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... Show moreIn 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. Show less
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... Show moreIn 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. Show less
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... Show moreKidney 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. Show less
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... Show moreIntroduction: 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, calcu-lated 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. Show less
Cardol, C.K.; Meuleman, Y.; Middendorp, H. van; Boog, P.J. van der; Hilbrands, L.B.; Navis, G.; ... ; E-GOAL Study Grp 2023
Rationale & Objective: Patients with chronic kid-ney disease (CKD) not receiving dialysis, including kidney transplant recipients, often experience diffi-culties regarding self-management. An... Show moreRationale & Objective: Patients with chronic kid-ney disease (CKD) not receiving dialysis, including kidney transplant recipients, often experience diffi-culties regarding self-management. An important barrier for adherence to self-management recommendations may be the presence of psychological distress, consisting of depressive and anxiety symptoms. We investigated relationships between psychological distress and adherence to self-management recommendations. Study Design: Cross-sectional online question-naire data as part of the E-GOAL study. Setting & Participants: Patients with CKD (esti-mated glomerular filtration rate, 20-89 mL/min/ 1.73 m2) were recruited from April 2018 to October 2020 at 4 hospitals in The Netherlands and completed online screening questionnaires. Exposures: Psychological distress, depressive symptoms, and anxiety symptoms. Outcomes: Dietary adherence, physical activity, medication adherence, smoking, body mass index, and a CKD self-management index (ie, the sum of 5 binary indicators of nonadherence to the recommended self-management factors). Analytical Approach: Adjusted multivariable regression and ordinal logistic regression analyses. Results: In our sample (N = 460), 27.2% of pa-tients reported psychological distress, and 69.8% were nonadherent to 1 or more recommendations. Higher psychological distress was significantly associated with poorer dietary adherence (3adj, -0.13; 95% CI, -0.23 to -0.0 4), less phys-ical activity (3adj, -0.13; 95% CI, -0.22 to -0.03), and lower medication adherence (3adj, -0.15; 95% CI, -0.24 to -0.05), but not with smoking and body mass index. Findings were similar for depressive symptoms, whereas anxiety was only associated with poorer dietary and medication adherence. Every 1-point higher psychological distress was also associated with a higher likelihood of being nonadherent to an accumulating number of different recommendations (adjusted OR, 1.04; 95% CI, 1.02-1.07). Limitations: Cross-sectional design, possible re-sidual confounding, and self-report. Conclusions: Many people with CKD experience psychological distress, of whom most have diffi-culties self-managing their CKD. Given the relationship between psychological distress and adherence to CKD self-management recommendations, behavioral interventions are needed to identify and treat psychological distress as a potential barrier to CKD self-management. Show less
Cardol, C.K.; Meuleman, Y.; Middendorp, H. van; Boog, P.J.M. van der; Hilbrands, L.B.; Navis, G.; ... ; Dijk, S. van 2023
Background An urgent need exists to improve the suboptimal COVID-19 vaccine response in kidney transplant recipients (KTRs). We aimed to compare three alternative strategies with a control single... Show moreBackground An urgent need exists to improve the suboptimal COVID-19 vaccine response in kidney transplant recipients (KTRs). We aimed to compare three alternative strategies with a control single dose mRNA-1273 vaccination: a double vaccine dose, heterologous vaccination, and temporary discontinuation of mycophenolate mofetil or mycophenolic acid.Methods This open-label randomised trial, done in four university medical centres in the Netherlands, enrolled KTRs without seroconversion after two or three doses of an mRNA vaccine. Between Oct 20, 2021, and Feb 2, 2022, 230 KTRs were randomly assigned block-wise per centre by a web-based system in a 1:1:1 manner to receive 100 mu g mRNA-1273, 2 x 100 mu g mRNA-1273, or Ad26.COV2-S vaccination. In addition, 103 KTRs receiving 100 mu g mRNA-1273, were randomly assigned 1:1 to continue (mycophenolate mofetil+) or discontinue (mycophenolate mofetil-) mycophenolate mofetil or mycophenolic acid treatment for 2 weeks. The primary outcome was the percentage of participants with a spike protein (S1)-specific IgG concentration of at least 10 binding antibody units per mL at 28 days after vaccination, assessed in all participants who had a baseline measurement and who completed day 28 after vaccination without SARS-CoV-2 infection. Safety was assessed as a secondary outcome in all vaccinated patients by incidence of solicited adverse events, acute rejection or other serious adverse events. This trial is registered with ClinicalTrials.gov, NCT05030974 and is closed.Findings Between April 23, 2021, and July 2, 2021, of 12 158 invited Dutch KTRs, 3828 with a functioning kidney transplant participated in a national survey for antibody measurement after COVID-19 vaccination. Of these patients, 1311 did not seroconvert after their second vaccination and another 761 not even after a third. From these seronegative patients, 345 agreed to participate in our repeated vaccination study. Vaccination with 2 x mRNA-1273 or Ad26.COV2-S was not superior to single mRNA-1273, with seroresponse rates of 49 (68%) of 72 (95% CI 56-79), 46 (63%) of 73 (51-74), and 50 (68%) of 73 (57-79), respectively. The difference with single mRNA-1273 was -0middot4% (-16 to 15; p=0middot96) for 2 x mRNA-1273 and -6% (-21 to 10; p=0middot49) for Ad26.COV2-S. Mycophenolate mofetil- was also not superior to mycophenolate mofetil+, with seroresponse rates of 37 (80%) of 46 (66-91) and 31 (67%) of 46 (52-80), and a difference of 13% (-5 to 31; p=0middot15). Local adverse events were more frequent after a single and double dose of mRNA-1273 than after Ad26.COV2-S (65 [92%] of 71, 67 [92%] of 73, and 38 [50%] of 76, respectively; p<0middot0001). No acute rejection occurred. There were no serious adverse events related to vaccination.Interpretation Repeated vaccination increases SARS-CoV-2-specific antibodies in KTRs, without further enhancement by use of a higher dose, a heterologous vaccine, or 2 weeks discontinuation of mycophenolate mofetil or mycophenolic acid. To achieve a stronger response, possibly required to neutralise new virus variants, repeated booster vaccination is needed.Funding The Netherlands Organization for Health Research and Development and the Dutch Kidney Foundation.Copyright (c) 2022 Elsevier Ltd. All rights reserved. Show less
Cardol, C.K.; Middendorp, H. van; Dusseldorp, E.; Boog, P.J.M. van der; Hilbrands, L.B.; Navis, G.; ... ; E GOAL Study Grp 2023
Objective: Psychological distress is common among patients with chronic kidney disease and can interfere with disease self-management. We assessed the effectiveness of the personalized E-GOAL... Show moreObjective: Psychological distress is common among patients with chronic kidney disease and can interfere with disease self-management. We assessed the effectiveness of the personalized E-GOAL electronic health care pathway with screening and cognitive-behavioral therapy including self-management support, aimed to treat psychological distress and facilitate self-management among people with chronic kidney disease not on dialysis (N = 121). Methods: Primary outcome of the open two-arm parallel randomized controlled trial in four Dutch hospitals was psychological distress at posttest directly after the intervention and at 3-month follow-up. Secondary outcomes were physical and mental health-related quality of life, self-efficacy, chronic disease self-management, and personalized outcomes, that is, perceived progress compared with the previous time point on functioning (e.g., mood or social functioning) and self-management (e.g., dietary or medication adherence) outcomes that were prioritized by each individual. Results: Linear mixed-effects analyses showed no significant time-by-group interaction effects for psychological distress, health-related quality of life, self-efficacy, and chronic condition self-management, whereas analyses of covariance showed significantly more perceived progress in the intervention group at posttest on personally prioritized areas of functioning (b = 0.46, 95% confidence interval = 0.07-0.85) and self-management (b = 0.55, 95% confidence interval = 0.16-0.95), with Cohen d values of 0.46 and 0.54 (medium effects), respectively. Effects on personalized outcomes were maintained at follow-up. Conclusions: Compared with regular care only, the electronic health intervention did not reduce psychological distress, whereas personalized outcomes did improve significantly after intervention. Future studies could consider personalized outcomes that reflect individually relevant areas and treatment goals, matching person-tailored treatments. Show less
Cardol, C.K.; Middendorp, H. van; Dusseldorp, E.M.L.; Boog, P.J.M. van der; Navis, G.; Hilbrands, L.B.; ... ; Dijk, S. van 2022
Introduction Kidney failure negatively affects opportunities for work participation. Little is known about work functioning of employed CKD patients. This study investigates work-related outcomes,... Show moreIntroduction Kidney failure negatively affects opportunities for work participation. Little is known about work functioning of employed CKD patients. This study investigates work-related outcomes, and examines associations between patient characteristics and employment status. Methods We performed a cross-sectional survey study in nine nephrology outpatient clinics in the Netherlands among working age (18-67 years) CKD Stage G3b-G5, dialysis and transplant patients (n = 634; mean age 53.4 years (SD 10); 53% male; 47% Stage G3b-G5, 9% dialysis, 44% transplantation). We assessed employment status, work disability, work-related characteristics (i.e., work situation, working hours, job demands), work functioning (i.e., perceived ability to work, productivity loss, limitations in work), work environment (i.e., work accommodations, psychosocial work environment), as well as health status and fatigue. Results Sixty-five percent were employed reporting moderate work ability. Of those, 21% received supplementary work disability benefits, 37% were severely fatigued, 7% expected to drop out of the workforce, and 49% experienced CKD-related work limitations. Work accommodations included reduced working hours, working at a slower pace, adjustment of work tasks or work schedule, and working from home. Multivariable analysis of sustained employment showed associations with younger age, male gender, higher level of education, better general and physical health and pre-emptive transplantation. Transplant patients had the highest work ability and highest expectation to maintain work. Dialysis patients had the highest productivity loss and perceived the most limitations regarding functioning in work. Stage G3b-G5 patients reported the lowest social support from colleagues and highest conflict in work and private life. Conclusions Employed CKD patients experience difficulties regarding functioning in work requiring adjustment of work or partial work disability. In addition to dialysis patients, stage G3b-G5 patients are vulnerable concerning sustained employment and work functioning. Show less
Background: Work can have a major positive impact on health and wellbeing. Employment of kidney transplant recipients (KTR) of working age is much lower than in the general population. The first... Show moreBackground: Work can have a major positive impact on health and wellbeing. Employment of kidney transplant recipients (KTR) of working age is much lower than in the general population. The first aim of this study was to examine the impact of a preemptive kidney transplantation (PKT) on employment, in addition to other possible influencing factors. The second aim was to explore differences in work ability, absenteeism and work performance among employed KTR with different types of transplantations. Methods: A cross-sectional survey study was conducted between 2018 and 2019 in nine Dutch hospitals. PKT as potential predictor of employment was examined. Furthermore, work ability, absenteeism and loss of work performance were compared between employed preemptive recipients with a living donor (L-PKT) and non-preemptive recipients with a living donor (L-nPKT) and with a deceased donor (D-nPKT). Results: Two hundred and twenty four KTR participated; 71% reported having paid work. Paid work was more common among PKT recipients (82% vs. 65% in L-nPKT and 55% in D-nPKT) and recipients who were younger (OR .950, 95%CI .913-.989), had no comorbidities (1 comorbidity: OR .397, 95%CI .167-.942; 2 comorbidities: OR .347, 95%CI .142-.844), had less fatigue (OR .974, 95%CI .962-.987) and had mentally demanding work tasks (only in comparison with physically demanding tasks, OR .342, 95%CI .145-.806). If recipients were employed, D-nPKT recipients worked fewer hours (mean 24.6 +/- 11.3 vs. PKT 31.1 +/- 9.6, L-nPKT 30.1 +/- 9.5) and D-nPKT and L-nPKT recipients received more often supplemental disability benefits (32 and 33.3%, respectively) compared to PKT recipients (9.9%). No differences were found for self-reported ability to work, sick leave (absenteeism) and loss of work performance with the exception of limitations in functioning at work. Conclusions: Preemptive kidney transplantation recipients with a kidney from a living donor are employed more often, work more hours per week (only in comparison with D-nPKT) and have a partial disability benefit less often than nPKT recipients. More knowledge regarding treatments supporting sustainable participation in the labor force is needed as work has a positive impact on recipients' health and wellbeing and is also beneficial for society as a whole. Show less
Tommel, J.; Evers, A.W.M.; Hamersvelt, H.W. van; Dijk, S. van; Chavannes, N.H.; Wirken, G.A.A.; ... ; Middendorp, H. van 2022
Background: Kidney failure and dialysis treatment have a large impact on a patient's life. Patients experience numerous, complex symptoms and usually have multiple comorbid conditions. Despite the... Show moreBackground: Kidney failure and dialysis treatment have a large impact on a patient's life. Patients experience numerous, complex symptoms and usually have multiple comorbid conditions. Despite the multitude of problems, patients often have priorities for improvement of specific aspects of their functioning, which would be helpful for clinicians to become informed of. This highlights a clear need for patient-centered care in this particular patient group, with routine screening as a vital element to timely recognize symptoms and tailored treatment to match individual patients' needs and priorities. By also providing feedback on patient's screening results to the patient itself, the patient is empowered to actively take control in one's mostly uncontrollable disease process. The current paper describes the study design of a multicenter randomized controlled trial evaluating the effectiveness of the "E-HEealth treatment in Long-term Dialysis" (E-HELD) intervention. This therapist-guided Internet-based cognitive-behavioral therapy (ICBT) intervention is focused on and personalized to the myriad of problems that dialysis patients experience and prioritize. Methods: After a screening procedure on adjustment problems, 130 eligible dialysis patients will be randomized to care as usual or the E-HELD intervention. Patients will complete questionnaires on distress (primary outcome measure), several domains of functioning (e.g., physical, psychological, social), potential predictors and mediators of treatment success, and the cost-effectiveness of the intervention, at baseline, 6-month follow-up, and 12-month follow-up. In addition, to take account of the personalized character of the intervention, the Personalized Priority and Progress Questionnaire (PPPQ) will be administered which is a personalized instrument to identify, prioritize, and monitor individual problems over time. Discussion: The present study design will provide insight in the effectiveness of tailored ICBT in patients with kidney failure who are treated with dialysis. When proven effective, the screening procedure and the subsequent ICBT intervention could be implemented in routine care to detect, support, and treat patients struggling with adjustment problems. Show less
Tommel, J.; Evers, A.W.M.; van Hamersvelt, H.W.; Jordens, R.; Dijk, S. van; Hilbrands, L.B.; ... ; Middendorp, H. van 2022
Background In the general population with coronavirus disease 2019 (COVID-19), obesity is associated with an increased risk of mortality. Given the typically observed obesity paradox among patients... Show moreBackground In the general population with coronavirus disease 2019 (COVID-19), obesity is associated with an increased risk of mortality. Given the typically observed obesity paradox among patients on kidney function replacement therapy (KFRT), especially dialysis patients, we examined the association of obesity with mortality among dialysis patients or living with a kidney transplant with COVID-19. Methods Data from the European Renal Association COVID-19 Database (ERACODA) were used. KFRT patients diagnosed with COVID-19 between 1 February 2020 and 31 January 2021 were included. The association of Quetelet's body mass index (BMI) (kg/m(2)), divided into: <18.5 (lean), 18.5-24.9 (normal weight), 25-29.9 (overweight), 30-34.9 (obese I) and >= 35 (obese II/III), with 3-month mortality was investigated using Cox proportional-hazards regression analyses. Results In 3160 patients on KFRT (mean age: 65 years, male: 61%), 99 patients were lean, 1151 normal weight (reference), 1160 overweight, 525 obese I and 225 obese II/III. During follow-up of 3 months, 28, 20, 21, 23 and 27% of patients died in these categories, respectively. In the fully adjusted model, the hazard ratios (HRs) for 3-month mortality were 1.65 [95% confidence interval (CI): 1.10, 2.47], 1 (ref.), 1.07 (95% CI: 0.89, 1.28), 1.17 (95% CI: 0.93, 1.46) and 1.71 (95% CI: 1.27, 2.30), respectively. Results were similar among dialysis patients (N = 2343) and among those living with a kidney transplant (N = 817) (P-interaction = 0.99), but differed by sex (P-interaction = 0.019). In males, the HRs for the association of aforementioned BMI categories with 3-month mortality were 2.07 (95% CI: 1.22, 3.52), 1 (ref.), 0.97 (95% CI: 0.78. 1.21), 0.99 (95% CI: 0.74, 1.33) and 1.22 (95% CI: 0.78, 1.91), respectively, and in females corresponding HRs were 1.34 (95% CI: 0.70, 2.57), 1 (ref.), 1.31 (95% CI: 0.94, 1.85), 1.54 (95% CI: 1.05, 2.26) and 2.49 (95% CI: 1.62, 3.84), respectively. Conclusion In KFRT patients with COVID-19, on dialysis or a kidney transplant, obesity is associated with an increased risk of mortality at 3 months. This is in contrast to the obesity paradox generally observed in dialysis patients. Additional studies are required to corroborate the sex difference in the association of obesity with mortality. Show less
Wirken, G.A.A.; Middendorp, H. van; Hooghof, C.W.; Sanders, J.S.; Dam, R.; Pant, K. van der; ... ; Evers, A.W.M. 2022
A high intrapatient variability (IPV) in tacrolimus exposure is a risk factor for poor long-term outcomes after kidney transplantation. The main objective of this trial was to investigate whether... Show moreA high intrapatient variability (IPV) in tacrolimus exposure is a risk factor for poor long-term outcomes after kidney transplantation. The main objective of this trial was to investigate whether tacrolimus IPV decreases after switching patients from immediate-release (IR)-tacrolimus to either extended-release (ER)-tacrolimus or LifeCyclePharma (LCP)-tacrolimus. In this randomized, prospective, open-label, cross-over trial, adult kidney transplant recipients on a stable immunosuppressive regimen, including IR-tacrolimus, were randomized for conversion to ER-tacrolimus or LCP-tacrolimus, and for the order in which IR-tacrolimus and the once-daily formulations were taken. Patients were followed 6 months for each formulation, with monthly tacrolimus predose concentration assessments to calculate the IPV. The IPV was defined as the coefficient of variation (%) of dose corrected predose concentrations. Ninety-two patients were included for analysis of the primary outcome. No significant differences between the IPV of IR-tacrolimus (16.6%) and the combined once-daily formulations (18.3%) were observed (% difference +1.7%, 95% confidence interval [CI] -1.1% to -4.5%, p = 0.24). The IPV of LCP-tacrolimus (20.1%) was not significantly different from the IPV of ER-tacrolimus (16.5%, % difference +3.6%, 95% CI -0.1% to 7.3%, p = 0.06). In conclusion, the IPV did not decrease after switching from IR-tacrolimus to either ER-tacrolimus or LCP-tacrolimus. These results provide no arguments to switch kidney transplant recipients from twice-daily (IR) tacrolimus formulations to once-daily (modified-release) tacrolimus formulations when the aim is to lower the IPV. Show less
Peereboom, E.T.M.; Matern, B.M.; Tomosugi, T.; Niemann, M.; Drylewicz, J.; Joosten, I.; ... ; Spierings, E. 2021
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.... Show moreCD4(+) 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. Show less
Gielis, E.M.; Anholts, J.D.H.; Beelen, E. van; Haasnoot, G.W.; Fijter, H.W. de; Bajema, I.; ... ; Eikmans, M. 2021
Background. There is an unmet need for noninvasive tools for diagnosis of rejection after kidney transplantation. The aim of this study was to determine the discriminative value of a combined... Show moreBackground. There is an unmet need for noninvasive tools for diagnosis of rejection after kidney transplantation. The aim of this study was to determine the discriminative value of a combined cellular and molecular biomarker platform in urine for the detection of rejection. Methods. First, microRNA (miR) molecules were screened in transplant biopsies and urine sediments of patients with acute rejection and patients without rejection and stable graft function. Second, the expression of 15 selected miRs was quantified in an independent set of 115 urine sediments of patients with rejection and 55 urine sediments of patients without histological signs of rejection on protocol biopsy. Additionally, CXCL-9 and CXCL-10 protein levels were quantified in the urine supernatant. Results. Levels of miR-155-5p (5.7-fold), miR-126-3p (4.2-fold), miR-21-5p (3.7-fold), miR-25-3p (2.5-fold), and miR-615-3p (0.4-fold) were significantly different between rejection and no-rejection urine sediments. CXCL-9 and CXCL-10 levels were significantly elevated in urine from recipients with rejection. In a multivariable model (sensitivity: 89.1%, specificity: 75.6%, area under the curve: 0.94, P < 0.001), miR-155-5p, miR-615-3p, and CXCL-9 levels were independent predictors of rejection. Stratified 10-fold cross validation of the model resulted in an area under the curve of 0.92. Conclusions. A combined urinary microRNA and chemokine profile discriminates kidney transplant rejection from stable graft conditions. Show less
Tommel, J.; Evers, A.W.M.; Hamersvelt, H.W. van; Jordens, R.; Dijk, S. van; Hilbrands, L.B.; Middendorp, H. van 2021
