The sodium/proton exchanger NHA2 regulates blood pressure through a WNK4-NCC dependent pathway in the kidney.

NHA2 is a sodium/proton exchanger associated with arterial hypertension in humans, but the role of NHA2 in kidney function and blood pressure homeostasis is currently unknown. Here we show that NHA2 localizes almost exclusively to distal convoluted tubules in the kidney. NHA2 knock-out mice displayed reduced blood pressure, normocalcemic hypocalciuria and an attenuated response to the thiazide diuretic hydrochlorothiazide. Phosphorylation of the thiazide-sensitive sodium/chloride cotransporter NCC and its upstream activating kinase Ste20/SPS1-related proline/alanine rich kinase (SPAK), as well as the abundance of with no lysine kinase 4 (WNK4), were significantly reduced in the kidneys of NHA2 knock-out mice. In vitro experiments recapitulated these findings and revealed increased WNK4 ubiquitylation and enhanced proteasomal WNK4 degradation upon loss of NHA2. The effect of NHA2 on WNK4 stability was dependent from the ubiquitylation pathway protein Kelch-like 3 (KLHL3). More specifically, loss of NHA2 selectively attenuated KLHL3 phosphorylation and blunted protein kinase A- and protein kinase C-mediated decrease of WNK4 degradation. Phenotype analysis of NHA2/NCC double knock-out mice supported the notion that NHA2 affects blood pressure homeostasis by a kidney-specific and NCC-dependent mechanism. Thus, our data show that NHA2 as a critical component of the WNK4-NCC pathway and is a novel regulator of blood pressure homeostasis in the kidney.

Increased urinary excretion of kynurenic acid is associated with non-recovery from acute kidney injury in critically ill patients.

BACKGROUND: Acute kidney injury (AKI) is often observed in critically ill patients and is associated with high morbidity and mortality. Non-recovery from AKI has a negative impact on the prognosis of affected patients and early risk stratification seems key to improve clinical outcomes. We analyzed metabolites of a conserved key inflammatory pathway (i.e. tryptophan degradation pathway) in serial urine samples of patients with AKI. METHODS: One hundred twelve ICU patients with AKI were included in a prospective observational analysis. After exclusion criteria, 92 patients were eligible for analysis. Serial urine samples were collected and tryptophan levels including key tryptophan metabolites were measured using tandem mass spectrometry. RESULTS: Sixty-seven patients recovered in the first 7 days of AKI (early recovery, ER) whereas n = 25 had late-/non-recovery (LNR). Urinary concentrations of tryptophan, kynurenine, 3-OH anthranillic acid, serotonine, and kynurenine/tryptophan were significantly lower in LNR patients. In contrast, creatinine normalized excretion of kynurenic acid (KynA) was substantially increased in LNR patients (7.59 ± 6.81 vs. 3.19 ± 3.44 (ER) µmol/mmol, p <  0.005). High urinary KynA excretion was associated with higher RIFLE class, longer AKI duration, increased need for RRT, and 30-day mortality. Logistic regression revealed KynA as the single most important predictor of renal recovery on days 1 and 2 of AKI. CONCLUSIONS: Increased urinary levels of kynurenic acid, a key inflammatory metabolite of the tryprophan degradation pathway, are associated with adverse renal and clinical outcomes in critically ill patients with AKI. Urinary KynA may serve as an early risk stratificator in respective patients with AKI.

Clinical Validation of a Peritoneal Dialysis Prescription Model in the PatientOnLine Software.

Peritoneal transport characteristics and residual renal function require regular control and subsequent adjustment of the peritoneal dialysis (PD) prescription. Prescription models shall facilitate the prediction of the outcome of such adaptations for a given patient. In the present study, the prescription model implemented in the PatientOnLine software was validated in patients requiring a prescription change. This multicenter, international prospective cohort study with the aim to validate a PD prescription model included patients treated with continuous ambulatory peritoneal dialysis. Patients were examined with the peritoneal function test (PFT) to determine the outcome of their current prescription and the necessity for a prescription change. For these patients, a new prescription was modeled using the PatientOnLine software (Fresenius Medical Care, Bad Homburg, Germany). Two to four weeks after implementation of the new PD regimen, a second PFT was performed. The validation of the prescription model included 54 patients. Predicted and measured peritoneal Kt/V were 1.52 ± 0.31 and 1.66 ± 0.35, and total (peritoneal + renal) Kt/V values were 1.96 ± 0.48 and 2.06 ± 0.44, respectively. Predicted and measured peritoneal creatinine clearances were 42.9 ± 8.6 and 43.0 ± 8.8 L/1.73 m(2)/week and total creatinine clearances were 65.3 ± 26.0 and 63.3 ± 21.8 L/1.73 m(2) /week, respectively. The analysis revealed a Pearson's correlation coefficient for peritoneal Kt/V of 0.911 and Lin's concordance coefficient of 0.829. The value of both coefficients was 0.853 for peritoneal creatinine clearance. Predicted and measured daily net ultrafiltration was 0.77 ± 0.49 and 1.16 ± 0.63 L/24 h, respectively. Pearson's correlation and Lin's concordance coefficient were 0.518 and 0.402, respectively. Predicted and measured peritoneal glucose absorption was 125.8 ± 38.8 and 79.9 ± 30.7 g/24 h, respectively, and Pearson's correlation and Lin's concordance coefficient were 0.914 and 0.477, respectively. With good predictability of peritoneal Kt/V and creatinine clearance, the present model provides support for individual dialysis prescription in clinical practice. Peritoneal glucose absorption and ultrafiltration are less predictable and are likely to be influenced by additional clinical factors to be taken into consideration.

[Renal replacement therapies ­ Past, present and future]. / Nierenersatzverfahren - gestern, heute und morgen.

Extracorporeal renal replacement therapy is one of the most successful stories of artificial organ replacement. The current article describes the important steps in the evolution of renal replacement therapy towards modern state of the art peritoneal dialysis and hemodialysis. Open questions and possibilities for future developments are discussed. Today patients have a choice with respect to the method used to replace their failing kidney. However, in order to carefully plan and select the best possible method for a patient, he has to be seen and confronted with the various methods by a nephrologist at least six month before the necessity to start renal replacement therapy. Late referral increases mortality and the necessity for a temporary central venous access represents an additional thrombotic and infectious risk. A patient first seen by the nephrologist at the occasion of an emergeny dialysis will never have the possibility to profit from a preemptive living kidney donation. Furthermore, such patients usually stay in the center and are difficult to motivate for home or selfcare dialysis.

[A new bone anchored hemodialysis access]. / Neuartiger knochenverankerter Hämodialysezugang.

When classic arteriovenous fistulas or grafts fail, dialysis patients have a vital requirement for a catheter to ensure vascular access. Permanent central venous catheters penetrate the cervical and thoracic soft tissues and the skin without rigid fixation. The infection rate for such devices is high, often requiring explantation. Bone anchored hearing aids are an established treatment in patients with conductive hearing loss. The implant is firmly fixed on the temporal bone and the abutment permanently penetrates the skin. Severe infections requiring explantation are very rare. We suppose that one of the main reasons for the low complication rate is the firm fixation of the implant to the temporal bone, which minimizes the movement of the skin relative to the underlying bone. Based on the experience with implantable hearing devices we developed a percutaneous bone anchored port fixed to the skull in the region of the temporal bone. Such a bone anchored port could be a beneficial alternative to conventional central venous catheters for patients undergoing hemodialysis. In the course of the development process we investigated the individual anatomy to locate the correct implantation site with sufficient bone thickness; we studied screw stability in bone; we developed the titanium implant that houses the port system as well as the surgical tools and procedure for save implantation; we tested flow rate, leak tightness and purification on mockups; we defined the Seldinger-insertion of the catheter into the internal jugular vein via a small neck incision. Our results show the technical feasibility of a temporal bone anchored port and form the basis of a now-approved clinical pilot study.

Identification of IGFBP-7 by urinary proteomics as a novel prognostic marker in early acute kidney injury.

Early diagnosis of acute kidney injury (AKI) and accurate prognostic stratification is a prerequisite for optimal medical management. To identify novel prognostic markers of AKI, urine was collected on the first day of AKI in critically ill patients. Twelve patients with early recovery and 12 matching patients with late/non-recovery were selected and their proteome analyzed by gel electrophoresis and mass spectrometry. We identified eight prognostic candidates including α-1 microglobulin, α-1 antitrypsin, apolipoprotein D, calreticulin, cathepsin D, CD59, insulin-like growth factor-binding protein 7 (IGFBP-7), and neutrophil gelatinase-associated lipocalin (NGAL). Subsequent quantification by ELISA showed that IGFBP-7 was the most potent predictor of renal recovery. IGFBP-7 and NGAL were then chosen for further analyses in an independent verification group of 28 patients with and 12 control patients without AKI. IGFBP-7 and NGAL discriminated between early and late/non-recovery patients and patients with and without AKI. Significant upregulation of the urinary markers predicted mortality (IGFBP-7: AUC 0.68; NGAL: AUC 0.81), recovery (IGFBP-7: AUC 0.74; NGAL: AUC 0.70), and severity of AKI (IGFBP-7: AUC 0.77; NGAL: AUC 0.69), and were associated with the duration of AKI. IGFBP-7 was a more accurate predictor of renal outcome than NGAL. Thus, IGFBP-7 is a novel prognostic urinary marker that warrants further investigation.

Arterial stiffness depends on serum ionized calcium levels during dialysis with regional citrate anticoagulation.

Hemodynamic effects related to changes in serum ionized calcium (iCa) are difficult to determine during conventional hemodialysis (HD) using a fixed dialysate concentration of calcium. Regional citrate anticoagulation (RCA) allows the study of the effects of predefined iCa changes on arterial stiffness and blood pressure (BP) during a single dialysis session. In a crossover study, 15 patients with end-stage renal disease underwent two HD sessions with RCA. Each session was divided into two study phases in which iCa was titrated either to 0.8-1.0 mm or to 1.1-1.4 mm. The sequence of phases was randomly chosen and alternated for the second session. After reaching a stable iCa level, pulse wave velocity (PWV), arterial BP, and heart rate were measured. iCa levels were modified during sequence 1 (iCa low-high) from a predialysis baseline value of 1.15 ± 0.09 mm, first to 0.92 ± 0.05 mm (time point 1; P < 0.001 vs. baseline) and then to 1.18 ± 0.05 (time point 2; ns). During sequence 2 (iCa high-low), iCa levels were modified from 1.15 ± 0.12 mm first to 1.20 ± 0.05 mm (time point 1; ns vs. baseline) and then to 0.93 ± 0.03 (time point 2; P < 0.001). Assuming a basic linear repeated measures model, PWV was positively related to iCa levels (P < 0.03) independent of systolic or diastolic BP, heart rate, or ultrafiltration rate. PWV is closely related to acute changes in serum iCa levels in HD patients using RCA. RCA provides an interesting opportunity to study the effects of acute iCa changes during one dialysis procedure.

Randomized, double-blind trial of the effect of fluid composition on electrolyte, acid-base, and fluid homeostasis in patients early after subarachnoid hemorrhage.

BACKGROUND: Hyper- and hyponatremia are frequently observed in patients after subarachnoidal hemorrhage, and are potentially related to worse outcome. We hypothesized that the fluid regimen in these patients is associated with distinct changes in serum electrolytes, acid-base disturbances, and fluid balance. METHODS: Thirty-six consecutive patients with SAH were randomized double-blinded to either normal saline and hydroxyethyl starch dissolved in normal saline (Voluven(®); saline) or balanced crystalloid and colloid solutions (Ringerfundin(®) and Tetraspan(®); balanced, n = 18, each) for 48 h. Laboratory samples and fluid balance were evaluated at baseline and at 24 and 48 h. RESULTS: Age [57 ± 13 years (mean ± SD; saline) vs. 56 ± 12 years (balanced)], SAPS II (38 ± 16 vs. 34 ± 17), Hunt and Hess [3 (1-4) (median, range) vs. 2 (1-4)], and Fischer scores [3.5 (1-4) vs. 3.5 (1-4)] were similar. Serum sodium, chloride, and osmolality increased in saline only (p ≤ 0.010, time-group interaction). More patients in saline had Cl >108 mmol/L [16 (89 %) vs. 8 (44 %); p = 0.006], serum osmolality >300 mosmol/L [10 (56 %) vs. 2 (11 %); p = 0.012], a base excess <-2 [12 (67 %) vs. 2 (11 %); p = 0.001], and fluid balance >1,500 mL during the first 24 h [11 (61 %) vs. 5 (28 %); p = 0.046]. Hyponatremia and hypo-osmolality were not more frequent in the balanced group. CONCLUSIONS: Treatment with saline-based fluids resulted in a greater number of patients with hyperchloremia, hyperosmolality, and positive fluid balance >1,500 mL early after SAH, while administration of balanced solutions did not cause more frequent hyponatremia or hypo-osmolality. These results should be confirmed in larger studies.

Protocolised early de-resuscitation in septic shock (REDUCE): protocol for a randomised controlled multicentre feasibility trial.

BACKGROUND: Fluid overload is associated with excess mortality in septic shock. Current approaches to reduce fluid overload include restrictive administration of fluid or active removal of accumulated fluid. However, evidence on active fluid removal is scarce. The aim of this study is to assess the efficacy and feasibility of an early de-resuscitation protocol in patients with septic shock. METHODS: All patients admitted to the intensive care unit (ICU) with a septic shock are screened, and eligible patients will be randomised in a 1:1 ratio to intervention or standard of care. INTERVENTION: Fluid management will be performed according to the REDUCE protocol, where resuscitation fluid will be restricted to patients showing signs of poor tissue perfusion. After the lactate has peaked, the patient is deemed stable and assessed for active de-resuscitation (signs of fluid overload). The primary objective of this study is the proportion of patients with a negative cumulative fluid balance at day 3 after ICU. Secondary objectives are cumulative fluid balances throughout the ICU stay, number of patients with fluid overload, feasibility and safety outcomes and patient-centred outcomes. The primary outcome will be assessed by a logistic regression model adjusting for the stratification variables (trial site and chronic renal failure) in the intention-to-treat population. ETHICS AND DISSEMINATION: The study was approved by the respective ethical committees (No 2020-02197). The results of the REDUCE trial will be published in an international peer-reviewed medical journal regardless of the results. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT04931485.

Modeling of red blood cell life-spans in hematologically normal populations.

Despite the impact of red blood cell (RBC) Life-spans in some disease areas such as diabetes or anemia of chronic kidney disease, there is no consensus on how to quantitatively best describe the process. Several models have been proposed to explain the elimination process of RBCs: random destruction process, homogeneous life-span model, or a series of 4-transit compartment model. The aim of this work was to explore the different models that have been proposed in literature, and modifications to those. The impact of choosing the right model on future outcomes prediction--in the above mentioned areas--was also investigated. Both data from indirect (clinical data) and direct life-span measurement (biotin-labeled data) methods were analyzed using non-linear mixed effects models. Analysis showed that: (1) predictions from non-steady state data will depend on the RBC model chosen; (2) the transit compartment model, which considers variation in life-span in the RBC population, better describes RBC survival data than the random destruction or homogenous life-span models; and (3) the additional incorporation of random destruction patterns, although improving the description of the RBC survival data, does not appear to provide a marked improvement when describing clinical data.

Donor effect on cortical perfusion intensity in renal allograft recipients: a paired kidney analysis.

BACKGROUND: The contributions of donor- and recipient-related factors to renal allograft hemodynamics are difficult to dissect due to methodological reasons. We analyzed 28 pairs of kidneys (each pair from the same donor) transplanted to 56 different recipients in order to define the contributions of the donor and the recipient to allograft hemodynamics. METHODS: Two different techniques based on color-coded duplex ultrasound were used: renal resistance index (RI; measured in 3 different segmental arteries) and cortical perfusion intensity (PI; calculated as the average PI of selected cortical parenchymal regions during one heart cycle in standardized registered and processed ultrasound videos). All measurements were performed during the same study visit. RESULTS: Donor age was 56 years (median, range 17-78) and recipient age at examination 54 years (range 30-77). Median time after transplant (at the date of examination) was 2.4 years (range 0.7-5.5). RI correlated with pulse pressure (r = 0.64; p < 0.001) and recipient age (r = 0.42; p < 0.03), but not with donor age or transplant function expressed as estimated glomerular filtration rate (eGFR) or PI. In within- and between-pairs ANOVA, donor-derived factors determined eGFR (p < 0.02) and cortical PI (p < 0.03), but not RI. CONCLUSIONS: Intrinsic donor-derived factors are associated with GFR and cortical parenchymal perfusion intensity, but not the RI of segmental arteries in renal allografts.

Randomized, double-blind comparative trial of subunit and virosomal influenza vaccines for immunocompromised patients.

BACKGROUND: To our knowledge, no study to date has compared the effects of a subunit influenza vaccine with those of a virosomal influenza vaccine on immunocompromised patients. METHODS: A prospective, double-blind, randomized study was conducted to compare the immunogenicity and reactogenicity of subunit and virosomal influenza vaccines for adult patients who had an immunosuppressive disease or who were immunocompromised as a result of treatment. RESULTS: There were 304 patients enrolled in our study: 131 with human immunodeficiency virus (HIV) infection, 47 with a chronic rheumatologic disease, 74 who underwent a renal transplant, 47 who received long-term hemodialysis, and 5 who had some other nephrologic disease. There were 151 patients who received the subunit vaccine and 153 patients who received the virosomal vaccine. A slightly higher percentage of patients from the subunit vaccine group were protected against all 3 influenza vaccine strains after being vaccinated, compared with patients from the virosomal vaccine group (41% vs. 30% of patients; P = .03). Among HIV-infected patients, the level of HIV RNA, but not the CD4 cell count, was an independent predictor of vaccine response. Among renal transplant patients, treatment with mycophenolate significantly reduced the immune response to vaccination. The 2 vaccines were comparable with regard to the frequency and severity of local and systemic reactions within 7 days after vaccination. Disease-specific scores for the activity of rheumatologic diseases did not indicate flare-ups 4-6 weeks after vaccination. CONCLUSIONS: For immunosuppressed patients, the subunit vaccine was slightly more immunogenic than the virosomal vaccine. The 2 vaccines were comparable with regard to reactogenicity. Vaccine response decreased with increasing degree of immune suppression. Among HIV-infected patients, the viral load, rather than the CD4 cell count, predicted the protective immune response to the vaccine. CLINICAL TRIALS REGISTRATION: NCT00783380 .

Glycyrrhetinic acid food supplementation lowers serum potassium concentration in chronic hemodialysis patients.

Hyperkalemia is a common life-threatening problem in hemodialysis patients. Because glycyrrhetinic acid (GA) inhibits the enzyme 11beta-hydroxy-steroid dehydrogenase II and thereby increases cortisol availability to the colonic mineralocorticoid receptor, it has the potential to lower serum potassium concentrations. To test this, 10 patients in a 6 month prospective, double-blind, placebo-controlled crossover study were given cookies or bread rolls supplemented with glycyrrhetinic acid or placebo. Twenty-four-hour blood pressure measurements were performed at baseline and week 6 and 12 of each treatment period. The ratio of plasma cortisol/cortisone was significantly increased in all patients on GA as compared to baseline or placebo, indicating appropriate enzyme inhibition. Nine of the 10 patients had a persistent decrease in predialysis serum potassium concentration. On GA, mean predialysis serum potassium was significantly lower than at baseline or on placebo. On placebo, serum potassium was significantly elevated above the upper limit of normal in 76% compared to 30% of measurements during GA treatment. Furthermore, on this treatment the frequency of severe hyperkalemia significantly decreased from 9% to 0.6%. No differences were found in parameters reflecting sodium retention. Although these studies show that prolonged GA supplementation persistently lowers serum potassium in dialysis patients, a long-term toxicity study will be mandatory before we recommend the routine use of this treatment.

Treatment of acute renal failure in the intensive care unit: lower costs by intermittent dialysis than continuous venovenous hemodiafiltration.

Intermittent and continuous renal replacement therapies (RRTs) are available for the treatment of acute renal failure (ARF) in the intensive care unit (ICU). Although at present there are no adequately powered survival studies, available data suggest that both methods are equal with respect to patient outcome. Therefore, cost comparison between techniques is important for selecting the modality. Expenditures were prospectively assessed as a secondary end point during a controlled, randomized trial comparing intermittent hemodialysis (IHD) with continuous venovenous hemodiafiltration (CVVHDF). The outcome of the primary end points of this trial, that is, ICU and in-hospital mortality, has been previously published. One hundred twenty-five patients from a Swiss university hospital ICU were randomized either to CVVHDF or IHD. Out of these, 42 (CVVHDF) and 34 (IHD) were available for cost analysis. Patients' characteristics, delivered dialysis dose, duration of stay in the ICU or hospital, mortality rates, and recovery of renal function were not different between the two groups. Detailed 24-h time and material consumption protocols were available for 369 (CVVHDF) and 195 (IHD) treatment days. The mean daily duration of CVVHDF was 19.5 +/- 3.2 h/day, resulting in total expenditures of Euro 436 +/- 21 (21% for human resources and 79% for technical devices). For IHD (mean 3.0 +/- 0.4 h/treatment), the costs were lower (Euro 268 +/- 26), with a larger proportion for human resources (45%). Nursing time spent for CVVHDF was 113 +/- 50 min, and 198 +/- 63 min per IHD treatment. Total costs for RRT in ICU patients with ARF were lower when treated with IHD than with CVVHDF, and have to be taken into account for the selection of the method of RRT in ARF on the ICU.

Effect of transcutaneous electrical muscle stimulation and passive cycling movements on blood pressure and removal of urea and phosphate during hemodialysis.

BACKGROUND: Intradialytic exercise has been described to improve blood pressure stability and dialysis efficacy. However, comorbid conditions in the dialysis population often preclude the widespread use of active intradialytic exercise. Therefore, we investigated the effect of intradialytic transcutaneous muscle stimulation (TEMS) and passive cycling movements (PCMs) on blood pressure and dialysis efficacy in patients. STUDY DESIGN: Prospective, controlled, randomized, crossover investigation. SETTING & PARTICIPANTS: Ten patients were randomly allocated to TEMS, PCMs, or no intervention (NI) for 9 consecutive dialysis sessions. INTERVENTION: Participants were studied with NI, PCMs using a motor-driven ergometer, and bilateral TEMS of the leg musculature. Individual dialysis prescriptions were unchanged during the investigation. OUTCOMES & MEASUREMENTS: The effect of TEMS and PCMs on blood pressure and dialysis efficacy in patients was assessed. RESULTS: Mean blood pressure increased from 121/64 +/- 21/15 mm Hg with NI to 132/69 +/- 21/15 mm Hg (P < 0.001) during sessions with PCMs and 125/66 +/- 22/16 mm Hg (P < 0.05) during sessions with TEMS. Urea and phosphate removal during dialysis were significantly (P < 0.001) greater with TEMS (19.4 +/- 3.7 g/dialysis and 1,197 +/- 265 mg/dialysis) or PCMs (20.1 +/- 3.4 g/dialysis and 1,172 +/- 315 mg/dialysis) than with NI (15.1 +/- 3.9 g/dialysis and 895 +/- 202 mg/dialysis). Body weight, ultrafiltration, Kt/V, and increases in hemoglobin and albumin levels during dialysis did not differ among the NI, PCMs, and TEMS groups. LIMITATIONS: The study design does not allow extension of the findings to prolonged treatment. CONCLUSION: Future studies during longer observation periods will have to prove the persistence of these acute findings. Both TEMS and PCMs deserve future investigations in dialysis patients because they increase intradialytic blood pressure and facilitate urea and phosphate removal when applied short term.

Red cell survival in relation to changes in the hematocrit: more important than you think.

The management of anemia in patients with chronic renal failure has greatly improved with the availability of recombinant human erythropoietin in the late 1980s, leading to a considerable reduction in mortality and morbidity and to an improvement in quality of life. The findings from recent controlled clinical outcome trials have resulted in a rather narrow, generally accepted therapeutic hematocrit target range. However, currently available dosing algorithms do not permit achievement and maintenance of target values within the therapeutic range in many patients. One possible explanation for this failure may be the ignorance of a finite erythrocyte lifespan not integrated into most algorithms. The purpose of this article is to underline the essential role played by the erythrocyte lifespan in the erythropoietic response to recombinant human erythropoietin and to encourage the integration of this concept in the future development of computer-assisted decision support systems.

Reality check: primary vascular access creation today.

INTRODUCTION: In Switzerland, the outcome of vascular access creation in the 4500 current dialysis patients is unknown, mainly because there is no prospective registry for patients undergoing vascular access surgery for renal replacement therapy. The aim of the study was to assess the quality of vascular access creation and to compare it with the current literature and guidelines, in order to define strategies to improve clinical outcome. METHODS: Retrospective single-centre study in a tertiary referral centre. All consecutive patients over 18 years of age undergoing primary vascular access creation between January 2013 and December 2014 were included. Follow-up data for at least 12 months were collected. RESULTS: During the study period, 365 patients had a surgical intervention for renal replacement therapy. A primary vascular access was created in 74 patients (20%), who were further analysed in our study: 63 (85%) had an arteriovenous fistula (AVF) and 11 (15%) an arteriovenous graft (AVG). The intervention-free survival (primary patency rate) of the primary vascular access at 1 year was 46% (95% confidence interval [CI] 33-58%) for AVF and 30% (95% CI 7-58%) for AVG, with a secondary patency rate at 1 year of 75% (95% CI 63-84%) for AVF and 50% (95% CI 18-75%) for AVG. Twenty-seven patients (36%) with primary vascular access underwent central venous catheter (CVC) placement (tunnelled or non-tunnelled) before the access creation. Thirty-seven (50%) patients had their first dialysis through a CVC. Thirty-one patients (42%) never received a CVC. CONCLUSIONS: The primary patency of vascular access was unexpectedly low, and the number of CVC requests unexpectedly high. In light of this, we consider it essential that centres creating vascular access should register their activities and compare their outcomes with current guidelines to check and improve clinical management. To facilitate this, there is an initiative starting in 2018 encouraging all Swiss vascular surgeons to provide data on vascular access interventions, including 1-year follow-up, in the national online registry "SwissVasc 2.0".

Cerebral microembolism in the critically ill with acute kidney injury (COMET-AKI trial): study protocol for a randomized controlled clinical trial.

BACKGROUND: Microembolism is a frequent pathological event during extracorporeal renal replacement therapy (RRT). Some previous data indicate that microemboli are generated in patients who are undergoing RRT and that these may contribute to increased cerebrovascular and neurocognitive morbidity in patients with end-stage renal disease. The current trial aims to quantify the microembolic load and respective qualitative composition that effectively reaches the intracerebral circulation in critically ill patients treated with different RRT modalities for acute kidney injury (AKI). METHODS/DESIGN: The COMET-AKI trial is a prospective, randomized controlled clinical trial with a 2-day clinical assessment period and follow-up visits at 6 and 12 months. Consecutive critically ill patients with AKI on continuous renal replacement therapy (CRRT) scheduled for a switch to intermittent renal replacement therapy (IRRT) will be randomized to either switch to IRRT within the next 24 h or continued CRRT for an additional 24 h. Cerebral microembolic load will be determined at baseline, i.e., before switch (on CRRT for both groups) and on IRRT versus CRRT, whichever group they were randomized to. The primary endpoint is defined as the difference in mean total cerebral microemboli count during the measurement period on CRRT versus IRRT following randomization. Microemboli will be assessed within the RRT circuit by a 1.5-MHz ultrasound detector attached to the venous RRT tubing and cerebral microemboli will be measured in the middle cerebral artery using a 1.6-MHz robotic transcranial Doppler system with automatic classification of Doppler signals as solid or gaseous. In addition to Doppler measurements, patients will be examined by magnetic resonance imaging and neurocognitive tests to gain better understanding into the potential morphological and clinical consequences of embolization. DISCUSSION: The results of COMET-AKI may help to gain a better insight into RRT modality-associated differences regarding microbubble generation and the cerebral microembolic burden endured by RRT recipients. Furthermore, identification of covariates of microbubble formation and distribution may help to encourage the evolution of next-generation RRT circuits including machinery and/or filters. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02621749 . Registered on 3 December 2015.

Use of the pentasaccharide fondaparinux as an anticoagulant during haemodialysis.

No data about the use of the pentasaccharide fondaparinux, a highly selective indirect inhibitor of factor Xa, in patients treated with haemodialysis are available. Therefore, we investigated the pharmacokinetics and -dynamics of fondaparinux in 12 patients during haemodialysis. The anti-Xa activity (expressed as fondaparinux equivalent) was monitored, a semiquantitative clotting scale (SQCS) ranging from 0 (no visible traces of coagula) to 3 (complete clotting of the dialysis circuit) was applied, and the digital compression time necessary to achieve haemostasis at the puncture site was determined. After an initial period, when the regular heparin dose was replaced once weekly by fondaparinux, 0.05 mg/kg, the pentasaccharide was administered for nine consecutive haemodialysis sessions. Peak anti-Xa activity increased from 0.61 +/- 0.14 microg/l after the first dose to 0.89 +/- 0.24 microg/l after dose 9 (P < 0.001), whereas predialysis anti-Xa activity steadily rose to 0.32 +/- 0.09 microg/l (P < 0.001). A sufficient but slightly less effective anticoagulation with a mean SQCS of 1.19 +/- 0.71 (n = 121) was obtained by fondaparinux as compared with 0.65 +/- 0.58 (n = 60, P < 0.005) by 4,825 +/- 1,703 U of unfractionated heparin. Mean digital compression time rose slightly during fondaparinux from 23.7 +/- 7.4 minutes to 24.8 +/- 7.5 minutes (P < 0.05) and, more important, six of the 12 patients reported minor bleeding problems during the interdialytic interval. Thus, fondaparinux can be used to prevent circuit clotting during haemodialysis; however, accumulation results in an interdialytic increase of anti-Xa activity. Therefore, fondaparinux should be reserved for patients requiring systemic anticoagulation on the days off dialysis.