The impact of repeated mismatches in kidney transplantations performed after nonrenal solid organ transplantation.

The aim of this study was to determine whether kidney transplantations performed after previous nonrenal solid organ transplants are associated with worse graft survival when there are repeated HLA mismatches (RMM) with the previous donor(s). We performed a retrospective cohort study using data from the Scientific Registry of Transplant Recipients. Our cohort comprised 6624 kidney transplantations performed between January 1, 1990 and January 1, 2015. All patients had previously received 1 or more nonrenal solid organ transplants. RMM were observed in 35.3% of kidney transplantations and 3012 grafts were lost over a median follow-up of 5.4 years. In multivariate Cox regression analyses, we found no association between overall graft survival and either RMM in class 1 (hazard ratio [HR]: 0.97, 95% confidence interval [CI] 0.89-1.07) or class 2 (HR: 0.95, 95% CI 0.85-1.06). Results were similar for the associations between RMM, death-censored graft survival, and patient survival. Our results suggest that the presence of RMM with previous donor(s) does not have an important impact on allograft survival in kidney transplant recipients who have previously received a nonrenal solid organ transplant.

Survival Analysis in the Presence of Competing Risks: The Example of Waitlisted Kidney Transplant Candidates.

Competing events (or risks) preclude the observation of an event of interest or alter the probability of the event's occurrence and are commonly encountered in transplant outcomes research. Transplantation, for example, is a competing event for death on the waiting list because receiving a transplant may significantly decrease the risk of long-term mortality. In a typical analysis of time-to-event data, competing events may be censored or incorporated into composite end points; however, the presence of competing events violates the assumption of "independent censoring," which is the basis of standard survival analysis techniques. The use of composite end points disregards the possibility that competing events may be related to the exposure in a way that is different from the other components of the composite. Using data from the Scientific Registry of Transplant Recipients, this paper reviews the principles of competing risks analysis; outlines approaches for analyzing data with competing events (cause-specific and subdistribution hazards models); compares the estimates obtained from standard survival analysis, which handle competing events as censoring events; discusses the appropriate settings in which each of the two approaches could be used; and contrasts their interpretation.

HLA-DR and -DQ eplet mismatches and transplant glomerulopathy: a nested case-control study.

We conducted a nested case-control study from a cohort of adult kidney transplant recipients to assess the risk of transplant glomerulopathy (TG) as a function of donor and recipient HLA-DR and -DQ incompatibility at the eplet level. Cases (n = 52) were defined as patients diagnosed with transplant glomerulopathy based on biopsies showing glomerular basement membrane duplication without immune complex deposition. Controls (n = 104) with a similar follow-up from transplantation were randomly selected from the remaining cohort. HLAMatchmaker was used to ascertain the number of DRB1/3/4/5, DQA1 and DQB1 related eplet mismatches (eplet load). Multivariable conditional logistic regression models demonstrated an increase in the odds of TG (odds ratios [OR] of 2.84 [95% confidence interval (CI): 1.03, 7.84] and 4.62 [95% CI: 1.51, 14.14]) in the presence of 27-43 and >43 HLA-DR + DQ related eplet mismatches versus <27 eplet mismatches, respectively. When the eplet load was modeled as a continuous variable, the OR for TG was 1.25 (95% CI: 1.04, 1.50) for every 10 additional HLA-DR + DQ eplet mismatches. Our study suggests that minimization of HLA-DR + DQ eplet mismatches may decrease the incidence of transplant glomerulopathy diagnosed by indication biopsies. The role of eplet immunogenicity/antigenicity as determinants of allograft outcomes requires further study.

Genome Canada precision medicine strategy for structured national implementation of epitope matching in renal transplantation.

Advances in immunology support the understanding that precise structural epitopes on the antibody-accessible region of the HLA molecule determine antigenicity and challenge the need for identity across the full HLA molecule to minimize graft immunogenicity. Retrospective studies confirm that quantitative measurement of epitope-level mismatching between donor and recipient is an informative marker of graft rejection and survival and suggest that prospective allocation of donor organs based on this principle may improve graft survival. Here we describe the process for rigorous prospective evaluation of this hypothesis in a formal national proof-of-concept program for epitope-based matching. This encompasses broad societal consultation to engage the public, patients and providers; the development of clear allocation policies with strategies to support candidates who may be difficult to match; molecular and sequencing methods and web-based calculators enabling rapid epitope typing and recipient selection; precise immunological monitoring of the graft response; information systems permitting real-time monitoring of clinical outcomes; and assessment of health benefit and economic cost. The results of this objective evaluation can then be provided to payers and policy-makers for review, and adoption if of proven benefit.

Inaccuracies in epitope repertoire estimations when using Multi-Locus Allele-Level hla genotype imputation tools.

BACKGROUND: Limited availability of allele-level HLA genotypes prompts their imputation from allele-group genotypes to estimate epitope mismatches. We evaluated the accuracy of epitope load and repertoire assignment when imputing allele-level HLA genotypes. METHODS: Analyses were conducted on 175 hematopoietic stem cell (HSC) donors from the Héma-Québec registry (HQR) and 57 HSC donor-recipient pairs from McGill University Health Centre (MUHC), Québec, Canada, genotyped for HLA-A, -B, -C, -DRB1 and -DQB1. Multi-locus allele-level imputation was performed using HaploStats. Disagreement in B- and T-cell epitope assignment and epitope mismatches were ascertained for imputed vs. measured allele-level HLA genotypes in HSC donors and donor-recipient pairs, respectively. RESULTS: Imputation resulted in no differences in overall eplet mismatches and PIRCHE-II for HLA-A, -B, and -C in 83.4% and 93.7% of HQR donors and 87.7% and 87.7% of MUHC donors, respectively. HLA-DRB1- and -DQB1-derived eplet mismatches and PIRCHE-II were correctly assigned in 72.0% and 85.1% of HQR donors and 70.2% and 71.9% of MUHC donors, respectively. No discrepancies in eplet load or PIRCHE-II were observed in 96.5% and 86.0% of HSC donor-recipient pairs and in 70.2% and 70.1% of pairs for HLA-A, -B and -C and -DRB1 and -DQB1, respectively. Kappa statistics of 0.9708 and 0.9725, 0.8724 and 0.8177, 0.9827 and 0.9022, 0.5644 and 0.4939, 0.5085 and 0.6361 were demonstrated when assessing agreement between eplet mismatches and PIRCHE-II of imputed vs. measured HLA-A, -B, -C, -DRB1 and -DQB1 types, respectively. CONCLUSIONS: To avoid inaccuracies in epitope compatibility estimation, mainly for class II HLA, multi-locus allele-level genotype measurement is recommended. This article is protected by copyright. All rights reserved.

Eye-movement responses to disparity vergence stimuli with artificial monocular scotomas.

The effects of artificial monocular scotomas on eye-movement responses to horizontal disparity vergence stimuli were studied in six subjects with normal binocular vision. Subjects viewed stereoscopic 1.5 degrees horizontal step disparity vergence stimuli through liquid crystal shutter glasses. The central portion of the stimulus presented to the right eye was removed to simulate monocular artificial scotomas of variable diameters (2 degrees to 10 degrees ). Eye movements were recorded with a binocular head-mounted eye tracker. Responses included pure vergence, vergence followed by saccades, and pure saccadic eye movements. The rate of responses with saccadic eye movements increased with the diameter of the artificial scotoma (p < 0.0001); there was an increase in the rate of responses starting with saccades (p < 0.0001), as well as an increase in the rate of saccades after initial vergence responses (p < 0.01). The probability of saccades after initial vergence responses was affected by the open-loop gain of the vergence response (p < 0.001). The open-loop gain decreased with increased diameters of the artificial scotomas (p < 0.0001). As the diameter of the artificial scotomas increased, the amplitude of the initial vergence eye-movement responses decreased, and the prevalence of saccadic eye movements and asymmetric vergence increased. The effects of the diameter of artificial monocular scotomas on eye-movement responses in subjects with normal binocular vision are consistent with the effects of diameter of suppression scotomas on eye-movement responses to disparity vergence stimuli in patients with infantile esotropia.