Improve in-depth immunological risk assessment to optimize genetic-compatibility and clinical outcomes in child and adolescent recipients of parental donor kidney transplants: protocol for the INCEPTION study.

BACKGROUND: Parental donor kidney transplantation is the most common treatment option for children and adolescents with kidney failure. Emerging data from observational studies have reported improved short- and medium-term allograft outcomes in recipients of paternal compared to maternal donors. The INCEPTION study aims to identify potential differences in immunological compatibility between maternal and paternal donor kidneys and ascertain how this affects kidney allograft outcomes in children and adolescents with kidney failure. METHODS: This longitudinal observational study will recruit kidney transplant recipients aged ≤18 years who have received a parental donor kidney transplant across 4 countries (Australia, New Zealand, United Kingdom and the Netherlands) between 1990 and 2020. High resolution human leukocyte antigen (HLA) typing of both recipients and corresponding parental donors will be undertaken, to provide an in-depth assessment of immunological compatibility. The primary outcome is a composite of de novo donor-specific anti-HLA antibody (DSA), biopsy-proven acute rejection or allograft loss up to 60-months post-transplantation. Secondary outcomes are de novo DSA, biopsy-proven acute rejection, acute or chronic antibody mediated rejection or Chronic Allograft Damage Index (CADI) score of > 1 on allograft biopsy post-transplant, allograft function, proteinuria and allograft loss. Using principal component analysis and Cox proportional hazards regression modelling, we will determine the associations between defined sets of immunological and clinical parameters that may identify risk stratification for the primary and secondary outcome measures among young people accepting a parental donor kidney for transplantation. This study design will allow us to specifically investigate the relative importance of accepting a maternal compared to paternal donor, for families deciding on the best option for donation. DISCUSSION: The INCEPTION study findings will explore potentially differential immunological risks of maternal and paternal donor kidneys for transplantation among children and adolescents. Our study will provide the evidence base underpinning the selection of parental donor in order to achieve the best projected long-term kidney transplant and overall health outcomes for children and adolescents, a recognized vulnerable population. TRIAL REGISTRATION: The INCEPTION study has been registered with the Australian New Zealand Clinical Trials Registry, with the trial registration number of ACTRN12620000911998 (14th September 2020).

Equally Interchangeable? How Sex and Gender Affect Transplantation.

Organ transplantation as an option to overcome end-stage diseases is common in countries with advanced healthcare systems and is increasingly provided in emerging and developing countries. A review of the literature points to sex- and gender-based inequity in the field with differences reported at each step of the transplant process, including access to a transplantation waiting list, access to transplantation once waitlisted, as well as outcome after transplantation. In this review, we summarize the data regarding sex- and gender-based disparity in adult and pediatric kidney, liver, lung, heart, and hematopoietic stem cell transplantation and argue that there are not only biological but also psychological and socioeconomic issues that contribute to disparity in the outcome, as well as an inequitable access to transplantation for women and girls. Because the demand for organs has always exceeded the supply, the transplant community has long recognized the need to ensure equity and efficiency of the organ allocation system. In the spirit of equity and equality, the authors call for recognition of these inequities and the development of policies that have the potential to ensure that girls and women have equitable access to transplantation.

Sensitization in Transplantation: Assessment of Risk (STAR) 2017 Working Group Meeting Report.

The presence of preexisting (memory) or de novo donor-specific HLA antibodies (DSAs) is a known barrier to successful long-term organ transplantation. Yet, despite the fact that laboratory tools and our understanding of histocompatibility have advanced significantly in recent years, the criteria to define presence of a DSA and assign a level of risk for a given DSA vary markedly between centers. A collaborative effort between the American Society for Histocompatibility and Immunogenetics and the American Society of Transplantation provided the logistical support for generating a dedicated multidisciplinary working group, which included experts in histocompatibility as well as kidney, liver, heart, and lung transplantation. The goals were to perform a critical review of biologically driven, state-of-the-art, clinical diagnostics literature and to provide clinical practice recommendations based on expert assessment of quality and strength of evidence. The results of the Sensitization in Transplantation: Assessment of Risk (STAR) meeting are summarized here, providing recommendations on the definition and utilization of HLA diagnostic testing, and a framework for clinical assessment of risk for a memory or a primary alloimmune response. The definitions, recommendations, risk framework, and highlighted gaps in knowledge are intended to spur research that will inform the next STAR Working Group meeting in 2019.

Mechanisms and risk assessment of steroid resistance in acute kidney transplant rejection.

Ever since the first successful kidney transplantation, the occurrence of acute rejection has been a dominant risk factor for adverse graft outcome, as it is associated with reduced graft survival and the development of chronic transplant dysfunction. Although the majority of acute renal allograft rejection episodes can be adequately treated with glucocorticoid therapy, 25 to 30% of the rejection episode cannot be reversed with glucocorticoids alone. At present, the diagnosis of steroid resistance primarily relies on post-transplantation follow-up of clinical parameters reflecting renal allograft function. However, it remains difficult to predict the response to the response to antirejection treatment. Prediction of steroid resistance could prevent unnecessary exposure to high-dose corticosteroid therapy and avoid the development and progression of irreversible nephron. This impact of steroid-refractory rejection on graft integrity stresses the need for tools to assess the response to AR treatment in an early stage. Here, we discuss our current understanding of resistance to anti-rejection treatment with glucocorticoids, and provide an overview of biomarkers for the detection and/or prediction of steroid resistance in kidney transplantation.

Modeling the benefits and costs of integrating an acceptable HLA mismatch allocation model for highly sensitized patients.

BACKGROUND: The Eurotransplant acceptable mismatch program has improved transplantation access for highly sensitized recipients. However, the benefits and costs of implementing such a program remain unknown. METHODS: Using decision analytical modeling, we compared the average waiting time for transplantation, overall survival gains (in life-years and quality-adjusted life-years gained), and costs of integrating an acceptable mismatch allocation model compared with the current deceased-donor kidney allocation model in Australia. RESULTS: Acceptable mismatches were identified in 12 of 28 (43%) highly sensitized recipients using HLAMatchmaker. Inclusion of acceptable mismatches in the current allocation model improved the transplantation access for four (14%) highly sensitized recipients, with an average reduction in waiting time of 34 months (from 86 to 52 months). Compared with the current allocation model, incorporating an acceptable mismatch allocation model achieved an overall lifetime gain of 0.034 quality-adjusted life-years and savings of over $4,000 per highly sensitized patient, with a small consequential loss of 0.005 quality-adjusted life-years and extra costs of $800 for every reallocated patient. CONCLUSIONS: Despite modest overall health gains, application of an acceptable mismatch allocation model is an equitable approach to improve transplantation access for highly sensitized transplant candidates without compromising the overall health benefits among the other patients on the deceased-donor waitlist in Australia.

Coordinating unspecified living kidney donation and transplantation across the blood-type barrier in kidney exchange.

BACKGROUND: This article studies multicenter coordination of unspecified living kidney donation and transplantation across the blood-type barrier in kidney exchange. Important questions are whether such coordination should use domino paired donation or non simultaneous extended altruistic donor chains, what the length of the segments in such chains should be, when they should be terminated, and how much time should be allowed between matching rounds. Furthermore, it is controversial whether the different modalities should be coordinated centrally or locally and independently. METHODS: Kidney exchange policies are simulated using actual data from the Dutch national kidney exchange program. Sensitivity analysis is performed on the composition of the population, the time unspecified and bridge donors wait before donating to the wait list, the time between matching rounds, and donor renege rates. RESULTS: Central coordination of unspecified donation and transplantation across the blood-type barrier can increase transplants by 10% (PG0.001). Especially highly sensitized and blood type O patients benefit. Sufficient time between matching rounds is essential: three-monthly exchanges result in 31% more transplants than weekly exchanges. Benefits of non simultaneous extended altruistic donor chains are limited in case of low numbers of highly sensitized patients and sufficient unspecified donors. Chains are best terminated when no further segment is part of an optimal exchange within 3 months. CONCLUSIONS: There is clear synergy in the central coordination of both unspecified donation and transplantation across the blood-type barrier in kidney exchange. The best configuration of a national program depends on the composition of the patient Y donor population.

The functional polymorphism Ala258Ser in the innate receptor gene ficolin-2 in the donor predicts improved renal transplant outcome.

BACKGROUND: Innate immunity plays a role in controlling adaptive immune responses. METHODS: We investigated the clinical relevance of single nucleotide polymorphisms in 22 genes encoding innate, secreted, and signaling pattern recognition receptors in a total of 520 donor-recipient pairs of postmortem, human leukocyte antigen-DR-compatible kidney transplantations. Associations with rejection incidence were tested in an a priori randomized training set and validation set. RESULTS: Polymorphisms in TLR-3 (rs3775296) in the recipients and in ficolin-2 (rs7851696; Ala258Ser) and C1qR1 (rs7492) in the donors showed the strongest association with severe rejection. In multivariate analysis, presence of the ficolin-2 Ala258Ser variant in the donor predicted lower incidence of severe rejection (odds ratio=0.3; 95% confidence interval, 0.1-0.9; P=0.024) and of graft loss (hazard ratio=0.5; 95% confidence interval, 0.2-1.0; P=0.046) independently of clinical risk factors. Ficolin-2 messenger RNA expression was detected in pretransplantation biopsies from 69 donor grafts. Serum and tissue ficolin-2 levels were unaffected by genotype. Ficolin-2 protein, which bound to dying cells, was detected in donor kidneys in a passenger leukocyte-like pattern. Indeed, monocytes, monocyte-derived macrophages, and peripheral blood mononuclear cells expressed ficolin-2. Donor grafts with the ficolin-2 Ala258Ser variant contained significantly elevated expression of interleukin 6, having ascribed cytoprotective effects. It has been described that Ala258Ser leads to increased binding capacity of ficolin-2 to N-acetylglucosamine. CONCLUSIONS: Presence of the ficolin-2 Ala258Ser polymorphism in the donor independently predicts improved graft outcome. Based on mechanistic data, we propose that this functional polymorphism leads to more efficient handling of injured cells by phagocytozing cells, resulting in decreased intragraft exposure to danger signals and dampened alloimmune responses.

Quantitative polymerase chain reaction profiling of immunomarkers in rejecting kidney allografts for predicting response to steroid treatment.

BACKGROUND: Steroid-resistant acute rejection is a risk factor for inferior renal allograft outcome. METHODS: From 873 kidney transplant recipients (1995-2005), 108 patients with a first rejection episode were selected for study using strict inclusion criteria and clinical endpoint definition. We aimed to predict response to corticosteroid treatment using gene expression of 65 transcripts. These reflect cytokines, chemokines, and surface and activation markers of various cell types including T cells, macrophages, B cells, and granulocytes. Steroid resistance (40% of the patients) was defined as requirement for antithymocyte globulin treatment within 2 weeks after corticosteroid treatment. RESULTS: None of the clinical and histomorphologic parameters showed a significant association with response to treatment. Univariate logistic regression analysis resulted in 11 messenger RNA markers, including T-cell-related transcripts CD25, lymphocyte activation gene-3, Granzyme B, and interleukin-10, and macrophage-specific transcripts mannose receptor and S100 calcium-binding protein A9, which significantly discriminated steroid resistant from steroid-responsive rejections (P<0.05). In multivariate logistic regression, the combination of T-cell activation markers CD25:CD3e ratio (odds ratio, 8.7; confidence interval, 2.4-31.2) and lymphocyte activation gene-3 (odds ratio, 3.3; confidence interval, 1.4-7.7) represented the best predictive model for steroid response (P<0.0001). Specificity and sensitivity were 78% and 60%, respectively. After internal stratified 10-fold cross-validation, the model remained significant. Inclusion of clinical variables into the model with molecular variables did not enhance prediction. CONCLUSIONS: Differences in intragraft expression profiles reflect variability in the response to antirejection treatment. In acute rejection, molecular markers, particularly those reflecting T-cell activation, offer superior prognostic value compared with conventional parameters.

Eight years of outcomes of the Dutch Living Donor Kidney Exchange Program.

In January 2004, the Dutch transplant centers agreed on a protocol for a national Living Donor Kidney Exchange Program for ABO blood type incompatible and positive cross match donor-recipient pairs. Here, we report the results of that program. All transplants performed within the Living Donor Kidney Exchange Program between January 2004 and December 2011 were analysed. We collected demographic data of recipients and donors. Univariate and multivariate Cox proportional hazard analyses were performed, including recipient age, donor age, and reason for participation in the exchange program. We studied overall uncensored survival and graft survival censored for death in both ABO blood type incompatible and positive cross match groups. We enrolled 472 donor-recipient combinations, consisting of 269 ABO blood type incompatible pairs and 203 positive cross match pairs. In the end, we performed 187 kidney transplants (40% of those enrolled) with 83 ABO blood type incompatible and 104 positive cross match pairs. Most of the transplanted recipients (119/187, 64%) had an age difference of less than 5 years with their original incompatible donors. The age differences with their actual donors varied widely, but the number of recipients with a donor > 5 years older was comparable to the number of recipients with a donor > 5 years younger. In the multivariate Cox analysis, age as a continuous variable was found to have a significant influence on graft failure. Nevertheless, the 5-year uncensored survival (85%) and the graft survival censored for death (89%) were excellent and comparable to the results of direct living donation. No differences were found between the ABO incompatible and the positive cross match groups. The Dutch Living Donor Kidney Exchange Program has a high transplant rate of 40%, with excellent 5 year graft survival.

The optimal chain length for kidney paired exchanges: an analysis of the Dutch program.

Living donor kidney exchange programs offer incompatible donor-recipient pairs the opportunity to be transplanted. To increase the number of these transplants, we examined in our actual donor-recipient couples how to reach the maximum number of matches by using different chain lengths. We performed 20 match procedures in which we constructed four different chain lengths: two, up to three, up to four and unlimited. The actual inflow and outflow of donor-recipient couples for each run were taken into consideration in this analysis. The total number of matched pairs increased from 148 pairs for only two-way exchanges to 168 for three-way exchanges. When a chain length of 4 was allowed five extra couples could be matched over a period of 5 years. Unlimited chain length did not significantly affect the results. The optimal chain length for living donor kidney exchange programs is 3. Longer chains with their inherent logistic burden do not lead to significantly more transplants.

Towards kidney allocation on basis of HLA-DR compatibility.

In the past years immunosuppressive regiments were mainly directed against T cell reactivity. Recently, alloreactivity by B cells and HLA antibodies have received more attention often triggered by the proposal of Terasaki on the "humoral theory of transplantation". Alloantibodies are not only a relevant factor before transplantation, but are also a cause of allograft dysfunction after transplantation. In the present report we advocate the possibility to reduce the effect of these detrimental, donor specific antibodies in organ transplantation. We propose to introduce fully HLA-DR compatibility in renal transplantation to increase the possibility of the patient to receive an adequately matched organ leading to an increased graft survival. This procedure is associated with a lower degree of allosensitization towards the donor HLA antigens and in case of graft failure, a higher chance to be retransplanted. This step can be seen as the first in a series of possibilities to diminish allosensitization without the need of additional immunosuppressive treatments.

A flexible national living donor kidney exchange program taking advantage of a central histocompatibility laboratory: the Dutch model.

The shortage of deceased donor kidneys for transplantation has resulted in the expansion of living donation programs. A number of possibilities have been explored, since it became clear that donors do not need to be genetically related to their recipients. Apart from classical direct donation, other options such as paired exchange, list exchange, altruistic donation and domino paired exchange programs have been implemented. In the Netherlands, patients who cannot be transplanted with their potential living donor because of ABO blood group incompatibility or a positive crossmatch, have the option to participate in a national paired kidney exchange program. The practical issues related to this program are described. The 5-years experience with the Dutch kidney exchange program is very positive as, so far, 42% of the recipients included have been transplanted. Recommendations are given for a successful implementation of a common kidney exchange program of different transplantation centers focusing on the advantage of a central histocompatibility laboratory.

Simpler and equitable allocation of kidneys from postmortem donors primarily based on full HLA-DR compatibility.

BACKGROUND: The introduction of human leukocyte antigen (HLA)-matching in nonliving kidney transplantation has resulted into a better graft outcome, but also in an increase of waiting time, especially for patients with rare HLA phenotypes. We addressed the question of the differential influence of HLA-DR-matching versus HLA-A,B in clinical kidney transplantation. METHODS: We used Kaplan-Meier product limit method to estimate survival rates, and Cox proportional hazard regression for the estimation of relative risks (Hazard-ratios) for different variables. RESULTS: A single center study (n=456 transplants, performed between 1985 and 1999) showed that full HLA-DR compatibility leads to a lower incidence of biopsy confirmed acute rejections in the first 180 posttransplantation days. These results were substantiated using the Eurotransplant database (n=39,205 transplants performed between 1985 and 2005) where graft survival in the full HLA-DR compatible group was significantly better than in the incompatible. An additional positive effect of HLA-A,B matching was only found in the full HLA-DR compatible group. In both studies, the introduction of a single HLA-DR incompatibility eliminates the HLA-A,B matching effect. CONCLUSIONS: We propose to allocate postmortem kidneys only to patients with full HLA-DR compatibility, and use HLA-A,B compatibility as an additional selection criterion. All patients, irrespective of their ethnic origin, will profit since the polymorphism of HLA-DR is by far lower than that of HLA-A,B. Excessive kidney travel and cold ischemia time will be significantly reduced.

Rapid assessment of the antigenic integrity of tetrameric HLA complexes by human monoclonal HLA antibodies.

The ability of tetrameric major histocompatibility complex (MHC) class I-peptide complexes (tetramers) to detect antigen-specific T lymphocyte responses has yielded significant information about the generation of in vivo immunity in numerous antigenic systems. Here we present a novel method for rapid validation of tetrameric HLA molecules based on the presence of allodeterminants. Human monoclonal antibodies (mAbs) recognizing polymorphic determinants on HLA class I were immobilized on polystyrene microparticles and used to probe the structural integrity of tetrameric HLA class I molecules by flow cytometry. A total of 22 tetramers, based on HLA-A1, A2, A3, A24, B7 and B8 were reactive with their counterpart mAbs, thus confirming their antigenic integrity. A positive outcome of this mAb test ensures that tetrameric HLA class I can be used with greater confidence in subsequent functional assays.

The Dutch national living donor kidney exchange program.

The wait time for deceased-donor kidney transplantation has increased to 4-5 years in the Netherlands. Strategies to expand the donor pool include a living donor kidney exchange program. This makes it possible that patients who cannot directly receive a kidney from their intended living donor, due to ABO blood type incompatibility or a positive cross match, exchange donors in order to receive a compatible kidney. All Dutch kidney transplantation centers agreed on a common protocol. An independent organization is responsible for the allocation, cross matches are centrally performed and exchange takes place on an anonymous basis. Donors travel to the recipient centers. Surgical procedures are scheduled simultaneously. Sixty pairs participated within 1 year. For 9 of 29 ABO blood type incompatible and 17 of 31 cross match positive combinations, a compatible pair was found. Five times a cross match positive couple was matched to a blood type incompatible one, where the recipients were of blood type O. The living donor kidney exchange program is a successful approach that does not harm any of the candidates on the deceased donor kidney waitlist. For optimal results, both ABO blood type incompatible and cross match positive pairs should participate.

Extending options for highly sensitized patients to receive a suitable kidney graft.

Highly sensitized patients (anti-HLA) on the kidney waiting list wait longer for a suitable crossmatch negative organ. At the moment there are two strategies to enhance transplantation of these patients. One approach is the determination of acceptable HLA mismatches and application of this knowledge for the selection of crossmatch negative donors, and the second is the desensitization of patients with intravenous immunoglobulin-based protocols to enable transplantation of an organ from a donor towards which antibodies were originally present. Both approaches have advantages and disadvantages and are only successful in a proportion of the patients. The optimal solution is an integrated strategy whereby desensitization is used for those patients for whom the acceptable mismatch approach is not successful.

It takes six to boogie: allocating cadaver kidneys in Eurotransplant.

In March 1996, a new allocation point system for cadaver kidneys, the Eurotransplant (ET) Kidney Allocation System (KAS), was introduced in ET, the first multinational organ exchange organization. The aims of ETKAS were to reduce average and maximum waiting time, to allow patients with rare human leukocyte antigen (HLA) phenotypes or combinations to receive an "optimal" offer, to keep the exchange rates between the participating countries balanced, and finally to keep optimal graft survival, by means of HLA matching. Elderly patients and highly sensitized patients profit in addition from special programs, the ET Senior Program and the Acceptable Mismatch Program, respectively. All kidneys are offered to the pool and are allocated according to the degree of HLA matching, mismatch probability, waiting time, distance from the donor center, and balance between the countries participating in ET. A summary of 6 years' experience with the ETKAS is presented in this article.