J, Kukuruga D, Schweitzer E, Hess J, Gurk-Turner C, Jacobs S, Drachenberg C, Bartlett S, Cooper M (2009) Positive cross-match living donor kidney transplantation: longer-term outcome. Am J Transplant 9:536–542
Tydén G, Donauer J, Wadström J, Kumlien G, Wilpert J, Nilsson T, Genberg H, Pisarski P, Tufveson G (2007) Implementation of a protocol for AB0-incompatible kidney transplantation-a three-center experience with 60 consecutive transplantations. Transplantation 83(9):1153–1155
Stegall MD, Diwan T, Raghvaiah S, Cornell LD, Burns J, Dean PG, Cosio FG, Gandhi MJ, Kremers W, Gloor JM (2011) Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients. Am J Transplant 11:2405–2413
Everly M, Terasaki P, Trivedi H (2012) Durability of antibody removal following proteasome inhibitor-based therapy. Transplantation 93:572–577
Zuber J, Le Quintrec M, Krid S, Bertoye C, Gueutin V, Lahoche A, Heyne N, Ardissino G, Chatelet V, Noël LH, Hourmant M, Niaudet P, Frémeaux-Bacchi V, Rondeau E, Legendre C, Loirat C, French Study Group for Atypical HUS (2012) French Study Group for Atypical HUS. Eculizumab for atypical hemolytic uremic syndrome recurrence in renal transplantation. Am J Transplant 12(12):3337–3354
Dello Strologo L, Guzzo I, Laurenzi C, Vivarelli M, Parodi A, Barbano G, Camilla R, Scozzola F, Amore A, Ginevri F, Murer L (2009) Use of rituximab in focal glomerulosclerosis relapses after renal transplantation. Transplantation 88(3):417–420
Kumar J, Shatat I, Skversky A, Woroniecki R, Del Rio M, Perelstein EM, Johnson VL, Mahesh S (2013) Rituximab in post-transplant pediatric recurrent focal segmental sclerosis. Pediatr Nephrol 28:333–338
Chaudhuri A, Kambham N, Sutherland S, Grimm P, Alexander S, Concepcion W, Sarwal M, Wong C (2012) Rituximab treatment for recurrence of nephrotic syndrome in a pediatric patient after renal transplantation for congenital nephrotic syndrome of Finnish type. Pediatr Transplant 16(5):E183–187
Zarkhin V, Li L, Kambham N, Sigdel T, Salvatierra O, Sarwal MM (2008) A randomized prospective trial of rituximab for acute rejection in pediatric transplantation. Am J Transplant 8:2607–2617
Upadhyay K, Midgley L, Mougdil A (2012) Safety and efficacy of alemtuzumab in the treatment of late acute renal allograft rejection. Pediatr Transplant 16:286–293
Clatworthy M, Friend P, Calne R, Rebello PR, Hale G, Waldmann H, Watson CJ (2009) Alemtuzumab (CAMPATH-1H) for the treatment of acute rejection in kidney transplant recipients: long-term follow-up. Transplantation 87:1092–1095
Kranz B, Kelsch R, Kuwertz-Bröking E, Bröcker V, Wolters HH, Konrad M (2011) Acute antibody-mediated rejection in paediatric renal transplant recipients. Pediatr Nephrol 26:1149–1156
Jordan SC, Reinmoen N, Peng A, Lai CH, Cao K, Villicana R, Toyoda M, Kahwaji J, Vo AA (2010) Advances in diagnosing and managing antibody-mediated rejection. Pediatr Nephrol 25:2035–2048
Waiser J, Budde K, Schǜtz M (2012) Comparison between bortezomib and rituximab in the treatment of antibody-mediated renal allograft rejection. Nephrol Dial Transplant 27:1246–1251
Walsh RC, Brailey P, Girnita A, Alloway RR, Shields AR, Wall GE, Sadaka BH, Cardi M, Tevar A, Govil A, Mogilishetty G, Roy-Chaudhury P, Woodle ES (2011) Early and late acute antibody- mediated rejection differ in immunologically and in response to proteasome inhibition. Transplantation 91:1218–1226
Ghirardo G, Benetti E, Poli F, Vidal E, Della Vella M, Cozzi E, Murer L (2014) Plasmapheresis-resistant acute humoral rejection successfully treated with anti-C5 antibody. Pediatr Transplant 18:E1–E5
Gonzales-Roncero F, Suner M, Bernal G, Cabello V, Toro M, Pereira P, Angel Gentil M (2012) Eculizumab treatment of acute antibody-mediated rejection in renal transplantation: case reports. Transplant Proc 44:2690–2694
Kocak B, Arpali E, Demiralp E, Yelken B, Karatas C, Gorcin S, Gorgulu N, Uzunalan M, Turkmen A, Kalayoglu M (2013) Eculizumab for salvage treatment of refractory antibody-mediated rejection in kidney transplant patients: case reports. Transpl Proc 45:1022–1025
Billing H, Rieger S, Ovens J, Süsal C, Melk A, Waldherr R, Opelz G, Tönshoff B (2008) Successful treatment of chronic antibody mediated rejection with IVIG and rituximab in pediatric renal transplant recipients. Transplantation 86:1214–1221
Billing H, Rieger S, Susal C, Waldherr R, Opelz G, Wühl E, Tönshoff B (2012) IVIG and rituximab for treatment of chronic antibody-mediated rejection: a prospective study in paediatric renal transplantion with 2-year follow-up. Transplant Int 25:1165–1173
Cicora F, Paz M, Mos F, Roberti J (2013) Use of bortezomib in renal transplant recipients: a single-center experience. Transplant Immunol 29:7–10
Opelz G, Daniel V, Naukojat C, Döhler B (2009) Epidemiology of pretransplant EBV and CMV serostatus in relation to posttransplant non-Hodgkin lymphoma. Transplantation 88:962–967
Opelz G, Döhner B (2003) Lymphomas after solid organ transplantation: a Collaborative Transplant Study report. Am J Transplant 4:222–230
Kirk A, Cherikh W, Ring M, Burke G, Kaufman D, Knechtle SJ, Potdar S, Shapiro R, Dharnidharka VR, Kauffman HM (2007) Dissociation of depletional induction and post transplant lymphoproliferative disease in kidney recipients treated with alemtuzumAb Am J Transplant 7:2619–2625
Dharnidharka VR, Lamb KE, Gregg JA, Meier-Kriesche HU (2012) Associations between EBV serostatus and organ transplant type in PTLD risk: an analysis of the SRTR National Registry Data in the United States. Am J Transplant 12:976–83
Puliyanda DP, Stablein DM, Dharnidharka VR (2007) Younger age and antibody induction increase the risk for infection in pediatric renal transplantation: a NAPRTCS report. Am J Transplant 7(3):662–666
Smith JM, Dhanidharka VR, Talley L, Martz K, McDonald RA (2007) BK virus nephropathy in pediatric renal transplant recipients: an analysis of North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) registry. Clin J Am Soc Nephrol 2(5):1037–1042
Kamar N, Mengelle C, Rostaing L (2009) Incidence of JC-Virus replication after rituximab therapy in solid-organ transplant patients. Am J Transplant 9:244–245
Bitzan M, Anselmo M, Carpineta L (2009) Rituximab (B-cell depleting antibody) associated lung injury (RALI): a pediatric case report and systematic review of the literature. Pediatr Pulmonol 44:922–934
Conflict of interests
None.
Questions (answers are provided following the reference list)
1. Monoclonal antibodies (Ab) used in renal transplantation:
a. Are always depleting Ab
b. Are aimed to B cells only
c. May be depleting or blocking Ab
d. Are used only to treat rejection
e. Are not used in children
2. The effect of biologics on specific cell-target receptors:
a. Is always longer with the use of polyclonal Ab
b. Is never longer than 2 weeks after a single dose
c. Is shorter in tacrolimus-treated patients
d. Is drug and dose dependent and may last from 2 weeks to > 12 months
e. Has no clinical importance, as this depends on maintenance immunosuppression
3. The risk of PTLD is higher in young children receiving biologic agents after renal transplantation because:
a. They are more frequently desensitized than adolescents
b. They have higher risk of recurrence of primary disease
c. They need more blood transfusions after transplantation
d. They are more often EBV-seronegative < 10 years of age
e. They often have tonsillitis
4. Combination of IVIG and rituximab, used for desensitization or treatment of humoral rejection:
a. Is given to block T-cell-derived cytokines
b. Allows removal of circulating DSA and blocks their further production by B cells
c. Decreases the risk of rituximab-related infectious complications by IVIG
d. Is not used in children
e. Is used in minimization protocols
5. While administering depletional antibodies:
a. There is no need for monitoring
b. Monitoring drug concentration is mandatory
c. Monitoring target-cell count is useful to assess the effect and sometimes adjust the next dose
d. Monitoring concomitant CNI concentration is necessary, as there is CYP3P-driven interaction
e. Every dose must be adjusted to current CD4/CD8 ratio
Author information
Authors and Affiliations
Corresponding author
Additional information
Correct answers
1: c; 2: d; 3: d; 4: b; 5: c
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
About this article
Cite this article
Grenda, R. Biologics in renal transplantation. Pediatr Nephrol 30, 1087–1098 (2015). https://doi.org/10.1007/s00467-014-2886-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00467-014-2886-4