Kidney transplantation is the preferred treatment for end-stage renal failure in children but remains a rare procedure with only 100 to 120 pediatric kidney transplants per year in France. Although ...the main principles of kidney transplantation are the same in children and adults, some specificities regarding underlying kidney diseases, surgical technique, immunosuppressive drugs metabolism and the risk of infectious complications require a specific expertise to care for these patients. Similarly, the major morbidity of dialysis in children and the need for repeated transplants during the patient's life justify pediatric specificities in the choice of donors and the allocation of grafts in most kidney allocation systems worldwide. The objectives of this review are to present the history and specificities of pediatric kidney transplantation, to describe the current activity in France and to discuss future developments while emphasizing the need for basic and clinical research focused on the pediatric population.
La transplantation rénale est le traitement de choix de l’insuffisance rénale terminale chez l’enfant, mais cela reste une procédure rare avec, en France, seulement 100 à 120 transplantations rénales ...pédiatriques par an. Si les grands principes de la transplantation rénale sont identiques chez l’enfant et chez l’adulte, certaines spécificités en lien avec les maladies rénales sous-jacentes, la technique chirurgicale, le métabolisme des immunosuppresseurs et le risque de complication infectieuse, justifient une prise en charge particulière des jeunes patients. La morbidité de la dialyse, particulière chez l’enfant, et le besoin de transplantations répétées au cours de la vie du patient expliquent des spécificités pédiatriques dans le choix des donneurs et l’allocation des greffons sur la liste d’attente nationale. L’objectif de cette revue est de présenter l’histoire et les spécificités de la transplantation rénale pédiatrique, de décrire l’état actuel de cette activité en France et d’évoquer les perspectives futures en soulignant le besoin de recherches fondamentale et clinique focalisées sur la population pédiatrique.
Kidney transplantation is the preferred treatment for end-stage renal failure in children but remains a rare procedure with only 100 to 120 pediatric kidney transplants per year in France. Although the main principles of kidney transplantation are the same in children and adults, some specificities regarding underlying kidney diseases, surgical technique, immunosuppressive drugs metabolism and the risk of infectious complications require a specific expertise to care for these patients. Similarly, the major morbidity of dialysis in children and the need for repeated transplants during the patient’s life justify pediatric specificities in the choice of donors and the allocation of grafts in most kidney allocation systems worldwide. The objectives of this review are to present the history and specificities of pediatric kidney transplantation, to describe the current activity in France and to discuss future developments while emphasizing the need for basic and clinical research focused on the pediatric population.
Transplantation is the only curative treatment for patients with kidney failure but it poses unique immunological challenges that must be overcome to prevent allograft rejection and ensure long-term ...graft survival. Alloreactive T cells are important contributors to graft rejection, and a clearer understanding of the mechanisms by which these cells recognize donor antigens - through direct, indirect or semi-direct pathways - will facilitate their therapeutic targeting. Post-T cell priming rejection responses can also be modified by targeting pathways that regulate T cell trafficking, survival cytokines or innate immune activation. Moreover, the quantity and quality of donor-reactive memory T cells crucially shape alloimmune responses. Of note, many fundamental concepts in transplant immunology have been derived from models of infection. However, the programmed differentiation of allograft-specific T cell responses is probably distinct from that of pathogen-elicited responses, owing to the dearth of pathogen-derived innate immune activation in the transplantation setting. Understanding the fundamental (and potentially unique) immunological pathways that lead to allograft rejection is therefore a prerequisite for the rational development of therapeutics that promote transplantation tolerance.
Abstract
Background and Aims
Belatacept is a co-stimulation blocker associated with better long-term outcomes in adult patients compared to CNI based regimens. Data on its use in older children and ...young adults are lacking. We are the 1st to report outcomes for 45 pediatric kidney transplant recipients converted to belatacept.
Method
45 patients were included from 4 centers (USA and France) between 05/2018 and 12/2021. Patients received an induction with basiliximab (n = 39) or ATG (n = 6). Maintenance immunosuppression included CNI, MMF +/− steroids. Patients’ viral status (EBV, CMV) were monitored monthly and allograft biopsies were performed prior and ∼6 months after starting belatacept. The first 5 belatacept injections were administered at 5 mg/kg/dose (10 mg/kg/dose if early conversion) every 2 weeks, then monthly. CNI were progressively reduced and stopped. MMF doses were also increased at CNI withdrawal.
Results
Median age at conversion was 17.7 y (range 10.3-20.6). 7/45 patients received an early conversion (median: 1 month post-transplant, IQR 0.5-1.2): 6 patients because of delayed graft function and 1 to avoid CNI toxicity (post-transplant diabetes). 38/45 patients were converted after a median of 4.1 years post-transplant (IQR 1.7-6.0). Conversion indication was based on the need for long term CNI avoidance: either because of toxicity (histology, post-transplant diabetes, tremors; n = 13) or sub-optimal creatinine (n = 12) or to improve adherence (e.g. monthly IV-treatment, n = 13). CNI were withdrawn in 42/45 patients by a median of 2.4 months (IQR 1.4-6.0). GFR was stable or improved over a median follow-up time of 1.6 years (IQR 1.1-2.4), Fig 1 A. Rejection episodes were observed in 10/45 patients (22%) after a median of 10.2 months (IQR 6.1-15.8) and included 7 TCMR, 2 ABMR and 1 mixed rejection. None of these patients were converted early (<3 m), 5 had been converted for non-adherence, 4 had pre-existing DSA and 4 had prior history of rejection. Evolution of GFR in rejectors is shown in Fig 1 B. CNI were reintroduced for 6/10 and belatacept stopped for 3/10. Regarding viral complications, 1 severe BKv nephropathy required the discontinuation of belatacept. All patients were EBV+ at conversion (4 were EBV- at the time of transplant). No EBV replication was observed.
Conclusion
Selected pediatric kidney recipients benefit from long-term CNI toxicity avoidance, but selection criteria need to be refined to avoid rejection under costimulation blockade.
During SARS-CoV-2 pandemic, the assessment of immune protection of people at risk of severe infection was an important goal. The appearance of VOCs (Variant of Concern) highlighted the limits of ...evaluating immune protection through the humoral response. While the humoral response partly loses its neutralizing activity, the anti-SARS-CoV-2 memory T cell response strongly cross protects against VOCs becoming an indispensable tool to assess immune protection. We compared two techniques available in laboratory to evaluate anti-SARS-CoV-2 memory T cell response in a cohort of infected or vaccinated patients with different levels of risk to develop a severe disease: the ELISpot assay and the T-Cell Lymphocyte Proliferation Assay respectively exploring IFNγ production and cell proliferation. We showed that the ELISpot assay detected more anti-Spike memory T cell response than the Lymphocyte Proliferation Assay. We next observed that the use of two different suppliers as antigenic source in the ELISpot assay did not affect the detection of anti-Spike memory T cell response. Finally, we explored a new approach for defining the positivity threshold, using unsupervised mixed Gaussian modeling, challenging the traditional ROC curve used by the supplier. That will be helpful in endemic situation where it could be difficult to recruit “negative” patients.
•Quantification of anti-SARS-CoV-2 memory T cell response using IFNγ-ELISpot assay was higher as compared to T-cell LPA.•The use of different peptide pools did not impact detection of anti-SARS-CoV-2 memory T cell response by IFNγ-ELISpot assay.•We used an innovative approach, the mixed Gaussian modeling, to define new thresholds of anti-Spike memory T cell response.
The adoption of de novo belatacept in kidney transplant (kTx) recipients was hampered by an increased risk of acute cellular rejection (ACR) with variation in adopted belatacept based ...immunosuppressive therapies across centers. We used data from the Scientific Registry of Transplant Recipients (SRTR) to evaluate the temporal trends in belatacept use and describe the associated induction and maintenance regimens in US adult kTx recipients transplanted between June 2011 and December 2018. The number of patients receiving de novo‐belatacept based immunosuppressive therapy increased from .74% in 2011 to 3.11% in 2016. In 2016, 66/207 centers used de novo belatacept‐based regimen with 3.03% using it in over 50% of their patients. The use of T‐cell depleting agents increased with time. Since 2012, the rate of calcineurin inhibitor (CNI) use in combination with belatacept remained stable around 50% and ∼30% remained under belatacept/CNI combination at 1‐year post‐transplantation. The adoption of belatacept as de novo immunosuppressive regimen has been slow and its use remains low in the United States. Various regimens have been used to modulate the risk of ACR. Further studies evaluating the long‐term outcomes of these regimens and assessing their safety especially with regard to the risk of infection are needed.
Between 5 and 50% of atypical hemolytic uremic syndrome (aHUS) cases in children are caused by autoantibodies against complement factor H (CFH). Given the acquired autoimmune nature of the disease, ...plasma exchange (PE) and various immunosuppressive treatments have been used. More recently, eculizumab has been proposed.
In this multicenter, retrospective study, we report outcomes of 12 children with anti-FH antibody-associated HUS treated with eculizumab associated with various immunosuppressive regimens.
Patients were treated with eculizumab for 15.5 9.5;23.0 months and 3 received PE or IgG adsorption. Three patients received mycophenolate mofetil (MMF) alone, 1 patient received MMF and steroids, 1 patient received MMF and rituximab, 3 patients received MMF/steroids and rituximab, and 4 patients did not receive any immunosuppression. Anti-FH antibody levels significantly decreased but no difference was observed based on the immunosuppressive regimen. Eculizumab was discontinued in 7/10 patients after 11 7.5;15.5 months and MMF in 6/8 patients after 36 35;40 months. Anti-FH titers at MMF discontinuation ranged from 257 to 3425 UI/L. None of these patients relapsed and eGFR at last follow-up was above 70 mL/min/1.73 m
in all patients.
Eculizumab is effective and safe in inducing and maintaining remission in aHUS secondary to anti-FH antibodies and renders reduction of anti-FH titers less urgent. Anti-FH antibody titers decreased in most patients irrespective of the immunosuppressive treatment chosen, so that a strategy consisting of combining eculizumab with MMF monotherapy seems sufficient at least in non-Indian or less severe forms of anti-FH antibody-associated HUS.
In this retrospective cohort study, we analyze the early humoral and cellular response in 64 adolescents KTx recipients, after two or three doses of mRNA vaccine BNT162b2 against different variants ...of COVID-19. After 2 doses, 77.8% % of children with no history of infection had a positive humoral response with a median anti-S IgG level of 1107 (IQR, 593-2,658) BAU/mL. All the patients with a history of infection responded with a higher median IgG level (3,265 (IQR, 1,492-8,178) BAU/mL). In non-responders after 2 doses, 75% responded after a third dose with a median Ab titer at 355 (IQR, 140-3,865 BAU/mL). Neutralizing activity was significantly lower against the delta and the omicron variants compared to the wild-type strain and did not improve after a 3rd dose, while infection did provide higher levels of neutralizations against the variants. T cell specific response correlated with humoral response and no patient displayed a cellular response without a humoral response. Adolescent KTx recipients exhibit a high seroconversion rate after only two doses. A third injection, induces a response in the majority of the non-responders patients but did not counterbalance the strong decrease in neutralizing antibody activities against variants highlighting the need for boosters with specific vaccines.
