Safety and performance of the Clearum™ high flux hemodialyzer.

BACKGROUND: Clearum™ is a high flux steam sterilized dialyzer for patients with hemodialysis or hemodiafiltration. This study evaluated the safety and performance of the Clearum high flux steam sterilized hemodialyzer in the removal of small and middle-sized toxins. METHODS: A prospective, interventional, nonrandomized study enrolled twenty end-stage renal disease patients undergoing hemodialysis. The Clearum high flux steam sterilized dialyzer was compared to Fresenius FX dialyzers for baseline comparison. The duration of the trial was 2 weeks for the FX dialyzer and 6 weeks with the Clearum high flux steam sterilized dialyzer. In vitro studies with dextrans of varying sizes were performed to compare the membrane characteristics and sieving coefficient curves for the two dialyzers. RESULTS: The primary objective of a mean urea reduction ratio >65% was met, with no significant difference in mean urea reduction ratio between the Clearum high flux steam sterilized and Fresenius FX-series of dialyzers (p = 0.86). No dialyzer-related adverse events were reported in the study. ß-2-microglobulin reduction with the Clearum high flux steam sterilized dialyzer was statistically higher than the FX-series dialyzer (66.5% vs. 53.6%; p < 0.0001). Predialysis interleukin-6 and C-reactive protein concentrations, blood-rest scores (residual blood after blood restitution), and thrombin-anti-thrombin values were comparable. Albumin remained stable during the 6 weeks of Clearum high flux steam sterilized dialyzer use, with no appreciable differences compared to the Fresenius FX-series. CONCLUSION: The Clearum high flux steam sterilized dialyzer showed good mid-term effectivity for small and middle molecule removal with no reported dialyzer-related adverse events.

Calcific uraemic arteriolopathy (calciphylaxis): data from a large nationwide registry.

Background: Calcific uraemic arteriolopathy (CUA, calciphylaxis) is a rare disease predominantly in dialysis patients and associated with high mortality. Painful skin ulcerations and calcification of cutaneous arterioles characterize calciphylaxis. Methods: We established an observational, Internet-based registry allowing online notification for all German CUA cases. The registry recorded data about patient characteristics, biochemistry and therapies. Blood samples were stored in a central biobank. Results: Between 2006 and 2015, 253 CUA patients were recorded: median age 70 [interquartile range (IQR) 61-76] years, 60% females and 86% ( n = 207) dialysis patients, translating into an estimated annual incidence rate of 0.04% in German dialysis patients. Fifty-two per cent received vitamin K antagonists (VKAs) prior to CUA. Skin lesions were localized in 71% on the legs or gluteal region. In dialysis CUA patients median total serum calcium was 2.20 (IQR 2.06-2.37) mmol/L, phosphorus 1.67 (IQR 1.35-2.03) mmol/L, intact parathyroid hormone 147 (IQR 72-276) pg/mL and fetuin-A 0.21 (IQR 0.16-0.26) g/L (normal range 0.35-0.95). Median sclerostin, osteoprotegerin, TRAP5b, bone-specific alkaline phosphatase and c-terminal FGF23 levels were all elevated. The most frequently recorded therapeutic procedures in dialysis CUA patients were as follows: wound debridement (29% of cases), stopping VKA (25%), lowering calcium supply (24%), sodium thiosulphate (22%), application of vitamin K (18%), increase of dialysis duration/frequency (17%) and stoping active vitamin D (16%). Conclusions: Approximately 50% of CUA patients used VKA. Our data suggest that uncontrolled hyperparathyroidism is not the key determinant of calciphylaxis. Therapeutic strategies were heterogeneous. The experience of the German registry will help substantially to initiate a large-scale multinational CUA registry.

Gas6 protein: its role in cardiovascular calcification.

BACKGROUND: Cardiovascular calcifications can be prevented by vitamin K and are accelerated by vitamin K antagonists. These effects are believed to be mainly mediated by the vitamin K-dependent matrix Gla protein. Another vitamin K-dependent protein, Gas6, is also expressed in vascular smooth muscle cells (VSMC). In vitro Gas6 expression was shown to be regulated in VSMC calcification and apoptotic processes. METHODS: We investigated the role of Gas6 in vitro using VSMC cultures and in vivo in young and old Gas6-deficient (Gas6(-/-)) and wildtype (WT) mice. In addition, Gas6(-/-) and WT mice were challenged by (a) warfarin administration, (b) uninephrectomy (UniNX) plus high phosphate diet, or (c) UniNX plus high phosphate plus electrocautery of the residual kidney. RESULTS: In vitro VSMC from WT and Gas6(-/-) mice exposed to warfarin showed increased apoptosis and calcified similarly. In vivo, aortic, cardiac and renal calcium content in all groups was similar, except for a lower cardiac calcium content in Gas6(-/-) mice (group a). Von Kossa staining revealed small vascular calcifications in both WT and Gas6(-/-) mice (groups a-c). In aging, non-manipulated mice, no significant differences in vascular calcification were identified between Gas6(-/-) and WT mice. Gas6(-/-) mice exhibited no upregulation of matrix Gla protein in any group. Cardiac output was similar in all treatment groups. CONCLUSIONS: Taken together, in our study Gas6 fails to aggravate calcification against the previous assumption.

Surface Electromyography Reliably Records Electrophysiologically Evoked Internal Anal Sphincter Activity: A More Minimally Invasive Approach for Monitoring Extrinsic Innervation.

BACKGROUND: Even in the case of minimally invasive pelvic surgery, sparing of the autonomic nerve supply is a prerequisite for maintaining anal sphincter function. Internal anal sphincter (IAS) innervation could be electrophysiologically identified based on processed electromyographic (EMG) recordings with conventional bipolar needle electrodes (NE). This experimental study aimed for the development of a minimally invasive approach via intra-anal surface EMG for recordings of evoked IAS activity. METHODS: Six male pigs underwent nerve-sparing low anterior rectal resection. Electric autonomic nerve stimulations were performed under online-processed EMG of the IAS. EMG recordings were simultaneously carried out with conventional bipolar NE as the reference method and newly developed intra-anal surface electrodes (SE) in different designs. RESULTS: In all experiments, the IAS activity could be continuously visualized via EMG recordings based on NE and SE. The median number of bipolar electric stimulations per animal was 27 (range 5-52). The neurostimulations resulted in significant EMG amplitude increases for both recording types [NE: median 3.0 µV (interquartile range, IQR 2.8-3.5) before stimulation vs. 7.1 µV (IQR 3.9-13.8) during stimulation, p < 0.001; SE: median 3.6 µV (IQR 3.1-4.3) before stimulation vs. 6.8 µV (IQR 4.8-10.3) during stimulation, p < 0.001]. CONCLUSIONS: Intra-anal SE enabled reliable EMG of electrophysiologically evoked IAS activity similar to the conventional recording via NE. The transfer of the method to access platforms for transanal total mesorectal excision or robotics may offer a practical more minimally invasive approach for monitoring extrinsic innervation.

Serum levels of C-peptide are associated with coronary artery calcification in patients with rheumatoid arthritis.

C-peptide has pro-atherogenic effects in animal models, and elevated C-peptide levels are associated with cardiovascular and all-cause mortality in patients undergoing coronary angiography. This cross-sectional study investigated the association between C-peptide serum levels and coronary artery calcification (CAC) in patients with rheumatoid arthritis (RA), a high-risk group for cardiovascular events. Fifty-four patients with RA were recruited from an arthritis outpatient department at the University Hospital in Aachen, Germany. CAC was measured by multi-slice CT scan, and blood samples were drawn from all patients for the analysis of C-peptide and other cardiovascular biomarkers. Mean serum levels of C-peptide (1.187 ± 0.771 vs 0.745 ± 0.481 nmol/L, p = 0.02), YKL-40, LDL cholesterol, and triglycerides were significantly higher in patients with CAC (n = 32, 59 %) compared to those without CAC (n = 22, 41 %). Univariate analysis revealed a significant association of C-peptide [OR 4.7, 95 % CI (1.1, 20.2)], YKL-40, triglycerides, hypertension, smoking, age, and male sex with the presence of CAC. After adjustment for body mass index, cholesterol, diabetes, adiponectin, calcium, and phosphate, C-peptide was still significantly associated with CAC in a multivariate logistic regression model. In conclusion, C-peptide serum levels are independently associated with the presence of CAC in patients with RA. These data suggest a potential role of C-peptide in cardiovascular disease in patients with RA.

DICOM for Clinical Research: PACS-Integrated Electronic Data Capture in Multi-Center Trials.

Providing surrogate endpoints in clinical trials, medical imaging has become increasingly important in human-centered research. Nowadays, electronic data capture systems (EDCS) are used but binary image data is integrated insufficiently. There exists no structured way, neither to manage digital imaging and communications in medicine (DICOM) data in EDCS nor to interconnect EDCS with picture archiving and communication systems (PACS). Manual detours in the trial workflow yield errors, delays, and costs. In this paper, requirements for a DICOM-based system interconnection of EDCS and research PACS are analysed. Several workflow architectures are compared. Optimized for multi-center trials, we propose an entirely web-based solution integrating EDCS, PACS, and DICOM viewer, which has been implemented using the open source projects OpenClinica, DCM4CHEE, and Weasis, respectively. The EDCS forms the primary access point. EDCS to PACS interchange is integrated seamlessly on the data and the context levels. DICOM data is viewed directly from the electronic case report form (eCRF), while PACS-based management is hidden from the user. Data privacy is ensured by automatic de-identification and re-labelling with study identifiers. Our concept is evaluated on a variety of 13 DICOM modalities and transfer syntaxes. We have implemented the system in an ongoing investigator-initiated trial (IIT), where five centers have recruited 24 patients so far, performing decentralized computed tomography (CT) screening. Using our system, the chief radiologist is reading DICOM data directly from the eCRF. Errors and workflow processing time are reduced. Furthermore, an imaging database is built that may support future research.

Impaired vitamin K recycling in uremia is rescued by vitamin K supplementation.

In chronic kidney disease, vitamin K-dependent proteins, including the calcification inhibitor matrix Gla protein, are largely uncarboxylated indicating that functional vitamin K deficiency may contribute to uremic vascular calcification. Since the effects of uremia on the vitamin K cycle are unknown, we investigated the influence of uremia and vitamin K supplementation on the activity of the vitamin K cycle and extraosseous calcification. Uremia was induced in rats by an adenine-supplemented diet and vitamin K1 or K2 was administered over 4 and 7 weeks. After 4 weeks of adenine diet, the activity of the vitamin K cycle enzyme γ-carboxylase but not the activities of DT-diaphorase or vitamin K epoxide reductase were reduced. Serum levels of undercarboxylated matrix Gla protein increased, indicating functional vitamin K deficiency. There was no light microscopy-detectable calcification at this stage but chemically determined aortic and renal calcium content was increased. Vitamin K treatment reduced aortic and renal calcium content after 4 weeks. Seven weeks of uremia induced overt calcification in the aorta, heart, and kidneys; however, addition of vitamin K restored intrarenal γ-carboxylase activity and overstimulated it in the liver along with reducing heart and kidney calcification. Thus, uremic vitamin K deficiency may partially result from a reduction of the γ-carboxylase activity which possibly contributes to calcification. Pharmacological vitamin K supplementation restored the vitamin K cycle and slowed development of soft tissue calcification in experimental uremia.

Management of intraocular hypertension during hemodialysis by intravenous glucose administration.

A 64-year-old woman with end-stage renal disease and retinopathy secondary to type 2 diabetes mellitus presented with recurrent episodes of left ocular pain and acute loss of visual acuity during hemodialysis. During these episodes, markedly elevated intraocular pressures were measured. Several local and systemic antiglaucoma drugs were administered without improvement of intraocular pressure, resulting in the necessity of a glaucoma drainage device (Ahmed valve). Due to a local infection, it had to be removed, after which intraocular pressure elevations recurred during hemodialysis. Assuming that intraocular changes in osmolality during hemodialysis caused the intraocular pressure increases, intradialytic administration of a 20% glucose solution (100mL/h) was initiated. This completely abrogated the development of both intraocular pain and increases in intraocular pressure.

Clinical predictors of individual cognitive fluctuations in patients undergoing hemodialysis.

BACKGROUND: Cognitive impairment in hemodialysis (HD) patients is frequent and mediated by several factors. It is unclear which patients are more susceptible to cognitive variations around the dialysis cycle and which clinical factors may play a mediator role. We aimed to answer these issues by investigating intraindividual changes within the dialysis cycle. STUDY DESIGN: Cross-sectional observational study with repeated measures. SETTING & PARTICIPANTS: 47 HD patients and 40 controls without kidney disease, both without history of neurologic disease. PREDICTORS: Dialysis vintage, disease duration, vascular risk factors, comorbidity index score, intradialytic weight change, frequency of hypotensive episodes, and biochemical levels (hemoglobin, leukocytes, urea, creatinine, sodium, and potassium). Covariates included demographics (age, education, and sex). OUTCOMES & MEASUREMENTS: Significant individual deterioration in attention and executive functions (phasic and intrinsic alertness, Stroop test, and Trail Making Test) after dialysis, as measured by a regression-based reliable change method. Regression models were used to identify clinical predictors of individual cognitive decline after dialysis. RESULTS: After dialysis, patients primarily showed prolonged reaction times and psychomotor slowing. However, individual-based analyses revealed that fluctuations in attention and executive functions were present in only a minority of patients. Significant individual fluctuations on particular attention and executive tasks were associated moderately with intradialytic hypotensive episodes, as well as with psychoactive medication, and were predicted weakly by blood leukocyte count, sodium level, dialysis vintage, and volume. LIMITATIONS: Small sample size; patient group younger and healthier than the overall HD population, limiting generalizability. CONCLUSIONS: Only a minority of patients exhibit significant individual cognitive fluctuations, predominantly showing deterioration after dialysis in attention and executive functions. Susceptibility to such fluctuations was predicted in part by both HD-dependent and -independent factors.

Warfarin induces cardiovascular damage in mice.

OBJECTIVE: Vascular calcification is an independent risk factor for cardiovascular disease. Once thought to be a passive process, vascular calcification is now known to be actively prevented by proteins acting systemically (fetuin-A) or locally (matrix Gla protein). Warfarin is a vitamin K antagonist, widely prescribed to reduce coagulation by inhibiting vitamin K-dependent coagulation factors. Recently, it became clear that vitamin K antagonists also affect vascular calcification by inactivation of matrix Gla protein. Here, we investigated functional cardiovascular characteristics in a mouse model with warfarin-induced media calcification. APPROACH AND RESULTS: DBA/2 mice received diets with variable concentrations of warfarin (0.03, 0.3, and 3 mg/g) with vitamin K1 at variable time intervals (1, 4, and 7 weeks). Von Kossa staining revealed that warfarin treatment induced calcified areas in both medial layer of aorta and heart in a dose- and time-dependent fashion, which could be inhibited by simultaneous vitamin K2 treatment. With ongoing calcification, matrix Gla protein mRNA expression decreased, and inactive matrix Gla protein expression increased. TdT-mediated dUTP-biotin nick end labeling-positive apoptosis increased, and vascular smooth muscle cell number was concomitantly reduced by warfarin treatment. On a functional level, warfarin treatment augmented aortic peak velocity, aortic valve-peak gradient, and carotid pulse-wave velocity. CONCLUSION: Warfarin induced significant calcification with resulting functional cardiovascular damage in DBA/2 wild-type mice. The model would enable future researchers to decipher mechanisms of vascular calcification and may guide them in the development of new therapeutic strategies.

Vitamin K antagonists: beyond bleeding.

Warfarin is the most widely used oral anticoagulant in clinical use today. Indications range from prosthetic valve replacement to recurrent thromboembolic events due to antiphospholipid syndrome. In hemodialysis (HD) patients, warfarin use is even more frequent than in the nonrenal population due to increased cardiovascular comorbidities. The use of warfarin in dialysis patients with atrial fibrillation requires particular caution because side effects may outweigh the assumed benefit of reduced stroke rates. Besides increased bleeding risk, coumarins exert side effects which are not in the focus of clinical routine, yet they deserve special consideration in dialysis patients and should influence the decision of whether or not to prescribe vitamin K antagonists in cases lacking clear guidelines. Issues to be taken into consideration in HD patients are the induction or acceleration of cardiovascular calcifications, a 10-fold increased risk of calciphylaxis and problems related to maintaining a target INR range. New anticoagulants like direct thrombin inhibitors are promising but have not yet been approved for ESRD patients. Here, we summarize the nontraditional side effects of coumarins and give recommendations about the use of vitamin K antagonists in ESRD patients.

Sailing between Scylla and Charybdis: oral long-term anticoagulation in dialysis patients.

End-stage renal disease (ESRD) patients exhibit an increased risk of bleeding compared with non-chronic kidney disease (CKD) patients due to uraemic platelet dysfunction, altered vessel architecture and other factors. This renders any long-term oral anticoagulation potentially difficult. While there is little doubt that ESRD patients with recurrent thromboembolism or a mechanical cardiac valve should receive vitamin K antagonists (coumarins), the use of coumarins in ESRD patients with atrial fibrillation is a matter of debate. In non-CKD patients, current guidelines strongly recommend the use of oral anticoagulants for stroke prophylaxis in atrial fibrillation if certain risk factors are present (CHA2DS2-VASc score). This recommendation is often extrapolated to patients with advanced CKD or ESRD but data supporting this practice are weak to absent. Besides an increased bleeding risk in ESRD patients, coumarins will also accelerate cardiovascular calcification and are potent risk factors for the development of calcific uraemic arteriolopathy (calciphylaxis). Novel coumarin alternatives such as direct thrombin inhibitors are promising but none is currently approved for use in ESRD patients. Whether interventional treatment strategies such as atrial appendage occlusion are safe and effective options in advanced CKD is also as yet unresolved. This review attempts to balance the potential risks and benefits of coumarin usage in ESRD patients and to give the best possible recommendations for everyday patient care.

Relationship between sclerostin and cardiovascular calcification in hemodialysis patients: a cross-sectional study.

BACKGROUND: Sclerostin is a Wnt pathway antagonist regulating osteoblast activity and bone turnover. Here, we assessed the potential association of sclerostin with the development of coronary artery (CAC) and aortic valve calcifications (AVC) in haemodialysis (HD) patients. METHODS: We conducted a cross-sectional multi-slice computed tomography (MS-CT) scanning study in 67 chronic HD patients (59.4 ± 14.8 yrs) for measurement of CAC and AVC. We tested established biomarkers as well as serum sclerostin (ELISA) regarding their association to the presence of calcification. Fifty-four adults without relevant renal disease served as controls for serum sclerostin levels. Additionally, sclerostin expression in explanted aortic valves from 15 dialysis patients was analysed ex vivo by immunohistochemistry and mRNA quantification (Qt-RT-PCR). RESULTS: CAC (Agatston score > 100) and any AVC were present in 65% and in 40% of the MS-CT patient group, respectively. Serum sclerostin levels (1.53 ± 0.81 vs 0.76 ± 0.31 ng/mL, p < 0.001) were significantly elevated in HD compared to controls and more so in HD patients with AVC versus those without AVC (1.78 ± 0.84 vs 1.35 ± 0.73 ng/mL, p = 0.02). Multivariable regression analysis for AVC revealed significant associations with higher serum sclerostin. Ex vivo analysis of uraemic calcified aortic valves (n = 10) revealed a strong sclerostin expression very close to calcified regions (no sclerostin staining in non-calcified valves). Correspondingly, we observed a highly significant upregulation of sclerostin mRNA in calcified valves compared to non-calcified control valves. CONCLUSION: We found a strong association of sclerostin with calcifying aortic heart valve disease in haemodialysis patients. Sclerostin is locally produced in aortic valve tissue adjacent to areas of calcification.

Magnesium Improves Cardiac Function in Experimental Uremia by Altering Cardiac Elastin Protein Content.

Cardiovascular complications are accompanied by life-threatening complications and represent the major cause of death in patients with chronic kidney disease (CKD). Magnesium is important for the physiology of cardiac function, and its deficiency is common in CKD. In the present study, we investigated the impact of oral magnesium carbonate supplementation on cardiac function in an experimental model of CKD induced in Wistar rats by an adenine diet. Echocardiographic analyses revealed restoration of impaired left ventricular cardiac function in animals with CKD. Cardiac histology and real-time PCR confirmed a high amount of elastin protein and increased collagen III expression in CKD rats supplemented with dietary magnesium as compared with CKD controls. Both structural proteins are crucial in maintaining cardiac health and physiology. Aortic calcium content increased in CKD as compared with tissue from control animals. Magnesium supplementation numerically lowered the increases in aortic calcium content as it remained statistically unchanged, compared with controls. In summary, the present study provides evidence for an improvement in cardiovascular function and aortic wall integrity in a rat model of CKD by magnesium, as evidenced by echocardiography and histology.

A fluorescent method to determine vitamin K-dependent gamma-glutamyl carboxylase activity.

The gamma (γ)-glutamyl carboxylase is a key enzyme in vitamin K-dependent carboxylation of proteins involved in hemostasis and inflammation. It is an endoplasmic enzyme posttranslationally converting glutamic acid residues into γ-carboxyglutamic acid residues in proteins. The activity of tissue derived γ-glutamyl carboxylase is commonly assayed by incorporation of H¹4CO3⁻ into synthetic peptides and subsequent quantification using liquid scintillation counting. We present a nonradioactive assay using a fluorescein isothiocyanate-labeled short peptide that can be readily detected in its unmodified and γ-glutamyl carboxylated form by reversed-phase HPLC. This method offers a convenient alternative to the established radioactive labeling techniques.

Prognostic impact of renal arterial resistance index upon renal allograft survival: the time point matters.

BACKGROUND: The renal arterial resistance index (RI) is reported to be a significant predictive parameter for renal allograft failure or death. The influence of the time point after renal transplantation on its predictive power has not been sufficiently evaluated. We performed a retrospective analysis of RI and its power to predict renal allograft failure or death with special emphasis on the time point of RI measurement. METHODS: The present analysis is based on ultrasonographically recorded intrarenal arterial RI measurements, routinely obtained in our outpatient department, over a period of 13 years. Altogether, 88 patients with an RI measurement 0-3, 3-6 and 12-18 months after transplantation were included and retrospectively stratified into two groups according to the RI: those with an index >0.75 and those with an index of ≤0.75. RESULTS: Twenty patients (23%) reached the combined end point, i.e. allograft failure with a return to dialysis or death. The RI measured early after transplantation (0-3 and 3-6 months) did not predict the end point, whereas the RI obtained between 12 and 18 months showed a significant predictive value for renal transplant failure or death in a univariate approach [Wald test, P = 0.0013, hazard ratio (HR) 4.787, 95% confidence interval (CI) 1.846-12.411]. At 12-18 months after transplantation, 14% (12 patients) of the study population had an RI >0.75. Seven (58%) of these patients reached the end point versus 13 of 76 patients (17%) with an RI ≤0.75. In a multivariate Cox model, the RI measured between 12 and 18 months after transplantation exhibited the highest hazard ratio (HR 6.191, 95% CI 2.288-16.756, P = 0.0003) for transplant failure or death. CONCLUSION: In our hands, the RI obtained during the first 6 months after transplantation failed to predict renal allograft failure or death, whereas the RI measured 12-18 months after transplantation appeared useful to predict long-term allograft outcomes.

Circulating nonphosphorylated carboxylated matrix gla protein predicts survival in ESRD.

The mechanisms for vascular calcification and its associated cardiovascular mortality in patients with ESRD are not completely understood. Dialysis patients exhibit profound vitamin K deficiency, which may impair carboxylation of the calcification inhibitor matrix gla protein (MGP). Here, we tested whether distinct circulating inactive vitamin K-dependent proteins associate with all-cause or cardiovascular mortality. We observed higher levels of both desphospho-uncarboxylated MGP (dp-ucMGP) and desphospho-carboxylated MGP (dp-cMGP) among 188 hemodialysis patients compared with 98 age-matched subjects with normal renal function. Levels of dp-ucMGP correlated with those of protein induced by vitamin K absence II (PIVKA-II; r = 0.62, P < 0.0001). We found increased PIVKA-II levels in 121 (64%) dialysis patients, indicating pronounced vitamin K deficiency. Kaplan-Meier analysis showed that patients with low levels of dp-cMGP had an increased risk for all-cause and cardiovascular mortality. Multivariable Cox regression confirmed that low levels of dp-cMGP increase mortality risk (all-cause: HR, 2.2; 95% CI, 1.1 to 4.3; cardiovascular: HR, 2.7; 95% CI, 1.2 to 6.2). Furthermore, patients with higher vascular calcification scores showed lower levels of dp-cMGP. In 17 hemodialysis patients, daily supplementation with vitamin K2 for 6 weeks reduced dp-ucMGP levels by 27% (P = 0.003) but did not affect dp-cMGP levels. In conclusion, the majority of dialysis patients exhibit pronounced vitamin K deficiency. Lower levels of circulating dp-cMGP may serve as a predictor of mortality in dialysis patients. Whether vitamin K supplementation improves outcomes requires further study.

Possibilities offered by implantable miniaturized cuff-electrodes for insect neurophysiology.

Recent advances in microsystems technology led to a miniaturization of cuff-electrodes, which suggests these electrodes not just for long-term neuronal recordings in mammalians, but also in medium-sized insects. In this study we investigated the possibilities offered by cuff-electrodes for neuroethology using insects as a model organism. The implantation in the neck of a tropical bushcricket resulted in high quality extracellular nerve recordings of different units responding to various acoustic, vibratory, optical and mechanical stimuli. In addition, multi-unit nerve activity related to leg movements was recorded in insects walking on a trackball. A drawback of bi-polar nerve recordings obtained during tethered flight was overlay of nerve activity with large amplitude muscle potentials. Interestingly, cuff-electrode recordings were robust to withstand walking and flight activity so that good quality nerve recordings were possible even three days after electrode implantation. Recording multi-unit nerve activity in intact insects required an elaborate spike sorting algorithm in order to discriminate neuronal units responding to external stimuli from background activity. In future, a combination of miniaturized cuff-electrodes and light-weight amplifiers equipped with a wireless transmitter will allow the investigation of neuronal processes underlying natural behavior in freely moving insects. By this means cuff-electrodes may contribute to the development of realistic neuronal models simulating neuronal processes underlying natural insect behavior, such like mate choice and predator avoidance.

Impact of sucroferric oxyhydroxide on the oral and intestinal microbiome in hemodialysis patients.

Hyperphosphatemia is a consequence of chronic kidney disease associated with mineral/bone impairment, increased cardiovascular events and mortality. Therapeutically, most dialysis patients have to take phosphate binders. Here, we investigated effects of the Fe(3+)-based phosphate binder sucroferric oxyhydroxide (SFOH) on the oral and gastrointestinal microbiome of 11 hemodialysis patients. Saliva, dental plaque and stool were collected at baseline, one and four weeks of SFOH intake and subjected to 16S rRNA gene (V3-V4 region) directed Illumina MiSeq-based analysis. Total Fe, Fe(2+) and Fe(3+) were determined in stool and saliva. Overall, the microbiome did not change significantly. However, some patient-, sample- and taxon-specific differences were noted, which allowed patients to be divided into those with a shift in their microbiome (6/11) and those without a shift (5/11). Total Fe and Fe(2+) were highest after one week of SFOH, particularly in patients who exhibited a shift in microbiome composition. Eight bacterial taxa showed significant unidirectional changes during treatment. In-depth microbiome analysis revealed that taxa that significantly benefited from iron plethora had no iron-binding siderophores or alternatives, which was in contrast to taxa that significantly declined under iron plethora. Patients with microbiome-shift were significantly younger and had higher serum phosphate concentrations. In conclusion, this study sheds light on the impact of iron on the microbiome of hemodialysis patients.