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1.  Uric acid: association with rate of renal function decline and time until start of dialysis in incident pre-dialysis patients 
BMC Nephrology  2014;15:91.
Background
In patients with chronic kidney disease (CKD) hyperuricemia is common. Evidence that hyperuricemia might also play a causal role in vascular disease, hypertension and progression of CKD is accumulating. Therefore, we studied the association between baseline uric acid (UA) levels and the rate of decline in renal function and time until start of dialysis in pre-dialysis patients.
Methods
Data from the PREPARE-2 study were used. The PREPARE-2 study is an observational prospective cohort study including incident pre-dialysis patients with CKD stages IV-V in the years between 2004 and 2011. Patients were followed for a median of 14.9 months until start of dialysis, kidney transplantation, death, or censoring. Main outcomes were the change in the rate of decline in renal function (measured as estimated glomerular filtration rate (eGFR)) estimated using linear mixed models, and time until start of dialysis estimated using Cox proportional hazards models.
Results
In this analysis 131 patients were included with a baseline UA level (mean (standard deviation (SD)) of 8.0 (1.79) mg/dl) and a mean decline in renal function of -1.61 (95% confidence interval (CI), -2.01; -1.22) ml/min/1.73 m2/year. The change in decline in GFR associated with a unit increase in UA at baseline was -0.14 (95% CI -0.61;0.33, p = 0.55) ml/min/1.73 m2/year. Adjusted for demography, comorbidities, diet, body mass index (BMI), blood pressure, lipids, proteinuria, diuretic and/or allopurinol usage the change in decline in eGFR did not change. The hazard ratio (HR) for starting dialysis for each mg/dl increase in UA at baseline was 1.08 (95% CI, 0.94;1.24, p = 0.27). After adjustment for the same confounders the HR became significant at 1.26 (95% CI, 1.06;1.49, p = 0.01), indicating an earlier start of dialysis with higher levels of UA.
Conclusion
Although high UA levels are not associated with an accelerated decline in renal function, a high serum UA level in incident pre-dialysis patient is a risk factor for an earlier start of dialysis.
doi:10.1186/1471-2369-15-91
PMCID: PMC4075499  PMID: 24939671
Uric acid; CKD progression; Pre-dialysis; Prospective cohort
2.  Single Nucleotide Variants in the Protein C Pathway and Mortality in Dialysis Patients 
PLoS ONE  2014;9(5):e97251.
Background
The protein C pathway plays an important role in the maintenance of endothelial barrier function and in the inflammatory and coagulant processes that are characteristic of patients on dialysis. We investigated whether common single nucleotide variants (SNV) in genes encoding protein C pathway components were associated with all-cause 5 years mortality risk in dialysis patients.
Methods
Single nucleotides variants in the factor V gene (F5 rs6025; factor V Leiden), the thrombomodulin gene (THBD rs1042580), the protein C gene (PROC rs1799808 and 1799809) and the endothelial protein C receptor gene (PROCR rs867186, rs2069951, and rs2069952) were genotyped in 1070 dialysis patients from the NEtherlands COoperative Study on the Adequacy of Dialysis (NECOSAD) cohort) and in 1243 dialysis patients from the German 4D cohort.
Results
Factor V Leiden was associated with a 1.5-fold (95% CI 1.1–1.9) increased 5-year all-cause mortality risk and carriers of the AG/GG genotypes of the PROC rs1799809 had a 1.2-fold (95% CI 1.0–1.4) increased 5-year all-cause mortality risk. The other SNVs in THBD, PROC, and PROCR were not associated with 5-years mortality.
Conclusion
Our study suggests that factor V Leiden and PROC rs1799809 contributes to an increased mortality risk in dialysis patients.
doi:10.1371/journal.pone.0097251
PMCID: PMC4016291  PMID: 24816905
3.  Course of Symptoms and Health-Related Quality of Life during Specialized Pre-Dialysis Care 
PLoS ONE  2014;9(4):e93069.
Background
Concerns are present on the limited value of renal function alone in defining the optimal moment to start dialysis. Disease-related symptoms and health-related quality of life (HRQOL) may have additional clinical value in defining this moment, but little is known about how these parameters change during pre-dialysis care. The aims of our study were to describe the course of symptoms and HRQOL during pre-dialysis care and to investigate their association with poor health outcomes.
Methods
In the prospective PREPARE-2 cohort, incident patients starting specialized pre-dialysis care were included when referred to one of the 25 participating Dutch outpatient clinics (2004–2011). In the present analysis, 436 patients with data available on symptoms and HRQOL were included. Clinical data, symptoms (revised illness perception questionnaire), and HRQOL (short form-36 questionnaire; physical and mental summary score) were collected every 6-month interval. A time-dependent Cox proportional hazard model was used to associate symptoms and HRQOL with the combined poor health outcome (i.e. starting dialysis, receiving a kidney transplant, and death).
Results
All symptoms increased, especially fatigue and loss of strength, and both the physical and mental summary score decreased over time, with the most pronounced change during the last 6–12 months of follow-up. Furthermore, each additional symptom (adjusted HR 1.04 (95% CI, 1.00–1.09)) and each 3-point lower physical and mental summary score (adjusted HR 1.04 (1.02–1.06) and 1.04 (1.02–1.06) respectively) were associated with a higher risk of reaching the combined poor health outcome within the subsequent 6 months.
Conclusions
The number of symptoms increased and both the physical and mental HRQOL score decreased during pre-dialysis care and these changes were associated with starting dialysis, receiving a kidney transplant, and death. These results may indicate that symptoms and HRQOL are good markers for the medical condition and disease stage of pre-dialysis patients.
doi:10.1371/journal.pone.0093069
PMCID: PMC3974712  PMID: 24699666
4.  Predicting Mortality in Patients with Diabetes Starting Dialysis 
PLoS ONE  2014;9(3):e89744.
Background
While some prediction models have been developed for diabetic populations, prediction rules for mortality in diabetic dialysis patients are still lacking. Therefore, the objective of this study was to identify predictors for 1-year mortality in diabetic dialysis patients and use these results to develop a prediction model.
Methods
Data were used from the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD), a multicenter, prospective cohort study in which incident patients with end stage renal disease (ESRD) were monitored until transplantation or death. For the present analysis, patients with DM at baseline were included. A prediction algorithm for 1-year all-cause mortality was developed through multivariate logistic regression. Candidate predictors were selected based on literature and clinical expertise. The final model was constructed through backward selection. The model's predictive performance, measured by calibration and discrimination, was assessed and internally validated through bootstrapping.
Results
A total of 394 patients were available for statistical analysis; 82 (21%) patients died within one year after baseline (3 months after starting dialysis therapy). The final prediction model contained seven predictors; age, smoking, history of macrovascular complications, duration of diabetes mellitus, Karnofsky scale, serum albumin and hemoglobin level. Predictive performance was good, as shown by the c-statistic of 0.810. Internal validation showed a slightly lower, but still adequate performance. Sensitivity analyses showed stability of results.
Conclusions
A prediction model containing seven predictors has been identified in order to predict 1-year mortality for diabetic incident dialysis patients. Predictive performance of the model was good. Before implementing the model in clinical practice, for example for counseling patients regarding their prognosis, external validation is necessary.
doi:10.1371/journal.pone.0089744
PMCID: PMC3942369  PMID: 24594735
5.  Effect of Erythropoiesis-Stimulating Agents on Blood Pressure in Pre-Dialysis Patients 
PLoS ONE  2013;8(12):e84848.
Introduction
Erythropoiesis-Stimulating Agents (ESA) are hypothesized to increase cardiovascular mortality in patients with chronic kidney disease. One of the proposed mechanisms is the elevation of blood pressure (BP) by ESA. Therefore, we aimed to determine whether the use of ESA was associated with antihypertensive treatment and higher BP.
Materials and Methods
In this cohort 502 incident pre-dialysis patients were included who started specialized pre-dialysis care in 25 clinics in the Netherlands. Data on medication including ESA use and dose, co-morbidities and BP were routinely collected every 6 months. Antihypertensive treatment and BP were compared for patients with and without ESA at baseline. Differences in antihypertensive medication and BP during pre-dialysis care were estimated with linear mixed models adjusted for age, sex, body mass index, cardiovascular disease, diabetes mellitus and estimated glomerular filtration rate.
Results
At baseline, 95.6% of patients with ESA were treated with antihypertensive medication and 73.1% of patients without ESA. No relevant difference in BP was found. During pre-dialysis care patients with ESA used 0.77 (95% CI 0.63;0.91) more classes of antihypertensive drugs. The adjusted difference in systolic blood pressure (SBP) was −0.3 (95% CI −2.7;2.0) mmHg and in diastolic blood pressure (DBP) was −1.0 (95% CI −2.1;0.3) mmHg for patients with ESA compared to patients without ESA. Adjusted SBP was 3.7 (95% CI −1.6;9.0) mmHg higher in patients with a high ESA dose compared to patients with a low ESA dose.
Conclusions
Our study confirms the hypertensive effect of ESA, since ESA treated patients received more antihypertensive agents. However, no relevant difference in BP was found between patients with and without ESA, thus the increase in BP seems to be controlled for by antihypertensive medication.
doi:10.1371/journal.pone.0084848
PMCID: PMC3877353  PMID: 24391978
6.  Time Course of Peritoneal Function in Automated and Continuous Peritoneal Dialysis 
♦ Background and Objectives: In automated peritoneal dialysis (APD), a patient’s peritoneal membrane is more intensively exposed to fresh dialysate than it is in continuous ambulatory peritoneal dialysis (CAPD). Our aim was to study, in incident peritoneal dialysis (PD) patients, the influence of APD—compared with that of CAPD—on peritoneal transport over 4 years.
♦ Design, Setting, Participants, and Measurements: Patients were included if at least 2 annual standard permeability analyses (SPAs) performed with 3.86% glucose were available while the patient was using the same modality with which they had started PD (APD or CAPD). Patients were followed until their first modality switch. Differences in the pattern of SPA outcomes over time were tested using repeated-measures models adjusted for age, sex, comorbidity, primary kidney disease, and year of PD start.
♦ Results: The 59 CAPD patients enrolled were older than the 47 APD patients enrolled (mean age: 58 ± 14 years vs 49 ± 14 years; p < 0.01), and they had started PD earlier (mean start year: 2000 vs 2002). Over time, no differences in solute (p > 0.19) or fluid transport (p > 0.13) were observed. Similarly, free water transport (p = 0.43) and small-pore transport (p = 0.31) were not different between the modalities. Over time, patients on APD showed a faster decline in effective lymphatic absorption rate (ELAR: p = 0.02) and in transcapillary ultrafiltration (TCUF: p = 0.07, adjusted p = 0.05). Further adjustment did not change the results.
♦ Conclusions: Compared with patients starting on CAPD, those starting on APD experienced a faster decline in ELAR and TCUF. Other transport parameters were not different over time between the groups.
doi:10.3747/pdi.2011.00166
PMCID: PMC3524901  PMID: 22473037
Automated peritoneal dialysis; continuous ambulatory peritoneal dialysis; effective lymphatic absorption rate; peritoneal transport; ultrafiltration; standard peritoneal permeability analysis
7.  Erythropoiesis-stimulating agent resistance and mortality in hemodialysis and peritoneal dialysis patients 
BMC Nephrology  2013;14:200.
Background
Responsiveness to erythropoiesis-stimulating agents (ESAs) varies widely among dialysis patients. ESA resistance has been associated with mortality in hemodialysis (HD) patients, but in peritoneal dialysis (PD) patients data is limited. Therefore we assessed the relation between ESA resistance in both HD and PD patients.
Methods
NECOSAD is a Dutch multi-center prospective cohort study of incident dialysis patients who started dialysis between January 1997 and January 2007. ESA resistance was defined as hemoglobin level < 11 g/dL with an above median ESA dose (i.e. 8,000 units/week in HD and 4,000 units/week in PD patients). Unadjusted and adjusted Cox regression analysis for all-cause 5-year mortality was performed for HD and PD patients separately.
Results
1013 HD and 461 PD patients were included in the analysis. ESA resistant HD patients had an adjusted hazard ratio of 1.37 (95% CI 1.04-1.80) and ESA resistant PD patients had an adjusted hazard ratio of 2.41 (1.27-4.57) as compared to patients with a good response.
Conclusions
ESA resistance, as defined by categories of ESA and Hb, is associated with increased mortality in both HD and PD patients. The effect of ESA resistance, ESA dose and hemoglobin are closely related and the exact mechanism remains unclear. Our results strengthen the need to investigate and treat causes of ESA resistance not only in HD, but also in PD patients.
doi:10.1186/1471-2369-14-200
PMCID: PMC3849281  PMID: 24066978
Cohort study; Erythropoietin; ESA Resistance; Hemodialysis; Mortality; Peritoneal dialysis
8.  Achieving research competences through medical education 
doi:10.1007/s40037-013-0084-x
PMCID: PMC3792234  PMID: 24049044
9.  Tuning research competences for Bologna three cycles in medicine: report of a MEDINE2 European consensus survey 
Medical curricula, like healthcare systems and medical practice, have a strong cultural component and vary considerably between countries. Increasing mobility of medical graduates, and increasing pressure to ensure they are all fit for practice, have highlighted an urgent need to establish common ground in learning outcomes at all stages of training. A research-based approach, developed by the Tuning project, was used previously by the MEDINE Thematic Network to gain consensus on core learning outcomes/competences for primary medical degrees (www.tuning-medicine.com), but no consensus was reached for learning outcomes relating to research. As part of MEDINE2, a focussed Tuning project was undertaken to explore opinions on more detailed core learning outcomes in research for all three Bologna cycles (Bachelor, Master, and Doctor). Responses from 417 stakeholders, representing 29 European and 13 non-European countries, revealed a relatively high degree of consensus. The findings strongly suggest that these stakeholders think that learning outcomes related both to ‘using research’ and ‘doing research’ should be core components of medical curricula in Europe. The challenge now, however, is to promote further local and international discussion on these issues, and to find ways of achieving these competences within the context of already crowded medical curricula.
doi:10.1007/s40037-013-0066-z
PMCID: PMC3792236  PMID: 24101579
Tuning; Research competences; Medical curricula; Learning outcomes; Bologna process
10.  Type of arteriovenous vascular access and association with patency and mortality 
BMC Nephrology  2013;14:79.
Background
There are only a few risk factors known for primary patency loss in patients with an arteriovenous graft or fistula. Furthermore, a limited number of studies have investigated the association between arteriovenous access modality and primary patency loss and mortality. The aim of this study was to investigate risk factors for patency loss and to investigate the association between graft versus fistula use and outcomes (patency loss and mortality).
Methods
We prospectively followed 919 incident hemodialysis patients and calculated hazard ratios (HRs) for putative risk factors of primary patency loss using Cox regression. Furthermore, HRs were calculated to study the association between graft versus fistula use and two-year primary patency loss and two-year mortality.
Results
Cardiovascular disease, prior catheter use, lowest tertile of albumin, highest tertile of hsCRP, and lowest tertile of fetuin-A were associated with primary patency loss in both patients with grafts and fistulas. Increased age, female sex, and diabetes mellitus were only associated with primary patency loss in patients with a fistula. We did not observe an association between primary patency loss and BMI, residual GFR, levels of calcium, phosphorus, and total cholesterol. Furthermore, graft use as compared with fistula use was associated with an 1.4-fold (95% CI 1.0-1.9) increased risk of primary patency loss and with an 1.5-fold(95% CI 1.0-2.2) increased mortality risk.
Conclusion
Cardiovascular disease, prior catheter use, albumin, hsCRP, and fetuin-A are risk factors for patency loss. Graft use as compared with fistula use was associated with an increased risk of patency loss and mortality.
doi:10.1186/1471-2369-14-79
PMCID: PMC3621613  PMID: 23557085
Hemodialysis; Fistula; Graft; Patency; Mortality; Epidemiology
11.  Survival in dialysis patients is not different between patients with diabetes as primary renal disease and patients with diabetes as a co-morbid condition 
BMC Nephrology  2011;12:69.
Background
On dialysis, survival among patients with diabetes mellitus is inferior to survival of non-diabetic patients. We hypothesized that patients with diabetes as primary renal disease have worse survival compared to patients with diabetes as a co-morbid condition and aimed to compare all-cause mortality between these patient groups.
Methods
Data were collected from the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD), a multicenter, prospective cohort study in which new patients with end stage renal disease (ESRD) were monitored until transplantation or death. Patients with diabetes as primary cause of ESRD were compared with patients with diabetes as co-morbid condition and both of these patient groups were compared to patients without diabetes. Analysis was performed using Kaplan-Meier and Cox regression.
Results
Fifteen % of the patients had diabetic nephropathy as primary renal disease (N = 281); 6% had diabetes as co-morbid condition (N = 107) and 79% had no diabetes (N = 1465). During follow-up 42% of patients (N = 787) died. Compared to non-diabetic patients, mortality risk was increased for both patients with diabetes as primary renal disease HR: 1.9 (95% CI 1.6, 2.3) and for patients with diabetes as co-morbid condition HR: 1.7 (95% CI 1.3, 2.2). Mortality was not significantly higher in patients with diabetes as primary renal disease compared to patients with diabetes as co-morbid condition (HR 1.06; 95% CI 0.79, 1.43).
Conclusions
This study in patients with ESRD showed no survival difference between patients with diabetes as primary renal disease and patients with diabetes as a co-morbid condition. Both conditions were associated with increased mortality risk compared to non-diabetic patients.
doi:10.1186/1471-2369-12-69
PMCID: PMC3259092  PMID: 22182634
12.  Chronic kidney disease in patients with diabetes mellitus type 2 or hypertension in general practice 
Background
The prevalence and severity of chronic kidney disease (CKD) in primary care patients with diabetes or hypertension is unknown.
Aim
To assess the prevalence and severity of CKD in patients with diabetes and hypertension; and identify whether age, sex, diabetes, and hypertension are associated with CKD.
Design of study
Cross-sectional survey.
Setting
Two Dutch primary health care centres (15 954 enlisted patients).
Method
Patients, aged ≥25 years, with known diabetes type 2 (n = 471) or hypertension (n = 960), were selected on 1 October 2006. Initial screening uptake rates were assessed from the electronic patient records, and patients were invited when blood or urine measurements were missing. The presence of albuminuria was determined, glomerular filtration rate estimated, and clinical characteristics extracted.
Results
Initial screening uptake rates were 93% and 69% for diabetes and hypertension, respectively, and increased to 97% (n = 455) and 87% (n = 836) after active invitation. The prevalence of CKD was 28% in diabetes and 21% in hypertension only. The presence of diabetes was independently associated with albuminuria (odds ratio [OR] 4.23; 95% confidence interval [CI] = 2.67 to 6.71), but not with decreased estimated GFR (eGFR) (OR 0.75; 95% CI = 0.54 to 1.04). Age showed the strongest association with decreased eGFR (OR 2.73; 95% CI = 2.02 to 3.70).
Conclusion
In primary care, more than one-quarter of patients with diabetes and about one-fifth of patients with hypertension have CKD. The high prevalence justifies longitudinal follow-up in order to evaluate whether intensified cardiovascular risk management is beneficial in this primary care population.
doi:10.3399/bjgp10X544041
PMCID: PMC2991741  PMID: 21144198
diabetes; hypertension; kidney disease, chronic; prevalence; primary care; screening
13.  Association of blood pressure with decline in renal function and time until the start of renal replacement therapy in pre-dialysis patients: a cohort study 
BMC Nephrology  2011;12:38.
Background
To investigate whether high blood pressure accelerates renal function decline in patients with advanced chronic kidney disease (CKD), we studied the association of systolic (SBP) and diastolic blood pressure (DBP) with decline in renal function and time until the start of renal replacement therapy (RRT) in patients with CKD stages IV-V on pre-dialysis care.
Methods
In the PREPARE-1 cohort 547 incident pre-dialysis patients, referred as part of the usual care to outpatient clinics of eight Dutch hospitals, were included between 1999 and 2001 and followed until the start of RRT, mortality, or end of follow-up (January 1st 2008). Main outcomes were rate of decline in renal function, estimated as the slope of available eGFR measurements, and time until the start of RRT.
Results
A total of 508 patients, 57% men and median (IQR) age of 63 (50-73) years, were available for analyses. Mean (SD) decline in renal function was 0.35 (0.75) ml/min/1.73 m2/month. Every 10 mmHg increase in SBP or DBP resulted in an accelerated decline in renal function (adjusted additional decline 0.04 (0.02;0.07) and 0.05 (0.00;0.11) ml/min/1.73 m2/month respectively) and an earlier start of RRT (adjusted HR 1.09 (1.04;1.14) and 1.16 (1.05;1.28) respectively). Furthermore, patients with SBP and DBP above the BP target goal of < 130/80 mmHg experienced a faster decline in renal function (adjusted additional decline 0.31 (0.08;0.53) ml/min/1.73 m2/month) and an earlier start of RRT (adjusted HR 2.08 (1.25;3.44)), compared to patients who achieved the target goal (11%). Comparing the decline in renal function and risk of starting RRT between patients with only SBP above the target (≥ 130 mmHg) and patients with both SBP and DBP below the target (< 130/80 mmHg), showed that the results were almost similar as compared to patients with both SBP and DBP above the target (adjusted additional decline 0.31 (0.04;0.58) ml/min/1.73 m2/month and adjusted HR 2.24 (1.26;3.97)). Therefore, it seems that especially having SBP above the target is harmful.
Conclusions
In pre-dialysis patients with CKD stages IV-V, having blood pressure (especially SBP) above the target goal for CKD patients (< 130/80 mmHg) was associated with a faster decline in renal function and a later start of RRT.
doi:10.1186/1471-2369-12-38
PMCID: PMC3171298  PMID: 21835038
blood pressure; chronic kidney disease stages IV-V; estimated glomerular filtration rate; pre-dialysis care; renal replacement therapy
14.  Association Between CNDP1 Genotype and Diabetic Nephropathy Is Sex Specific 
Diabetes  2010;59(6):1555-1559.
OBJECTIVE
The 5-5 homozygous CNDP1 (carnosinase) genotype is associated with a reduced risk of diabetic nephropathy. We investigated whether this association is sex specific and independent of susceptibility for type 2 diabetes.
RESEARCH DESIGN AND METHODS
Three separate groups of 114, 90, and 66 patients with type 2 diabetes and diabetic nephropathy were included in this study and compared with 93 patients with type 2 diabetes for >15 years without diabetic nephropathy and 472 population control subjects. The diabetes control group was used to determine an association in the three patient groups separately, and the population control group was used to estimate the genotype risk [odds ratio (CI)] for the population in a pooled analysis. The population control subjects were also compared with 562 patients with type 2 diabetes without diabetic nephropathy to determine whether the association was independent of type 2 diabetes. The CNDP1 genotype was determined by fragment analysis after PCR amplification.
RESULTS
The frequency of the 5-5 homozygous genotype was 28, 36, and 41% in the three diabetic nephropathy patient groups and 43 and 42% in the diabetic and population control subjects, respectively. The 5-5 homozygous genotype occurred significantly less frequently in women in all three patient groups compared with diabetic control subjects. The genotype risk for the population was estimated to be 0.5 (0.30–0.68) in women and 1.2 (0.77–1.69) in men. The 562 patients with type 2 diabetes without diabetic nephropathy did not differ from the general population (P = 0.23).
CONCLUSIONS
This study suggests that the association between the CNDP1 gene and diabetic nephropathy is sex specific and independent of susceptibility for type 2 diabetes.
doi:10.2337/db09-1377
PMCID: PMC2874718  PMID: 20332346
15.  Real patient learning integrated in a preclinical block musculoskeletal disorders. Does it make a difference? 
Clinical Rheumatology  2011;30(8):1029-1037.
Although musculoskeletal disorders are the most common reason for general practitioner visits, training did not keep pace. Implementation of learning from patients with rheumatologic disorders linked together with the teaching of theoretical knowledge in the preclinical medical education might be an important step forward in the improvement of quality of care for these patients. The Leiden Medical School curriculum has implemented two non-obligatory real patient learning (RPL) practicals integrated within the preclinical block musculoskeletal disorders. This study investigates the educational effectiveness of the practicals, the expectations students have of RPL, and students’ satisfaction. Participants’ grades on the end-of-block test served as the test results of the educational effectiveness of the practicals and were compared with those of the non-participants. Qualitative data was collected by means of questionnaires generated by focus groups. The participants in practicals scored significantly higher at the end-of-block test. The expected effects of the contact with real patients concerned positive effects on cognition and skills. ‘Contextualizing of the theory’, ‘better memorizing of clinical pictures’, and ‘understanding of the impact of the disease’ were the most frequently mentioned effects of the practicals. Overall, the participants were (very) enthusiastic about this educational format. The RPL practicals integrated within a preclinical block musculoskeletal disorders are a valuable addition to the Leiden medical curriculum. This relatively limited intervention exhibits a strong effect on students’ performance in tests. Future research should be directed towards the long-term effects of this intervention.
doi:10.1007/s10067-011-1708-3
PMCID: PMC3145092  PMID: 21347603
Focus groups; Medical; Medical education; Musculoskeletal diseases; Patients; Questionnaires; Students; Undergraduate
16.  Pre-dialysis patients' perceived autonomy, self-esteem and labor participation: associations with illness perceptions and treatment perceptions. A cross-sectional study 
BMC Nephrology  2010;11:35.
Background
Compared to healthy people, patients with chronic kidney disease (CKD) participate less in paid jobs and social activities. The aim of the study was to examine a) the perceived autonomy, self-esteem and labor participation of patients in the pre-dialysis phase, b) pre-dialysis patients' illness perceptions and treatment perceptions, and c) the association of these perceptions with autonomy, self-esteem and labor participation.
Methods
Patients (N = 109) completed questionnaires at home. Data were analysed using bivariate and multivariate analyses.
Results
The results showed that the average autonomy levels were not very high, but the average level of self-esteem was rather high, and that drop out of the labor market already occurs during the pre-dialysis phase. Positive illness and treatment beliefs were associated with higher autonomy and self-esteem levels, but not with employment. Multiple regression analyses revealed that illness and treatment perceptions explained a substantial amount of variance in autonomy (17%) and self-esteem (26%). The perception of less treatment disruption was an important predictor.
Conclusions
Patient education on possibilities to combine CKD and its treatment with activities, including paid work, might stimulate positive (realistic) beliefs and prevent or challenge negative beliefs. Interventions focusing on these aspects may assist patients to adjust to CKD, and ultimately prevent unnecessary drop out of the labor market.
doi:10.1186/1471-2369-11-35
PMCID: PMC3019121  PMID: 21138597
17.  Interactive seminars or small group tutorials in preclinical medical education: results of a randomized controlled trial 
BMC Medical Education  2010;10:79.
Background
Learning in small group tutorials is appreciated by students and effective in the acquisition of clinical problem-solving skills but poses financial and resource challenges. Interactive seminars, which accommodate large groups, might be an alternative. This study examines the educational effectiveness of small group tutorials and interactive seminars and students' preferences for and satisfaction with these formats.
Methods
Students in year three of the Leiden undergraduate medical curriculum, who agreed to participate in a randomized controlled trial (RCT, n = 107), were randomly allocated to small group tutorials (n = 53) or interactive seminars (n = 54). Students who did not agree were free to choose either format (n = 105). Educational effectiveness was measured by comparing the participants' results on the end-of-block test. Data on students' reasons and satisfaction were collected by means of questionnaires. Data was analyzed using student unpaired t test or chi-square test where appropriate.
Results
There were no significant differences between the two educational formats in students' test grades. Retention of knowledge through active participation was the most frequently cited reason for preferring small group tutorials, while a dislike of compulsory course components was mentioned more frequently by students preferring interactive seminars. Small group tutorials led to greater satisfaction.
Conclusions
We found that small group tutorials leads to greater satisfaction but not to better learning results. Interactive learning in large groups might be might be an effective alternative to small group tutorials in some cases and be offered as an option.
doi:10.1186/1472-6920-10-79
PMCID: PMC3000405  PMID: 21073744
18.  Vitamin D deficiency is associated with sudden cardiac death, combined cardiovascular events, and mortality in haemodialysis patients 
European Heart Journal  2010;31(18):2253-2261.
Aims
Dialysis patients experience an excess mortality, predominantly of sudden cardiac death (SCD). Accumulating evidence suggests a role of vitamin D for myocardial and overall health. This study investigated the impact of vitamin D status on cardiovascular outcomes and fatal infections in haemodialysis patients.
Methods and results
25-hydroxyvitamin D [25(OH)D] was measured in 1108 diabetic haemodialysis patients who participated in the German Diabetes and Dialysis Study and were followed up for a median of 4 years. By Cox regression analyses, we determined hazard ratios (HR) for pre-specified, adjudicated endpoints according to baseline 25(OH)D levels: SCD (n = 146), myocardial infarction (MI, n = 174), stroke (n = 89), cardiovascular events (CVE, n = 414), death due to heart failure (n = 37), fatal infection (n = 111), and all-cause mortality (n = 545). Patients had a mean age of 66 ± 8 years (54% male) and median 25(OH)D of 39 nmol/L (interquartile range: 28–55). Patients with severe vitamin D deficiency [25(OH)D of≤ 25 nmol/L] had a 3-fold higher risk of SCD compared with those with sufficient 25(OH)D levels >75 nmol/L [HR: 2.99, 95% confidence interval (CI): 1.39–6.40]. Furthermore, CVE and all-cause mortality were strongly increased (HR: 1.78, 95% CI: 1.18–2.69, and HR: 1.74, 95% CI: 1.22–2.47, respectively), all persisting in multivariate models. There were borderline non-significant associations with stroke and fatal infection while MI and deaths due to heart failure were not meaningfully affected.
Conclusion
Severe vitamin D deficiency was strongly associated with SCD, CVE, and mortality, and there were borderline associations with stroke and fatal infection. Whether vitamin D supplementation decreases adverse outcomes requires further evaluation.
doi:10.1093/eurheartj/ehq246
PMCID: PMC2938469  PMID: 20688781
Vitamin D; Sudden cardiac death; Mortality; Dialysis; Kidney; Cardiovascular
19.  Reduced renal length and volume 20 years after very preterm birth 
Intrauterine growth retardation is presumed to be associated with decreased renal size and impaired renal function as a result of stunted kidney development and nephron deficit. To study whether very preterm birth also affects renal size at young adulthood, we sonographically measured bipolar kidney length and volume in 51 very premature individuals (<32 weeks of gestation), either small (SGA) or appropriate (AGA) for gestational age (22 SGA and 29 AGA), and 30 full-term controls 20 years after birth. Relative kidney length and volume were calculated. Both absolute and relative left kidney length and volume were significantly lower in SGA and AGA individuals, notably in women. Renal size did not differ between SGA and AGA individuals. In 70% of controls, the left kidney was larger than the right one compared with 40.9% in SGA [relative risk (RR) 1.7; 95% confidence interval (CI) 1.0−3.0] and 48.3% in AGA (RR 1.5; 95% CI 0.9−2.3) individuals. Renal structural anomalies were present in eight prematurely born participants only. Our data suggest that kidney growth is stunted after preterm birth, especially on the left side, and in the female gender.
doi:10.1007/s00467-009-1371-y
PMCID: PMC2810374  PMID: 20013294
Renal growth; Kidney development; Developmental origins of health and disease; Renal ultrasound; Preterm birth; Intrauterine growth retardation
20.  Very preterm birth is a risk factor for increased systolic blood pressure at a young adult age 
Children born very prematurely who show intrauterine growth retardation (IUGR) are suggested to be at risk of developing high blood pressure as adults. Renal function may already be impaired by young adult age. To study whether very preterm birth affects blood pressure in young adults, we measured 24-h ambulatory blood pressure (Spacelabs™ 90207 device) and renin concentration in 50 very premature individuals (<32 weeks of gestation), either small (SGA) or appropriate (AGA) for gestational age (21 SGA, 29 AGA), and 30 full-term controls who all were aged 20 years at time of measurement. The mean (standard deviation) daytime systolic blood pressure in SGA and AGA prematurely born individuals, respectively, was 122.7 (8.7) and 123.1 (8.5) mmHg. These values were, respectively, 3.6 mmHg [95% confidence interval (CI) −0.9 to 8.0] and 4.2 mmHg (95% CI 0.4−8.0) higher than in controls [119.6 (7.6)]. Daytime diastolic blood pressure and nighttime blood pressure did not differ between groups. We conclude that individuals born very preterm have higher daytime systolic blood pressure and higher risk of hypertension at a young adult age.
doi:10.1007/s00467-009-1373-9
PMCID: PMC2810359  PMID: 20012998
Hypertension; Intrauterine growth retardation; Premature birth; Developmental origins of health and disease; Ambulatory blood pressure monitor; Blood pressure
21.  The association between parathyroid hormone and mortality in dialysis patients is modified by wasting 
Nephrology Dialysis Transplantation  2009;24(10):3151-3157.
Background. The association between parathyroid hormone (PTH) level and mortality in dialysis patients is controversial. We hypothesized that wasting, a common condition potentially related to adynamic bone disease, modifies the association of PTH with mortality and cardiovascular events (CVE), respectively.
Methods. We analysed data from 1255 diabetic haemodialysis patients, participating in the German Diabetes and Dialysis Study between 1998 and 2004. The patients were stratified by the presence or absence of wasting (albumin ≤3.8 versus albumin >3.8 g/dL; BMI ≤23 versus BMI >23 kg/m2). Using Cox regression analyses, we calculated the risks of (1) all-cause mortality and (2) CVE according to baseline PTH levels. All analyses were adjusted for age, sex, atorvastatin treatment, duration of dialysis, comorbidity, HbA1c, phosphate, calcium, blood pressure, haemoglobin and C-reactive protein.
Results. Patients had a mean age of 66 ± 8 years, and 54% were male. Among patients without wasting (albumin >3.8 g/dL, n = 586), the risks of death and CVE during 4 years of follow-up significantly increased by 23% and 20% per unit increase in logPTH. Patients in the highest PTH tertile had a 74% higher risk of death (HRadj 1.74, 95% CI 1.27–2.40) and a 49% higher risk of CVE (HRadj 1.49, 95% CI 1.05–2.11) compared to patients in the lowest PTH tertile. In contrast, no effect was found in patients with wasting. Accordingly, additional analyses in strata of BMI showed that PTH significantly impacted on death and CVE [HR(logPTH)adj 1.15 and 1.14, respectively] only in patients without, but not in patients with, wasting.
Conclusions. Wasting modifies the association of PTH with adverse outcomes in diabetic dialysis patients. High PTH levels are of concern in the patients without wasting, while the effect of PTH on mortality is nullified in the patients with wasting.
doi:10.1093/ndt/gfp260
PMCID: PMC2747498  PMID: 19474272
cardiovascular events; haemodialysis; mortality; parathyroid hormone; wasting
22.  The diagnostic work up of growth failure in secondary health care; An evaluation of consensus guidelines 
BMC Pediatrics  2008;8:21.
Background
As abnormal growth might be the first manifestation of undetected diseases, it is important to have accurate referral criteria and a proper diagnostic work-up. In the present paper we evaluate the diagnostic work-up in secondary health care according to existing consensus guidelines and study the frequency of underlying medical disorders.
Methods
Data on growth and additional diagnostic procedures were collected from medical records of new patients referred for short stature to the outpatient clinics of the general paediatric departments of two hospitals (Erasmus MC – Sophia Children's Hospital, Rotterdam and Spaarne Hospital, Haarlem) between January 1998 and December 2002. As the Dutch Consensus Guideline (DCG) is the only guideline addressing referral criteria as well as diagnostic work-up, the analyses were based on its seven auxological referral criteria to determine the characteristics of children who are incorrectly referred and the adequacy of workup of those who are referred.
Results
Twenty four percent of children older than 3 years were inappropriately referred (NCR). Of the correctly referred children 74–88% were short corrected for parental height, 40–61% had a height SDS <-2.5 and 21% showed height deflection (Δ HSDS < -0.25/yr or Δ HSDS < -1). In none of the children a complete detailed routine diagnostic work up was performed and in more than 30% no routine laboratory examination was done at all. Pathologic causes of short stature were found in 27 children (5%).
Conclusion
Existing guidelines for workup of children with suspected growth failure are poorly implemented. Although poorly implemented the DCG detects at least 5% pathologic causes of growth failure in children referred for short stature. New guidelines for referral are required with a better sensitivity and specificity, wherein distance to target height should get more attention. The general diagnostic work up for short stature should include testing for celiac disease in all children and for Turner syndrome in girls.
doi:10.1186/1471-2431-8-21
PMCID: PMC2422838  PMID: 18477383
23.  Referral patterns of children with poor growth in primary health care 
BMC Public Health  2007;7:77.
Background
To promote early diagnosis and treatment of short stature, consensus meetings were held in the mid nineteen nineties in the Netherlands and the UK. This resulted in guidelines for referral. In this study we evaluate the referral pattern of short stature in primary health care using these guidelines, comparing it with cut-off values mentioned by the WHO.
Methods
Three sets of referral rules were tested on the growth data of a random sample (n = 400) of all children born between 01-01-1985 and 31-12-1988, attending school doctors between 1998 and 2000 in Leiden and Alphen aan den Rijn (the Netherlands): the screening criteria mentioned in the Dutch Consensus Guideline (DCG), those of the UK Consensus Guideline (UKCG) and the cut-off values mentioned in the WHO Global Database on Child growth and Malnutrition.
Results
Application of the DCG would lead to the referral of too many children (almost 80%). The largest part of the referrals is due to the deflection of height, followed by distance to target height and takes primarily place during the first 3 years. The deflection away from the parental height would also lead to too many referrals. In contrast, the UKCG only leads to 0.3% referrals and the WHO-criteria to approximately 10%.
Conclusion
The current Dutch consensus guideline leads to too many referrals, mainly due to the deflection of length during the first 3 years of life. The UKCG leads to far less referrals, but may be relatively insensitive to detect clinically relevant growth disorders like Turner syndrome. New guidelines for growth monitoring are needed, which combine a low percentage of false positive results with a good sensitivity.
doi:10.1186/1471-2458-7-77
PMCID: PMC1884145  PMID: 17493282
24.  Screening strategies for chronic kidney disease in the general population: follow-up of cross sectional health survey 
BMJ : British Medical Journal  2006;333(7577):1047.
Objective To find an effective screening strategy for detecting patients with chronic kidney disease and to describe the natural course of the disease.
Design Eight year follow-up of a cross sectional health survey (the HUNT II study).
Setting Nord-Trøndelag County, Norway
Participants 65 604 people (70.6 % of all adults aged ≥20 in the county).
Main outcome measures Incident end stage renal disease (ESRD) and cardiovascular mortality monitored by individual linkage to central registries.
Results 3069/65 604 (4.7%) people had chronic kidney disease (estimated glomerular filtration rate <60 ml/min/1.73 m2), so we would need to screen 20.6 people (95% confidence interval 20.0 to 21.2) to identify one case. Restriction of screening to those with hypertension, diabetes, or age >55 would identify 93.2% (92.4% to 94.0%) of patients with chronic kidney disease, with a number needed to screen of 8.7 (8.5 to 9.0). Restriction of screening according to guidelines of the United States kidney disease outcomes quality initiative (US KDOQI) gave similar results, but restriction according to the United Kingdom's chronic kidney disease guidelines detected only 60.9% (59.1% to 62.8%) of cases. Screening only people with previously known diabetes or hypertension detected 44.2% (42.7% to 45.7%) of all cases, with a number needed to screen of six. During the eight year follow-up only 38 of the 3069 people with chronic kidney disease progressed to end stage renal disease, and the risk was especially low in people without diabetes or hypertension, women, and those aged ≥70 or with a glomerular filtration rate 45-59 ml/min/1.73 m2 at screening. In contrast, there was a high cardiovascular mortality: 3.5, 7.4, and 10.1 deaths per 100 person years among people with a glomerular filtration rate 45-59, 30-44, and <30 ml/min/1.73 m2, respectively.
Conclusion Screening people with hypertension, diabetes mellitus, or age >55 was the most effective strategy to detect patients with chronic kidney disease, but the risk of end stage renal disease among those detected was low.
doi:10.1136/bmj.39001.657755.BE
PMCID: PMC1647344  PMID: 17062598

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