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1.  Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without hypertension: a meta-analysis 
Lancet  2012;380(9854):1649-1661.
Background
Hypertension is the most prevalent comorbidity in individuals with chronic kidney disease (CKD). It is unknown, however, whether the association of the CKD measures, estimated glomerular filtration rate (eGFR) and albuminuria, with mortality or end-stage renal disease (ESRD) differs by hypertensive status.
Methods
We performed a meta-analysis of 45 cohorts (25 general population, 7 high-risk and 13 CKD cohorts), including 1,127,656 participants (364,344 with hypertension). Adjusted hazard ratios (HRs) for all-cause mortality (84,078 deaths from 40 cohorts) and ESRD (7,587 events from 21 cohorts) by hypertensive status were obtained for each study and pooled using random-effects models.
Findings
Low eGFR and high albuminuria were associated with mortality in both non-hypertensive and hypertensive individuals in the general population and high-risk cohorts. Mortality risk was higher in hypertensives as compared to non-hypertensives at preserved eGFR but a steeper relative risk gradient among non-hypertensives than hypertensives at eGFR range 45-75 ml/min/1.73m2 led to similar mortality risk at lower eGFR. With a reference eGFR of 95 mL/min/1.73m2 in each group to explicitly assess interaction, adjusted HR for all-cause mortality at eGFR 45 mL/min/1.73m2 was 1.77 (95% CI, 1.57-1.99) in non-hypertensives versus 1.24 (1.11-1.39) in hypertensives (P for overall interaction =0.0003). Similarly, for albumin-creatinine ratio (ACR) of 300 mg/g (vs. 5 mg/g), HRs were 2.30 (1.98-2.68) in non-hypertensives versus 2.08 (1.84-2.35) in hypertensives (P for overall interaction=0.019). Similar results were observed for cardiovascular mortality. The associations of eGFR and albuminuria with ESRD, however, did not differ by hypertensive status. Results in CKD cohorts were comparable to results in general and high-risk population cohorts.
Interpretation
Low eGFR and elevated albuminuria were more strongly associated with mortality among individuals without hypertension than in those with hypertension, but the associations with ESRD were similar. CKD should be considered at least an equally relevant risk factor for mortality and ESRD in non-hypertensive as it is in hypertensive individuals.
Funding
The US National Kidney Foundation (sources include Abbott and Amgen).
doi:10.1016/S0140-6736(12)61272-0
PMCID: PMC3993095  PMID: 23013600
2.  Evidence and Consequences of the Central Role of the Kidneys in the Pathophysiology of Sympathetic Hyperactivity 
Chronic elevation of the sympathetic nervous system has been identified as a major contributor to the complex pathophysiology of hypertension, states of volume overload – such as heart failure – and progressive kidney disease. It is also a strong determinant for clinical outcome. This review focuses on the central role of the kidneys in the pathogenesis of sympathetic hyperactivity. As a consequence, renal denervation may be an attractive option to treat sympathetic hyperactivity. The review will also focus on first results and the still remaining questions of this new treatment option.
doi:10.3389/fphys.2012.00029
PMCID: PMC3282535  PMID: 22363298
renal denervation; sympathetic activity; kidney disease; hypertension
3.  Resistance to Erythropoiesis Stimulating Agents in Patients Treated with Online Hemodiafiltration and Ultrapure Low-Flux Hemodialysis: Results from a Randomized Controlled Trial (CONTRAST) 
PLoS ONE  2014;9(4):e94434.
Resistance to erythropoiesis stimulating agents (ESA) is common in patients undergoing chronic hemodialysis (HD) treatment. ESA responsiveness might be improved by enhanced clearance of uremic toxins of middle molecular weight, as can be obtained by hemodiafiltration (HDF). In this analysis of the randomized controlled CONvective TRAnsport STudy (CONTRAST; NCT00205556), the effect of online HDF on ESA resistance and iron parameters was studied. This was a pre-specified secondary endpoint of the main trial. A 12 months' analysis of 714 patients randomized to either treatment with online post-dilution HDF or continuation of low-flux HD was performed. Both groups were treated with ultrapure dialysis fluids. ESA resistance, measured every three months, was expressed as the ESA index (weight adjusted weekly ESA dose in daily defined doses [DDD]/hematocrit). The mean ESA index during 12 months was not different between patients treated with HDF or HD (mean difference HDF versus HD over time 0.029 DDD/kg/Hct/week [−0.024 to 0.081]; P = 0.29). Mean transferrin saturation ratio and ferritin levels during the study tended to be lower in patients treated with HDF (−2.52% [−4.72 to −0.31]; P = 0.02 and −49 ng/mL [−103 to 4]; P = 0.06 respectively), although there was a trend for those patients to receive slightly more iron supplementation (7.1 mg/week [−0.4 to 14.5]; P = 0.06).
In conclusion, compared to low-flux HD with ultrapure dialysis fluid, treatment with online HDF did not result in a decrease in ESA resistance.
Trial Registration
ClinicalTrials.gov NCT00205556
doi:10.1371/journal.pone.0094434
PMCID: PMC3990567  PMID: 24743493
4.  Differences between hospitals in attainment of parathyroid hormone treatment targets in chronic kidney disease do not reflect differences in quality of care 
BMC Nephrology  2012;13:82.
Background
Transparency in quality of care (QoC) is stimulated and hospitals are compared and judged on the basis of indicators of performance on specific treatment targets. In patients with chronic kidney disease, QoC differed significantly between hospitals. In this analysis we explored additional parameters to explain differences between centers in attainment of parathyroid hormone (PTH) treatment targets.
Methods
Using MASTERPLAN baseline data, we selected one of the worst (center A) and one of the best (center B) performing hospitals. Differences between the two centers were analyzed from the year prior to start of the MASTERPLAN study until the baseline evaluation. Determinants of PTH were assessed.
Results
101 patients from center A (median PTH 9.9 pmol/l, in 67 patients exceeding recommended levels) and 100 patients from center B (median PTH 6.5 pmol/l, in 34 patients exceeding recommended levels), were included. Analysis of clinical practice did not reveal differences in PTH management between the centers. Notably, hyperparathyroidism resulted in a change in therapy in less than 25% of patients. In multivariate analysis kidney transplant status, MDRD-4, and treatment center were independent predictors of PTH. However, when MDRD-6 (which accounts for serum urea and albumin) was used instead of MDRD-4, the center effect was reduced. Moreover, after calibration of the serum creatinine assays treatment center no longer influenced PTH.
Conclusions
We show that differences in PTH control between centers are not explained by differences in treatment, but depend on incomparable patient populations and laboratory techniques. Therefore, results of hospital performance comparisons should be interpreted with great caution.
doi:10.1186/1471-2369-13-82
PMCID: PMC3467173  PMID: 22867424
Chronic kidney disease; Parathyroid hormone; Quality of care; Treatment targets
5.  Fibroblast growth factor 23 is associated with proteinuria and smoking in chronic kidney disease: An analysis of the MASTERPLAN cohort 
BMC Nephrology  2012;13:20.
Background
Fibroblast growth factor 23 (FGF23) has emerged as a risk factor for cardiovascular disease and mortality throughout all stages of chronic kidney disease (CKD), independent from established risk factors and markers of mineral homeostasis. The relation of FGF23 with other renal and non-renal cardiovascular risk factors is not well established.
Methods
Using stored samples, plasma FGF23 was determined in 604 patients with moderate to severe kidney disease that participated in the MASTERPLAN study (ISRCTN73187232). The association of FGF23 with demographic and clinical parameters was evaluated using multivariable regression models.
Results
Mean age in the study population was 60 years and eGFR was 37 (± 14) ml/min/1.73 m2. Median proteinuria was 0.3 g/24 hours [IQR 0.1-0.9]. FGF23 level was 116 RU/ml [67-203] median and IQR. Using multivariable analysis the natural logarithm of FGF23 was positively associated with history of cardiovascular disease (B = 0.224 RU/ml; p = 0.002), presence of diabetes (B = 0.159 RU/ml; p = 0.035), smoking (B = 0.313 RU/ml; p < 0.001), phosphate level (B = 0.297 per mmol/l; p = 0.0024), lnPTH (B = 0.244 per pmol/l; p < 0.001) and proteinuria (B = 0.064 per gram/24 hrs; p = 0.002) and negatively associated with eGFR (B = -0.022 per ml/min/1.73 m2; p < 0.001).
Conclusions
Our study demonstrates that in patients with CKD, FGF23 is related to proteinuria and smoking. We confirm the relation between FGF23 and other cardiovascular risk factors.
doi:10.1186/1471-2369-13-20
PMCID: PMC3366907  PMID: 22530966
Cardiovascular disease; CKD; FGF23; Phosphate; Proteinuria; Smoking
6.  Left Ventricular Mass in Dialysis Patients, Determinants and Relation with Outcome. Results from the COnvective TRansport STudy (CONTRAST) 
PLoS ONE  2014;9(2):e84587.
Background and Objectives
Left ventricular mass (LVM) is known to be related to overall and cardiovascular mortality in end stage kidney disease (ESKD) patients. The aims of the present study are 1) to determine whether LVM is associated with mortality and various cardiovascular events and 2) to identify determinants of LVM including biomarkers of inflammation and fibrosis.
Design, Setting, Participants, & Measurements
Analysis was performed with data of 327 ESKD patients, a subset from the CONvective TRAnsport STudy (CONTRAST). Echocardiography was performed at baseline. Cox regression analysis was used to assess the relation of LVM tertiles with clinical events. Multivariable linear regression models were used to identify factors associated with LVM.
Results
Median age was 65 (IQR: 54–73) years, 203 (61%) were male and median LVM was 227 (IQR: 183–279) grams. The risk of all-cause mortality (hazard ratio (HR) = 1.73, 95% CI: 1.11–2.99), cardiovascular death (HR = 3.66, 95% CI: 1.35–10.05) and sudden death (HR = 13.06; 95% CI: 6.60–107) was increased in the highest tertile (>260grams) of LVM. In the multivariable analysis positive relations with LVM were found for male gender (B = 38.8±10.3), residual renal function (B = 17.9±8.0), phosphate binder therapy (B = 16.9±8.5), and an inverse relation for a previous kidney transplantation (B = −41.1±7.6) and albumin (B = −2.9±1.1). Interleukin-6 (Il-6), high-sensitivity C-reactive protein (hsCRP), hepcidin-25 and connective tissue growth factor (CTGF) were not related to LVM.
Conclusion
We confirm the relation between a high LVM and outcome and expand the evidence for increased risk of sudden death. No relationship was found between LVM and markers of inflammation and fibrosis.
Trial Registration
Controlled-Trials.com ISRCTN38365125
doi:10.1371/journal.pone.0084587
PMCID: PMC3914777  PMID: 24505249
7.  Differences in quality of life of hemodialysis patients between dialysis centers 
Quality of Life Research  2011;21(2):299-307.
Purpose
Hemodialysis patients undergo frequent and long visits to the clinic to receive adequate dialysis treatment, medical guidance, and support. This may affect health-related quality of life (HRQOL). Although HRQOL is a very important management aspect in hemodialysis patients, there is a paucity of information on the differences in HRQOL between centers. We set out to assess the differences in HRQOL of hemodialysis patients between dialysis centers and explore which modifiable center characteristics could explain possible differences.
Methods
This cross-sectional study evaluated 570 hemodialysis patients from 24 Dutch dialysis centers. HRQOL was measured with the Kidney Disease Quality Of Life-Short Form (KDQOL-SF).
Results
After adjustment for differences in case-mix, three HRQOL domains differed between dialysis centers: the physical composite score (PCS, P = 0.01), quality of social interaction (P = 0.04), and dialysis staff encouragement (P = 0.001). These center differences had a range of 11–21 points on a scale of 0–100, depending on the domain. Two center characteristics showed a clinical relevant relation with patients’ HRQOL: dieticians’ fulltime-equivalent and the type of dialysis center.
Conclusion
This study showed that clinical relevant differences exist between dialysis centers in multiple HRQOL domains. This is especially remarkable as hemodialysis is a highly standardized therapy.
doi:10.1007/s11136-011-9942-3
PMCID: PMC3276757  PMID: 21633878
Quality of life; Center differences; Hemodialysis; Dialysis staff encouragement
8.  An animal paired crossover ePTFE arteriovenous graft model 
Purpose
Previously, we developed a porcine model for Arterio Venous Graft (AVG) failure to allow assessment of new access strategies. This model was limited concerning graft length. In the present technical report, we describe a modification of our model allowing the assessment of long AVGs.
Technique
In 4 pigs, AVGs of 15 cm length were created bilaterally in a cross-over fashion between the carotid artery and the contralateral jugular vein. Two days (2 pigs) and two weeks (2 pigs) after AV shunting, graft patency was evaluated by angiography, showing all four grafts to be patent, with no sign of angiographic or macroscopic narrowing at the anastomoses sites.
Conclusions
In this modified pig AVG failure model, implantation of a bilateral cross-over long AVG is a feasible approach. The present model offers a suitable tool to study local interventions or compare various long graft designs aimed at improvement of AVG patency.
doi:10.1186/1750-1164-4-7
PMCID: PMC3006397  PMID: 21110903
9.  Haemodiafiltration—optimal efficiency and safety 
NDT Plus  2009;3(1):8-16.
Haemodiafiltration (HDF) is the blood purification therapy of choice for those who want significant removal of uraemic solutes beyond the traditional range of small molecules. Combining diffusive and convective solute transport, a HDF treatment comprises the largest number of variables among blood purification therapies, and it is important to understand how they interact in order to optimize the therapy. This review discusses the parameters that determine the efficiency of HDF and how they can be controlled in the different forms of HDF and ‘HDF-like’ therapies practised today. The key to safe and effective HDF therapy is to have access to large volumes of high-quality fluids. Starting with ultrapure dialysis fluid, on-line preparation of a sterile, non-pyrogenic substitution solution can be made an integral part of the treatment, and we describe the necessary conditions for this. On-line HDF can provide the largest removal of the widest range of solutes among available dialysis therapies, and the potential clinical benefits of this are within practical reach for the increasing number of patients dialysed with high-flux membranes and ultrapure dialysis fluid.
doi:10.1093/ndtplus/sfp149
PMCID: PMC2808132  PMID: 20090878
convection; haemodiafiltration; on-line fluid preparation; postdilution; predilution
10.  Multifactorial approach and superior treatment efficacy in renal patients with the aid of nurse practitioners. Design of The MASTERPLAN Study [ISRCTN73187232] 
Trials  2006;7:8.
Background
Patients with chronic kidney disease (CKD) are at a greatly increased risk of developing cardiovascular disease. Recently developed guidelines address multiple risk factors and life-style interventions. However, in current practice few patients reach their targets.
A multifactorial approach with the aid of nurse practitioners was effective in achieving treatment goals and reducing vascular events in patients with diabetes mellitus and in patients with heart failure. We propose that this also holds for the CKD population.
Design
MASTERPLAN is a multicenter randomized controlled clinical trial designed to evaluate whether a multifactorial approach with the aid of nurse-practicioners reduces cardiovascular risk in patients with CKD. Approximately 800 patients with a creatinine clearance (estimated by Cockcroft-Gault) between 20 to 70 ml/min, will be included. To all patients the same set of guidelines will be applied and specific cardioprotective medication will be prescribed. In the intervention group the nurse practitioner will provide lifestyle advice and actively address treatment goals. Follow-up will be five years. Primary endpoint is the composite of myocardial infarction, stroke and cardiovascular mortality. Secondary endpoints are cardiovascular morbidity, overall mortality, decline of renal function, change in markers of vascular damage and change in quality of life. Enrollment has started in April 2004 and the study is on track with 700 patients included on October 15th, 2005. This article describes the design of the MASTERPLAN study.
doi:10.1186/1745-6215-7-8
PMCID: PMC1459200  PMID: 16573836
11.  Effect of increased convective clearance by on-line hemodiafiltration on all cause and cardiovascular mortality in chronic hemodialysis patients – the Dutch CONvective TRAnsport STudy (CONTRAST): rationale and design of a randomised controlled trial [ISRCTN38365125] 
Background
The high incidence of cardiovascular disease in patients with end stage renal disease (ESRD) is related to the accumulation of uremic toxins in the middle and large-middle molecular weight range. As online hemodiafiltration (HDF) removes these molecules more effectively than standard hemodialysis (HD), it has been suggested that online HDF improves survival and cardiovascular outcome. Thus far, no conclusive data of HDF on target organ damage and cardiovascular morbidity and mortality are available. Therefore, the CONvective TRAnsport STudy (CONTRAST) has been initiated.
Methods
CONTRAST is a Dutch multi-center randomised controlled trial. In this trial, approximately 800 chronic hemodialysis patients will be randomised between online HDF and low-flux HD, and followed for three years. The primary endpoint is all cause mortality. The main secondary outcome variables are fatal and non-fatal cardiovascular events.
Conclusion
The study is designed to provide conclusive evidence whether online HDF leads to a lower mortality and less cardiovascular events as compared to standard HD.
doi:10.1186/1468-6708-6-8
PMCID: PMC1156925  PMID: 15907201
End stage renal disease; hemodialysis; hemodiafiltration; convective transport; middle molecules; mortality; cardiovascular disease; outcome
12.  Should We Still Focus That Much on Cardiovascular Mortality in End Stage Renal Disease Patients? The CONvective TRAnsport STudy 
PLoS ONE  2013;8(4):e61155.
Background
We studied the distribution of causes of death in the CONTRAST cohort and compared the proportion of cardiovascular deaths with other populations to answer the question whether cardiovascular mortality is still the principal cause of death in end stage renal disease. In addition, we compared patients who died from the three most common death causes. Finally, we aimed to study factors related to dialysis withdrawal.
Methods
We used data from CONTRAST, a randomized controlled trial in 714 chronic hemodialysis patients comparing the effects of online hemodiafiltration versus low-flux hemodialysis. Causes of death were adjudicated. The distribution of causes of death was compared to that of the Dutch dialysis registry and of the Dutch general population.
Results
In CONTRAST, 231 patients died on treatment. 32% died from cardiovascular disease, 22% due to infection and 23% because of dialysis withdrawal. These proportions were similar to those in the Dutch dialysis registry and the proportional cardiovascular mortality was similar to that of the Dutch general population. cardiovascular death was more common in patients <60 years. Patients who withdrew were older, had more co-morbidity and a lower mental quality of life at baseline. Patients who withdrew had much co-morbidity. 46% died within 5 days after the last dialysis session.
Conclusions
Although the absolute risk of death is much higher, the proportion of cardiovascular deaths in a prevalent end stage renal disease population is similar to that of the general population. In older hemodialysis patients cardiovascular and non-cardiovascular death risk are equally important. Particularly the registration of dialysis withdrawal deserves attention. These findings may be partly limited to the Dutch population.
doi:10.1371/journal.pone.0061155
PMCID: PMC3631204  PMID: 23620729
13.  Hepcidin-25 in Chronic Hemodialysis Patients Is Related to Residual Kidney Function and Not to Treatment with Erythropoiesis Stimulating Agents 
PLoS ONE  2012;7(7):e39783.
Hepcidin-25, the bioactive form of hepcidin, is a key regulator of iron homeostasis as it induces internalization and degradation of ferroportin, a cellular iron exporter on enterocytes, macrophages and hepatocytes. Hepcidin levels are increased in chronic hemodialysis (HD) patients, but as of yet, limited information on factors associated with hepcidin-25 in these patients is available. In the current cross-sectional study, potential patient-, laboratory- and treatment-related determinants of serum hepcidin-20 and -25, were assessed in a large cohort of stable, prevalent HD patients. Baseline data from 405 patients (62% male; age 63.7±13.9 [mean SD]) enrolled in the CONvective TRAnsport STudy (CONTRAST; NCT00205556) were studied. Predialysis hepcidin concentrations were measured centrally with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Patient-, laboratory- and treatment related characteristics were entered in a backward multivariable linear regression model. Hepcidin-25 levels were independently and positively associated with ferritin (p<0.001), hsCRP (p<0.001) and the presence of diabetes (p = 0.02) and inversely with the estimated glomerular filtration rate (p = 0.01), absolute reticulocyte count (p = 0.02) and soluble transferrin receptor (p<0.001). Men had lower hepcidin-25 levels as compared to women (p = 0.03). Hepcidin-25 was not associated with the maintenance dose of erythropoiesis stimulating agents (ESA) or iron therapy. In conclusion, in the currently studied cohort of chronic HD patients, hepcidin-25 was a marker for iron stores and erythropoiesis and was associated with inflammation. Furthermore, hepcidin-25 levels were influenced by residual kidney function. Hepcidin-25 did not reflect ESA or iron dose in chronic stable HD patients on maintenance therapy. These results suggest that hepcidin is involved in the pathophysiological pathway of renal anemia and iron availability in these patients, but challenges its function as a clinical parameter for ESA resistance.
doi:10.1371/journal.pone.0039783
PMCID: PMC3396629  PMID: 22808058

Results 1-13 (13)