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1.  The influence of Erythropoietin on platelet activation, thrombin generation and FVII/active FVII in patients with AMI 
Thrombosis Journal  2014;12:18.
Erythropoietin (Epo) has been shown to improve myocardial function in models of experimental myocardial infarction, but has also been associated with a rise in thromboembolic events. Thus, the aim of this study was to investigate the influence of Epo on platelet activation and coagulation in patients with acute myocardial infarction (AMI).
The study was designed as a substudy of the randomised, double-blind, placebo controlled REVIVAL-3 (REgeneration of VItal Myocardium in ST-Segment EleVation MyocardiAL Infarction by Erythropoietin) study that investigated the effects of recombinant human Epo in AMI. Serial venous blood samples were collected before and after study medication. Circulating prothrombin fragment F1 + 2, FVII, active FVII, beta thromboglobulin (TG) and P-Selectin were measured before and 60 hours after randomization by immunoassay (n = 94). In a randomly selected subgroup platelet aggregation was measured using whole blood aggregometry (Multiplate Analyzer, n = 45).
After 5 days an increase in FVII was observed after Epo as compared to placebo (P = 0.02), yet active FVII and prothrombin fragment F1 + 2 remained unchanged. Moreover, no statistically significant differences in circulating TG or P-selectin were observed between the groups. As an expected response to peri-interventional therapy with clopidogrel and aspirin, platelet aggregation after stimulation with ADP, TRAP, ASPI or collagen decreased 12 hours and 2 days after PCI. However, no difference between the Epo and the placebo group was observed.
After treatment with Epo in patients with AMI a slight increase in circulating FVII after Epo was not associated with an increase in active FVII, prothrombin fragment F1 + 2, TG or P-selectin. Moreover, platelet aggregation was not altered after treatment with Epo as compared to placebo.
Trial registration Identifier: NCT01761435
PMCID: PMC4165375  PMID: 25228850
Platelet activation; Erythropoietin; AMI; PCI
2.  The dysfunctional endothelium in CKD and in cardiovascular disease: mapping the origin(s) of cardiovascular problems in CKD and of kidney disease in cardiovascular conditions for a research agenda 
Endothelial dysfunction resulting in disintegration of vascular structure and function is a key element in the progression of chronic kidney disease (CKD). Many risk factors—traditional and non-traditional—are thought to have a role in the progression and development of cardiovascular disease (CVD) in patients with CKD. However, many risk factors await definitive confirmation of their clinical relevance obtained from intervention trials. Moreover, the investigation of the relative contribution of these factors to the twin-risk problem of CVD and progression in patients with CKD is one of the most important future challenges for nephrologists.
PMCID: PMC4089605  PMID: 25018895
biomarkers; cardiovascular disease; chronic kidney disease; endothelium
3.  The complexity of the cardio–renal link: taxonomy, syndromes, and diseases 
Bidirectional mechanisms exist that link diseases affecting the heart and kidney. This link is complex and remains poorly understood; therefore, charting the shared territory of cardiovascular (CV) and renal medicine poses major problems. Until now, no convincing rationale for delineating new syndromes existed. The multiple connections of the arterial system and the heart and kidney with other systems, from energy and protein balance to the musculoskeletal, clearly require special focus and rigorous framing. Nephrologists have yet to fully understand why the application of dialysis has had only limited success in halting the parallel burdens of CV and non-CV death in patients with end-stage renal disease. Cardiologists, intensivists, and nephrologists alike should settle whether and when extracorporeal ultrafiltration benefits patients with decompensated heart failure. These sparse but interconnected themes spanning from the basic science–clinical transition phase to clinical science, epidemiology, and medical technology already form the basis for the young discipline of ‘CV and renal medicine'.
PMCID: PMC4089616  PMID: 25028622
cardio-renal; cardiovascular risk; CKD; death; ESRD; progression of CKD
4.  The lingering dilemma of arterial pressure in CKD: what do we know, where do we go? 
Despite many advances in the management of hypertensive chronic kidney disease (CKD) patients, both on and off dialysis, there exist several gaps in our knowledge. Although the modern techniques to measure blood pressure (BP) indirectly have been available for a long time, among those with CKD, how to best assess hypertension and the level to which it should be lowered are mired in controversy. Other controversial areas relate to a lack of a consensus definition of hypertension among hemodialysis patients, uncertainty in the definition and assessment of volume excess, and the lack of adequately powered randomized trials to evaluate the level to which BP can be lowered in those on dialysis. This review discusses the limitations of the available evidence base and suggests areas for future research. Suggestions include evaluation of techniques to assess volume, randomized trials to target different levels of BP among hypertensive hemodialysis patients, evaluation of ambulatory BP monitoring, and non-pharmacological means to lower BP in CKD. It is hoped that among patients with CKD these data will improve the dismal cardiovascular outcomes.
PMCID: PMC4089679  PMID: 25018898
ambulatory blood pressure; cardiovascular disease; CKD; hypervolemia; outcome studies; risk factors
5.  Arterial aging and arterial disease: interplay between central hemodynamics, cardiac work, and organ flow—implications for CKD and cardiovascular disease 
Cardiovascular disease is an important cause of morbidity and mortality in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD). All epidemiological studies have clearly shown that accelerated arterial and cardiac aging is characteristic of these populations. Arterial premature aging is heterogeneous. It principally involves the aorta and central capacitive arteries, and is characterized by preferential aortic stiffening and disappearance of stiffness/impedance gradients between the central and peripheral arteries. These changes have a double impact: on the heart, upstream, with left ventricular hypertrophy and decreased coronary perfusion; and, downstream, on renal and brain microcirculation (decrease in glomerular filtration and cognitive functions). Multifactorial at origin, the pathophysiology of aortic ‘progeria' and microvascular disorders in CKD/ESRD is not well understood and should be the focus of interest in future studies.
PMCID: PMC4089718  PMID: 25018896
aging; arteriosclerosis; arterial stiffness; end-stage renal disease; pressure waves
6.  Cardiovascular and non-cardiovascular mortality in dialysis patients: where is the link? 
Over the past decade, the research agenda in dialysis has been dominated by studies on risk factors associated with cardiovascular mortality. It has now become increasingly clear that in dialysis patients, non-cardiovascular causes of death are increased to the same extent as cardiovascular mortality, and therefore research efforts in this area deserve an equally prominent place on the nephrology research agenda. As previous research has suggested an association between cardiovascular disease and infections, more research on potential links between the causal pathways of cardiovascular events and infections is also warranted.
PMCID: PMC4089722  PMID: 25028623
cardiovascular disease; cardiovascular mortality; dialysis; mortality; non-cardiovascular mortality; renal replacement therapy
7.  Major pathways of the reno–cardiovascular link: the sympathetic and renin–angiotensin systems 
Chronic kidney disease is often characterized by enhanced activity of the renin–angiotensin system (RAS) and the sympathetic nervous system. Independent of their effect on blood pressure, these systems also contribute to the pathogenesis of both structural and functional cardiovascular abnormalities and contribute importantly to clinical outcome. There is much evidence that the diseased kidneys are of central importance in the pathogenesis of both abnormalities. Inhibitors of the RAS also reduce sympathetic overactivity. Future research should be aimed at addressing the pathophysiological mechanisms causing the enhanced activities. Given the fact that even a small kidney lesion can cause enhanced activity of the RAS and the sympathetic nervous system, it is likely that these pathophysiological mechanisms are operational in more disease conditions, including essential hypertension, heart failure, and obesity/metabolic syndrome.
PMCID: PMC4089777  PMID: 25018897
chronic kidney disease; hypertension; renin angiotensin; sympathetic activity
8.  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.
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.
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.
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.
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.
PMCID: PMC4075499  PMID: 24939671
Uric acid; CKD progression; Pre-dialysis; Prospective cohort
9.  Single Nucleotide Variants in the Protein C Pathway and Mortality in Dialysis Patients 
PLoS ONE  2014;9(5):e97251.
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.
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.
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.
Our study suggests that factor V Leiden and PROC rs1799809 contributes to an increased mortality risk in dialysis patients.
PMCID: PMC4016291  PMID: 24816905
10.  Course of Symptoms and Health-Related Quality of Life during Specialized Pre-Dialysis Care 
PLoS ONE  2014;9(4):e93069.
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.
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).
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.
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.
PMCID: PMC3974712  PMID: 24699666
11.  Predicting Mortality in Patients with Diabetes Starting Dialysis 
PLoS ONE  2014;9(3):e89744.
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.
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.
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.
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.
PMCID: PMC3942369  PMID: 24594735
12.  Effect of Erythropoiesis-Stimulating Agents on Blood Pressure in Pre-Dialysis Patients 
PLoS ONE  2013;8(12):e84848.
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.
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.
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.
PMCID: PMC3877353  PMID: 24391978
13.  Survival prognosis after the start of a renal replacement therapy in the Netherlands: a retrospective cohort study 
BMC Nephrology  2013;14:258.
There is no single model available to predict the long term survival for patients starting renal replacement therapy (RRT). The available models either predict survival on dialysis until transplantation, survival on the transplant waiting list, or survival after transplantation. The aim of this study was to develop a model that includes dialysis survival and survival after an eventual transplantation.
From the Dutch renal replacement registry, patients of 16 years of age or older were included if they started RRT between 1995 and 2005, still underwent RRT at baseline (90 days after the start of RRT) and were not registered at a non-renal organ transplant waiting list (N = 13868). A prediction model of 10-year patient survival after baseline was developed through multivariate Cox regression analysis, in one half of the research group. Age at start, sex, primary renal disease (PRD) and therapy at baseline were included as possible predictors. A sensitivity analysis has been performed to determine whether listing on the transplant waiting list should be added. The predictive performance of the model was internally validated. Calibration and discrimination were computed in the other half of the research group. Another sensitivity analysis was to assess whether the outcomes differed if the model was developed and tested in two geographical regions, which were less similar than the original development and validation group. No external validation has been performed.
Survival probabilities were influenced by age, sex, PRD and therapy at baseline (p < 0.001). The calibration and discrimination both showed very reasonable results for the prediction model (C-index = 0.720 and calibration slope for the prognostic index = 1.025, for the 10 year survival). Adding registration on the waiting list for renal transplantation as a predictor did not improve the discriminative power of the model and was therefore not included in the model.
With the presented prediction model, it is possible to give a reasonably accurate estimation on the survival chances of patients who start with RRT, using a limited set of easily available data.
PMCID: PMC4225578  PMID: 24256551
14.  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.
PMCID: PMC3524901  PMID: 22473037
Automated peritoneal dialysis; continuous ambulatory peritoneal dialysis; effective lymphatic absorption rate; peritoneal transport; ultrafiltration; standard peritoneal permeability analysis
15.  Erythropoiesis-stimulating agent resistance and mortality in hemodialysis and peritoneal dialysis patients 
BMC Nephrology  2013;14:200.
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.
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.
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.
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.
PMCID: PMC3849281  PMID: 24066978
Cohort study; Erythropoietin; ESA Resistance; Hemodialysis; Mortality; Peritoneal dialysis
16.  Achieving research competences through medical education 
PMCID: PMC3792234  PMID: 24049044
17.  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 (, 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.
PMCID: PMC3792236  PMID: 24101579
Tuning; Research competences; Medical curricula; Learning outcomes; Bologna process
18.  Type of arteriovenous vascular access and association with patency and mortality 
BMC Nephrology  2013;14:79.
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).
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.
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.
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.
PMCID: PMC3621613  PMID: 23557085
Hemodialysis; Fistula; Graft; Patency; Mortality; Epidemiology
19.  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.
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.
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.
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).
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.
PMCID: PMC3259092  PMID: 22182634
20.  Chronic kidney disease in patients with diabetes mellitus type 2 or hypertension in general practice 
The prevalence and severity of chronic kidney disease (CKD) in primary care patients with diabetes or hypertension is unknown.
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.
Two Dutch primary health care centres (15 954 enlisted patients).
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.
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).
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.
PMCID: PMC2991741  PMID: 21144198
diabetes; hypertension; kidney disease, chronic; prevalence; primary care; screening
21.  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.
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.
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.
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.
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.
PMCID: PMC3171298  PMID: 21835038
blood pressure; chronic kidney disease stages IV-V; estimated glomerular filtration rate; pre-dialysis care; renal replacement therapy
22.  Association Between CNDP1 Genotype and Diabetic Nephropathy Is Sex Specific 
Diabetes  2010;59(6):1555-1559.
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.
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.
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).
This study suggests that the association between the CNDP1 gene and diabetic nephropathy is sex specific and independent of susceptibility for type 2 diabetes.
PMCID: PMC2874718  PMID: 20332346
23.  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.
PMCID: PMC3145092  PMID: 21347603
Focus groups; Medical; Medical education; Musculoskeletal diseases; Patients; Questionnaires; Students; Undergraduate
24.  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.
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.
Patients (N = 109) completed questionnaires at home. Data were analysed using bivariate and multivariate analyses.
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.
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.
PMCID: PMC3019121  PMID: 21138597
25.  Interactive seminars or small group tutorials in preclinical medical education: results of a randomized controlled trial 
BMC Medical Education  2010;10:79.
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.
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.
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.
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.
PMCID: PMC3000405  PMID: 21073744

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