The 2020 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation is intended to assist health care ...professionals worldwide who evaluate and manage potential candidates for deceased or living donor kidney transplantation. This guideline addresses general candidacy issues such as access to transplantation, patient demographic and health status factors, and immunological and psychosocial assessment. The roles of various risk factors and comorbid conditions governing an individual's suitability for transplantation such as adherence, tobacco use, diabetes, obesity, perioperative issues, causes of kidney failure, infections, malignancy, pulmonary disease, cardiac and peripheral arterial disease, neurologic disease, gastrointestinal and liver disease, hematologic disease, and bone and mineral disorder are also addressed. This guideline provides recommendations for evaluation of individual aspects of a candidate's profile such that each risk factor and comorbidity are considered separately. The goal is to assist the clinical team to assimilate all data relevant to an individual, consider this within their local health context, and make an overall judgment on candidacy for transplantation. The guideline development process followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Guideline recommendations are primarily based on systematic reviews of relevant studies and our assessment of the quality of that evidence, and the strengths of recommendations are provided. Limitations of the evidence are discussed with differences from previous guidelines noted and suggestions for future research are also provided.
To optimize strategies that mitigate the risk of graft loss associated with HLA incompatibility, we evaluated whether sequence defined HLA targets (eplets) that result in donor-specific antibodies ...are associated with transplant outcomes. To define this, we fit multivariable Cox proportional hazard models in a cohort of 118 382 United States first kidney transplant recipients to assess risk of death-censored graft failure by increments of ten antibody-verified eplet mismatches. To verify robustness of our findings, we conducted sensitivity analysis in this United States cohort and assessed the role of antibody-verified eplet mismatches as autonomous predictors of transplant glomerulopathy in an independent Canadian cohort. Antibody-verified eplet mismatches were found to be independent predictors of death-censored graft failure with hazard ratios of 1.231 95% confidence interval 1.195, 1. 268, 1.268 1.231, 1.305 and 1.411 1.331, 1.495 for Class I (HLA-A, B, and C), -DRB1 and -DQB1 loci, respectively. To address linkage disequilibrium between HLA-DRB1 and -DQB1, we fit models in a subcohort without HLA-DQB1 eplet mismatches and found hazard ratios for death-censored graft failure of 1.384 1.293, 1.480 for each additional antibody-verified HLA-DRB1 eplet mismatch. In a subcohort without HLA-DRB1 mismatches, the hazard ratio was 1.384 1.072, 1.791 for each additional HLA-DQB1 mismatch. In the Canadian cohort, antibody-verified eplet mismatches were independent predictors of transplant glomerulopathy with hazard ratios of 5.511 1.442, 21.080 for HLA-DRB1 and 3.640 1.574, 8.416 for -DRB1/3/4/5. Thus, donor-recipient matching for specific HLA eplets appears to be a feasible and clinically justifiable strategy to mitigate risk of graft loss.
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Summary
The impact of donor specific HLA antibodies (DSA) on solid organ transplant outcomes has been recognised for over half a century. This article reviews the mechanisms of DSA formation, details ...the laboratory methods for detecting DSA, discusses the clinical and histological manifestations of DSA in the allograft and explores the options for management of DSA. The challenges posed by pre‐existing and de novo DSA are explored with current therapeutic strategies described. A method for stratifying the risk associated with pre‐existing DSA is explained and the importance of understanding immunological risk associated with transplantation to facilitate optimal personalised decision making for transplant recipients is highlighted. Future directions for further managing the risk associated with DSA are proposed.
Due to the ongoing shortage of deceased-donor organs, novel strategies to augment kidney transplantation rates through expanded living donation strategies have become essential. These include ...desensitization in antibody-incompatible transplants and kidney paired donation (KPD) programs. KPD enables kidney transplant candidates with willing but incompatible living donors to join a registry of other incompatible pairs in order to find potentially compatible transplant solutions. Given the significant immunologic barriers with fewer donor options, single-center or small KPD programs may be less successful in transplanting the more sensitized patients; the optimal solution for the difficult-to-match patient is access to more potential donors and large multicenter or national registries are essential. Multicenter KPD programs have become common in the last decade, and now represent one of the most promising opportunities to improve transplant rates. To maximize donor-recipient matching, and minimize immunologic risk, these multicenter KPD programs use sophisticated algorithms to identify optimal match potential, with simultaneous two-, three- or more complex multiway exchanges. The article focuses on the recent progresses in KPD and it also reviews some of the differences and commonalities across four different national KPD programs.
Kidney retransplantation is a risk factor for decreased allograft survival. Repeated mismatched HLA antigens between first and second transplant may be a stimulus for immune memory responses and ...increased risk of alloimmune damage to the second allograft. Historical data identified a role of repeated HLA mismatches in allograft loss. However, evolution of HLA testing methods and a modern transplant era necessitate re-examination of this role to more accurately risk-stratify recipients. We conducted a contemporary registry analysis of data from 13,789 patients who received a second kidney transplant from 1995 to 2011, of which 3868 had one or more repeated mismatches. Multivariable Cox proportional hazards modeling revealed no effect of repeated mismatches on all-cause or death-censored graft loss. Analysis of predefined subgroups, however, showed that any class 2 repeated mismatch increased the hazard of death-censored graft loss, particularly in patients with detectable panel-reactive antibody before second transplant (hazard ratio HR, 1.15; 95% confidence interval 95% CI, 1.02 to 1.29). Furthermore, in those who had nephrectomy of the first allograft, class 2 repeated mismatches specifically associated with all-cause (HR, 1.30; 95% CI, 1.07 to 1.58) and death-censored graft loss (HR, 1.41; 95% CI, 1.12 to 1.78). These updated data redefine the effect of repeated mismatches in retransplantation and challenge the paradigm that repeated mismatches in isolation confer increased immunologic risk. We also defined clear recipient categories for which repeated mismatches may be of greater concern in a contemporary cohort. Additional studies are needed to determine appropriate interventions for these recipients.
Cardiovascular mortality is the leading cause of death in ESRD. Whereas innate and adaptive immunity have established roles in cardiovascular disease, the role of humoral immunity is unknown. We ...conducted a retrospective cohort study in first-time adult kidney transplant candidates (N=161,308) using data from the Scientific Registry of Transplant Recipients and the Centers for Medicare and Medicaid Services to evaluate whether anti-human leukocyte antigen antibodies, measured as panel reactive antibodies (PRAs), are related to mortality in ESRD. Relationships between time-varying PRAs and all-cause or cardiovascular mortality were assessed using Cox proportional hazards models. The analysis was repeated in subcohorts of candidates at lower risk for significant comorbidities, activated on the waiting list after 2007, or unsensitized at activation. Competing risks analyses were also conducted. Fully adjusted models showed increased hazard ratios (HRs 95% confidence intervals) for all-cause mortality (HR, 1.02 95% CI, 0.99 to 1.06; HR, 1.11 95% CI,1.07 to 1.16; and HR,1.21 95% CI,1.15 to 1.27) and cardiovascular mortality (HR, 1.05 95% CI,1.00 to 1.10; HR,1.11 95% CI,1.05 to 1.18; and HR,1.21 95% CI,1.12 to 1.31) in PRA 1%-19%, PRA 20%-79%, and PRA 80%-100% categories compared with PRA 0%, respectively. Associations between PRA and the study outcomes were accentuated in competing risks models and in lower-risk patients and persisted in other subcohorts. Our findings suggest that PRA is an independent predictor of mortality in wait-listed kidney transplant candidates. The mechanisms by which PRA confers an incremental mortality risk in sensitized patients, and the role of transplantation in modifying this risk, warrant further study.
Delayed graft function (DGF) associates with an increased risk for graft failure, but its link with death with graft function (DWGF) is unknown. We used the US Renal Data System to assemble a cohort ...of all first, adult, deceased-donor kidney transplant recipients from January 1, 1998, through December 31, 2004. In total, 11,542 (23%) of 50,246 recipients required at least one dialysis session in the first week after transplantation. Compared with patients without DGF, patients with DGF were significantly more likely to die with a functioning graft (relative hazard 1.83 95% confidence interval 1.73 to 1.93 and 1.53 95% CI 1.45 to 1.63 for unadjusted and fully adjusted models, respectively). The risk for DWGF was slightly higher among women with DGF than among men. There was no significant heterogeneity among other subgroups, and the results were robust to sensitivity analyses. Acute rejection within the first year attenuated the DGF-DWGF association. Cardiovascular and infectious deaths were slightly more prevalent in the DGF group, but the relative hazards of cause-specific death were similar between DWGF and deaths during total follow-up. In summary, DGF associates with an increased risk for DWGF; the mechanisms underlying the negative impact of DGF require further study.
Autoantibodies directed against endogenous proteins including contractile proteins and endothelial antigens are frequently detected in patients with heart failure and after heart transplantation. ...There is evidence that these autoantibodies contribute to cardiac dysfunction and correlate with clinical outcomes. Currently, autoantibodies are detected in patient sera using individual ELISA assays (one for each antigen). Thus, screening for many individual autoantibodies is laborious and consumes a large amount of patient sample. To better capture the broad-scale antibody reactivities that occur in heart failure and post-transplant, we developed a custom antigen microarray technique that can simultaneously measure IgM and IgG reactivities against 64 unique antigens using just five microliters of patient serum. We first demonstrated that our antigen microarray technique displayed enhanced sensitivity to detect autoantibodies compared to the traditional ELISA method. We then piloted this technique using two sets of samples that were obtained at our institution. In the first retrospective study, we profiled pre-transplant sera from 24 heart failure patients who subsequently received heart transplants. We identified 8 antibody reactivities that were higher in patients who developed cellular rejection (2 or more episodes of grade 2R rejection in first year after transplant as defined by revised criteria from the International Society for Heart and Lung Transplantation) compared with those who did have not have rejection episodes. In a second retrospective study with 31 patients, we identified 7 IgM reactivities that were higher in heart transplant recipients who developed antibody-mediated rejection (AMR) compared with control recipients, and in time course studies, these reactivities appeared prior to overt graft dysfunction. In conclusion, we demonstrated that the autoantibody microarray technique outperforms traditional ELISAs as it uses less patient sample, has increased sensitivity, and can detect autoantibodies in a multiplex fashion. Furthermore, our results suggest that this autoantibody array technology may help to identify patients at risk of rejection following heart transplantation and identify heart transplant recipients with AMR.
This editorial contextualizes a multicenter study's report (Hachem et al, page 2285) of the frequency and clinical implications of donor‐specific HLA antibodies in the early post–lung transplant ...period.
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