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Patients with kidney disease have an uncertain future, with prognosis varying greatly per patient. To get a better idea of what the future holds and tailor interventions to the individual patient, prediction models can be of great value. Before a prediction model can be applied in practice, its performance should be measured in target populations of interest (i.e. external validation) and whether or not it helps improve clinical practice (i.e. whether it impacts clinical practice) should be determined. The impact would ideally be determined using an impact trial, but such a trial is often not feasible, and the impact of prediction models is therefore rarely assessed. As a result, prediction models that may not be so impactful may end up in clinical practice and impactful models may not be implemented due to a lack of impact studies. Ultimately, many prediction models end up never being implemented, resulting in much research waste. To allow researchers to get an indication of a prediction model's impact on clinical practice, alternative methods to assess a prediction model's impact are important. In this paper, we discuss several alternatives, including interviews, case-based surveys, decision comparisons, outcome modelling, before-after analyses and decision curve analyses. We discuss the general idea behind these approaches, including what information can be gathered from such studies and important pitfalls. Lastly, we provide examples of the different alternatives., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Individuals carrying a germline CDKN2A pathogenic variant (PV) are at a high risk of developing pancreatic ductal adenocarcinoma. Risk stratification could allow tailored surveillance., Objective: To develop a Fine-Gray prediction model for the risk of PDAC in carriers of a CDKN2A PV., Methods: Data from two large Dutch pancreatic cancer surveillance programs were used. A limited set of predictor variables were selected bsased on previous literature and the clinical expertise of the study group., Results: A total of 506 CDKN2A PV carriers were included, among whom we showed a substantial lifetime risk of PDAC (23%). The model identifies having a first-degree relative with PDAC (B = 0.7256) and a history of smoking (B = 0.4776) as significant risk factors. However, the model shows limited discrimination (c-statistic 0.64) and calibration., Conclusion: Our study highlights the high lifetime risk of PDAC in carriers of a CDKN2A PV. While identifying significant risk factors such as family history of PDAC and smoking, our prediction model shows limited precision, highlighting the need for additional factors such as biomarkers to improve its clinical utility for tailored surveillance of high-risk individuals., (© 2024 The Author(s). United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Background: Risk-based thresholds for arteriovenous (AV) access creation has been proposed to aid vascular access planning. We aimed to assess the clinical impact of implementing the Kidney Failure Risk Equation (KFRE) for vascular access referral., Methods: A total of 16 102 nephrology-referred chronic kidney disease (CKD) patients from the Swedish Renal Registry 2008-18 were included. The KFRE was calculated repeatedly, and the timing was identified for when the KFRE risk exceeded several pre-defined thresholds and/or the estimated glomerular filtration rate was <15 mL/min/1.73 m2 (eGFR15). To assess the utility of the KFRE/eGFR thresholds, cumulative incidence curves of kidney replacement therapy (KRT) or death, and decision-curve analyses were computed at 6 and 12 months, and 2 years. The potential impact of using the different thresholds was illustrated by an example from the Swedish access registry., Results: The 12-month specificity for KRT initiation was highest for KFRE >50% {94.5 [95% confidence interval (CI) 94.3-94.7]} followed by KFRE >40% [90.0 (95% CI 89.7-90.3)], while sensitivity was highest for KFRE >30% [79.3 (95% CI 78.2-80.3)] and eGFR <15 mL/min/1.73 m2 [81.2 (95% CI 80.2-82.2)]. The 2-year positive predictive value was 71.5 (95% CI 70.2-72.8), 61.7 (95% CI 60.4-63.0) and 47.2 (95% CI 46.1-48.3) for KFRE >50%, KFRE >40% and eGFR <15, respectively. Decision curve analyses suggested the largest net benefit for KFRE >40% over 2 years and KFRE >50% over 12 months when it is important to avoid the harm of possibly unnecessary surgery. In Sweden, 54% of nephrology-referred patients started hemodialysis in a central venous catheter (CVC), of whom only 5% had AV access surgery >6 months before initiation. Sixty percent of the CVC patients exceeded KFRE >40% a median of 0.8 years (interquartile range 0.4-1.5) before KRT initiation., Conclusions: The utility of using KFRE >40% and KFRE >50% is higher compared with the more traditionally used eGFR threshold <15 mL/min/1.73 m2 for vascular access planning., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Advancing age and chronic kidney disease (CKD) are risk factors for polypharmacy. Polypharmacy is associated with negative healthcare outcomes. Deprescribing, the systematic rationalization of potentially inappropriate medications, is a proposed way of addressing polypharmacy. The aim of this study was to describe longitudinal prescribing patterns of oral medications in a cohort of older people with advanced CKD in their last years of life., Methods: The European QUALity (EQUAL) study is a European, prospective cohort study of people ≥65 years with an incident estimated glomerular filtration rate (eGFR) of ≤20 mL/min/1.73 m 2 . We analysed a decedent subcohort, using generalized additive models to explore trends in the number and types of prescribed oral medications over the years preceding death., Results: Data from 563 participants were analysed (comprising 2793 study visits) with a median follow-up time of 2.2 years (interquartile range 1.1-3.8) pre-death. Participants' numbers of prescribed oral medications increased steadily over the years approaching death-7.3 (95% confidence interval 6.9-7.7) 5 years pre-death and 8.7 (95% confidence interval 8.4-9.0) at death. Over the years pre-death, the proportion of people prescribed (i) proton-pump inhibitors and opiates increased and (ii) statins, calcium-channel blockers and renin-angiotensin-aldosterone system inhibitors decreased, whilst (iii) beta-blockers, diuretics and gabapentinoids remained stable. At their final visits pre-death 14.6% and 5.1% were prescribed opiates and gabapentinoids, respectively., Conclusion: Elderly people with advanced CKD experienced persistent and increasing levels of polypharmacy as they approached the end of life. There was evidence of cessation of certain classes of medications, but at a population level this was outweighed by new prescriptions. This work highlights the potential for improved medication review in this setting to reduce the risks associated with polypharmacy. Future work should focus at the individual patient-clinician level to better understand the decision-making process underlying the observed prescribing patterns., Competing Interests: F.C. reports grant funding from ERA and NIHR for conducting the EQUAL study. K.J.J. also reports grant funding from ERA to conduct the EQUAL study, and registry funding from the European Society of Paediatric Nephrology. M.E. reports payment for advisory boards, lectures by Fresenius Medical Care, Baxter Healthcare, Astellas Pharma, Vifor Pharma, Boehringer-Ingelheim and AstraZeneca, and institutional grants from AstraZeneca and Astellas Pharma. M.E. is also a member of the steering committee for the Swedish Renal Registry. C.W. had no conflict in respect to the present research. Outside this research, honoraria for consultancy and lecturing were received from Amgen, Amicus, AstraZeneca, Bayer, Boehringer-Ingelheim, Eli-Lilly, GSK, MSD, Novo Nordisk and Sanofi. All remaining authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Non-traumatic lower extremity amputation (LEA) is a severe complication during dialysis. To inform decision-making for physicians, we developed a multivariable prediction model for LEA after starting dialysis., Methods: Data from the Swedish Renal Registry (SNR) between 2010 and 2020 were geographically split into a development and validation cohort. Data from Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD) between 1997 and 2009 were used for validation targeted at Dutch patients. Inclusion criteria were no previous LEA and kidney transplant and age ≥40 years at baseline. A Fine-Gray model was developed with LEA within 3 years after starting dialysis as the outcome of interest. Death and kidney transplant were treated as competing events. One coefficient, ordered by expected relevance, per 20 events was estimated. Performance was assessed with calibration and discrimination., Results: SNR was split into an urban development cohort with 4771 individuals experiencing 201 (4.8%) events and a rural validation cohort with 4.876 individuals experiencing 155 (3.2%) events. NECOSAD contained 1658 individuals experiencing 61 (3.7%) events. Ten predictors were included: female sex, age, diabetes mellitus, peripheral artery disease, cardiovascular disease, congestive heart failure, obesity, albumin, haemoglobin and diabetic retinopathy. In SNR, calibration intercept and slope were -0.003 and 0.912, respectively. The C-index was estimated as 0.813 (0.783-0.843). In NECOSAD, calibration intercept and slope were 0.001 and 1.142 respectively. The C-index was estimated as 0.760 (0.697-0.824). Calibration plots showed good calibration., Conclusion: A newly developed model to predict LEA after starting dialysis showed good discriminatory performance and calibration. By identifying high-risk individuals this model could help select patients for preventive measures., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Introduction: Chronic kidney disease (CKD) etiology varies greatly between developed and developing countries. In addition, differences in underlying pathogenesis and therapeutic options affect the progression towards advanced-CKD. This meta-analysis aims to identify the etiology of advanced-CKD in Southeast Asia., Methods: A systematic search in four electronic-databases and complementary search on national kidney registries and repository libraries was conducted until July 20, 2023. The risk of bias was assessed using Newcastle-Ottawa Scale for observational studies and Version-2 of Cochrane for intervention studies. A random-effects model was used to estimate pooled prevalence. The protocol is registered in the International Prospective Register of Systematic Reviews PROSPERO; Registration ID:CRD42022300786., Results: We analyzed 81 studies involving 32,834 subjects. The pooled prevalence of advanced-CKD etiologies are diabetic kidney disease (DKD) 29.2% (95%CI 23.88-34.78), glomerulonephritis 20.0% (95%CI 16.84-23.38), hypertension 16.8% (95%CI 14.05-19.70), other 8.6% (95%CI 6.97-10.47), unknown 7.5% (95%CI 4.32-11.50), and polycystic kidney disease 0.7% (95%CI 0.40-1.16). We found a significant increase in DKD prevalence from 21% (9.2%, 95%CI 0.00-33.01) to 30% (95%CI 24.59-35.97) before and after the year 2000. Among upper-middle-income and high-income countries, DKD is the most prevalent (26.8%, 95%CI 21.42-32.60 and 38.9%, 95%CI 29.33-48.79, respectively), while glomerulonephritis is common in lower-middle-income countries (33.8%, 95%CI 15.62-54.81)., Conclusion: The leading cause of advanced-CKD in Southeast Asia is DKD, with a substantial proportion of glomerulonephritis. An efficient screening program targeting high-risk populations (diabetes mellitus and glomerulonephritis) is needed, with the aim to delay CKD progression., (© 2024. The Author(s).)

Cynthia J Janmaat,1 Merel van Diepen,1 Cheyenne CE van Hagen,1 Joris I Rotmans,2 Friedo W Dekker,1 Olaf M Dekkers1,2 1Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands, 2Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands Purpose: Substantial heterogeneity exists in reported kidney function decline in pre-dialysis chronic kidney disease (CKD). By design, kidney function decline can be studied in CKD 3–5 cohorts or dialysis-based studies. In the latter, patients are selected based on the fact that they initiated dialysis, possibly leading to an overestimation of the true underlying kidney function decline in the pre-dialysis period. We performed a systematic review and meta-analysis to compare the kidney function decline during pre-dialysis in CKD stage 3–5 patients, in these two different study types. Patients and methods: We searched PubMed, EMBASE, Web of Science and Cochrane to identify eligible studies reporting an estimated glomerular filtration rate (eGFR) decline (mL/min/1.73 m2) in adult pre-dialysis CKD patients. Random-effects meta-analysis was performed to obtain weighted mean annual eGFR decline. Results: We included 60 studies (43 CKD 3–5 cohorts and 17 dialysis-based studies). The meta-analysis yielded a weighted annual mean (95% CI) eGFR decline during pre-dialysis of 2.4 (95% CI: 2.2, 2.6) mL/min/1.73 m2 in CKD 3–5 cohorts compared to 8.5 (95% CI: 6.8, 10.1) in dialysis-based studies (difference 6.0 [95% CI: 4.8, 7.2]). Conclusion: To conclude, dialysis-based studies report faster mean annual eGFR decline during pre-dialysis than CKD 3–5 cohorts. Thus, eGFR decline data from CKD 3–5 cohorts should be used to guide clinical decision making in CKD patients and for power calculations in randomized controlled trials with CKD progression during pre-dialysis as the outcome. Keywords: meta-analysis, systematic review, kidney function decline, dialysis, chronic kidney disease, pre-dialysis, CKD progression

Pauline WM Voskamp,1 Friedo W Dekker,1 Maarten B Rookmaaker,2 Marianne C Verhaar,2 Willem Jan W Bos,3 Merel van Diepen,1 Gurbey Ocak2 1Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands; 2Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, the Netherlands; 3Department of Nephrology, Sint Antonius Hospital, Nieuwegein, the Netherlands Purpose: A post hoc analysis of a recent trial on direct oral anticoagulants versus vitamin K antagonists showed that amongst patients with mildly decreased kidney function, use of vitamin K antagonists was associated with a greater decline in renal function than use of direct oral anticoagulants. Whether these vitamin K antagonist effects are the same in pre-dialysis patients is unknown. Therefore, the aim of this study was to investigate the association between vitamin K antagonist use and the rate of renal function decline and time until start of dialysis in incident pre-dialysis patients.Methods: Data from 984 patients from the PREdialysis PAtient REcord study, a multicenter follow-up study of patients with chronic kidney disease who started pre-dialysis care in the Netherlands (1999–2011), were analyzed. Of these patients, 101 used a vitamin K antagonist. Linear mixed models were used to compare renal function decline between vitamin K antagonist users and non-users. Cox proportional hazards models were used to estimate the HR with 95% CI for starting dialysis.Results: Vitamin K antagonist use was associated with an extra change in renal function of –0.09 (95% CI –1.32 to 1.13) mL/min/1.73 m2 per year after adjustment for confounding. The adjusted HR for the start of dialysis was 1.20 (95% CI 0.85 to 1.69) in vitamin K antagonist users, compared to non-users. Conclusion: In incident pre-dialysis patients, the use of vitamin K antagonists was not associated with an accelerated kidney function decline or an earlier start of dialysis compared to non-use. The lack of knowledge on the indication for vitamin K antagonist use could lead to confounding by indication. Keywords: coumarins, epidemiology, chronic kidney disease, glomerular filtration rate

True linear relationships are rare in clinical data. Despite this, linearity is often assumed during analyses, leading to potentially biased estimates and inaccurate conclusions. In this introductory paper, we aim to first describe - in a non-mathematical manner - how to identify non-linear relationships. Various methods are then discussed that can be applied to deal with non-linearity, including transformations, polynomials, splines, and Generalized Additive Models (GAMs), along with their strengths and weaknesses. Finally, we illustrate the use of these methods with a practical example from nephrology, providing guidance on how to report the results from non-linear relationships., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Prognostic uncertainty is a recurring theme among patients with chronic kidney disease (CKD). We developed a survey to explore whether CKD patients want to know more about their future, and if so, which topics they prioritize. In addition, we explored differences between several subgroups., Methods: A survey was constructed and tested in collaboration with the Dutch Kidney Patients Association. The survey consisted of three parts: (i) demographics, (ii) considerations about the future, and (iii) prognostic information. The survey was distributed among CKD patients (all stages) through patient associations and via healthcare professionals in two Dutch hospitals. Descriptive statistics were used to summarize the results. All results were stratified by population, sex, and age., Results: A total of 163 patients (45 CKD, 26 dialysis, and 92 kidney transplantation) participated in the survey. The mean age was 63.9 (SD 12.0) and 48.5% was male. Most patients think about their future with CKD occasionally (56.4%) or often (35.0%). Nearly half of the patients (49.7%) discuss the future with their nephrologist, some (19.6%) do not but would like to, and 20 (15.3%) prefer not to. Most patients (73.6%) want more prognostic information, regardless of it being positive or negative. Key topics to receive prognostic information about were laboratory values, symptoms, and physical well-being. Dialysis patients prioritized mental over physical well-being. CKD patients without kidney replacement therapy (KRT) indicated thinking about, and discussing their future more regularly than KRT patients., Conclusions: Patients with CKD contemplate their future regularly and express interest in receiving prognostic information on a variety of topics. One in five patients currently do not discuss their future with CKD with their nephrologist, despite wanting to do so. These findings underline the need to tailor prognostic information provision to patients' preferences, advocating more attention to this subject both in research and clinical practice., Competing Interests: The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Although medical courses are frequently evaluated via surveys with Likert scales ranging from " strongly agree " to " strongly disagree ," low response rates limit their utility. In undergraduate medical education, a new method with students predicting what their peers would say, required fewer respondents to obtain similar results. However, this prediction-based method lacks validation for continuing medical education (CME), which typically targets a more heterogeneous group than medical students., Methods: In this study, 597 participants of a large CME course were randomly assigned to either express personal opinions on a five-point Likert scale (opinion-based method; n = 300) or to predict the percentage of their peers choosing each Likert scale option (prediction-based method; n = 297). For each question, we calculated the minimum numbers of respondents needed for stable average results using an iterative algorithm. We compared mean scores and the distribution of scores between both methods., Results: The overall response rate was 47%. The prediction-based method required fewer respondents than the opinion-based method for similar average responses. Mean response scores were similar in both groups for most questions, but prediction-based outcomes resulted in fewer extreme responses (strongly agree/disagree)., Conclusions: We validated the prediction-based method in evaluating CME. We also provide practical considerations for applying this method., Competing Interests: The authors do not have competing interests., (© 2024 Chua, van Diepen, Trietsch, Dekker, Schönrock-Adema, Bustraan; licensee Synergies Partners.)

Chava L Ramspek,1 Pauline WM Voskamp,1 Frans J van Ittersum,2 Raymond T Krediet,3 Friedo W Dekker,1 Merel van Diepen1 On behalf of the NECOSAD study group 1Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, 2Department of Nephrology, VU University Medical Center, 3Department of Nephrology, Academic Medical Center, Amsterdam, The Netherlands Objective: In medicine, many more prediction models have been developed than are implemented or used in clinical practice. These models cannot be recommended for clinical use before external validity is established. Though various models to predict mortality in dialysis patients have been published, very few have been validated and none are used in routine clinical practice. The aim of the current study was to identify existing models for predicting mortality in dialysis patients through a review and subsequently to externally validate these models in the same large independent patient cohort, in order to assess and compare their predictive capacities.Methods: A systematic review was performed following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. To account for missing data, multiple imputation was performed. The original prediction formulae were extracted from selected studies. The probability of death per model was calculated for each individual within the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD). The predictive performance of the models was assessed based on their discrimination and calibration.Results: In total, 16 articles were included in the systematic review. External validation was performed in 1,943 dialysis patients from NECOSAD for a total of seven models. The models performed moderately to well in terms of discrimination, with C-statistics ranging from 0.710 (interquartile range 0.708–0.711) to 0.752 (interquartile range 0.750–0.753) for a time frame of 1 year. According to the calibration, most models overestimated the probability of death.Conclusion: Overall, the performance of the models was poorer in the external validation than in the original population, affirming the importance of external validation. Floege et al’s models showed the highest predictive performance. The present study is a step forward in the use of a prediction model as a useful tool for nephrologists, using evidence-based medicine that combines individual clinical expertise, patients’ choices, and the best available external evidence. Keywords: external validation, prediction, nephrology, dialysis, mortality

Cynthia J Janmaat,1 Merel van Diepen,1 Raymond T Krediet,2 Marc H Hemmelder,3 Friedo W Dekker1 On behalf of the NECOSAD study group 1Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, 2Department of Nephrology, Academic Medical Center, Amsterdam, 3Department of Internal Medicine, Nefrovisie Foundation, Utrecht, Netherlands Purpose: Current clinical guidelines recommend to initiate dialysis in the presence of symptoms or signs attributable to kidney failure, often with a glomerular filtration rate (GFR) of 5–10 mL/min/1.73 m2. Little evidence exists about the optimal kidney function to start dialysis. Thus far, most observational studies have been limited by lead-time bias. Only a few studies have accounted for lead-time bias, and showed contradictory results. We examined the effect of GFR at dialysis initiation on survival in chronic kidney disease patients, and the role of lead-time bias therein. We used both kidney function based on 24-hour urine collection (measured GFR [mGFR]) and estimated GFR (eGFR). Materials and methods: A total of 1,143 patients with eGFR data at dialysis initiation and 852 patients with mGFR data were included from the NECOSAD cohort. Cox regression was used to adjust for potential confounders. To examine the effect of lead-time bias, survival was counted from the time of dialysis initiation or from a common starting point (GFR 20 mL/min/1.73 m2), using linear interpolation models. Results: Without lead-time correction, no difference between early and late starters was present based on eGFR (hazard ratio [HR] 1.03, 95% confidence interval [CI] 0.81–1.3). However, after lead-time correction, early initiation showed a survival disadvantage (HR between 1.1 [95% CI 0.82–1.48] and 1.33 [95% CI 1.05–1.68]). Based on mGFR, the potential survival benefit for early starters without lead-time correction (HR 0.8, 95% CI 0.62–1.03) completely disappeared after lead-time correction (HR between 0.94 [95% CI 0.65–1.34] and 1.21 [95% CI 0.95–1.56]). Dialysis start time differed about a year between early and late initiation. Conclusion: Lead-time bias is not only a methodological problem but also has clinical impact when assessing the optimal kidney function to start dialysis. Therefore, lead-time bias is extremely important to correct for. Taking account of lead-time bias, this controlled study showed that early dialysis initiation (eGFR >7.9, mGFR >6.6 mL/min/1.73 m2) was not associated with an improvement in survival. Based on kidney function, this study suggests that in some patients, dialysis could be started even later than an eGFR

Prognostic models can strongly support individualized care provision and well-informed shared decision making. There has been an upsurge of prognostic research in the field of nephrology, but the uptake of prognostic models in clinical practice remains limited. Therefore, we map out the research field of prognostic models for kidney patients and provide directions on how to proceed from here. We performed a scoping review of studies developing, validating, or updating a prognostic model for patients with CKD. We searched all published models in PubMed and Embase and report predicted outcomes, methodological quality, and validation and/or updating efforts. We found 602 studies, of which 30.1% concerned CKD populations, 31.6% dialysis populations, and 38.4% kidney transplantation populations. The most frequently predicted outcomes were mortality ( n =129), kidney disease progression ( n =75), and kidney graft survival ( n =54). Most studies provided discrimination measures (80.4%), but much less showed calibration results (43.4%). Of the 415 development studies, 28.0% did not perform any validation and 57.6% performed only internal validation. Moreover, only 111 models (26.7%) were externally validated either in the development study itself or in an independent external validation study. Finally, in 45.8% of development studies no useable version of the model was reported. To conclude, many prognostic models have been developed for patients with CKD, mainly for outcomes related to kidney disease progression and patient/graft survival. To bridge the gap between prediction research and kidney patient care, patient-reported outcomes, methodological rigor, complete reporting of prognostic models, external validation, updating, and impact assessment urgently need more attention., (Copyright © 2023 by the American Society of Nephrology.)

Objective: To examine the level of overestimation (LO), associated factors, and identify the group of severe overestimators, among recreational skiers., Design: Cross-sectional observational study., Setting: An intermediate difficulty slope in an artificial snow indoor ski hall, and one in the mountains (Flachau, Austria)., Participants: Dutch recreational skiers., Independent Variables: Participants were asked to rate themselves (SRSS, self-reported skill score). While skiing downhill they were objectively evaluated by 2 expert assessors (OSS, observed skill score). Potential associated factors and predictors for severe overestimation were assessed by a questionnaire., Main Outcome Measures: The LO, calculated by subtracting the OSS from the SRSS, was categorized into "no," "mild," and "severe." Potential differences between these groups were analyzed, and regression analyses were performed to identify the factors associated with severe overestimation. To construct a profile of severe overestimators, the dataset was stratified based on 3 variables., Results: Overestimation was largely present (79.8%), and was severe in 32%. The LO decreased toward the more skilled skiers. Severe overestimators were mainly male, skied the least hours per day, were more avoidant, and showed the highest proportions of beginners and slightly advanced skiers. The profile of "severe overestimator" is characterized by physically unprepared males, avoidant for certain weather circumstances., Conclusions: Overestimation among recreational Dutch skiers is largely present, particularly among physically unprepared males, avoidant of certain snow and weather conditions. These features may function as a proxy to identify "severe overestimators" in comparable populations. Preventive strategies should focus to increase awareness particularly among these subjects., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

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.)

Objectives: To (1) explore trends of risk of bias (ROB) in prediction research over time following key methodological publications, using the Prediction model Risk Of Bias ASsessment Tool (PROBAST) and (2) assess the inter-rater agreement of the PROBAST., Study Design and Setting: PubMed and Web of Science were searched for reviews with extractable PROBAST scores on domain and signaling question (SQ) level. ROB trends were visually correlated with yearly citations of key publications. Inter-rater agreement was assessed using Cohen's Kappa., Results: One hundred and thirty nine systematic reviews were included, of which 85 reviews (containing 2,477 single studies) on domain level and 54 reviews (containing 2,458 single studies) on SQ level. High ROB was prevalent, especially in the Analysis domain, and overall trends of ROB remained relatively stable over time. The inter-rater agreement was low, both on domain (Kappa 0.04-0.26) and SQ level (Kappa -0.14 to 0.49)., Conclusion: Prediction model studies are at high ROB and time trends in ROB as assessed with the PROBAST remain relatively stable. These results might be explained by key publications having no influence on ROB or recency of key publications. Moreover, the trend may suffer from the low inter-rater agreement and ceiling effect of the PROBAST. The inter-rater agreement could potentially be improved by altering the PROBAST or providing training on how to apply the PROBAST., Competing Interests: Declaration of competing interest The work on this study by R.J.J. and M.v.D. was supported by a grant from the Dutch Kidney Foundation (20OK016). All other authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Despite a large number of patients requiring dialysis, the etiology of kidney failure is poorly documented in Indonesia. With the aim to reduce the disease burden, it is essential to obtain more insight in the etiology of chronic kidney disease (CKD)., Objectives: In the present study, we attempted to investigate the primary renal disease of kidney failure patients from five tertiary-care centers in Jakarta., Methods: This is a multicenter, cross-sectional study of kidney failure patients receiving kidney replacement therapy (KRT), from December 2021 to July 2022. We recruited patients aged ≥18 years, had been receiving dialysis for at least three months or a kidney transplantation., Findings: This study included 1,152 patients treated with hemodialysis (68.1%), peritoneal dialysis (7.5%), and kidney transplantation (24.4%). At the start of KRT, the median (interquartile-range [IQR]) age was 48 [37-58] years with low eGFR (median [IQR]: 5.9 [4.0-8.34] ml/minute/1.73 m 2 ). Hypertension was the main comorbidity (74.2%), followed by diabetes mellitus (30.1%). The major primary kidney disease was diabetic kidney disease (27.2%), followed by glomerulonephritis (13.0%), hypertension (11.5%), and urolithiasis (10.3%). Lupus nephritis was the common underlying etiology of secondary glomerulonephritis (91%). A high rate of unknown cause (31.1%) was also observed., Conclusions: Our results suggest that diabetic kidney disease is the leading cause of kidney failure in Jakarta, followed by glomerulonephritis. This study highlights the need for a better approach on primary prevention of diabetes mellitus as well as to better recognize glomerulonephritis at earlier stage might have a significant impact on reduction of the rate of kidney failure in Indonesia., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2023 The Author(s).)

Background: Various prediction models have been developed to predict the risk of kidney failure in patients with CKD. However, guideline-recommended models have yet to be compared head to head, their validation in patients with advanced CKD is lacking, and most do not account for competing risks., Methods: To externally validate 11 existing models of kidney failure, taking the competing risk of death into account, we included patients with advanced CKD from two large cohorts: the European Quality Study (EQUAL), an ongoing European prospective, multicenter cohort study of older patients with advanced CKD, and the Swedish Renal Registry (SRR), an ongoing registry of nephrology-referred patients with CKD in Sweden. The outcome of the models was kidney failure (defined as RRT-treated ESKD). We assessed model performance with discrimination and calibration., Results: The study included 1580 patients from EQUAL and 13,489 patients from SRR. The average c statistic over the 11 validated models was 0.74 in EQUAL and 0.80 in SRR, compared with 0.89 in previous validations. Most models with longer prediction horizons overestimated the risk of kidney failure considerably. The 5-year Kidney Failure Risk Equation (KFRE) overpredicted risk by 10%-18%. The four- and eight-variable 2-year KFRE and the 4-year Grams model showed excellent calibration and good discrimination in both cohorts., Conclusions: Some existing models can accurately predict kidney failure in patients with advanced CKD. KFRE performed well for a shorter time frame (2 years), despite not accounting for competing events. Models predicting over a longer time frame (5 years) overestimated risk because of the competing risk of death. The Grams model, which accounts for the latter, is suitable for longer-term predictions (4 years)., (Copyright © 2021 by the American Society of Nephrology.)

OA18.04 R. Chapman (1); C. Adams (1); A. Keyser (1); M. van Diepen (1); N. Douglass (1); L. Morris (2); P. Moore (2); A.-L. Williamson (1) and G. Chege (3) [...], Background: We previously reported establishment of a simian-human immunodeficiency virus (SHIV) challenge model using Chinese-origin rhesus macaques (ChRM) for testing the efficacy of HIV vaccines in South Africa. In the current study, we sought to establish proof of concept using a vaccine regimen that had elicited autologous Tier 2 neutralising antibodies (NAbs) in rabbits. Methods: The Env glycoprotein consensus sequence of the ChRM-adapted SHIV was determined and utilised in the vaccines designed in this study. DNA and MVA vaccines expressing SIV Gag and HIV Env antigens were constructed and in vitro expression confirmed. A soluble gp140 protein was expressed from a stable HEK293 cell line and purified using lectin affinity chromatography and gel filtration. Six ChRM were inoculated with two DNA, followed by two MVA and finally two protein vaccinations on weeks 0, 4, 8, 12, 20 and 28. Vaccine-induced T cell immunity was measured by IFN-[gamma] ELISPOT using peptide pools derived from SIV Gag and subtype C consensus Env while the NAbs were evaluated against Tier 1A (MW965.26), Tier 1B (6644.v2.c33) and Tier 2 (ZM109.B4) pseudovirions. The macaques were then challenged weekly from week 32 until they became infected. An unvaccinated control group was also challenged weekly until they became infected. Results: The expression and secretion of HIV-1 Env and SIV Gag by all three vaccine vectors was verified in vitro. Following vaccination, all the animals developed IFN-[gamma] ELISPOT responses after the DNA vaccinations (median: 255 sfu/million) which were boosted by the MVA inoculations (median: 1031 sfu/million). After protein boost, all animals had NAbs to MW965.26 (median titre: 426.5) and ZM109.B4 (median titre: 29.5) pseudovirions and 3 of 6 to 6644.v2.c33 pseudovirions. The animals in the vaccine group became infected following challenge at a similar rate to the controls, however, median peak viraemia in the vaccine group (1.8x[10.sup.3] copies/ml) was lower than the controls (1.6x[10.sup.3]/ml). Viral replication kinetics were similar in all animals with rapid decline to undetectable levels by 12 weeks post infection. Conclusions: These data provide proof of concept regarding the utility of our ChRM virus challenge model and support further testing of our novel vaccines using this model.

Background: Mortality prediction is critical on long-term kidney replacement therapy (KRT), both for individual treatment decisions and resource planning. Many mortality prediction models already exist, but as a major shortcoming most of them have only been validated internally. This leaves reliability and usefulness of these models in other KRT populations, especially foreign, unknown. Previously two models were constructed for one- and two-year mortality prediction of Finnish patients starting long-term dialysis. These models are here internationally validated in KRT populations of the Dutch NECOSAD Study and the UK Renal Registry (UKRR)., Methods: We validated the models externally on 2051 NECOSAD patients and on two UKRR patient cohorts (5328 and 45493 patients). We performed multiple imputation for missing data, used c-statistic (AUC) to assess discrimination, and evaluated calibration by plotting average estimated probability of death against observed risk of death., Results: Both prediction models performed well in the NECOSAD population (AUC 0.79 for the one-year model and 0.78 for the two-year model). In the UKRR populations, performance was slightly weaker (AUCs: 0.73 and 0.74). These are to be compared to the earlier external validation in a Finnish cohort (AUCs: 0.77 and 0.74). In all tested populations, our models performed better for PD than HD patients. Level of death risk (i.e., calibration) was well estimated by the one-year model in all cohorts but was somewhat overestimated by the two-year model., Conclusions: Our prediction models showed good performance not only in the Finnish but in foreign KRT populations as well. Compared to the other existing models, the current models have equal or better performance and fewer variables, thus increasing models' usability. The models are easily accessible on the web. These results encourage implementing the models into clinical decision-making widely among European KRT populations., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Haapio et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The combination of mosaic Gag and CAP256 envelope in an HIV vaccine regimen comprising DNA prime and modified vaccinia Ankara (MVA) boost followed by protein boost has previously been shown to generate robust autologous Tier 2 neutralizing antibodies (nAbs) in rabbits. Further refinements of this strategy have been investigated to improve antibody responses. The delivery of both DNA and recombinant MVA vaccines with a needle-free device was compared to delivery by injection, and the effect of formulating the DNA vaccine with adjuvant CpG ODN 1826 was determined. The Pharmajet Stratis ® needle-free injection device (PharmaJet, Golden, CO, USA) improved binding antibody responses to the DNA vaccine as well as both binding and neutralizing antibody responses to the MVA vaccines. Formulation of the DNA vaccines with CpG adjuvant further improved the antibody responses. A shortened vaccination regimen of a single DNA inoculation followed by a single MVA inoculation did not elicit Tier 1B nor Tier 2 neutralization responses as produced by the two DNA, followed by two MVA vaccination regimen. This study showed the immunogenicity of HIV DNA and MVA vaccines administered in a DDMM regimen could be improved using the PharmaJet Stratis needle-free injection device and formulation of the DNA vaccines with CpG adjuvant.

Skiing and snowboarding are both popular recreational alpine sports, with substantial injury risk of variable severity. Although skills level has repeatedly been associated with injury risk, a validated measure to accurately estimate the actual skills level without objective assessment is missing. This study aimed to develop a practical validated instrument, to better estimate the actual skills level of recreational skiers, based on the criteria of the Dutch Skiing Federation (DSF), and covering five different skill domains. A sample of Dutch recreational skiers (n = 84) was asked to fill in a questionnaire reflecting seven, a priori chosen predictors by expert opinion, to ski downhill and to be objectively evaluated by expert assessors. The instrument was developed to have a multidimensional character and was validated according to the TRIPOD guideline (Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis). The sample reported an overall incorrect self-reported estimation of their skills, compared with the observed skill score. The instrument showed good calibration and underwent multiple validation methods. The estimated skills score showed to be closer to the observed scores, than self-reportage. Our study provides a practical, multidimensional, and validated instrument to estimate the actual skills level. It proved to better reflect the actual skills levels compared with self-reportage among recreational skiers., (© 2022 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Aims: Multiple risk scores to predict ischaemic stroke (IS) in patients with atrial fibrillation (AF) have been developed. This study aims to systematically review these scores, their validations and updates, assess their methodological quality, and calculate pooled estimates of the predictive performance., Methods and Results: We searched PubMed and Web of Science for studies developing, validating, or updating risk scores for IS in AF patients. Methodological quality was assessed using the Prediction model Risk Of Bias ASsessment Tool (PROBAST). To assess discrimination, pooled c-statistics were calculated using random-effects meta-analysis. We identified 19 scores, which were validated and updated once or more in 70 and 40 studies, respectively, including 329 validations and 76 updates-nearly all on the CHA2DS2-VASc and CHADS2. Pooled c-statistics were calculated among 6 267 728 patients and 359 373 events of IS. For the CHA2DS2-VASc and CHADS2, pooled c-statistics were 0.644 [95% confidence interval (CI) 0.635-0.653] and 0.658 (0.644-0.672), respectively. Better discriminatory abilities were found in the newer risk scores, with the modified-CHADS2 demonstrating the best discrimination [c-statistic 0.715 (0.674-0.754)]. Updates were found for the CHA2DS2-VASc and CHADS2 only, showing improved discrimination. Calibration was reasonable but available for only 17 studies. The PROBAST indicated a risk of methodological bias in all studies., Conclusion: Nineteen risk scores and 76 updates are available to predict IS in patients with AF. The guideline-endorsed CHA2DS2-VASc shows inferior discriminative abilities compared with newer scores. Additional external validations and data on calibration are required before considering the newer scores in clinical practice., Clinical Trial Registration: ID CRD4202161247 (PROSPERO)., Competing Interests: Conflicts of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aim: Half of heart failure (HF) patients have chronic kidney disease (CKD) complicating their pharmacological management. We evaluated physicians' and patients' patterns of use of evidence-based medical therapies in HF across CKD stages., Methods and Results: We studied HF patients with reduced (HFrEF) and mildly reduced (HFmrEF) ejection fraction enrolled in the Swedish Heart Failure Registry in 2009-2018. We investigated the likelihood of physicians to prescribe guideline-recommended therapies to patients with CKD, and of patients to fill the prescriptions within 90 days of incident HF (initiating therapy), to adhere (proportion of days covered ≥80%) and persist (continued use) on these treatments during the first year of therapy. We identified 31 668 patients with HFrEF (median age 74 years, 46% CKD). The proportions receiving a prescription for angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors (ACEi/ARB/ARNi) were 96%, 92%, 86%, and 68%, for estimated glomerular filtration rate (eGFR) ≥60, 45-59, 30-44, and <30 ml/min/1.73 m 2 , respectively; for beta-blockers 94%, 93%, 92%, and 92%, for mineralocorticoid receptor antagonists (MRAs) 45%, 44%, 37%, 24%; and for triple therapy (combination of ACEi/ARB/ARNi + beta-blockers + MRA) 38%, 35%, 28%, and 15%. Patients with CKD were less likely to initiate these medications, and less likely to adhere to and persist on ACEi/ARB/ARNi, MRA, and triple therapy. Among stoppers, CKD patients were less likely to restart these medications. Results were consistent after multivariable adjustment and in patients with HFmrEF (n = 15 114)., Conclusions: Patients with HF and CKD are less likely to be prescribed and to fill prescriptions for evidence-based therapies, showing lower adherence and persistence, even at eGFR categories where these therapies are recommended and have shown efficacy in clinical trials., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Heterologous glycoprotein production relies on host glycosylation-dependent folding. When the biosynthetic machinery differs from the usual expression host, there is scope to remodel the assembly pathway to enhance glycoprotein production. Here we explore the integration of chaperone coexpression with glyco-engineering to improve the production of a model HIV-1 envelope antigen. Calreticulin was coexpressed to support protein folding together with Leishmania major STT3D oligosaccharyltransferase, to improve glycan occupancy, RNA interference to suppress the formation of truncated glycans, and Nicotiana benthamiana plants lacking α1,3-fucosyltransferase and β1,2-xylosyltransferase was used as an expression host to prevent plant-specific complex N-glycans forming. This approach reduced the formation of undesired aggregates, which predominated in the absence of glyco-engineering. The resulting antigen also exhibited increased glycan occupancy, albeit to a slightly lower level than the equivalent mammalian cell-produced protein. The antigen was decorated almost exclusively with oligomannose glycans, which were less processed compared with the mammalian protein. Immunized rabbits developed comparable immune responses to the plant-produced and mammalian cell-derived antigens, including the induction of autologous neutralizing antibodies when the proteins were used to boost DNA and modified vaccinia Ankara virus-vectored vaccines. This study demonstrates that engineering glycosylation-directed folding offers a promising route to enhance the production of complex viral glycoproteins in plants., (© 2022 The Authors. Biotechnology and Bioengineering published by Wiley Periodicals LLC.)

Introduction: Predicting the timing and occurrence of kidney replacement therapy (KRT), cardiovascular events, and death among patients with advanced chronic kidney disease (CKD) is clinically useful and relevant. We aimed to externally validate a recently developed CKD G4+ risk calculator for these outcomes and to assess its potential clinical impact in guiding vascular access placement., Methods: We included 1517 patients from the European Quality (EQUAL) study, a European multicentre prospective cohort study of nephrology-referred advanced CKD patients aged ≥65 years. Model performance was assessed based on discrimination and calibration. Potential clinical utility for timing of referral for vascular access placement was studied with diagnostic measures and decision curve analysis (DCA)., Results: The model showed a good discrimination for KRT and "death after KRT," with 2-year concordance (C) statistics of 0.74 and 0.76, respectively. Discrimination for cardiovascular events (2-year C-statistic: 0.70) and overall death (2-year C-statistic: 0.61) was poorer. Calibration was fairly accurate. Decision curves illustrated that using the model to guide vascular access referral would generally lead to less unused arteriovenous fistulas (AVFs) than following estimated glomerular filtration rate (eGFR) thresholds., Conclusion: This study shows moderate to good predictive performance of the model in an older cohort of nephrology-referred patients with advanced CKD. Using the model to guide referral for vascular access placement has potential in combating unnecessary vascular surgeries., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Background: The coronavirus disease 2019 (COVID-19) presents an urgent threat to global health. Prediction models that accurately estimate mortality risk in hospitalized patients could assist medical staff in treatment and allocating limited resources., Aims: To externally validate two promising previously published risk scores that predict in-hospital mortality among hospitalized COVID-19 patients., Methods: Two prospective cohorts were available; a cohort of 1028 patients admitted to one of nine hospitals in Lombardy, Italy (the Lombardy cohort) and a cohort of 432 patients admitted to a hospital in Leiden, the Netherlands (the Leiden cohort). The endpoint was in-hospital mortality. All patients were adult and tested COVID-19 PCR-positive. Model discrimination and calibration were assessed., Results: The C-statistic of the 4C mortality score was good in the Lombardy cohort (0.85, 95CI: 0.82-0.89) and in the Leiden cohort (0.87, 95CI: 0.80-0.94). Model calibration was acceptable in the Lombardy cohort but poor in the Leiden cohort due to the model systematically overpredicting the mortality risk for all patients. The C-statistic of the CURB-65 score was good in the Lombardy cohort (0.80, 95CI: 0.75-0.85) and in the Leiden cohort (0.82, 95CI: 0.76-0.88). The mortality rate in the CURB-65 development cohort was much lower than the mortality rate in the Lombardy cohort. A similar but less pronounced trend was found for patients in the Leiden cohort., Conclusion: Although performances did not differ greatly, the 4C mortality score showed the best performance. However, because of quickly changing circumstances, model recalibration may be necessary before using the 4C mortality score., (Copyright © 2022. Published by Elsevier B.V.)

Background: It is unknown whether stopping renin-angiotensin system (RAS) inhibitor therapy in patients with advanced CKD affects outcomes., Methods: We studied patients referred to nephrologist care, listed on the Swedish Renal Registry during 2007-2017, who developed advanced CKD (eGFR<30 ml/min per 1.73 m 2 ) while on RAS inhibitor therapy. Using target trial emulation techniques on the basis of cloning, censoring, and weighting, we compared the risks of stopping within 6 months and remaining off treatment versus continuing RAS inhibitor therapy. These included risks of subsequent 5-year all-cause mortality, major adverse cardiovascular events, and initiation of kidney replacement therapy (KRT)., Results: Of 10,254 prevalent RAS inhibitor users (median age 72 years, 36% female) with new-onset eGFR <30 ml/min per 1.73 m 2 , 1553 (15%) stopped RAS inhibitor therapy within 6 months. Median eGFR was 23 ml/min per 1.73 m 2 . Compared with continuing RAS inhibition, stopping this therapy was associated with a higher absolute 5-year risk of death (40.9% versus 54.5%) and major adverse cardiovascular events (47.6% versus 59.5%), but with a lower risk of KRT (36.1% versus 27.9%); these corresponded to absolute risk differences of 13.6 events per 100 patients, 11.9 events per 100 patients, and -8.3 events per 100 patients, respectively. Results were consistent whether patients stopped RAS inhibition at higher or lower eGFR, across prespecified subgroups, after adjustment and stratification for albuminuria and potassium, and when modeling RAS inhibition as a time-dependent exposure using a marginal structural model., Conclusions: In this nationwide observational study of people with advanced CKD, stopping RAS inhibition was associated with higher absolute risks of mortality and major adverse cardiovascular events, but also with a lower absolute risk of initiating KRT., (Copyright © 2021 by the American Society of Nephrology.)