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1.  A Peritoneal Dialysis Regimen Low in Glucose and Glucose Degradation Products Results in Increased Cancer Antigen 125 and Peritoneal Activation 
♦ Background: Glucose and glucose degradation products (GDPs) in peritoneal dialysis fluids (PDFs) are both thought to mediate progressive peritoneal worsening.
♦ Methods: In a multicenter, prospective, randomized crossover study, incident continuous ambulatory peritoneal dialysis patients were treated either with conventional lactate-buffered PDF (sPD regimen) or with a regimen low in glucose and GDPs: Nutrineal×1, Extraneal×1, and Physioneal×2 (NEPP regimen; all solutions: Baxter Healthcare, Utrecht, Netherlands). After 6 months, patients were switched to the alternative regimen for another 6 months. After 6 weeks of run-in, before the switch, and at the end of the study, 4-hour peritoneal equilibration tests were performed, and overnight effluents were analyzed for cells and biomarkers. Differences between the regimens were assessed by multivariate analysis corrected for time and regimen sequence.
♦ Results: The 45 patients who completed the study were equally distributed over both groups. During NEPP treatment, D4/D0 glucose was lower (p < 0.01) and D/P creatinine was higher (p = 0.04). In NEPP overnight effluent, mesothelial cells (p < 0.0001), cancer antigen 125 (p < 0.0001), hyaluronan (p < 0.0001), leukocytes (p < 0.001), interleukins 6 (p = 0.001) and 8 (p = 0.0001), and vascular endothelial growth factor (VEGF, p < 0.0001) were increased by a factor of 2 – 3 compared with levels in sPD effluent. The NEPP regimen was associated with higher transport parameters, but that association disappeared after the addition of VEGF to the model. The association between NEPP and higher effluent levels of VEGF could not be attributed to glucose and GDP loads.
♦ Conclusions: Study results indicate preservation of the mesothelium and increased peritoneal activation during NEPP treatment. Whether the increase in VEGF reflects an increase in mesothelial cell mass or whether it points to another, undesirable mechanism cannot be determined from the present study. Longitudinal studies are needed to finally evaluate the usefulness of the NEPP regimen for further clinical use.
PMCID: PMC3525441  PMID: 22045100
Biocompatibility; CA125; CAPD; clinical trial; glucose; glucose degradation products; mesothelial regeneration; icodextrin; amino acids
2.  Premature Aging of the Microcirculation in Patients with Advanced Chronic Kidney Disease 
Nephron Extra  2012;2(1):283-292.
Increasing age and advanced chronic kidney disease (CKD) are both associated with an attenuated vasodilator response of the skin microcirculation. In the present study, we investigated the effect of aging on microvascular reactivity in patients with advanced CKD.
Acetylcholine (ACh)-mediated endothelium-dependent vasodilation and sodium nitroprusside (SNP)-mediated endothelium-independent vasodilation were assessed by iontophoresis combined with laser Doppler flowmetry. Microvascular function was compared between 52 patients with advanced CKD (stage 4–5: n = 16; end-stage renal disease: n = 36) and 33 healthy control subjects. As aging has an important effect on microvascular function, both control subjects and CKD patients were divided in subgroups younger and older than 45 years. Linear regression analysis was applied to assess potential associations between microvascular function and various demographic and clinical parameters.
There were three main findings. (1) In young patients with advanced CKD, both ACh- and SNP-mediated vasodilations were impaired if compared to young healthy controls (p = 0.04 and p = 0.056, respectively). (2) In young patients with advanced CKD, microvascular function was similar to old healthy controls and elderly patients with advanced CKD. (3) Whereas age was inversely associated with microvascular function in healthy controls (log ACh-mediated vasodilation R = −0.41; p = 0.02 and log SNP-mediated vasodilation R = −0.38; p = 0.03), no such relation was found in patients with advanced CKD.
Our results are consistent with premature aging of the microvascular vasodilatory capacity in patients with advanced CKD.
PMCID: PMC3521446  PMID: 23243413
Microcirculation; Iontophoresis; Endothelial function; Aging; Chronic kidney disease
3.  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.
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.
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.
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).
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.
PMCID: PMC3366907  PMID: 22530966
Cardiovascular disease; CKD; FGF23; Phosphate; Proteinuria; Smoking
4.  Bioincompatible Impact of Different Peritoneal Dialysis Fluid Components and Therapeutic Interventions as Tested in a Rat Peritoneal Dialysis Model 
Peritoneal dialysis (PD) is associated with functional and structural changes of the peritoneal membrane. In this paper, we describe the impact of different factors contributing to peritoneal incompatibility of PD fluid installation including presence of a catheter, volume loading, and the PD fluid components itself. These factors initiate recruitment and activation of peritoneal immune cells such as macrophages and mast cells, as well as activation of peritoneal cells as mesothelial cells in situ. We provide an overview of PD-associated changes as seen in our rat PD-exposure model. Since these changes are partly reversible, we finally discuss therapeutic strategies in the rat PD model with possible consequences of long-term PD in the relevant human setting.
PMCID: PMC3150195  PMID: 21826269
5.  Differences in quality of life of hemodialysis patients between dialysis centers 
Quality of Life Research  2011;21(2):299-307.
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.
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).
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.
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.
PMCID: PMC3276757  PMID: 21633878
Quality of life; Center differences; Hemodialysis; Dialysis staff encouragement
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.
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.
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 ISRCTN38365125
PMCID: PMC3914777  PMID: 24505249
7.  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.
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.
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.
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.
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.
PMCID: PMC3631204  PMID: 23620729
8.  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.
PMCID: PMC3396629  PMID: 22808058
9.  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] 
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.
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.
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.
PMCID: PMC1156925  PMID: 15907201
End stage renal disease; hemodialysis; hemodiafiltration; convective transport; middle molecules; mortality; cardiovascular disease; outcome

Results 1-9 (9)