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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.)

The availability of electronic health records and access to a large number of routine measurements of serum creatinine and urinary albumin enhance the possibilities for epidemiologic research in kidney disease. However, the frequency of health care use and laboratory testing is determined by health status and indication, imposing certain challenges when identifying patients with kidney injury or disease, when using markers of kidney function as covariates, or when evaluating kidney outcomes. Depending on the specific research question, this may influence the interpretation, generalizability, and/or validity of study results. This review illustrates the heterogeneity of working definitions of kidney disease in the scientific literature and discusses advantages and limitations of the most commonly used approaches using 3 examples. We summarize ways to identify and overcome possible biases and conclude by proposing a framework for reporting definitions of exposures and outcomes in studies of kidney disease using routinely collected health care data., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Trimethylamine N-oxide (TMAO), a metabolite from red meat and fish consumption, plays a role in promoting cardiovascular events. However, data regarding TMAO and its impact on clinical outcomes are inconclusive, possibly due to its undetermined dietary source., Objectives: We hypothesized that circulating TMAO derived from fish intake might cause less harm compared with red meat sources by examining the concomitant level of 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), a known biomarker of fish intake, and investigated the association between TMAO, CMPF, and outcomes., Methods: Patients were recruited from the European QUALity (EQUAL) Study on treatment in advanced chronic kidney disease among individuals aged ≥65 y whose estimated glomerular filtration rate (eGFR) had dropped for the first time to ≤20 mL/min per 1.73 m2 during the last 6 mo. The association between TMAO, CMPF, and outcomes including all-cause mortality and kidney replacement therapy (KRT) was assessed among 737 patients. Patients were further stratified by median cutoffs of TMAO and CMPF, suggesting high/low red meat and fish intake., Results: During a median of 39 mo of follow-up, 232 patients died. Higher TMAO was independently associated with an increased risk of all-cause mortality (multivariable HR: 1.46; 95% CI: 1.17, 1.83). Higher CMPF was associated with a reduced risk of both all-cause mortality (HR: 0.79; 95% CI: 0.71, 0.89) and KRT (HR: 0.80; 95% CI: 0.71, 0.90), independently of TMAO and other clinically relevant confounders. In comparison to patients with low TMAO and CMPF, patients with low TMAO and high CMPF had reduced risk of all-cause mortality (adjusted HR: 0.49; 95% CI: 0.31, 0.73), whereas those with high TMAO and high CMPF showed no association across adjusted models., Conclusions: High CMPF conferred an independent role in health benefits and might even counteract the unfavorable association between TMAO and outcomes. Whether higher circulating CMPF concentrations are due to fish consumption, and/or if CMPF is a protective factor, remains to be verified., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

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: To investigate the comparative effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP1-RA) on cardiovascular outcomes in routine clinical practice, which have never been directly compared in head-to-head outcome trials., Methods: We compared outcomes of adults who newly started SGLT2i or GLP1-RA therapy in Stockholm, Sweden, during 2013-2019. The primary outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular (CV) death, myocardial infarction and stroke. Secondary outcomes included the individual MACE components and hospitalization for heart failure. Cox regression with propensity score overlap weighting was used to estimate hazard ratios (HRs) with 95% confidence intervals and adjust for 57 covariates., Results: We included 12,375 individuals, of which 5489 initiated SGLT2i and 6886 GLP1-RA therapy, followed for median 1.6 years. Mean age was 61 years and 37.6% were women. Compared with GLP1-RA, SGLT2i new users had similar risk of MACE risk (adjusted HR 1.04; 95% CI 0.83-1.31). The adjusted HRs (95% CI) for SGLT2i vs. GLP1-RA were 0.80 (0.59-1.09) for heart failure hospitalization, 0.95 (0.58-1.55) for cardiovascular death, 0.91 (0.67-1.24) for myocardial infarction and 1.71 (1.14-2.59) for ischemic stroke (5-year absolute risk difference for stroke 1.9% [95% CI 0.8-3.0])., Conclusions: In a largely primary-prevention population of people undergoing routine care, no differences were observed in MACE risk among initiators of SGLT2i and GLP1-RA. However, compared with GLP1RA, the use of SGLT2i was associated with an increased risk of ischemic stroke that was small in absolute magnitude., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Lung congestion is a risk factor for all-cause and cardiovascular mortality in patients on chronic hemodialysis, and its estimation by ultrasound may be useful to guide ultrafiltration and drug therapy in this population. In an international, multi-center randomized controlled trial (NCT02310061) we investigated whether a lung ultrasound-guided treatment strategy improved a composite end point (all-cause death, non-fatal myocardial infarction, decompensated heart failure) vs usual care in patients receiving chronic hemodialysis with high cardiovascular risk. Patient-Reported Outcomes (Depression and the Standard Form 36 Quality of Life Questionnaire, SF36) were assessed as secondary outcomes. A total of 367 patients were enrolled: 183 in the active arm and 180 in the control arm. In the active arm, the pre-dialysis lung scan was used to titrate ultrafiltration during dialysis and drug treatment. Three hundred and seven patients completed the study: 152 in the active arm and 155 in the control arm. During a mean follow-up of 1.49 years, lung congestion was significantly more frequently relieved in the active (78%) than in the control (56%) arm and the intervention was safe. The primary composite end point did not significantly differ between the two study arms (Hazard Ratio 0.88; 95% Confidence Interval: 0.63-1.24). The risk for all-cause and cardiovascular hospitalization and the changes of left ventricular mass and function did not differ among the two groups. A post hoc analysis for recurrent episodes of decompensated heart failure (0.37; 0.15-0.93) and cardiovascular events (0.63; 0.41-0.97) showed a risk reduction for these outcomes in the active arm. There were no differences in patient-reported outcomes between groups. Thus, in patients on chronic hemodialysis with high cardiovascular risk, a treatment strategy guided by lung ultrasound effectively relieved lung congestion but was not more effective than usual care in improving the primary or secondary end points of the trial., (Copyright © 2021. Published by Elsevier Inc.)

With a rising demand for kidney transplantation, reliable pre-transplant assessment of organ quality becomes top priority. In clinical practice, physicians are regularly in doubt whether suboptimal kidney offers from older donors should be accepted. Here, we externally validate existing prediction models in a European population of older deceased donors, and subsequently developed and externally validated an adverse outcome prediction tool. Recipients of kidney grafts from deceased donors 50 years of age and older were included from the Netherlands Organ Transplant Registry (NOTR) and United States organ transplant registry from 2006-2018. The predicted adverse outcome was a composite of graft failure, death or chronic kidney disease stage 4 plus within one year after transplantation, modelled using logistic regression. Discrimination and calibration were assessed in internal, temporal and external validation. Seven existing models were validated with the same cohorts. The NOTR development cohort contained 2510 patients and 823 events. The temporal validation within NOTR had 837 patients and the external validation used 31987 patients in the United States organ transplant registry. Discrimination of our full adverse outcome model was moderate in external validation (C-statistic 0.63), though somewhat better than discrimination of the seven existing prediction models (average C-statistic 0.57). The model's calibration was highly accurate. Thus, since existing adverse outcome kidney graft survival models performed poorly in a population of older deceased donors, novel models were developed and externally validated, with maximum achievable performance in a population of older deceased kidney donors. These models could assist transplant clinicians in deciding whether to accept a kidney from an older donor., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Objectives: Maintenance of independence is a challenge for nursing home residents whose pain is often substantial. The objective of this study was to explore the relationship between pain perception and care dependency in a population of Dutch nursing home residents., Design: Prospective cohort study., Setting and Participants: Dutch nursing home residents aged 65 or older, excluding residents with a severe cognitive impairment., Methods: The Numeric Rating Scale (NRS) was used to rate pain perception from 0 to 10 in half-point increments and the Care Dependency Scale (CDS) to measure care dependency, with scores ranging from 15 (completely care dependent) to 75 (fully independent). Both measurements were repeated after a 2-month follow-up. Multiple linear regression analysis was used to adjust for potential confounders. Missing data were dealt with by performing tenfold multiple imputation., Results: A total of 1256 residents (65% women, mean age 83 years) were included. At baseline, the median NRS pain score was 3.0 (interquartile range 0.0-6.0) and the mean CDS score was 55.9 (SD 11.5). Cross-sectionally, for 1-point increase in pain score, care dependency increased 0.65 points [95% confidence interval (CI) 0.46-0.83]. More pain at baseline was associated with slightly lower care dependency after 2 months (beta 0.20, 95% CI 0.01-0.39). Compared with residents whose pain decreased over 2 months, residents with stable pain or increased pain had a 2.27-point (95% CI 0.83-3.70) and 2.39-point (95% CI 0.87-3.90) greater increase in care dependency, respectively., Conclusions and Implications: Pain perception and care dependency are associated in a population of older nursing home residents, and stable or increased pain is associated with increased care dependency progression. The findings of this study emphasize that pain and care dependency should not be assessed nor treated independently., (Copyright © 2020 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: The objective of this study was to systematically review and externally assess the predictive performance of models for ischemic stroke in incident dialysis patients., Study Design and Setting: Two reviewers systematically searched and selected ischemic stroke models. Risk of bias was assessed with the PROBAST. Predictive performance was evaluated within The Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD), a large prospective multicenter cohort of incident dialysis patients. For discrimination, c-statistics were calculated; calibration was assessed by plotting predicted and observed probabilities for stroke, and calibration-in-the-large., Results: Seventy-seven prediction models for stroke were identified, of which 15 were validated. Risk of bias was high, with all of these models scoring high risk in one or more domains. In NECOSAD, of the 1,955 patients, 127 (6.5%) suffered an ischemic stroke during the follow-up of 2.5 years. Compared with the original studies, most models performed worse with all models showing poor calibration and discriminative abilities (c-statistics ranging from 0.49 to 0.66). The Framingham showed reasonable calibration; however, with a c-statistic of 0.57 (95% CI 0.50-0.63), the discrimination was poor., Conclusion: This external validation demonstrates the weak predictive performance of ischemic stroke models in incident dialysis patients. Instead of using these models in this fragile population, either existing models should be updated, or novel models should be developed and validated., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Current guidelines on hypertension treatment in chronic kidney disease (CKD) patients discourage combined angiotensin-converting enzyme inhibitor (ACEi) and angiotensin II receptor blocker (ARB) use due to the risk of an increased kidney function decline. However, dual compared to single renin-angiotensin system (RAS) blockade may have more efficacy with regard to hypertension and proteinuria. Among incident predialysis patients (CKD 4-5), we compared dual with no or single RAS blockade regarding kidney function decline and risk of renal replacement therapy (RRT) or death. In a multicenter cohort study, 495 incident predialysis patients (>18 years) were included between 2004 and 2011 and followed until RRT, death, or October 2016. At baseline, patients were divided into four categories: nonuser, single or dual user of ACEi and/or ARB. Cox models were used to estimate the hazard ratio for the combined end point RRT or death. Differences in decline of kidney function among the four drug groups were compared with a linear mixed model. A total of 119 patients were nonusers, 164 ACEi users, 133 ARB users, and 79 dual RAS users. Compared to nonusers, the multivariable adjusted hazard ratio (95% confidence interval) for the combined end point was 0.75 (0.65 to 0.86) for ACEi users, 0.87 (0.76 to 1.00) for ARB users, and 0.79 (0.67 to 0.94) for dual RAS users. The average annual decline in kidney function did not differ among the four groups. We observed in predialysis patients that compared to no RAS blockade, both dual RAS blockade and single ACEi use were associated with about 20%-25% lower risk of RRT or death, without difference in kidney function decline., (Copyright © 2017 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Introduction: Frailty and muscle wasting, a component of frailty, are common in advanced stage chronic kidney disease (CKD). Whether frailty is associated with low urinary creatinine excretion (UCrE) as a measure of muscle mass in this population is unknown. Furthermore, reference values of UCrE are lacking. We first defined low UCrE and studied correlates of low UCrE, and subsequently studied cross-sectional associations of frailty with low UCrE in patients with advanced CKD., Methods: A total of 2748 healthy individuals of the general population-based PREVEND study were included to define low UCrE (UCrE indexed for height, below the age- and sex-specific 5th percentile of the distribution). Frailty was defined using a modification of the Fried frailty phenotype. In a CKD population that included 320 and 967 participants of the PREPARE-2 and NECOSAD studies, respectively, cross-sectional associations of self-reported frailty, the individual components that define self-reported frailty, and frailty-associated variables with low UCrE were evaluated using multivariate logistic and linear regression models., Results: Low UCrE was found in 38% of the CKD patients. A lower glomerular filtration rate was strongly associated with low UCrE. Self-reported frailty (adjusted odds ratio: 2.19; 95% confidence interval: 1.28-3.77) and the individual components were associated with low UCrE, independent of comorbidities. The frailty-associated variables hemoglobin and albumin were inversely associated with low UCrE, and parathyroid hormone was positively associated with low UCrE., Discussion: Lower kidney function is a strong correlate of low UCrE and self-reported frailty, and the individual frailty components are associated with low UCrE as well, independent of comorbidities.

Residual kidney function contributes substantially to solute clearance in dialysis patients but cannot be assessed without urine collection. We used serum filtration markers to develop dialysis-specific equations to estimate urinary urea clearance without the need for urine collection. In our development cohort, we measured 24-hour urine clearances under close supervision in 44 patients and validated these equations in 826 patients from the Netherlands Cooperative Study on the Adequacy of Dialysis. For the development and validation cohorts, median urinary urea clearance was 2.6 and 2.4 ml/min, respectively. During the 24-hour visit in the development cohort, serum β-trace protein concentrations remained in steady state but concentrations of all other markers increased. In the validation cohort, bias (median measured minus estimated clearance) was low for all equations. Precision was significantly better for β-trace protein and β2-microglobulin equations and the accuracy was significantly greater for β-trace protein, β2-microglobulin, and cystatin C equations, compared with the urea plus creatinine equation. Area under the receiver operator characteristic curve for detecting measured urinary urea clearance by equation-estimated urinary urea clearance (both 2 ml/min or more) were 0.821, 0.850, and 0.796 for β-trace protein, β2-microglobulin, and cystatin C equations, respectively; significantly greater than the 0.663 for the urea plus creatinine equation. Thus, residual renal function can be estimated in dialysis patients without urine collections., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Previous studies have suggested that living kidney donors maintain long-term renal function and experience no increase in cardiovascular or all-cause mortality. However, most analyses have included control groups less healthy than the living donor population and have had relatively short follow-up periods. Here we compared long-term renal function and cardiovascular and all-cause mortality in living kidney donors compared with a control group of individuals who would have been eligible for donation. All-cause mortality, cardiovascular mortality, and end-stage renal disease (ESRD) was identified in 1901 individuals who donated a kidney during 1963 through 2007 with a median follow-up of 15.1 years. A control group of 32,621 potentially eligible kidney donors was selected, with a median follow-up of 24.9 years. Hazard ratio for all-cause death was significantly increased to 1.30 (95% confidence interval 1.11-1.52) for donors compared with controls. There was a significant corresponding increase in cardiovascular death to 1.40 (1.03-1.91), while the risk of ESRD was greatly and significantly increased to 11.38 (4.37-29.6). The overall incidence of ESRD among donors was 302 cases per million and might have been influenced by hereditary factors. Immunological renal disease was the cause of ESRD in the donors. Thus, kidney donors are at increased long-term risk for ESRD, cardiovascular, and all-cause mortality compared with a control group of non-donors who would have been eligible for donation.

Objective: To suggest a behavioural research agenda for patients with end-stage renal disease (ESRD) based on a concise review of seven stages of psychosocial research, a literature review, and current behavioural research in other chronic somatic diseases., Methods: Historical behavioural ESRD research was classified. The specialized register of the Cochrane Behavioral Medicine Field was also checked, and additional papers were selected by screening reference lists and related behavioural science journals, to identify promising areas for future research., Results: The top-five topics identified via the literature search pertain to (1) psychological aspects and interventions, (2) adaptation, coping, and depression, (3) exercise, (4) counseling and education, and (5) compliance. 'Illness and treatment beliefs', 'sexuality', 'suicide', 'family support', and 'self-management interventions', were identified on the basis of research in other chronic illnesses as topics for future research. Regarding theory, the Common-Sense Model (CSM) was judged to offer useful theoretical perspectives; regarding methods, qualitative methods can be a valuable addition to quantitative research methods., Conclusion: Illness beliefs, treatment beliefs, and self-management behaviours are promising concepts in the assessment and clinical care of ESRD-patients. Cognitive-behavioural treatments appear to have potential and should be specified and elaborated for specific categories and problems of ESRD-patients., Practice Implications: This research agenda is in line with moves towards patient-centred disease-management to improve the quality of medical care for ESRD-patients., ((c) 2009 Elsevier Ireland Ltd. All rights reserved.)

Systematic reviews and meta-analyses are increasingly popular study designs in clinical research. A systematic review is a summary of the medical literature that uses explicit and reproducible methods for searching the literature and critical appraisal of individual studies; in contrast, a meta-analysis is a mathematical synthesis of the results of these individual studies. These study designs can be useful tools for summarizing the increasing amount of knowledge that is gained from scientific papers on a certain topic. In addition, combining individual studies in a meta-analysis increases statistical power, resulting in more precise effect estimates. Although the specific methodology of systematic reviews includes steps to minimize bias in all stages of the process, investigators should be aware of potential biases such as poor quality of included studies, heterogeneity between studies, and the presence of publication and outcome reporting bias. This paper explains how systematic reviews and meta-analyses should be performed and how to interpret and implement their results. In addition, we discuss when meta-analyses are useful and when they are not.

Screening refers to the early detection of individuals with unrecognized disease or with early stages of disease among a population. Early detection allows early medical intervention, which may ultimately slow progression of the disease and reduce both morbidity and mortality. As such, screening is an important tool in improving public health. In 1968, Wilson and Jungner proposed 10 criteria to consider prior to starting screening for a disease. This review discusses these criteria when applied to screening for chronic kidney disease with additional focus on (1) the validity of the test to be used for screening; (2) which part of the population to screen; and (3) forms of bias to consider in screening.

Adiponectin is an adipocyte-specific cytokine that has a protective role in the development of cardiovascular morbidities. As chronic kidney disease progresses, adiponectin levels increase and cardiovascular risk profiles change. Here we determined the association of baseline and longitudinal changes in adiponectin with different cardiovascular outcomes in 1255 type 2 diabetic hemodialysis patients in the German Diabetes and Dialysis Study. Within 4 years of follow-up, the hazard ratios to reach pre-specified, adjudicated end points were determined. The increased risk of cardiovascular events observed with high adiponectin levels at baseline was associated with high risks of sudden death and stroke but not of myocardial infarction. Adiponectin was negatively correlated with C-reactive protein and positively correlated with NT-pro-BNP, the latter significantly attenuating the associations with adverse outcome. Increased longitudinal levels of adiponectin during follow-up were associated with higher risks of adverse cardiovascular outcomes and death; associations weakened by a confounding effect of increased NT-pro-BNP. Our study suggests that high basal and increasing adiponectin levels in the dialysis population largely reflect a consequence of disease circumstances. Most likely, this rise is a counter-regulatory response to worsening health in keeping with adiponectin's potential to counteract inflammation.

Clinical practice commonly demands 'yes or no' decisions; and for this reason a clinician frequently needs to convert a continuous diagnostic test into a dichotomous test. Receiver operating characteristic (ROC) curve analysis is an important test for assessing the diagnostic accuracy (or discrimination performance) of quantitative tests throughout the whole range of their possible values, and it helps to identify the optimal cutoff value. The value of this analysis is not confined to diagnosis in that it may also be applied to assess the prognostic value of biomarkers and to compare their predictive value. ROC curve analysis may also serve to estimate the accuracy of multivariate risk scores aimed at categorizing individuals as affected/unaffected by a given disease/condition. However, one should be aware that, when applied to prognostic questions, ROC curves don't consider time to event and right censoring, and may therefore produce results that differ from those provided by classical survival analysis techniques like Kaplan-Meier or Cox regression analyses.

For most physicians, use of diagnostic tests is part of daily routine. This paper focuses on their usefulness by explaining the different measures of accuracy, the interpretation of test results, and the implementation of a diagnostic strategy. Measures of accuracy include sensitivity and specificity. Although these measures are often considered fixed properties of a diagnostic test, in reality they are subject to multiple sources of variation such as the population case mix and the severity of the disease under study. Furthermore, when evaluating a new diagnostic test, it must be compared to a reference standard, although the latter is usually not perfect. In daily practice diagnostic tests are not used in isolation. Several issues will influence the interpretation of their results. First, clinicians have a prior assumption about the patient's chances of having the disease under investigation, based on the patient's characteristics, symptoms, and the disease prevalence in similar populations. Second, diagnostic tests are usually part of a diagnostic strategy. Therefore, it is not sufficient to determine the accuracy of a single test; one also needs to determine its additional value to the patient's diagnosis, treatment, or outcome as part of a diagnostic strategy.

Clinical epidemiological studies investigate whether an exposure, or risk factor, is causally related to the development or progression of a disease or mortality. It might be of interest to study whether this relation is different in different types of patients. To address such research questions, the presence of interaction among risk factors can be examined. Causal interaction between two risk factors is considered most clinically relevant in epidemiology. Causal interaction occurs when two risk factors act together in causing disease and is explicitly defined as a deviation from additivity on a risk difference scale. Statistical interaction can be evaluated on both an additive (absolute risk) and multiplicative (relative risk) scale, depending on the model that is used. When using logistic regression models, which are multiplicative models, several measures of additive interaction are presented to evaluate whether the magnitude of an association differs across subgroups: the relative excess risk due to interaction (RERI), the attributable proportion due to interaction (AP), or the synergy index (S). For a transparent presentation of interaction effects the recent Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement advises reporting the separate effect of each exposure as well as the joint effect compared with the unexposed group as a joint reference category to permit evaluation of both additive and multiplicative interaction.

Background: The subjective global assessment of nutritional status (SGA) is used to assess the nutritional status of chronic dialysis patients, but longitudinal data in relation to mortality risk are lacking., Objective: Our objective was to study the long-term and time-dependent associations of the SGA with mortality risk in chronic dialysis patients., Design: In a prospective, longitudinal, observational, multicenter study of incident dialysis patients, the 7-point SGA [7 = normal nutritional status; 1 = severe protein-energy wasting (PEW)] was assessed 3 and 6 mo after the start of dialysis and subsequently every 6 mo during 7 y of follow-up. With Cox regression analysis, we calculated hazard ratios (HRs) of the baseline and time-dependent SGA measurements, adjusted for age, sex, treatment modality, primary kidney diseases, and comorbidity., Results: In total, 1601 patients were included [mean (+/-SD) age: 59 +/- 15 y; 61% men; 23% with moderate PEW (SGA(4-5)), and 5% with severe PEW (SGA(1-3))]. There was a dose-dependent trend of the 7-point SGA with mortality. Compared with a normal nutritional status at baseline, SGA(4-5) (HR: 1.6; 95% CI: 1.3, 1.9) and SGA(1-3) (HR: 2.1; 95% CI: 1.5, 2.8) were associated with an increase in 7-y mortality. Time-dependently, these associations were stronger: SGA(4-5) (HR: 2.1; 95% CI: 1.7, 2.5) and SGA(1-3) (HR: 5.0; 95% CI: 3.8, 6.5)., Conclusions: In dialysis patients, PEW at baseline assessed with SGA was associated with a 2-fold increased mortality risk in 7 y of follow-up. Time-dependently, this association was even stronger, which indicated that PEW was associated with a remarkably high risk of short-term mortality. These data imply that the 7-point SGA may validly distinguish different degrees of PEW associated with increasing risks of mortality.

Vascular calcification is a recognized risk factor for cardiovascular mortality in patients with end-stage renal disease. The aim of this study was to identify risk factors for vascular access calcification and to determine if patients with this disorder are at increased risk of death. Vascular access calcification was found in 49 of 212 hemodialysis patients as measured by plain X-ray (arteriovenous fistula or synthetic graft) in two dimensions. Male gender, diabetes mellitus, and length of time on dialysis were independent predictors for access calcification determined by logistic regression multivariate analysis. Serum parameters were not independently related to access calcification. Kaplan-Meier analysis showed an increased mortality risk, and Cox regression analysis confirmed that vascular access calcification was an independent mortality predictor. Our study suggests that detection of vascular access calcification is a cost-effective method to identify patients at increased mortality risk.

Etiological research aims to investigate the causal relationship between putative risk factors (or determinants) and a given disease or other outcome. In contrast, prognostic research aims to predict the probability of a given clinical outcome and in this perspective the pathophysiology of the disease is not an issue. Multivariate modeling is a fundamental tool both to infer causality and to investigate prognostic factors in epidemiological research. The analytical approaches to etiological and prognostic studies are strictly dependent on the research question and imply knowledge of the main statistical procedures for model building and data interpretation. In this paper we describe the application of multivariate statistical modeling in etiological and prognostic research. We will mainly focus on the differences in model building and data interpretation between these two areas of epidemiologic research.

Before new tests are implemented, it is important to compare their results with those of other measurement methods that are already in use. In the determination of this so-called agreement between methods, one may choose between several statistical approaches. The correlation coefficient is a popular approach to determine the agreement between measurement methods. It is easy to calculate, but has important limitations: it does not provide any information on the type of association and it is extremely sensitive to the range of values within the study. Finally, a correlation coefficient does not reveal whether any difference between two measurements is systematic or random. Therefore, it is highly preferable to use Bland-Altman plots instead, as these reveal both systematic and random errors. Bland-Altman plots are also preferable in case of repeated measurements and calibrations.

Objective: Indicators of reproducibility for log-transformed variables can often not be calculated straightforwardly and are subsequently incorrectly interpreted., Methods and Results: We discuss meaningful Coefficients of Variation (CV) for log-transformed variables, which can be derived directly from the standard error of the log-transformed measurements. To provide easy interpretable Bland and Altman plots, we calculated limits of inter and intraobserver agreement (LA) for log-transformed variables and transform them back to the original scale. These LAs for agreement are subsequently plotted on the original scale in a conventional Bland and Altman plot. Both approaches were illustrated in a clinical example on the reproducibility of skinfold thickness measurements., Conclusion: In reproducibility, it is important to calculate meaningful CVs, LAs, and Bland-Altman plots for log-transformed variables. We provide a practical approach in which existing statistical methods are applied in the field of reproducibility, thus leading to parameters of reproducibility which can be interpreted on the original scale.

In traditional Kaplan-Meier or Cox regression analysis, usually a risk factor measured at baseline is related to mortality thereafter. During follow-up, however, things may change: either the effect of a fixed baseline risk factor may vary over time, resulting in a weakening or strengthening of associations over time, or the risk factor itself may vary over time. In this paper, short-term versus long-term effects (so-called time-dependent effects) of a fixed baseline risk factor are addressed. An example is presented showing that underweight is a strong risk factor for mortality in dialysis patients, especially in the short run. In contrast, overweight is a risk factor for mortality, which is stronger in the long run than in the short run. In addition, the analysis of how time-varying risk factors (so-called time-dependent risk factors) are related to mortality is demonstrated by paying attention to the pitfall of adjusting for sequelae. The proper analysis of effects over time should be driven by a clear research question. Both kinds of research questions, that is those of time-dependent effects as well those of time-dependent risk factors, can be analyzed with time-dependent Cox regression analysis. It will be shown that using time-dependent risk factors usually implies focusing on short-term effects only.

What is this patient's prognosis regarding graft rejection? Do patients using a particular drug live longer than those not using it? How does this co-morbidity affect access to transplantation? To answer this type of questions one needs to perform survival analysis. This paper focuses on the Kaplan-Meier method, the most popular method used for survival analysis. It makes it possible to calculate the incidence rate of events like recovery of renal function, myocardial infarction or death by using information from all subjects at risk for these events. It explains how the method works, how survival probabilities are calculated, survival data can be summarized and survival in groups can be compared using the logrank test for hypothesis testing. In addition, it provides some guidance regarding the presentation of survival plots. Finally, it discusses the limitations of the Kaplan-Meier method and refers to other methods that better serve additional purposes.

How much does the survival of one group differ from the survival of another group? How do differences in age in these two groups affect such a comparison? To obtain a quantity to compare the survival of different patient groups and to account for confounding effects, a multiple regression technique for survival data is needed. Cox regression is perhaps the most popular regression technique for survival analysis. This paper explains how Cox regression works, what the proportionality assumption means and how to interpret the results of univariate and multiple Cox regression models.

Objectives: Reliability studies are frequently organized within the context of a large (multicenter) study, with only a small sample of subjects measured by the observers of the large study. To estimate interobserver reliability, data from the large study are not frequently used. In this article, the advantages of combining data from the reliability study and the large study to improve the estimation of intra-class correlation coefficients (ICCs) are highlighted., Study Design and Setting: This was done within the scope of estimating fat percentages in the Project On Preterm and Small-for-gestational-age infants-19 (POPS-19) study and with simulations. To calculate ICCs, three approaches were used: (1) the classical approach using data from a reliability study only, (2) the combined variances approach using inter-subject variances from the POPS-19 study, and (3) the maximum likelihood approach using all data., Results: The ICCs (95% confidence interval [CI]) for fat percentage calculated by the three approaches were 0.84 (0.57, 0.99), 0.94 (0.90, 0.97), and 0.94 (0.88, 0.97), respectively., Conclusion: The efficient use of data by combining data from a small reliability study with the data from the large study itself for the calculation of ICCs will lead to more precise ICCs.

Background and Objective: A continued controversy exists whether the assessment of the influence of low birth weight on adult blood pressure necessitates adjustment for adult weight in the analysis on the fetal origins of adult diseases hypothesis. Here we first explain the difficulty in understanding an adjusted multivariate regression model, and then propose another way of writing the regression model to make the interpretation of the separate influence of birth weight and changes in weight later in life more straightforward., Study Design and Setting: We used a multivariate regression model containing birth weight (standard deviation score; SDS), and residual adult weight (SDS) to explore the effect on blood pressure (or any other outcome) separately. Residual adult weight was calculated as the difference between actual adult weight and the expected adult weight (SDS) given on a certain birth weight (SDS)., Results: The coefficients of birth weight and residual adult weight show directly the effect on the analyzed outcome variable., Conclusions: We prefer to use this regression model with unexplained residuals when the adjusted variable is in the causal pathway in the analyses of data referring to the fetal origins of adult diseases hypothesis.

Background: In dialysis patients, only a few follow-up studies have addressed the relationship between the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene and mortality, but the available data are contradictory., Methods: A cohort of 453 consecutive patients starting dialysis between January 1999 and January 2002 and participating in a Dutch multicenter prospective study was examined. Patients who died within 3 months after the start of dialysis were excluded. Patients were followed until date of death or censoring in November 2003., Results: The ACE II, ID, and DD genotype frequencies were 24.3% (N = 110), 50.1% (N = 227), and 25.6% (N = 116). Besides a slightly higher number of Caucasians in the DD group, all other patient characteristics of the 3 ACE groups were similar at the start of dialysis. After adjustment for age, comorbidity, and ethnic background, patients with the ID and DD genotype showed an increased hazard ratio (HR) for all-cause mortality of 1.55 (95% CI 1.00-2.42) and 2.30 (95% CI 1.41-3.75), compared to patients with the II genotype. Slightly lower HRs were found for cardiovascular mortality. All groups of primary kidney disease showed a 2- to 3-fold increased adjusted HR for DD., Conclusion: The DD genotype identifies dialysis patients at an increased risk for mortality.

Background: Since 1998, an increase of anti-erythropoietin (anti-EPO) antibody-induced pure red cell aplasia (PRCA) has been reported. As data up to now consisted mostly of spontaneously reported cases the question arose about the frequency of this increase in EPO-induced PRCA. The objectives of this study were to determine the incidence and causes of recombinant EPO hyporesponse, of antibodies to EPO in patients on dialysis, and to relate the detection of anti-EPO antibodies to the presence of PRCA., Method: This multicenter cohort study used existing patient data and serum samples collected at 6-month intervals from 1677 patients with incident end-stage renal disease (ESRD) participating in The Netherlands Cooperative Study on the Adequacy of Dialysis-2 (NECOSAD-2)., Results: Fifty-seven patients had an inadequate EPO response, which resulted in an incidence of 16.7 per 1000 patient-years on EPO while on dialysis. All available sera specimens (N = 232) of these patients were screened for anti-EPO antibodies. The sera specimens of two of these 57 patients tested positive. Of the 57 patients with inadequate EPO response, one had clinical PRCA (incidence 0.29 per 1000 patient-years on EPO and on dialysis). Of the 1346 patients without symptoms of inadequate EPO response, one patient tested borderline positive for anti-EPO antibodies. In total, three patients developed EPO antibodies during follow-up, leading to an estimated incidence of 1.27/1000 (95% CI 0.3 to 3.7/1000) patient-years since the start of dialysis., Conclusion: The incidence of inadequate EPO response in our population of dialysis patients is in concordance with tentative calculations found in the literature. Furthermore, we found the incidence of EPO-induced PRCA and EPO antibodies to be low.

Background: Residual glomerular filtration rate (GFR) is a much more important determinant of survival in peritoneal dialysis patients, than peritoneal solute clearances. However, anuric peritoneal dialysis patients are solely dependent on peritoneal solute clearances. The aim of the study was to analyze the effects of peritoneal small solute clearances and ultrafiltration on survival in anuric patients, and to establish the minimum levels of small solute clearances and net ultrafiltration. These objectives were investigated in a prospective cohort study in incident peritoneal dialysis patients who had become anuric during follow-up., Methods: The Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD) is a prospective multicenter cohort study in which new adult dialysis patients are included and followed during 6 months intervals. Included were 542 peritoneal dialysis patients. Of these, 166 developed anuria, 130 of which could be included in the study., Results: Two-year patient survival after the outset of anuria was 67%, technique survival 73%, and the combined 2-year patient and technique survival was 50%. Risk factors associated with mortality were age, comorbidity, the duration of peritoneal dialysis before anuria, and a low serum albumin. Peritoneal solute clearances were analyzed time-dependently. These parameters were not associated with survival when analyzed as continuous variables and also not when the analyses were done in quintiles, although the time-dependent approach was almost significant for Kt/V(urea). On the other hand, when the results were analyzed dichotomously using predefined cutoff points, Kt/V(urea) <1.5 per week and creatinine clearance <40 L/week/1.73 m2 were associated with an increase in the relative risk of death. Also peritoneal ultrafiltration was significantly associated with survival., Conclusion: The survival of anuric peritoneal dialysis patients is in line with expectations based on the duration of dialysis. The risk factors for death are the same as in the dialysis population as a whole. Besides an association with ultrafiltration, our study enabled us to define the lower limits of adequate peritoneal dialysis, that is Kt/V(urea) <1.5 per week and creatinine clearance <40 L/week/1.73 m2.

Background: Increasing evidence indicates that adult body composition is associated with prenatal and infancy weight gain, but the relative importance of different time periods has not been elucidated., Objective: The objective was to study the association between prenatal, early postnatal, and late infancy weight gain and body mass index (BMI), fat mass, and fat distribution in young adulthood., Design: We included 403 men and women aged 19 y from a Dutch national prospective follow-up study who were born at <32 wk of gestation. BMI, waist circumference, and waist-to-hip ratio SD scores and subscapular-to-triceps ratio, percentage body fat, fat mass, and fat-free mass at age 19 y were studied in relation to birth weight SD scores, weight gain from preterm birth until 3 mo postterm (early postnatal weight gain), and weight gain from 3 mo until 1 y postterm (late infancy weight gain)., Results: Birth weight SD scores were positively associated with weight, height, BMI SD scores, and fat-free mass at age 19 y but not with fat mass, percentage body fat, or fat distribution. Early postnatal and late infancy weight gain were positively associated with adult height, weight, BMI, waist circumference SD scores, fat mass, fat-free mass, and percentage body fat but not with waist-to-hip ratio SD scores or subscapular-to-triceps ratio., Conclusions: In infants born very preterm, weight gain before 32 wk of gestation is positively associated with adult body size but not with body composition and fat distribution. More early postnatal and, to a lesser extent, late infancy weight gain are associated with higher BMI SD scores and percentage body fat and more abdominal fat at age 19 y.

Background: Chronic transplant glomerulopathy is an uncommon cause of chronic transplant dysfunction of unknown pathogenesis. We evaluated the epidemiologic, clinical, and histologic features of chronic transplant glomerulopathy. To determine the possible contribution of humoral immune responses, we assessed glomerular deposition of C4d., Methods: From a cohort of 1111 kidney transplants (1983 to 2001) with at least 6 months of graft function, we identified 18 cases with chronic transplant glomerulopathy (1.6%) showing double contours of the glomerular basement membrane (GBM) on light microscopy. To assess the risk factors, this group was compared with 739 patients with stable function using multivariate Cox regression analysis. Paraffin sections of 11/18 biopsies were stained with polyclonal C4d antibodies. Sera of 13/18 patients could be tested for antidonor human leukocyte antigen (HLA) antibodies by enzyme-linked immunosorbent assay (ELISA). Patients with chronic allograft nephropathy without chronic transplant glomerulopathy or predominant cyclosporine nephrotoxicity were used as controls., Results: Chronic transplant glomerulopathy was diagnosed at a median of 8.3 (range 2.6-12.5) years posttransplantation. Panel reactive antibodies at time of transplantation, RR 1.23 (1.05-1.45) per 10% increase, and late acute rejection episodes, RR 7.6 (1.8-31.7), were independently associated with chronic transplant glomerulopathy. We found glomerular C4d deposits in 10/11 biopsies showing chronic transplant glomerulopathy and in only 2/13 controls. Peritubular capillary C4d deposits and donor-specific anti-HLA antibodies were demonstrated in 4 and 3 of the 10 patients with glomerular C4d deposits, respectively., Conclusion: Presensitization and late acute rejection episodes were the risk factors identified. Glomerular C4d deposits suggest that chronic transplant glomerulopathy emerges from in situ humoral rejection. Chronic transplant glomerulopathy should be considered as a manifestation of immune-mediated injury.

Background: Up-until-now, the survival and health-related quality of life of hemodialysis and peritoneal dialysis patients has only been compared in observational studies. These studies have reported small and opposing differences between both modalities. The aim of this study was to compare the outcome of hemodialysis as initial chronic dialysis treatment with that of peritoneal dialysis in a randomized controlled trial., Methods: All new dialysis patients from 38 dialysis centers in The Netherlands without indications against either modality were invited to participate. Patients were assigned to start with hemodialysis or peritoneal dialysis. The primary outcome was mean quality-adjusted life year (QALY) score. Secondary outcome was survival., Results: Due to the low inclusion rate, the trial was prematurely stopped after which 38 patients had been randomized: 18 patients to hemodialysis and 20 to peritoneal dialysis. The mean QALY score in the first 2 years was 59.1 (SD 12) for hemodialysis patients versus 54.0 (SD 19) for peritoneal dialysis patients, which constitutes a small difference in favor of hemodialysis of 5.1 (95%CI -7.3 to 17.6) After 5 years of follow-up, nine hemodialysis and five peritoneal dialysis patients had died, a significant difference in survival; hazard ration of hemodialysis versus peritoneal dialysis of 3.8 (95%CI 1.1 to 12.6). After adjustment for age, comorbidity, and primary kidney disease the hazard ratio was 3.6 (0.8 to 15.4)., Conclusion: Only a small difference in QALY score was observed between patients who started with hemodialysis compared to patients who started with peritoneal dialysis, lending support for the equivalence hypothesis. The significant difference in longer-term survival, which favored peritoneal dialysis in this small group of patients, could be used to posit that incident dialysis patients might benefit from starting on peritoneal dialysis.

Background/objectives: The goal of this study was to determine the influence of chronic obstructive pulmonary disease (COPD) on health-related quality of life (HRQL) independent of comorbidity., Methods: Patients with COPD in general practice, >/=40 years, were selected. To recruit controls, a random sample of persons without COPD and >/=40 years, was taken. HRQL was assessed with the SF-36 and comorbidity was determined by questionnaire., Results: The influence of COPD on HRQL independent of comorbidity (represented by adjusted regression coefficients) was significant for physical functioning (-27.6), role functioning due to physical problems (-21.6), vitality (-14.4), and general health (-25.7), and was minor and not significant for social functioning (-5.6), mental health (-1.3), role functioning due to emotional problems (-2.7), and bodily pain (-2.5). Comorbidity contributed significantly to the HRQL of all domains (-7.6 to -27.1)., Conclusions: COPD patients can be impaired in all domains of HRQL. However, impairments in physical functioning, vitality, and general health are related to COPD and to some extent to comorbidity, while impairments in social and emotional functioning do not seem to be related to COPD, but only to comorbidity.

Background: Little is known about the late effects of juvenile end-stage renal disease (ESRD) on bone integrity. To establish clinical manifestations of metabolic bone disease and bone mineral density (BMD) in young adult patients with juvenile ESRD, we performed a long-term outcome study., Methods: A cohort was formed of all Dutch patients with onset of ESRD between 1972 and 1992 at age 0 to 14 years, born before 1979. Data were collected by review of medical charts, current history, physical examination, and performing dual energy x-ray absorptiometry (DEXA) of the lumbar spine and the femoral neck., Results: Clinical information was retrieved in 247 out of 249 patients. Of all of these patients, 61.4% had severe growth retardation (<-2 SD), 36.8% had clinical symptoms of bone disease, and 17.8% were disabled by bone disease. Growth retardation and clinical bone disease were associated with a long duration of dialysis. DEXA was performed in 140 out of 187 living patients. Mean BMD +/- SD corrected for gender and age (Z score) of the lumbar spine was -2.12 +/- 1.4 and of the femoral neck was -1.77 +/- 1.4. A low lean body mass was associated with a low lumbar spine and a low femoral neck BMD; male gender, physical inactivity and aseptic bone necrosis were associated with a low lumbar spine BMD., Conclusion: Bone disease is a major clinical problem in young adults with pediatric ESRD. Further follow-up is needed to establish the impact of the low bone mineral densities found in these patients.

Background: Residual renal function (RRF) influences morbidity, mortality and quality of life in chronic dialysis patients. Few studies have been published on risk factors for loss of RRF in dialysis patients. These studies were either retrospective, performed in a small number of patients, or estimated GFR without a urine collection., Methods: We analyzed the decline rates of residual GFR (rGFR) prospectively in 522 incident HD and PD patients who had structured follow-up assessments. GFR was measured as the mean of urea and creatinine clearance, calculated from urine collections. The initial value was obtained 0 to 4 weeks before the start of dialysis. The measurements were repeated 3, 6, and 12 months after the start of dialysis treatment. After logarithmic transformation, differences in rGFR changes over time were analyzed using repeated measurement analysis of variance., Results: Baseline factors that were negatively associated with rGFR at 12 months were a higher diastolic blood pressure (P < 0.001) and a higher urinary protein loss (P < 0.001). Primary kidney disease did not affect rGFR. Averaged over time, PD patients had a higher rGFR (P < 0.001) than HD patients. This relative difference increased over time (P = 0.04). Investigation of possible effects of the dialysis procedure on the decline rate between 0 and three months showed that dialysis hypotension (P = 0.02) contributed to the decline in HD and the presence of episodes with dehydration contributed in PD (P = 0.004)., Conclusions: rGFR is better maintained in PD patients than in HD patients. The associated factors such as a higher diastolic blood pressure, proteinuria, dialysis hypotension and dehydration can either be treated or avoided.