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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 (CTS; n = 125 250) and from the American Scientific Registry of Transplant Recipients (SRTR; 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 post-transplant 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., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Identification of differences in mortality risk between female and male heart transplant recipients may prompt sex-specific management strategies. Because worldwide, males of all ages have higher absolute mortality rates than females, we aimed to compare the excess risk of mortality (risk above the general population) in female vs male heart transplant recipients., Methods: We used relative survival models conducted separately in SRTR and CTS cohorts from 1988-2019, and subsequently combined using 2-stage individual patient data meta-analysis, to compare the excess risk of mortality in female vs male first heart transplant recipients, accounting for the modifying effects of donor sex and recipient current age., Results: We analyzed 108,918 patients. When the donor was male, female recipients 0-12 years (Relative excess risk (RER) 1.13, 95% CI 1.00-1.26), 13-44 years (RER 1.17, 95% CI 1.10-1.25), and ≥45 years (RER 1.14, 95% CI 1.02-1.27) showed higher excess mortality risks than male recipients of the same age. When the donor was female, only female recipients 13-44 years showed higher excess risks of mortality than males (RER 1.09, 95% CI 1.00-1.20), though not significantly (p = 0.05)., Conclusions: In the setting of a male donor, female recipients of all ages had significantly higher excess mortality than males. When the donor was female, female recipients of reproductive age had higher excess risks of mortality than male recipients of the same age, though this was not statistically significant. Further investigation is required to determine the reasons underlying these differences., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: 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., Methods: 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., Results: 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., Conclusions: 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., Competing Interests: A.J.V. has accepted consulting fees and fellowship grant funding from Paladin Labs Inc. A.M. is supported by grants from the German Research Foundation (DFG; ME 3696/5-1 and ME3696/3-1) and the Lower Saxony Ministry of Science and Culture. C.S. is supported by the European Union’s Horizon 2020 Research and Innovation Programme (grant 952512). G.W. is supported by National Health and Medical Research Council Investigator (APP 1195414) and Career Development Fellowship (APP 1147657). R.S.-P. is supported by a Fonds de recherche du Quebec—Santé chercheur boursier clinician award (grant 254386) and Canadian Institutes of Health Research (grant FRN-156730). The other authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: 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., Methods: First, deceased donor kidney transplant recipients (1988-2019, n = 461 364) 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 ≥60 years. Results from cohort-specific Cox models were combined using individual patient data meta-analysis., Results: Among female recipients of donors aged <60 years, graft loss hazards did not differ by donor sex; recipients of female donors ≥60 years 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 <50 years were associated with significantly higher graft loss hazards than same-aged male donors (5-19 years: aHR 1.11, 95% CI 1.02-1.21; 20-34 years: aHR 1.08, 95% CI 1.02-1.15; 35-49 years: 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 ≥50 years., Conclusion: 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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Worldwide and at all ages, males have a higher mortality risk than females. This mortality bias should be preserved in kidney transplant recipients unless there are sex differences in the effects of transplantation. Here we compared the excess risk of mortality (risk above the general population) in female versus male recipients of all ages recorded in three large transplant databases. This included first deceased donor kidney transplant recipients and accounted for the modifying effects of donor sex and recipient age. After harmonization of variables across cohorts, relative survival models were fitted in each cohort separately and results were combined using individual patient data meta-analysis among 466,892 individuals (1988-2019). When the donor was male, female recipients 0-12 years (Relative Excess Risk 1.54, 95% Confidence Interval 1.20-1.99), 13-24 years (1.17, 1.01-1.34), 25-44 years (1.11, 1.05-1.18) and 60 years and older (1.05, 1.02-1.08) showed higher excess mortality risks than male recipients of the same age. When the donor was female, the Relative Excess Risk for those over 12 years were similar to those when the donor was male. There is a higher excess mortality risk in female than male recipients with differences larger at younger than older ages and only statistically significant when the donor was male. While these findings may be partly explained by the known sex differences in graft loss risks, sex differences in the risks of death with graft function may also contribute. Thus, higher risks in females than males suggest that management needs to be modified to optimize transplant outcomes among females., (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Background: Sex differences in kidney graft loss rates were reported in the United States. Whether these differences are present in other countries is unknown., Methods: 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., Results: 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)., Conclusions: There is an association between recipient sex and kidney transplantation survival that is modified by recipient age and donor sex., Competing Interests: A.J.V. has accepted consulting fees and fellowship grant funding from Paladin Labs Inc. A.M. is supported by grants from the German Research Foundation (DFG; ME 3696/5-1 and ME3696/3-1) and the Lower Saxony Ministry of Science and Culture. G.W. is supported by NHMRC Investigator (APP 1195414) and Career Development Fellowship (APP 1147657). R.S.-P. is supported by a Fonds de recherche du Quebec—Santé chercheur boursier clinician award (grant no. 254386) and CIHR (grant FRN-156730). This study was supported by funding from the Canadian Institutes of Health Research PJT-165832. The other authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Split-liver transplantation offers a solution to the organ shortage problem. However, the outcomes of extended right lobe liver transplantation (ERLT) and whether it is a suitable alternative to full-size liver transplantation (FSLT) remain controversial. We compared the outcomes of ERLT and FSLT in adult recipients of 43,409 first deceased donor liver transplantations using Cox regression. We also analyzed 612 ERLT and 1224 FSLT 1:2 matched cases to identify factors that affect ERLT outcome. The risk of graft loss was significantly higher following ERLT than following FSLT during the first posttransplantation year in the matched and unmatched collective (hazard ratio [HR], 1.39 and 1.27 and P = 0.01 and 0.006, respectively). Every additional hour of cold ischemia time (CIT) increased the risk of 1-year graft loss by 10% in the ERLT group compared with only 3% in the FSLT group (P = 0.003 and <0.001, respectively). Importantly, the outcome of ERLT and FSLT did not differ significantly if the CIT was below 10 hours (HR, 0.71; P = 0.22). One-year graft and patient survival were lower in high-risk ERLT recipients with a Model for End-Stage Liver Disease (MELD) score of ≥20 (HR, 1.88; P = 0.03 and HR, 2.03; P = 0.02). In the male recipient-male donor combination, ERLT recipients had a higher risk of 1-year graft loss than FSLT recipients (HR, 2.44; P = 0.006). This was probably because of the significantly higher MELD score in ERLT recipients (P = 0.004). ERLT in adults is an adequate alternative to FSLT and offers an elegant solution to the problem of organ shortage as long as the cold storage is less than 10 hours and the recipient's MELD score is <20., (© 2021 The Authors. Liver Transplantation published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: 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., Methods: 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., Results: 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)., Conclusions: Calcineurin inhibitor selection has no significant influence on death-censored graft survival, mortality, and overall infection risk in ≥60-y-old kidney transplant recipients., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Vietzen, Döhler, Tran, Süsal, Halloran, Eskandary, Herz, Mayer, Kozakowski, Wahrmann, Ely, Haindl, Puchhammer-Stöckl and Böhmig.)

Main problem: Soluble urokinase plasminogen activator receptor (suPAR) is an immunological risk factor for kidney disease and a prognostic marker for cardiovascular events. Methods: We measured serum suPAR levels in a total of 1,023 kidney transplant recipients either before (cohort 1, n = 474) or at year 1 after transplantation (cohort 2, n = 549). The association of suPAR levels and all-cause and cardiovascular mortality was evaluated by multivariable Cox regression analysis. Results: The highest suPAR tertile compared to the two lower tertiles had a significantly higher risk of all-cause mortality in both cohorts separately (cohort 1: hazard ratio (HR) 1.92, 95% confidence interval (CI) 1.20-3.08, p = 0.007; cohort 2: HR = 2.78, 95% CI 1.51-5.13, p = 0.001) and combined ( n = 1,023, combined HR = 2.14, 95% CI 1.48-3.08, p < 0.001). The association remained significant in the subgroup of patients with normal kidney function (cohort 2: HR = 5.40, 95% CI 1.42-20.5, p = 0.013). The increased mortality risk in patients with high suPAR levels was attributable mainly to an increased rate of cardiovascular death ( n = 1,023, HR = 4.24, 95% CI 1.81-9.96, p < 0.001). Conclusion: A high suPAR level prior to and at 1 year after kidney transplantation was associated with an increased risk of patient death independent of kidney function, predominantly from cardiovascular cause., Competing Interests: CM and MZ, together with the University of Heidelberg, are co-founders of TolerogenixX GmbH, Heidelberg, Germany, a biotechnology company that holds licenses for cell therapies. CM, CSü, and MZ filed a patent application for a cell therapy. JR is cofounder of Trisaq, a biotechnology company developing drugs targeting suPAR. SH and JR are members of the scientific advisory board of Trisaq. JR holds patents and licenses related to suPAR. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Morath, Hayek, Döhler, Nusshag, Sommerer, Zeier, Reiser and Süsal.)

Background: 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., Methods: Using the international Collaborative Transplant Study (CTS) database, we analyzed epidemiological data of 7247 children and adolescents aged <18 years 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., Results: In the recipient age group 1-4 years, the rate of treated rejection episodes in recipients of kidneys from maternal donors (N = 195) during the first 2 years 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 5-9 years. The 5-year death-censored graft survival in children aged 1-4 years with a maternal or paternal donor was comparable., Conclusions: 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., (© 2021 The Authors. Pediatric Transplantation published by Wiley Periodicals LLC.)

Objectives: Our country Croatia is among the global leaders regarding deceased donation rates, yet we are facing organ shortage and concurrently a sharp decline in our acceptance rates for kidney offers. To reevaluate our organ acceptance policy, we retrospectively analyzed the factors that influenced the posttransplant outcomes of kidneys from elderly deceased donors at our center during a 20-year period and the changes to our organ acceptance criteria during Eurotransplant membership., Materials and Methods: We studied all kidney transplants from donors ≥60 years old during the two 5-year episodes of Eurotransplant membership from 2007 to 2017 (period II and period III) and compared those data to data from the decade before Eurotransplant membership (period I, 1997-2007). Differences in acceptance rates and reasons for the decline of kidney offers between the two 5-year periods of Eurotransplant membership were analyzed., Results: In period I, 14.1% of all kidney allografts were obtained from donors ≥60 years old; in period II and period III the rates were nearly 2-fold higher (27.0% and 25.7%, respectively; P = .007 and P = .008). During the first 5-year period of Eurotransplant membership (period II), we accepted significantly more grafts from marginal donors with a higher number of human leukocyte antigen mismatches compared with period I. Consequently, the 3-month survival rate of kidneys from donors ≥60 years old dropped from 91.1% to as low as 74.2% (P = .034). After application of morestringent human leukocyte antigen matching, especially in human leukocyte antigen DR, and morestringent donor acceptance criteria in period III, graft survival improved to 91.1%., Conclusions: Our experience indicates that careful selection of kidneys from elderly deceased donors and allocation to human leukocyte antigen-matched recipients is important to improve transplant outcomes.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Houben, Schimmack, Unterrainer, Döhler, Mehrabi and Süsal.)

Background: 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., Methods: 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)., Results: 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., Conclusions: CIT, as long it is kept ≤18 h, has no significant impact on survival of kidney transplants, even from ≥70-y-old ECDs., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)