Short-term effects of sevelamer-carbonate on fibroblast growth factor 23 and pulse wave velocity in patients with normophosphataemic chronic kidney disease Stage 3.

BACKGROUND: High concentrations of both phosphate and fibroblast growth factor 23 (FGF23) observed in chronic kidney disease (CKD) are associated with an increased risk of cardiovascular morbidity and mortality. Pulse wave velocity (PWV) is a surrogate marker for cardiovascular events and all-cause mortality. It is not known whether a reduction of FGF23 or phosphate alters cardiovascular risk. Sevelamer has shown to have the ability to reduce both phosphate and FGF23 concentrations. Furthermore, reduction of PWV is reported with sevelamer use as well, but it is unclear if this is mediated by decline of phosphate or FGF23. We investigated if sevelamer induced a decline in PWV and if this was associated with a reduction in FGF23. METHODS: In all, 24 normophosphataemic CKD Stage 3 patients started treatment with a fixed dose of sevelamer-carbonate (Renvela®) 2.4 g twice daily, with their usual diet for 8 weeks in a single-arm study. PWV was measured and blood samples were obtained before, during and after washout of treatment with sevelamer. Vascular calcification was quantified using the Kauppila Index (KI). The primary outcome was the change of PWV from baseline to 8 weeks of treatment and the secondary endpoint was the difference of FGF23 following treatment with sevelamer. One of the linear mixed models was used to analyse the association between treatment and outcome. Mediation analysis was performed as a sensitivity analysis. The study was registered in the Dutch trial register (http://www.trialregister.nl: NTR2383). RESULTS: A total of 18 patients completed 8 weeks of treatment with sevelamer and were analysed. Overall, treatment with sevelamer did not induce a significant reduction of PWV (ß = -0.36, P = 0.12). However, in patients with less vascular calcification (lower KI score), there was a statistically significant reduction of PWV, adjusted for mean arterial pressure, after treatment (ß = 0.63, P = 0.02). Addition of FGF23 to the model did not alter this association. Mediation analysis yielded similar results. FGF23 did not decrease during treatment with sevelamer. CONCLUSION: In this short-term pilot study in normophosphataemic CKD patients, treatment with sevelamer did not improve PWV. In subgroup analysis, however, PWV improved in patients with no or limited abdominal aorta calcifications. This was not associated with a decline of FGF23.

Global prevalence of protein-energy wasting in kidney disease: A meta-analysis of contemporary observational studies from the international society of renal nutrition and metabolism

Objective: To better define the prevalence of protein-energy wasting (PEW) in kidney disease is poorly defined. Methods: We performed a meta-analysis of PEW prevalence from contemporary studies including more than 50 subjects with kidney disease, published during 2000-2014 and reporting on PEW prevalence by subjective global assessment or malnutrition-inflammation score. Data were reviewed throughout different strata: (1) acute kidney injury (AKI), (2) pediatric chronic kidney disease (CKD), (3) nondialyzed CKD 3-5, (4) maintenance dialysis, and (5) subjects undergoing kidney transplantation (Tx). Sample size, period of publication, reporting quality, methods, dialysis technique, country, geographical region, and gross national income were a priori considered factors influencing between-study variability. Results: Two studies including 189 AKI patients reported a PEW prevalence of 60% and 82%. Five studies including 1776 patients with CKD stages 3-5 reported PEW prevalence ranging from 11% to 54%. Finally, 90 studies from 34 countries including 16,434 patients on maintenance dialysis were identified. The 25th-75th percentiles range in PEW prevalence among dialysis studies was 28-54%. Large variation in PEW prevalence across studies remained even when accounting for moderators. Mixed-effects meta-regression identified geographical region as the only significant moderator explaining 23% of the observed data heterogeneity. Finally, two studies including 1067 Tx patients reported a PEW prevalence of 28% and 52%, and no studies recruiting pediatric CKD patients were identified. Conclusion: By providing evidence-based ranges of PEW prevalence, we conclude that PEW is a common phenomenon across the spectrum of AKI and CKD. This, together with the well-documented impact of PEW on patient outcomes, justifies the need for increased medical attention.

Global Prevalence of Protein-Energy Wasting in Kidney Disease: A Meta-analysis of Contemporary Observational Studies From the International Society of Renal Nutrition and Metabolism.

OBJECTIVE: To better define the prevalence of protein-energy wasting (PEW) in kidney disease is poorly defined. METHODS: We performed a meta-analysis of PEW prevalence from contemporary studies including more than 50 subjects with kidney disease, published during 2000-2014 and reporting on PEW prevalence by subjective global assessment or malnutrition-inflammation score. Data were reviewed throughout different strata: (1) acute kidney injury (AKI), (2) pediatric chronic kidney disease (CKD), (3) nondialyzed CKD 3-5, (4) maintenance dialysis, and (5) subjects undergoing kidney transplantation (Tx). Sample size, period of publication, reporting quality, methods, dialysis technique, country, geographical region, and gross national income were a priori considered factors influencing between-study variability. RESULTS: Two studies including 189 AKI patients reported a PEW prevalence of 60% and 82%. Five studies including 1776 patients with CKD stages 3-5 reported PEW prevalence ranging from 11% to 54%. Finally, 90 studies from 34 countries including 16,434 patients on maintenance dialysis were identified. The 25th-75th percentiles range in PEW prevalence among dialysis studies was 28-54%. Large variation in PEW prevalence across studies remained even when accounting for moderators. Mixed-effects meta-regression identified geographical region as the only significant moderator explaining 23% of the observed data heterogeneity. Finally, two studies including 1067 Tx patients reported a PEW prevalence of 28% and 52%, and no studies recruiting pediatric CKD patients were identified. CONCLUSION: By providing evidence-based ranges of PEW prevalence, we conclude that PEW is a common phenomenon across the spectrum of AKI and CKD. This, together with the well-documented impact of PEW on patient outcomes, justifies the need for increased medical attention.

Role of Albumin Assay on Calcium Levels and Prescription of Phosphate Binders in Chronic Hemodialysis Patients.

BACKGROUND/AIMS: In hemodialysis (HD) patients, the bromcresol green (BCG) assay overestimates, whereas the bromcresol purple (BCP) assay underestimates albumin concentration. Since corrected calcium concentrations depend on albumin, the albumin assay may have implications for the management of bone mineral disorders. METHODS: A subset of patients from CONTRAST, a cohort of prevalent HD patients, was analyzed. Bone mineral parameters and prescription of medication were compared between patients in whom albumin was assessed by BCP versus BCG. RESULTS: Albumin was assessed by BCP in 331 patients (9 of 25 centers) and by BCG in 175 patients (16 of 25 centers). Albumin was the lowest in the BCP group (34.5 ± 4.2 vs. 40.3 ± 3.1 g/L; p < 0.0005). Measured calcium levels and the prescription of calcium-based phosphate binders were similar in both groups. Corrected calcium levels, however, were markedly higher in the BCP group (2.45 ± 0.18 vs. 2.33 ± 0.18 mmol/L; p < 0.0005). CONCLUSION: These findings suggest that calcium levels are not corrected for albumin in clinical practice when considering the prescription of calcium-free or calcium-based phosphate-binders in dialysis patients.

FGF23 impairs peripheral microvascular function in renal failure.

Cardiovascular diseases account for ~50% of mortality in patients with chronic kidney disease (CKD). Fibroblast growth factor 23 (FGF23) is independently associated with endothelial dysfunction and cardiovascular mortality. We hypothesized that CKD impairs microvascular endothelial function and that this can be attributed to FGF23. Mice were subjected to partial nephrectomy (5/6Nx) or sham surgery. To evaluate the functional role of FGF23, non-CKD mice received FGF23 injections and CKD mice received FGF23-blocking antibodies after 5/6Nx surgery. To examine microvascular function, myocardial perfusion in vivo and vascular function of gracilis resistance arteries ex vivo were assessed in mice. 5/6Nx surgery blunted ex vivo vasodilator responses to acetylcholine, whereas responses to sodium nitroprusside or endothelin were normal. In vivo FGF23 injections in non-CKD mice mimicked this endothelial defect, and FGF23 antibodies in 5/6Nx mice prevented endothelial dysfunction. Stimulation of microvascular endothelial cells with FGF23 in vitro did not induce ERK phosphorylation. Increased plasma asymmetric dimethylarginine concentrations were increased by FGF23 and strongly correlated with endothelial dysfunction. Increased FGF23 concentration did not mimic impaired endothelial function in the myocardium of 5/6Nx mice. In conclusion, impaired peripheral endothelium-dependent vasodilatation in 5/6Nx mice is mediated by FGF23 and can be prevented by blocking FGF23. These data corroborate FGF23 as an important target to combat cardiovascular disease in CKD. NEW & NOTEWORTHY In the present study, we provide the first evidence that fibroblast growth factor 23 (FGF23) is a cause of peripheral endothelial dysfunction in a model of early chronic kidney disease (CKD) and that endothelial dysfunction in CKD can be prevented by blockade of FGF23. This pathological effect on endothelial cells was induced by long-term exposure of physiological levels of FGF23. Mechanistically, increased plasma asymmetric dimethylarginine concentrations were strongly associated with this endothelial dysfunction in CKD and were increased by FGF23.

Fluid balance-adjusted creatinine at initiation of continuous venovenous hemofiltration and mortality. A post-hoc analysis of a multicenter randomized controlled trial.

INTRODUCTION: Acute kidney injury (AKI) requiring renal replacement therapy (RRT) is associated with high mortality. The creatinine-based stage of AKI is considered when deciding to start or delay RRT. However, creatinine is not only determined by renal function (excretion), but also by dilution (fluid balance) and creatinine generation (muscle mass). The aim of this study was to explore whether fluid balance-adjusted creatinine at initiation of RRT is related to 28-day mortality independent of other markers of AKI, surrogates of muscle mass and severity of disease. METHODS: We performed a post-hoc analysis on data from the multicentre CASH trial comparing citrate to heparin anticoagulation during continuous venovenous hemofiltration (CVVH). To determine whether fluid balance-adjusted creatinine was associated with 28-day mortality, we performed a logistic regression analysis adjusting for confounders of creatinine generation (age, gender, body weight), other markers of AKI (creatinine, urine output) and severity of disease. RESULTS: Of the 139 patients, 32 patients were excluded. Of the 107 included patients, 36 died at 28 days (34%). Non-survivors were older, had higher APACHE II and inclusion SOFA scores, lower pH and bicarbonate, lower creatinine and fluid balance-adjusted creatinine at CVVH initiation. In multivariate analysis lower fluid balance-adjusted creatinine (OR 0.996, 95% CI 0.993-0.999, p = 0.019), but not unadjusted creatinine, remained associated with 28-day mortality together with bicarbonate (OR 0.869, 95% CI 0.769-0.982, P = 0.024), while the APACHE II score non-significantly contributed to the model. CONCLUSION: In this post-hoc analysis of a multicentre trial, low fluid balance-adjusted creatinine at CVVH initiation was associated with 28-day mortality, independent of other markers of AKI, organ failure, and surrogates of muscle mass, while unadjusted creatinine was not. More tools are needed for better understanding of the complex determinants of "AKI classification", "CVVH initiation" and their relation with mortality, fluid balance is only one.

High Fibroblast Growth Factor 23 concentrations in experimental renal failure impair calcium handling in cardiomyocytes.

The overwhelming majority of patients with chronic kidney disease (CKD) die prematurely before reaching end-stage renal disease, mainly due to cardiovascular causes, of which heart failure is the predominant clinical presentation. We hypothesized that CKD-induced increases of plasma FGF23 impair cardiac diastolic and systolic function. To test this, mice were subjected to 5/6 nephrectomy (5/6Nx) or were injected with FGF23 for seven consecutive days. Six weeks after surgery, plasma FGF23 was higher in 5/6Nx mice compared to sham mice (720 ± 31 vs. 256 ± 3 pg/mL, respectively, P = 0.034). In cardiomyocytes isolated from both 5/6Nx and FGF23 injected animals the rise of cytosolic calcium during systole was slowed (-13% and -19%, respectively) as was the decay of cytosolic calcium during diastole (-15% and -21%, respectively) compared to controls. Furthermore, both groups had similarly decreased peak cytosolic calcium content during systole. Despite lower cytosolic calcium contents in CKD or FGF23 pretreated animals, no changes were observed in contractile parameters of cardiomyocytes between the groups. Expression of calcium handling proteins and cardiac troponin I phosphorylation were similar between groups. Blood pressure, the heart weight:tibia length ratio, α-MHC/ß-MHC ratio and ANF mRNA expression, and systolic and diastolic function as measured by MRI did not differ between groups. In conclusion, the rapid, CKD-induced rise in plasma FGF23 and the similar decrease in cardiomyocyte calcium transients in modeled kidney disease and following 1-week treatment with FGF23 indicate that FGF23 partly mediates cardiomyocyte dysfunction in CKD.

Depressive and Anxiety Symptoms in Dutch Immigrant and Native Dialysis Patients.

Due to continuing migration there is more interest in the mental health status of immigrants. The aim of this study is to determine the prevalence of depressive/anxiety symptoms in immigrant and native dialysis patients, and to explore if patient characteristics can explain differences. The Beck depression inventory and the beck anxiety inventory were used. Differences between native and immigrant patients were explored using logistic regression models adjusted for patient characteristics. The prevalence of depressive symptoms was 35% for 245 native patients and 50% for 249 immigrant patients. The prevalence of anxiety symptoms was 35% for native patients and 50% for immigrant patients. In addition, the prevalence for co-morbid depressive and anxiety symptoms was 20% for native patients and 32% for immigrant patients. Crude ORs for depressive/anxiety symptoms for immigrant patients versus native patients were 1.8 (1.2-2.5) and 1.7 (1.2-2.5), respectively. After adjustment for patient characteristics ORs remained the same. Clinicians should be aware that immigrant dialysis patients are more prone to develop depressive and anxiety symptoms. Cultural factors might play a role and should therefore be assessed in future research.

Effects of Oral Paricalcitol and Calcitriol Treatment on Peritoneal Membrane Characteristics of Peritoneal Dialysis Patients - A Pilot Study.

BACKGROUND: Long-term peritoneal dialysis (PD) is frequently complicated by technique failure preceded by peritoneal remodeling. Vitamin D has potent immunomodulatory characteristics: anti-inflammatory, anti-angiogenic, anti-fibrotic properties, and influences on the macrophage phenotype. Little is known about the relation between pleiotropic effects attributed to vitamin D3 and the peritoneal membrane and what is the most appropriate vitamin D sterol in prevention of peritoneal remodeling in PD patients. Animal studies have suggested that paricalcitol has advantageous effects: decrease in plasma markers of inflammation, less peritoneal fibrosis, less pronounced PD-induced omental angiogenesis, and prevention of loss of ultrafiltration. We investigated whether paricalcitol is advantageous over calcitriol in PD patients. METHOD: A multicenter open-label 1:1 randomized non-blinded clinical pilot study enrolled prevalent continous ambulatory PD (CAPD) patients for a period of 6 months comparing paricalcitol with calcitriol. All patients were treated with biocompatible PD fluids. The primary endpoint was peritoneal transport parameters, exploratory endpoints were biomarkers of peritoneal damage and cell analysis (including M1/M2 macrophages), and safety endpoints were metabolic parameters. RESULTS: Twenty-seven patients were included. Fourteen were randomized to treatment with paricalcitol. There was no difference in peritoneal transport parameters between the groups. We found similar Kt/V, D/P creatinine, D/D0 glucose, ultrafiltration, residual renal function and 24-h urine volume during the study. There was no difference in biomarker concentrations in peritoneal effluents, and no difference in leucocyte differentiation or mesothelial cells between the groups at any time point. Parathyroid hormone (PTH) levels decreased after administration of calcitriol after 12 and 24 weeks compared with baseline (p = 0.001; p = 0.025). Parathyroid hormone levels in the paricalcitol group did not change significantly. CONCLUSION: In this pilot study we investigated the effect of active vitamin D in PD patients. We found no specific benefit of active vitamin D3 in vitamin D3-sufficient PD patients. Additional studies in preferably incident patients, with an adequate PTH suppression in the intervention groups and during a longer period, are required to test the beneficial effects of active vitamin D3 over no treatment and to investigate whether in 25(OH)D3-deficient PD patients the type of active vitamin D3 matters.

Mediterranean diet as the diet of choice for patients with chronic kidney disease.

Traditional dietary management of chronic kidney disease (CKD) focuses on the quantity within the diet of energy and protein, and the restriction of single micronutrients, with little mention of dietary quality. Dietary patterns that are more plant-based, lower in meat (including processed meat), sodium and refined sugar, and have a higher content of grains and fibres are now included in multiple clinical guidelines for chronic disease prevention. The Mediterranean diet (MD) has been associated with reduced cardiovascular disease incidence in both observational and interventional studies. A wealth of evidence links MD with other beneficial effects on chronic diseases such as diabetes, obesity or cognitive health. This review examines each constituent of the classical MD and evaluates their suitability for the management of patients with CKD. We also evaluate the potential hyperkalaemia risk of increasing fruit and vegetable intake. Overall, a decrease in net endogenous acid production and increase in fibre may lead to a better control of metabolic acidosis. This, together with other putative favourable effects of MD on endothelial function, inflammation, lipid profile and blood pressure, provide mechanistic pathways to explain the observed reduced renal function decline and improved survival in CKD patients adhering to an MD.

Initiation of peritoneal dialysis in the first weeks after catheter insertion: A comparison of a neutral-pH, low-GDP PD fluid and a conventional PD fluid
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BACKGROUND: Chronic exposure to peritoneal dialysis (PD) fluid is associated with development of functional and structural alterations of the peritoneal membrane. The exact time point at which these changes actually occur is not known. Whether changes to the peritoneum occur immediately after installation of PD fluids and whether there is a difference between neutral-pH, low glucose degradation product (low-GDP) PD fluids and conventional PD fluids is not known either. MATERIALS AND METHODS: We performed an observational study. Markers related to inflammation, fibrosis, mesothelial activation, and cytokines/growth factors were measured in effluents immediately after PD-catheter insertion and during the first days and weeks of PD treatment in patients using either dianeal® or physioneal®. RESULTS: Peritoneal response was observed instantly upon insertion of the PD catheter and instillation of PD fluids and persisted during daily PD therapy. Particularly during the first contacts of the peritoneum with PD fluids, high levels of cytokines and biomarkers were observed. In general, CA125 is slightly higher with dianeal. There is no difference between the fluids in hyaluronic acid (HA), IL-6, IL-8, MCP-1, VEGF, and TGFß-1 levels. CONCLUSION: Implantation of the Tenckhoff catheter and installation of PD fluids induce inflammation, which in the first days resembles an acute inflammatory response. More continuous infusion of PD fluids further enhances peritoneal inflammation. The use of the bicarbonate/lactate-buffered, neutral-pH, low-GDP PD fluid physioneal exerts lower CA125 levels, lower D/P4 creatinine, but similar inflammatory response compared to conventional dianeal PD fluids in this early stage of PD therapy.
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Effects of Conversion to a Bicarbonate/Lactate-Buffered, Neutral-pH, Low-GDP PD Regimen in Prevalent PD: A 2-Year Randomized Clinical Trial.

♦ BACKGROUND: The use of pH-neutral peritoneal dialysis (PD) fluids low in glucose degradation products (GDP) may better preserve the peritoneal membrane and have fewer systemic effects. The effects of conversion from conventional to neutral-pH, low-GDP PD fluids in prevalent patients are unclear. Few studies on the role of neutral-pH, low-GDP PD have studied residual renal function, ultrafiltration, peritonitis incidence and technique failure, transport characteristics, and local and systemic markers of inflammation in prevalent PD patients. ♦ METHODS: In a multi-center open-label randomized clinical trial (RCT), we randomly assigned 40 of 78 stable continuous ambulatory PD (CAPD) and automated PD (APD) patients to treatment with bicarbonate/lactate, neutral-pH, low-GDP PD fluid (Physioneal; Baxter Healthcare Corporation, Deerfield, IL, USA) and compared them with 38 patients continuing their current standard lactate-buffered PD fluid (PDF) (Dianeal; Baxter Healthcare Corporation, Deerfield, IL, USA) during 2 years. Primary outcome was residual renal function (RRF) and ultrafiltration (UF) during peritoneal equilibration test (PET); peritonitis incidence was a secondary outcome. Furthermore, clinical parameters as well as several biomarkers in effluents and serum were measured. ♦ RESULTS: During follow-up, RRF did not differ between the groups. In the Physioneal group ultrafiltration (UF) during PET remained more or less stable (-20 mL [confidence interval (CI): -163.5 - 123.5 mL]; p = 0.7 over 24 months), whereas it declined in the Dianeal group (-243 mL [CI: -376.6 to -109.4 mL]; p < 0.0001 over 24 months), resulting in a difference of 233.7 mL [95% CI 41.0 - 425.5 mL]; p = 0.017 between the groups at 24 months. The peritonitis rate was lower in the Physioneal group: adjusted odds ratio (OR) 0.38 (0.15 - 0.97) p = 0.043. No differences were observed between the 2 groups in peritoneal adequacy or transport characteristics nor effluent markers of local inflammation (cancer antigen [CA]125, hyaluronan [HA], vascular endothelial growth factor [VEGF], macrophage chemo-attractant protein [MCP]-1, HA and transforming growth factor [TGF]ß-1). ♦ CONCLUSION: In prevalent PD patients, our study did not find a difference in RRF after conversion from conventional to neutral-pH, low-GDP PD fluids, although there is a possibility that the study was underpowered to detect a difference. Decline in UF during standardized PET was lower after 2 years in the Physioneal group.

Improved Outcome of Enteric Peritonitis in Peritoneal Dialysis Patients Aged 50 Years and Older with Temporary Discontinuation of Peritoneal Dialysis and Intravenous Meropenem.

♦ BACKGROUND: Peritonitis is a major cause of morbidity, mortality, and technique failure in peritoneal dialysis (PD) patients, especially when caused by enteric microorganisms (EM). We have implemented a treatment protocol specifically aimed at improving the outcome in EM peritonitis. The adapted protocol was applied in all PD patients 50 years and older presenting with peritonitis who were considered to be at risk of EM peritonitis and involves 3 interventions: 1) temporary discontinuation of PD without removing the catheter (peritoneal rest), 2) intravenous meropenem, and 3) meropenem intracatheter as lock (Mero-PerRest protocol). ♦ METHODS: In this observational study, we compared the outcome of 203 peritonitis episodes in 71 patients treated with the Mero-PerRest protocol, with 217 episodes in 104 patients treated with a more traditional intraperitoneal gentamicin-rifampicin-based regimen. ♦ RESULTS: In EM peritonitis episodes, the Mero-PerRest protocol resulted in a higher primary cure rate (90.0% vs 65.3%, adjusted odds ratio [OR] 4.54 [95% confidence interval (CI) 1.46 - 14.15]) and better technique survival (90.0% vs 69.4%, adjusted OR 3.41 [95% CI 1.07 - 10.87]). This effect was most distinct in patients with polymicrobial EM peritonitis (cure rate 87.5% vs 34.8%, p = 0.0003). Interestingly, primary cure rate (95.6% vs 84.7%, adjusted OR 3.92 [95% CI 1.37 - 11.19]) and technique survival (95.6% vs 85.6%, adjusted OR 3.60 [95% CI 1.25 - 10.32]) were also excellent in non-EM peritonitis episodes. Patient survival did not differ significantly. ♦ CONCLUSION: The poor outcome of peritonitis caused by EM in PD patients aged 50 years and older could be improved by applying a treatment protocol involving temporary discontinuation of PD without catheter removal and intravenous and intracatheter meropenem.

As we grow old: nutritional considerations for older patients on dialysis.

The number of older people on dialysis is increasing, along with a need to develop specialized health care to manage their needs. Aging-related changes occur in physiological, psychosocial and medical aspects, all of which present nutritional risk factors ranging from a decline in metabolic rate to assistance with feeding-related activities. In dialysis, these are compounded by the metabolic derangements of chronic kidney disease (CKD) and of dialysis treatment per se, leading to possible aggravation of protein-energy wasting syndrome. This review discusses the nutritional derangements of the older patient on dialysis, debates the need for specific renal nutrition guidelines and summarizes potential interventions to meet their nutritional needs. Interdisciplinary collaborations between renal and geriatric clinicians should be encouraged to ensure better quality of life and outcomes for this growing segment of the dialysis population.

Phosphate Binding Therapy to Lower Serum Fibroblast-Growth-Factor-23 Concentrations in Chronic Kidney Disease: Rationale and Study Design of the Sevelamer on FGF23 Trial (SoFT).

BACKGROUND: Increased levels of phosphate and fibroblast growth factor-23 (FGF23) are strong predictors of cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). Preliminary data suggest that interventions lowering gastro-intestinal phosphate uptake lowers serum FGF23 concentrations and improves cardiovascular risk and subsequently survival. However, data are lacking about the magnitude of effects, the effect in different stages of CKD and whether there is a dose-effect relationship. METHODS: Therefore, the Sevelamer on FGF23 Trial (SoFT) is designed as an open-label, single-arm, clinical pilot study aiming to demonstrate the feasibility of a phosphate-restricted diet in combination with the phosphate binder sevelamer to induce an effective, predictable and sustained decrease in FGF23 level in patients with an estimated glomerular filtration rate (eGFR) of 15-90 or >90 ml/min/1.73 m2 with proteinuria >1.0 g in 24 h urine collection, despite optimally dosed RAAS blockade, without inducing hypophosphatemia using a forced uptitration treatment regimen aimed at restricting phosphate uptake.

The association of acculturation and depressive and anxiety symptoms in immigrant chronic dialysis patients.

OBJECTIVE: Among immigrant chronic dialysis patients, depressive and anxiety symptoms are common. We aimed to examine the association of acculturation, i.e. the adaptation of immigrants to a new cultural context, and depressive and anxiety symptoms in immigrant chronic dialysis patients. METHODS: The DIVERS study is a prospective cohort study in five urban dialysis centers in the Netherlands. The association of five aspects of acculturation ("Skills", "Social integration", "Traditions", "Values and norms" and "Loss") and the presence of depressive and anxiety symptoms was determined using linear regression analyses, both univariate and multivariate. RESULTS: A total of 249 immigrant chronic dialysis patients were included in the study. The overall prevalence of depressive and anxiety symptoms was 51% and 47%, respectively. "Skills" and "Loss" were significantly associated with the presence of depressive and anxiety symptoms, respectively ("Skills" ß=0.34, CI: 0.11-0.58, and "Loss" ß=0.19, CI: 0.01-0.37; "Skills" ß=0.49, CI: 0.25-0.73, and "Loss" ß=0.33, CI: 0.13-0.53). The associations were comparable after adjustment. No significant associations were found between the other subscales and depressive and anxiety symptoms. CONCLUSION: This study demonstrates that less skills for living in the Dutch society and more feelings of loss are associated with the presence of both depressive and anxiety symptoms in immigrant chronic dialysis patients.

Protective Effects of Paricalcitol on Peritoneal Remodeling during Peritoneal Dialysis.

Peritoneal dialysis (PD) is associated with structural and functional alterations of the peritoneal membrane, consisting of fibrosis, angiogenesis, and loss of ultrafiltration capacity. Vitamin D receptor activation (VDRA) plays an important role in mineral metabolism and inflammation, but also antiangiogenic and antifibrotic properties have been reported. Therefore, the effects of active vitamin D treatment on peritoneal function and remodeling were investigated. Rats were either kept naïve to PDF exposure or daily exposed to 10 mL PDF and were treated for five or seven weeks with oral paricalcitol or vehicle control. Non-PDF-exposed rats showed no peritoneal changes upon paricalcitol treatment. Paricalcitol reduced endogenous calcitriol but did not affect mineral homeostasis. However, upon PDF exposure, loss of ultrafiltration capacity ensued which was fully rescued by paricalcitol treatment. Furthermore, PD-induced ECM thickening was significantly reduced and omental PD-induced angiogenesis was less pronounced upon paricalcitol treatment. No effect of paricalcitol treatment on total amount of peritoneal cells, peritoneal leukocyte composition, and epithelial to mesenchymal transition (EMT) was observed. Our data indicates that oral VDRA reduces tissue remodeling during chronic experimental PD and prevents loss of ultrafiltration capacity. Therefore, VDRA is potentially relevant in the prevention of treatment technique failure in PD patients.

Putative novel mediators of acute kidney injury in critically ill patients: handling by continuous venovenous hemofiltration and effect of anticoagulation modalities.

BACKGROUND: Novel putative mediators of acute kidney injury (AKI) include immune-cell derived tumour necrosis factor-like weak inducer of apoptosis (TWEAK), angiopoietin-2 (Ang-2) and protein pentraxin-3 (PTX3). The effect of continuous venovenous hemofiltration (CVVH) and different anticoagulation regimens on plasma levels were studied. METHODS: At 0, 10, 60, 180 and 720 min of CVVH, samples were collected from pre- and postfilter blood and ultrafiltrate. No anticoagulation (n = 13), unfractionated heparin (n = 8) or trisodium citrate (n = 21) were compared. RESULTS: Concentrations of TWEAK, Ang-2 and PTX3 were hardly affected by CVVH since the mediators were not (TWEAK, PTX3) or hardly (Ang-2) detectable in ultrafiltrate, indicating negligible clearance by the filter in spite of molecular sizes (TWEAK, PTX3) at or below the cutoff of the membrane. Heparin use, however, was associated with an increase in in- and outlet plasma TWEAK. CONCLUSION: Novel AKI mediators are not cleared nor produced by CVVH. However, heparin anticoagulation increased TWEAK levels in patient's plasma whereas citrate did not, favouring the latter as anticoagulant in CVVH for AKI.

Coagulation, Fibrinolysis and Inhibitors in Failing Filters during Continuous Venovenous Hemofiltration in Critically Ill Patients with Acute Kidney Injury: Effect of Anticoagulation Modalities.

INTRODUCTION: The mechanisms of early filter failure and clotting with different anticoagulation modalities during continuous venovenous hemofiltration (CVVH) are largely unknown. METHODS: Citrate, heparin and no anticoagulation were compared. Blood was drawn pre- and post filter up to 720 min. Concentrations of the thrombin-antithrombin (TAT), activated protein C-protein C inhibitor (APC-PCI), and type I plasminogen activator inhibitor (PAI-1) were determined. RESULTS: In case of early filter failure (<24 h), inlet concentrations of TAT and APC-PCI were higher over time, irrespective of anticoagulation. There was more production of APC-PCI and platelet-derived PAI-1 in the filter after 10 min in the heparin group than in other groups. In clotting filters, production of APC-PCI and PAI was also higher with heparin than citrate. CONCLUSION: Coagulation activation in plasma and inhibition of anticoagulation in plasma and filter may partly determine early CVVH filter failure due to clotting, particularly when heparin is used. Regional anticoagulation by citrate circumvents the inhibition of anticoagulation and fibrinolysis by platelet activation following heparin.

Fibroblast growth factor 23 and the antiproteinuric response to dietary sodium restriction during renin-angiotensin-aldosterone system blockade.

BACKGROUND: Residual proteinuria during renin-angiotensin-aldosterone system (RAAS) blockade is a major renal and cardiovascular risk factor in chronic kidney disease. Dietary sodium restriction potentiates the antiproteinuric effect of RAAS blockade, but residual proteinuria remains in many patients. Previous studies linked high fibroblast growth factor 23 (FGF-23) levels with volume overload; others linked higher serum phosphate levels with impaired RAAS-blockade efficacy. We hypothesized that FGF-23 reduces the capacity of dietary sodium restriction to potentiate RAAS blockade, impairing the antiproteinuric effect. STUDY DESIGN: Post hoc analysis of cohort data from a randomized crossover trial with two 6-week study periods comparing proteinuria after a regular-sodium diet with proteinuria after a low-sodium diet, both during background angiotensin-converting enzyme inhibition. SETTING & PARTICIPANTS: 47 nondiabetic patients with CKD with residual proteinuria (median protein excretion, 1.9 [IQR, 0.8-3.1] g/d; mean age, 50±13 [SD] years; creatinine clearance, 69 [IQR, 50-110] mL/min). PREDICTOR: Plasma carboxy-terminal FGF-23 levels. OUTCOMES: Difference in residual proteinuria at the end of the regular-sodium versus low-sodium study period. Residual proteinuria during the low-sodium diet period adjusted for proteinuria during the regular-sodium diet period. RESULTS: Higher baseline FGF-23 level was associated with reduced antiproteinuric response to dietary sodium restriction (standardized ß=-0.46; P=0.001; model R(2)=0.71). For every 100-RU/mL increase in FGF-23 level, the antiproteinuric response to dietary sodium restriction was reduced by 10.6%. Higher baseline FGF-23 level was a determinant of more residual proteinuria during the low-sodium diet (standardized ß=0.27; P=0.003) in linear regression analysis adjusted for baseline proteinuria (model R(2)=0.71). There was no interaction with creatinine clearance (P interaction=0.5). Baseline FGF-23 level did not predict changes in systolic or diastolic blood pressure upon intensified antiproteinuric treatment. LIMITATIONS: Observational study, limited sample size. CONCLUSIONS: FGF-23 levels are associated independently with impaired antiproteinuric response to sodium restriction in addition to RAAS blockade. Future studies should address whether FGF-23-lowering strategies may further optimize proteinuria reduction by RAAS blockade combined with dietary sodium restriction.