Search

Objective: The aim of this study was to explore the changes in nutritional status before dialysis initiation and to identify modifiable risk factors of nutritional status decline in older adults with advanced renal disease.& nbsp;Design and Methods: The European Quality Study on treatment in advanced chronic kidney disease (EQUAL) is a prospective, observational cohort study involving six European countries. We included 1,103 adults > 65 years with incident estimated glomerular filtration rate < 20 mL/min/1.73 m(2) not on dialysis, attending nephrology care. Nutritional status was assessed with the 7-point Subjective Global Assessment tool (7-p SGA), patient-reported outcomes with RAND-36 and the Dialysis Symptom Index. Logistic regression was used to estimate the associations between potential risk factors and SGA decline.& nbsp;Results: The majority of the patients had a normal nutritional status at baseline, 28% were moderately malnourished (SGA = 2 points). The proportion of patients with low SGA (

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 WGs to gain expert advice from agencies with specific know-how, the ERA-EDTA has adopted a competitive approach. The best research projects proposed by WGs and consortia of other European investigators will receive seed funding to cover the costs of consultancy by expert agencies. Via its broader platforms, the EKHA and the BMA, the ERA-EDTA will strive towards broader recognition of kidney disease and related clusters of non-communicable diseases, by European and national agencies, as major threats to the qualities of life of their populations and their economies.

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.

Background: In Europe, the number of elderly end-stage kidney disease patients is increasing. Few of those patients receive peritoneal dialysis (PD), as many cannot perform PD autonomously. Assisted PD programmes are available in most European countries, but the percentage of patients receiving assisted PD varies considerably. Hence, we assessed which factors are associated with the availability of an assisted PD programme at a centre level and whether the availability of this programme is associated with proportion of home dialysis patients. Methods: An online survey was sent to healthcare professionals of European nephrology units. After selecting one respondent per centre, the associations were explored by χ 2 tests and (ordinal) logistic regression. Results: In total, 609 respondents completed the survey. Subsequently, 288 respondents from individual centres were identified; 58% worked in a centre with an assisted PD programme. Factors associated with availability of an assisted PD programme were Western European and Scandinavian countries (OR: 5.73; 95% CI: 3.07–10.68), non-academic centres (OR: 2.01; 95% CI: 1.09–3.72) and centres with a dedicated team for education (OR: 2.87; 95% CI: 1.35–6.11). Most Eastern & Central European respondents reported that the proportion of incident and prevalent home dialysis patients was 30% for both incident and prevalent home dialysis patients. Availability of an assisted PD programme was associated with a higher incidence (cumulative OR: 1.91; 95% CI: 1.21–3.01) and prevalence (cumulative OR: 2.81; 95% CI: 1.76–4.47) of patients on home dialysis. Conclusions: Assisted PD was more commonly offered among non-academic centres with a dedicated team for education across Europe, especially among Western European and Scandinavian countries where higher incidence and prevalence of home dialysis patients was reported.

In this article we introduce the concept of inverse probability of treatment weighting (IPTW) and describe how this method can be applied to adjust for measured confounding in observational research, illustrated by a clinical example from nephrology. IPTW involves two main steps. First, the probability—or propensity—of being exposed to the risk factor or intervention of interest is calculated, given an individual’s characteristics (i.e. propensity score). Second, weights are calculated as the inverse of the propensity score. The application of these weights to the study population creates a pseudopopulation in which confounders are equally distributed across exposed and unexposed groups. We also elaborate on how weighting can be applied in longitudinal studies to deal with informative censoring and time-dependent confounding in the setting of treatment-confounder feedback.

BackgroundThe use of patient-reported outcome measures (PROMs) is becoming increasingly important in healthcare. However, incorporation of PROMs into routine nephrological care is challenging. This study describes the first experience with PROMs in Dutch routine dialysis care.MethodsA pilot study was conducted in dialysis patients in 16 centres. Patients were invited to complete PROMs at baseline and 3 and 6 months. PROMs consisted of the 12-item short-form and Dialysis Symptom Index to assess health-related quality of life (HRQoL) and symptom burden. Response rates, HRQoL and symptom burden scores were analysed. Qualitative research methods were used to gain insight into patients’ views on using PROMs in clinical practice.ResultsIn total, 512 patients (36%) completed 908 PROMs (24%) across three time points. Response rates varied from 6 to 70% among centres. Mean scores for physical and mental HRQoL were 35.6 [standard deviation (SD) 10.2] and 47.7 (SD 10.6), respectively. Patients experienced on average 10.8 (SD 6.1) symptoms with a symptom burden score of 30.7 (SD 22.0). Only 1–3% of the variation in PROM scores can be explained by differences between centres. Patients perceived discussing their HRQoL and symptom scores as insightful and valuable. Individual feedback on results was considered crucial.ConclusionsThe first results show low average response rates with high variability among centres. Dialysis patients experienced a high symptom burden and poor HRQoL. Using PROMs at the individual patient level is suitable and may improve patient–professional communication and shared decision making. Further research is needed to investigate how the collection and the use of PROMs can be successfully integrated into routine care to improve healthcare quality and outcomes.

Background Hospital readmission after transplantation is common in kidney transplant recipients (KTRs). In this study, we aim to compare the risk of 3-month hospital readmission after kidney transplantation with different donor types in the overall population and in both young ( Methods We included all first-time adult KTRs from 2016 to 2018 in the Netherlands Organ Transplant Registry. Multivariable logistic regression models were used to estimate the effect while adjusting for baseline confounders. Results Among 1917 KTRs, 615 (32.1%) had at least one hospital readmission. Living donor kidney transplantation (LDKT) recipients had an adjusted OR of 0.76 (95%CI, 0.61 to 0.96; p = 0.02) for hospital readmission compared to deceased donor kidney transplantation (DDKT) recipients. In the young and elderly, the adjusted ORs were 0.69 (95%CI, 0.52 to 0.90, p = 0.01) and 0.93 (95%CI, 0.62 to 1.39, p = 0.73) and did not differ significantly from each other (p-value for interaction = 0.38). In DDKT, the risk of hospital readmission is similar between recipients with donation after cardiac death (DCD) or brain death (DBD) and the risk was similar between the young and elderly. Conclusion A lower risk of post-transplant 3-month hospital readmission was found in recipients after LDKT compared to DDKT, and this benefit of LDKT might be less dominant in elderly patients. In DDKT, having either DCD or DBD donors is not associated with post-transplant 3-month hospital readmission, regardless of age. Tailored patient management is needed for recipients with DDKT and elderly KTRs.

Aims The increasing prevalence of ischaemic stroke (IS) can partly be explained by the likewise growing number of patients with chronic kidney disease (CKD). Risk scores have been developed to identify high-risk patients, allowing for personalized anticoagulation therapy. However, predictive performance in CKD is unclear. The aim of this study is to validate six commonly used risk scores for IS in atrial fibrillation (AF) patients across the spectrum of kidney function. Methods and results Overall, 36 004 subjects with newly diagnosed AF from SCREAM (Stockholm CREAtinine Measurements), a healthcare utilization cohort of Stockholm residents, were included. Predictive performance of the AFI, CHADS2, Modified CHADS2, CHA2DS2-VASc, ATRIA, and GARFIELD-AF risk scores was evaluated across three strata of kidney function: normal kidney function [estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m2], mild CKD (eGFR 30–60 mL/min/1.73 m2), and advanced CKD (eGFR, Graphical Abstract Weighing stroke and bleeding risk is essential for individualized medicine.

Background People with chronic kidney disease (CKD) are at high risk of polypharmacy. However, no previous study has investigated international prescribing patterns in this group. This article aims to examine prescribing and polypharmacy patterns among older people with advanced CKD across the countries involved in the European Quality (EQUAL) study. Methods The EQUAL study is an international prospective cohort study of patients ≥65 years of age with advanced CKD. Baseline demographic, clinical and medication data were analysed and reported descriptively. Polypharmacy was defined as ≥5 medications and hyperpolypharmacy as ≥10. Univariable and multivariable linear regressions were used to determine associations between country and the number of prescribed medications. Univariable and multivariable logistic regression were used to determine associations between country and hyperpolypharmacy. Results Of the 1317 participants from five European countries, 91% were experiencing polypharmacy and 43% were experiencing hyperpolypharmacy. Cardiovascular medications were the most prescribed medications (mean 3.5 per person). There were international differences in prescribing, with significantly greater hyperpolypharmacy in Germany {odds ratio (OR) 2.75 [95% confidence interval (CI) 1.73–4.37]; P Conclusions Hyperpolypharmacy is common among older people with advanced CKD, with significant international differences in the number of medications prescribed. Practice variation may represent a lack of consensus regarding appropriate prescribing for this high-risk group for whom pharmacological treatment has great potential for harm as well as benefit.

Introduction Preservation of peritoneal function is essential in long-term peritoneal dialysis. Biocompatible dialysis solutions might prevent or postpone the membrane alteration resulting in ultrafiltration failure and consecutive morbidity and mortality. Methods We conducted an observational cohort study in which we made a longitudinal comparison between the course of peritoneal solute and fluid transport during treatment with conventional and biocompatible solutions. Therefore, prospectively collected peritoneal transport data from the yearly standard peritoneal permeability analysis were analyzed in 251 incident patients treated between 1994 and censoring in 2016. Fluid transport included small pore and free water transport. Solute transport was assessed by creatinine mass transfer area coefficient and glucose absorption. Linear mixed models including change point analyses were performed. Interaction with peritonitis was examined. Results One hundred thirty-five patients received conventional and 116 biocompatible solutions. Sixty-seven percent (conventional) and 64% (biocompatible) of these underwent minimally three transport measurements. Initially, biocompatible fluids showed higher small solute transport and lower ultrafiltration than conventional fluids up to 3 years. Thereafter, conventional fluids showed an increase in small solute transport (+2.7 ml/min per year; 95% confidence interval [CI]: 0.9 to 4.5) and a decrease of free water transport (−28.0 ml/min per year; 95% CI: −60.4 to 4.4). These were minor or absent in biocompatible treatment. Peritonitis induced a decrease of transcapillary ultrafiltration after 2 years on dialysis with conventional solutions (−291 ml/min per year; 95% CI: −550 to −32) while this was absent in biocompatible treatment. Conclusion Despite a higher initial solute transport with biocompatible solutions, these have less influence on functional long-term peritoneal alterations than conventional solutions., Graphical abstract

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 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.

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., SUMMARY AT A GLANCE The statistical review provides insights into the use and interpretation of funnel plots by presenting an overview of the basic principles, pitfalls and considerations when applied to patient‐reported outcomes using examples from Dutch routine dialysis care.

Physical activity potentially improves health outcomes in patients with chronic kidney disease (CKD) and recipients of kidney transplants. Although studies have demonstrated the beneficial effects of physical activity and exercise for primary and secondary prevention of non-communicable diseases, evidence for kidney patients is limited. To enlarge this evidence, valid assessment of physical activity and exercise is essential. Furthermore, CKD is associated with a decline in physical function, which may result in severe disabilities and dependencies. Assessment of physical function may help clinicians to monitor disease progression and frailty in patients receiving dialysis. The attention on physical function and physical activity has grown and new devices have been developed and (commercially) launched on the market. Therefore the aims of this review were to summarize different measures of physical function and physical activity, provide an update on measurement instruments and discuss options for easy-to-use measurement instruments for day-to-day use by CKD patients. This review demonstrates that large variation exists in the different strategies to assess physical function and activity in clinical practice and research settings. To choose the best available method, accuracy, content, preferable outcome, necessary expertise, resources and time are important issues to consider.

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 unintended effects 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., SUMMARY AT A GLANCE In evidence‐based medicine, clinical research questions may be addressed by different study designs. In this article, we explain that randomized controlled trials and observational study designs are inherently different, and depending on the study aim, they each have their own strengths and weaknesses.

In clinical epidemiology, experimental studies usually take the form of randomized controlled clinical trials (RCTs). The data analysis of an RCT can be performed by using two complementary strategies, that is according to the intention to treat (ITT) principle and the per protocol (PP) analysis. By using the ITT approach, investigators aim to assess the effect of assigning a drug whereas by adopting the PP analysis, researchers investigate the effect of receiving the assigned treatment, as specified in the protocol. Both ITT and PP analyses are essentially valid but they have different scopes and interpretations dependent on the context.

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.

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 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., SUMMARY AT A GLANCE This article discusses the different types of selection bias and information bias that are found in studies, indicate the type of studies where they most frequently occur and proposes suggestions for their prevention.

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 dif-ference 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.

Rationale & Objective Both hypo- and hyperkalemia can cause fatal cardiac arrhythmias. Although predialysis serum potassium level is a known modifiable risk factor for death in patients receiving hemodialysis, especially for hypokalemia, this risk may be underestimated. Therefore, we investigated the relationship between predialysis serum potassium level and death in incident hemodialysis patients and whether there is an optimum level. Study Design Prospective multicenter cohort study. Setting & Participants 1,117 incident hemodialysis patients (aged >18 years) from the Netherlands Cooperative Study on the Adequacy of Dialysis-2 study were included and followed from their first hemodialysis treatment until death, transplantation, switch to peritoneal dialysis, or a maximum of 10 years. Exposure Predialysis serum potassium levels were obtained every 6 months and divided into 6 categories: ≤4.0 mmol/L, >4.0 mmol/L to ≤4.5 mmol/L, >4.5 mmol/L to ≤5.0 mmol/L, >5.0 mmol/L to ≤5.5 mmol/L (reference), >5.5 mmol/L to ≤6.0 mmol/L, and >6.0 mmol/L. Outcomes 6-month all-cause mortality. Analytical Approach Cox proportional hazards and restricted cubic spline analyses with time-dependent predialysis serum potassium levels were used to calculate the adjusted HRs for death. Results At baseline, the mean age of the patients was 63 years (standard deviation, 14 years), 58% were men, 26% smoked, 24% had diabetes, 32% had cardiovascular disease, the mean serum potassium level was 5.0 mmol/L (standard deviation, 0.8 mmol/L), 7% had a low subjective global assessment score, and the median residual kidney function was 3.5 mL/min/1.73 m2 (IQR, 1.4-4.8 mL/min/1.73 m2). During the 10-year follow-up, 555 (50%) deaths were observed. Multivariable adjusted HRs for death according to the 6 potassium categories were as follows: 1.42 (95% CI, 1.01-1.99), 1.09 (95% CI, 0.82-1.45), 1.21 (95% CI, 0.94-1.56), 1 (reference), 0.95 (95% CI, 0.71-1.28), and 1.32 (95% CI, 0.97-1.81). Limitations Shorter intervals between potassium measurements would have allowed for more precise mortality risk estimations. Conclusions We found a U-shaped relationship between serum potassium level and death in incident hemodialysis patients. A low predialysis serum potassium level was associated with a 1.4-fold stronger risk of death than the optimal level of approximately 5.1 mmol/L. These results may imply the cautious use of potassium-lowering therapy and a potassium-restricted diet in patients receiving hemodialysis., Graphical abstract

Background Health-related quality of life (HRQOL) is becoming an increasingly important outcome in kidney transplantation (KT). To describe HRQOL in kidney transplant recipients (KTRs), this systematic review summarizes literature that compared HRQOL among KTRs and other relevant populations [i.e. patients receiving dialysis, patients on the waiting list (WL) for KT, patients with chronic kidney disease (CKD) not receiving renal replacement therapy (RRT), the general population (GP) and healthy controls (HCs)] and themselves before KT. Methods The literature search was conducted in PubMed, Embase, Web of Science and the Cochrane Library. Eligible studies published between January 2000 and October 2020 were included. Results Forty-four studies comprising 6929 KTRs were included in this systematic review. Despite the study heterogeneity, KTRs reported a higher HRQOL after KT compared with pre-transplantation and compared with patients receiving dialysis with or without being on the WL, especially in disease-specific domains (i.e. burden and effects of kidney disease). Additionally, KTRs had similar to marginally higher HRQOL compared with patients with CKD Stages 3–5 not receiving RRT. When compared with HCs or the GP, KTRs reported similar HRQOL in the first 1 or 2 years after KT and lower physical HRQOL and lower to comparable mental HRQOL in studies with longer post-transplant time. Conclusions The available evidence suggests that HRQOL improves after KT and can be restored to but not always maintained at pre-CKD HRQOL levels. Future studies investigating intervention targets to improve or maintain post-transplant HRQOL are needed.

AQP1 Promoter Variant and Peritoneal Dialysis Variability in ultrafiltration influences prescriptions and outcomes in patients treated with peritoneal dialysis. This study showed that a common variant in AQP1, the gene that encodes the water channel aquaporin-1, was associated with decreased ultrafiltration and an increased risk of death or technique failure among such patients.Background Variability in ultrafiltration influences prescriptions and outcomes in patients with kidney failure who are treated with peritoneal dialysis. Variants in AQP1, the gene that encodes the archetypal water channel aquaporin-1, may contribute to that variability. Methods We gathered clinical and genetic data from 1851 patients treated with peritoneal dialysis in seven cohorts to determine whether AQP1 variants were associated with peritoneal ultrafiltration and with a risk of the composite of death or technique failure (i.e., transfer to hemodialysis). We performed studies in cells, mouse models, and samples obtained from humans to characterize an AQP1 variant and investigate mitigation strategies. Results The common AQP1 promoter variant rs2075574 was associated with peritoneal ultrafiltration. Carriers of the TT genotype at rs2075574 (10 to 16% of patients) had a lower mean (+/- SD) net ultrafiltration level than carriers of the CC genotype (35 to 47% of patients), both in the discovery phase (506 +/- 237 ml vs. 626 +/- 283 ml, P=0.007) and in the validation phase (368 +/- 603 ml vs. 563 +/- 641 ml, P=0.003). After a mean follow-up of 944 days, 139 of 898 patients (15%) had died and 280 (31%) had been transferred to hemodialysis. TT carriers had a higher risk of the composite of death or technique failure than CC carriers (adjusted hazard ratio, 1.70; 95% confidence interval [CI], 1.24 to 2.33; P=0.001), as well as a higher risk of death from any cause (24% vs. 15%, P=0.03). In mechanistic studies, the rs2075574 risk variant was associated with decreases in AQP1 promoter activity, aquaporin-1 expression, and glucose-driven osmotic water transport. The use of a colloid osmotic agent mitigated the effects of the risk variant. Conclusions A common variant in AQP1 was associated with decreased ultrafiltration and an increased risk of death or technique failure among patients treated with peritoneal dialysis. (Funded by the Swiss National Science Foundation and others.)

Rationale & Objective Explore priorities related to outcomes and barriers of adults with chronic kidney disease (CKD) regarding person centred care and care planning. Study design Systematic review of qualitative studies. Search Strategy & Sources In July 2018 six bibliographic databases, and reference lists of included articles were searched for qualitative studies that included adults with CKD stages 1–5, not on dialysis or conservative management, without a previous kidney transplantation. Analytical Approach Three independent reviewers extracted and inductively coded data using thematic synthesis. Reporting quality was assessed using the COREQ and the review reported according to PRISMA and ENTREQ statements. Results Forty-six studies involving 1493 participants were eligible. The period after diagnosis of CKD is characterized by feelings of uncertainty, social isolation, financial burden, resentment and fear of the unknown. Patients show interest in ways to return to normality and remain in control of their health in order to avoid further deterioration of kidney function. However, necessary information is often unavailable or incomprehensible. Although patients and healthcare professionals share the predominant interest of whether or not dialysis or transplantation is necessary, patients value many more outcomes that are often unrecognized by their healthcare professionals. We identified 4 themes with 6 subthemes that summarize these findings: ‘pursuing normality and control’ (‘pursuing normality’; ‘a search for knowledge’); ‘prioritizing outcomes’ (‘reaching kidney failure’; ‘experienced health’; ‘social life’; ‘work and economic productivity’); ‘predicting the future’; and ‘realising what matters’. Reporting quality was moderate for most included studies. Limitations Exclusion of non-English articles. Conclusions The realisation that patients’ priorities do not match those of the healthcare professionals, in combination with the prognostic ambiguity, confirms fatalistic perceptions of not being in control when living with CKD. These insights may contribute to greater understanding of patients’ perspectives and a more person-centred approach in healthcare prioritization and care planning within CKD care.

ObjectivesMedicine is facing a physician-scientist shortage. By offering extracurricular research programmes (ERPs), the physician-scientist training pipeline could already start in undergraduate phases of medical training. However, previous studies into the effects of ERPs are mainly retrospective and lack baseline measurements and control groups. Therefore, the current study mimics a randomised controlled trial to examine the effects of an ERP.DesignProspective cohort study with baseline measurement and comparable control group.SettingOne cohort of 315 medical undergraduates in one Dutch University Medical Center are surveyed yearly. To examine the effects of the ERP on academic achievement and motivational factors, regression analyses were used to compare ERP students to students showing ERP-interest only, adjusted for relevant baseline scores.ParticipantsOut of the 315 students of the whole cohort, 56 participated within the ERP and are thus included. These ERP students are compared with 38 students showing ERP-interest only (ie, control group).Primary outcome measureAcademic achievement after 2 years (ie, in-time bachelor completion, bachelor grade point average (GPA)) and motivational factors after 18 months (ie, intrinsic motivation for research, research self-efficacy, perceptions of research, curiosity).ResultsERP participation is related to a higher odds of obtaining a bachelor degree in the appointed amount of time (adjusted OR=2.95, 95% CI 0.83 to 10.52). Furthermore, starting the ERP resulted in higher levels of intrinsic motivation for research, also after adjusting for gender, age, first-year GPA and motivational baseline scores (β=0.33, 95% CI 0.04 to 0.63). No effect was found on research self-efficacy beliefs, perceptions of research and curiosity.ConclusionsPrevious research suggested that intrinsic motivation is related to short-term and long-term research engagement. As our findings indicate that starting the ERP is related to increased levels of intrinsic motivation for research, ERPs for undergraduates could be seen as an important first step in the physician-scientist pipeline.

Etiological research aims to uncover causal effects, whilst prediction research aims to forecast an outcome with the best accuracy. Causal and prediction research usually require different methods, and yet their findings may get conflated when reported and interpreted. The aim of the current study is to quantify the frequency of conflation between etiological and prediction research, to discuss common underlying mistakes and provide recommendations on how to avoid these. Observational cohort studies published in January 2018 in the top-ranked journals of six distinct medical fields (Cardiology, Clinical Epidemiology, Clinical Neurology, General and Internal Medicine, Nephrology and Surgery) were included for the current scoping review. Data on conflation was extracted through signaling questions. In total, 180 studies were included. Overall, 26% (n = 46) contained conflation between etiology and prediction. The frequency of conflation varied across medical field and journal impact factor. From the causal studies 22% was conflated, mainly due to the selection of covariates based on their ability to predict without taking the causal structure into account. Within prediction studies 38% was conflated, the most frequent reason was a causal interpretation of covariates included in a prediction model. Conflation of etiology and prediction is a common methodological error in observational medical research and more frequent in prediction studies. As this may lead to biased estimations and erroneous conclusions, researchers must be careful when designing, interpreting and disseminating their research to ensure this conflation is avoided. Supplementary Information The online version contains supplementary material available at 10.1007/s10654-021-00794-w.

Background Non-dialytic conservative care (CC) has been proposed as a viable alternative to maintenance dialysis for selected older patients to treat end-stage kidney disease (ESKD). This systematic review compares both treatment pathways on health-related quality of life (HRQoL) and symptoms, which are major outcomes for patients and clinicians when deciding on preferred treatment. Methods We searched PubMed, Embase, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature (CINAHL) Plus and PsycINFO from inception to 1 October 2019 for studies comparing patient-reported HRQoL outcomes or symptoms between patients who chose either CC or dialysis for ESKD. Results Eleven observational cohort studies were identified comprising 1718 patients overall. There were no randomized controlled trials. Studies were susceptible to selection bias and confounding. In most studies, patients who chose CC were older and had more comorbidities and worse functional status than patients who chose dialysis. Results were broadly consistent across studies, despite considerable clinical and methodological heterogeneity. Patient-reported physical health outcomes and symptoms appeared to be worse in patients who chose CC compared with patients who chose dialysis but had not yet started, but similar compared with patients on dialysis. Mental health outcomes were similar between patients who chose CC or dialysis, including before and after dialysis start. In patients who chose dialysis, the burden of kidney disease and impact on daily life increased after dialysis start. Conclusions The available data, while heterogeneous, suggest that in selected older patients, CC has the potential to achieve similar HRQoL and symptoms compared with a dialysis pathway. High-quality prospective studies are needed to confirm these provisional findings.

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 delivery of better individual health.

Clinical kidney journal : CKJ 14(6), 1579-1585 (2021). doi:10.1093/ckj/sfaa161, Published by Oxford Univ. Press, Oxford

Background Only a minority of dialysis patients with depressive symptoms are diagnosed and receive treatment. Depressive symptoms are highly prevalent in this population and are associated with adverse clinical outcomes. Underlying factors for this undertreatment may be the lack of evidence for the safety and effectivity of antidepressant medication, the reluctance of patients to adhere to antidepressant medication, the lack of mental healthcare provision in somatic healthcare environments and end-stage renal disease (ESRD) related physical limitations that complicate face-to-face psychotherapy. Guided Internet-based self-help treatment has demonstrated to be effective for depressive symptoms in other chronic patient populations and may overcome these barriers. The aim of this study is to investigate the (cost) effectiveness of a guided Internet-based self-help intervention for symptoms of depression in dialysis patients. Methods This study is a cluster randomized controlled trial (RCT) that investigates the effectiveness of a 5-week Internet-based self-help Problem Solving Therapy (PST) for depressive symptoms in dialysis patients. Depressive symptoms will be measured using the Beck Depression Inventory – second edition (BDI-II), with a cut-off score of ≥10. We aim to include 206 dialysis patients with depressive symptoms who will be cluster randomized to the intervention or the Care as Usual (CAU) control group. Secondary outcomes will include anxiety symptoms, quality of life, economic costs and clinical outcomes, such as inflammatory factors and hair cortisol levels. Assessments will take place at baseline (T0), 2 weeks after intervention (T1) and 6 months (T2), 12 months (T3) and 18 months (T4) after intervention. The control group will be measured at the same time points. Analysis will be based on the intention-to-treat principle. Mixed models will be used to assess the changes within each condition between pre-treatment and post-treatment. Discussion If demonstrated to be (cost) effective, Internet-based PST will offer new possibilities to treat dialysis patients with depressive symptoms and to improve their quality of care. Trial registration Dutch Trial Register: Trial NL6648 (NTR6834) (prospectively registered 13th November 2017).

Background Persistent, low-grade inflammation likely participates in the pathophysiology of both atherosclerosis and kidney disease. Although high-sensitivity C-reactive protein (hsCRP) predicts future cardiovascular risk in patients with chronic kidney disease (CKD), it is unknown whether hsCRP levels predict adverse renal outcomes in patients with cardiovascular disease.Methods We studied all myocardial infarction (MI) survivors undergoing hsCRP testing >30 days after their MI during routine health care in Stockholm, Sweden (2006-2011), with available information on estimated glomerular filtration rate (eGFR). HsCRP tests measured during hospitalization/emergency room visits, followed by antibiotics or indicative of acute illness, were excluded, together with patients with ongoing/recent cancer, chronic infections, or immunosuppression. Inflammation was defined over a 3-month baseline window. Study outcomes were CKD progression (composite of doubling plasma creatinine, renal replacement therapy, or renal death) and acute kidney injury (AKI, acute creatinine peaks according to Kidney Disease: Improving Global Outcomes criteria). Multivariable Cox regression was used to adjust for age, sex, eGFR, hemoglobin, time since MI, comorbidities, undertaken procedures, and medications.Results A total of 12,905 patients (62% men, mean age 73 years and 3 years since MI) were included, of whom 35% had an eGFR= 2 mg/L were at higher risk of both CKD progression (adjusted hazard ratio 1.42; 95% CI 1.21-1.66) and AKI (1.29; 1.13-1.47) compared to those with hsCRP 10 mg/L). Results were robust across subgroups of patients and after exclusion of events occurring during the first 6-12 months.Conclusions In post-MI patients undergoing routine health care, elevated hsCRP was associated with subsequent risk of AKI and progression of CKD, irrespective of baseline kidney function.

Introduction Engagement of clinicians in research is important for the integration of science and clinical practice. However, at this moment, there is a shortage of clinician-scientists. Success experiences can stimulate student interest in a research career. Conducting actual research leading to publication is a potential method to gain success experience. This study assessed whether publication as a medical student is associated with publication after graduation. We determined whether medical students in the Netherlands who are involved in research, as measured by publication in international journals before graduation: 1) are more likely to publish, 2) publish a greater number of papers, and 3) have higher citation impact scores after graduation. Methods We matched 2005–2008 MD graduates (with rare names, n = 4145 in total) from all eight Dutch university medical centres to their publications indexed in the Web of Science and published between 6 years before and 6 years after graduation. For sensitivity analysis we performed both automatic assignment on the whole group and manual assignment on a 10% random sample. Results Students who had published before graduation: 1) were 1.9 times as likely to publish, 2) published more papers, and 3) had a slightly higher citation impact after graduation. Discussion Medical students who conducted research leading to a publication before graduation were more likely to be scientifically active after graduation. While this is not a causal relationship per se, these results cautiously suggest that successful early involvement in research could influence the long-term scientific activity of clinicians.

Supplemental digital content is available in the text., Objective Unraveling specific dimensions of depressive symptoms may help to improve screening and treatment in dialysis patients. We aimed to identify the best-fitting factorial structure for the Beck Depression Inventory-II (BDI) in dialysis patients and to assess the relation of these structure dimensions with quality of life (QoL), hospitalization, and mortality. Methods This prospective study included chronic dialysis patients from 10 dialysis centers in five hospitals between 2012 and 2017. Dimensions of depressive symptoms within the BDI were analyzed using confirmatory factor analysis. To investigate the clinical impact of these dimensions, the associations between symptom dimensions and QoL, hospitalization rate, and mortality were investigated using logistic, Poisson, and Cox proportional hazard regression models. Multivariable regression models included demographic, social, and clinical variables. Results In total, 687 dialysis patients were included. The factor model that included a general and a somatic factor provided the best-fitting structure of the BDI-II. Only the somatic dimension scores were associated with all-cause mortality (hazard ratio of 1.7 [1.2–2.5], p < .007) in the multivariable model. All dimensions were associated with increased hospitalization rate and reduced QoL. Conclusions The somatic dimension of the BDI-II in dialysis patients was associated with all-cause mortality, increased hospitalization rate, and reduced QoL. Other dimensions were associated with hospitalization rate and decreased QoL. These findings show that symptom dimensions of depression have differential association with adverse clinical outcomes. Future studies should take symptom dimensions into account when investigating depression-related pathways, screening, and treatment effects in dialysis patients.

Background Bleeding risk scores have been created to identify patients with an increased bleeding risk, which could also be useful in dialysis patients. However, the predictive performances of these bleeding risk scores in dialysis patients are unknown. Therefore, the aim of this study was to validate existing bleeding risk scores in dialysis patients. Methods A cohort of 1745 incident dialysis patients was prospectively followed for 3 years during which bleeding events were registered. We evaluated the discriminative performance of the Hypertension, Abnormal kidney and liver function, Stroke, Bleeding, Labile INR, Elderly and Drugs or alcohol (HASBLED), the AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA), the Hepatic or kidney disease, Ethanol abuse, Malignancy, Older age, Reduced platelet count or Reduced platelet function, Hypertension, Anaemia, Genetic factors, Excessive fall risk and Stroke (HEMORR2HAGES) and the Outcomes Registry for Better Informed Treatment (ORBIT) bleeding risk scores by calculating C-statistics with 95% confidence intervals (CI). In addition, calibration was evaluated by comparing predicted and observed risks. Results Of the 1745 dialysis patients, 183 patients had a bleeding event, corresponding to an incidence rate of 5.23/100 person-years. The HASBLED [C-statistic of 0.58 (95% CI 0.54–0.62)], ATRIA [C-statistic of 0.55 (95% CI 0.51–0.60)], HEMORR2HAGES [C-statistic of 0.56 (95% CI 0.52–0.61)] and ORBIT [C-statistic of 0.56 (95% CI 0.52–0.61)] risk scores had poor discriminative performances in dialysis patients. Furthermore, the calibration analyses showed that patients with a low risk of bleeding according to the HASBLED, ATRIA, HEMORR2HAGES and ORBIT bleeding risk scores had higher incidence rates for bleeding in our cohort than predicted. Conclusions The HASBLED, ATRIA, HEMORR2HAGES and ORBIT bleeding risk scores had poor predictive abilities in dialysis patients. Therefore, these bleeding risk scores may not be useful in this population.

Rationale & Objective: It is unknown whether initiating renin-angiotensin system (RAS) inhibitor therapy in patients with advanced chronic kidney disease (CKD) is superior to alternative antihypertensive agents such as calcium channel blockers (CCBs). We compared the risks for kidney replacement therapy (KRT), mortality, and major adverse cardiovascular events (MACE) in patients with advanced CKD in routine nephrology practice who were initiating either RAS inhibitor or CCB therapy.Study Design: Observational study in the Swedish Renal Registry, 2007 to 2017.Settings & Participants: 2,458 new users of RAS inhibitors and 2,345 CCB users with estimated glomerular filtration rates < 30 mL/min/1.73 m(2) (CKD G4-G5 without KRT) who were being followed up by a nephrologist. As a positive control cohort, new users of the same drugs with CKD G3 (estimated glomerular filtration rate, 30-60 mL/min/1.73 m(2)) were evaluated.Exposures: RAS inhibitor versus CCB therapy initiation.Outcome: Initiation of KRT (maintenance dialysis or transplantation), all-cause mortality, and MACE (composite of cardiovascular death, myocardial infarction, or stroke).Analytical Approach: HRs with 95% CIs were estimated using propensity score-weighted Cox proportional hazards regression adjusting for demographic, clinical, and laboratory covariates.Results: Median age was 74 years, 38% were women, and median follow-up was 4.1 years. After propensity score weighting, there was significantly lower risk for KRT after new use of RAS inhibitors compared with new use of CCBs (adjusted HR, 0.79 [95% CI, 0.69-0.89]) but similar risks for mortality (adjusted HR, 0.97 [95% CI, 0.88-1.07]) and MACE (adjusted HR, 1.00 [95% CI, 0.88-1.15]). Results were consistent across subgroups and in as-treated analyses. The positive control cohort of patients with CKD G3 showed similar KRT risk reduction (adjusted HR, 0.67 [95% CI, 0.56-0.80]) with RAS inhibitor therapy compared with CCBs.Limitations: Potential confounding by indication.Conclusions: Our findings provide evidence from real-world clinical practice that initiation of RAS inhibitor therapy compared with CCBs may confer kidney benefits among patients with advanced CKD, with similar cardiovascular protection.

Background and Aims Differences between the sexes are apparent in the epidemiology of CKD. Cross-sectional studies show that women consistently report a poorer health-related quality of life (QoL) than men, however, longitudinal studies are lacking. Here we investigate the sex-specific evolution of QoL over time in advanced CKD. As a secondary aim, we explore the sex-specific determinants of QoL. Method EQUAL is an observational prospective cohort study in stages 4 and 5 CKD patients ≥65 years not on dialysis with an incident estimated glomerular filtration rate (eGFR) < 20 ml/min/1.73m². Data on QoL (measured using the RAND-36), clinical and demographic patient characteristics were collected between April 2012 and September 2020. QoL trajectories were modelled by sex using linear mixed models, and joint models were applied to deal with informative censoring. We followed patients until death or dialysis initiation. Results We included 5151 QoL measurements in 1416 patients over a total of 1986 person years of follow-up. Overall, the physical component summary (PCS) declined with 2.0 (95% CI 1.4-2.6) points and the mental component summary (MCS) by 2.4 (95% CI 1.8-3.0) points per year. Although women had overall lower QoL scores, figure 1 demonstrates that PCS and MCS declined more than twice as fast in men (PCS: 2.4 per year, 95% CI 1.7 – 3.1, MCS: 2.9 per year, 95% CI 2.2 – 3.6) compared with women (PCS: 1.1 per year, 95% CI -0.2 – 2.0, MCS: 1.5 per year, 95% CI 0.5 – 2.4). We identified a non-linear interaction effect between sex and eGFR levels on QoL, demonstrating a stronger negative effect of decreased eGFR on both PCS (p=0.02) and MCS (p=0.04) in men compared with women. Subsequent adjustment for renal decline attenuated the difference in rate of QoL decline between men and women (difference after adjustment; PCS: 1.1, 95% CI -0.1 – 2.2, MCS: 1.2, 95% 0.0 – 2.3). In univariable analyses, higher serum haemoglobin was more beneficial to QoL in men compared to women (p-value for interaction; PCS: p=0.03, MCS: p=0.01). Higher serum phosphate had a strong harmful effect on both PCS and MCS in men, but not in women (PCS & MCS: p Conclusion Despite the higher overall QoL reported by men, both their physical and mental QoL declined approximately twice as fast compared with women. The faster decline in men was mediated in part by their lower levels of renal function, which had a stronger impact on their QoL as compared with women. Furthermore, in exploratory analyses we identified that high levels of phosphate, low levels of haemoglobin, and pre-existing diabetes were more detrimental to QoL in men than in women.

Background and Aims The number of older (≥65y) people with ESKD starting chronic dialysis increased substantially the past decade because of ageing of the population due to improved health care. In addition, older age is no longer a contraindication for dialysis. Finally, older individuals are more often ineligible for kidney transplantation. Many older people with stage 5 CKD non-dialysis have a low health-related quality of life (HRQOL) and high symptom burden. In this group, improving HRQOL and lowering symptom burden may be deemed more important than solely the prolongation of life. Little is known about the effect of dialysis treatment on HRQOL and symptom burden. Therefore, we investigated the evolution of HRQOL and symptoms before and after the start of dialysis in older ESKD patients. Method The European Quality (EQUAL) study is an ongoing European prospective multi-center follow-up study in late stage 4/5 CKD patients aged ≥65 years. For the present analyses, we included all patients who started dialysis. HRQOL was assessed every 3-6 months using the RAND-36 questionnaire, resulting in a physical component summary (PCS) and a mental component summary (MCS) score. Component scores ranged from 0-100 with higher scores indicating a better HRQOL. Kidney disease-related symptom burden was assessed every 3-6 months using the dialysis symptom index (DSI). The sum score for symptom number ranged from 0 to 30 and for symptom severity from 0 to 150, with higher scores indicating a higher symptom burden. We used linear mixed models (LMM) to explore the evolution of mental and physical HRQOL, symptom number and symptom severity during the year preceding and following dialysis initiation. Results In total, 571 older dialysis patients were included. At baseline (dialysis initiation), mean (SD) age was 76 (6) years, 74% were men, 47% had diabetes, 9% were current smokers, 34% had cardiovascular disease and the mean (SD) residual kidney function was 8.6 (4.4) ml/min/1.73m2. Mean (SD) MSC was 55 (23), PSC was 43 (21), and the number of symptoms was 15 (7) with a symptom severity of 88 (18). Overall, LMM showed that in the year preceding dialysis MCS decreased by 15.7 (95% CI: 11.9 to 19.5), PCS decreased by 12.0 (8.2 to 15.7), symptom number increased by 3.5 (2.5 to 4.6) and symptom severity increased by 5.3 (1.8 to 8.8). In the year following dialysis, MCS increased by 1.9 (-2.7 to 6.5), PCS decreased by 2.1 (-6.9 to 2.8), symptom number decreased by 0.9 (-0.3 to 2.1) and symptom severity decreased by 7.6 (2.8 to 12.4). Conclusion Both mental and physical HRQOL, as well as symptom number and severity, worsened considerably during the year preceding dialysis, but stabilized after dialysis initiation. These results could aid nephrologists in informing older ESKD patients who consider starting dialysis and improve the shared decision making process.

Background and Aims While clinical trials have demonstrated the efficacy of SGLT2 inhibitors on preventing cardiovascular and renal damage, few studies have expanded this evidence to routine-care settings. Method We compared clinical outcomes of adults who started SGLT2i or DPP4i therapy in Stockholm, Sweden, during 2013-2019. The primary outcome was a composite of cardiovascular (CV) death and hospitalization for heart failure (HF). Secondary outcomes included major adverse cardiovascular events (MACE; composite of cardiovascular death, myocardial infarction, stroke), all-cause mortality and the rate of eGFR decline (eGFR slope). Propensity score weighted Cox regression was used to balance 55 variables and estimate intention-to-treat hazard ratios with 95% confidence intervals. Differences in eGFR slope were calculated with linear mixed models. Results We identified 7136 individuals starting SGLT2i and 13,618 starting DPP4i therapy. Median age was 64 years (37% women) and median eGFR 86 ml/min/1.73m2. During median follow-up of 2.1 years, 211 individuals developed the primary outcome, 269 experienced MACE and 178 died. After propensity score weighting, patients starting SGLT2i therapy were at lower risk for the composite of CV death/HF hospitalization (HR 0.71; 95% CI 0.53-0.94) compared with DPP4i, and showed a tendency towards lower MACE (0.84; 95% CI 0.67-1.04) and all-cause mortality (0.85; 95% CI 0.62-1.18). There were a median of 4 (interquartile range: 2-8) eGFR measurements during follow-up per patient to estimate their eGFR slopes. In adjusted models, new users of SGLT2i had a slower rate of kidney function decline compared with DPP4i (eGFR slope difference of 0.43 (95% CI 0.15-0.72) ml/min/1.73m2 per year). Results for the primary outcome were consistent across 7 pre-specified subgroups, including eGFR (eGFR ≥60: HR 0.79 [95% CI 0.57-1.08]; eGFR Conclusion In patients undergoing routine care, initiation of SGLT2i was associated with fewer cardiovascular outcomes and less rapid kidney function decline compared with DPP4i initiation.

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., SUMMARY AT A GLANCE The review provides 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, ie minimal detectable change, minimal important change and response shift.

Background and Aims End stage kidney disease (ESKD) and dialysis treatment are associated with high morbidity, frequently resulting in hospitalisation. However, studies comparing hospitalisation between different dialysis modalities report conflicting results. Some studies report an equal number and length of hospital admissions, while others conclude that peritoneal dialysis (PD) patients are more likely to be hospitalised. In addition, most studies only analyse data of patients that remain on their initial dialysis modality. However, a transition from one dialysis modality to another, e.g. from PD to in-centre haemodialysis (ICHD), certainly occurs in current dialysis practice. Therefore, the aim of this study was to compare hospitalisations between PD and ICHD patients, taking into account transfers between dialysis modalities. Method The retrospective Dutch nOcturnal and hoME dialysis Study To Improve Clinical Outcomes (DOMESTICO) collected hospitalisation data of ESKD patients who started dialysis treatment between 2012 and 2017. Eligible patients had a minimum dialysis duration of 3 months. For baseline comparison, groups were defined based on the dialysis modality (i.e. PD or ICHD) 3 months after dialysis initiation. Primary outcome was hospitalisation rate, which was analysed with a multi-state model that attributed each hospitalisation to the dialysis modality the patient was treated with at that the time. Secondary outcomes were time to first hospitalisation, number of hospitalisations and length of hospitalisation. Time to first hospitalisation was analysed with Cox regression analysis, with dialysis modality as a time-varying covariate. Number of hospitalisations was analysed with negative binomial regression, and length of stay with Poisson regression. All analyses were adjusted for potential confounders. Results In total, 252 PD and 443 ICHD patients from 31 Dutch dialysis centres were included. Baseline characteristics of the groups were comparable, apart from a lower dialysis vintage and a slightly lower comorbidity score in the PD group. Patients transferred more often from PD to ICHD (33%), than from ICHD to PD (11%) during a median follow-up period of 22.0 months [IQR 11.1-36.4]. The crude hospitalisation rate for PD was 2.3 (±5.0) and for ICHD 1.4 (±3.2) hospitalisations per patient-year. Using a multistate model, the adjusted hazard ratio (HR) for hospitalisation rate was 1.1 (95%CI 1.02-1.3) for PD compared to ICHD patients. Cox regression analysis showed a significant difference in time to first hospitalisation with an adjusted HR of 1.3 (95%CI 1.1 - 1.6) for PD compared to ICHD patients in the first year after dialysis initiation. After the first year, the time to first hospitalisation had an adjusted HR of 1.9 (95%CI 1.4–2.5) for PD compared to ICHD patients. The number of hospitalisations was significantly higher, while the length of stay was non-significantly higher for PD patients. In PD patients, the most common cause of all hospitalisations was peritonitis (23%). In ICHD patients, the most common cause was access-related (33%). Conclusion PD was associated with a higher hospitalisation rate, a shorter time to first hospitalisation and more hospitalisations compared to ICHD. One explanation might be that the threshold for admission to hospital is lower for PD patients compared to ICHD patients.

Observational pharmacoepidemiological studies using routinely collected healthcare data are increasingly being used in the field of nephrology to answer questions on the effectiveness and safety of medications. This review discusses a number of biases that may arise in such studies and proposes solutions to minimize them during the design or statistical analysis phase. We first describe designs to handle confounding by indication (e.g. active comparator design) and methods to investigate the influence of unmeasured confounding, such as the E-value, the use of negative control outcomes and control cohorts. We next discuss prevalent user and immortal time biases in pharmacoepidemiology research and how these can be prevented by focussing on incident users and applying either landmarking, using a time-varying exposure, or the cloning, censoring and weighting method. Lastly, we briefly discuss the common issues with missing data and misclassification bias. When these biases are properly accounted for, pharmacoepidemiological observational studies can provide valuable information for clinical practice.

Background and Aims There is currently no direct evidence to inform a specific glomerular filtration rate (GFR) to initiate maintenance dialysis. Previous studies are limited by the number of kidney function thresholds compared, immortal time or lead time biases, or small sample sizes. The only randomised trial (IDEAL) found no difference between early versus late start, but confidence intervals were wide. Method Nationwide observational cohort study using data from the Swedish Renal Registry between January 1, 2007 and December 31, 2016, with follow-up until June 1, 2017. Included individuals were receiving nephrologist care and had an eGFR between 10-20 ml/min/1.73m2. A randomized trial was emulated using the cloning, censoring and weighting method. Our primary analysis compared late (at an eGFR 5-7 ml/min/1.73m2 [eGFR5-7]), intermediate (eGFR7-10) and early (eGFR10-14) dialysis initiation to validate our analytical methods by comparison with IDEAL. Our secondary analysis compared fifteen dialysis initiation strategies with eGFR values ranging between 4 and 19 ml/min/1.73m2 in increments of 1 ml/min/1.73m2. Study outcomes were 5-year all-cause mortality and major adverse cardiovascular events (MACE; composite of cardiovascular death, non-fatal myocardial infarction and stroke). Adjusted hazard ratios [HR] and cumulative survival proportions were estimated using a dynamic marginal structural model. Results Among 10,290 individuals with advanced CKD (median age 73 years; 36% women; median eGFR 16.8 ml/min/1.73m2), 3725 individuals initiated dialysis, 4160 died and 2446 experienced MACE. In trial emulation, the 5-year mortality risk was 53.0% for eGFR5-7, 50.3% for eGFR7-10 and 49.7% for eGFR10-14. Compared with eGFR5-7, the 5-year absolute mortality risk difference was -2.7% (95% CI, -4.6% to -0.7%) for eGFR7-10 and -3.3% (95% CI, -5.2% to -1.3%) for eGFR10-14, with a HR of 0.97 (0.94-0.99) and 0.96 (0.94-0.99), respectively. The 5-year absolute MACE risk differences were -1.1% (95% CI, -3.8% to 2.1%) for eGFR7-10 and -3.6% (95% CI, -6.0% to -1.0%) for eGFR10-14 compared with eGFR5-7, with a HR of 1.00 (0.97-1.04) and 0.96 (0.97-1.00), respectively. When analysing fifteen eGFR thresholds, initiation at eGFR15-16 was associated with the largest reduction in mortality (absolute difference, -5.9% [95% CI, -8.0% to -3.1%]; HR, 0.88 [95% CI, 0.85-0.92]) and MACE (absolute difference, -4.5% [95% CI, -7.6% to -1.4%]; HR, 0.92 [95% CI, 0.89-0.97]), compared with eGFR4-5. This -5.9% absolute risk difference translates to a mean postponement of death of 1.8 months over 5-years of follow-up. However, dialysis would need to be initiated on average 14 months earlier. Conclusion Early dialysis initiation was associated with a modest reduction in mortality and cardiovascular events. Such a reduction may not outweigh the burden of longer dialysis treatment duration for the patient.

Background Initiation of renal replacement therapy often results from a combination of kidney function deterioration and symptoms related to chronic kidney disease (CKD) progression. We investigated the association between kidney function decline and symptom development in patients with advanced CKD. Methods In the European Quality study on treatment in advanced CKD (EQUAL study), a European prospective cohort study, patients with advanced CKD aged ≥65 years and a kidney function that dropped Results At least one kidney function estimate with symptom number or overall symptom severity was available for 1109 and 1019 patients, respectively. The mean (95% confidence interval) annual kidney function decline was 1.70 (1.32; 2.08) mL/min/1.73 m2. The mean overall increase in symptom number and severity was 0.73 (0.28; 1.19) and 2.93 (1.34; 4.52) per year, respectively. A cross-sectional association between the level of kidney function and symptoms was lacking. Furthermore, kidney function at cohort entry was not associated with symptom development. However, each mL/min/1.73 m2 of annual kidney function decline was associated with an extra annual increase of 0.23 (0.07; 0.39) in the number of symptoms and 0.87 (0.35; 1.40) in overall symptom severity. Conclusions A faster kidney function decline was associated with a steeper increase in both symptom number and severity. Considering the modest association, our results seem to suggest that repeated thorough assessment of symptom development during outpatient clinic visits, in addition to the monitoring of kidney function decline, is important for clinical decision-making.

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) 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., SUMMARY AT A GLANCE A summary of steps to carry out etiological research, including main points of attention.

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.

Background Cohort studies are among the most robust of observational studies but have issues with external validity. This study assesses threats to external validity (generalizability) in the European QUALity (EQUAL) study, a cohort study of people >65 years of age with Stage 4/5 chronic kidney disease. Methods Patients meeting the EQUAL inclusion criteria were identified in The Health Improvement Network database and stratified into those attending renal units, a secondary care cohort (SCC) and a not primary care cohort (PCC). Survival, progression to renal replacement therapy (RRT) and hospitalization were compared. Results The analysis included 250, 633 and 2464 patients in EQUAL, PCC and SCC. EQUAL had a higher proportion of men compared with PCC and SCC (60.0% versus 34.8% versus 51.4%). Increasing age ≥85 years {odds ratio [OR] 0.25 [95% confidence interval (CI) 0.15–0.40]} and comorbidity [Charlson Comorbidity Index ≥4, OR 0.69 (95% CI 0.52–0.91)] were associated with non-participation in EQUAL. EQUAL had a higher proportion of patients starting RRT at 1 year compared with SCC (8.1% versus 2.1%; P Conclusions This study provides evidence of how participants in a cohort study can differ from the broader population of patients, which is essential when considering external validity and application to local practice.

BACKGROUND: It is unknown whether stopping renin-angiotensin system (RAS) inhibitor therapy in patients with advanced CKD affects outcomes. METHODS: We studied patients referred to nephrologist care, listed on the Swedish Renal Registry during 2007–2017, who developed advanced CKD (eGFR

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 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.

Graft function and patient survival are traditionally the most used parameters to assess the objective benefits of kidney transplantation. Monitoring graft function, along with therapeutic drug concentrations and transplant complications, comprises the essence of outpatient management in kidney transplant recipients (KTRs). However, the patient’s perspective is not always included in this process. Patients’ perspectives on their health after kidney transplantation, albeit subjective, are increasingly acknowledged as valuable healthcare outcomes and should be considered in order to provide patient-centred healthcare. Such outcomes are known as patient-reported outcomes (PROs; e.g. health-related quality of life and symptom burden) and are captured using PRO measures (PROMs). So far, PROMs have not been routinely used in clinical care for KTRs. In this review we will introduce PROMs and their potential application and value in the field of kidney transplantation, describe commonly used PROMs in KTRs and discuss structural PROMs implementation into kidney transplantation care.

Background: While clinical trials have demonstrated efficacy for SGLT2 inhibitors (SGLT2i) on preventing cardiovascular and kidney damage, few high-quality studies have expanded to routine-care settings of low-risk patients. Previous observational studies were limited by immortal time bias or did not adjust for laboratory measurements. Methods: We compared clinical outcomes of adults who started SGLT2i or DPP4i therapy in Stockholm, Sweden, during 2013-2019. The primary outcome was a composite of cardiovascular (CV) death and hospitalization for heart failure (HHF). Secondary outcomes included major adverse cardiovascular events (MACE), all-cause mortality, atrial fibrillation, hyperkalemia and kidney disease progression (composite kidney failure and doubling of serum creatinine). Propensity score weighted Cox regression was used to estimate hazard ratios and balance 56 covariates. Results: We included 16,537 individuals (5526 SGLT2i; 11,011 DPP4i users), followed for median 1.9 years. Median age was 64 years (36% women), median estimated glomerular filtration rate 87 ml/min/1.73m2 and 31% had albuminuria. After weighting, patients starting SGLT2i therapy were at lower risk for the composite of CV death/HHF (HR 0.65; 95% CI 0.47-0.89) and hyperkalemia (HR 0.41; 95% CI 0.20-0.83) compared with DPP4i, without an increase in hypokalemia (HR 0.98; 95% CI 0.72-1.34). The adjusted HRs (95% CI) were 0.82 (0.64-1.06) for MACE, 0.74 (0.52-1.06) for all-cause mortality, 0.95 (0.68-1.33) for atrial fibrillation and 0.54 (0.27-1.08) for kidney disease progression. Conclusions: SGLT2i use compared with DPP4i was associated with a reduction in cardiovascular and kidney outcomes similar in magnitude to trials, as well as a lower risk of hyperkalemia. Funding: Research reported in this publication was supported by the Swedish Research Council (#2019-01059), the Swedish Heart and Lung Foundation and the Westman Foundation. ELF acknowledges support by a Rubicon Grant of the Netherlands Organization for Scientific Research (NWO). Declaration of Interests: JC acknowledges consultancy for Baxter and AstraZeneca, and grant support to Karolinska Institutet from AstraZeneca, Viforpharma and Astellas, all outside the submitted work. CMC has received consultation, advisory board membership or research funding from the Ontario Ministry of Health, Sanofi, Johnson & Johnson, Pfizer, Leo Pharma, Astellas, Janssen, Amgen, Boehringer-Ingelheim and Baxter, all outside the submitted work. None of the other authors declare relevant financial interests that would represent a conflict of interest. MJJ is responsible for research programs that have received unrestricted funding from Gambro, Baxter, Commonwealth Serum Laboratories (CSL), Amgen, Eli Lilly, and Merck; has served on advisory boards and steering committees sponsored by Akebia, Baxter, Boehringer Ingelheim, CSL, Janssen, and Vifor; and spoken at scientific meetings sponsored by Janssen, Amgen, and Roche, with any consultancy, honoraria, or travel support paid to her institution. Ethics Approval Statement: The study utilized only de-identified data and thus was deemed not to require informed consent, being approved by the regional ethical review boards and the Swedish National Board of Welfare.

Background Conservative care (CC) may be a valid alternative to dialysis for certain older patients with advanced chronic kidney disease (CKD). A model that predicts patient prognosis on both treatment pathways could be of value in shared decision-making. Therefore, the aim is to develop a prediction tool that predicts the mortality risk for the same patient for both dialysis and CC from the time of treatment decision. Methods CKD Stage 4/5 patients aged ≥70 years, treated at a single centre in the Netherlands, were included between 2004 and 2016. Predictors were collected at treatment decision and selected based on literature and an expert panel. Outcome was 2-year mortality. Basic and extended logistic regression models were developed for both the dialysis and CC groups. These models were internally validated with bootstrapping. Model performance was assessed with discrimination and calibration. Results In total, 366 patients were included, of which 126 chose CC. Pre-selected predictors for the basic model were age, estimated glomerular filtration rate, malignancy and cardiovascular disease. Discrimination was moderate, with optimism-corrected C-statistics ranging from 0.675 to 0.750. Calibration plots showed good calibration. Conclusions A prediction tool that predicts 2-year mortality was developed to provide older advanced CKD patients with individualized prognosis estimates for both dialysis and CC. Future studies are needed to test whether our findings hold in other CKD populations. Following external validation, this prediction tool could be used to compare a patient’s prognosis on both dialysis and CC, and help to inform treatment decision-making.

ObjectivesTo assess the difference in completeness of reporting and methodological conduct of published prediction models before and after publication of the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) statement.MethodsIn the seven general medicine journals with the highest impact factor, we compared the completeness of the reporting and the quality of the methodology of prediction model studies published between 2012 and 2014 (pre-TRIPOD) with studies published between 2016 and 2017 (post-TRIPOD). For articles published in the post-TRIPOD period, we examined whether there was improved reporting for articles (1) citing the TRIPOD statement, and (2) published in journals that published the TRIPOD statement.ResultsA total of 70 articles was included (pre-TRIPOD: 32, post-TRIPOD: 38). No improvement was seen for the overall percentage of reported items after the publication of the TRIPOD statement (pre-TRIPOD 74%, post-TRIPOD 76%, 95% CI of absolute difference: −4% to 7%). For the individual TRIPOD items, an improvement was seen for 16 (44%) items, while 3 (8%) items showed no improvement and 17 (47%) items showed a deterioration. Post-TRIPOD, there was no improved reporting for articles citing the TRIPOD statement, nor for articles published in journals that published the TRIPOD statement. The methodological quality improved in the post-TRIPOD period. More models were externally validated in the same article (absolute difference 8%, post-TRIPOD: 39%), used measures of calibration (21%, post-TRIPOD: 87%) and discrimination (9%, post-TRIPOD: 100%), and used multiple imputation for handling missing data (12%, post-TRIPOD: 50%).ConclusionsSince the publication of the TRIPOD statement, some reporting and methodological aspects have improved. Prediction models are still often poorly developed and validated and many aspects remain poorly reported, hindering optimal clinical application of these models. Long-term effects of the TRIPOD statement publication should be evaluated in future studies.