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Introduction: In parallel with a tremendous increase in medical PhD enrolments, concerns have risen about PhD candidates' poor well-being, increasing attrition rates for PhD programmes, and, eventually, a decline in clinician-scientists. According to the Self-Determination Theory, autonomous motivation is strongly linked to positive aspects of well-being and other positive outcomes such as study completion and success. In this way, motivation has a pivotal role in successful completion of medical doctoral programmes. In this study we explored factors affecting motivation during the PhD journey and aimed to contribute to engaging doctoral education environments, and, eventually, a sustainable clinician-scientist workforce., Methods: This constructivist qualitative interview study was conducted among ten medical PhD candidates in the final phase of their PhD. We used timeline assisted interviews to identify meaningful experiences throughout their PhD journey. Thematic analyses as an iterative process resulted in overarching themes., Results: We identified six themes influencing autonomous and controlled motivation along the challenging PhD journey: (1) Initial motivation to start a PhD matters; (2) Autonomy as a matter of the right dose at the right time; (3) PhD as proof of competence and/or learning trajectory?; (4) It takes two to tango; (5) Peers can make or break your PhD; (6) Strategies to stay or get back on track., Conclusion: This study revealed factors that contribute positively and/or negatively to autonomous and controlled motivation. Some factors impacted motivation differently depending on the PhD phase and individual strategies. Additionally, some factors could coincide and change from positive to negative and vice versa, showing that a successful journey cannot simply be reduced to an absence of negative experiences., (© 2024. The Author(s).)

Balancing immunosuppression to prevent rejection in solid organ transplant (SOT) recipients remains challenging. Torque teno virus (TTV), a commensal non-pathogenic virus, has been proposed as marker of functional immunity: higher loads correspond to over-immunosuppression, and lower loads to under-immunosuppression. This review offers an overview of the current evidence of the association between TTV-load and infection and rejection after SOT. A systematic literature search strategy, deposited in the PROSPERO registry, resulted in 548 records. After screening, 23 original and peer-reviewed articles were assessed investigating the association between TTV-load, infection and/or rejection in SOT. The Quality in Prognostic Studies (QUIPS)-tool was used to assess the risk of bias. Meta-analysis with random-effects was performed on results with similar outcomes and exposure measures. Most of the included studies involved retrospective cohorts in which the TTV-load was measured longitudinally, within the first 2 years post-transplantation. Infection outcomes differed between studies and included viral, bacterial, parasitic and fungal infections. Rejection was defined by biopsy confirmation or initiation of rejection treatment. Twelve out of 16 studies reported an association between high TTV-load and infections, whereas 13 out of 15 reported an association between low TTV-load and rejection. Meta-analysis showed an increased risk of infection (OR: 1.16, 95% CI: 1.03-1.32; HR: 1.05, 95% CI: 0.97-1.14) and a decreased risk of rejection (OR: 0.90, 95% CI: 0.87-0.94; HR: 0.74, 95% CI: 0.71-0.76) per 1 log TTV-load increase. The qualitative assessment showed varying risks of bias in the included studies. This systematic review and meta-analysis indicates that blood TTV-load measured within the first 2 years after SOT is associated with the risk of infection or allograft rejection, although substantial risk of bias in the studies included warrant cautious interpretation. The results in this review provide a rationale for larger, prospective, studies into TTV as marker of infection and rejection after SOT., (© 2022 The Authors. Reviews in Medical Virology published by John Wiley & Sons Ltd.)

Background: Reviews of qualitative studies allow for deeper understanding of concepts and findings beyond the single qualitative studies. Concerns on study reporting quality led to the publication of the COREQ-guidelines for qualitative studies in 2007, followed by the ENTREQ-guidelines for qualitative reviews in 2012. The aim of this meta-review is to: 1) investigate the uptake of the COREQ- and ENTREQ- checklists in qualitative reviews; and 2) compare the quality of reporting of the primary qualitative studies included within these reviews prior- and post COREQ-publication., Methods: Reviews were searched on 02-Sept-2020 and categorized as (1) COREQ- or (2) ENTREQ-using, (3) using both, or (4) non-COREQ/ENTREQ. Proportions of usage were calculated over time. COREQ-scores of the primary studies included in these reviews were compared prior- and post COREQ-publication using T-test with Bonferroni correction., Results: 1.695 qualitative reviews were included (222 COREQ, 369 ENTREQ, 62 both COREQ/ENTREQ and 1.042 non-COREQ/ENTREQ), spanning 12 years (2007-2019) demonstrating an exponential publication rate. The uptake of the ENTREQ in reviews is higher than the COREQ (respectively 28% and 17%), and increases over time. COREQ-scores could be extracted from 139 reviews (including 2.775 appraisals). Reporting quality improved following the COREQ-publication with 13 of the 32 signalling questions showing improvement; the average total score increased from 15.15 to 17.74 (p-value < 0.001)., Conclusion: The number of qualitative reviews increased exponentially, but the uptake of the COREQ and ENTREQ was modest overall. Primary qualitative studies show a positive trend in reporting quality, which may have been facilitated by the publication of the COREQ., (© 2021. The Author(s).)

Proton pump inhibitors are widely used, and generally considered safe. In this clinical lesson two cases are presented with a strong suspicion of proton pump inhibitor induced decline of kidney function. This adverse event has only recently been identified in epidemiological studies. Our cases illustrate that chronic proton pump inhibitor nephrotoxicity can manifest subtle and may therefore be difficult to recognize. We discuss the current epidemiological evidence to support these observations, and the pathophysiology and clinical manifestations of proton pump inhibitor nephrotoxicity. In case a subject using a proton pump inhibitor shows kidney function decline, without a clear cause, withdrawal of this medication is advised. Although for an individual patient the risk may not be high, the large number of proton pump users makes that this adverse event is important on a population level.

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., (© 2020 International Society of Nephrology. Published by Elsevier Inc.)

Background: The potential benefit of surgery of the primary tumour in patients with asymptomatic metastatic colorectal cancer is debated. This EURECCA international comparison analyses treatment strategies and overall survival in the Netherlands and Norway in patients with incurable metastatic colorectal cancer., Methods: National cohorts (2007-2013) from the Netherlands and Norway including all patients with synchronous metastatic colorectal cancer were compared on treatment strategy and overall survival. Using country as an instrumental variable, we assessed the effect of different treatment strategies on mortality in the first year., Results: Of 21,196 patients (16,144 Dutch and 5052 Norwegian), 38.6% Dutch and 51.5% (p < 0.001) Norwegian patients underwent resection of the primary tumour. In the Netherlands, 58.2% received chemotherapy compared with 21.4% in Norway. Radiotherapy was given in 9.5% of Dutch patients and 7.2% of Norwegian patients. Using the Netherlands as reference, the adjusted HR for overall survival was 0.96 (95% CI 0.93-0.99; p = 0.024). Instrumental variable analysis showed an adjusted OR of 1.00 (95% CI 0.99-1.02; p = 0.741)., Conclusions: Treatment strategies varied significantly between the Netherlands and Norway, with more surgery and less radiotherapy in Norway. Adjusted overall survival was better in Norway for all patients and patients <75 years, but not for patients ≥75 years. Instrumental variable analysis showed no benefit in one-year mortality for a treatment strategy with a higher proportion of surgery and a lower proportion of radiotherapy. Our findings emphasise the need for further research to select patients with incurable metastatic colorectal cancer for different treatment options., Competing Interests: Declaration of competing interest We declare no competing interests., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

For immigrant chronic dialysis patients, religious behavior and religious coping may have a different impact on depressive symptoms compared to native patients. This study aims to describe both cross-sectional and longitudinal associations between religious behavior and coping with symptoms of depression for 281 native and 277 immigrant dialysis patients in the Netherlands. A higher prevalence of depressive symptoms was found in immigrant compared to native patients (49% vs. 36%). No significant cross-sectional or longitudinal associations were found in both groups between religious behavior and positive religious coping with depressive symptoms. Strong significant cross-sectional associations were found between negative religious coping items and depressive symptoms in both groups, while no longitudinal associations were found. So, similar impact of religiousness on the presence of depressive symptoms was found for both native and immigrant dialysis patients. Therefore, these results do not explain the higher prevalence of depressive symptoms found in immigrant chronic dialysis patients compared to native patients.

Background: More than 6200 End Stage Renal Disease patients in the Netherlands are dependent on dialysis, either performed at home or in a dialysis centre. Visiting a dialysis centre three times a week is considered a large burden by many patients. However, recent data regarding the effects of dialysis at home on quality of life, clinical outcomes, and costs compared with in-centre haemodialysis are lacking., Methods: The Dutch nOcturnal and hoME dialysis Study To Improve Clinical Outcomes (DOMESTICO) is a nationwide, prospective, observational cohort study that will include adult patients starting with a form of dialysis. Health-related quality of life, as the primary outcome, clinical outcomes and costs, as secondary outcomes, will be measured every 3-6 months in patients on home dialysis, and compared with a control group consisting of in-centre haemodialysis patients. During a 3-year period 800 home dialysis patients (600 peritoneal dialysis and 200 home haemodialysis patients) and a comparison group of 800 in-centre haemodialysis patients will be included from 53 Dutch dialysis centres (covering 96% of Dutch centres) and 1 Belgian dialysis centre (covering 4% of Flemish centres)., Discussion: DOMESTICO will prospectively investigate the effect of home dialysis therapies on health-related quality of life, clinical outcomes and costs, in comparison with in-centre haemodialysis. The findings of this study are expected to ameliorate the shared decision-making process and give more guidance to healthcare professionals, in particular to assess which type of patients may benefit most from home dialysis., Trial Registration: The DOMESTICO study is registered with the National Trial Register on (number: NL6519 , date of registration: 22 August 2017) and the Central Committee on Research Involving Human Subjects (CCMO) (number: NL63277.029.17).

Essentials Mortality due to bleeding vs. arterial thrombosis in dialysis patients is unknown. We compared death causes of 201 918 dialysis patients with the general population. Dialysis was associated with increased mortality risks of bleeding and arterial thrombosis. Clinicians should be aware of the increased bleeding and thrombosis risks., Summary: Background Dialysis has been associated with both bleeding and thrombotic events. However, there is limited information on bleeding as a cause of death versus arterial thrombosis as a cause of death. Objectives To investigate the occurrence of bleeding, myocardial infarction and stroke as causes of death in the dialysis population as compared with the general population. Methods We included 201 918 patients from 11 countries providing data to the ERA-EDTA Registry who started dialysis treatment between 1994 and 2011, and followed them for 3 years. Age-standardized and sex-standardized mortality rate ratios for bleeding, myocardial infarction and stroke as causes of death were calculated in dialysis patients as compared with the European general population. Associations between potential risk factors and these causes of death in dialysis patients were investigated by calculating hazard ratios (HRs) with 95% confidence intervals (CIs) by the use of Cox proportional-hazards regression. Results As compared with the general population, the age-standardized and sex-standardized mortality rate ratios in dialysis patients were 12.8 (95% CI 11.9-13.7) for bleeding as a cause of death (6.2 per 1000 person-years among dialysis patients versus 0.3 per 1000 person-years in the general population), 13.4 (95% CI 13.0-13.9) for myocardial infarction (22.5 versus 0.9 per 1000 person-years), and 12.4 (95% CI 11.9-12.9) for stroke (14.3 versus 0.7 per 1000 person-years). Conclusion Dialysis patients have highly increased risks of death caused by bleeding and arterial thrombosis as compared with the general population. Clinicians should be aware of the increased mortality risks caused by these conditions., (© 2018 International Society on Thrombosis and Haemostasis.)

Background: More older patients with end-stage renal disease (ESRD) are starting dialysis. Elderly patients often prefer treatments that focus on quality of life rather than primarily extending life and a substantial group of elderly dialysis patients might regret their decision to start dialysis. Healthcare provider and patient-related factors may be involved. Our objective was to measure the percentage of patients in the Netherlands who regretted their decision to start dialysis., Methods: Cross-sectional Dutch national survey of dialysis patients. A short questionnaire about age, satisfaction with pre-dialysis education, present treatment, dialysis initiation, regret about decision to start dialysis and key figures in decision-making was developed., Results: A total of 1371 questionnaires were returned for analysis from 28 dialysis units. Of the patients 7.4% regretted their decision to start dialysis, 50.5% reported the nephrologist's opinion to be crucial in decision-making and these patients experienced more regret than those who made the decision themselves (odds ratio, OR: 1.81). When family influenced decision-making more regret was experienced compared with those who decided themselves (OR: 2.73). Older age was associated with less regret (p = 0.02) and higher treatment satisfaction (p < 0.001); 52.8% of participants described dialysis initiation as being sudden., Conclusion: The majority of patients did not regret their decision to start dialysis. Older patients were more satisfied with their treatment and felt less regret. The nephrologist's and the family's opinion were directional in decision-making on ESRD treatment options and were associated with more regret, especially in younger patients.

The share of peritoneal dialysis (PD) in the spectrum of chronic dialysis has decreased markedly in the Netherlands in the last 15 years. Consequently, the knowledge of nephrologists and nursing staff on PD has declined leading to a negative spiral in which loss of experience resulted in loss of enthusiasm to offer PD to patients and also in less interest in the new PD developments. All these changes took place while the results of PD improved and patient survival was at least similar to that on haemodialysis. The aim of this review is first to give a summary of the principles and practice of patient and staff education and to describe the role of the medical contribution in decision-making. On this basis, the second aim is to update internist-nephrologists on a number of issues that have been underexposed in the past. Recent patient and technique survival data of PD patients is reviewed, and also the new insights into dialysis adequacy. The presence of residual renal function is the main determinant of patient survival together with prevention of overhydration. Urea and creatinine removal are not important at all when patients are still passing urine. Many early problems with PD are due to the peritoneal catheter and suggestions are made for improvement of its function. The prevention and management of infections is reviewed, and also the regular assessment of peritoneal function. Free water transport is a predictor of encapsulating peritoneal sclerosis (EPS), which should be assessed regularly. The pathogenesis of EPS, treatment and the decreasing incidence are discussed.

Background: The purpose of this study was to identify the ten most frequent complications after surgery for stage I-III colon cancer and to assess the association between these complications and overall survival, conditional overall survival, and recurrences., Methods: All patients who underwent surgery for stage I-III colon cancer in five hospitals in the Western region of the Netherlands were identified. Crude and adjusted Cox proportional hazards models were used to study the association between complications and 1-year overall survival, 5-year overall survival, 5-year conditional overall survival, and 5-year disease-free period., Results: Data from 761 patients were used for the analyses. Complications were associated with decreased 1-year overall survival (hazard ratio (HR) 2.87, 95 % confidence interval (CI) 1.82-4.51; p < 0.001), 5-year overall survival (HR 1.59, 95 % CI 1.25-2.04; p < 0.001), and 5-year conditional overall survival (HR 1.34, 95 % CI 1.06-1.69; p = 0.016), whereas an increasing number of complications had no additional impact. Anastomotic leakage, excessive blood loss, and (abdominal) sepsis were associated with reduced 1-year overall survival, anastomotic leakage, delirium, abscess, and (abdominal) sepsis with reduced 5-year overall survival, and anastomotic leakage, delirium, and abscess with reduced 5-year conditional overall survival. Anastomotic leakage, electrolyte disorders, and abscess were risk factors for recurrence within five years., Conclusions: Our results demonstrate the serious impact of the most frequent complications after surgery for colon cancer on short-term and long-term outcomes. This study confirms the prolonged impact of surgery and demonstrates that complications result not only in reduced 1-year survival, but also in reduced long-term outcomes.

Physicians need to stay up-to-date with new developments in their field of expertise. This expectation has been made explicit by competency-based educational outcomes in the domain of scholar in the Dutch blueprint. There is a great diversity in teaching methods that aim to achieve a better understanding of scientific knowledge. Applying a constructivist approach to learning in acquiring research competencies we wonder how a research-intensive course is evaluated early in the curriculum and what learning gain students perceive. In a collaborative research-intensive course, the class of 300s-year students rated the quality of 150 preselected randomized controlled trials (RCT) using JAMA Users' Guides, and the pharmaceutical advertisements in which they were referenced. Each student rated two RCTs. Data were analyzed to answer a relevant research question. After the course students completed an evaluation survey. We did this in five consecutive years to capture student experience in relation to fostering a scientific mindset (n = 1,500). In addition we studied outcome of this scientific mindset as scientific output (publications) in journals. Survey data indicate that it is feasible to successfully implement a research-intensive course based on a large cohort using a constructivist paradigm early in the curriculum. Students consider it challenging and report high learning gain in several domains. Aggregated data have even led to four publications in journals. Implementing an active learning research experience early in the curriculum can foster student attitudes, provided the level of difficulty correctly matches the learners' prior knowledge. Further research is required to determine how to improve these active research curricula to maximize impact on learners.

Aims/hypothesis: A previous study in Dutch dialysis patients showed no survival difference between patients with diabetes as primary renal disease and those with diabetes as a co-morbid condition. As this was not in line with our hypothesis, we aimed to verify these results in a larger international cohort of dialysis patients., Methods: For the present prospective study, we used data from the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry. Incident dialysis patients with data on co-morbidities (n = 15,419) were monitored until kidney transplantation, death or end of the study period (5 years). Cox regression was performed to compare survival for patients with diabetes as primary renal disease, patients with diabetes as a co-morbid condition and non-diabetic patients., Results: Of the study population, 3,624 patients (24%) had diabetes as primary renal disease and 1,193 (11%) had diabetes as a co-morbid condition whereas the majority had no diabetes (n = 10,602). During follow-up, 7,584 (49%) patients died. In both groups of diabetic patients mortality was higher compared with the non-diabetic patients. Mortality was higher in patients with diabetes as primary renal disease than in patients with diabetes as a co-morbid condition, adjusted for age, sex, country and malignancy (HR 1.20, 95% CI 1.10, 1.30). An analysis stratified by dialysis modality yielded similar results., Conclusions/interpretation: Overall mortality was significantly higher in patients with diabetes as primary renal disease compared with those with diabetes as a co-morbid condition. This suggests that survival in diabetic dialysis patients is affected by the extent to which diabetes has induced organ damage.

Background: Although an association between venous thrombosis and chronic kidney disease has recently been established, it is unknown which patients with chronic kidney disease are most likely to benefit from thromboprophylaxis., Objective: The aim of this study was to assess the association between venous thrombosis and chronic kidney disease in combination with arterial thrombosis, malignancy, surgery and thrombophilia to identify high-risk groups as a basis for personalized prevention., Methods: This study included 2473 consecutive patients with first venous thrombosis and 2936 controls from a case-control study (the MEGA study)., Results: Moderately decreased kidney function (eGFR 30-60 mL min(-1) ) was associated with a 2.5-fold (95% CI, 1.9-3.4) increased risk and severely decreased kidney function (eGFR < 30 mL min(-1) ) was associated with a 5.5-fold (95% CI 1.8-16.7) increased risk of venous thrombosis, compared with those with normal kidney function (eGFR > 90 mL min(-1) ). The risk of venous thrombosis was additionally increased for moderately and severely reduced kidney function in combination with arterial thrombosis (odds ratio, 4.9; 95% CI, 2.2-10.9), malignancy (5.8; 95% CI, 2.8-12.1), surgery (14.0; 95%, CI 5.0-39.4), immobilization (17.1; 95% CI, 6.8-43.0) or thrombophilia (odds ratios, 4.3-9.5), with particularly high risks when three or more risk factors were present (odds ratio, 56.3; 95% CI, 7.6-419.3)., Conclusion: Decreased kidney function is associated with an increased risk of venous thrombosis. The risk increased substantially in the presence of one or more other risk factors for thrombosis., (© 2013 International Society on Thrombosis and Haemostasis.)

Background: The risk of venous thrombosis associated with major illnesses is not well known, and neither is the risk associated with the combined effect of immobilization and thrombophilia. The aim of this study was to assess the effect on the development of venous thrombosis of several major illnesses in combination with immobilization, body mass index, and thrombophilia, to identify high-risk groups that may provide a basis for personalized prevention., Methods: This study included 4311 consecutive patients with a first episode of venous thrombosis, and 5768 controls from a case-control study (MEGA study). We calculated odds ratios (ORs) for venous thrombosis for patients with a self-reported history of major illnesses., Results: Venous thrombosis risk was increased for all investigated major illnesses: liver disease, OR 1.7 (95% confidence interval [CI]1.0-2.9); kidney disease, OR 3.7 (95% CI 2.3-5.9); rheumatoid arthritis, OR 1.5 (95% CI 1.2-1.9); multiple sclerosis, OR 2.4 (95% CI 1.3-4.3); heart failure, OR 1.7 (95% CI 1.2-2.3); hemorrhagic stroke, OR 4.9 (95% CI 2.4-9.9); arterial thrombosis, OR 1.5 (95% CI 1.2-1.8); and the presence of any of the above major illnesses, OR 1.7 (95% CI 1.5-1.9). Combinations of major illnesses with immobilization and increased factor VIII (OR 79.9; 95% CI 33.2-192.2), increased FIX (OR 35.3; 95% CI 14.2-87.8), increased von Willebrand factor (OR 88.0; 95% CI 33.9-228.3), FV Leiden (OR 84.2; 95% CI 19.5-363.6), and blood group non-O (OR 53.1; 95% CI 30.9-91.4) were associated with increased venous thrombosis risks., Conclusions: All of the major illnesses reported here were associated with an increased risk of venous thrombosis. These risks were most pronounced at the time of immobilization or in the presence of thrombophilia., (© 2012 International Society on Thrombosis and Haemostasis.)

Unlabelled: The success of universal newborn hearing screening (UNHS) programmes is usually evaluated by determining the effect of the early detection of hearing loss on developmental outcome. However, in practice, these programmes do not detect all children with permanent childhood hearing impairment. In this study we determine the sensitivity of the current UNHS programme and analyse the characteristics of the children not detected by UNHS. We performed a nationwide, population-based, retrospective follow-up study in The Netherlands. All children born in 2003-05 and screened in a hearing screening programme (well babies and neonatal intensive care (NICU) graduates) were included for study. The main outcome measure was the sensitivity of the UNHS programme (based on the proportion of children known to have a permanent childhood hearing impairment in 2008 who were identified by UNHS). We also evaluated age at diagnosis, severity, and aetiology of hearing impairment in the children not detected by UNHS. We found that the sensitivity of the current UNHS programme was 0.83 (0.79 for well babies and 0.96 for NICU graduates). Permanent childhood hearing impairment was confirmed before 36 months of age in 96% of the study cohort. Of the children unidentified by the UNHS, > 50% had moderate hearing loss. No predominant cause of hearing impairment was found in these children., Conclusion: Our current UNHS programme identified the majority of children with a permanent hearing impairment of congenital cause.

Background: It is has been suggested that dialysis patients have lower mortality rates for pulmonary embolism than the general population, because of platelet dysfunction and bleeding tendency. However, there is limited information whether dialysis is indeed associated with a decreased mortality risk from pulmonary embolism., Objective: The aim of our study was to evaluate whether mortality rate ratios for pulmonary embolism were lower than for myocardial infarction and stroke in dialysis patients compared with the general population., Methods: Cardiovascular causes of death for 130,439 incident dialysis patients registered in the ERA-EDTA Registry were compared with the cardiovascular causes of death for the European general population., Results: The age- and sex-standardized mortality rate (SMR) from pulmonary embolism was 12.2 (95% CI 10.2-14.6) times higher in dialysis patients than in the general population. The SMRs in dialysis patients compared with the general population were 11.0 (95% CI 10.6-11.4) for myocardial infarction, 8.4 (95% CI 8.0-8.8) for stroke, and 8.3 (95% CI 8.0-8.5) for other cardiovascular diseases. In dialysis patients, primary kidney disease due to diabetes was associated with an increased mortality risk due to pulmonary embolism (HR 1.9; 95% CI 1.0-3.8), myocardial infarction (HR 4.1; 95% CI 3.4-4.9), stroke (HR 3.5; 95% CI 2.8-4.4), and other cardiovascular causes of death (HR 3.4; 95% CI 2.9-3.9) compared with patients with polycystic kidney disease., Conclusions: Dialysis patients were found to have an unexpected highly increased mortality rate for pulmonary embolism and increased mortality rates for myocardial infarction and stroke., (© 2012 International Society on Thrombosis and Haemostasis.)

The timing of the start of dialysis in elderly patients is driven by the desire to optimize the quantity and quality of life. Limited data exist on how the level of renal function, and uraemic signs and symptoms can be used to determine when dialysis should be initiated in elderly patients. EQUAL, an international prospective cohort study, aims to address these issues. To this end, it will enroll 3500 patients >65 years of age with CKD of various aetiologies under the care of nephrologists. These patients will be followed until death, discharge from the nephrology clinic to primary care or until the end of the observation period after 4 years of follow-up. At the time of enrollment, patients must have an estimated glomerular filtration rate (eGFR) of 20 mL/min/1.73 m(2) or lower, but should not yet be on dialysis. Standardized data collection will include demographics, lifestyle, comorbidities, uraemic signs and symptoms, nutritional status, medication and routine blood and urine biochemistry. It will also comprise quality of life data, information on decision making including patients preferences and patients satisfaction.

In medicine, before replacing an old device by a new one, we need to know whether the results of the old and new device are similar. This is called determining the agreement between methods. In this paper, we will first discuss various ways to determine the agreement between methods to measure continuous variables, including the t test, the correlation coefficient and the Bland-Altman plot. In the second part, we will discuss methods to determine the agreement between categorical variables, like the χ(2) test and Cohen's ĸ. The latter are often used when studying the agreement between clinicians, definitions, formulas or different data sources., (Copyright © 2012 S. Karger AG, Basel.)

The most frequently used model to describe the exponential increase in mortality rate over age is the Gompertz equation. Logarithmically transformed, the equation conforms to a straight line, of which the slope has been interpreted as the rate of senescence. Earlier, we proposed the derivative function of the Gompertz equation as a superior descriptor of senescence rate. Here, we tested both measures of the rate of senescence in a population of patients with end-stage renal disease. It is clinical dogma that patients on dialysis experience accelerated senescence, whereas those with a functional kidney transplant have mortality rates comparable to the general population. Therefore, we calculated the age-specific mortality rates for European patients on dialysis (n=274 221; follow-up=594 767 person-years), for European patients with a functioning kidney transplant (n=61 286; follow-up=345 024 person-years), and for the general European population. We found higher mortality rates, but a smaller slope of logarithmic mortality curve for patients on dialysis compared with both patients with a functioning kidney transplant and the general population (P<0.001). A classical interpretation of the Gompertz model would imply that the rate of senescence in patients on dialysis is lower than in patients with a functioning transplant and lower than in the general population. In contrast, the derivative function of the Gompertz equation yielded the highest senescence rates for patients on dialysis, whereas the rate was similar in patients with a functioning transplant and the general population. We conclude that the rate of senescence is better described by the derivative function of the Gompertz equation., (© 2010 The Authors. Aging Cell © 2010 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.)

Background: End-stage renal disease has been associated with venous thrombosis (VT). However, the risk of VT in the early stages of chronic kidney disease (CKD) has not yet been investigated. The aim of this study was to investigate whether CKD patients with stage 1-3 disease are at increased risk of VT., Methods: Eight thousand four hundred and ninety-five subjects were included in a prospective cohort study, in which renal function and albuminuria were assessed, starting in 1997-1998, and were followed for the occurrence of VT until 1 June 2007. CKD patients were staged according to the Kidney Disease Outcomes Quality Initiative guidelines, on the basis of 24-h urine albumin excretion and estimated glomerular filtration rates. Objectively verified symptomatic VT was considered to be the endpoint., Results: Of the 8495 subjects, 243 had CKD stage 1, 856 CKD stage 2, and 491 CKD stage 3. During a median follow-up period of 9.2 years, 128 individuals developed VT. The hazard ratios (HRs) for CKD stages 1, 2 and 3 were, respectively, 2.2 [95% confidence interval (CI) 0.9-5.1], 1.9 (95% CI 1.1-3.1) and 1.6 (95% CI 0.9-2.8) relative to those without CKD after adjustment for age, sex, body mass index, hypertension, diabetes, malignancy, and high-sensitivity C-reactive protein. Subjects with CKD stage 3 and albuminuria (≥ 30 mg d(-1)) had an adjusted HR of 3.0, and subjects with CKD stage 3 without albuminuria had an adjusted HR of 1.0., Conclusions: CKD stages 1 and 2, and CKD stage 3 in the presence of albuminuria, are risk factors for VT. The risk of VT is more related to albuminuria than to impaired glomerular filtration rate., (© 2010 International Society on Thrombosis and Haemostasis.)

Aims: To provide an overview of the existing data on non-Caucasian dialysis patients within Europe, and to explore whether these data confirm differences between non-Caucasian and Caucasian dialysis patients that were found in other parts of the world., Method: A query consisting of the combination "dialysis", "ethnicity", and "Europe" was applied in PubMed, EMBASE, Web of Science, CINAHL, and the Cochrane Library., Results: Ten papers were included in this study. Studies from the United Kingdom (UK) and the Netherlands confirm the higher incidence of end-stage renal disease (ESRD) in non-Caucasians. In other European countries these findings were not confirmed. In studies from the UK, the Netherlands, and Spain a younger age at initiation of dialysis treatment for non-Caucasians compared to Caucasians was reported, this is also found in non-European studies. Regarding comorbid conditions at the start of renal replacement therapy (RRT), vascular disease was less common, while diabetes was more common among non-Caucasians compared to Caucasians. Large non-European studies also demonstrated less vascular disease among non-Caucasians initiating RRT than among Caucasians. The survival advantage for non-Caucasian compared to Caucasian RRT patients is confirmed in one large study from the UK and in a Dutch study. Reasons for the better survival of non-Caucasians are not understood completely., Conclusions: Only a few studies are available on non-Caucasian dialysis patients in Europe. The available data confirm findings of other studies throughout the world on racial differences on dialysis. More research is needed to understand the higher incidence and better survival in non-Caucasian patients, and also in countries where there are currently no relevant data.

Background/aim: Anemia is associated with increased mortality and morbidity in both early and very late stages of chronic kidney disease (CKD). The aim of this study was to assess whether anemia is a risk factor for mortality or hospitalization in CKD stage 4-5 predialysis patients not yet on dialysis., Methods: Incident predialysis patients were included between 1999 and 2001 and followed until January 2008 or death. Anemia was defined as mean hemoglobin (Hb) < or =11 g/dl in the 3 months before the start of predialysis. Associations were assessed by Cox regression, linear and logistic regression analysis., Results: A total of 472 patients were included (median follow-up time 12 months, 11% died, 79% started dialysis). Mean Hb was 11.2 g/dl (minimum 7.6, maximum 16.9). Forty-eight percent of patients had anemia at the start of predialysis care. The adjusted mortality risk (hazard ratio, 95% confidence interval) for anemic compared to nonanemic patients was 1.92 (1.04, 3.52). Anemia tended to be related to all-cause but not to non-dialysis-related hospitalization risk., Conclusion: At the start of predialysis care, 48% of patients had anemia. Anemia as defined in guideline targets is not associated with an increase in hospitalizations not related to renal replacement therapy, but is likely an important risk factor for mortality in predialysis patients., (Copyright 2010 S. Karger AG, Basel.)

In confounding, the effect of the exposure of interest is mixed with the effect of another variable. It is important to identify relevant confounders and remove the confounding effect as much as possible. There are three criteria that need to be fulfilled to determine whether a variable could be considered a potential confounder. The first criterion is that the variable needs to be associated with the exposure. The second criterion is that the variable needs to be associated with the outcome or disease. The third criterion is that the variable should not be an intermediate variable in the causal pathway between exposure and outcome. Only if all the criteria are fulfilled is the variable under question a confounder. If one incorrectly adjusts for a variable that is not a confounder, one risks overadjustment or adjustment for spurious associations. Confounders can be prevented from entering the study, during the design of a study, or if this is not possible, one can try to remove it during the analysis phase., (Copyright © 2010 S. Karger AG, Basel.)

Since about three decades, inhibitors of the renin-angiotensin system have been available in clinical practice. Although angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) were primarily aimed at treatment of hypertension and heart failure, more of their positive effects were discovered later on. Patients with chronic kidney disease were recognised to profit the most from treatment with these agents; however some blind spots are still present. Patients with advanced renal failure are almost always excluded from the trials; patients with end-stage renal disease form the least studied population of all and outcomes of treatment with ACEi/ARB are still uncertain in these cohorts. The aim of this review is to summarise and update the evidence about effects of AII inhibitors in patients with chronic kidney disease with the specific emphasis on patients treated with dialysis. Lately a novel indication for ACEi/ARB administration, especially for peritoneal dialysis patients, has been proposed. It is based on the capacity of these drugs to inhibit the local tissue renin-angiotensin system, which results in less development of peritoneal fibrosis and a longer life for the peritoneal membrane. The most recent available data are presented in this review.

Background: Claims made in advertisements in medical journals might not always be supported by high-quality evidence, and referenced studies may have been sponsored by the pharmaceutical industry itself. We studied to what extent randomised controlled trials (RCTs) support the claims in advertisements in leading medical journals., Methods: Consecutive unique advertisements were selected from nine different medical journals, and evaluated by 250 medical students using a standardised score form. The quality of RCTs that were referenced in these advertisements was assessed with an instrument based on the Chalmers' score., Results: 158 RCTs from 94 advertisements were used in the study. In total 55% of the RCTs had a high-quality score, 44% intermediate, and <1% had a low-quality score. Almost 40% of the RCTs had a high-quality score and at the same time supported the claim for which they were cited, while only 17% were also not sponsored by a pharmaceutical company., Conclusion: RCTs used to support claims in medical advertisements are often not a high-quality and independent source of evidence. This distracts from the credibility of claims in advertisements, even in the high-ranked journals.

Background: A significant number of asymptomatic newborns infected with congenital cytomegalovirus (CMV) will present with permanent childhood hearing impairment (PCHI) during early childhood., Objectives: To investigate the role of congenital CMV infection in causing PCHI in the Netherlands, and assess the efficacy of two different hearing screening strategies and the developmental outcome following each strategy., Study Design: We included 192 children with PCHI at the age of 3-5 years, who were offered hearing screening in their first year of life. Dried blood spots from 171 children were available for CMV detection using real-time PCR. The results of eight previously tested samples were also available. Clinical baseline characteristics were collected from medical records and the Child Development Inventory was used to investigate the developmental outcome., Results: The rate of congenital CMV among the 179 children was 8% (14/179) and 23% (9/39) among children with profound PCHI. Two of eight CMV-positive children with PCHI at the age of 3-5 years had passed the newborn hearing screening (NHS) test. Developmental outcome measures showed a significantly greater delay in language comprehension in children with both PCHI and congenital CMV infection (the largest in symptomatic children) than in the children with PCHI without congenital CMV infection., Conclusions: Congenital CMV infection is important in the etiology of PCHI. Universal NHS is not a guarantee of normal hearing and development in childhood for children with congenital CMV infection. This is a problem which might be solved by universal congenital CMV screening.

Background: Because of limited treatment options for congenital cytomegalovirus (CMV) infection, preventive strategies are important. Knowledge and awareness are essential for the success of preventive strategies., Objectives: To investigate the knowledge of congenital CMV among doctors involved in mother and child care in the Netherlands., Study Design: A questionnaire on CMV infection was sent to doctors by snowball sampling. Knowledge concerning epidemiology, transmission, symptoms and signs of CMV infection in adults and children, and treatment options were evaluated., Results: The questionnaire was completed by 246 doctors involved in mother and child care. The respondents estimated a prevalence of congenital CMV varying between 0.1 and 500 per 1000 live-born infants. The mean knowledge scores regarding transmission and postnatal symptoms increased with a more advanced career stage (i.e. older age). Gender and parenthood did not contribute to knowledge, but the field of expertise did. Respondents in the field of pediatrics had the highest mean score on postnatal symptoms and long-term effects. Respondents working in the field of gynecology and obstetrics were unaware of the precise transmission route of CMV. More than one-third of the respondents assumed that treatment was readily available for congenital CMV infection., Conclusions: The knowledge of CMV infection among doctors in the Netherlands contained several gaps. Increasing knowledge and awareness is expected to enhance the prevention of transmission, to improve recognition, and to stimulate diagnostic investigations and follow-up programs.

Background: Measuring GFR using exogenous markers without a bladder catheter, errors can be easily made due to incomplete urine collection. The aim was to quantify agreement for 125I-iothalamate GFR measurements with and without a correction for inaccurate urine collection using 131I-hippuran., Methods: The last available GFR measurement of adult patients was included. GFR was measured in two subsequent clearance periods with 125I-iothalamate by the standard method with correction for inaccurate urine collections using 131I-hippuran. The uncorrected and corrected GFR measurements were compared within and between the time periods for each individual patient. To study the agreement between both methods, intraclass correlation coefficients (ICC) were calculated and Bland-Altman plots, with accompanying accuracies and precisions, were used. Cohen's kappa was calculated to analyze the agreement of both methods for classifying patients according to the stages of chronic kidney disease (CKD)., Results: For the 332 stable included patients, the mean GFR of the uncorrected measurements was 77.8 ml/min (34.7) and the mean GFR of the corrected measurements was 81.0 ml/min (34.9). The ICC was 0.80 for the uncorrected measurements with an accuracy of 7.3 ml/min and a precision of 21.7 ml/min. For the corrected GFR measurements the ICC was 0.98, with an accuracy of 2.1 ml/min and a precision of 6.5 ml/min. Comparison between the methods showed an ICC of 0.95, an accuracy of 3.2 and a precision of 11.0. In total, 86% of the patients were classified similarly into CKD stages with both methods, overall Cohen's kappa was 0.81., Conclusion: Agreement was better for GFR measurements corrected for inaccurate urine collections. Therefore, GFR measurements with 125I-iothalamate should be corrected for inaccurate urine collections using 131I-hippuran. Without such correction the GFR is easily underestimated which may lead to overtreatment.

The CYP3A5*1 allele has been linked to high expression of CYP3A5 and metabolism of cyclosporine. We evaluated the role of CYP3A5*1 for long-term survival in renal transplant patients in a cohort of 399 patients who underwent cadaveric or living donor kidney allograft transplantation. All patients were treated with a similar cyclosporine-based immunosuppressive maintenance therapy protocol. The mean duration of follow-up was 8.6+/-3.7 years. In univariate survival analysis, the presence of the CYP3A5*1 allele in recipients significantly increased patient survival P=0.028 (log-rank), resulting in a hazard ratio (HR) of 0.52 (95% CI=0.29-0.94). When the presence of the CYP3A5*1 allele was included in multivariate Cox regression analyses accounting for major risk factors for patient death, CYP3A5*1 still conferred a protective effect. Further, haplotype analysis at the CYP3A5 locus confirmed that CYP3A5*1 might indeed be responsible for this survival benefit.

Background: A single course of maternal glucocorticoid treatment is effective in reducing neonatal mortality after preterm birth. However, in animals, maternal glucocorticoid treatment is associated with lifelong hyperglycaemia and hypertension, and impaired nephrogenesis in offspring. Findings from studies in humans on this topic are highly contradictory due to a number of methodological flaws, and renal function after glucocorticoid exposure has never been assessed., Objectives: To assess in individuals born <32 gestational weeks whether antenatal glucocorticoid treatment for preterm birth is associated with long-term metabolical risks, including renal function, in adulthood., Design: Birth cohort study., Setting: Multicentre study., Patients: 412 19 year olds born <32 gestational weeks from the Project On Preterm and Small-for-gestational-age infants (POPS) cohort., Interventions: Maternal betamethasone 12 mg administered twice with a 24 h interval., Main Outcome Measures: Body composition, insulin resistance, the serum lipid profile, blood pressure and estimated renal function., Results: We did not find any long-term adverse effects of antenatal betamethasone, with the exception of an effect on glomerular filtration rate (GFR). In 19-year-old survivors, GFR was lower after betamethasone: -5.2 ml/min (95% CI -8.9 to -1.4) per 1.73 m(2)., Conclusions: The reduction in neonatal mortality associated with a single course of maternal betamethasone is not accompanied by long-term metabolical risks in survivors of preterm birth. The only adverse effect found was lower GFR. Although this difference was not clinically relevant at 19 years, it might predict an increased risk of chronic renal failure in prematurely born individuals who were exposed antenatally to betamethasone.

In previous articles of this series, we focused on relative risks and odds ratios as measures of effect to assess the relationship between exposure to risk factors and clinical outcomes and on control for confounding. In randomized clinical trials, the random allocation of patients is hoped to produce groups similar with respect to risk factors. In observational studies, exposed and unexposed individuals may differ not only for the presence of the risk factor being tested but also for a series of other factors that are potentially related to the study outcome, thus making 'confounding' very likely. One of the most important uses of multivariate modeling is precisely that 'of controlling for confounding' to let emerge the effect of the risk factor of interest on the study outcome. In this paper, we will discuss linear regression analysis for the examination of continuous outcome data and logistic regression analysis for the study of categorical outcome data. Furthermore, we focus on the most important application of multiple linear and logistic regression analyses.

We studied the longitudinal relation between disease severity and titers of antigen-specific IgG subclasses in sera of patients with myasthenia gravis and antibodies to Muscle Specific Kinase (MuSK MG). Six patients were included of whom 55 samples had been collected during 2.5-13.4 years. Anti-MuSK antibodies were determined by ELISA and with a cell-based immunofluorescence assay. Disease severity was scored on a semi continuous scale. Only antigen-specific IgG4, and not IgG1, titers were significantly associated with disease severity in a linear mixed effect model (p = 0.036). Levels of IgG4 antibodies were above IgG1 in all samples except in one patient who went into clinical remission while switching from IgG4 to IgG1. The results support an important role for IgG4 in the pathogenesis of MuSK MG, in contrast to MG with anti-acetylcholine receptor antibodies.

As confounding obscures the 'real' effect of an exposure on outcome, investigators performing etiological studies do their utmost best to prevent or control confounding. Unfortunately, in this process, errors are frequently made. This paper explains that to be a potential confounder, a variable needs to satisfy all three of the following criteria: (1) it must have an association with the disease, that is, it should be a risk factor for the disease; (2) it must be associated with the exposure, that is, it must be unequally distributed between exposure groups; and (3) it must not be an effect of the exposure; this also means that it may not be part of the causal pathway. In addition, a number of different techniques are described that may be applied to prevent or control for confounding: randomization, restriction, matching, and stratification. Finally, a number of examples outline commonly made errors, most of which result from 'overadjustment' for variables that do not satisfy the criteria for potential confounders. Such an example of an error frequently occurring in the literature is the incorrect adjustment for blood pressure while studying the relationship between body mass index and the development of end-stage renal disease. Such errors will introduce new bias instead of preventing it.

The quality of a clinical study depends on internal and external factors. Studies have internal validity when, random error apart, reported differences between exposed and unexposed individuals can be attributed only to the exposure under investigation. Internal validity may be affected by bias, that is, by any systematic error that occurs in the design or in the conduction of a clinical research. Here we focus on two major categories of bias: selection bias and information bias. We describe three types of selection biases (incidence-prevalence bias, loss-to-follow-up bias, and publication bias) and a series of information biases (i.e. misclassification bias--recall bias, interviewer bias, observer bias, and regression dilution bias--and lead-time bias).

To establish the prevalence of elevated liver enzymes in children transplanted in a Dutch haematopoietic stem cell transplantation (HSCT) centre, we retrospectively assessed AST and ALT values at 2 years after HSCT. Age, sex, diagnosis, type of transplant, conditioning regimen and early post-transplant complications involving the liver (veno-occlusive disease, acute GVHD, viral reactivation) were analysed as risk factors. AST and ALT values were available at 2 years after HSCT in 216 of 290 patients (75%) alive at that time and were above normal in 53 (25%) and at least twice normal in 17 (8%) patients. Older age at HSCT and a diagnosis of benign haematological disease are risk factors for abnormal liver enzymes late after HSCT. In half of the patients with benign haematological disease, iron overload is the most likely aetiological factor. Chronic hepatitis B or C is uncommon in our centre. In conclusion, the prevalence of abnormal liver enzymes late after HSCT in our centre is lower than reported in previous studies. Abnormal liver enzymes occur more often in children who are older at HSCT and transplanted for benign haematological disease. Long-term follow-up is crucial to establish if elevated liver enzymes precede clinical liver disease.

Epidemiological studies aim at assessing the relationship between exposures and outcomes. Clinicians are interested in knowing not only whether a link between a given exposure (e.g. smoking) and a certain outcome (e.g. myocardial infarction) is statistically significant, but also the magnitude of this relationship. The 'measures of effect' are indexes that summarize the strength of the link between exposures and outcomes and can help the clinician in taking decisions in every day clinical practice. In epidemiological studies, the effect of exposure can be measured both in relative and absolute terms. The risk ratio, the incidence rate ratio, and the odds ratio are relative measures of effect. Risk difference is an absolute measure of effect and it is calculated by subtracting the risk of the outcome in exposed individuals from that of unexposed.

Background: After reports of emerging outbreaks in Canada and the United States, Clostridium difficile-associated disease (CDAD) due to polymerase chain reaction ribotype 027 was detected in 2 medium-to-large hospitals in The Netherlands in 2005., Methods: National surveillance was initiated to investigate the spread and the epidemiology of CDAD. Microbiologists were asked to send strains recovered from patients with a severe course of CDAD or recovered when an increased incidence of CDAD was noted. A standardized questionnaire was used to collect demographic, clinical, and epidemiological patient data. Strains were characterized by polymerase chain reaction ribotyping, toxinotyping, the presence of toxin genes, and antimicrobial susceptibility., Results: During the period from February 2005 through November 2006, 1175 stool samples from 863 patients were sent from 50 health care facilities. Of these patients, 218 (25.3%) had CDAD due to ribotype 027, and 645 patients (74.7%) had CDAD due to other ribotypes, mainly 001 (17.8%) and 014 (7.2%). Polymerase chain reaction ribotype 027 was more frequently present in general hospitals than in academic hospitals (odds ratio [OR], 4.38; 95% confidence interval [CI], 1.60-12.0). Outbreaks of CDAD were observed in 10 hospitals and in 1 nursing home. Patients infected with ribotype 027 were significantly older (OR, 2.18; 95% CI, 1.43-3.33), and significantly more patients used fluoroquinolones (OR, 2.88; 95% CI, 1.01-8.20), compared with those who were infected with other ribotypes. Clear trends were observed for more severe diarrhea (OR, 1.99; 95% CI, 0.83-4.73), higher attributable mortality (6.3% vs. 1.2%; OR, 3.30; 95% CI, 0.41-26.4), and more recurrences (OR, 1.44; 95% CI, 0.94-2.20)., Conclusions: Ribotype 027 was found in 20 (18.3%) of 109 hospitals in The Netherlands, with a geographic concentration in the western and central parts of the country. The clinical syndrome in patients with CDAD differed on the basis of ribotype. Thus, early recognition of the ribotype has benefits.

The purpose of this paper is to discuss whether the randomized clinical trial (RCT) is indeed the gold standard among epidemiological studies. This paper illustrates to what extent different study designs may contribute to the answer of the following therapeutic research question based on a study of Wanner et al.: 'Is the use of a statin associated to less cardiac mortality in patients with type 2 diabetes mellitus who receive hemodialysis?' If a therapeutic study is feasible, like the research question of the clinical example, the RCT is almost unbeatable: the problems that may occur in the other study designs do not exist or to a lesser extent using an RCT. The main advantage of an RCT is that the randomization procedure helps to prevent selection bias by the clinician by breaking the link between the clinician's therapy prescription and the patient's prognosis. Within observational studies, however, selection by the clinician may occur, and, even after adjustment for potential confounders in the statistical analysis, it may not be possible to make a fair comparison between the groups. Usually, results from observational studies are needed to come to a hypothesis that can subsequently be tested within an RCT. Moreover, observational data are most often more useful than RCTs for non-therapeutic studies.

In studies on the effects of therapy (or other interventions), the randomized controlled trial (RCT) is an almost unbeatable standard in clinical research. The value of RCTs leaves unabated the valuable contributions of observational studies to medicine. This paper discusses some limitations of RCTs providing examples where these are not possible, inappropriate, inadequate, or unnecessary. Thereafter, it focuses on observational studies and gives a number of examples of studies on etiology, diagnosis, prognosis, and adverse effects, where observational designs have provided answers to research questions that could not have been answered by RCTs. Strengths and weaknesses of the different observational study designs are discussed. Finally, it is concluded that both observational studies and RCTs fulfill a complementary and valuable role in nephrology.

Different measures may be used to describe how often disease (or another health event) occurs in a population. Incidence expresses the development of new cases and is mostly used against the background of prevention, to assess disease etiology or to determine the risk factors of disease. Depending on the specific study question, incidence may be reported as risk or as incidence rate. This paper discusses that it is preferable to use incidence rate in case of a dynamic population or in cases where the observation period is sufficiently long for competing risks or loss to follow-up to play a significant role. Prevalence is the number of existing cases, which is affected by both the number of incident cases and the length of disease time. It reflects the burden of disease on a population that may, among others, be measured in terms of costs or morbidity. Knowledge about this burden can be used for the planning of health-care facilities. This paper discusses the different measures of disease occurrence using a number of examples taken from the nephrology literature.

Calcifying atherosclerosis is an active process, which is controlled by calcification inhibitors and inducers. Fetuin-A, an acute phase glycoprotein, is one of the more powerful circulating inhibitors of hydroxyapatite formation. A prospective multicenter cohort study was initiated to include both hemodialysis (HD) and peritoneal dialysis (PD) patients in an evaluation of the association of serum fetuin-A levels with both cardiovascular (CV) and non-CV mortality. An increase in the serum fetuin-A concentration of 0.1 g/l was associated with a significant reduction in all-cause mortality of 13%. There was a significant 17% reduction in non-CV mortality and a near significant reduction in CV mortality. This association of fetuin-A and mortality rates was comparable in both HD and PD patients even when corrected for factors, including but not limited to age, gender, primary kidney disease, C-reactive protein levels, and nutritional status. We conclude that serum fetuin-A concentrations may be a general predictor of mortality in dialysis patients.

Incidence rates of cervical cancer and its precursors vary considerably, with the highest rates found in developing countries. Differences are influenced by endogenous and exogenous factors. Comparing cytologic abnormality incidence rates from a high-risk population in the original high-risk area, with those of women from this high-risk population who have immigrated to a low-risk area could give insight in the significance of endogenous versus environmental factors. Smears collected from Surinamese women attending the Surinamese screening program and smears collected from immigrant Surinamese women attending the Dutch screening program were cytologically analyzed using the Dutch microscopical coding system KOPAC. Statistical analysis was performed by using logistic regression to calculate (age-adjusted) odds ratios (ORs). The age-adjusted ORs of having dysplasia were higher for Surinamese women living in Suriname versus Surinamese immigrant women and increased with increasing P-scores: 0.77 (0.31-1.91) for borderline changes, 1.62 (0.58-4.57) for mild dysplasia, and 3.20 (1.55-6.60) for moderate to severe dysplasia/neoplasia. We conclude that fewer cases with dysplasia are present in a high-risk population that has immigrated to a low-risk area for cervical cancer than in the high-risk population continuously living in a high-risk area. This finding emphasizes the importance of environmental factors.

In Europe there is considerable variation in mortality on renal replacement therapy (RRT). The causes of this variation are still poorly understood. We hypothesized that differences in mortality in the general population contribute to differences in mortality on RRT. To evaluate this relationship, we studied general population statistics obtained from Eurostat and the individual data of 67,692 patients on RRT from 15 national and regional renal registries. These 15 registries were divided into two geographical regions: North and South Europe. Cox regression was used to assess the relative risk of death (RR) for each region with adjustment for age, gender, diabetes, and additionally general population mortality. In patients on RRT the age, gender and diabetes adjusted RR of death was 0.65 (95% CI (0.64-0.66)) for South compared to North, while in the general population the age and gender standardized RR of death was 0.91. After adjustment for general population mortality in addition to age, gender, and diabetes, the RR of death for patients on RRT in the South changed from 0.65 to 0.74 (95% CI (0.72-0.75)), which indicates that general population mortality accounted for 26% of the region-related mortality difference on RRT. In conclusion, within Europe there exist considerable international differences in the mortality of patients on RRT. Twenty-six percent of the European north-south mortality difference in RRT could be attributed to differences in general population mortality. Our data support the hypothesis that general population mortality is an important factor to take into account when making RRT mortality comparisons.

Objectives: In rheumatology, five different billion-dollar drugs have emerged in recent years, making this subspecialty the focus of extensive advertising campaigns. Considering this development and the fact that the scientific content of advertisements has been questioned, we initiated a study to determine how evidence-based advertisements are in four leading journals of rheumatology., Methods: Advertisements were extracted from the journals Arthritis and Rheumatism, Rheumatology, Seminars in Arthritis and Rheumatism and the Journal of Rheumatology, and were evaluated using a standardized score form., Results: In total, 353 advertisements were obtained, of which 84 were unique. Of the 300 references provided by these unique advertisements, 53 (18%) were considered 'supporting'. In addition, 87 (29%) of the 300 references referred to randomized controlled trials (RCTs), of which 49% supported the claim. The vast majority of RCTs (97%) were sponsored by the advertising company. In the 84 unique advertisements 288 claims were made, of which 190 provided one or more references. Of these 190 claims, 33 (17%) were judged 'well supported'. In total, only four (5%) of the 84 different advertisements were judged 'well supported' and 11 (13%) of the 84 were judged 'misleading' because they contained one or more misleading claims, i.e. claims with references to articles contradicting the claim., Conclusions: This study indicates that few advertisements in rheumatology journals are entirely evidence-based.

Aims/hypothesis: An increased risk of type 2 diabetes mellitus is associated with low birthweight after full-term gestation, including amplification of this risk by weight gain during infancy and adult body composition. Premature birth is also associated with insulin resistance, but studies conducted so far have not provided follow-up into adulthood. We studied the effects of (1) lower birthweight (as standard deviation score [SDS]) and infancy weight gain on insulin resistance in 19-year-olds born before 32 weeks of gestation, and (2) the interaction between lower birthweight SDS and infancy weight gain, as well as between lower birthweight and adult body composition, on insulin resistance., Methods: This was a prospective follow-up study in 346 subjects from the Project on Preterm and Small-for-gestational-age infants cohort, in whom fasting glucose, insulin and C-peptide levels were measured at 19 years. Insulin resistance was calculated with homeostatic modelling (homeostatic model assessment for insulin resistance index [HOMA-IR])., Results: Birthweight SDS was unrelated to the outcomes. Rapid infancy weight gain until 3 months post-term was weakly associated with higher insulin level (p=0.05). Adult fatness was positively associated with insulin and C-peptide levels and HOMA-IR (all p<0.001). On these parameters, there was a statistical interaction between birthweight SDS and adult fat mass (p=0.002 to 0.03)., Conclusions/interpretation: In subjects born very preterm, rapid infancy weight gain until 3 months predicted higher insulin levels at 19 years, but the association was weak. Adult obesity strongly predicted higher insulin and C-peptide levels as well as HOMA-IR. The effect of adult fat mass on these parameters was dependent on its interaction with birthweight SDS.

Objective: Studies about the association between birth weight and circulating cortisol level have been published from 1998 onwards. However, their findings were inconsistent. To quantitatively assess the overall association between birth weight and circulating cortisol level, we aimed to perform a meta-analysis of the published literature., Methods: A literature search was conducted in PubMed, and selected papers were systematically reviewed. A pooled regression coefficient was calculated for the entire group as well as for males and females separately., Results: Data from 11 study populations were pooled (n = 2301). These populations differed with respect to geographical area, age, sex distribution, inclusion criteria and gestational age. We found a statistically significant inverse association between birth weight and circulating cortisol level: a 1 kg lower birth weight was associated with a 25.3 nmol/l (95% confidence interval (CI): 5.9-44.8) higher cortisol level. Separate results were reported for males and females in six study populations. The association in males was 20.6 nmol/l per kg (95% CI: 4.2-37.0) and in females it was 30.9 nmol/l per kg (95% CI: 7.4-54.4)., Conclusion: Differences between study populations hampered the comparability of the included studies. Although the majority of studies were underpowered, by using a meta-analytic approach we found an inverse association between birth weight and circulating cortisol level. Thus, our findings suggest that there is some evidence for a possible role of the hypothalamus-pituitary-adrenal axis in the epidemiological association between birth weight and cardiovascular disease. However, the strength of the overall association between birth weight and circulating cortisol level was weak.

Background/aims: Growth monitoring is almost universally performed, but few data are available on which referral criteria and diagnostic work-up are used worldwide for children with short stature., Methods: A short questionnaire, containing questions on auxological screening and on diagnostic criteria for short stature, was sent to all members of the European Society of Paediatric Endocrinology (ESPE) and to several pediatric endocrinologists outside Europe., Results: Responses were received from 36 countries. In 27 (75%) a child health care program existed and in 14 (39%) there was a protocol for referral of children with growth retardation. Height for age was mostly used as a referral criterion. Sixteen countries (45%) reported having a guideline in secondary health care for diagnostic work-up. Although all countries agreed on having biochemical, radiological and/or genetic tests in the diagnostic work-up, there was a wide variety of recommended tests., Conclusions: There is little consensus on referral criteria and diagnostic work-up of children with short stature among industrialized countries. There is a need to establish evidence-based guidelines.

Objective: The concept of disease activity in Graves' ophthalmopathy (GO) might explain why as many as one-third of patients do not respond to immunosuppressive treatment, because only patients in the active stage of disease are expected to respond. The hypothesis was adopted that a parameter used to measure disease activity should be able to predict a response to immunosuppressive treatment. The aim of this study was to develop a multivariate prediction model in which all previous tested activity parameters are integrated., Design and Patients: We included 66 consecutive patients with untreated moderately severe GO who had been euthyroid for at least 2 months. All patients were treated with radiotherapy. Measurements Treatment efficacy after 6 months follow-up was used as the primary outcome measure. Disease severity and 15 different disease activity parameters were assessed before treatment. Univariate and multivariate logistic regression models were used to predict response (model 1) or no change (model 2)., Results: In multivariate analyses, we found that duration of GO, soft tissue involvement, elevation, soluble interleukin-2 receptor (sIL-2R), soluble CD30 (sCD30), eye muscle reflectivity and octreotide uptake ratio were significant predictors of a response to radiotherapy. Gender, duration of GO, soft tissue involvement, eye muscle reflectivity, IL-6 and urinary glycosaminoglycan (GAG) excretion were significant predictors of no change upon radiotherapy. Prognostic score charts were developed for use in clinical practice to calculate the probability of response (model 1) and the probability of no change (model 2) for each new patient. Finally we used a combination of both models to define a recommended treatment modality for each individual patient, based on both the predicted probabilities of response and no change. We were able to identify the correct treatment (based on a comparison with the observed response) in 89% of the patients., Conclusions: Although we strongly recommend that our results should be confirmed in other studies, our findings are the first evidence for the idea that disease (in)activity should determine which kind of treatment should be used.