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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, The 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, D(4)/D(0) 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.

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 m(2). 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 m(2); 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.

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.

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.

Background/aims: Guidelines for the management of anemia and iron deficiency in chronic hemodialysis (HD) patients have been developed to standardize therapy and improve clinical outcome. The present study evaluated compliance with anemia guidelines and investigated whether differences between centers were present., Methods: Data on anemia management from patients in the baseline cohort of the CONTRAST study (NCT00205556) were analyzed. 598 chronic HD patients (62% male, age 63.6 ± 14.0 years) from 26 Dutch dialysis centers were included., Results: Mean hemoglobin (Hb) level was 11.9 ± 1.3 g/dl and Hb was ≥11.0 g/dl in 81% of the patients. Compliance with all anemia targets (Hb 11.0-12.0 g/dl, transferrin saturation ratio ≥20%, ferritin 100-500 ng/ml) was reached in 11.6% (95% CI 7.8-17.0) of the patients, with a wide range among centers (4-26%, adjusted for case mix, treatment-related factors and center-specific characteristics)., Conclusion: Compliance with anemia targets in stable HD patients was poor and showed a wide variation between treatment facilities., (Copyright © 2012 S. Karger AG, Basel.)

Background/aims: Patients value health-related quality of life (HRQOL) over survival. It was our aim to study the relation between attainment of widely accepted performance targets and HRQOL in hemodialysis patients., Methods: This study included baseline data from 715 hemodialysis patients from 29 dialysis centers. Six clinical performance targets, as recommended by the Kidney Disease Outcomes Quality Initiative (KDOQI), were evaluated: single-pool Kt/V (≥1.2), hemoglobin (11-13 g/dl), vascular access (fistula), phosphorus (2.3-4.5 mg/dl), parathyroid hormone (150-300 pg/ml), and blood pressure (predialysis <140/90 and postdialysis <130/ 80 mm Hg)., Results: After correction for case-mix and multiple comparisons, no association was found between the 6 KDOQI clinical performance targets and the 14 HRQOL domains, or between the number of performance targets reached and HRQOL., Conclusion: Attainment with widely accepted clinical performance targets was not related to the HRQOL of hemodialysis patients. Hence, in clinical guidelines, HRQOL should be adopted as an explicit treatment goal for these individuals., (Copyright © 2011 S. Karger AG, Basel.)

Background: 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., Methods: 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., Results: 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., Conclusions: Our results are consistent with premature aging of the microvascular vasodilatory capacity in patients with advanced CKD.

Background: Standard peritoneal dialysis (PD) solutions contain high levels of glucose and glucose degradation products (GDPs), both contributing to the formation of advanced glycation end products (AGEs). We studied the contribution to plasma GDP and AGE levels of 2 PD regimens that differ in glucose and GDP loads: high load [standard PD (sPD) using 4 glucose-lactate exchanges] and low load [1 amino acid exchange, 1 icodextrin exchange, and 2 glucose-bicarbonate/lactate exchanges ("NEPP")]., Methods: In a prospective crossover study (2 periods of 24 weeks), new continuous ambulatory PD patients were randomized to NEPP-sPD (n = 23) or to sPD-NEPP (n = 27)., Results: After the start of PD, absolute increases were observed in plasma levels of 3-deoxyglucosone (3-DG, 220.4 nmol/L, p < 0.0001) and in N(ε)-(carboxymethyl) lysine (CML) in plasma proteins (0.02 μmol/L CML per 1 mol/L lysine, p < 0.0001). During the first 6 weeks, 3-DG tended to increase more with sPD treatment (p = 0.08), and CML, with NEPP treatment (p = 0.002). In both groups, N(ε)-(carboxyethyl)lysine (CEL) in plasma proteins declined significantly with the start of PD. Treatment with NEPP resulted in higher levels of methylglyoxal (MGO) and lower levels of 3-DG and CEL. Pentosidine in the albumin fraction tended to increase less during NEPP treatment., Conclusions: A low glucose and GDP PD regimen (NEPP) resulted in plasma levels of 3-DG and CEL that were lower than those with a glucose-based sPD regimen. Starting PD with NEPP was associated with a steeper increase in CML, and continuing treatment with NEPP resulted in higher MGO levels.

Background: In patients with chronic kidney disease (CKD), disorders of mineral metabolism are associated with vascular calcifications and mortality. Microvascular dysfunction, by affecting flow resistance and tissue perfusion, may explain the cardiovascular sequelae of CKD-associated disorders of mineral metabolism. We investigated whether advanced CKD is associated with a decrease in the functional and structural number of capillaries in skin and subsequently whether capillary rarefaction is related to mineral metabolism., Methods: Capillary density was measured by nailfold microscopy in 19 predialysis and 35 CKD Stage 5 (CKD5) patients and 19 controls. In CKD patients, calcium, phosphorus, parathyroid hormone, 25-hydroxyvitaminD3 (25vitD3) and 1,25-dihydroxyvitaminD3 (1,25vitD3) were analysed as well., Results: Capillary density at baseline was 42 ± 15/mm(2) in predialysis patients, 45 ± 17/mm(2) in CKD5 patients and 56 ± 20/mm(2) in controls (patients versus controls, respectively, P < 0.05 and P = 0.05). Absolute capillary recruitment during post-occlusive reactive hyperaemia was 17 ± 7/mm(2), 14 ± 6/mm(2) and 23 ± 8/mm(2), respectively (P < 0.05 for both patients and controls). Capillary density during venous occlusion was 59 ± 20/mm(2), 59 ± 21/mm(2) and 77 ± 21/mm(2), respectively (P < 0.05 for both patients and controls). In multiple regression analysis, both serum phosphorus and bicarbonate values were independently and inversely associated with capillary density at baseline (r(2) of model = 19%) as well as during venous occlusion (r(2) of model = 28%). Furthermore, both serum phosphorus and bicarbonate were inversely and female gender positively correlated with capillary density during recruitment (r(2) of model = 37%)., Conclusion: Advanced CKD is characterized by an impaired functional and structural capillary density in skin, which is related to both high phosphorus and bicarbonate values.

There is increasingly evidence that the interactions between vitamin D, fibroblast growth factor 23 (FGF-23), and klotho form an endocrine axis for calcium and phosphate metabolism, and derangement of this axis contributes to the progression of renal disease. Several recent studies also demonstrate negative regulation of the renin gene by vitamin D. In chronic kidney disease (CKD), low levels of calcitriol, due to the loss of 1-alpha hydroxylase, increase renal renin production. Activation of the renin-angiotensin-aldosterone system (RAAS), in turn, reduces renal expression of klotho, a crucial factor for proper FGF-23 signaling. The resulting high FGF-23 levels suppress 1-alpha hydroxylase, further lowering calcitriol. This feedback loop results in vitamin D deficiency, RAAS activation, high FGF-23 levels, and renal klotho deficiency, all of which associate with progression of renal damage. Here we examine current evidence for an interaction between the RAAS and the vitamin D-FGF-23-klotho axis as well as its possible implications for progression of CKD.

Objective: Health-related quality of life (HRQOL) is an important outcome in dialysis care. Previous research has related protein-energy nutritional status to generic HRQOL domains, but it is still not clear as to how it relates to HRQOL domains that are unique to hemodialysis patients. Therefore, our aim was to study the relation between protein-energy nutritional status and kidney disease-specific HRQOL domains in hemodialysis patients., Design: This was a cross-sectional study., Setting: This study was performed at multiple centers., Patients or Other Participants: We evaluated the first 590 hemodialysis patients who had enrolled in the Convective Transport Study., Determinants: We measured protein-energy nutritional status by using the Subjective Global Assessment, albumin, normalized nitrogen appearance, creatinine, body mass index, and cholesterol., Main Outcome Measure: HRQOL was assessed by using the Kidney Disease Quality Of Life-Short Form., Results: In all, 83% of the cohort was found to be well-nourished on the basis of the Subjective Global Assessment. Multiple nutritional parameters were positively related to the physical summary of generic HRQOL and to the following kidney disease-specific HRQOL scales: the effects of the kidney disease on daily life, the burden of the kidney disease, and overall health., Conclusions: This study showed that, even in predominantly well-nourished hemodialysis patients, protein-energy nutritional status was significantly related to kidney disease-specific HRQOL., (Copyright © 2011 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Protein-energy wasting is tightly associated with mortality in haemodialysis patients. An expert panel of the International Society of Renal Nutrition and Metabolism (ISRNM) has published a consensus on the parameters that define protein-energy nutritional status and posed the question, 'which scoring system most effectively predicts outcome?' The aim of our study was therefore to develop a composite score of protein-energy nutritional status (cPENS) and to assess its prediction of all-cause mortality., Methods: We used the data of 560 haemodialysis patients participating in the CONvective TRAnsport STudy (CONTRAST). All participants were followed for occurrence of death. Internationally recommended nutritional targets were used as components of the cPENS, including the subjective global assessment (target score ≥ 6), albumin (≥ 4.0 g/dL), normalized protein nitrogen appearance (≥ 0.8 g/kg/day), cholesterol (≥ 100 mg/dL), creatinine (≥ 10 mg/dL) and BMI (> 23 kg/m(2)). A Cox regression model was used to analyse the relation between different cPENS variants and mortality., Results: The median follow-up time was 1.4 years (max 4.2). One hundred and five patients (19%) died. A cPENS variant based on albumin, BMI, creatinine and the nPNA yielded the strongest relation with mortality (hazard ratio 0.63, 95% confidence interval 0.54-0.74, P < 0.001), after adjustments for confounders. Some of the individual parameters of the cPENS, notably albumin and creatinine, were related to mortality with similar strength and magnitude., Conclusions: In conclusion, albumin reflects mortality risk similarly to multiple nutritional parameters combined. This questions the clinical value of the proposed diagnostic criteria for protein-energy wasting.

Background: Improving the health-related quality of life (HRQOL) for haemodialysis patients is a considerable challenge. The aim of the present study was to compare changes in HRQOL in haemodialysis patients with those observed in the general population over a 10-year period and explore factors that might explain possible differences., Methods: We compared 126 haemodialysis patients assessed in 1995 in the Netherlands Cooperative Study on the Adequacy of Dialysis-1 (NECOSAD-I) with 515 patients enrolled in 2006 in the ongoing Convective Transport Study (CONTRAST). Changes in HRQOL in these cohorts were compared with two representative samples from the general Dutch population, assessed in 1992 (n = 1,063) and 2001 (n = 10,600). HRQOL was measured with the SF-36 questionnaire. Differences in HRQOL were analysed with ANCOVA to adjust for demographic variables. To assess possible differences, we used multivariable regression analysis., Results: HRQOL in haemodialysis patients in 2006 [CONTRAST, mean age 63 ± 14 years (SD), 62% male] was significantly better than in 1995 (NECOSAD-I, 59 ± 16 years, 53% male) in four domains of the SF-36: bodily pain (+ 5 points, P = 0.009), vitality (+ 7, P < 0.001), role-emotional (+ 14, P < 0.001) and mental health (+ 8, P < 0.001), after adjusting for demographic variables. This increment could partly be explained by improved haemoglobin and phosphate levels. Compared to the general population, HRQOL improvement was most outspoken in two domains: bodily pain (+ 6, P = 0.01) and role-emotional (+ 8, P = 0.007)., Conclusions: This study showed an improvement of HRQOL in haemodialysis patients over an 11-year period of time, independent of global changes in the general population.

Background and Objectives: Little is known about the influence of dietary phosphate intake on fibroblast growth factor-23 (FGF23) and its subsequent effects on vitamin D levels. This study addresses changes in intact FGF23 (iFGF23) and C-terminal FGF23 (cFGF23), phosphaturia, and levels of vitamin D on high and low phosphate and calcium intake., Design, Setting, Participants, & Measurements: Ten healthy subjects adhered to a diet low or high in phosphate and calcium content for 36 hours each with a 1-week interval during which subjects adhered to their usual diet. Serum phosphate, calcium, vitamin D metabolites, parathyroid hormone (PTH), and FGF23 levels (cFGF23 and iFGF23) were measured several times a day. Phosphate, calcium, and creatinine excretion was measured in 24-hour urine on all study days., Results: Serum phosphate levels and urinary phosphate increased during high dietary phosphate intake (from 1.11 to 1.32 mmol/L, P<0.0001 and 21.6 to 28.8 mmol/d, P=0.0005, respectively). FGF23 serum levels increased during high dietary phosphate/calcium intake (cFGF23 from 60 to 72 RU/ml, P<0.001; iFGF23 from 33 to 37 ng/L, P=0.003), whereas PTH declined. 1,25-dihydroxyvitamin D (1,25D) showed an inverse relation with FGF23., Conclusions: Variation in dietary phosphate and calcium intake induces changes in FGF23 (on top of a circadian rhythm) and 1,25D blood levels as well as in urinary phosphate excretion. These changes are detectable the day after the change in the phosphate content of meals. Higher FGF23 levels are associated with phosphaturia and a decline in 1,25D levels.

Background and Objectives: There is increasing awareness that residual renal function (RRF) has beneficial effects in hemodialysis (HD) patients. The aim of this study was to investigate the role of RRF, expressed as GFR, in phosphate and anemia management in chronic HD patients., Design, Setting, Participants, & Measurements: Baseline data of 552 consecutive patients from the Convective Transport Study (CONTRAST) were analyzed. Patients with a urinary output≥100 ml/24 h (n=295) were categorized in tertiles on the basis of degree of GFR and compared with anuric patients (i.e., urinary output<100 ml/24 h, n=274). Relations between GFR and serum phosphate and erythropoiesis-stimulating agent (ESA) index (weekly ESA dose per kg body weight divided by hematocrit) were analyzed with multivariable regression models., Results: Phosphate levels were between 3.5 and 5.5 mg/dl in 68% of patients in the upper tertile (GFR>4.13 ml/min per 1.73 m2), as compared with 46% in anuric patients despite lower prescription of phosphate-binding agents. Mean hemoglobin levels were 11.9±1.2 g/dl with no differences between the GFR categories. The ESA index was 31% lower in patients in the upper tertile as compared with anuric patients. After adjustments for patient characteristics, patients in the upper tertile had significantly lower serum phosphate levels and ESA index as compared with anuric patients., Conclusions: This study suggests a strong relation between RRF and improved phosphate and anemia control in HD patients. Efforts to preserve RRF in HD patients could improve outcomes and should be encouraged.

Long-term exposure to peritoneal dialysis fluid induces morphological alterations, including angiogenesis, leading to a loss of ultrafiltration (UF) capacity. We discuss the effect of different factors in peritoneal dialysis (PD) on angiogenesis. In addition, we describe the process of angiogenesis and the possible role of different cell types in the peritoneum upon PD contributing to new blood vessel formation. Furthermore, we review several interventions used in our rat PD exposure model to decrease angiogenesis in PD. Moreover, we show new data on the use of sunitinib to inhibit angiogenesis in this rat model. Although various interventions seem to be promising, well-randomised clinical trials showing absolute prevention of angiogenesis and UF failure are, yet, still missing. To make real progress in PD treatment, the aim should be to prevent angiogenesis as well as peritoneal fibrosis and PD-induced inflammation., (Copyright © 2011 S. Karger AG, Basel.)

Background: As few data exist on treatment of peritonitis in patients on automated peritoneal dialysis (APD), and as pharmacokinetics of several antibiotics are reported to be unfavorable in APD, some favor switching to continuous ambulant PD (CAPD) while treating APD-related peritonitis. We explored whether treating peritonitis with patients continuing their usual PD modality had an effect on outcome., Methods: We performed a retrospective analysis of the 508 episodes of PD-associated peritonitis seen in 205 patients in our center from January 1993 to January 2007. During this period, the standard initial therapy for PD-related peritonitis was a combination of intraperitoneal gentamicin and rifampicin., Results: There was no difference in cure rate between CAPD and APD groups. Likewise, initial and maximal leukocyte counts in the PD fluid (PDF), relapse rates, catheter removal rates, and death during treatment of peritonitis were similar in the CAPD and APD groups. Median (interquartile range) duration of elevated leukocyte count in PDF was longer in APD: 5.0 (3.0 - 9.0) days versus 4.0 (2.5 - 7.0) days in CAPD (p <0.001). APD patients were treated with antibiotics longer than CAPD patients: 16.0 (12.5 - 21.0) versus 15.0 (12.0 - 18.0) days (p = 0.036). Also, after correction for possible confounders, odds ratios for death and for the combined end point death or catheter removal showed no difference when patients treated for peritonitis stayed on their own modality., Conclusion: Regarding rate of relapse, mortality, or the combined end point mortality plus catheter removal, we found no difference between CAPD and APD patients continuing their own PD modality during treatment of PD-related peritonitis. Intermediate end points such as duration of elevated PDF leukocyte count and duration of antibiotic treatment were longer in APD patients.

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.

Background: The nocturnal endogenous melatonin rise, which is associated with the onset of sleep propensity, is absent in haemodialysis patients. Information on melatonin rhythms in chronic kidney disease (CKD) is limited. Clear relationships exist between melatonin, core body temperature and cortisol in healthy subjects. In CKD, no data are available on these relationships. The objective of the study was to characterize the rhythms of melatonin, cortisol and temperature in relation to renal function in patients with CKD., Methods: From 28 patients (mean age 71 years) with various degrees of renal function, over a 24-h period, blood samples were collected every 2 h. An intestinal telemetric sensor was used to measure core temperature. The presence of diurnal rhythms was examined for melatonin, temperature and cortisol. Correlation analysis was performed between Cockcroft-Gault GFR (GFR), melatonin, cortisol and temperature parameters., Results: The mean GFR was 57 +/- 30 ml/min. The subjects exhibited melatonin (n = 24) and cortisol (n = 22) rhythms. GFR was significantly correlated to melatonin amplitude (r = 0.59, P = 0.003) and total melatonin production (r = 0.51, P = 0.01), but not to temperature or cortisol rhythms. Interestingly, no associations were found between the rhythms of temperature, melatonin and cortisol., Conclusions: As melatonin amplitude and melatonin rhythm decreased with advancing renal dysfunction, follow-up research into circadian rhythms in patients with CKD is warranted.

Background and Objectives: Removal of beta2-microglobulin (beta2M) can be increased by adding convective transport to hemodialysis (HD). The aim of this study was to investigate the change in beta2M levels after 6-mo treatment with hemodiafiltration (HDF) and to evaluate the role of residual kidney function (RKF) and the amount of convective volume with this change., Design, Setting, Participants, & Measurements: Predialysis serum beta2M levels were evaluated in 230 patients with and 176 patients without RKF from the CONvective TRAnsport STudy (CONTRAST) at baseline and 6 mo after randomization for online HDF or low-flux HD. In HDF patients, potential determinants of change in beta2M were analyzed using multivariable linear regression models., Results: Mean serum beta2M levels decreased from 29.5 +/- 0.8 (+/-SEM) at baseline to 24.3 +/- 0.6 mg/L after 6 mo in HDF patients and increased from 31.9 +/- 0.9 to 34.4 +/- 1.0 mg/L in HD patients, with the difference of change between treatment groups being statistically significant (regression coefficient -7.7 mg/L, 95% confidence interval -9.5 to -5.6, P < 0.001). This difference was more pronounced in patients without RKF as compared with patients with RKF. In HDF patients, beta2M levels remained unchanged in patients with GFR >4.2 ml/min/1.73 m2. The beta2M decrease was not related to convective volume., Conclusions: This study demonstrated effective lowering of beta2M levels by HDF, especially in patients without RKF. The role of the amount of convective volume on beta2M decrease appears limited, possibly because of resistance to beta2M transfer between body compartments.

Background: Daily peritoneal exposure to peritoneal dialysis fluid (PDF) induces severe morphological alterations including fibrosis and angiogenesis that lead to a loss of peritoneal ultrafiltration (UF) capacity. Since cyclooxygenase (COX)-2 is involved in fibrosis and angiogenesis, we investigated the in vivo effects of a selective COX-2 inhibitor (celecoxib) in a rat-PD model., Methods: Sixteen rats daily received 10 ml of conventional PDF for 4-5 weeks intraperitoneally. Half of them (n = 8) daily received celecoxib (20 mg/kg BW) via oral gavage, and the other half (n = 8) received vehicle via oral gavage. The study also included two control groups (no PDF instillations), each consisting of n = 8 animals that daily received celecoxib or vehicle, respectively, via oral gavage. Functional, morphological and cellular parameters were analysed., Results: PDF exposure induced an inflammatory condition evidenced by the increased leucocyte number and synthesis of MCP-1, VEGF and hyaluronic acid. After PDF exposure, the omentum showed intense angiogenesis and milky spots formation. Parietal peritoneum showed increased angiogenesis, lymphangiogenesis, submesothelial matrix thickness and enhanced expression of mesothelial aquaporin1 (Aqp1). Concomitant PDF and celecoxib exposure drastically reduced PGE2 levels, angiogenesis, lymphangiogenesis, fibrosis and milky spot formation in studied tissues, but did not modify mesothelial Aqp1 expression nor the tissue expression of VEGF and inflammatory markers. PDF exposure induced severe UF failure that celecoxib treatment completely prevented., Conclusions: Altogether, celecoxib treatment improves UF capacity and reduces morphological alterations in our rat PD model.

Background: Cardiovascular disease (CVD) is the leading cause of death in patients with end-stage renal disease (ESRD). Platelet (PLT) dysfunction, which is a well-known phenomenon in advanced chronic renal failure, corresponds positively with CVD in these patients. The accumulation of retained uraemic toxins might play an important role in this respect. During haemodialysis (HD), both an increase in the expression of the platelet (PLT) cell surface molecule P-selectin (CD62p) and the release of intra-granular substances, such as platelet factor 4 (PF4) and ss-thromboglobulin (BTG), have been described. As the removal of uraemic toxins is superior during haemodiafiltration (HDF), this form of treatment may have quite another impact on PLTs than HD., Methods: Nineteen chronic HD patients who were treated with low-flux HD for at least 2 months were included in the Dutch CONvective TRAnsport STudy (CONTRAST). After randomization, 10 patients continued low-flux HD and 9 patients switched to post-dilution HDF. The present study describes various parameters of PLT activation and degranulation at baseline (during HD) and after 3 months (during HDF) in the latter group of patients. At both time points, multiple blood samples were drawn. During the first 30 min of treatment, differences over the extracorporeal circuit (ECC) were calculated by taking samples from both afferent (arterial) and efferent (venous) lines. Correlations between various parameters were calculated in the total group of patients after 3 months., Results: Immediately after the start of HD, PLT counts dropped over the ECC. During HDF, PLT counts decreased even more and reached a nadir at t30. CD62p expression increased early during HD and returned to baseline thereafter. During HDF, these changes were more pronounced and more protracted. With respect to degranulation, rather dissimilar results were obtained. During HD, both PF4 and BTG increased over time, whereas during HDF, PF4 increased but BTG did not change. Haemoconcentration and transmembrane pressure (TMP) within the dialyser were, respectively, approximately 10 and 3x higher during HDF than during HD. There was a striking correlation between the changes in haemoconcentration and the changes in both PLT counts and CD62p over the ECC., Summary and Conclusions: PLT activation, as measured by the expression of CD62p, was more pronounced and more protracted during HDF than during HD. During HDF, PLTs were trapped abundantly within the ECC, not only after first passage, but also thereafter. The degranulation product BTG increased during HD, but did not change during HDF. These observations may well be explained by the greater haemoconcentration and/or higher TMP during HDF on the one hand, and superior convective transport at the other. Whether the potential harmful effects of enhanced PLT activation are counterbalanced by the beneficial effects of an increased convective transport of degranulation products remains to be established.

Background: Large convective volumes are recommended for online haemodiafiltration (HDF) to maximize solute removal. There has been little systematic evaluation of factors that determine convective volumes in routine clinical practice., Methods: In the present study, potential patient- and treatment-related determinants of convective volume were analysed in 235 consecutive patients on post-dilution HDF using multivariable linear regression models. All patients (age 64 +/- 14 years; 61% male) participated in the ongoing CONvective TRAnsport STudy (CONTRAST). Additionally, differences in convective volumes between dialysers were evaluated., Results: The mean convective volume was 19.4 +/- 4.0 L (+/-SD) per treatment, with a large variation between the participating centres (centre means ranging from 13.4 +/- 0.9 L to 24.5 +/- 0.12 L, +/- SE). The mean filtration fraction of the blood flow was 25.9 +/- 3.6. In the multivariable analysis, factors that were significantly related to convective volume were haematocrit [inversely, regression coefficient (B) = -1.4 +/- 0.4 L per 10%], serum albumin (positively, B = 1.0 +/- 0.4 L per 10 g/L), blood flow rate (positively, B = 0.4 +/- 0.04 L per 10 mL/min) and treatment time (positively, B = 5.1 +/- 0.4 L/h). In addition, significant differences between dialysers were observed, likely explained by different operational conditions., Conclusions: Apart from increasing the treatment time and blood flow rate, convective volumes could be optimized by increasing the filtration fraction in each individual, provided that transmembrane pressures are well within safe limits. The precise role of dialyser characteristics on maximal achievable convective volumes in clinical practice is a topic for further research.

The combination of working in dialysis as well as in general medicine/nephrology after a good training program-along with ongoing interest in clinical research-makes it sufficiently appealing for many trainees to pursue a career in nephrology in the Netherlands.

During online hemodiafiltration, patients are directly infused with sterile substitution solutions to maintain fluid balance. Adequate water treatment and a well-organized quality control process are essential to provide non-pyrogenic fluids with consistent optimal quality. We sought to assess water quality, the water treatment system, and the methods for surveillance of microbiological water quality in 10 Dutch dialysis centers that routinely treat patients with hemodiafiltration. Microbiological monitoring results (micro-organisms and endotoxins) were collected over a 1-year period representing 11,258 hemodiafiltration sessions covering 97 patients. In all centers, water purification was based on a reverse osmosis module in combination with a second reverse osmosis and/or an electrodeionizer. All centers regularly and routinely monitored the microbiological purity of the dialysis water with adequate analytical methods but with variable monitoring frequency. Microbiological assessments were compliant with reference quality levels in 3923 of 3961 samples. Our study suggests that non-pyrogenic substitution fluids can be produced online for a prolonged period of time. It is likely that the current Dutch Quality of Care Guideline has contributed to high-quality water treatment and a well-organized control process.

Although immediate pain sensation at the injection site is reported by patients, only limited data on comparison of pain at the injection site between erythropoiesis stimulating agents are available. Therefore, we compared the effect of subcutaneous epoietin-beta on immediate pain sensation to that of subcutaneous darbepoietin-alpha in a double blind, randomized controlled study. Adult patients, aged 18 - 75 years, treated with peritoneal dialysis or with stage 4 chronic kidney disease who in our unit are treated with subcutaneous darbepoietin-alpha for renal anemia for at least 3 months, were eligible for the study. After informed consent, patients received on one day four subcutaneous injections, two in each upper leg, in a fixed sequence, blinded to the patient and blinded to the investigator. Injections contained in a random order single dose epoietin-beta (0,3 ml = 4000 IU), darbepoietin-alpha (0,5 ml = 20 microg) and volume matched saline 0.9% placebo injections. Immediately after the four injections, whilst remaining sitting, the subject was requested to fill out one pain scale (Visual Analogue Scale (VAS)) and to verbally evaluate the pain experience (Verbal Pain Score (VPS)). Finally, the subject was requested to rank the four injections from least to most painful (Treatment Ranking). A total of 42 patients (22 male) participated in the study with a mean age of 56.8 +/- 1.9 years. The average VAS was lower for epoietin-beta (26.8 +/- 4.5 mm) compared to darbepoietin-alpha (58.1 +/- 4.6 mm; p < 0.01). Mean VAS for epoietin-beta did not differ from that of the two placebo saline solutions (0,3 ml 26.3 +/- 4.4 mm; 0,5 ml 18.4 +/- 3.2 mm). Mean VAS for darbepoietin-alpha was significantly higher than placebo (both p < 0.01). Similar observations were obtained for VPS (mean for epoietin-beta 1,3 +/- 0.2 and for darbepoietin-alpha 2.9 +/- 0.2; p < 0.01) and Treatment Ranking (mean for epoietin-beta 2.0 +/- 0.2 and for darbepoietin-alpha 3.2 +/- 0.2; p < 0.01). From the results it can be concluded that subcutaneous epoietin-beta caused statistically significant less pain sensation immediately after injection compared to subcutaneous darbepoietin-alpha . The pain caused by subcutaneous epoietin-beta injection was similar to that caused by placebo control injections whereas subcutaneous darbepoietin-alpha injection was significantly more painful than subcutaneous placebo injections.

Background: Fibroblast growth factor 23 (FGF-23) is a recently discovered hormone, which plays a key role in phosphate regulation. To investigate whether FGF-23 can be determined reliably, we validated the three available FGF-23 assays., Methods: Currently, two intact FGF-23 assays (Kainos; Immutopics) and one C-terminal FGF-23 assay (Immutopics) are available. We determined intra- and inter-assay variation, linearity and matrix interference in these assays. Moreover, we compared assay results from healthy subjects with those of patient groups with expected high FGF-23 concentrations., Results: Intra-assay variation was reasonably good in all three assays. Inter-assay variation and linearity were poor for the intact Immutopics assay but reasonable for both other assays. Immutopics assays gave best results in ethylenediaminetetraacetic acid (EDTA) plasma, while the Kainos assay showed comparable reproducibility in EDTA plasma and serum. Although the manual of the Kainos assay states that an automatic washing machine can be used, acceptable results were only found by manual washing. Patients with kidney disease and patients with hypophosphatemic osteomalacia had increased C-terminal FGF-23 concentrations compared with healthy controls., Conclusion: Two assays of reasonable quality are available for FGF-23, the intact FGF-23 assay (Kainos) provided proper attention is paid to the washing procedure, and the C-terminal assay (Immutopics).

Background: Chronic kidney disease (CKD) is associated with an increased incidence of cardiovascular disease (CVD). A few studies have demonstrated elevated plasma adiponectin and leptin levels in CKD. The aims of this study were to assess whether 1) estimated glomerular filtration rate (eGFR) is associated with plasma leptin and adiponectin; and 2) adiponectin and leptin (partly) explain associations of CKD with endothelial dysfunction, insulin resistance, and low-grade inflammation in patients with K/DOQI Stage 3 - 5 CKD., Methods: Baseline data from 91 patients with Stage 3 - 4 CKD in the anti-oxidant therapy in chronic renal insufficiency study, a randomized, double-blind, placebo-controlled trial, in which the effects of oxidative stress-lowering treatment on vascular function and structure were studied, and from 50 dialysis naïve patients, who took part in an open-label, randomized study that compared two peritoneal dialysis regimens, used in the analysis. All subjects for both the studies were recruited in the same centres., Results: The association between eGFR and adiponectin was non-linear. In multivariate analysis, log-eGFR (unstandardized beta = 8.303 microg/ml, p < 0.0001) was the strongest determinant of adiponectin, and body mass index the strongest determinant of leptin (beta = 2.477 ng/ml, p < 0.0001). Plasma adiponectin and leptin did not modify the associations between eGFR and plasma von Willebrand factor or soluble vascular adhesion molecule-1. Plasma leptin had the strongest association with the homeostatic model assessment (HOMA-IR) index. Plasma C-reactive protein had no association with adiponectin or leptin., Conclusions: In patients with K/DOQI Stage 3 - 5 CKD, renal function had a significant non-linear inverse association with and was the strongest predictor of adiponectin. BMI was the strongest predictor of plasma leptin. Plasma adiponectin and leptin did not explain, and thus presumably are not involved in, the association between eGFR and some markers of endothelial dysfunction.

End-stage renal disease (ESRD) is an increasing health problem worldwide. Given the increasing prevalence of this disease, the high cost of hemodialysis treatment and the burden of hemodialysis on a patient's life, more research on improving the clinical outcomes and the quality of life of hemodialysis-treated patients is warranted. Sleep disturbances are much more prevalent in the dialysis population than in the general population. Several studies investigating the effect and importance of sleep problems on quality of life in dialysis patients revealed that sleep disturbances have a major influence on the vitality and general health of these patients. Sleep disturbances in this patient group are caused both by the pathology of the renal disease and by the dialysis treatment itself. This Review focuses on circadian sleep-wake rhythm disturbances in individuals with ESRD. The possible external and internal influences on sleep-wake rhythmicity in patients with ESRD, such as the effect of dialysis, medications, melatonin and biochemical parameters, are presented. In addition, possible approaches for strengthening the synchronization of the circadian sleep-wake rhythm, such as nocturnal hemodialysis, exogenous melatonin, dialyzate temperature, exogenous erythropoietin, use of bright light and exercise during dialysis treatment, are explored. Further research in this area is warranted, and a greater awareness of sleep problems is needed to improve the quality of life of patients with ESRD.

Background: Peritoneal dialysis (PD) is associated with functional and structural alterations of the peritoneal membrane, particularly new vessel formation and fibrosis. In addition to anticoagulant effects, heparin displays anti-inflammatory and angiostatic properties. Therefore, the effects of administration of heparins on function and morphology of the peritoneal membrane were studied in a rat PD model., Methods: Rats received 10 mL conventional PD fluid (PDF) daily, with or without the addition of unfractionated heparin (UFH) or low molecular weight heparin (LMWH) in the PDF (1 mg/10 mL intraperitoneally) via a mini access port. Untreated rats served as controls. After 5 weeks, a 90-minute functional peritoneal transport test was performed and tissues and peritoneal leukocytes were taken., Results: PD treatment induced loss of ultrafiltration (p<0.01), a twofold increase in glucose absorption (p<0.03), increased urea transport (p<0.02), and loss of sodium sieving (p<0.03), which were also found in the PDF+heparin groups. Increased peritoneal cell influx and hyaluronan production (p<0.02) as well as an exchange of mast cells and eosinophils for neutrophils after PD treatment were observed in PD rats; addition of heparin did not affect those changes. Mesothelial regeneration, submesothelial blood vessel and matrix formation, and accumulation of tissue macrophages were seen in PD animals. Spindle-shaped vimentin-positive and cytokeratin-negative cells indicated either partial injury and denudation of mesothelial cells or epithelial-to-mesenchymal transition. Neither UFH nor LMWH affected any of these morphological changes., Conclusion: Within 5 weeks, PD treatment induces a chronic inflammatory condition in the peritoneum, evidenced by high transport, leukocyte recruitment, tissue remodeling, and induction of spindle-shaped cells in the mesothelium. Addition of LMWH or UFH to the PDF did not prevent these adverse PDF-induced peritoneal changes.

Aim: The aim of this study was to investigate the effects of exogenous melatonin on sleep-wake rhythm in haemodialysis patients., Methods: The study design is a randomized, double-blind, placebo-controlled, cross-over study of 3 x 6 weeks melatonin 3 mg at 22.00 h every night. Haemodialysis patients were asked to fill out a sleep questionnaire and to wear an actometer to record their sleep problems objectively. Furthermore, melatonin concentrations in saliva were sampled the night after daytime haemodialysis and the consecutive night. Actometers, the sleep questionnaire and melatonin concentrations were repeated during the study., Results: In total, 20 patients (six female, median age 71 years) completed the investigation. On nights after daytime dialysis, objective sleep onset latency decreased significantly from a median of 44.5 (placebo) to a median of 15.5 min with melatonin (P < 0.01). Sleep efficiency increased from 67.3 to 73.1% with melatonin (P < 0.05). Actual sleep time increased from 376 min (placebo) to 388 min with melatonin (P < 0.01), and sleep fragmentation decreased from 4.5 to 3.1 (P < 0.01). Furthermore, subjective sleep parameters improved also. Patients reported less time needed to fall asleep (P < 0.05) and fewer wake periods (P < 0.05) on the nights with and without daytime dialysis and an increase in sleep time on the night of daytime dialysis (P < 0.05). Furthermore, the nocturnal melatonin rise was recovered., Conclusion: Treatment with melatonin resulted in an improvement of subjective and objective sleep parameters, as well as a recovered nocturnal melatonin rhythm.

Background: Sleep disturbances have a major influence on quality of life. A commonly used measure of sleep disturbances is sleep efficiency. The purpose of this study was to investigate the prevalence of decreased subjective sleep efficiency in hemodialysis patients. An additional goal was to identify clinical, dialysis or laboratory parameters that are independently associated with decreased sleep efficiency., Methods: Adult stable hemodialysis patients (n = 112) filled out a sleep questionnaire during a three day investigation period. In addition, healthy control subjects (n = 44) filled out the same questionnaire. From this questionnaire sleep efficiency (ratio of total sleep time to time spent in bed) was derived as a measure for sleep disturbances in this population. Laboratory, demographic and dialysis data were collected during the investigation period. For statistical analysis linear regression models were used., Results: Median subjective sleep efficiency in hemodialysis patients was 80%, which was significantly less compared to the median subjective sleep efficiency of control subjects of 88% (p pound 0.05). Approximately 40% of the patients used sleep medication. However, less than 20% of them indicated improved sleep behavior when using these drugs. Elevated levels of phosphate and urea correlated independently with impaired sleep efficiency. Hemoglobin levels between 10 and 12 g/dl were associated with better sleep efficiency., Conclusion: In conclusion, decreased sleep efficiency was frequently reported in hemodialysis patients and can be associated with biochemical parameters. Hemoglobin, phosphate and urea levels can affect subjective sleep efficiency.

The most important challenge in peritoneal dialysis (PD) is long-term preservation of peritoneal membrane structure and function. Introduction of dialysis fluids into the peritoneal cavity induces changes. These changes are related to duration of dialysis, occurrence of peritonitis and components of the dialysis solution. Bioincompatibility is considered to be the major cause of the development of morphological changes of the peritoneal membrane. pH neutral PD fluids that are low in glucose degradation products (GDP) seem to better preserve the peritoneal membrane and have less systemic effects than the conventional ones. However, the long-term effects are not clear. An overview of the effects of conventional PD fluids and glucose-based PD fluids with neutral pH in ex vivo and in vivo animal and clinical studies is presented.

Renal functional reserve could be relevant for the maintenance of renal function after kidney donation. Low-dose dopamine induces renal vasodilation with a rise in glomerular filtration rate (GFR) in healthy subjects and is thought to be a reflection of reserve capacity (RC). Older age and higher body mass index (BMI) may be associated with reduced RC. We therefore investigated RC in 178 consecutive living kidney donors (39% males, age 48 +/- 11 years, BMI 25.5 +/- 4.1). RC was determined as the rise in GFR ((125)I-iothalamate), 4 months before and 2 months after donor nephrectomy. Before donor nephrectomy, GFR was 114 +/- 20 mL/min, with a reduction to 72 +/- 12 mL/min after donor nephrectomy. The dopamine-induced rise in GFR of 11 +/- 10% was reduced to 5 +/- 7% after donor nephrectomy (p < 0.001). Before donor nephrectomy, older age and higher BMI did not affect reserve capacity. After donor nephrectomy, the response of GFR to dopamine independently and negatively correlated with older age and higher BMI. Moreover, postdonation reserve capacity was absent in obese donors. The presence of overweight had more impact on loss of RC in younger donors. In conclusion, donor nephrectomy unmasked an age- and overweight-induced loss of reserve capacity. Younger donors with obesity should be carefully monitored.

The high incidence of cardiovascular disease in patients with moderate renal impairment is not fully explained by traditional atherothrombotic risk factors. Independently from these factors, blood platelet activation may increase the cardiovascular disease risk of patients with mild-to-moderate renal impairment. Blood platelet activation has not been studied in nondiabetic patients with mild-to-moderate renal impairment. Therefore, we measured the extent of platelet activation by means of fluorescence cytometry in 93 nondiabetic patients with MDRD-estimated creatinine clearance ranging from 13 - 63 ml/min/1.73 m2. As platelet activation parameters we used the expression of CD62P (P-selectin), CD 63 (glycoprotein 53), PAC-1 (activated fibrinogen receptor), CD42b (von Willebrand factor receptor) and CD41 (fibrinogen receptor) on the platelet surface membrane. The expression of CD62p, CD63 and PAC-1 was statistically significantly inversely related to the estimated glomerular filtration rate in these patients (standardized b -0.28, -0.32 and -0.39, respectively). We conclude that nondiabetic mild-to-moderate renal impairment is associated with blood platelet activation. Whether this contributes to the increased cardiovascular risk in these patients needs further study.

Aim and Methods: Obesity in humans is associated with proteinuria and an increased glomerular filtration, possibly related to an increase in glomerular capillary pressure. We investigated in obese and lean Zucker rats (10-12 weeks old) whether this might be related to alterations in the diameter of preglomerular and postglomerular microvessels and their reactivity to the resistance regulator angiotensin II (AngII), using the hydronephrotic kidney model., Results: The obese rats exhibited a hyperinsulinaemic, euglycaemic state and hypertension. Urinary protein concentration and fluid intake were both increased threefold. Basal diameters of distal interlobular arteries (ILAs) and afferent arterioles (AAs) were larger in the obese rat than in the lean rat (ILA: 25.7 +/- 0.3 vs. 23.0 +/- 0.4 microm and AA: 18.8 +/- 0.3 vs. 16.7 +/- 0.5 microm, respectively; p

Background: Patients with chronic kidney disease (CKD) have an increased risk of cardiovascular disease (CVD). Preliminary evidence suggests a role for global DNA hypomethylation in the pathogenesis of atherosclerotic complications in CKD. The aims of this study in patients with stage 2-4 CKD were (1) to assess the association between renal function and DNA methylation, (2) to assess the association between DNA methylation and two markers of atherosclerosis [common carotid intima-media thickness (CCA-IMT)] and brachial artery endothelium-dependent, flow-mediated dilatation (BA-FMD) and (3) to examine the effect of a multi-step treatment strategy on DNA methylation., Methods: In the Anti-Oxidant Therapy In Chronic Renal Insufficiency study (ATIC-study), 93 patients with stage 2-4 CKD were included. In a randomized, double-blind, placebo-controlled design, the treatment group received pravastatin to which vitamin E was added after 6 months and homocysteine-lowering B-vitamin therapy after another 6 months. DNA methylation was assessed using tandem mass spectrometry. CCA-IMT and BA-FMD were assessed using B-mode ultrasonography., Results: At baseline, global DNA methylation was not associated with the estimated glomerular filtration rate (P = 0.32) or with CCA-IMT (P = 0.62) or BA-FMD (P = 0.51). No effect of the treatment strategy including B-vitamin on global DNA methylation was found either in the total study group or within separate strata of homocysteine concentration and renal function., Conclusion: In patients with stage 2-4 CKD, global DNA methylation is not associated with renal function or with CCA-IMT or BA-FMD. A treatment strategy that includes B-vitamins did not alter global DNA methylation in these patients. These data do not support the role of DNA hypomethylation in CKD-associated vascular disease in patients with stage 2-4 CKD.

Background: Untunnelled straight jugular catheters (USC) are uncomfortable for patients and cannot be well fixated. This could be a reason for the high incidence of catheter-related complications., Methods: We prospectively analysed the outcome of a novel designed untunnelled precurved catheter (UPC) with better fixation properties and compared it with the outcome of USC. The outcome was also related to data on tunnelled cuffed catheters (TCC)., Results: The outcome of USC was documented over a 32-month period. Thereafter, we switched to an UPC. The same catheter care protocol was used and not changed over time. A total of 104 USC and 65 UPC were inserted. Compared to USC, less UPC had to be removed for a complication (53 versus 15%; P < 0.001) and less periods of catheter-related bacteraemia were observed in UPC compared to USC [0 versus 5.6 per 1000 catheter days (cd); P < 0.01]. Removal for flow problems was similar. Compared to 64 TCC, inserted in the same period, UPC had more flow problems. Other outcomes and complication rates were similar. Complication rates for TCC inserted before and after the switch from USC to UPC were similar., Conclusions: UPC have better patency rates and a lower risk for bacteraemia and exit-site infection compared to USC.

Heparan sulfate proteoglycans (HSPGs) are well known for their proposed role in glomerular filtration. In addition, HSPGs can bind the leukocyte adhesion molecule l-selectin and chemokines, suggesting a role in inflammation. We examined a panel of biopsies representing different human primary kidney diseases for l-selectin and monocyte chemoattractant protein-1 (MCP-1) binding. In various renal diseases, l-selectin and MCP-1 binding to interstitial perivascular matrix HSPGs is increased, which is significantly associated with leukocyte influx. In proteinuric diseases, including membranous glomerulopathy, minimal change disease, but also IgA nephropathy and lupus nephritis, increased binding of l-selectin and MCP-1 to tubular epithelial cell (TEC) HSPGs is observed, which colocalizes with increased basolateral syndecan-1 and anti-heparan sulfate 10E4 staining. Short-hairpin RNA-mediated silencing demonstrates that syndecan-1 on TECs indeed mediates l-Selectin binding. Increased TEC expression of IL-8 in biopsies of proteinuric patients suggests that the increase in luminal protein may activate TECs to increase expression of l-selectin and MCP-1 binding syndecan-1. Strikingly, urinary syndecan-1 from proteinuric patients is less capable of binding l-selectin compared with urinary syndecan-1 from healthy controls, although syndecan-1 concentrations are similar in both groups. Together, our data show pronounced tubulointerstitial HSPG alterations in primary kidney disease, which may affect the inflammatory response.

Over the past decade new solutions for peritoneal dialysis have been developed in an effort to reduce the bioincompatibility of conventional glucose-containing, lactate-buffered solutions, and thereby to improve the clinical outcomes of peritoneal dialysis. The new solutions contain either other non-glucose osmotic agents, such as glucose polymers or amino acids, or have a neutral pH; the buffer content is altered in some of the new solutions. In vitro and in vivo studies have shown the biocompatibility of these new solutions to be superior to that of standard solutions. In this paper, available clinical data on the use of these new solutions are reviewed. In general, the data indicate improved biocompatibility of the new solutions; a number of studies, however, detected no superiority when levels of accepted markers of biocompatibility, such as vascular endothelial growth factor or hyaluronic acid, were measured. This finding could be explained by the assumption that the new peritoneal dialysis solutions not only induce less damage to the peritoneal membrane but also better maintain repair mechanisms, which apparently are associated with enhanced release of such markers.

Evidence indicates that prostaglandin E(2) (PGE(2)) preferentially affects preglomerular renal vessels. However, whether this is limited to small-caliber arterioles or whether larger vessels farther upstream also respond to PGE(2) is currently unclear. In the present study, we first investigated the effects of PGE(2) along the preglomerular vascular tree and subsequently focused on proximal interlobular arteries (ILAs). Proximal ILAs in hydronephrotic rat kidneys as well as isolated vessels from normal kidneys constricted in response to PGE(2), both under basal conditions and after the induction of vascular tone. By contrast, smaller vessels, i.e., distal ILAs and afferent arterioles, exhibited PGE(2)-induced vasodilation. Endothelium removal and pretreatment of single, isolated proximal ILAs with an EP1 receptor blocker (SC51322, 1 micromol/l) or a thromboxane A(2) receptor blocker (SQ29548, 1 micromol/l) did not prevent vasoconstriction to PGE(2). Furthermore, in the presence of SC51322, responses of these vessels to PGE(2) and the EP1/EP3 agonist sulprostone were superimposable, indicating that PGE(2)-induced vasoconstriction is mediated by EP3 receptors on smooth muscle cells. Immunohistochemical staining of proximal ILAs confirmed the presence of EP3 receptor protein on these cells and the endothelium. Adding PGE(2) to normal isolated kidneys induced a biphasic flow response, i.e., an initial flow increase at PGE(2) concentrations

Objectives: To compare oral health, salivary flow rate, xerostomia and thirst in end stage renal disease (ESRD) patients remaining on dialysis treatment and after renal transplantation., Design: Longitudinal observation., Setting: ESRD patients recruited from dialysis centres in Amsterdam, The Hague and Utrecht, The Netherlands., Method: At baseline and after two years, salivary flow rates, xerostomia and thirst were determined in 43 ESRD patients. The number of decayed missing filled teeth/surfaces (DMFT/DMFS) was recorded, and periodontal status assessed., Results: After renal transplantation (n = 20), the salivary flow rate increased significantly from UWS = 0.30 +/- 0.21 ml/min to 0.44 +/- 0.29 ml/min (p <0.001) and the level of xerostomia and thirst decreased. After two years, the percentage of bleeding on probing in dialysis patients (n = 23) decreased from 29.5 +/- 25.4% to 10.3 +/- 12.3%, (p <0.05). No differences in DMFT and DMFS were observed between dialysis and renal transplant patients., Conclusions: DMFT, dental plaque, gingival bleeding and periodontal indices did not change remarkably after two years, comparing dialysis and renal transplant patients. Renal transplantation enhances salivary flow and decreases symptoms of xerostomia and thirst, and hence enhances the potential to improve the quality of life of affected individuals.

Initiation of peritoneal dialysis (PD) induces several changes both locally in the peritoneum and systemically. We performed a pilot study to generate insights into the early clinical and systemic changes after catheter insertion and the first weeks of PD. The study included 11 new PD patients (7 men, 4 women). The study period started just before implantation of the Tenckhoff catheter and finished 6 weeks after the start of PD. All patients were treated with lactate-buffered dialysis solutions. Clinical parameters, routine laboratory tests and markers of systemic inflammation were determined. The mean (+/- standard deviation) age of the patients was 52.6 +/- 12.1 years, mean weight was 81.3 +/- 14.7 kg, and mean blood pressure was 143.3/ 87.8 +/- 18.5/8.2 mmHg. Weight and blood pressure did not change significantly during the first weeks of PD. Throughout the study, 24-hour urine production declined by 6.9 mL/day (p = 0.006). Daily residual creatinine clearance (CCr) decreased by 0.036 mL/min (p = 0.008). High-sensitivity C-reactive protein (hs-CRP) was significantly higher in patients who had undergone hemodialysis before the start of the study (p < 0. 0001) and declined during the study in that group (p = 0.001). No significant change in hs-CRP was found in the group that started dialysis with PD. In this pilot study, we found no significant changes in the clinical parameters of weight and blood pressure during the first weeks of PD. However, urine production and residual CCr declined significantly during the study period, starting from the moment of catheter insertion. Levels of the systemic inflammatory marker hs-CRP were higher in patients who had previously undergone hemodialysis; its level in those patients decreased after hemodialysis ended.

Background/aims: Continuous venovenous hemofiltration (CVVH) requires anticoagulation to prevent circuit clotting and its use is contraindicated in patients with high bleeding risk. The aim of this study was to compare CVVH with and without regional citrate anticoagulation (RCA) with respect to filter life, azotemic control and cost., Methods: This was a prospective sequential cohort study. The first cohort of patients with a high bleeding risk and acute renal failure was treated by anticoagulant-free predilution CVVH (n = 31). In the second cohort, CVVH was applied with RCA (n = 20)., Results: The median filter life was 41 h (interquartile range 20-62) with RCA and 12 h (8-28) without RCA (p = 0.001). The azotemic control was better in the group with RCA. The hourly cost was comparable between the two groups., Conclusion: Regional anticoagulation with citrate-based replacement solution improved filter life compared to anticoagulant-free predilution CVVH. This regimen appeared safe, feasible and without metabolic complications or increased costs., (Copyright 2007 S. Karger AG, Basel.)

Aims: To evaluate acute effects of hemodialysis (HD) on the salivary flow rate, pH and biochemical composition before, during and after completion of a dialysis session., Material and Methods: Unstimulated whole saliva (UWS) and chewing-stimulated whole saliva (CH-SWS) were collected in 94 HD patients. Salivary flow rate, pH, concentrations of total protein, albumin, cystatin C, secretory immunoglobulin A (S-IgA) and of sodium, potassium and urea were measured., Results: HD had an acute stimulating effect on the salivary flow rate (UWSbefore = 0.30+/-0.22 ml/min, UWSduring = 0.39+/-0.25 ml/min, p < 0.005). The mean pH of UWS showed a small but significant increase during HD mainly due to an increased watery secretion from the salivary glands. The salivary biochemical constituents changed markedly, but no significant difference in output was found. The electrolyte concentration did not change significantly during dialysis. The level of urea in CH-SWS declined to 40% (Ureabefore = 25.+/-6.4 mmol/l, Ureaduring = 15.3+/-4.5 mmol/1)., Conclusions: This study shows that HD has significant acute effects on both salivary secretion rate and protein concentrations in saliva. We conclude that the observed changes in salivary concentrations and proteins are mainly due to an increased watery secretion from the salivary glands.

Because of its dynamic structure, the omentum plays a key role in the immunity of the peritoneal cavity by orchestrating peritoneal cell recruitment. Because mast cells accumulate in the omentum upon experimental peritoneal dialysis (PD) and may produce angiogenic/profibrotic factors, it was hypothesized that mast cells mediate omental tissue remodeling during PD. Daily treatment with conventional PD fluid (PDF) for 5 wk resulted in a strong omental remodeling response, characterized by an approximately 10-fold increase in mast cell density (P < 0.01), an approximately 20-fold increase in vessel density (P < 0.02), an approximately 20-fold increase in the number of milky spots (P < 0.01), and a four-fold increase in submesothelial matrix thickness (P < 0.0003) in wild-type rats. In contrast, all PDF-induced omental changes were significantly reduced in mast cell-deficient Ws/Ws rats or in wild-type rats that were treated orally with a mast cell stabilizer cromoglycate. A time-course experiment showed mast cell accumulation immediately before the formation of blood vessels and milky spots. Functionally, PDF evoked a peritoneal cell influx, which was significantly reduced in Ws/Ws rats (P < 0.04) and in wild-type rats that were treated with cromoglycate (P < 0.03). Cromoglycate treatment also completely prevented PDF-induced omental adhesions to the catheter tip (P = 0.0002). Mesothelial damage, angiogenesis, and fibrosis of mesentery and parietal peritoneum as well as glucose absorption rate and ultrafiltration capacity proved to be mast cell independent. Data strongly support the hypothesis that mast cells mediate PDF-induced omental tissue remodeling and, subsequently, peritoneal cell influx and adhesion formation, providing therapeutic possibilities of modulating omental function.

Removal of uraemic toxins can be increased by online haemodiafiltration. At present, it is unclear whether online haemodia-filtration ultimately improves clinical outcomes in chronic haemodialysis patients. The Dutch 'Convective transport study' (CONTRAST) is an ongoing trial comparing standard haemodialysis with online haemodiafiltration. This randomised controlled trial will provide substantial clinical evidence on the effects of haemodiafiltration on fatal and non-fatal cardiovascular events and all-cause mortality, compared with standard haemodialysis.

Adequate performance measurement should be based on evidence-based guidelines. The recently published update of the International Society for Peritoneal Dialysis recommendations for peritoneal dialysis-related infections provides an opportunity to define a limited set of quality indicators as suitable for performance measurement and useful as targets for the improvement of dialysis care. Suitable quality indicators seem the incidence of peritonitis (target less than one episode every 18 months) and the percentage of culture-negative episodes (<20%). The lack of uniformity in definitions and the lack of studies providing evidence for firm recommendations are major limitations for further improvements in prevention, diagnosis and outcome of peritoneal dialysis-related infectious complications.