Rationale & Objective: Cardiovascular disease is the leading cause of morbidity and mortality in chronic kidney disease (CKD). We investigated 184 inflammatory and cardiovascular proteins to... Show moreRationale & Objective: Cardiovascular disease is the leading cause of morbidity and mortality in chronic kidney disease (CKD). We investigated 184 inflammatory and cardiovascular proteins to determine their potential as biomarkers for major cardiovascular events (MACEs).Study Design: The European Quality (EQUAL) is an observational cohort study that enrolled people aged >= 65 years with an estimated glomerular filtration rate <= 20 mL/min/1.73 m(2).Setting & Participants: Recruited participants were split into the discovery (n = 611) and replication cohorts (n = 292).Exposure: Levels of 184 blood proteins were measured at the baseline visit, and each protein was analyzed individually.Outcome: MACE.Analytical Approach: Cox proportional hazard models adjusted for age, sex, estimated glomerular filtration rate, previous MACE, and country were used to determine the risk of MACE. Proteins with false discovery rate adjusted P values of <0.05 in the discovery cohort were tested in the replication cohort. Sensitivity analyses were performed by adjusting for traditional risk factors, CKD-specific risk factors, and level of proteinuria and segregating atherosclerotic and nonatherosclerotic MACE.Results: During a median follow-up of 2.9 years, 349 people (39%) experienced a MACE. Forty-eight proteins were associated with MACE in the discovery cohort; 9 of these were reproduced in the replication cohort. Three of these proteins maintained a strong association with MACE after adjustment for traditional and CKD-specific risk factors and proteinuria. Tenascin (TNC), fibroblast growth factor-23 (FGF-23), and V-set and immunoglobulin domain-containing protein 2 (VSIG2) were associated with both atherosclerotic and nonatherosclerotic MACE. All replicated proteins except carbonic anhydrase 1 and carbonic anhydrase 3 were associated with nonatherosclerotic MACE.Limitations: Single protein concentration measurements and limited follow-up time.Conclusions: Our findings corroborate previously reported relationships between FGF-23, vascular cell adhesion protein-1, TNC, and placental growth factor with cardiovascular outcomes in CKD. We identify 5 proteins not previously linked with MACE in CKD that may be targets for future therapies. Show less
Canney, M.; Induruwage, D.; Tang, M.L.; Pinho, N.A. de; Er, L.; Zhao, Y.S.; ... ; ISN INET-CKD Investigators 2023
Introduction: Despite recognized geographic and sex-based differences in hemoglobin in the general population, these factors are typically ignored in patients with chronic kidney disease (CKD) in... Show moreIntroduction: Despite recognized geographic and sex-based differences in hemoglobin in the general population, these factors are typically ignored in patients with chronic kidney disease (CKD) in whom a single therapeutic range for hemoglobin is recommended. We sought to compare the distribution of hemoglobin across international nondialysis CKD populations and evaluate predictors of hemoglobin.Methods: In this cross-sectional study, hemoglobin distribution was evaluated in each cohort overall and stratified by sex and estimated glomerular filtration rate (eGFR). Relationships between candidate predictors and hemoglobin were assessed from linear regression models in each cohort. Estimates were subsequently pooled in a random effects model.Results: A total of 58,613 participants from 21 adult cohorts (median eGFR range of 17-49 ml/min) and 3 pediatric cohorts (median eGFR range of 26-45 ml/min) were included with broad geographic representation. Hemoglobin values varied substantially among the cohorts, overall and within eGFR categories, with particularly low mean hemoglobin observed in women from Asian and African cohorts. Across the eGFR range, women had a lower hemoglobin compared to men, even at an eGFR of 15 ml/min (mean difference 5.3 g/l, 95% confidence interval [CI] 3.7-6.9). Lower eGFR, female sex, older age, lower body mass index, and diabetic kidney disease were all independent predictors of a lower hemoglobin value; however, this only explained a minority of variance (R-2 7%-44% across cohorts).Conclusion: There are substantial regional differences in hemoglobin distribution among individuals with CKD, and the majority of variance is unexplained by demographics, eGFR, or comorbidities. These findings call for a renewed interest in improving our understanding of hemoglobin determinants in specific CKD populations. Show less
Rationale & Objective: Hypokalemia may accelerate kidney function decline. Both hypo- and hyperkalemia can cause sudden cardiac death. However, little is known about the relationship between... Show moreRationale & Objective: Hypokalemia may accelerate kidney function decline. Both hypo- and hyperkalemia can cause sudden cardiac death. However, little is known about the relationship between serum potassium and death or the occurrence of kidney failure requiring replacement therapy (KRT). We investigated this relationship in older people with chronic kidney disease (CKD) stage 4-5.Study Design: Prospective observational cohort study.Setting & Participants: We followed 1,714 patients (>= 65 years old) from the European Quality (EQUAL) study for 8 years from their first estimated glomerular filtration rate (eGFR) < 20 mL/min/1.73 m(2) measurement. Exposure: Serum potassium was measured every 3 to 6 months and categorized as <= 3.5, >3.5-<= 4.0, >4.0-<= 4.5, >4.5-<= 5.0 (reference), >5.0-<= 5.5, >5.5-<= 6.0, and >6.0 mmol/L.Outcome: The combined outcome death before KRT or start of KRT.Analytical Approach: The association between categorical and continuous time-varying potassium and death or KRT start was examined using Cox proportional hazards and restricted cubic spline analyses, adjusted for age, sex, diabetes, cardiovascular disease, renin-angiotensin-aldosterone system (RAAS) inhibition, eGFR, and subjective global assessment (SGA).Results: At baseline, 66% of participants were men, 42% had diabetes, 47% cardiovascular disease, and 54% used RAAS inhibitors. Their mean age was 76 +/- 7 (SD) years, mean eGFR was 17 +/- 5 (SD) mL/min/1.73 m(2), and mean SGA was 6.0 +/- 1.0 (SD). Over 8 years, 414 (24%) died before starting KRT, and 595 (35%) started KRT. Adjusted hazard ratios for death or KRT according to the potassium categories were 1.6 (95% CI, 1.1-2.3), 1.4 (95% CI, 1.1-1.7), 1.1 (95% CI, 1.0-1.4), 1 (reference), 1.1 (95% CI, 0.9-1.4), 1.8 (95% CI, 1.4-2.3), and 2.2 (95% CI, 1.5-3.3). Hazard ratios were lowest at a potassium of about 4.9 mmol/L.Limitations: Shorter intervals between potassium measurements would have allowed for more precise estimations.Conclusions: We observed a U-shaped relationship between serum potassium and death or KRT start among patients with incident CKD 4- 5, with a nadir risk at a potassium level of 4.9 mmol/L. These findings underscore the potential importance of preventing both high and low potassium in patients with CKD 4-5. Show less
Background Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a common complication of CKD; it is associated with higher mortality in dialysis patients, while its impact in non-dialysis... Show moreBackground Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a common complication of CKD; it is associated with higher mortality in dialysis patients, while its impact in non-dialysis patients remains mostly unknown. We investigated the associations between parathyroid hormone (PTH), phosphate and calcium (and their interactions), and all-cause, cardiovascular (CV) and non-CV mortality in older non-dialysis patients with advanced CKD. Methods We used data from the European Quality study, which includes patients aged & GE;65 years with estimated glomerular filtration rate & LE;20 mL/min/1.73 m(2) from six European countries. Sequentially adjusted Cox models were used to assess the association between baseline and time-dependent CKD-MBD biomarkers and all-cause, CV and non-CV mortality. Effect modification between biomarkers was also assessed. Results In 1294 patients, the prevalence of CKD-MBD at baseline was 94%. Both PTH [adjusted hazard ratio (aHR) 1.12, 95% confidence interval (CI) 1.03-1.23, P = .01] and phosphate (aHR 1.35, 95% CI 1.00-1.84, P = .05), but not calcium (aHR 1.11, 95% CI 0.57-2.17, P = .76), were associated with all-cause mortality. Calcium was not independently associated with mortality, but modified the effect of phosphate, with the highest mortality risk found in patients with both hypercalcemia and hyperphosphatemia. PTH level was associated with CV mortality, but not with non-CV mortality, whereas phosphate was associated with both CV and non-CV mortality in most models. Conclusions CKD-MBD is very common in older non-dialysis patients with advanced CKD. PTH and phosphate are independently associated with all-cause mortality in this population. While PTH level is only associated with CV mortality, phosphate seems to be associated with both CV and non-CV mortality. Show less
Astley, M.; Caskey, F.J.; Evans, M.; Torino, C.; Szymczak, M.; Drechsler, C.; ... ; EQUAL Study Investigators 2023
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,... Show moreBackground. 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 compared with men (hazard ratio 0.82; 95% confidence interval 0.69-0.97; P =.02), which was attenuated after adjusting for pre-existing cardiometabolic comorbidities and cardiovascular risk factors. There were no significant gender differences in the risk of recurrent MACE or fatal MACE. The risk difference in MACE by gender was larger in patients aged 65-75 years, compared with patients over 75 years.Conclusions. In a cohort of older adults with advanced CKD, women had lower risks of MACE. These risk differences were partially explained by pre-existing cardiometabolic comorbidities and cardiovascular risk factors.[GRAPHICS]. Show less
Lay Summary Our study compared the incidence of dialysis, the most common treatment modality for kidney failure, in the Netherlands with 11 other European countries/regions between 2001 and 2019.... Show moreLay Summary Our study compared the incidence of dialysis, the most common treatment modality for kidney failure, in the Netherlands with 11 other European countries/regions between 2001 and 2019. We observed a decline in the dialysis incidence in the last decade, most marked among patients aged >= 65 years. Similar trends were found in Austria, Denmark, England/Wales, Finland, Scotland, and Sweden. Although the number of kidney transplantations increased significantly, this can only explain a minor part of the observed decrease in the dialysis incidence among these older patients. An increase in the number of patients choosing to forego dialysis (i.e. conservative care) or improvement of preventive care for cardiovascular- or kidney disease, are likely explanations. Our study stresses the need for registration of patients with earlier stages of chronic kidney disease and patients that choose conservative care. This would allow for better assessment of healthcare utilization and outcomes in these patient groups.Introduction After decades of increasing dialysis incidence, we observed a decreasing trend in the Netherlands in the last decade. We compared this trend with trends in other European countries. Materials and Methods Aggregated data for calendar years 2001-2019 from the Dutch registries of kidney replacement therapy patients and the European Renal Association Registry were used. Dialysis incidence in the Netherlands was compared with that in 11 other European countries/regions using three age groups: 20-64, 65-74, and >= 75 years, taking into account pre-emptive kidney transplantation (PKT) incidence. Time trends were assessed as annual percentage change (APC) with 95% confidence intervals (CI) using joinpoint regression analysis. Results Between 2001 and 2019 the Dutch dialysis incidence decreased slightly among patients aged 20-64 years (APC -0.9, 95% CI -1.4; -0.5). For patients 65-74 and >= 75 years old, a peak was seen in 2004 and 2009, respectively. Afterwards, the decrease was most marked in patients aged >= 75 years: APC -3.2 (-4.1; -2.3) versus APC -1.8 (-2.2; -1.3) for patients 65-74 years old. PKT incidence increased significantly during the study period but remained limited compared to the observed decrease in dialysis incidence, especially among older patients. Large differences in dialysis incidence were observed among European countries/regions. A decreasing dialysis incidence among older patients was also seen in Austria, Denmark, England/Wales, Finland, Scotland, and Sweden. Conclusions The Dutch dialysis incidence decreased most profoundly among older patients. This was also observed in several other European countries/regions. Although PKT incidence increased, it can only explain a minor part of the decrease in dialysis incidence. Show less
Background The aim of this study was to identify trends in total, deceased donor (DD) and living donor (LD) kidney transplantation (KT) rates in European countries. Methods The European Renal... Show moreBackground The aim of this study was to identify trends in total, deceased donor (DD) and living donor (LD) kidney transplantation (KT) rates in European countries. Methods The European Renal Association (ERA) Registry and the Global Observatory on Donation and Transplantation (GODT) databases were used to obtain the number of KTs in individual European countries between 2010 and 2018. General population counts were obtained from Eurostat or the national bureaus of statistics. The KT rate per million population (p.m.p.) and the average annual percentage change (APC) were calculated. Results The total KT rate in the 40 participating countries increased with 1.9% annually [95% confidence interval (CI) 1.5, 2.2] from 29.6 p.m.p. in 2010 to 34.7 p.m.p. in 2018, reflecting an increase of 3.4 p.m.p. in the DD-KT rate (from 21.6 p.m.p. to 25.0 p.m.p.; APC 1.9%; 95% CI 1.3, 2.4) and of 1.5 p.m.p. in the LD-KT rate (from 8.1 p.m.p. to 9.6 p.m.p.; APC 1.6%; 95% CI 1.0, 2.3). The trends in KT rate varied widely across European countries. An East-West gradient was observed for DD-KT rate, with Western European countries performing more KTs. In addition, most countries performed fewer LD-KTs. In 2018, Spain had the highest DD-KT rate (64.6 p.m.p.) and Turkey the highest LD-KT rate (37.0 p.m.p.). Conclusions The total KT rate increased due to a rise in the KT rate from DDs and to a lesser extent from LDs, with large differences between individual European countries. Show less
Janse, R.J.; Hoekstra, T.; Jager, K.J.; Zoccali, C.; Tripepi, G.; Dekker, F.W.; Diepen, M. van 2021
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... Show moreThe 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. Show less
Epidemiological studies often aim to investigate the causal contribution of a risk factor to a disease or other outcome. In etiological research, one is usually interested in the (biological)... Show moreEpidemiological studies often aim to investigate the causal contribution of a risk factor to a disease or other outcome. In etiological research, one is usually interested in the (biological) mechanism(s) underlying the studied relationship. Inappropriate conduct of an etiological study may have major implications for the correctness of the results and interpretation of the findings. Therefore, in this paper, we aim to describe step by step how etiological research should be carried out, together with its common pitfalls. These steps involve finding and formulating a well-defined etiological research question, choosing an appropriate study design including a suitable comparison group, adequate modelling, and adequate reporting and interpretation of the results. Show less
Roumeliotis, S.; Abd ElHafeez, S.; Jager, K.J.; Dekker, F.W.; Stel, V.S.; Pitino, A.; ... ; Tripepi, G. 2021
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.,... Show moreEcological 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 studies is the ecological fallacy, a bias which occurs when conclusions about individuals are erroneously deduced from results about the group to which those individuals belong. In this paper, by using a series of examples, we provide a general explanation of the ecological studies and provide some useful elements to recognize or suspect ecological fallacy in this type of studies. Show less
Ramspek, C.L.; Jager, K.J.; Dekker, F.W.; Zoccali, C.; Diepen, M. van 2021
Prognostic models that aim to improve the prediction of clinical events, individualized treatment and decision-making are increasingly being developed and published. However, relatively few models... Show morePrognostic models that aim to improve the prediction of clinical events, individualized treatment and decision-making are increasingly being developed and published. However, relatively few models are externally validated and validation by independent researchers is rare. External validation is necessary to determine a prediction model's reproducibility and generalizability to new and different patients. Various methodological considerations are important when assessing or designing an external validation study. In this article, an overview is provided of these considerations, starting with what external validation is, what types of external validation can be distinguished and why such studies are a crucial step towards the clinical implementation of accurate prediction models. Statistical analyses and interpretation of external validation results are reviewed in an intuitive manner and considerations for selecting an appropriate existing prediction model and external validation population are discussed. This study enables clinicians and researchers to gain a deeper understanding of how to interpret model validation results and how to translate these results to their own patient population. Show less
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... Show moreIn 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 theintendedeffect 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 onunintendedeffects of interventions (ie, effects of an intervention that are not intended or foreseen), observational analytic studies are the most suitable study designs, provided that there is no link between the allocation of the intervention and the unintended effect. Furthermore, non-analytic studies (ie, descriptive studies) also rely on observational study designs. In summary, RCTs and observational study designs are inherently different, and depending on the study aim, they each have their own strengths and weaknesses. Show less
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... Show moreIn 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. Show less
Study quality depends on a number of factors, one of them being internal validity. Such validity can be affected by random and systematic error, the latter also known as bias. Both make it more... Show moreStudy quality depends on a number of factors, one of them being internal validity. Such validity can be affected by random and systematic error, the latter also known as bias. Both make it more difficult to assess a correct frequency or the true relationship between exposure and outcome. Where random error can be addressed by increasing the sample size, a systematic error in the design, the conduct or the reporting of a study is more problematic. In this article, we will focus on bias, discuss different types of selection bias (sampling bias, confounding by indication, incidence-prevalence bias, attrition bias, collider stratification bias and publication bias) and information bias (recall bias, interviewer bias, observer bias and lead-time bias), indicate the type of studies where they most frequently occur and provide suggestions for their prevention. Show less
