Pairing Exchange Research Articles

The Canadian Living Donor Exchange Programme: Success at Four Years.

The Canadian LDE Program, established in 2009 by Canadian Blood Services and the Canadian Renal Transplant community, is fully funded by government (gov’t). In general, donors (D) have travelled to recipient (R) sites for surgery with coverage of travel and accommodation costs. Match points have been allocated to maximize transplant (Tx) number,minimize travel, equity for high need patient groups, and optimal matches. HLA Laboratories standardized antibody testing such that the agreement between virtual and flow cross match testing was 98.6%. Standard criteria defined an unacceptable HLA antigen. All Tx were virtual and flow cross match negative. Match runs are performed every 4 months with optimized, computer based allocation. The maximum number of pairs was arbitrarily set at 5. There were no bridge donors by design. From Jan 2009 to Nov 2013, 468 pairs with 439 Rs and 56 non-directed Ds have registered. 240 Tx have been performed, 194 to registered Rs and 46 to wait listed Rs. 10 were from paired exchange,16 from closed chains, and 47 from domino exchanges. 28 matches are under review. 39% of Tx Rs were A, 36% O, 19% B, and 6% AB. 65% of Tx Rs had cPRA of 0-79% (51% of registered Rs), 19% had cPRA 80-94% (12% of registered Rs), and 16% had cPRA ≥95% (37% of registered Rs). 58% of proposed matches and 62% of proposed chains were completed. Tx were performed on the same day, or over 2, 3, or 4 days in 49%, 42%, 6%, or 3% respectively. The mean time from match proposal to completion of all Tx in the chain was 101 days for PE, 129 days for CC and 117 days for DC. The mean time from D registration after medical clearance to nephrectomy was 252 days for Ds registered as pairs and 134 days for non directed Ds. Donor travel was required in 54% of cases. 7 kidneys were shipped. 1 year D and R survival is 100%, graft survival 97% and mean serum creatinine 1.2 mg%.The Canadian LDE accounted for 10% of living donor renal Tx in 2012 and has been responsible for maintaining a stable number of living donor Tx in Canada as other living donor renal Tx has fallen. A successful National LDE Program is feasible with national collaboration, standardized antibody testing, workup and acceptance criteria for donors, centralized allocation software, operational oversight, dedicated central support staff, and gov’t funding of logistics for organization and travel.

Contact Between Living Anonymous Donors and Recipients: Current Practice and Patient Education Guidelines.

PURPOSE: This presentation will review current practice, policies, and ethical dilemmas regarding contact between Living Anonymous Donors (LADs) and Recipients and will propose guidelines including patient education brochures for LADs and Recipients. BACKGROUND: Transplant Recipients sometimes request help to express gratitude to their liver or kidney or kidney paired exchange LADs. LADs sometimes wish to communicate with and to meet their Recipients before and/or after donation. Transplant programmes may be uncertain about what kind(s) of contact they should enable between LADs and Recipients and how to facilitate this while protecting confidentiality. Organ procurement organizations often support communication via anonymous cards/letters or facilitate meetings between Recipients and families of Deceased Donors. When Living Donors (LDs) and Recipients know each other, Recipients can thank their LDs in person, and LDs may benefit from seeing the Recipient's health improve post-transplant. Should transplant programmes extend this benefit by facilitating communication and meetings between LADs and Recipients? How should written communication be screened and who should do this? Face to face meetings may result in disappointment, unrequited wishes for continued contact, or problematic behaviours. Transplant programmes are unable to protect LADs and Recipients from unwanted consequences of contact after they have met. METHODS: A review of relevant literature was completed and the practices and experiences of centres in North America and Europe were summarized. Ethically challenging case scenarios and current practice were reviewed by a multidisciplinary working group at the Multi-Organ Transplant Program, Toronto General Hospital, University Health Network. RESULTS: Through a series of consensus steps, a standard operating procedure and practice guidelines were developed to ensure consistent practice and to clarify responsibilities of involved parties. Bioethics and Social Work also created guidelines for LADs and Recipients via patient education brochures. CONCLUSION: We conclude that programmes that facilitate contact between LADs and Recipients should develop policies and standard operating procedures. We propose ways to inform LADs and Recipients about the options for contact and specific guidelines for written contact via anonymous cards/letters.

Transplant Patientsʼ Concerns About Participating in Kidney Paired Exchanges.

Transplant patients' concerns about kidney paired exchanges (KPE) may be contributing to its underutilization. We examined the KPE concerns of transplant candidates and recipients who, in the last 3 yrs in our program, had a potential donor undergo initial screening but were found to be ABO incompatible/crossmatch-positive. Patients completed the Attitudes about Kidney Exchanges - Recipients (AKE-R, 23 items, score range=23 to 92, higher scores=more KPE concerns, Cronbach's α=0.88) and the Revised Health Care System Distrust (HCSD) scale. To date, 71 patients (44 wait-listed, 27 recipients) have completed surveys, with a mean age 54.0±12 yrs, 56% female, 66% white, 56% attended college, and 38% employed. Only 21 patients (30%) expressed an interest in KPE participation when informed of the potential donor's incompatibility and 4 (6%) received a KPE kidney. The most common concerns about KPE were: not receiving a kidney after their friend or family member donates (56%), receiving a kidney of lesser quality than the intended donor (55%), the wait would be too long and disruptive to the donor's life (53%), not knowing anything about the person whose kidney would be received as part of KPE (51%), the intended donor might be uncomfortable with the idea that his/her kidney would go to someone else (50%), the intended donor might feel more pressure to go through with donation as part of KPE (45%), and the donor's costs in KPE would be too high (44%). Minorities had higher total AKE-R scores (i.e., more concerns) than white patients (59.0±9 vs. 52.4±12, t=2.3, P=0.02). Patients who did not want to pursue KPE with the incompatible potential donor had higher AKE-R scores than those who wanted to move forward with possible KPE (57.4±9 vs. 48.2±14, t=3.2, P=0.002). More KPE concerns were associated with more health care distrust (r=0.27, P=0.03). Age, gender, education, work status, donor-recipient relationship type, and perceived emotional closeness with the intended donor were not significantly associated with KPE concerns. Many patients, particularly minorities and those with higher levels of health care system distrust, have important psychological and practical concerns about KPE that may affect willingness to engage in KPE. Targeted educational approaches may help to increase KPE willingness.

Histocompatibility testing for organ transplantation purposes in Albania: a single center experience.

Histocompatibility testing (HT) which includes donor-recipient human leukocyte antigen (HLA) matching, cross-match testing (XMT) and anti-HLA antibody searching are crucial examinations in solid organ transplantation aiming to avoid the hyperacute graft rejection and also to predict the immunological outcome of the graft. The aim of this study was to analyse the tissue typing data collected at the Laboratory of Immunology and Histocompatibility of the University Hospital Center of Tirana, Albania, in order to define those actions that should be taken for improvements in the situation of kidney transplantation in Albania. Descriptive study. The donor/recipient cross-match testing was performed through a standard complement-dependent cytotoxicity (CDC) assay using separated donor T and B cells that were tested in parallel with the recipient serum sample. All recipient sera were screened for anti-Class I and anti-Class II HLA antibodies using a bead based Luminex anti-HLA antibody screening test. In the case of detected positivity, an allele-specific anti-HLA antibody determination was conducted with the respective Luminex anti-Class I and Class II HLA antibody determination kits. A total of 174 recipients and 202 donors were typed for the purpose of living donor kidney transplantation at our laboratory between January 2006 and December 2012. The mean age and female gender proportion of patients were 34.9 years and 34.5%, respectively, and 48.0 years and 65.3% for the donors, respectively. Here, 25.9% of the patients reported a positive complement-dependent cytotoxicity cross-match test and/or a positive anti-HLA antibody testing result. Eighteen patients that were negative for the complement-dependent cytotoxicity cross-match test were positive for anti-HLA antibodies. The predominant causes of end-stage renal disease (ESRD) in our patient population are chronic pyelonephritis and glomerulonephritis. The female gender is significantly more frequent among donors, which emphasises the need for more gender equity as far as the altruistic willingness for organ donation is concerned. The significant number of patients with Luminex anti-HLA antibody positivity combined with complement-dependent cytotoxicity cross-match negative results underlines the necessity of using additional methods like cell-based flow cytometry or bead-based Luminex anti-HLA antibody assays for the detection of anti-donor-specific antibodies. We also suggest that the number of kidney transplantations in Albania needs to be increased significantly by expanding it with paired exchange living donation and also by implementing an efficient deceased donor kidney transplantation program.

Strategies to increase the donor pool and access to kidney transplantation: an international perspective.

In this position article, DESCARTES (Developing Education Science and Care for Renal Transplantation in European States) board members describe the current strategies aimed at expanding living and deceased donor kidney pools. The article focuses on the recent progress in desensitization and kidney paired exchange programmes and on the expanded criteria for the use of donor kidneys and organs from donors after circulatory death. It also highlights differences in policies and practices across different regions with special regard to European Union countries. Living donor kidney paired exchange, the deceased donor Acceptable Mismatch Programme and kidneys from donors after circulatory death are probably the most promising innovations for expanding kidney transplantation in Europe over the coming decade. To maximize success, an effort is needed to standardize transplant strategies, policies and legislation across European countries.

New regimes of the stringy (holographic) Pomeron and high-multiplicityppandpAcollisions

Holographic AdS/QCD models of the Pomeron unite a string-based description of hadronic reactions of the pre-QCD era with the perturbative BFKL approach. The specific version we will use due to Stoffers and Zahed, is based on a semiclassical quantization of a "tube" (closed string exchange or open string virtual pair production) in its Euclidean formulation using the scalar Polyakov action. This model has a number of phenomenologically successful results. The periodicity of a coordinate around the tube allows the introduction of a Matsubara time and therefore an effective temperature Teff on the string. We observe that at the LHC energies and for sufficiently small impact parameter, Teff approaches and even exceeds the Hagedorn temperature of the QCD strings. Based on studies of the stringy thermodynamics of pure gauge theories we suggest that there should exist two new regimes of the Pomeron: the "near-critical" and the "post-critical" ones. In the former one, string excitations create a high entropy "string ball", with high energy and entropy but small pressure/free energy. If heavy enough this ball becomes a (dual) black hole (BH). As the intrinsic temperature of the string exceeds the Hagedorn temperature, the ball becomes a post-critical explosive "QGP ball". The hydrodynamical explosion resulting from this scenario was predicted by us to have radial flow exceeding that ever seen even in heavy ion collisions, which was recently confirmed by CMS and ALICE at LHC. We also discuss the elastic scattering profile, finding some hints for new phases in it, as well as two-particle correlations.

Dynamics of a small number of droplets in microfluidic Hele–Shaw cells

We investigate the dynamics of a small number of droplets (N = 1, 2, 3) in microfluidic Hele–Shaw cells. We study the cases N = 1, 2, and 3 droplets and analyze the influence of the side walls. In the course of the study, we observe spontaneous alignment of droplet pairs, pair exchanges, droplet escape, multiple reflections between walls, i.e., a number of phenomena that have not been reported yet. As a whole, using pairwise far-field dipolar interactions between droplets, along with treating the walls as mirrors, allows to reproduce the observations, even though limitations in the predictability of the model are pointed out in a few cases. From a more practical prospective, the work shows that the behavior of elementary droplet assemblies can be put under acceptable experimental control in a wide variety of situations, a feature potentially interesting for self-assembly, mixing, or transport of particles in microfluidic environments.

Structure/function studies on the allosteric mechanism of Rad51 recombinase (549.8)

Eukaryotic Rad51 recombinase plays a central role in maintaining genome stability by promoting homology‐directed repair of DNA double‐strand breaks and stalled replication forks. Rad51 forms presynaptic filaments on single‐stranded DNA, which activates the ATPase, homologous pairing, and DNA strand exchange activities of the enzyme. Structure/function studies of yeast Rad51 reveal that coordination between the ATP and DNA binding sites is mediated by residues at the protomer‐protomer interface and in DNA binding loops L1 and L2. Conserved interface residues Phe‐187 and His‐352 play central roles in sensing the ATP‐bound state of Rad51‐ssDNA filaments and inducing conformational changes in the filament that are necessary for DNA strand exchange. An F187A mutant is proficient in ssDNA‐dependent ATPase activity but deficient in DNA strand exchange, suggesting an inability to couple ATP binding to the homology search function of Rad51. Mutations at the His‐352 locus affect ssDNA‐binding affinity and catalytic turnover. An H352Y mutant catalyzes a single round of DNA strand exchange and subsequently fails due to a nucleotide exchange defect. Meanwhile, new X‐ray crystallographic structures reveal previously unseen details of the DNA and ATP binding surfaces of Rad51. The structures indicate that conserved aromatic residue Phe‐290 is important for stabilizing a conformation of L1 that allows optimal contacts between conserved Arg‐293 and DNA. Results of this work will facilitate modeling of the structural transitions that occur in Rad51 filaments during recombination.Grant Funding Source: NIH grant no. P02 CA098993

Finding the perfect match: the living donor paired exchange system.

Patients on the kidney transplant waiting list can often face substantial waiting times for an organ from a deceased donor. Furthermore, the number of patients requiring a kidney transplant is increasing. This article discusses an emerging solution – the living donor kidney exchange system.

Matrix concentration inequalities via the method of exchangeable pairs

This paper derives exponential concentration inequalities and polynomial moment inequalities for the spectral norm of a random matrix. The analysis requires a matrix extension of the scalar concentration theory developed by Sourav Chatterjee using Stein's method of exchangeable pairs. When applied to a sum of independent random matrices, this approach yields matrix generalizations of the classical inequalities due to Hoeffding, Bernstein, Khintchine and Rosenthal. The same technique delivers bounds for sums of dependent random matrices and more general matrix-valued functions of dependent random variables.

Cluster algebras arising from cluster tubes

We study the cluster algebras arising from cluster tubes with rank bigger than $1$. Cluster tubes are $2-$Calabi-Yau triangulated categories which contain no cluster tilting objects, but maximal rigid objects. Fix a certain maximal rigid object $T$ in the cluster tube $\mathcal{C}_n$ of rank $n$. For any indecomposable rigid object $M$ in $\mathcal{C}_n$, we define an analogous $X_M$ of Caldero-Chapton's formula (or Palu's cluster character formula) by using the geometric information of $M$. We show that $X_M, X_{M'}$ satisfy the mutation formula when $M,M'$ form an exchange pair, and that $X_{?}: M\mapsto X_M$ gives a bijection from the set of indecomposable rigid objects in $\mathcal{C}_n$ to the set of cluster variables of cluster algebra of type $C_{n-1}$, which induces a bijection between the set of basic maximal rigid objects in $\mathcal{C}_n$ and the set of clusters. This strengths a surprising result proved recently by Buan-Marsh-Vatne that the combinatorics of maximal rigid objects in the cluster tube $\mathcal{C}_n$ encode the combinatorics of the cluster algebra of type $B_{n-1}$ since the combinatorics of cluster algebras of type $B_{n-1}$ or of type $C_{n-1}$ are the same by a result of Fomin and Zelevinsky. As a consequence, we give a categorification of cluster algebras of type $C$.

Bounds on convergence for the empirical vector of the Curie–Weiss–Potts model with a non-zero external field vector

Abstract In the present paper we obtain rates of convergence for limit theorems via Stein’s Method of exchangeable pairs in the context of the Curie–Weiss–Potts model and we consider only the case of non-zero external field h ∈ R q . Our interest is in the limit distribution of the empirical vector of the spin variables and we obtain bounds for multivariate normal approximation.

Organ Donation and Transplantation in the UK—The Last Decade

Over the decade between 2003 and 2012, the UK has seen major changes in how organ donation and transplantation is delivered. The number of deceased organ donors has increased from 709 (12.0 per million population [pmp]) to 1,164 (18.3 pmp); this increase has been predominantly a result of an increase in donors after circulatory death (DCD) (from 1.1 pmp to 7.9 pmp) while the numbers of donors after brain death (DBD) has remained broadly stable (around 10.5 pmp). The donor population has become older (from 14% 60 years or over to 35%) and heavier (from 14% with body mass index >=30 kg/m2 to 23%). Despite these changes in demographic factors, the number of organs retrieved from DBD donors has risen from a mean of 3.6 to 4.0 per donor and for DCD donors from 2.2 to 2.6. The number of transplants in adults in 2012 was 2,709 (967 DBD, 708 DCD, and 1,034 living) for kidney alone, 246 pancreas (including 172 kidney and pancreas), 792 (611 DBD, 142 DCD, 36 living, and 3 domino) for liver, 136 for heart only, and 179 (145 DBD and 34 DCD) for lung only. Median waiting times to transplant for adult patients were 1,167, 339, 141, 293, and 311 days, respectively. The proportion of adult non-urgent registrants in 2009 (2007 for kidneys) who were removed from the waiting list or died awaiting a graft within 1 year was 3% for kidneys, 6% for pancreas, 19% for liver, 27% for heart, and 24% for lung. Outcomes after solid organ transplants are improving; for adult patients grafted between 2003 and 2005, 5-year graft survival for kidney is 84% (DBD), 87% (DCD), and 92% (living donor), for simultaneous kidney and pancreas 72%, and for pancreas alone 50% (DBD). Five-year patient survival for liver is 77% (DBD) and 68% (DCD), heart 67%, and lung 52% (DBD). Although rates of organ donation and transplantation have increased in the UK, this has been almost solely because of a rise in DCD donation. Although donor age and weight is increasing, graft survival has generally improved. Despite a recent fall in the number of patients on the transplant waiting list, there remains a significant gap between the need for transplantation and the number of organs available from deceased and living donors. The implementation of a new strategy following the recommendations of the Organ Donation Task Force in 2008 has had a major impact in bringing together clinicians involved in both organ donation and transplantation, and these changes and clinical enthusiasm have been instrumental in achieving success. With an emphasis on the need to increase the family consent rate for organ donation, which has failed to show any improvement over the last 5 years, a new UK strategy for organ donation and transplantation, introduced in 2013, will further increase organ transplantation in the UK.

Paired Exchange: A New Innovation in Live Donor Kidney Transplantation

Barriers to traditional living-donor kidney transplantation include ABO incompatibility and positive cross-match. Paired exchange kidney transplantation (PEKT) is a viable an increasingly popular method to increase live donation. We discuss the pros and cons as well as the various ways to achieve PEKT along with a review of existing literature. To achieve the full potential of PEKT, the transplant community at large needs to work toward a national kidney paired donation program along with a centralized financial intermediary.

The convex distance inequality for dependent random variables, with applications to the stochastic travelling salesman and other problems

We prove concentration inequalities for general functions of weakly dependent random variables satisfying the Dobrushin condition. In particular, we show Talagrand's convex distance inequality for this type of dependence. We apply our bounds to a version of the stochastic salesman problem, the Steiner tree problem, the total magnetisation of the Curie-Weiss model with external field, and exponential random graph models. Our proof uses the exchangeable pair method for proving concentration inequalities introduced by Chatterjee (2005). Another key ingredient of the proof is a subclass of $(a,b)$-self-bounding functions, introduced by Boucheron, Lugosi and Massart (2009).

An Improved Understanding of Li+ Hopping Pathways and Rates in Li3Fe2(PO4)3 Using Selective Inversion 6Li NMR Spectroscopy

6Li selective inversion NMR experiments are used to reveal Li ion exchange rates and energy barriers for Li ion hopping in monoclinic Li3Fe2(PO4)3. The three crystallographically unique Li sites in this material are well resolved by magic-angle spinning, thus allowing for the examination of all three exchange processes. We have revisited this material using selective inversion to probe dynamics, and energy barriers over the temperature range 268–397 K are found to be 0.37 ± 0.07, 0.53 ± 0.02, and 0.52 ± 0.03 eV for the three unique exchange pairs. The results presented here are consistent with the known Li3Fe2(PO4)3 crystal structure. The selective inversion experiment is more robust than 2D EXSY for the determination of energy barriers by NMR; this can be attributed to the efficiency of the one-dimensional technique, and an exchange model that accounts for multisite exchange and fast spin–lattice relaxation. Moreover, bond valence sum density maps provide a meaningful depiction of lithium ion diffusion p...

Financial Incentives to Increase Canadian Organ Donation: Quick Fix or Fallacy?

Unlike the United States, the potential to increase organ donation in Canada may be sufficient to meet the need for transplantation. However, there has been no national coordinated effort to increase organ donation. Strategies that do not involve payment for organs, such as investment in health care resources to support deceased donor organ donation and introduction of a remuneration framework for the work of deceased organ donation, should be prioritized for implementation. Financial incentives that may be permitted under existing legislation and that pose little risk to existing donation sources should be advanced, including the following: payment of funeral expenses for potential donors who register their decision on organ donation during life (irrespective of the decision to donate or actual organ donation) and removal of disincentives for directed and paired exchange living donation, such as payment of wages, payment for pain and suffering related to the donor surgery, and payment of directed living kidney donors for participation in Canada's paired exchange program. In contrast, it would be premature to contemplate a regulated system of organ sales that would require a paradigm shift in the current approach to organ donation and legislative change to implement.

LMX1B mutations with nails and kneecaps: a new paradigm?

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2-P

Aim The method of choice in most of the HLA laboratories for the identification of anti HLA antibodies is the solid phase assay Luminex technology. This method is very sensitive and it is being used for virtual crossmatching as well as for paired kidney exchange (PKE) programs. The most challenging factor for the paired kidney exchange programs is the high sensitization level of the listed couples determined by Luminex-IgG MFI. Now it is increasingly believed that the complement fixing donor specific antibodies (DSA) are the more clinically relevant than non-complement fixing antibodies. In this study we determined impact of using Luminex C1q instead of Luminex-IgG in the pool of the couples listed in our PKE program. Methods A cohort of 12 patients was chosen randomly from the total of 28 couples constituting our HLA incompatible PKE program. All samples were tested by Luminex-IgG and Luminex-C1q (One Lambda) for HLA class I and II antibodies. The unacceptable antigens listed in the PKE are those with more than 6000 MFI for HLA-A,B,DR and DQ. For HLA-C it was 10000 MFI. Results The percentage of complement fixing antibodies detected for HLA class I and II were 36% and 35% respectively. When the unacceptable antigens entered in the PKE program were those Luminex-IgG positive, there were no exchangeable pairs. However when the unacceptable antigens entered in the PKE program were only those C1q positive, we found four one-way exchangeable pairs. Conclusions Our data suggest that we should consider listing unacceptable antigens in the PKE program using the Luminex-C1q positive instead of Luminex-IgG positive. Listing unacceptable antigen in the PKE program solely based on Luminex-IgG will deprive many patients from being transplanted with compatible pairs.

MCMC2 (version 1.1): A Monte Carlo code for multiply-charged clusters

MCMC2 (version 1.1): A Monte Carlo code for multiply-charged clusters