Collaborative Transplant Study Research Articles

222.5: Predictors of post-transplant CMV disease in kidney transplant recipients – A Collaborative Transplant Study (CTS) report.

222.5: Predictors of post-transplant CMV disease in kidney transplant recipients – A Collaborative Transplant Study (CTS) report.

344.6: Development of early-onset cancer incidence in 14- to 49-year-old kidney transplant recipients over the last 30 years – A collaborative transplant study report.

344.6: Development of early-onset cancer incidence in 14- to 49-year-old kidney transplant recipients over the last 30 years – A collaborative transplant study report.

360.8: Repeat HLA Class II but not Class I mismatches are associated with increased loss of second kidney grafts: A contemporary Collaborative Transplant Study (CTS) analysis.

360.8: Repeat HLA Class II but not Class I mismatches are associated with increased loss of second kidney grafts: A contemporary Collaborative Transplant Study (CTS) analysis.

A competing risks model to estimate the risk of graft failure and patient death after kidney transplantation using continuous donor-recipient age combinations

Graft failure and recipient death with functioning graft are important competing outcomes after kidney transplantation. Risk prediction models typically censor for the competing outcome thereby overestimating the cumulative incidence. The magnitude of this overestimation is not well described in real-world transplant data. This retrospective cohort study analyzed data from the European Collaborative Transplant Study (n = 125 250) and from the American Scientific Registry of Transplant Recipients (n = 190 258). Separate cause-specific hazard models using donor and recipient age as continuous predictors were developed for graft failure and recipient death. The hazard of graft failure increased quadratically with increasing donor age and decreased decaying with increasing recipient age. The hazard of recipient death increased linearly with increasing donor and recipient age. The cumulative incidence overestimation due to competing risk-censoring was largest in high-risk populations for both outcomes (old donors/recipients), sometimes amounting to 8.4 and 18.8 percentage points for graft failure and recipient death, respectively. In our illustrative model for posttransplant risk prediction, the absolute risk of graft failure and death is overestimated when censoring for the competing event, mainly in older donors and recipients. Prediction models for absolute risks should treat graft failure and death as competing events.

#1713 Blood pressure goals in kidney transplant recipients: an analysis of the collaborative transplant study

Abstract Background and Aims Hypertension is an independent risk factor for cardiovascular disease, the leading cause of death in kidney transplant recipients. Because there is no “one size fits all” approach to blood pressure targets, particularly in the heterogenous group of kidney transplant recipients, identification of subgroup-specific targets, considering factors like age and sex, may be appropriate. However, currently available studies are limited because of sample sizes, and no subgroup analyses have been performed examining the effects of different blood pressure targets on allograft and patient survival. The aim of our study was to investigate the impact of different ACC/AHA blood pressure categories on graft survival and patient mortality and to identify subgroup-specific targets. Method This large-scale retrospective study included 1-year blood pressure data from 62, 556 kidney transplant recipients reported to the Collaborative Transplant Study from 209 centers in 39 countries. Hypertension was categorized according to 2017 ACC/AHA guidelines. The primary outcomes were death-censored graft failure and patient mortality during post-transplant year 1 to 6. Multivariable Cox regression analysis was performed to control for immunologic and nonimmunologic confounders. Results One year after transplantation, 77% of kidney transplant recipients had hypertension. Hypertension stages 1 (130–139/80–89 mmHg), 2a (140–159/90–99 mmHg), and 2b (≥160/≥100 mmHg) were associated with an 8%, 34%, and 102% increased risk of death-censored graft failure, respectively, whereas elevated blood pressure levels (120–129/<80 mmHg) did not significantly increase the risk. Patient mortality was only significantly higher in those with hypertension stage 2b with a Hazard Ratio of 1.21 (95% CI, 1.08–1.36; P < .001). In addition, the impact of hypertension stages on death-censored graft failure varied in different subpopulations (Fig. 1). Female recipients, younger recipients, recipients who received kidneys from donors younger than 60 years, re-transplanted recipients, and recipients with pre-transplant HLA antibodies had a significantly increased risk of death-censored graft failure associated with higher blood pressure levels (Fig. 1). Kidney transplant recipients with hypertension stage 2 continued to have an increased risk of graft failure one year after transplantation, even when they achieved normal blood pressure in the second year. Conclusion This study highlights the importance of treating hypertension early after kidney transplantation to improve long-term graft and patient survival. Attention should be paid to female, younger, and sensitized recipients, who may particularly benefit from optimal blood pressure control.

A Multinational Cohort Study Examining Sex Differences in Excess Risk of Death With Graft Function After Kidney Transplant.

Kidney transplant recipients show sex differences in excess overall mortality risk that vary by donor sex and recipient age. However, whether the excess risk of death with graft function (DWGF) differs by recipient sex is unknown. In this study, we combined data from 3 of the largest transplant registries worldwide (Scientific Registry of Transplant Recipient, Australia and New Zealand Dialysis and Transplant Registry, and Collaborative Transplant Study) using individual patient data meta-analysis to compare the excess risk of DWGF between male and female recipients of a first deceased donor kidney transplant (1988-2019), conditional on donor sex and recipient age. Among 463 895 individuals examined, when the donor was male, female recipients aged 0 to 12 y experienced a higher excess risk of DWGF than male recipients (relative excess risk 1.68; 95% confidence interval, 1.24-2.29); there were no significant differences in other age intervals or at any age when the donor was female. There was no statistically significant between-cohort heterogeneity. Given the lack of sex differences in the excess risk of DWGF (other than in prepubertal recipients of a male donor kidney) and the known greater excess overall mortality risk for female recipients compared with male recipients in the setting of a male donor, future study is required to characterize potential sex-specific causes of death after graft loss.

Influence of donor sex and age on graft outcome in kidney transplantation.

There is a known recipient sex-dependent association between donor sex and kidney transplant survival. We hypothesized that donor age also modifies the association between donor sex and graft survival. First, deceased donor kidney transplant recipients (1988-2019, n=461364) recorded in the Scientific Registry of Transplant Recipients, the Australia and New Zealand Dialysis and Transplant Registry and the Collaborative Transplant Study were analyzed. We used multivariable Cox regression models to estimate the association between donor sex and death censored graft loss, accounting for the modifying effects of recipient sex and donor age; donor age was categorized as 5-19, 20-34, 35-49, 50-59 and ≥60years. Results from cohort-specific Cox models were combined using individual patient data meta-analysis. Among female recipients of donors aged <60years, graft loss hazards did not differ by donor sex; recipients of female donors ≥60years showed significantly lower graft loss hazards than recipients of male donors of the same age [combined adjusted hazard ratio (aHR) 0.90, 95% CI 0.86-0.94]. Among male recipients, female donors aged <50years were associated with significantly higher graft loss hazards than same-aged male donors (5-19years: aHR 1.11, 95% CI 1.02-1.21; 20-34years: aHR 1.08, 95% CI 1.02-1.15; 35-49years: aHR 1.07, 95% CI 1.04-1.10). There were no significant differences in graft loss by donor sex among male recipients of donors aged ≥50years. Donor age modifies the association between donor sex and graft survival. Older female donors were associated with similar or lower hazards of graft failure than older male donors in both male and female recipients, suggesting a better functional reserve of older female donor kidneys.

410.4: Diagnosis of SARS-CoV-2 Infection and Impact on Subsequent 1-Year Patient Survival in Kidney Transplant Recipients – A Report of the Collaborative Transplant Study

410.4: Diagnosis of SARS-CoV-2 Infection and Impact on Subsequent 1-Year Patient Survival in Kidney Transplant Recipients – A Report of the Collaborative Transplant Study

Deletion of the Natural Killer Cell Receptor NKG2C Encoding KLR2C Gene and Kidney Transplant Outcome.

Natural killer (NK) cells may contribute to antibody-mediated rejection (ABMR) of renal allografts. The role of distinct NK cell subsets in this specific context, such as NK cells expressing the activating receptor NKG2C, is unknown. Our aim was to investigate whether KLRC2 gene deletion variants which determine NKG2C expression affect the pathogenicity of donor-specific antibodies (DSA) and, if so, influence long-term graft survival. We genotyped the KLRC2 wt/del variants for two distinct kidney transplant cohorts, (i) a cross-sectional cohort of 86 recipients who, on the basis of a positive post-transplant DSA result, all underwent allograft biopsies, and (ii) 1,860 recipients of a deceased donor renal allograft randomly selected from the Collaborative Transplant Study (CTS) database. In the DSA+ patient cohort, KLRC2 wt/wt (80%) was associated with antibody-mediated rejection (ABMR; 65% versus 29% among KLRC2 wt/del subjects; P=0.012), microvascular inflammation [MVI; median g+ptc score: 2 (interquartile range: 0-4) versus 0 (0-1), P=0.002], a molecular classifier of ABMR [0.41 (0.14-0.72) versus 0.10 (0.07-0.27), P=0.001], and elevated NK cell-related transcripts (P=0.017). In combined analyses of KLRC2 variants and a functional polymorphism in the Fc gamma receptor IIIA gene (FCGR3A-V/F158), ABMR rates and activity gradually increased with the number of risk genotypes. In DSA+ and CTS cohorts, however, the KLRC2 wt/wt variant did not impact long-term death-censored graft survival, also when combined with the FCGR3A-V158 risk variant. KLRC2 wt/wt may be associated with DSA-triggered MVI and ABMR-associated gene expression patterns, but the findings observed in a highly selected cohort of DSA+ patients did not translate into meaningful graft survival differences in a large multicenter kidney transplant cohort not selected for HLA sensitization.

Influence of Calcineurin Inhibitor Choice on Outcomes in Kidney Transplant Recipients Aged ≥60 Y: A Collaborative Transplant Study Report.

Patients aged ≥60 y represent the fastest growing population among kidney transplant recipients and waitlist patients. They show an elevated infection risk and are frequently transplanted with multiple human leukocyte antigen mismatches. Whether the choice of calcineurin inhibitor influences graft survival, mortality, or key secondary outcomes such as infections in this vulnerable recipient population is unknown. A total of 31 177 kidney transplants from deceased donors performed between 2000 and 2019 at European centers and reported to the Collaborative Transplant Study were analyzed using multivariable Cox and logistic regression analyses. All recipients were ≥60 y old and received tacrolimus (Tac) or cyclosporine A on an intention-to-treat basis, combined with mycophenolic acid or azathioprine plus/minus steroids. The risk of 3-y death-censored graft loss and patient mortality did not differ significantly between Tac- and cyclosporine A-treated patients (hazard ratio 0.98 and 0.95, P = 0.74 and 0.20, respectively). No difference was found in the overall risk of hospitalization for infection (hazard ratio = 0.95, P = 0.19); however, a lower incidence of rejection treatment (hazard ratio = 0.81, P < 0.001) was observed in Tac-treated patients. Assessment of pathogen-specific hospitalizations revealed no difference in the risk of hospitalization due to bacterial infection (odds ratio = 1.00, P = 0.96), but a significantly higher risk of hospitalization due to human polyomavirus infection was found among Tac-treated patients (odds ratio = 2.45, P = 0.002). The incidence of de novo diabetes was higher for Tac-based immunosuppression (odds ratio = 1.79, P < 0.001). Calcineurin inhibitor selection has no significant influence on death-censored graft survival, mortality, and overall infection risk in ≥60-y-old kidney transplant recipients.

Age-dependent Sex Differences in Graft Loss After Kidney Transplantation.

Sex differences in kidney graft loss rates were reported in the United States. Whether these differences are present in other countries is unknown. We estimated the association between recipient sex and death-censored graft loss in patients of all ages recorded in the Scientific Registry of Transplant Recipients, Australia and New Zealand Dialysis and Transplant Registry, and Collaborative Transplant Study registries who received a first deceased donor kidney transplant (1988-2019). We used multivariable Cox regression models, accounting for the modifying effects of donor sex and recipient age, in each registry separately; results were combined using individual patient data meta-analysis. We analyzed 438 585 patients. Young female patients 13-24 y old had the highest crude graft loss rates (female donor: 5.66; male donor: 5.50 per 100 person-years). Among young recipients of male donors, females showed higher graft loss risks than males (0-12 y: adjusted hazard ratio [aHR] 1.42, (95% confidence interval [CI], 1.17-1.73); 13-24 y: 1.24 (1.17-1.32); 25-44 y: 1.09 (1.06-1.13)). When the donor was female, there were no significant differences by recipient sex among those of age <45 y; however, the aHR for females was 0.93 (0.89-0.98) in 45-59 y-old and 0.89 (0.86-0.93) in ≥ 60 y-old recipients. Findings were similar for all 3 registries in most age intervals; statistically significant heterogeneity was seen only among 13-24-y-old recipients of a female donor (I2 = 71.5%, P = 0.03). There is an association between recipient sex and kidney transplantation survival that is modified by recipient age and donor sex.

Rare Malignant Indications for Liver Transplantation: A Collaborative Transplant Study Report.

Introduction: Hepatocellular carcinoma (HCC) is by far the leading malignant indication for liver transplantation (LT). Few other malignancies, including cholangiocellular carcinoma (CCC), metastases from neuroendocrine tumors (NET), and sarcomas of the liver (LSAR), also are commonly accepted indications for LT. However, there is limited information on their outcome after LT.Methods: Graft and patient survival in 14,623 LTs performed in patients with hepatocellular carcinoma, CCC, NET, and LSAR from 1988 to 2017 and reported to the Collaborative Transplant Study were analyzed.Results: The study group consisted of 13,862 patients who had HCC (94.8%), 498 (3.4%) who had CCC, 100 (0.7%) who had NET, and 163 (1.1%) who had LSAR. CCC patients showed a 5-year graft survival rate of 32.1%, strikingly lower than the 63.2% rate in HCC, 51.6% rate in NET, and 64.5% rate in LSAR patients (P < 0.001 for all vs. CCC). Multivariable Cox regression analysis revealed a significantly higher risk of graft loss and death due to cancer during the first five post-transplant years in CCC vs. HCC patients (HR 1.77 and 2.56; P < 0.001 for both). The same risks were increased also in NET and LSAR patients but did not reach statistical significance.Conclusion: Among patients with rare malignant indications for LT, CCC patients showed significantly impaired graft as well as patient survival compared to HCC patients. The observed differences might challenge traditional decision-making processes for LT indication and palliative treatment in specific hepatic malignancies.

Influence of Cold Ischemia Time on the Outcome of Kidney Transplants from Donors Aged 70 Years and Above-A Collaborative Transplant Study Report.

The use of kidney allografts from ≥70-y-old donors has increased persistently over the last 20 y. Prolonged cold ischemia time (CIT) is well known to increase graft failure risk. However, despite their growing importance, no data are available on the impact of CIT, specifically on survival of allografts from ≥70-y-old donors. In total, 47 585 kidney transplantations from expanded criteria donors (ECDs) performed during 2000-2017 and reported to the Collaborative Transplant Study were analyzed. The impact of CIT on 5-y death-censored graft and patient survival was studied for transplantations from <70-y (n = 33 305) and ≥70-y-old ECDs (n = 14 280). Compared with the reference of ≤12 h CIT, a CIT of 13-18 h did not increase the risk of graft failure significantly, either for recipients of kidneys from <70-y or from ≥70-y-old ECDs. In contrast, graft failure risk increased significantly when CIT exceeded 18 h, both in recipients of kidneys from <70-y and, more pronounced, from ≥70-y-old ECDs (CIT 19-24 h: hazard ratio [HR] = 1.19 and 1.24; P < 0.001; CIT ≥24 h: HR = 1.28 and 1.32, P < 0.001 and P =0.003, respectively). Within the 18-h CIT interval, additional HLA matching further improved survival of ECD transplants significantly, whereas the negative impact of a prolonged CIT >18 h was stronger in ≥65-y-old recipients and for transplants with multiple HLA mismatches. The influence of CIT on patient survival was less pronounced. CIT, as long it is kept ≤18 h, has no significant impact on survival of kidney transplants, even from ≥70-y-old ECDs.

Maternal versus paternal living kidney transplant donation is associated with lower rejection in young pediatric recipients: A Collaborative Transplant Study report.

Approximately 1700 children per year with end-stage kidney disease undergo kidney transplantation in Europe and the United States of America; 30%-50% are living donor kidney transplantations. There may be immunological differences between paternal and maternal donors due to transplacental exchange of cells between the mother and fetus during pregnancy leading to microchimerism. We investigated whether the outcome of living-related kidney transplantation in young children is different after maternal compared with paternal organ donation. Using the international Collaborative Transplant Study (CTS) database, we analyzed epidemiological data of 7247 children and adolescents aged <18years who had received a kidney transplant from either mother or father. Risk of treated rejection episodes and death-censored graft failure were computed using the Kaplan-Meier method and multivariable Cox regression. In the recipient age group 1-4years, the rate of treated rejection episodes in recipients of kidneys from maternal donors (N=195) during the first 2years post-transplant was significantly lower (hazard ratio HR=0.47, p=.004) than in patients receiving kidneys from paternal donors (N=179). This association between donor sex and risk of treated rejections was not observed in children aged 5-9years. The 5-year death-censored graft survival in children aged 1-4years with a maternal or paternal donor was comparable. Maternal kidney donation in young pediatric renal transplant recipients is associated with an approximately 50% lower rate of treated rejection than paternal kidney donation. Whether this phenomenon is due to maternal microchimerism-induced donor-specific hyporesponsiveness must be evaluated in prospective mechanistic studies.

Can PIRCHE-II Matching Outmatch Traditional HLA Matching?

We analyzed in a cohort of 68,606 first deceased donor kidney transplantations reported to the Collaborative Transplant Study whether an epitope-based matching of donor-recipient pairs using the Predicted Indirectly ReCognizable HLA Epitopes algorithm (PIRCHE-II) is superior to currently applied HLA antigen matching. PIRCHE-II scores were calculated based on split antigen HLA-A, -B, -DRB1 typing and adjusted to the 0–6 range of HLA mismatches. PIRCHE-II scores correlated strongly with the number of HLA mismatches (Spearman ρ = 0.65, P < 0.001). In multivariable analyses both parameters were found to be significant predictors of 5-year death-censored graft loss with high prognostic power [hazard ratio (HR) per adjusted PIRCHE-II score = 1.102, per HLA mismatch = 1.095; z-value PIRCHE-II: 9.8, HLA: 11.2; P < 0.001 for both]. When PIRCHE-II scores and HLA mismatches were analyzed simultaneously, their predictive power decreased but remained significant (PIRCHE-II: P = 0.002; HLA: P < 0.001). Influence of PIRCHE-II was especially strong in presensitized and influence of HLA mismatches in non-sensitized recipients. If the level of HLA-incompatibility was low (0–3 mismatches), PIRCHE-II scores showed a low impact on graft survival (HR = 1.031) and PIRCHE-II matching did not have additional significant benefit (P = 0.10). However, if the level of HLA-incompatibility was high (4–6 mismatches), PIRCHE-II improved the positive impact of matching compared to applying the traditional HLA matching alone (HR = 1.097, P = 0.005). Our results suggest that the PIRCHE-II score is useful and can be included into kidney allocation algorithms in addition to HLA matching; however, at the resolution level of HLA typing that is currently used for allocation it cannot fully replace traditional HLA matching.

Association of graft survival with tacrolimus exposure and late intra-patient tacrolimus variability in pediatric and young adult renal transplant recipients-an international CTS registry analysis.

Adolescent and young adult age is a high-risk window with an alarmingly increased likelihood of premature kidney graft loss due to immunological rejection. Using the large database of the Collaborative Transplant Study, we analyzed whether a more intense and less variable exposure to tacrolimus could counteract this young age-related enhanced immunoreactivity. Kidney graft recipients aged 12-23years (n=964) with a 1-year tacrolimus trough level between 4.0 and 10.9ng/ml had a 5-year graft survival rate of 85.1%, significantly better than the poor 66.1% rate in patients with a trough level below 4.0ng/ml who showed a 2.38-fold increased risk of graft loss in the multivariable analysis (P<0.001). This association was not apparent in young children aged 0-11years (n=455) and less pronounced in adults aged 24-34years (n=1466). However, an intra-patient variability of tacrolimus (IPV) trough level ≥1.5 at post-transplant years 1 and 2 was associated with an increased graft loss risk in both 12- to 23-year-old and 0- to 11-year-old recipients (P<0.001 and P=0.045). Patients with high IPV made up as many as 30% of kidney graft recipients, indicating that a more intense and less variable exposure to tacrolimus could improve graft survival strongly in this high-risk group.

Impact of HLA compatibility in recipients of kidneys from expanded criteria donors: A Collaborative Transplant Study Report.

Due to a widespread organ shortage, the use of expanded criteria donors (ECDs) in kidney transplantation has increased persistently, reaching approximately 40% in recent years. Whether human leucocyte antigen (HLA) matching between donor and recipient should be part of allocation algorithms in transplantation of ECD kidneys, and especially of ECD kidneys from ≥70-year-old donors, is still in question. To this end, 135,529 kidney transplantations performed between 2000 and 2017 and reported to the Collaborative Transplant Study were analysed and the impact of HLA-A+B+DR mismatches on death-censored graft and patient survival as well as on rejection episodes was investigated. Results were stratified according to donor status (standard criteria donor (SCD) versus ECD) and age of ECD. HLA incompatibility increased the five-year death-censored graft failure risk similarly strong in recipients of ECD and SCD transplants (hazard ratio (HR) per HLA mismatch 1.078 and 1.075, respectively; p<.001 for both). Its impact on rejection treatments during the first post-transplant year was also significant but slightly weaker for recipients of ECD transplants (risk ratio (RR) per HLA mismatch 1.10 for ECD transplants and 1.13 for SCD transplants; p<.001 for both). Mortality increased gradually from zero to six HLA mismatches in recipients of SCD transplants, whereas for ECD transplants a significant increase was notable only from zero to more than zero mismatches. A significant but slightly less pronounced impact of HLA incompatibility on graft failure was observed in transplants from ≥70- compared with <70-year-old ECDs (HR per mismatch 1.047 and 1.093; p=.009 and<0.001, respectively). The influence of HLA mismatches on rejection treatments was the same for both ECD age groups (RR=1.10, p<.001 and p=.004, respectively). Our data indicate that HLA matching should be part of allocation algorithms not only in transplantation of kidneys from SCDs but also from ECDs.

PRE-TRANSPLANT HLA ANTIBODIES AND DELAYED GRAFT FUNCTION IN THE CURRENT ERA OF KIDNEY TRANSPLANTATION

Collaborative Transplant Study. Introduction: We reported previously that early adverse events in deceased donor kidney transplantation, such as delayed graft function (DGF) and rejection episodes, are associated with pre-transplant presence of HLA antibodies and that patients with adverse events show significantly impaired graft survival rates. In the meantime, the introduction of sensitive antibody detection techniques is expected to have diminished the involvement of overlooked HLA antibodies in DGF. On the other hand, DGF risk might have increased due to growing use of kidneys from elderly donors. The aim of the present multi-center study was to identify the immunological and non-immunological predictors of DGF and to determine its influence on outcome in the presence and absence of HLA antibodies in the new era of transplantation. Methods: 1,724 patients who received a deceased donor kidney transplant during 2008–2017 and on whom a pre-transplant serum sample and the information on immediate function within the first 24 hours after transplantation, dialysis during the first week, and biopsy-proven rejection during the first 3 months were available. Graft survival after day 7 during the first 3 years post-transplant was analyzed by multivariable Cox regression. Predictors of DGF and influence of DGF and pre-transplant HLA antibodies on biopsy-proven rejections during days 8–90 were determined by multivariable logistic regression. DGF was defined as either no graft function during the first 24 hours and/or dialysis during the first week. In 44% of cases, we were informed by the centers on the presence or absence of pre-transplant donor-specific antibodies (DSA) as determined by single antigen technique. Results and Discussion: Donor age ≥50 years, simultaneous presence of HLA class I and II antibodies pre-transplant, diabetes mellitus as original disease, cold ischemia time ≥18 hours, and time on dialysis >5 years were associated with an increased risk of DGF. DGF alone doubled the risk for all cause graft loss, more due to impaired death-censored graft than patient survival. In DGF patients, the risk of death-censored graft loss increased further if HLA antibodies (HR=4.75, P<0.001) or donor-specific HLA antibodies (DSA, HR=7.39, P<0.001) were present prior to transplantation. In the presence of HLA antibodies or DSA, the incidence of biopsy-proven rejections increased significantly in patients with as well as without DGF. Recipients without DGF and without biopsy-proven rejections during the first 3 months had the highest fraction of patients with good kidney function at year 1 post-transplant, whereas patients with both DGF and rejection showed the lowest rate of good kidney function. Our data indicate that, in the current era of transplantation, besides non-immunological factors, also the pre-transplant presence of HLA class I and II antibodies increase the risk of DGF. Conclusion: Patients with DGF require special attention, especially in the presence of HLA antibodies.

CAN EPITOPE MATCHING OUTMATCH TRADITIONAL HLA MATCHING?

Collaborative Transplant Study. Introduction: Pre-transplant presence and post-transplant development of alloantibodies against highly polymorphic human leukocyte antigen (HLA) allele mismatches (mm) play a major role in rejection of kidney allografts. However, antibodies recognize small sequences on HLA alleles called epitopes and the same epitope can be present on different alleles, impairing the precision of matching. Using the Collaborative Transplant Study database, we analyzed whether a T-cell epitope-based matching of donor-recipient pairs using the PIRCHE-II algorithm is a better predictor of graft survival than the currently applied allele group-based HLA-A, -B, -DR matching. Methods: 68,606 European deceased donor kidney-only transplantations during 1996–2016 were analyzed. PIRCHE-II mismatch score was calculated based on split typing using the 2007 NMDP haplotype frequency database and the PIRCHE matching service. Multivariable Cox regression analyses were performed to calculate hazard ratios (HRs) for death-censored graft loss. Correlation was analyzed with Spearman’s rank correlation. In order to achieve comparable HRs, a log-transformed PIRCHE-II score was used, followed by a linear transformation to match the value range of 0–6 HLA A+B+DR mm. Linear transformations in Cox regression analysis change the HR per point without changing the P- and Z-values. Results and Discussion: The HLA mismatch-derived PIRCHE-II score correlated strongly with the number of HLA mm (correlation coefficient ρ=0.65, P<0.001). Cox regression analyses revealed that Pirche II score and HLA mm are predictive confounders for death-censored graft loss at year 5 with highly significant prognostic power (Z-value for Pirche II: 9.8; for HLA: 11.2; P<0.001) (Table 1).The full Cox model per transformed PIRCHE-II score without HLA mm resulted in a hazard ratio (HR) for graft loss of 1.102 (95% CI=1.081–1.123; P<0.001). When HLA mm were added to the model, the HR per PIRCHE-II score decreased to 1.042 but remained statistically significant (95% CI=1.015–1.071; P=0.002) (Table 1). Overall, considering the HLA loci currently used for typing at split antigen level, HLA mm still had a higher predictive value than the PIRCHE-II score (11.2 vs. 9.8) regarding graft survival. As illustrated in Figure 1, the variance in PIRCHE-II score increased with higher number of HLA mm.Therefore, the possible clinical benefit of PIRCHE-II score matching improved with higher number of HLA mismatches. As demonstrated in Table 1, the risk of graft loss increases with each additional PIRCHE-II score. Conclusion: Our results indicate that PIRCHE-II score is useful and can be included into matching algorithms. However, it cannot fully replace traditional HLA matching. There seems to be information on immunological differences PIRCHE-II score cannot cover in its present form using HLA typing data at split level. This needs to be analyzed also for HLA matching at 4-digit molecular typing level.

ONCE- VERSUS TWICE-DAILY TACROLIMUS AND GRAFT SURVIVAL

Collaborative Transplant Study Introduction: Although the extended-release tacrolimus preparations have the added benefit of a convenient once-daily dosing, large-scale studies evaluating the impact of a possibly improved patient compliance with these preparations are lacking. We analyzed whether the type of tacrolimus at year 1 post-transplant influences subsequent graft survival in adult recipients of deceased donor kidney transplants. Materials and Methods: There were 12,325 patients who were transplanted since 2011 and were on once- or twice-daily tacrolimus at year 1 post-transplant. An exact 1:1 matching on center, transplant year, graft number, mycophenolate acid and steroids could be performed in 1,250 patients to account for a possible center, transplant year, number of transplant and immunosuppression bias. Univariate Kaplan-Meier analysis was performed before and after exact matching and multivariable Cox regression was applied after matching to adjust for additional confounders. Results and Discussion: The univariate analysis of graft survival after year 1 in once- and twice-daily tacrolimus patients before and after matching is illustrated in Figure 1.Fig. 1. Patients on once-daily formulation had a significantly better outcome (P<0.001 and 0.021, respectively). Figure 2 shows the missing graft survival difference between the two matched groups after year 3.Fig. 2. In the multivariable Cox analysis, compared to once-daily tacrolimus patients at year 1, matched twice-daily tacrolimus patients showed a significantly higher risk of death-censored (HR=3.61, P=0.006) and all-cause graft loss (HR=2.31, P=0.003) and a non-significantly higher risk of patient death (HR=1.80, P=0.076) during years 2 to 3. However, in line with the results of the univariate analysis shown in Figure 2, after year 3, the increased risk declined to a nonsignificant difference (HR=1.20, P=0.62; HR=0.69, P=0.19 for death-censored graft loss and patient death, respectively; HR=0.92, P=0.73 for all-cause graft loss). Retrospective comparison of the effects of different immunosuppressive agents is difficult due to a possible patient selection bias. Likely explanations for the observed short-lasting benefit of once- over twice-daily tacrolimus preparations are: a) the benefit is related to a psychological effect and positive motivation due to a “new” medication resulting in a stronger adherence to medication in once-daily tacrolimus patients for a certain time [1]. Indeed, 75% of once-daily tacrolimus patients at year 1 had started with twice-daily at time of transplantation and less than 10% switched to twice-daily at year 2; b) many of the twice-daily patients switched to once-daily, which could have diminished the difference. In the years 2 to 5 post-transplant, only 28% of the switches were from once to twice daily while 72% were from twice to once. Conclusion: Once-daily tacrolimus appears to have a short-term beneficial effect, mainly on death-censored graft survival.