Cross-sectional studies represent the second line of evidence (after case reports) in the ladder of evidence aimed at defining disease aetiology. This study design is used to generate hypotheses about the determinants of a given disease... more
Cross-sectional studies represent the second line of evidence (after case reports) in the ladder of evidence aimed at defining disease aetiology. This study design is used to generate hypotheses about the determinants of a given disease but also to investigate the accuracy of diagnostic tests and to assess the burden of a given disease in a population. The intrinsic limitation of cross-sectional studies, when applied to generate aetiological hypotheses, is that both the exposure under investigation and the disease of interest are measured at the same point in time. For this reason, generally the cross-sectional design does not provide definitive proofs about cause-and-effect relationships. An advantage of cross-sectional studies in aetiological and diagnostic research is that they allow researchers to consider many different putative risk factors/diagnostic markers at the same time. For example, in a hypothetical study aimed at generating hypotheses about the risk factors for left ventricular hypertrophy (LVH) in patients with chronic kidney disease, investigators could look at several risk factors as potential determinants of LVH (age, gender, cholesterol, blood pressure, inflammation, etc.) with minimal or no additional costs. In this article, we make examples derived from the nephrology literature to show the usefulness of cross-sectional studies in clinical and epidemiological research.
Research Interests: Nephrology, Epidemiology, Research Design, Inflammation, Medicine, and 14 moreHumans, Blood Pressure, Cholesterol, Disease, Etiology, Risk factors, Clinical Sciences, Sex Factors, Kidney Disease, Left ventricular hypertrophy, Age Factors, Risk Factors, Cross sectional Study, and Cross Sectional Studies
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Clinical epidemiological studies often focus on investigating the underlying causes of disease. For instance, a nephrologist may be interested in the association between blood pressure and the development of chronic kidney disease (CKD).... more
Clinical epidemiological studies often focus on investigating the underlying causes of disease. For instance, a nephrologist may be interested in the association between blood pressure and the development of chronic kidney disease (CKD). However, instead of focusing on the mere occurrence of CKD, the decline of kidney function over time might be the outcome of interest. For examining this kidney function trajectory, patients are typically followed over time with their kidney function estimated at several time points. During follow-up, some patients may drop out earlier than others and for different reasons. Furthermore, some patients may have greater kidney function at study entry or faster kidney function decline than others. Also, a substantial heterogeneity may exist in the number of kidney function estimates available for each patient. This heterogeneity with respect to kidney function, dropout and number of kidney function estimates is important to take into account when estimating kidney function trajectories. In general, two methods are used in the literature to estimate kidney function trajectories over time: linear regression to estimate individual slopes and the linear mixed-effects model (LMM), i.e. repeated measures analysis. Importantly, the linear regression method does not properly take into account the above-mentioned heterogeneity, whereas the LMM is able to retain all information and variability in the data. However, the underlying concepts, use and interpretation of LMMs are not always straightforward. Therefore we illustrate this using a clinical example and offer a framework of how to model and interpret the LMM.
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Research Interests: Epidemiology, Kidney diseases, Medicine, Population, Humans, and 15 moreChronic Disease, Disease, Psychological Intervention, Selection, Risk factors, Clinical Sciences, Risk Factor, Survival Rate, Kidney Disease, Intensive Care Medicine, Disease Progression, Risk Factors, Renal Replacement Therapy, Patient selection, and Cause of death
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Research Interests: Nephrology, Epidemiology, Dialysis, Medicine, Linear models, and 15 moreLogistic Regression, Humans, Kidney, Regression Analysis, Logistic Regression Analysis, Clinical Sciences, Odds ratio, Measures of Effectiveness, Randomized Clinical Trial, Linear Regression, Observational Study, Logistic Models, Relative Risk, confounding, and linear regression analysis
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Research Interests: Demography, Ethnic minorities, Medicine, Humans, Female, and 15 moreMale, Netherlands, Haemodialysis, Ethnic Groups, Clinical Sciences, Middle Aged, Ethnic Group, European Continental Ancestry Group, Asian Continental Ancestry Group, Ethnic Minorities, Chronic Kidney Failure, Creatinine, Marital Status, Cause of death, and hazard ratio
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Research Interests: Nephrology, Statistics, Kidney diseases, Dialysis, Performance, and 15 moreMedicine, Clinical Practice, Humans, Kidney, Cox Regression, ROC Curve, Accuracy, Clinical Sciences, Receiving Operating Characteristic, Precision, Diagnostic Accuracy, Diagnostic Test, Receiver Operating Characteristic, Risk Score, and cutoff
Research Interests: Mathematics, Nephrology, Statistics, Dialysis, Creatine, and 15 moreMedicine, Methods, Humans, Kidney, Calibration, Method, Agreement, Clinical Sciences, Repeated Measures, Reproducibility of Results, Correlation coefficient, Inulin, Statistical Approach, Glomerular Filtration Rate, and Limits of Agreement
Research Interests: Causality, Medicine, Comorbidity, Logistic Regression, Humans, and 15 moreKidney, Female, Male, Risk factors, Clinical Sciences, Cardiovascular Diseases, Interaction effect, Risk Factors, Indexation, Observational Study, Logistic Regression Model, Epidemiologic Studies, Logistic Models, Relative Risk, and Difference in Differences
Research Interests: Nephrology, Urology, Statistics, Kidney diseases, Bias, and 15 moreMedicine, Information, Humans, Biomedical Research, Animals, Information Bias, Selection, Medical Physiology, Sample Size, Publication Bias, Clinical Sciences, Reproducibility of Results, Selection Bias, Bias (Epidemiology), and confounding
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Kaplan-Meier analysis is a popular method used for analysing time-to-event data. In case of competing event analyses such as that of cardiovascular and non-cardiovascular mortality, however, the Kaplan-Meier method profoundly... more
Kaplan-Meier analysis is a popular method used for analysing time-to-event data. In case of competing event analyses such as that of cardiovascular and non-cardiovascular mortality, however, the Kaplan-Meier method profoundly overestimates the cumulative mortality probabilities for each of the separate causes of death. This article provides an introduction to the problem of competing events in Kaplan-Meier analysis. It explains cumulative incidence competing risk analysis and demonstrates on a cohort of elderly dialysis patients that, in contrast to the Kaplan-Meier method, application of this method yields unbiased estimates of the cumulative probabilities for cause-specific mortality.
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Research Interests: Nephrology, Epidemiology, Research Design, Randomization, Drug development, and 15 moreMedicine, Humans, Psychological Intervention, Medical Research, Selection, Medical Physiology, Renal Function, Clinical Sciences, Gold Standard, Randomized Controlled Trial, Chronic Kidney Failure, Renal Dialysis, Control Group, Randomized Controlled Trials as Topic, and Outcome Assessment Health Care(Medicine, Humans, Psychological Intervention, Medical Research, Selection, Medical Physiology, Renal Function, Clinical Sciences, Gold Standard, Randomized Controlled Trial, Chronic Kidney Failure, Renal Dialysis, Control Group, Randomized Controlled Trials as Topic, and Outcome Assessment Health Care)
(Medicine, Humans, Psychological Intervention, Medical Research, Selection, Medical Physiology, Renal Function, Clinical Sciences, Gold Standard, Randomized Controlled Trial, Chronic Kidney Failure, Renal Dialysis, Control Group, Randomized Controlled Trials as Topic, and Outcome Assessment Health Care)
Research Interests: Nephrology, Urology, Statistics, Stratification, Medicine, and 15 moreHumans, Medical Physiology, Sample Size, Birth Order, Clinical Sciences, Risk Factor, Sample Size Determination, Odds ratio, Case Control Study, Chronic Kidney Failure, Ratio, Case Control Studies, Cohort Studies, Relative Risk, and confounding
Research Interests: Nephrology, Statistics, Epidemiology, Kidney diseases, Survival Analysis, and 13 moreMedicine, Humans, Cox Regression, Regression, Regression Analysis, Confidence intervals, Medical Physiology, Clinical Sciences, Proportional hazards model, Proportional Hazards Models, Survival Analyses, Glomerular Filtration Rate, and confounding
Background and objectives In older people with kidney failure, improving health-related quality of life is often more important than solely prolonging life. However, little is known about the effect of dialysis initiation on... more
Background and objectives In older people with kidney failure, improving health-related quality of life is often more important than solely prolonging life. However, little is known about the effect of dialysis initiation on health-related quality of life in older patients. Therefore, we investigated the evolution of health-related quality of life before and after starting dialysis in older patients with kidney failure. Design, setting, participants, & measurements The European Quality study is an ongoing prospective, multicenter study in patients aged ≥65 years with an incident eGFR ≤20 ml/min per 1.73 m2. Between April 2012 and December 2021, health-related quality of life was assessed every 3–6 months using the 36-item Short-Form Health Survey (SF-36), providing a mental component summary (MCS) and a physical component summary (PCS). Scores range from zero to 100, with higher scores indicating better health-related quality of life. With linear mixed models, we explored the course...
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Research Interests: Nephrology, Urology, Dialysis, Survival Analysis, Medicine, and 14 moreHumans, Internal Medicine, Kidney, Diabetes mellitus, Cox Regression, Regression, Regression Analysis, Multiple Regression, Clinical Sciences, Proportional hazards model, Chronic Kidney Failure, Proportional Hazards Models, Univariate Analysis, and confounding
Research Interests: Nephrology, Chronic kidney disease, Inflammation, Medicine, Energy Metabolism, and 15 moreHumans, Metabolic diseases, Immunity, Animals, Disease, Lung Diseases, Fibroblast Growth Factor, Cells, Kidney Disease, Left ventricular hypertrophy, Intensive Care Medicine, Nervous System Diseases, Heart Diseases, Glomerular Filtration Rate, and Bone Diseases
Research Interests: Statistics, Research Design, Statistical Analysis, Medicine, Humans, and 15 moreFemale, Matching, Male, Cohort Study, Medical Physiology, Clinical Sciences, Sex Factors, Odds ratio, Case Control Study, Frequency Matching, Control Group, Case Control Studies, Cohort Studies, confounding, and Matching statistics
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Background We explore longitudinal trajectories of clinical indicators, patient-reported outcomes, and hospitalizations, in the years preceding death in a population of older patients with advanced chronic kidney disease (CKD). Methods... more
Background We explore longitudinal trajectories of clinical indicators, patient-reported outcomes, and hospitalizations, in the years preceding death in a population of older patients with advanced chronic kidney disease (CKD). Methods The EQUAL study is a European observational prospective cohort study with an incident eGFR <20 ml/min per 1.73 m2 and ≥65 years of age. The evolution of each clinical indicator was explored using generalized additive models during the 4 years preceding death. Results We included 661 decedents with a median time to death of 2.0 years (IQR 0.9–3.2). During the years preceding death, eGFR, Subjective Global Assessment score, and blood pressure declined, with accelerations seen at 6 months preceding death. Serum hemoglobin, hematocrit, cholesterol, calcium, albumin, and sodium values declined slowly during follow-up, with accelerations observed between 6 and 12 months preceding death. Physical and mental quality of life declined linearly throughout fol...
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Background Patients with chronic kidney disease (CKD) are at a higher risk of major adverse cardiovascular events (MACE) compared with the general population, but gender differences in this risk, especially in older adults, are not fully... more
Background Patients with chronic kidney disease (CKD) are at a higher risk of major adverse cardiovascular events (MACE) compared with the general population, but gender differences in this risk, especially in older adults, are not fully known. We aim to identify gender differences in the risk of MACE in older European CKD patients, and explore factors that may explain these differences. Methods The European Quality study (EQUAL) is a prospective study on stage 4–5 CKD patients, ≥65 years old, not on dialysis, from Germany, Italy, the Netherlands, Poland, Sweden and the UK. Cox regression and cumulative incidence competing risk curves were used to identify gender differences in MACE risks. Mediation analysis was used to identify variables which may explain risk differences between men and women. Results A total of 417 men out of 1134 (37%) and 185 women out of 602 women (31%) experienced at least one MACE, over a follow-up period of 5 years. Women had an 18% lower risk of first MACE...
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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... more
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 assesse...
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Ecological studies are observational studies commonly used in public health research. The main characteristic of this study design is that the statistical analysis is based on pooled (i.e., aggregated) rather than on individual data.... more
Ecological studies are observational studies commonly used in public health research. The main characteristic of this study design is that the statistical analysis is based on pooled (i.e., aggregated) rather than on individual data. Thus, patient‐level information such as age, gender, income and disease condition are not considered as individual characteristics but as mean values or frequencies, calculated at country or community level. Ecological studies can be used to compare the aggregated prevalence and incidence data of a given condition across different geographical areas, to assess time‐related trends of the frequency of a pre‐defined disease/condition, to identify factors explaining changes in health indicators over time in specific populations, to discriminate genetic from environmental causes of geographical variation in disease, or to investigate the relationship between a population‐level exposure and a specific disease or condition. The major pitfall in ecological stud...
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Translational research aims at reducing the gap between the results of studies focused on diagnosis, prognosis and therapy, and every day clinical practice. Prognosis is an essential component of clinical medicine. It aims at estimating... more
Translational research aims at reducing the gap between the results of studies focused on diagnosis, prognosis and therapy, and every day clinical practice. Prognosis is an essential component of clinical medicine. It aims at estimating the risk of adverse health outcomes in individuals, conditional to their clinical and non-clinical characteristics. There are three fundamental steps in prognostic research: development studies, in which the researcher identifies predictors, assigns the weights to each predictor, and assesses the model’s accuracy through calibration, discrimination and risk reclassification; validation studies, in which investigators test the model’s accuracy in an independent cohort of individuals; and impact studies, in which researchers evaluate whether the use of a prognostic model by clinicians improves their decision-making and patient outcome. This article aims at clarifying how to reduce the disconnection between the promises of prognostic research and the de...
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Background Patients with stage 4/5 chronic kidney disease (CKD) suffer from various symptoms. The retention of uremic solutes is thought to be associated with those symptoms. However, there are relatively few rigorous studies on the... more
Background Patients with stage 4/5 chronic kidney disease (CKD) suffer from various symptoms. The retention of uremic solutes is thought to be associated with those symptoms. However, there are relatively few rigorous studies on the potential links between uremic toxins and symptoms in patients with CKD. Methods The EQUAL study is an ongoing observational cohort study of non-dialyzed patients with stage 4/5 CKD. EQUAL patients from Germany, Poland, Sweden and the UK were included in the present study (n = 795). Data and symptom self-report questionnaires were collected between April 2012 and September 2020. Baseline uric acid and parathyroid hormone and 10 uremic toxins were quantified. We tested the association between uremic toxins and symptoms and adjusted P-values for multiple testing. Results Symptoms were more frequent in women than in men with stage 4/5 CKD, while levels of various uremic toxins were higher in men. Only trimethylamine N-oxide (TMAO; positive association with ...
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In nephrology, a great deal of information is measured repeatedly in patients over time, often alongside data on events of clinical interest. In this introductory article we discuss how these two types of data can be simultaneously... more
In nephrology, a great deal of information is measured repeatedly in patients over time, often alongside data on events of clinical interest. In this introductory article we discuss how these two types of data can be simultaneously analysed using the joint model (JM) framework, illustrated by clinical examples from nephrology. As classical survival analysis and linear mixed models form the two main components of the JM framework, we will also briefly revisit these techniques.
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The correlation coefficient is a statistical measure often used in studies to show an association between variables or to look at the agreement between two methods. In this paper, we will discuss not only the basics of the correlation... more
The correlation coefficient is a statistical measure often used in studies to show an association between variables or to look at the agreement between two methods. In this paper, we will discuss not only the basics of the correlation coefficient, such as its assumptions and how it is interpreted, but also important limitations when using the correlation coefficient, such as its assumption of a linear association and its sensitivity to the range of observations. We will also discuss why the coefficient is invalid when used to assess agreement of two methods aiming to measure a certain value, and discuss better alternatives, such as the intraclass coefficient and Bland–Altman’s limits of agreement. The concepts discussed in this paper are supported with examples from literature in the field of nephrology.
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In evidence‐based medicine, clinical research questions may be addressed by different study designs. This article describes when randomized controlled trials (RCT) are needed and when observational studies are more suitable. According to... more
In evidence‐based medicine, clinical research questions may be addressed by different study designs. This article describes when randomized controlled trials (RCT) are needed and when observational studies are more suitable. According to the Centre for Evidence‐Based Medicine, study designs can be divided into analytic and non‐analytic (descriptive) study designs. Analytic studies aim to quantify the association of an intervention (eg, treatment) or a naturally occurring exposure with an outcome. They can be subdivided into experimental (ie, RCT) and observational studies. The RCT is the best study design to evaluate the intended effect of an intervention, because the randomization procedure breaks the link between the allocation of the intervention and patient prognosis. If the randomization of the intervention or exposure is not possible, one needs to depend on observational analytic studies, but these studies usually suffer from bias and confounding. If the study focuses on unint...
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Patient‐reported outcome measures (PROMs) are increasingly being used in nephrology care. However, in contrast to well‐known clinical measures such as blood pressure, health‐care professionals are less familiar with PROMs and the... more
Patient‐reported outcome measures (PROMs) are increasingly being used in nephrology care. However, in contrast to well‐known clinical measures such as blood pressure, health‐care professionals are less familiar with PROMs and the interpretation of PROM scores is therefore perceived as challenging. In this paper, we provide insight into the interpretation of PROM scores by introducing the different types and characteristics of PROMs, and the most relevant concepts for the interpretation of PROM scores. Concepts such as minimal detectable change, minimal important change and response shift are explained and illustrated with examples from nephrology care.
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Background: Uncontrolled hypertension notwithstanding the use of at least three drugs or hypertension controlled with at least four drugs, the widely accepted definition of treatment-resistant hypertension (TRH), is considered as a common... more
Background: Uncontrolled hypertension notwithstanding the use of at least three drugs or hypertension controlled with at least four drugs, the widely accepted definition of treatment-resistant hypertension (TRH), is considered as a common problem in the hemodialysis population. However, to date there is no estimate of the prevalence of this condition in hemodialysis patients. Method: We estimated the prevalence of TRH by 44-h ambulatory BP monitoring (ABPM) in 506 hemodialysis patients in 10 renal units in Europe included in the registry of the European Renal and Cardiovascular Medicine (EURECAm,), a working group of the European Association, European Dialysis and Transplantation Association (ERA EDTA). In a sub-group of 114 patients, we tested the relationship between fluid overload (Body Composition monitor) and TRH. Results: The prevalence of hypertension with 44-h ABPM criteria was estimated at 85.6% (434 out of 506 patients). Of these, 296 (58%) patients were classified as unco...
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Medical societies have a social responsibility to disseminate knowledge and inform health authorities on threats to public health posed by various diseases. Advocacy for health protection programmes and for medical research funding is now... more
Medical societies have a social responsibility to disseminate knowledge and inform health authorities on threats to public health posed by various diseases. Advocacy for health protection programmes and for medical research funding is now embedded into the missions of most scientific societies. To promote kidney research funding in Europe, the European Renal Association – European Dialysis and Transplant Association (ERA-EDTA), rather than acting as an individual society advocating for the fight against kidney disease, has actively helped to create an alliance of national associations centred on kidney diseases, the European Kidney Health Alliance (EKHA), and joined the Biomedical Alliance (BMA). The ERA-EDTA is fully committed to supporting its working groups (WGs) and consortia of its members to allow them to produce valuable kidney research. The framing and formalization of projects, and the regulatory issues related to submission to the European Commission, are complex. To help ...
Research Interests: Research, Medicine, Scientific Societies, Kidney, Alliance, and 3 moreClinical Sciences, Funding, and Ckd
A funnel plot is a graphical method to evaluate health‐care quality by comparing hospital performances on certain outcomes. So far, in nephrology, this method has been applied to clinical outcomes like mortality and complications.... more
A funnel plot is a graphical method to evaluate health‐care quality by comparing hospital performances on certain outcomes. So far, in nephrology, this method has been applied to clinical outcomes like mortality and complications. However, patient‐reported outcomes (PROs; eg, health‐related quality of life [HRQOL]) are becoming increasingly important and should be incorporated into this quality assessment. Using funnel plots has several advantages, including clearly visualized precision, detection of volume‐effects, discouragement of ranking hospitals and easy interpretation of results. However, without sufficient knowledge of underlying methods, it is easy to stumble into pitfalls, such as overinterpretation of standardized scores, incorrect direct comparisons of hospitals and assuming a hospital to be in‐control (ie, to perform as expected) based on underpowered comparisons. Furthermore, application of funnel plots to PROs is accompanied by additional challenges related to the multidimensional nature of PROs and difficulties with measuring PROs. Before using funnel plots for PROs, high and consistent response rates, adequate case mix correction and high‐quality PRO measures are required. In this article, we aim to provide insight into the use and interpretation of funnel plots by presenting an overview of the basic principles, pitfalls and considerations when applied to PROs, using examples from Dutch routine dialysis care.
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Lung congestion, estimated by lung ultrasound is a risk factor for all-cause and cardiovascular mortality in patients on chronic hemodialysis and may be useful to guide ultrafiltration and drug therapy in this population. In an... more
Lung congestion, estimated by lung ultrasound is a risk factor for all-cause and cardiovascular mortality in patients on chronic hemodialysis and 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.