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The relationship between donor-recipient genetic distance and long-term kidney transplant outcome.

ABSTRACT: Background: We set out to quantify shared genetic ancestry between unrelated kidney donor-recipient pairs and test it as a predictor of time to graft failure. Methods: In a homogenous, unrelated, European cohort of deceased-donor kidney transplant pairs (n pairs = 1,808), we calculated, using common genetic variation, shared ancestry at the genic (n loci=40,053) and genomic level. We conducted a sub-analysis focused on transmembrane protein coding genes (n transcripts=8,637) and attempted replication of a previously published nonsynonymous transmembrane mismatch score. Measures of shared genetic ancestry were tested in a survival model against time to death-censored graft failure. Results: Shared ancestry calculated across the human leukocyte antigen (HLA) significantly associated with graft survival in individuals who had a high serological mismatch (n pairs = 186) with those who did not have any HLA mismatches indicating that shared ancestry calculated specific loci can capture known associations with genes impacting graft outcome. None of the other measures of shared ancestry at a genic level, genome-wide scale, transmembrane subset or nonsynonymous transmembrane mismatch score analysis were significant predictors of time to graft failure. Conclusions: In a large unrelated, deceased-donor European ancestry renal transplant cohort, shared donor-recipient genetic ancestry, calculated using common genetic variation, has limited value in predicting transplant outcome both on a genomic scale and at a genic level (other than at the HLA loci).

SUBMITTER: Stapleton CP

PROVIDER: S-EPMC7888353 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The relationship between donor-recipient genetic distance and long-term kidney transplant outcome.

Stapleton Caragh P CP Lord Graham M GM Conlon Peter J PJ Cavalleri Gianpiero L GL

HRB open research 20200729

<b>Background:</b> We set out to quantify shared genetic ancestry between unrelated kidney donor-recipient pairs and test it as a predictor of time to graft failure. <b>Methods:</b> In a homogenous, unrelated, European cohort of deceased-donor kidney transplant pairs (n pairs = 1,808), we calculated, using common genetic variation, shared ancestry at the genic (n loci=40,053) and genomic level. We conducted a sub-analysis focused on transmembrane protein coding genes (n transcripts=8,637) and ...[more]

PMID: 33655195

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Project description:ImportanceThe proportion of living donor kidney transplants from donors unrelated to their recipients is increasing in the US.ObjectiveTo examine the association between donor-recipient biological relationship and allograft survival after living donor kidney transplant.Design, setting, and participantsThis retrospective cohort study used Organ Procurement and Transplantation Network data on US adult living donor kidney transplants (n = 86 154) performed from January 1, 2000, to December 31, 2014, excluding cases in which recipients previously received a kidney transplant (n = 10 342) or key data were missing (n = 2832). Last follow-up was March 20, 2020.ExposuresDonor-recipient biological relationship.Main outcomes and measuresThe primary outcome was death-censored allograft failure. Univariate and multivariable time-to-event analyses were performed for death-censored allograft failure for the overall cohort, then separately for recipients with and without primary diagnoses of cystic kidney disease and for transplants from African American and non-African American donors.ResultsAmong the 72 980 transplant donor and recipients included in the study (median donor age, 41 years; interquartile range [IQR], 32-50 years; 43 990 [60%] female; 50 014 [69%] White), 43 174 (59%) donors and recipients were biologically related and 29 806 (41%) were unrelated. Donors related to their recipients were younger (median [IQR] age, 39 [31-48] vs 44 [35-52] years) and less likely to be female (24 848 [58%] vs 19 142 [64%]) or White (26 933 [62%] vs 23 081 [77%]). Recipients related to their donors were younger (median [IQR] age, 48 [34-58] vs 50 [40-58] years), more likely to be female (18 035 [42%] vs 10 530 [35%]), and less likely to have cystic kidney disease (2530 [6%] vs 4600 [15%]). Related pairs had fewer HLA mismatches overall (median [IQR], 3 [2-3] vs 5 [4-5]). After adjustment for HLA mismatches, donor and recipient characteristics, and transplant era, donor-recipient biological relationship was associated with higher death-censored allograft failure (hazard ratio, 1.05; 95% CI, 1.01-1.10; P = .03). When stratified by primary disease, this association persisted only for recipients without cystic kidney disease. When stratified by donor race, this association persisted only for transplants from African American donors.Conclusions and relevanceIn this cohort study, living donor kidney transplants from donors biologically related to their recipients had higher rates of allograft failure than transplants from donors unrelated to their recipients after HLA matching was accounted for. Further study is needed to determine which genetic or socioenvironmental factors are associated with this finding.

Project description:Background:Nephron endowment in renal transplantation is infrequently considered, but may have important implications for post kidney transplantation outcomes. In this population-cohort study, we analyzed the deceased-donor kidney transplant outcomes stratified by donor-to-recipient size ratios. Methods:Data for all deceased-donor adult kidney transplantation recipients between 2003 and 2015 were extracted from the UK Transplant Registry. We used weight as a surrogate marker for kidney size and defined the following mismatch categories (donor weight/recipient weight × 100): less than 75% (small donor kidney), 75% to 125% (weight matched kidney), and greater than 125% (large donor kidney). Univariable and multivariable analyses were undertaken to assess the relationship between this marker and patient outcomes. Results:Outcomes for 11 720 transplants were analyzed with weight mismatch stratified as follows; small donor kidney (n = 1608, 13.7%), weight matched kidney (n = 7247, 61.8%) and large donor kidney (n = 2865, 24.4%). On multivariable analysis, no significant differences were detected in overall (P = 0.876) or death-censored (P = 0.173) graft survival, or in rates of delayed graft function (P = 0.396) between these 3 groups. However, 12-month creatinine levels were found to decline progressively across the groups (P < 0.001), with adjusted averages of 144.2 ?mol/L for recipients of small donor kidneys, 134.7 ?mol/L in weight matched kidneys, and 124.9 ?mol/L in recipients of large donor kidneys. In addition, patient survival was found to be significantly shorter in recipients of larger kidneys than those with weight matched kidneys (hazard ratio, 1.21; 95% confidence interval, 1.05-1.40; P = 0.009), which is inconsistent with the existing literature. Conclusions:Our data demonstrate that 12-month creatinine is influenced by donor-to-recipient difference in body weight, but that no such difference is observed for either delayed graft function or death-censored graft survival. However, we observed increased mortality in recipients receiving larger kidneys; an observation which conflicts with the existing literature and warrants further investigation.

Project description:Despite early reports of an impact of complement C3 polymorphism on liver transplant patient and graft survival, subsequent evidence has been conflicting. Our aim was to clarify the contributions of donor and recipient C3 genotype, separately and together, on patient and graft outcomes and acute rejection incidence in liver transplant recipients. Eight donor/recipient groups were analyzed according to their genotype and presence or absence of C3 F allele (FFFS, FFSS, FSFF, FSFS, FSSS, SSFF, SSFS, and SSSS) and correlated with clinical outcomes of patient survival, graft survival, and rejection. The further impact of brain death vs. circulatory death during liver donation was also considered. Over a median 5.3 y follow-up of 506 patients with clinical information and matching donor and recipient tissue, five-year patient and graft survival (95% confidence interval) were 90(81-91)% and 77(73-85)%, respectively, and 72(69-94)% were rejection-free. Early disadvantages to patient survival were associated with donor C3 F variant, especially in brain-death donors. Recipient C3 genotype was an independent determinant of graft survival by Cox proportional hazards analysis (hazard ratio 0.26, P = 0.04), and the C3 F donor variant was again associated with worse liver graft survival, particularly in brain-death donors. C3 genotype did not independently determine rejection incidence, but a greater proportion of recipient C3 F carriers were rejection-free in the circulatory death, but not the brain-death cohort. Cox proportional hazards analysis revealed significant effects of acute rejection on patient survival (hazard ratio 0.24, P = 0.018), of retransplantation on rejection risk (hazard ratio 6.3, P = 0.009), and of donor type (circulatory-death vs. brain-death) on rejection incidence (hazard ratio 4.9, P = 0.005). We conclude that both donor and recipient complement C3 genotype may influence patient and graft outcomes after liver transplantation but that the type of liver donor is additionally influential, possibly via the inflammatory environment of the transplant.

Project description:Background and objectivesMany donors and recipients report an improved bond posttransplantation; however, unexpected conflicts and tension may also occur. Insights into the lived experiences of the donor-recipient relationship can inform strategies for interventions and support. We aimed to describe donor and recipient expectations and experiences of their relationship before and after living kidney donor transplantation.Design, setting and participantsSemistructured interviews were conducted with 16 donor-recipient pairs before the transplant and 11-14 months post-transplant. Transcripts were analysed thematically.ResultsWe identified seven themes (with respective subthemes): donation as enacting familial responsibility for care; analytical decision making to mitigate regret (avoiding anticipated regret and maintaining control, removing emotional impulsivity); strengthened interpersonal ties (gaining a deeper appreciation among family members, stronger empathy for each other, improving social participation); instability of relational impacts (anger and aggression threatening dynamics, unanticipated stress and emotional lability, triggering familial tension); renegotiating social roles (unexpected continuation of caregiving responsibilities, inability to relinquish the caregiving role, disappointment with unfulfilled renewal of intimacy, dissatisfaction over discrepant energy levels); guilt over unmet expectations and inevitability of the gift relationship (vague and transient indebtedness, expectation of reciprocity, transferring kidney ownership).ConclusionsDonor-recipient relationships may be improved through increased empathy, appreciation, and ability to participate in life together; however, unfulfilled expectations and behavioural and emotional changes in recipients (a side effect related to immunosuppression) remain unresolved consequences of living kidney donor transplantation. Education and counselling to help donors and recipients adjust to potential changes in relationship dynamics may help protect and foster relational stability postdonation.

Dataset Information

The relationship between donor-recipient genetic distance and long-term kidney transplant outcome.

Publications

The relationship between donor-recipient genetic distance and long-term kidney transplant outcome.

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