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Highly sensitized (HS) patients in need of kidney transplantation (KTx) typically spend a longer time waiting for compatible kidneys, are unlikely to receive an organ offer, and are at increased risk of antibody-mediated rejection (AMR). Desensitization using imlifidase, which is more rapid and removes total body immunoglobulin G (IgG) to a greater extent than other methods, enables transplantation to occur between HLA-incompatible (HLAi) donor–recipient pairs and allows patients to have greater access to KTx. However, when the project was launched there was limited data and clinical experience with desensitization in general and with imlifidase specifically. Hence, this Delphi methodology was used to reach a consensus from a multi-disciplinary team (MDT) of experts from 15 countries on the management of HS patients undergoing imlifidase HLAi from a deceased donor (DD) KTx. This Delphi consensus provides clinical practice guidance on the use of imlifidase in the end-to-end management of HS patients undergoing an HLAi DD KTx and supports centers in the development of guidelines for the utilization and integration of imlifidase into clinical practice. [ABSTRACT FROM AUTHOR]

BK polyomavirus‐associated nephropathy (BKPyVAN) is a well‐known complication of kidney transplantation (KTx). The mainstay of prevention is the reduction of immunosuppression upon detection of BK polyomavirus (BKPyV) DNAemia, which precedes BKPyVAN. However, this reduction may inadvertently increase the risk of alloimmunity particularly in patients with a high BKPyV DNA load, where significant immunosuppression reduction is often necessary. This single‐center, retrospective cohort study assesses the risk of de novo donor‐specific antibodies (dnDSA) development and biopsy‐proven acute rejection (BPAR) following high and low BKPyV DNAemia. All patients who underwent KTx at Leiden University Medical Center between 2011 and 2020 were included. Patients were grouped according to high (maximum BKPyV DNA load > 4log10 copies/mL), low (maximum serum BKPyV DNA load ≤ 10E4 copies/mL), and absent BKPyV DNAemia, and analyzed for the development of dnDSA and BPAR, using Cox regression. Of 1076 KTx recipients included, 108 (10%) developed a BKPyV DNAemia with a maximum DNA load below 4log10 copies/mL, whereas 121 (11.2%) developed a BKPyV DNAemia exceeding 4log10 copies/mL. The risk of dnDSA development was higher in patients with a high BKPyV DNAemia, compared to patients without DNAemia (adjusted hazard ratio of 1.9 (95% CI 1.1–3.2, p = 0.017). No significant difference in dnDSA risk was observed between patients with low and absent BKPyV DNAemia. Risk of BPAR did not differ between groups. Our study shows that higher BKPyV DNA loads in KTx patients are associated with a higher risk for dnDSA development, highlighting the importance of exploring additional strategies for the prevention and treatment of BKPyV infections in KTx recipients. [ABSTRACT FROM AUTHOR]

Background: In June 2021, the first robot‐assisted donor nephrectomy (RADN) was performed at the Leiden University Medical Center (LUMC), the Netherlands. The goal of this study was to investigate whether this procedure has been implemented safely and efficiently. Methods: RADN was retrospectively compared to laparoscopic donor nephrectomy (LDN) performed during the same time period (June 2021 until November 2022). Patients were assigned to RADN depending on the availability of the da Vinci robot and surgical team. The studied endpoints were postoperative complications, operative time, estimated blood loss, warm ischemic time (WIT), and postoperative pain experience. For analysis, the Student's t‐test and Chi‐squared test were used for, respectively, continuous and categorical data. Results: Forty RADN were compared to 63 LDN. Total insufflation time was significantly longer in RADN compared to LDN (188 min (169–214) versus 172 min (144–194); p = 0.02). Additionally, WIT was also found to be significantly higher in the robot‐assisted group (04:54 min vs. 04:07 min; p < 0.01). No statistical differences were found in postoperative outcomes (eGFR of the recipient at 3‐month follow‐up, RADN 54.08 mL/min ±18.79 vs. LDN 56.41 mL/min ±16.82; p = 0.52), pain experience, and complication rate. Conclusion: RADN was safely and efficiently implemented at the LUMC. It's results were not inferior to laparoscopic donor nephrectomy. Operative time and warm ischemic times were longer in RADN. This may relate to a learning curve effect. No clinically relevant effect on postoperative outcomes was observed. [ABSTRACT FROM AUTHOR]

The recommended immunosuppressive treatment after kidney transplantation consists of tacrolimus, mycophenolate mofetil, and low‐dose corticosteroids. Drug concentrations are monitored using therapeutic drug monitoring (TDM), which does not necessarily correlate with pharmacodynamic activity. To find the balance between optimal efficacy and minimal toxicity, it might be more informative to monitor patients' immunological status rather than drug concentrations. We selected a panel of T‐cell‐based immune assays, which were used for immunomonitoring of 14 stable kidney transplantation patients. Whole blood was incubated with a T‐cell stimulus, after which T‐cell proliferation, T‐cell activation marker expression and cytokine production were measured to study residual immune activity in vitro (before drug intake; drug added to the incubation) and ex vivo (after drug intake). T‐cell proliferation was completely suppressed in all patients over the full day, while IL‐2, IFN‐γ, CD71, and CD154 showed fluctuations over the day with a strong inhibition (75%–25%) at 2 h post‐dose. The level of inhibition was variable between patients and could not be related to pharmacokinetic parameters or the presence of regulatory or senescence immune cells. Moreover, the level of inhibition did not correlate with the in vitro tacrolimus drug effect as studied by incubating pre‐dose blood samples with additional tacrolimus. Overall, IL‐2, IFN‐γ, CD71, and CD154 seem to be good markers to monitor residual immune activity of transplantation patients. To evaluate the correlation between these pharmacodynamic biomarkers and clinical outcome, prospective observational studies are needed. [ABSTRACT FROM AUTHOR]

BackgroundThe COVID-19 pandemic has markedly affected renal transplant care. During this time of social distancing, limited in-person visits, and uncertainty, patients and donors are relying more than ever on telemedicine and web-based information. Several factors can influence patients’ understanding of web-based information, such as delivery modes (instruction, interaction, and assessment) and social-epistemological dimensions (choices in interactive knowledge building). ObjectiveThe aim of this study was to systemically evaluate the content, delivery modes, and social-epistemological dimensions of web-based information on COVID-19 and renal transplantation at time of the pandemic. MethodsMultiple keyword combinations were used to retrieve websites on COVID-19 and renal transplantation using the search engines Google.com and Google.nl. From 14 different websites, 30 webpages were examined to determine their organizational sources, topics, delivery modes, and social-epistemological dimensions. ResultsThe variety of topics and delivery modes was limited. A total of 13 different delivery modes were encountered, of which 8 (62%) were instructional and 5 (38%) were interactional; no assessment delivery modes were observed. No website offered all available delivery modes. The majority of delivery modes (8/13, 62%) focused on individual and passive learning, whereas group learning and active construction of knowledge were rarely encountered. ConclusionsBy taking interactive knowledge transfer into account, the educational quality of eHealth for transplant care could increase, especially in times of crisis when rapid knowledge transfer is needed.

Healthy individuals with hybrid immunity, due to a SARS-CoV-2 infection prior to first vaccination, have stronger immune responses compared to those who were exclusively vaccinated. However, little is known about the characteristics of antibody, B- and T-cell responses in kidney disease patients with hybrid immunity. Here, we explored differences between kidney disease patients and controls with hybrid immunity after asymptomatic or mild coronavirus disease-2019 (COVID-19). We studied the kinetics, magnitude, breadth and phenotype of SARS-CoV-2-specific immune responses against primary mRNA-1273 vaccination in patients with chronic kidney disease or on dialysis, kidney transplant recipients, and controls with hybrid immunity. Although vaccination alone is less immunogenic in kidney disease patients, mRNA-1273 induced a robust immune response in patients with prior SARS-CoV-2 infection. In contrast, kidney disease patients with hybrid immunity develop SARS-CoV-2 antibody, B- and T-cell responses that are equally strong or stronger than controls. Phenotypic analysis showed that Spike (S)-specific B-cells varied between groups in lymph node-homing and memory phenotypes, yet S-specific T-cell responses were phenotypically consistent across groups. The heterogeneity amongst immune responses in hybrid immune kidney patients warrants further studies in larger cohorts to unravel markers of long-term protection that can be used for the design of targeted vaccine regimens. [ABSTRACT FROM AUTHOR]

The KDIGO guideline for acute rejection treatment recommends use of corticosteroids and suggests using lymphocyte-depleting agents as second line treatment. Aim of the study was to determine the current practices of detection and treatment of TCMR of kidney allografts amongst European kidney transplant centres. An invitation was sent through ESOT/EKITA newsletters and through social media to transplant professionals in Europe for taking part in the survey. A total of 129 transplant professionals responded to the survey. There was equal representation of small and large sized transplant centres. The majority of centres treat borderline changes (BL) and TCMR (Grade IA-B, IIA-B) in indication biopsies and protocol biopsies with corticosteroids as first line treatment. Thymoglobulin is used mainly as second line treatment for TCMR Grade IA-B (80%) and TCMR IIA-B (85%). Treatment success is most often evaluated within one month of therapy. There were no differences observed between the large and small centres for the management of TCMR. This survey highlights the common practices and diversity in clinics for the management of TCMR in Europe. Testing new therapies for TCMR should be in comparison to the current standard of care in Europe. Better consensus on treatment success is crucial for robust study designs. [ABSTRACT FROM AUTHOR]

Kidney transplant recipients (KTRs) elicit an impaired immune response after COVID-19 vaccination; however, the exact clinical impact remains unclear. We therefore analyse the relationship between antibody levels after vaccination and the risk of COVID-19 in a large cohort of KTRs. All KTRs living in the Netherlands were invited to send a blood sample 28 days after their second COVID-19 vaccination for measurement of their IgG antibodies against the receptor-binding domain of the SARS-CoV-2 spike protein (anti-RBD IgG). Information on COVID-19 was collected from the moment the blood sample was obtained until 6 months thereafter. Multivariable Cox and logistic regression analyses were performed to analyse which factors affected the occurrence and severity (i.e., hospitalization and/or death) of COVID-19. In total, 12,159 KTRs were approached, of whom 2885 were included in the analyses. Among those, 1578 (54.7%) became seropositive (i.e., anti-RBD IgG level >50 BAU/mL). Seropositivity was associated with a lower risk for COVID-19, also after adjusting for multiple confounders, including socio-economic status and adherence to COVID-19 restrictions (HR 0.37 (0.19–0.47), p = 0.005). When studied on a continuous scale, we observed a log-linear relationship between antibody level and the risk for COVID-19 (HR 0.52 (0.31–0.89), p = 0.02). Similar results were found for COVID-19 severity. In conclusion, antibody level after COVID-19 vaccination is associated in a log-linear manner with the occurrence and severity of COVID-19 in KTRs. This implies that if future vaccinations are indicated, the aim should be to reach for as high an antibody level as possible and not only seropositivity to protect this vulnerable patient group from disease. [ABSTRACT FROM AUTHOR]

Background: Meltdose tacrolimus (Envarsus®) has been marketed as a formulation achieving a more consistent tacrolimus exposure. Due to the narrow therapeutic window of tacrolimus, dose individualization is essential. Relaxation of the upper age limits for kidney transplantations has resulted in larger numbers of elderly patients receiving tacrolimus. However, due to the physiological changes caused by aging, the tacrolimus pharmacokinetics (PK) might be altered. The primary aim was to develop a population PK model in elderly kidney transplant recipients. Secondary aims were the development and evaluation of a limited sampling strategy (LSS) for AUC estimation. Methods: A total of 34 kidney transplant recipients aged ≥65 years, starting on meltdose tacrolimus directly after transplantation, were included. An eight-point whole blood AUC0–24h and an abbreviated dried blood spot (DBS) AUC0–24h were obtained. The PK data were analyzed using nonlinear mixed effect modeling methods. Results: The PK data were best described using a two-compartment model, including three transit compartments and a mixture model for oral absorption. The best three-sample LSS was T = 0, 2, 6 h. The best four-sample LSSs were T = 0, 2, 6, 8 h and T = 0, 1, 6, 8 h. Conclusions: The developed population PK model adequately described the tacrolimus PK data in a population of elderly kidney transplant recipients. In addition, the developed population PK model and LSS showed an adequate estimation of tacrolimus exposure, and may therefore be used to aid in tacrolimus dose individualization. [ABSTRACT FROM AUTHOR]

Solid phase immunoassays improved the detection and determination of the antigen-specificity of donor-specific antibodies (DSA) to human leukocyte antigens (HLA). The widespread use of SPI in kidney transplantation also introduced new clinical dilemmas, such as whether patients should be monitored for DSA pre- or post-transplantation. Pretransplant screening through SPI has become standard practice and DSA are readily determined in case of suspected rejection. However, DSA monitoring in recipients with stable graft function has not been universally established as standard of care. This may be related to uncertainty regarding the clinical utility of DSA monitoring as a screening tool. This consensus report aims to appraise the clinical utility of DSA monitoring in recipients without overt signs of graft dysfunction, using the Wilson & Junger criteria for assessing the validity of a screening practice. To assess the evidence on DSA monitoring, the European Society for Organ Transplantation (ESOT) convened a dedicated workgroup, comprised of experts in transplantation nephrology and immunology, to review relevant literature. Guidelines and statements were developed during a consensus conference by Delphi methodology that took place in person in November 2022 in Prague. The findings and recommendations of the workgroup on subclinical DSA monitoring are presented in this article. [ABSTRACT FROM AUTHOR]

Evidence to define target ranges for tacrolimus (Tac) and mycophenolic acid (MPA) exposure after the first year of kidney transplantation is limited. We investigated the association of measurements at 1 year and repeated measurements of real‐world Tac‐trough levels (C0) and abbreviated area under the curve from zero to 12 hours (AUC0‐12h) of Tac and MPA with biopsy‐proven acute rejection (BPAR) between years 1 and 3 post‐transplant in 968 kidney transplant recipients (KTRs). Thirty‐five (3.6%) out of 968 KTRs experienced BPAR. Both Tac‐AUC0‐12h (hazard ratio (HR): 0.39, 95% confidence interval (CI): 0.30–0.50, P < 0.001), Tac‐C0 (HR: 0.46, 95% CI: 0.38–0.57, P < 0.001) and MPA‐AUC0‐12h at 1 year (HR: 0.80, 95% CI: 0.68–0.94, P = 0.006), as well as repeated measurements of Tac‐C0 (HR: 0.70, 95% credibility interval (CrI): 0.61–0.82, P < 0.001), and of MPA‐AUC0‐12h (HR: 0.75, 95% CrI: 0.62–0.93, P < 0.001) were associated with BPAR. In our population, the recommended target range for Tac‐AUC0‐12h at 1 year would be 75–95 ng*hour/mL and a Tac‐C0 5–7 ng/mL. The Tac‐AUC0‐12h predicted BPAR better than Tac‐C0 and identified KTRs with over‐ or underexposure despite supposedly adequate Tac‐C0. We did not find evidence to recommend another target than the consensus range of 30–60 mg*hour/L for MPA‐AUC0‐12h after the first year of transplantation. To our knowledge, this is a first study on the simultaneous exposure of Tac and MPA at year 1 and subsequent BPAR up to year 3, which may help define the therapeutic target window for the longer term. [ABSTRACT FROM AUTHOR]

Despite (repeated) boosting, kidney transplant recipients (KTRs) may remain at increased risk of severe COVID‐19 since a substantial number of individuals remain seronegative or with low antibody titers. In particular, mycophenolic acid use has been shown to affect antibody formation negatively and may be an important modifiable risk factor. We investigated the exposure–response relationship between mycophenolic acid 12‐hour area under the curve (AUC0–12h) exposure and seroconversion including antibody titers after vaccination using mRNA‐1273 SARS‐CoV‐2 vaccine (Moderna) in 316 KTRs from our center that participated in the national Dutch renal patients COVID‐19 vaccination – long term efficacy and safety of SARS‐CoV‐2 vaccination in kidney disease patients vaccination study. After two vaccination doses, 162 (51%) KTRs seroconverted. KTRs treated with mycophenolic acid showed less seroconversion and lower antibody titers compared with KTRs without mycophenolic acid (44% vs. 77%, and 36 binding antibody units (BAU)/mL vs. 340 BAU/mL; P < 0.001). The mean mycophenolic acid AUC0–12h exposure was significantly lower in KTRs who seroconverted compared with KTRs who did not (39 vs. 29 mg⋅h/L; P < 0.001). High mycophenolic acid exposure (±90 mg⋅h/L) and no exposure to mycophenolic acid resulted in a seroconversion rate ranging from 10% to 80%. Every 10 mg⋅h/L increase in mycophenolic acid AUC0–12h gave an adjusted odds ratio for seroconversion of 0.87 (95% confidence interval (CI), 0.79–0.97; P = 0.010) and 0.89 (95% CI, 0.85–0.93; P < 0.001) for KTRs on dual and triple maintenance immunosuppressive therapy, respectively. Higher mycophenolic acid AUC0–12h correlated with lower antibody titers (R = 0.44, P < 0.001). This study demonstrates the exposure–response relationship between gold standard mycophenolic acid exposure and antibody formation to support interventional studies investigating mycophenolic acid adjustment to improve antibody formation after further boosting. [ABSTRACT FROM AUTHOR]