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.

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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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.

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.

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.

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.

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.

The plasma level and biomarker value of neutrophil gelatinase-associated lipocalin in critically ill patients with acute kidney injury are not affected by continuous venovenous hemofiltration and anticoagulation applied.

INTRODUCTION: Neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker of acute kidney injury (AKI), and levels reflect severity of disease in critically ill patients. However, continuous venovenous hemofiltration (CVVH) may affect plasma levels by clearance or release of NGAL by activated neutrophils in the filter, dependent on the anticoagulation regimen applied. We therefore studied handling of NGAL by CVVH in patients with AKI. METHODS: Immediately before initiation of CVVH, prefilter blood was drawn. After 10, 60, 180, and 720 minutes of CVVH, samples were collected from pre- and postfilter (in- and outlet) blood and ultrafiltrate. CVVH with the following anticoagulation regimens was studied: no anticoagulation in case of a high bleeding tendency (n = 13), unfractionated heparin (n = 8), or trisodium citrate (n = 21). NGAL levels were determined with enzyme-linked immunosorbent assay (ELISA). RESULTS: Concentrations of NGAL at inlet and outlet were similar, and concentrations did not change over time in any of the anticoagulation groups; thus no net removal or production of NGAL occurred. Concentrations of NGAL at inlet correlated with disease severity at initiation of CVVH and at the end of a CVVH run. Concentrations of NGAL in the ultrafiltrate were lower with citrate-based CVVH (P = 0.03) and decreased over time, irrespective of anticoagulation administered (P < 0.001). The sieving coefficient and clearance of NGAL were low and decreased over time (P < 0.001). CONCLUSIONS: The plasma level and biomarker value of NGAL in critically ill patients with AKI are not affected by CVVH, because clearance by the filter was low. Furthermore, no evidence exists for intrafilter release of NGAL by neutrophils, irrespective of the anticoagulation method applied.

Citrate anticoagulation versus systemic heparinisation in continuous venovenous hemofiltration in critically ill patients with acute kidney injury: a multi-center randomized clinical trial.

INTRODUCTION: Because of ongoing controversy, renal and vital outcomes are compared between systemically administered unfractionated heparin and regional anticoagulation with citrate-buffered replacement solution in predilution mode, during continuous venovenous hemofiltration (CVVH) in critically ill patients with acute kidney injury (AKI). METHODS: In this multi-center randomized controlled trial, patients admitted to the intensive care unit requiring CVVH and meeting inclusion criteria, were randomly assigned to citrate or heparin. Primary endpoints were mortality and renal outcome in intention-to-treat analysis. Secondary endpoints were safety and efficacy. Safety was defined as absence of any adverse event necessitating discontinuation of the assigned anticoagulant. For efficacy, among other parameters, survival times of the first hemofilter were studied. RESULTS: Of the 139 patients enrolled, 66 were randomized to citrate and 73 to heparin. Mortality rates at 28 and 90 days did not differ between groups: 22/66 (33%) of citrate-treated patients died versus 25/72 (35%) of heparin-treated patients at 28 days, and 27/65 (42%) of citrate-treated patients died versus 29/69 (42%) of heparin-treated patients at 90 days (P = 1.00 for both). Renal outcome, i.e. independency of renal replacement therapy 28 days after initiation of CVVH in surviving patients, did not differ between groups: 29/43 (67%) in the citrate-treated patients versus 33/47 (70%) in heparin-treated patients (P = 0.82). Heparin was discontinued in 24/73 (33%) of patients whereas citrate was discontinued in 5/66 (8%) of patients (P < 0.001). Filter survival times were superior for citrate (median 46 versus 32 hours, P = 0.02), as were the number of filters used (P = 0.002) and the off time within 72 hours (P = 0.002). The costs during the first 72 hours of prescribed CVVH were lower in citrate-based CVVH. CONCLUSIONS: Renal outcome and patient mortality were similar for citrate and heparin anticoagulation during CVVH in the critically ill patient with AKI. However, citrate was superior in terms of safety, efficacy and costs. TRIAL REGISTRATION: Clinicaltrials.gov NCT00209378. Registered 13th September 2005.

Citrate confers less filter-induced complement activation and neutrophil degranulation than heparin when used for anticoagulation during continuous venovenous haemofiltration in critically ill patients.

BACKGROUND: During continuous venovenous haemofiltration (CVVH), regional anticoagulation with citrate may be superior to heparin in terms of biocompatibility, since heparin as opposed to citrate may activate complement (reflected by circulating C5a) and induce neutrophil degranulation in the filter and myeloperoxidase (MPO) release from endothelium. METHODS: No anticoagulation (n = 13), unfractionated heparin (n = 8) and trisodium citrate (n = 17) regimens during CVVH were compared. Blood samples were collected pre- and postfilter; C5a, elastase and MPO were determined by ELISA. Additionally, C5a was also measured in the ultrafiltrate. RESULTS: In the heparin group, there was C5a production across the filter which most decreased over time as compared to other groups (P = 0.007). There was also net production of elastase and MPO across the filter during heparin anticoagulation (P = 0.049 or lower), while production was minimal and absent in the no anticoagulation and citrate group, respectively. During heparin anticoagulation, plasma concentrations of MPO at the inlet increased in the first 10 minutes of CVVH (P = 0.024). CONCLUSION: Citrate confers less filter-induced, potentially harmful complement activation and neutrophil degranulation and less endothelial activation than heparin when used for anticoagulation during continuous venovenous haemofiltration in critically ill patients.

A European Renal Best Practice (ERBP) position statement on the Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines on Acute Kidney Injury: part 2: renal replacement therapy.

This paper provides an endorsement of the KDIGO guideline on acute kidney injury; more specifically, on the part that concerns renal replacement therapy. New evidence that has emerged since the publication of the KDIGO guideline was taken into account, and the guideline is commented on from a European perspective. Advice is given on when to start and stop renal replacement therapy in acute kidney injury; which modalities should be preferentially be applied, and in which conditions; how to gain access to circulation; how to measure adequacy; and which dose can be recommended.

Continuous venovenous haemofiltration with citrate-buffered replacement solution is safe and efficacious in patients with a bleeding tendency: a prospective observational study.

BACKGROUND: There is ongoing controversy concerning optimum anticoagulation and buffering in continuous venovenous haemofiltration (CVVH). Regional anticoagulation with trisodium citrate also acting as a buffer in the replacement fluid has several advantages and disadvantages over prefilter citrate administration alone. We analysed a large cohort of patients with acute kidney injury (AKI) treated by the former method and hypothesized that it is safe and efficacious. METHODS: Patients admitted at the intensive care unit with AKI and a high bleeding risk, without exclusion of liver disease, treated by CVVH with citrate in a custom-made replacement solution were prospectively included. Patient and CVVH characteristics, including citrate accumulation, were evaluated in outcome groups. A standardized mortality rate (SMR) was calculated using the simplified acute physiology score II. RESULTS: Ninety-seven patients were included; metabolic control was adequate and did not differ between outcome groups, apart from lower pH/bicarbonate in non-survivors. Citrate accumulation was proven in 9% and was timely identified. These patients had about threefold higher plasma transaminases and higher CVVH dose and mortality. The hospital mortality was 60% with a SMR of 1.1 (95% confidence interval 0.90-1.40): age and hyperlactatemia, rather than CVVH-characteristics and citrate accumulation, predicted mortality in multivariable analysis. CONCLUSION: In critically ill, patients with AKI at high risk of bleeding, CVVH with citrate-containing replacement solution is safe and efficacious. The risk for citrate accumulation is 9% and best predicted by levels of transaminases. It carries, when citrate is discontinued, no attributable mortality.

Effect of anticoagulation regimens on handling of interleukin-6 and -8 during continuous venovenous hemofiltration in critically ill patients with acute kidney injury.

OBJECTIVE: During continuous venovenous hemofiltration (CVVH) to replace renal function in acute kidney injury (AKI), anticoagulation of the filter is routinely required. A survival benefit for citrate has been reported, possibly due to reduced proinflammatory effects of the filter (bioincompatibility). We hypothesized that the type of anticoagulation modulates the immune response to, and clearance by CVVH of interleukin-6 (IL-6) and -8 (IL-8). METHODS: Three anticoagulation regimens were compared: trisodium citrate (n=17), unfractionated heparin (n=8) and no anticoagulation in case of bleeding tendency (n=13). Immediately before initiation of CVVH (cellulose triacetate membrane) pre-filter blood was drawn. Thereafter, at 10, 60, 180 and 720 min, samples were collected from the pre- and postfilter blood and from ultrafiltrate. IL-6 and IL-8 were determined by ELISA. RESULTS: High inlet levels of IL-6 and IL-8, particularly in the no anticoagulation group, were associated with non-survival. The inlet concentrations and mass rates of IL-6 and IL-8 decreased during CVVH. The course of fluxes across the filter were similar for the groups, however. Although increasing in time for IL-6 in the no anticoagulation group, mass removal and adsorption of IL-6 and IL-8 were low and did not differ among the anticoagulation groups. CONCLUSIONS: Blood to membrane contact, adsorption/clearance and anticoagulation do not increase nor attenuate high circulating levels of IL-6 and IL-8 during CVVH for AKI. This renders the hypothesis that the reported survival benefit for citrate anticoagulation is based on a reduction of bioincompatibility unlikely.

Comparison of the SF-36 Five-item Mental Health Inventory and Beck Depression Inventory for the screening of depressive symptoms in chronic dialysis patients.

BACKGROUND: The Beck Depression Inventory (BDI) is a standard and validated questionnaire to screen for depressive symptoms in chronic dialysis patients, but is relatively extensive to use repeatedly in clinical practice. We investigated whether the five-item Mental Health Inventory (MHI-5) of the 36-item Short-Form Health Survey Questionnaire (SF-36) could be applied to screen for depressive symptoms in dialysis patients. Moreover, we determined the optimal MHI-5 cut-off score to assess depressive symptoms. METHODS: Chronic dialysis patients from three centres filled out the SF-36 and the BDI. A receiver operating characteristic (ROC) curve was constructed for the MHI-5 score with BDI ≥ 16 as reference standard to (i) calculate the area under the curve to determine whether the MHI-5 could be considered as a useful screening instrument for depressive symptoms and (ii) proxy the optimal cut-off score of the MHI-5 to assess depressive symptoms. The optimal cut-off score was determined by the value for which the sum of sensitivity and specificity had an optimum. RESULTS: Of 133 included patients, 23% had depressive symptoms as determined with BDI ≥ 16. The correlation of the BDI with MHI-5 was -0.64. The area under the ROC curve was 0.82 (95% confidence interval 0.74-0.90). The optimal cut-off point of the MHI-5 was 70. MHI-5 ≤ 70 had 77 sensitivity, 72 specificity, 44 positive predicting value and 91% negative predicting value with the presence of depressive symptoms determined with BDI ≥ 16. CONCLUSIONS: The MHI-5 may help clinicians to screen for depressive symptoms in dialysis patients without using an additional depression screening questionnaire once the SF-36 is completed. A cut-off value of 70 can be used safely for the purposes of screening applications.

Nephrology in the Netherlands is not going under.

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.

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.

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.

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.