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Kidneys donated after circulatory death (DCD) perform similarly to kidneys donated after brain death (DBD). However, the respective incidences of delayed graft function (DGF) differ. This questions the donor type-specific impact of early graft function on long-term outcomes. Using competing risk and Cox-regression analysis, we compared death-censored graft loss between types of early graft function: DGF (temporary dialysis dependency started within 7 days after transplantation), slow graft function (3-day plasma creatinine decline less than 10% per day), and immediate graft function. In 1061 DBD and 1605 DCD graft recipients (January 2014 until January 2023), graft survival was similar. DGF was associated with death-censored graft loss in DBD and DCD (adjusted hazard ratios: DGF in DBD: 1.79 [1.04-2.91], P = .027, DGF in DCD: 1.84 [1.18-2.87], P = .008; Reference: no DGF). Slow graft function was associated with death-censored graft loss in DBD, but not significantly in DCD (adjusted hazard ratios DBD: 2.82 (1.34-5.93), P = .007, and DCD: 1.54 (0.72-3.35), P = .262; Reference: immediate graft function). Early graft dysfunction has a differential impact on graft outcome in DBD and DCD. The differences between DBD and DCD should be accounted for in research and the clinic., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Robust evidence for interventions to improve health-related quality of life (HRQoL) in people who receive a kidney transplant is scarce. We aimed to assess the effects of a lifestyle intervention in this context., Methods: We conducted a multicentre, open-label, parallel-group, randomised controlled trial among people who have received a kidney transplant. Participants from six hospitals across the Netherlands were randomly assigned 1:1:1 by an independent company into: usual care, exercise, and exercise plus diet. The exercise intervention encompassed two phases, a 3-month supervised exercise programme (twice weekly) followed by 12 months of lifestyle coaching, with 15 months of additional dietary counselling (12 sessions) for the exercise plus diet group. The primary outcome was HRQoL-domain physical functioning, assessed using the 36-item Short Form Survey at 15 months., Findings: From Oct 12, 2010 to Nov 18, 2016, 221 participants who had received a kidney transplant (138 [62%] male and 83 [38%] female, with a mean age of 52·5 [SD 13·5] years, who were a median of 5·5 [IQR 3·6-8·4] months post-transplant) were included and randomly assigned to usual care (n=74), exercise intervention (n=77), and exercise plus diet intervention (n=70). In the intention-to-treat analyses, at 15 months post-baseline, no significant differences in HRQoL-domain physical functioning were found for the exercise group (5·3 arbitrary units, 95% CI -4·2 to 14·9; p=0·27), and the exercise plus diet group (5·9 arbitrary units, -4·1 to 16·0; p=0·25) compared with control. Safety outcomes showed no safety concerns. After 3 months of supervised exercise intervention, HRQoL-domain physical functioning improved in the exercise group (7·3 arbitrary units, 95% CI 1·2 to 13·3; p=0·018) but not in the exercise plus diet group (5·8 arbitrary units, -0·5 to 12·1; p=0·072)., Interpretation: A lifestyle intervention is safe and feasible in people who have received kidney transplants, paving the way for lifestyle intervention studies in other multimorbid populations with polypharmacy. However, improving HRQoL for people who have received a kidney transplant is challenging. The lifestyle interventions in the current study did not show significant improvements in HRQoL at the end of the study at the total group level., Funding: Dutch Kidney Foundation, Innovation Fund of the Dutch Medical Insurance Companies, and University Medical Center Groningen., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Whenever the kidney standard allocation (SA) algorithms according to the Eurotransplant (ET) Kidney Allocation System or the Eurotransplant Senior Program fail, rescue allocation (RA) is initiated. There are 2 procedurally different modes of RA: recipient oriented extended allocation (REAL) and competitive rescue allocation (CRA). The objective of this study was to evaluate the association of patient survival and graft failure with RA mode and whether or not it varied across the different ET countries., Methods: The ET database was retrospectively analyzed for donor and recipient clinical and demographic characteristics in association with graft outcomes of deceased donor renal transplantation (DDRT) across all ET countries and centers from 2014 to 2021 using Cox proportional hazards methods., Results: Seventeen thousand six hundred seventy-nine renal transplantations were included (SA 15 658 [89%], REAL 860 [4.9%], and CRA 1161 [6.6%]). In CRA, donors were older, cold ischemia times were longer, and HLA matches were worse in comparison with REAL and especially SA. Multivariable analyses showed comparable graft and recipient survival between SA and REAL; however, CRA was associated with shorter graft survival. Germany performed 76% of all DDRTs after REAL and CRA and the latter mode reduced waiting times by up to 2.9 y., Conclusions: REAL and CRA are used differently in the ET countries according to national donor rates. Both RA schemes optimize graft utilization, lead to acceptable outcomes, and help to stabilize national DDRT programs, especially in Germany., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

In kidney transplantation, donor HLA antibodies are a risk factor for graft loss. Accessibility of donor eplets for HLA antibodies is predicted by the ElliPro score. The clinical usefulness of those scores in relation to transplant outcome is unknown. In a large Dutch kidney transplant cohort, Ellipro scores of pretransplant donor antibodies that can be assigned to known eplets (donor epitope specific HLA antibodies [DESAs]) were compared between early graft failure and long surviving deceased donor transplants. We did not observe a significant Ellipro score difference between the two cohorts, nor significant differences in graft survival between transplants with DESAs having high versus low total Ellipro scores. We conclude that Ellipro scores cannot be used to identify DESAs associated with early versus late kidney graft loss in deceased donor transplants., (© 2023 The Authors. HLA: Immune Response Genetics published by John Wiley & Sons Ltd.)

In kidney transplantation, survival rates are still partly impaired due to the deleterious effects of donor specific HLA antibodies (DSA). However, not all luminex-defined DSA appear to be clinically relevant. Further analysis of DSA recognizing polymorphic amino acid configurations, called eplets or functional epitopes, might improve the discrimination between clinically relevant vs. irrelevant HLA antibodies. To evaluate which donor epitope-specific HLA antibodies (DESAs) are clinically important in kidney graft survival, relevant and irrelevant DESAs were discerned in a Dutch cohort of 4690 patients using Kaplan-Meier analysis and tested in a cox proportional hazard (CPH) model including nonimmunological variables. Pre-transplant DESAs were detected in 439 patients (9.4%). The presence of certain clinically relevant DESAs was significantly associated with increased risk on graft loss in deceased donor transplantations (p < 0.0001). The antibodies recognized six epitopes of HLA Class I, 3 of HLA-DR, and 1 of HLA-DQ, and most antibodies were directed to HLA-B (47%). Fifty-three patients (69.7%) had DESA against one donor epitope (range 1-5). Long-term graft survival rate in patients with clinically relevant DESA was 32%, rendering DESA a superior parameter to classical DSA (60%). In the CPH model, the hazard ratio (95% CI) of clinically relevant DESAs was 2.45 (1.84-3.25) in deceased donation, and 2.22 (1.25-3.95) in living donation. In conclusion, the developed model shows the deleterious effect of clinically relevant DESAs on graft outcome which outperformed traditional DSA-based risk analysis on antigen level., (© 2024 The Authors. HLA: Immune Response Genetics published by John Wiley & Sons Ltd.)

Introduction: Transplant clinicians may disagree on whether or not to accept a deceased donor kidney offer. We investigated the interobserver variability between transplant nephrologists regarding organ acceptance and whether the use of a prediction model impacted their decisions., Methods: We developed an observational online survey with 6 real-life cases of deceased donor kidneys offered to a waitlisted recipient. Per case, nephrologists were asked to estimate the risk of adverse outcome and whether they would accept the offer for this patient, or for a patient of their own choice, and how certain they felt. These questions were repeated after revealing the risk of adverse outcome, calculated by a validated prediction model., Results: Sixty Dutch nephrologists completed the survey. The intraclass correlation coefficient of their estimated risk of adverse outcome was poor (0.20, 95% confidence interval [CI] 0.08-0.62). Interobserver agreement of the decision on whether or not to accept the kidney offer was also poor (Fleiss kappa 0.13, 95% CI 0.129-0.130). The acceptance rate before and after providing the outcome of the prediction model was significantly influenced in 2 of 6 cases. Acceptance rates varied considerably among transplant centers., Conclusion: In this study, the estimated risk of adverse outcome and subsequent decision to accept a suboptimal donor kidney varied greatly among transplant nephrologists. The use of a prediction model could influence this decision and may enhance nephrologists' certainty about their decision., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)

Background: Donor-characteristics and donor characteristics-based decision algorithms are being progressively used in the decision process whether or not to accept an available donor kidney graft for transplantation. While this may improve outcomes, the performance characteristics of the algorithms remains moderate. To estimate the impact of donor factors of grafts accepted for transplantation on transplant outcomes, and to test whether implementation of donor-characteristics-based algorithms in clinical decision-making is justified, we applied an instrumental variable analysis to outcomes for kidney donor pairs transplanted in different individuals., Methods: This analysis used (dis)congruent outcomes of kidney donor pairs as an instrument and was based on national transplantation registry data for all donor kidney pairs transplanted in separate individuals in the Netherlands (1990-2018, 2,845 donor pairs), and the United Kingdom (UK, 2000-2018, 11,450 pairs). Incident early graft loss (EGL) was used as the primary discriminatory factor. It was reasoned that a scenario with a dominant impact of donor variables on transplantation outcomes would result in high concordance of EGL in both recipients, whilst dominance of asymmetrical outcomes could indicate a more complex scenario, involving an interaction of donor, procedural and recipient factors., Findings: Incidences of congruent EGL (Netherlands: 1·2%, UK: 0·7%) were slightly lower than the arithmetical (stochastic) incidences, suggesting that once a graft has been accepted for transplantation, donor factors minimally contribute to incident EGL. A long-term impact of donor factors was explored by comparing outcomes for functional grafts from donor pairs with asymmetrical vs. symmetrical outcomes. Recipient survival was similar for both groups, but a slightly compromised graft survival was observed for grafts with asymmetrical outcomes in the UK cohort: (10-years Hazard Ratio for graft loss: 1·18 [1·03-1·35] p<0·018); and 5 years eGFR (48·6 [48·3-49·0] vs. 46·0 [44·5-47·6] ml/min in the symmetrical outcome group, p<0·001)., Interpretation: Our results suggest that donor factors for kidney grafts deemed acceptable for transplantation impact minimally on transplantation outcomes. A strong reliance on donor factors and/or donor-characteristics-based decision algorithms could result in unjustified rejection of grafts. Future efforts to optimize transplant outcomes should focus on a better understanding of the recipient factors underlying transplant outcomes., Funding: None., Competing Interests: The authors have nothing to disclose., (© 2022 The Author(s).)

Background: Informed consent for living kidney donation is paramount, as donors are healthy individuals undergoing surgery for the benefit of others. The informed consent process for living kidney donors is heterogenous, and the question concerns how well they are actually informed. Knowledge assessments, before and after donor education, can form the basis for a standardized informed consent procedure for live kidney donation., Methods: In this prospective, a multicenter national cohort study conducted in all eight kidney transplant centers in The Netherlands, we assessed the current status of the informed consent practice for live donor nephrectomy. All of the potential living kidney donors in the participating centers were invited to participate. They completed a pop quiz during their first outpatient appointment (Cohort A). Living kidney donors completed the same pop quiz upon admission for donor nephrectomy (Cohort B)., Results: In total, 656 pop quizzes were completed (417 in Cohort A, and 239 in Cohort B). The average donor knowledge score was 7.0/25.0 (±3.9, range 0-18) in Cohort A, and 10.5/25.0 (±2.8, range 0-17.5) in Cohort B. Cohort B scored significantly higher on overall knowledge, preparedness, and the individual item scores ( p < 0.0001), except for the long-term complications ( p = 0.91)., Conclusions: Donor knowledge generally improves during the live donor workup, but it is still quite disappointing. Long-term complications, especially, deserve more attention during living kidney donor education.

Kidney transplant candidates are blood group incompatible with roughly one out of three potential living donors. We compared outcomes after ABO-incompatible (ABOi) kidney transplantation with matched ABO-compatible (ABOc) living and deceased donor transplantation and analyzed different induction regimens. We performed a retrospective study with propensity matching and compared patient and death-censored graft survival after ABOi versus ABOc living donor and deceased donor kidney transplantation in a nationwide registry from 2006 till 2019. 296 ABOi were compared with 1184 center and propensity-matched ABOc living donor and 1184 deceased donor recipients (matching: recipient age, sex, blood group, and PRA). Patient survival was better compared with deceased donor [hazard ratio (HR) for death of HR 0.69 (0.49-0.96)] and non-significantly different from ABOc living donor recipients [HR 1.28 (0.90-1.81)]. Rate of graft failure was higher compared with ABOc living donor transplantation [HR 2.63 (1.72-4.01)]. Rejection occurred in 47% of 140 rituximab versus 22% of 50 rituximab/basiliximab, and 4% of 92 alemtuzumab-treated recipients (P < 0.001). ABOi kidney transplantation is superior to deceased donor transplantation. Rejection rate and graft failure are higher compared with matched ABOc living donor transplantation, underscoring the need for further studies into risk stratification and induction therapy [NTR7587, www.trialregister.nl]., (© 2021 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.)

CD4 + T-helper cells play an important role in alloimmune reactions following transplantation by stimulating humoral as well as cellular responses, which might lead to failure of the allograft. CD4 + memory T-helper cells from a previous immunizing event can potentially be reactivated by exposure to HLA mismatches that share T-cell epitopes with the initial immunizing HLA. Consequently, reactivity of CD4 + memory T-helper cells toward T-cell epitopes that are shared between immunizing HLA and donor HLA could increase the risk of alloimmunity following transplantation, thus affecting transplant outcome. In this study, the amount of T-cell epitopes shared between immunizing and donor HLA was used as a surrogate marker to evaluate the effect of donor-reactive CD4 + memory T-helper cells on the 10-year risk of death-censored kidney graft failure in 190 donor/recipient combinations using the PIRCHE-II algorithm. The T-cell epitopes of the initial theoretical immunizing HLA and the donor HLA were estimated and the number of shared PIRCHE-II epitopes was calculated. We show that the natural logarithm-transformed PIRCHE-II overlap score, or Shared T-cell EPitopes (STEP) score, significantly associates with the 10-year risk of death-censored kidney graft failure, suggesting that the presence of pre-transplant donor-reactive CD4 + memory T-helper cells might be a strong indicator for the risk of graft failure following kidney transplantation., Competing Interests: The authors of this manuscript have conflicts of interest to disclose. The UMC Utrecht has filed a patent application on the prediction of an alloimmune response against mismatched HLA. ES is listed as inventor on this patent. MN is employed by PIRCHE AG, which publishes the PIRCHE web-portal. 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 © 2021 Peereboom, Matern, Tomosugi, Niemann, Drylewicz, Joosten, Allebes, van der Meer, Hilbrands, Baas, van Reekum, Verhaar, Kamburova, Seelen, Sanders, Hepkema, Lambeck, Bungener, Roozendaal, Tilanus, Voorter, Wieten, van Duijnhoven, Gelens, Christiaans, van Ittersum, Nurmohamed, Lardy, Swelsen, van der Pant, van der Weerd, ten Berge, Bemelman, de Vries, de Fijter, Betjes, Roelen, Claas, Otten, Heidt, van Zuilen, Kobayashi, Geneugelijk and Spierings.)

The use of kidneys donated after circulatory death (DCD) remains controversial due to concerns with regard to high incidences of early graft loss, delayed graft function (DGF), and impaired graft survival. As these concerns are mainly based on data from historical cohorts, they are prone to time-related effects and may therefore not apply to the current timeframe. To assess the impact of time on outcomes, we performed a time-dependent comparative analysis of outcomes of DCD and donation after brain death (DBD) kidney transplantations. Data of all 11,415 deceased-donor kidney transplantations performed in The Netherlands between 1990-2018 were collected. Based on the incidences of early graft loss, two eras were defined (1998-2008 [n = 3,499] and 2008-2018 [n = 3,781]), and potential time-related effects on outcomes evaluated. Multivariate analyses were applied to examine associations between donor type and outcomes. Interaction tests were used to explore presence of effect modification. Results show clear time-related effects on posttransplant outcomes. The 1998-2008 interval showed compromised outcomes for DCD procedures (higher incidences of DGF and early graft loss, impaired 1-year renal function, and inferior graft survival), whereas DBD and DCD outcome equivalence was observed for the 2008-2018 interval. This occurred despite persistently high incidences of DGF in DCD grafts, and more adverse recipient and donor risk profiles (recipients were 6 years older and the KDRI increased from 1.23 to 1.39 and from 1.35 to 1.49 for DBD and DCD donors). In contrast, the median cold ischaemic period decreased from 20 to 15 hours. This national study shows major improvements in outcomes of transplanted DCD kidneys over time. The time-dependent shift underpins that kidney transplantation has come of age and DCD results are nowadays comparable to DBD transplants. It also calls for careful interpretation of conclusions based on historical cohorts, and emphasises that retrospective studies should correct for time-related effects., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Tacrolimus has a narrow therapeutic window. Measuring trough level (C 0 ) as surrogate for drug exposure (AUC) in renal transplant recipients has limitations. Therefore, limited sampling strategies (LSS's) have been developed. For the newer modified release, once-daily formulation (Tac QD) LSS's are based on either linear regression analysis (LRA) or population pharmacokinetics with maximum a posteriori Bayesian (MAPB) estimation. The predictive performances of both methods were compared, also to LSS's as described in literature., Methods: LSS's (maximally three sampling time points) were developed for Tac QD from full 24-h sampling by LRA in 27 Caucasian, stable renal transplant recipients. Performance for accuracy (mean absolute prediction error < 10%) and precision (root mean squared error < 15%) was quantified also after MAPB estimation in two independent groups (early and late post-transplant, n = 12 each)., Results: LRA determined a single 8 hours post-dose measurement (C 8 ) to fulfil predefined criteria for accuracy (MAPE 3.41%) and precision (RMSE 4.28%). The best LSS contained C 2 , C 8 and C 12 for the stable (MAPE 2.42%, RMSE 3.1%) and the early post-transplant group (MAPE 2.46%, RMSE 3.14%). LRA did not include C 0 for any LSS, unless it was forced into the model. MAPB estimation showed similar performance., Conclusions: In renal transplant patients, sampling in the elimination phase (C 8 ) accurately predicted Tac QD exposure, contrary to C 0 . The 3-point sampling C 2, C 8 and C 12 had the best performance and is also valid early post-transplant. These LSS's were similarly predictive with MAPB estimation. Dried blood spot could facilitate late sampling in clinical practice.

The objectives of this study were to assess long-term graft survival, patient survival, renal function, and acute rejections in de novo kidney transplant recipients, treated with once-daily prolonged-release tacrolimus-based therapy. The study was a 5-year non-interventional prospective follow-up of patients from the ADHERE study, a Phase IV 12-month open-label assessment of patients randomized to receive prolonged-release tacrolimus in combination with mycophenolate mofetil (MMF) (Arm 1) or sirolimus (Arm 2). From 838 patients in the randomized study, 587 were included in the long-term follow-up, of whom 510 completed the study at year 5. At 1 year post-transplant, graft and patient survival rates were 93.0% and 97.8%, respectively, and at 5 years were 84.0% and 90.8%, respectively. Cox proportional hazards analysis showed no association between graft loss, initial randomized treatment arm, donor age, donor type, or sex. The 5-year acute rejection-free survival rate was 77.4%, and biopsy-confirmed acute rejection-free survival rate was 86.0%. Renal function remained stable over the follow-up period: mean ± SD eGFR 4-variable modification diet in renal disease formula (MDRD4) was 52.3 ± 21.6 ml/min/1.73 m 2 at 6 months and 52.5 ± 23.0 ml/min/1.73 m 2 at 5 years post-transplant. These findings support the role of long-term once-daily prolonged-release tacrolimus-based immunosuppression, in combination with sirolimus or MMF, for renal transplant recipients in routine clinical practice., (© 2019 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.)

The clinical significance of non-HLA antibodies on renal allograft survival is a matter of debate, due to differences in reported results and lack of large-scale studies incorporating analysis of multiple non-HLA antibodies simultaneously. We developed a multiplex non-HLA antibody assay against 14 proteins highly expressed in the kidney. In this study, the presence of pretransplant non-HLA antibodies was correlated to renal allograft survival in a nationwide cohort of 4770 recipients transplanted between 1995 and 2006. Autoantibodies against Rho GDP-dissociation inhibitor 2 (ARHGDIB) were significantly associated with graft loss in recipients transplanted with a deceased-donor kidney (N = 3276) but not in recipients of a living-donor kidney (N = 1496). At 10 years after deceased-donor transplantation, recipients with anti-ARHGDIB antibodies (94/3276 = 2.9%) had a 13% lower death-censored covariate-adjusted graft survival compared to the anti-ARHGDIB-negative (3182/3276 = 97.1%) population (hazard ratio 1.82; 95% confidence interval, 1.32-2.53; P = .0003). These antibodies occur independently from donor-specific anti-HLA antibodies (DSA) or other non-HLA antibodies investigated. No significant relations with graft loss were found for the other 13 non-HLA antibodies. We suggest that pretransplant risk assessment can be improved by measuring anti-ARHGDIB antibodies in all patients awaiting deceased-donor transplantation., (© 2019 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Whereas regular allocation avoids unacceptable mismatches on the donor organ, allocation to highly sensitized patients within the Eurotransplant Acceptable Mismatch (AM) program is based on the patient's HLA phenotype plus acceptable antigens. These are HLA antigens to which the patient never made antibodies, as determined by extensive laboratory testing. AM patients have superior long-term graft survival compared with highly sensitized patients in regular allocation. Here, we questioned whether the AM program also results in lower rejection rates. From the PROCARE cohort, consisting of all Dutch kidney transplants in 1995-2005, we selected deceased donor single transplants with a minimum of 1 HLA mismatch and determined the cumulative 6-month rejection incidence for patients in AM or regular allocation. Additionally, we determined the effect of minimal matching criteria of 1 HLA-B plus 1 HLA-DR, or 2 HLA-DR antigens on rejection incidence. AM patients showed significantly lower rejection rates than highly immunized patients in regular allocation, comparable to nonsensitized patients, independent of other risk factors for rejection. In contrast to highly sensitized patients in regular allocation, minimal matching criteria did not affect rejection rates in AM patients. Allocation based on acceptable antigens leads to relatively low-risk transplants for highly sensitized patients with rejection rates similar to those of nonimmunized individuals., (© 2019 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Introduction: End-stage renal disease (ESRD) strongly associates with cardiovascular disease (CVD) risk. This risk is not completely mitigated by renal replacement therapy. Endothelial dysfunction (ED) and low-grade inflammation (LGI) may contribute to the increased CVD risk. However, data on serum biomarkers of ED and LGI during the transition to renal replacement therapy (dialysis and kidney transplantation) are scarce., Methods: We compared serum biomarkers of ED and LGI between 36 controls, 43 participants with chronic kidney disease (CKD) stage 5 non-dialysis (CKD5-ND), 20 participants with CKD stage 5 hemodialysis (CKD5-HD) and 14 participants with CKD stage 5 peritoneal dialysis (CKD5-PD). Further, in 34 and 15 participants repeated measurements were available during the first six months following dialysis initiation and kidney transplantation, respectively. Serum biomarkers of ED (sVCAM-1, E-selectin, P-selectin, thrombomodulin, sICAM-1, sICAM-3) and LGI (hs-CRP, SAA, IL-6, IL-8, TNF-α) were measured with a single- or multiplex array detection system based on electro-chemiluminescence technology., Results: In linear regression analyses adjusted for potential confounders, participants with ESRD had higher levels of most serum biomarkers of ED and LGI than controls. In addition, in CKD5-HD levels of serum biomarkers of ED and LGI were largely similar to those in CKD5-ND. In contrast, in CKD5-PD levels of biomarkers of ED were higher than in CKD5-ND and CKD5-HD. Similarly, in linear mixed model analyses sVCAM-1, thrombomodulin, sICAM-1 and sICAM-3 increased after PD initiation. In contrast, incident HD patients showed an increase in sVCAM-1, P-selectin and TNF-α, but a decline of hs-CRP, SAA and IL-6. Further, following kidney transplantation sVCAM-1, thrombomodulin, sICAM-3 and TNF-α were lower at three months post-transplantation and remained stable in the three months thereafter., Conclusions: Levels of serum biomarkers of ED and LGI were higher in ESRD as compared with controls. In addition, PD initiation and, less convincingly, HD initiation may increase levels of selected serum biomarkers of ED and LGI on top of uremia per se. In contrast to dialysis, several serum biomarkers of ED and LGI markedly declined following kidney transplantation., Competing Interests: The studies included in this article were supported by an unrestricted grant from Fresenius Medical Care Deutschland GmbH (study NL33129.068.10 and NL43381.068.13), a Baxter International extramural grant (study NL35039.068.10; grant reference number 11CECHHDEU1004) and the Dutch Kidney Foundation (study NL35039.068.10; grant reference number SB166). BC and AG, who are employees of Fresenius Medical Care and hold shares in the company, reviewed the manuscript. However, the funding sources had no role in the preparation or analysis of data, and the decision to publish. In addition, RJHM, NJHB and JPK are supported by an (un)restricted grant from Fresenius Medical Care. RJHM and NJHB received lectures fees from Fresenius Medical Care. MHC reports Astellas Travel support grants to visit the international conferences ESOT 2017 and TTS 2018. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: End-stage renal disease (ESRD) is strongly associated with cardiovascular disease (CVD) risk. Advanced glycation endproducts (AGEs) and dicarbonyls, major precursors of AGEs, may contribute to the pathophysiology of CVD in ESRD. However, detailed data on the courses of AGEs and dicarbonyls during the transition of ESRD patients to renal replacement therapy are lacking., Methods: We quantified an extensive panel of free and protein-bound serum AGEs [ N ∈ -(carboxymethyl)lysine (CML), N ∈ -(carboxyethyl)lysine (CEL), N δ -(5-hydro-5-methyl-4-imidazolon-2-yl)ornithine (MG-H1)], serum dicarbonyls [glyoxal (GO), methylglyoxal (MGO), 3-deoxyglucosone (3-DG)] and tissue AGE accumulation [estimated by skin autofluorescence (SAF)] in a combined cross-sectional and longitudinal observational study of patients with ESRD transitioning to dialysis or kidney transplantation (KTx), prevalent dialysis patients and healthy controls. Cross-sectional comparisons were performed with linear regression analyses, and courses following renal replacement therapy were analysed with linear mixed models., Results: Free and protein-bound AGEs, dicarbonyls and SAF were higher in chronic kidney disease (CKD) Stage 5 non-dialysis (CKD 5-ND; n = 52) and CKD Stage 5 dialysis (CKD 5-D; n = 35) than in controls ( n  = 42). In addition, free AGEs, protein-bound CML, GO and SAF were even higher in CKD 5-D than in CKD5-ND. Similarly, following dialysis initiation ( n  = 43) free and protein-bound AGEs, and GO increased, whereas SAF remained similar. In contrast, following KTx ( n  = 21), free and protein-bound AGEs and dicarbonyls, but not SAF, markedly declined., Conclusions: AGEs and dicarbonyls accumulate in uraemia, which is even exaggerated by dialysis initiation. In contrast, KTx markedly reduces AGEs and dicarbonyls. Given their associations with CVD risk in high-risk populations, lowering AGE and dicarbonyl levels may be valuable., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: Cardiovascular disease (CVD) related mortality and morbidity are high in end-stage renal disease (ESRD). The pathophysiology of CVD in ESRD may involve non-traditional CVD risk factors, such as accumulation of advanced glycation endproducts (AGEs), dicarbonyls, endothelial dysfunction (ED) and low-grade inflammation (LGI). However, detailed data on the relation of AGEs and dicarbonyls with ED and LGI in ESRD are limited., Methods: We examined cross-sectional Spearman's rank correlations of AGEs and dicarbonyls with serum biomarkers of ED and LGI in 43 individuals with chronic kidney disease (CKD) stage 5 not on dialysis (CKD5-ND). Free and protein-bound serum AGEs (N∈-(carboxymethyl)lysine (CML), N∈-(carboxyethyl)lysine (CEL), Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)ornithine (MG-H1)) and serum dicarbonyls (glyoxal, methylglyoxal, 3-deoxyglucosone) were analyzed with tandem mass spectrometry, and tissue AGE accumulation was estimated by skin autofluorescence (SAF). Further, serum biomarkers of ED and LGI included sVCAM-1, sE-selectin, sP-selectin, sThrombomodulin, sICAM-1, sICAM-3, hs-CRP, SAA, IL-6, IL-8 and TNF-α., Results: After adjustment for age, sex and diabetes status, protein-bound CML was positively correlated with sVCAM-1; free CEL with sVCAM-1 and sThrombomodulin; glyoxal with sThrombomodulin; and methylglyoxal with sVCAM-1 (correlation coefficients ranged from 0.36 to 0.44). In addition, free CML was positively correlated with SAA; protein-bound CML with IL-6; free CEL with hs-CRP, SAA and IL-6; free MG-H1 with SAA; protein-bound MG-H1 with IL-6; and MGO with hs-CRP and IL-6 (correlation coefficients ranged from 0.33 to 0.38). Additional adjustment for eGFR attenuated partial correlations of serum AGEs and serum dicarbonyls with biomarkers of ED and LGI., Conclusions: In individuals with CKD5-ND, higher levels of serum AGEs and serum dicarbonyls were related to biomarkers of ED and LGI after adjustment for age, sex and diabetes mellitus. Correlations were attenuated by eGFR, suggesting that eGFR confounds and/or mediates the relation of serum AGEs and dicarbonyls with ED and LGI., Competing Interests: The studies included in this article were supported by an unrestricted grant from Fresenius Medical Care Deutschland GmbH to JPK (study NL33129.068.10 and NL43381.068.13), a Baxter International extramural grant (study NL35039.068.10; grant reference number 11CECHHDEU1004 to TC) and the Dutch Kidney Foundation (study NL35039.068.10; grant reference number SB166 to TC). BC and AG, who are employees of Fresenius Medical Care, reviewed the manuscript. However, the funding sources had no role in the preparation or analysis of data, and the decision to publish. In addition, RJHM, NJHB and JPK are supported by an (un)restricted grant from Fresenius Medical Care. RJHM and NJHB received lectures fees from Fresenius Medical Care. MHLC reports Astellas Travel support grants to visit the international conferences ESOT 2017 and TTS 2018. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Few studies have evaluated the effect of different immunosuppressive strategies on long-term kidney transplant outcomes. Moreover, as they were usually based on historical data, it was not possible to account for the presence of pretransplant donor-specific human-leukocyte antigen antibodies (DSA), a currently recognized risk marker for impaired graft survival. The aim of this study was to evaluate to what extent frequently used initial immunosuppressive therapies increase graft survival in immunological low-risk patients., Methods: We performed an analysis on the PROCARE cohort, a Dutch multicentre study including all transplantations performed in the Netherlands between 1995 and 2005 with available pretransplant serum (n = 4724). All sera were assessed for the presence of DSA by a luminex single-antigen bead assay. Patients with a previous kidney transplantation, pretransplant DSA or receiving induction therapy were excluded from the analysis., Results: Three regimes were used in over 200 patients: cyclosporine (CsA)/prednisolone (Pred) (n = 542), CsA/mycophenolate mofetil (MMF)/Pred (n = 857) and tacrolimus (TAC)/MMF/Pred (n = 811). Covariate-adjusted analysis revealed no significant differences in 10-year death-censored graft survival between patients on TAC/MMF/Pred therapy (79%) compared with patients on CsA/MMF/Pred (82%, P = 0.88) or CsA/Pred (79%, P = 0.21). However, 1-year rejection-free survival censored for death and failure unrelated to rejection was significantly higher for TAC/MMF/Pred (81%) when compared with CsA/MMF/Pred (67%, P < 0.0001) and CsA/Pred (64%, P < 0.0001)., Conclusion: These results suggest that in immunological low-risk patients excellent long-term kidney graft survival can be achieved irrespective of the type of initial immunosuppressive therapy (CsA or TAC; with or without MMF), despite differences in 1-year rejection-free survival., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Pre-transplant donor-specific anti-human leucocyte antigen (HLA) antibodies (DSAs) are associated with impaired kidney graft survival while the clinical relevance of non-donor-specific anti-HLA antibodies (nDSAs) is more controversial. The aim of the present paired kidney graft study was to compare the clinical relevance of DSAs and nDSAs., Methods: To eliminate donor and era-dependent factors, a post hoc paired kidney graft analysis was performed as part of a Dutch multicentre study evaluating all transplantations between 1995 and 2005 with available pre-transplant serum samples. Anti-HLA antibodies were detected with a Luminex single-antigen bead assay., Results: Among 3237 deceased donor transplantations, we identified 115 recipient pairs receiving a kidney from the same donor with one recipient being DSA positive and the other without anti-HLA antibodies. Patients with pre-transplant DSAs had a significantly lower 10-year death-censored graft survival (55% versus 82%, P=0.0001). We identified 192 pairs with one recipient as nDSA positive (against Class I and/or II) and the other without anti-HLA antibodies. For the patients with nDSAs against either Class I or II, graft survival did not significantly differ compared with patients without anti-HLA antibodies (74% versus 77%, P = 0.79). Only in patients with both nDSAs Class I and II was there a trend towards a lower graft survival (58%, P = 0.06). Lastly, in a small group of 42 recipient pairs, 10-year graft survival in recipients with DSAs was 49% compared with 68% in recipients with nDSAs (P=0.11)., Conclusion: This paired kidney analysis confirms that the presence of pre-transplant DSAs in deceased donor transplantations is a risk marker for graft loss, whereas nDSAs in general are not associated with a lower graft survival. Subgroup analysis indicated that only in broadly sensitized patients with nDSAs against Class I and II, nDSAs may be a risk marker for graft loss in the long term., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: There is no consensus in the literature on the interpretation of single-antigen bead positive for a specific HLA antibody., Methods: To inform the debate, we studied the relationship between various single-antigen bead positivity algorithms and the impact of resulting donor-specific HLA antibody (DSA) positivity on long-term kidney graft survival in 3237 deceased-donor transplants., Results: First, we showed that the interassay variability can be greatly reduced when working with signal-to-background ratios instead of absolute median fluorescence intensities (MFIs). Next, we determined pretransplant DSA using various MFI cutoffs, signal-to-background ratios, and combinations thereof. The impact of the various cutoffs was studied by comparing the graft survival between the DSA-positive and DSA-negative groups. We did not observe a strong impact of various cutoff levels on 10-year graft survival. A stronger relationship between the cutoff level and 1-year graft survival for DSA-positive transplants was found when using signal-to-background ratios, most pronounced for the bead of the same HLA locus with lowest MFI taken as background., Conclusions: With respect to pretransplant risk stratification, we propose a signal-to-background ratio-6 (using the bead of the same HLA-locus with lowest MFI as background) cutoff of 15 combined with an MFI cutoff of 500, resulting in 8% and 21% lower 1- and 10-year graft survivals, respectively, for 8% DSA-positive transplants.

Background: Prospective studies combining physical functioning (PF), physical activity (PA), and body composition (BC) after living donor transplantation/donation are scarce. We aimed to study differences in these parameters between kidney transplant recipients and their living donors by examining changes in these parameters in the first post-operative year in both groups., Methods: Twenty-two kidney transplant recipients and 22 healthy kidney donors were included in this prospective longitudinal study with a follow-up until twelve months. PF was assessed by handgrip strength (HGS), and by the physical domains of health-related quality of life (HRQOL) using the Short Form-36 questionnaire [PF (SF-36 PF) and physical component summary (PCS) score]. BC was measured by the Body Composition Monitor©, and PA was measured by the SenseWear™ pro3., Results: At baseline, recipients had significantly lower HGS (after adjustment for sex and body weight), SF-36 PF, PCS, and PA, as compared with their donors. In recipients HGS significantly increased in the first year after transplantation, but PA did not change in the first six months after transplantation. Furthermore, no significant increase in lean tissue mass was observed. For healthy donors no significant changes in these parameters were observed, with exception of SF-36 PF, which declined in the first three months after donation, but equaled baseline values after twelve months., Conclusion: Recipients showed impressive improvements in PF and the physical domains of HRQOL in the first year after transplantation, reaching levels of healthy kidney donors already three to six months after transplantation. On the contrary, living kidney donation did not show any deterioration of the investigated parameters, supporting little impact for well-screened donors, while there is high benefit for transplant recipients.

The best treatment for patients with end-stage renal disease is kidney transplantation. Although graft survival rates have improved in the last decades, patients still may lose their grafts partly due to the detrimental effects of donor-specific antibodies (DSA) against human leukocyte antigens (HLA) and to a lesser extent also by antibodies directed against non-HLA antigens expressed on the donor endothelium. Assays to detect anti-HLA antibodies are already in use for many years and have been proven useful for transplant risk stratification. Currently, there is a need for assays to additionally detect multiple non-HLA antibodies simultaneously in order to study their clinical relevance in solid organ transplantation. This study describes the development, technical details and validation of a high-throughput multiplex assay for the detection of antibodies against 14 non-HLA antigens coupled directly to MagPlex microspheres or indirectly via a HaloTag. The non-HLA antigens have been selected based on a literature search in patients with kidney disease or following transplantation. Due to the flexibility of the assay, this approach can be used to include alternative antigens and can also be used for screening of other organ transplant recipients, such as heart and lung.

Background: Despite growing waiting lists for renal transplants, hesitations persist with regard to the use of deceased after cardiac death (DCD) renal grafts. We evaluated the outcomes of DCD donations in The Netherlands, the country with the highest proportion of DCD procedures (42.9%) to test whether these hesitations are justified., Methods: This study included all procedures with grafts donated after brain death (DBD) (n = 3611) and cardiac death (n = 2711) performed between 2000 and 2017. Transplant outcomes were compared by Kaplan Meier and Cox regression analysis, and factors associated with short (within 90 days of transplantation) and long-term graft loss evaluated in multi-variable analyses., Findings: Despite higher incidences of early graft loss (+ 50%) and delayed graft function (+ 250%) in DCD grafts, 10-year graft and recipient survival were similar for the two graft types (Combined 10-year graft survival: 73.9% (95% CI: 72.5-75.2), combined recipient survival: 64.5% (95 CI: 63.0-66.0%)). Long-term outcome equivalence was explained by a reduced impact of delayed graft function on DCD graft survival (RR: 0.69 (95% CI: 0.55-0.87), p < 0.001). Mid and long-term graft function (eGFR), and the impact of incident delayed graft function on eGFR were similar for DBD and DCD grafts., Interpretation: Mid and long term outcomes for DCD grafts are equivalent to DBD kidneys. Poorer short term outcomes are offset by a lesser impact of delayed graft function on DCD graft survival. This nation-wide evaluation does not justify the reluctance to use of DCD renal grafts. A strong focus on short-term outcome neglects the superior recovery potential of DCD grafts.

Human leukocyte antigen (HLA)-DRB3 is a functional HLA class II gene, which has a limited allele diversity in the human population. Furthermore, the HLA-DRB3 gene is only present in a subset of individuals. Therefore, in organ transplantation, this HLA molecule is frequently mismatched between patient and graft donor and thus antibodies against this mismatched HLA molecule can develop. In this study, we aimed to evaluate the prevalence and reactivity of these antibodies and aimed to identify factors that underlie antibody formation against HLA-DRB3. We showed in our patient cohort that HLA-DRB3 antibodies are identified in about 7% of all patients that were screened with solid phase assays. In these assays, we observed multiple antibody reactivity patterns indicating that HLA-DRB3 harbours multiple epitopes. In those cases, where we succeeded at tracing back the induction of these antibodies to the molecular HLA typing of the immunogenic event, we noticed a different frequency of HLA-DRB1 allele groups in the donors as compared to a control group. To a certain extent this distribution (e.g. HLA-DRB1*11 individuals) could be linked to an altered expression level. However, it also appears that different HLA-DRB3 alleles (e.g. HLA-DRB3*01 group) vary in their immunogenicity without having an expression difference. In conclusion, our study provides information on the immunogenicity and reactivity patterns of antibodies against HLA-DRB3 in kidney transplantation, and it points towards the possibility of HLA expression as a factor underlying antibody formation., Competing Interests: Gerard M.J. Bos is CEO of CiMaas BV, Maastricht, a start-up/spin-off company of Maastricht University. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

The presence of donor-specific anti-HLA antibodies (DSAs) is associated with increased risk of graft failure after kidney transplant. We hypothesized that DSAs against HLA class I, class II, or both classes indicate a different risk for graft loss between deceased and living donor transplant. In this study, we investigated the impact of pretransplant DSAs, by using single antigen bead assays, on long-term graft survival in 3237 deceased and 1487 living donor kidney transplants with a negative complement-dependent crossmatch. In living donor transplants, we found a limited effect on graft survival of DSAs against class I or II antigens after transplant. Class I and II DSAs combined resulted in decreased 10-year graft survival (84% to 75%). In contrast, after deceased donor transplant, patients with class I or class II DSAs had a 10-year graft survival of 59% and 60%, respectively, both significantly lower than the survival for patients without DSAs (76%). The combination of class I and II DSAs resulted in a 10-year survival of 54% in deceased donor transplants. In conclusion, class I and II DSAs are a clear risk factor for graft loss in deceased donor transplants, while in living donor transplants, class I and II DSAs seem to be associated with an increased risk for graft failure, but this could not be assessed due to their low prevalence., (© 2018 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Tacrolimus, a drug for prevention of rejection after kidney transplantation, has a narrow therapeutic window and is metabolized by the cytochrome P540 3A (CYP3A) system. Tacrolimus exposure increases after steroid tapering in many patients. The pregnane X receptor (PXR)-a mediator for CYP3A-has a steroid receptor and might regulate CYP3A5 activity depending on single nucleotide polymorphisms (SNPs) of CYP3A5 or PXR. This may contribute to differences in tacrolimus exposure after steroid tapering., Methods: In a cohort of renal transplant recipients, the influence of CYP3A5 and PXR SNPs (A7635G, C8055T and C25385T) on the dose-normalized Tacrolimus trough concentration (DnC0) and their potential interaction with each other after steroid taper were analysed by linear regression. Eligible were all 83 outpatient renal transplant patients on tacrolimus and steroids in a pharmacokinetic steady state at least 6 weeks after transplantation and whose blood was available for genetic analysis., Results: Compared with the CYP3A5*1/*3 genotype, the CYP3A5*3/*3 SNP showed a significantly stronger increase in DnC0 after steroid taper (+0.29 µg/L/mg; P = 0.002). Of the tested PXR SNPs, PXR G7635G individuals had a significantly stronger increase in DnC0 (compared with A7635A, +0.31 µg/L/mg; P = 0.02), with a weaker increase in A7635G heterozygotes (+0.17 µg/L/mg; P = 0.124). There was neither interaction nor association between CYP3A5 and PXR SNPs., Conclusions: The magnitude of the DnC0 increase due to steroid taper after renal transplantation is related to CYP3A5 SNPs. Independently, the PXR G7635G SNP is related to this increase, proving the role of PXR in tacrolimus metabolism.

Background Complement-fixing antibodies against donor HLA are considered a contraindication for kidney transplant. A modification of the IgG single-antigen bead (SAB) assay allows detection of anti-HLA antibodies that bind C3d. Because early humoral graft rejection is considered to be complement mediated, this SAB-based technique may provide a valuable tool in the pretransplant risk stratification of kidney transplant recipients. Methods Previously, we established that pretransplant donor-specific anti-HLA antibodies (DSAs) are associated with increased risk for long-term graft failure in complement-dependent cytotoxicity crossmatch-negative transplants. In this study, we further characterized the DSA-positive serum samples using the C3d SAB assay. Results Among 567 pretransplant DSA-positive serum samples, 97 (17%) contained at least one C3d-fixing DSA, whereas 470 (83%) had non-C3d-fixing DSA. At 10 years after transplant, patients with C3d-fixing antibodies had a death-censored, covariate-adjusted graft survival of 60%, whereas patients with non-C3d-fixing DSA had a graft survival of 64% (hazard ratio, 1.02; 95% confidence interval, 0.70 to 1.48 for C3d-fixing DSA compared with non-C3d-fixing DSA; P =0.93). Patients without DSA had a 10-year graft survival of 78%. Conclusions The C3d-fixing ability of pretransplant DSA is not associated with increased risk for graft failure., (Copyright © 2018 by the American Society of Nephrology.)

Individual HLA mismatches may differentially impact graft survival after kidney transplantation. Therefore, there is a need for a reliable tool to define permissible HLA mismatches in kidney transplantation. We previously demonstrated that donor-derived Predicted Indirectly ReCognizable HLA Epitopes presented by recipient HLA class II (PIRCHE-II) play a role in de novo donor-specific HLA antibodies formation after kidney transplantation. In the present Dutch multi-center study, we evaluated the possible association between PIRCHE-II and kidney graft failure in 2,918 donor-recipient couples that were transplanted between 1995 and 2005. For these donors-recipients couples, PIRCHE-II numbers were related to graft survival in univariate and multivariable analyses. Adjusted for confounders, the natural logarithm of PIRCHE-II was associated with a higher risk for graft failure [hazard ratio (HR): 1.13, 95% CI: 1.04-1.23, p  = 0.003]. When analyzing a subgroup of patients who had their first transplantation, the HR of graft failure for ln(PIRCHE-II) was higher compared with the overall cohort (HR: 1.22, 95% CI: 1.10-1.34, p  < 0.001). PIRCHE-II demonstrated both early and late effects on graft failure in this subgroup. These data suggest that the PIRCHE-II may impact graft survival after kidney transplantation. Inclusion of PIRCHE-II in donor-selection criteria may eventually lead to an improved kidney graft survival.

Kidney biopsy can result in bleeding complications. Prebiopsy testing using bleeding time (BT) is controversial. New whole blood haemostasis tests, such as platelet function analyser-100 (PFA-100) and multiple electrode aggregometry (MEA), might perform better. We postulated that PFA-100 would be suitable to replace BT prebiopsy. In 154 patients, transplanted kidney biopsies were performed after measurement of bleeding time, PFA-100, MEA and mean platelet volume (MPV). Bleeding outcome (haemoglobin (Hb) drop, haematuria (±bladder catheterization), ultrasound finding of a bleeding, need for (non)surgical intervention and/or transfusion) after the biopsy was correlated to each test. Male-female ratio was 2:1. 50% had a surveillance biopsy at either three or 12 months. Around 17% (had) used acetylsalicylic acid (ASA) prebiopsy. Of 17 bleeding events, one subject needed a transfusion. Most bleeding events were Hb reductions over 1 mmol/l and all resolved uneventful. BT, PFA-100, MEA and MPV did not predict a bleeding outcome; prior ASA use however could (odds ratio 3.19; 95%-CI 1.06 to 9.61). Diagnostic performance data and Bland-Altman analysis showed that BT could not be substituted by PFA-100. ASA use was the best determinant of bleeding after kidney biopsy. Routine haemostasis testing prebiopsy has no added value., (© 2017 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.)

Background: D antigens are not taken into account in the allocation of solid organs. Female transplant recipients with D antibodies as a consequence of D-mismatched kidney transplantation may develop hemolytic disease of the fetus and newborn in future pregnancies. We examined D antibody development in transplant recipients who received D-mismatched kidney transplantation in absence of D prophylaxis and in a setting of reduced immunosuppression., Study Design and Methods: From 1993 until 2015, a total of 1355 kidney patients received transplantations in our center of whom 156 received a D-mismatched graft. A retrospective analysis was conducted; frozen stored sera obtained from transplant recipients 3 months after transplantation were tested for irregular red blood cell (RBC) antibodies using a three-cell screening and an identification panel. In the case of D antibody positivity, additional testing was performed 1 month before transplantation., Results: In seven of 156 (4.5%) transplant recipients we found irregular RBC antibodies after transplantation, of which five (3.2%) were determined to be D antibodies. We observed only one (0.6%) recipient without D antibodies before transplantation., Conclusion: Although the risk of D antibody development is considerably lower after D-mismatched kidney transplantation than D-mismatched pregnancy, anti-D prophylaxis may still be advisable for female transplant recipients of childbearing age., (© 2017 AABB.)

Background: ADVANCE (NCT01304836) was a phase 4, multicenter, prospectively randomized, open-label, 24-week study comparing the incidence of posttransplantation diabetes mellitus (PTDM) with 2 prolonged-release tacrolimus corticosteroid minimization regimens., Methods: All patients received prolonged-release tacrolimus, basiliximab, mycophenolate mofetil and 1 bolus of intraoperative corticosteroids (0-1000 mg) as per center policy. Patients in arm 1 received tapered corticosteroids, stopped after day 10, whereas patients in arm 2 received no steroids after the intraoperative bolus. The primary efficacy variable was the diagnosis of PTDM as per American Diabetes Association criteria (2010) at any point up to 24 weeks postkidney transplantation. Secondary efficacy variables included incidence of composite efficacy failure (graft loss, biopsy-proven acute rejection or severe graft dysfunction: estimated glomerular filtration rate (Modification of Diet in Renal Disease-4) <30 mL/min per 1.73 m), acute rejection and graft and patient survival., Results: The full-analysis set included 1081 patients (arm 1: n = 528, arm 2: n = 553). Baseline characteristics and mean tacrolimus trough levels were comparable between arms. Week 24 Kaplan-Meier estimates of PTDM were similar for arm 1 versus arm 2 (17.4% vs 16.6%; P = 0.579). Incidence of composite efficacy failure, graft and patient survival, and mean estimated glomerular filtration rate were also comparable between arms. Biopsy-proven acute rejection and acute rejection were significantly higher in arm 2 versus arm 1 (13.6% vs 8.7%, P = 0.006 and 25.9% vs 18.2%, P = 0.001, respectively). Tolerability profiles were comparable between arms., Conclusions: A prolonged-release tacrolimus, basiliximab, and mycophenolate mofetil immunosuppressive regimen is efficacious, with a low incidence of PTDM and a manageable tolerability profile over 24 weeks of treatment. A lower incidence of biopsy-proven acute rejection was seen in patients receiving corticosteroids tapered over 10 days plus an intraoperative corticosteroid bolus versus those receiving an intraoperative bolus only.

Background: Organ shortage persists despite a high rate of donation after circulatory death (DCD) in the Netherlands. The median waiting time for a deceased donor kidney in 2013 was 3.5 years. Most DCD kidneys are from controlled DCD (cDCD; Maastricht category III). Experience with uncontrolled donors after cardiac death (uDCD), that is, donors with an unexpected and irreversible cardiac arrest (Maastricht categories I and II), is increasing; and its effect on transplant outcomes needs evaluation., Methods: We used the Dutch Organ Transplantation Registry to include recipients (≥18 years old) from all Dutch centers who received transplants from 2002 to 2012 with a first DCD kidney. We compared transplant outcome in uDCD (n = 97) and cDCD (n = 1441)., Results: Primary nonfunction in uDCD was higher than in the cDCD (19.6% vs 9.6%, P < 0.001, respectively). Delayed graft function was also higher in uDCD than in cDCD, but not significantly (73.7% vs 63.3%, P = .074, respectively). If censored for primary nonfunction, estimated glomerular filtration rates after 1 year and 5 years were comparable between uDCD and cDCD (1 year: uDCD, 44.3 (23.4) mL/min/m and cDCD, 45.8 (24.1) mL/min/m; P = 0.621; 5 years: uDCD, 49.1 (25.6) mL/min/m and cDCD, 47.7 (21.7) mL/min/m; P = 0.686). The differences in primary nonfunction between kidneys from uDCD and cDCD were explained by differences in the first warm ischemic period, cold ischemic time, and donor age., Conclusions: We conclude that uDCD kidneys have potential for excellent function and can constitute a valuable extension of the donor pool. However, further efforts are necessary to address the high rate of primary nonfunction.

The long-term effects of tacrolimus and cyclosporine on pancreatic islet cell function in renal transplant recipients are unclear. Therefore, a prospective, randomized, longitudinal study was performed that compared glucose metabolism in adult kidney allograft recipients on tacrolimus versus cyclosporine-based immunosuppression. Twenty-three white renal allograft recipients, randomized for either therapy with cyclosporine or tacrolimus, underwent intravenous glucose tolerance tests 6 times during the first 3 yr after transplantation. Concomitant therapy (low-dose steroids and azathioprine) was the same in both groups. Insulin sensitivity index (kG), insulin resistance (insulin/glucose ratio and homeostasis model assessment), and C-peptide and insulin secretion were calculated. Trough levels of tacrolimus and cyclosporine were measured. The occurrence of posttransplantation diabetes mellitus was prospectively monitored. Statistical analysis was performed by ANOVA for repeated measures, and parametric and nonparametric tests were also performed. Although only one patient treated with cyclosporine developed posttransplantation diabetes mellitus, kG levels were below normal in up to one-third of both patients who received tacrolimus and cyclosporine. The only significant difference between patients who received tacrolimus and those who received cyclosporine was in pancreatic secretion capacity at week 3 after transplantation, when the increment of C-peptide secretion was 57% lower and the increment of insulin secretion was 48% lower for patients receiving tacrolimus. In both groups, from week 3 to month 6, there was a tendency toward an increase in kG, despite a significant increase in fasting glucose and insulin resistance calculated by homeostasis model assessment. After month 6, there were no significant changes in any of the parameters of glucose metabolism, indicating that long-term use of either tacrolimus or cyclosporine does not cause chronic, cumulative pancreatic toxicity.

The relative role of steroids and tacrolimus in the development of glucose metabolic disorders and hyperlipidemia after renal transplantation has not yet been clearly established. Therefore, glucose metabolism was prospectively evaluated by intravenous glucose tolerance test, as was lipid profile, in fifteen white nondiabetic renal transplant recipients three times: before and after steroid withdrawal and after tacrolimus trough level reduction. After withdrawal of 10 mg of prednisolone, insulin resistance decreased (fasting C-peptide, 0.99 to 0.77 nmol/L [P < 0.0009]; fasting insulin, 9.5 to 8.1 mU/L [P = 0.09]; insulin/glucose ratio, 1.85 to 1.45 mU/mmol [P = 0.10]) and lipid levels decreased (total cholesterol, 5.1 to 4.2 mmol/L [P = 0.006]); HDL cholesterol, 1.4 to 1.1 mmol/L [P = 0.01]; LDL cholesterol, 3.0 to 2.5 mmol/L [P = 0.15]; triglycerides, 1.52 to 0.91 mmol/L [P = 0.02]). After tacrolimus trough level reduction from 9.5 to 6.4 ng/ml, pancreatic beta-cell secretion capacity improved (C-peptide secretion increased from 49.0 to 66.6 nmol x min/L [P = 0.04] and insulin secretion increased from 1134 to 1403 mU x min/L [P = 0.06]). HbA1c improved also, from 5.9 to 5.3% (P = 0.002). Lipids did not change. In conclusion, steroid withdrawal resulted in a decrease in insulin resistance and a reduction in lipids, and tacrolimus trough level reduction resulted in an improved pancreatic beta-cell secretion capacity. Therefore, these therapeutic measurements may contribute to the reduction of the cardiovascular morbidity and mortality in renal transplant recipients.

Most studies concerning the influence of tacrolimus on glucose metabolism have been performed either in animals or after organ transplantation. These clinical studies have largely been transversal with patients who were using steroids. Therefore, this prospective, longitudinal study investigated the influence of tacrolimus on glucose metabolism before and after transplantation. Eighteen Caucasian dialysis patients underwent an intravenous glucose tolerance test before and 5 d after the start of tacrolimus. Insulin sensitivity index (k(G)), insulin resistance (insulin/glucose ratio and homeostasis model assessment), and C-peptide and insulin secretion were calculated. Trough levels of tacrolimus were measured. After transplantation, the occurrence of posttransplantation diabetes mellitus (PTDM) was prospectively monitored. Statistical analysis was performed using the Wilcoxon signed ranks test and Spearman's rho for correlation. Before tacrolimus, k(G) was indeterminate in three patients. During tacrolimus, k(G) decreased in 16 of 18 patients, from a median of 1.74 mmol/L per min to 1.08 mmol/L per min (P<0.0001). The correlation between C-peptide and insulin data was excellent. Insulin secretion decreased from 851.0 mU x min/L to 558.0 mU x min/L (P = 0.014), whereas insulin resistance did not change. Insulin sensitivity correlated negatively with tacrolimus trough level. After transplantation, three patients developed PTDM; before tacrolimus, two had an indeterminate and one a low normal k(G). During tacrolimus administration, k(G) decreased in almost all patients as a result of a diminished insulin secretion response to a glucose load, whereas insulin resistance did not change. Patients with an abnormal or indeterminate k(G) seem to be at risk of developing PTDM while on tacrolimus.