Susceptibility of hepato-splanchnic perfusion to intra-abdominal pressure in peritoneal dialysis patients.

BACKGROUND: The impact of peritoneal filling on hepato-splanchnic perfusion during peritoneal dialysis has not been fully elucidated yet. METHODS: Measurements were done in 20 prevalent peritoneal dialysis patients during a peritoneal equilibration test (PET) with 2L of standard dialysate. Data were obtained in the drained state at baseline (T0), after instillation (T1), and after 2 h of dwell time (T2). Intra-abdominal pressure (IAP) was measured by Durand's approach. The hepatic clearance index (KI) of indocyanine-green (ICG) was determined as an indirect measure of hepato-splanchnic blood flow. Cardiac index (CI), heart rate (HR), and total peripheral resistance index (TPRI) were derived from continuous arterial pulse analysis. Fluid volume overload (VO) was evaluated by multifrequency bioimpedance analysis. Ejection fraction (EF) was obtained from echocardiographic examination. RESULTS: IAP was 5.8 ± 3.5 mmHg at baseline (T0), rose to 9.4 ± 2.8 mmHg after instillation of dialysate (T1), and further to 9.7 ± 2.8 mmHg after 2 h of dwell time (p < 0.001). KI slightly declined from 0.60 ± 0.22 L/min/m2 at T0 to 0.53 ± 0.15 L/min/m2 at T1 (p = 0.075), and returned to 0.59 ± 0.22 L/min/m2 at T2 (p = 0.052). CI, HR, and TPRI did not change significantly. In five patients with an EF < 40% KI was significantly lower at T1 (0.42 ± 0.12 L/min/m2; p = 0.039), and further decreased at T2 (0.40 ± 0.04 L/min/m2; p = 0.016) compared to patients with normal EF (T1: 0.58 ± 0.15 L/min/m2 and T2: 0.67 ± 0.22 L/min/m2). CONCLUSIONS: Overall, hepatic clearance of ICG as a marker of hepato-splanchnic blood flow is not affected by the filling of the peritoneal cavity.

Intradialytic techniques for automatic and everyday access monitoring.

Vascular access dysfunction is associated with reduced delivery of dialysis, unplanned admissions, patient symptoms, and loss of access, making assessment of vascular access a fundamental part of routine care in dialysis. Clinical trials to predict the risk of access thrombosis based on accepted reference methods of access performance have been disappointing. Reference methods are time-consuming, affect the delivery of dialysis, and therefore cannot repeatedly be used with every dialysis session. There is now a new focus on data continuously and regularly collected with every dialysis treatment, directly or indirectly associated with access function, and without interrupting or affecting the delivered dose of dialysis. This narrative review will focus on techniques that can be used continuously or intermittently during dialysis, taking advantage of methods integrated into the dialysis machine and which do not affect the delivery of dialysis. Examples include extracorporeal blood flow, dynamic line pressures, effective clearance, dose of delivered dialysis, and recirculation which are all routinely measured on most modern dialysis machines. Integrated information collected throughout every dialysis session and analyzed by expert systems and machine learning has the potential to improve the identification of accesses at risk of thrombosis.

Development of an Architecture to Implement Machine Learning Based Risk Prediction in Clinical Routine: A Service-Oriented Approach.

BACKGROUND: Patients at risk of developing a disease have to be identified at an early stage to enable prevention. One way of early detection is the use of machine learning based prediction models trained on electronic health records. OBJECTIVES: The aim of this project was to develop a software solution to predict cardiovascular and nephrological events using machine learning models. In addition, a risk verification interface for health care professionals was established. METHODS: In order to meet the requirements, different tools were analysed. Based on this, a software architecture was created, which was designed to be as modular as possible. RESULTS: A software was realised that is able to automatically calculate and display risks using machine learning models. Furthermore, predictions can be verified via an interface adapted to the need of health care professionals, which shows data required for prediction. CONCLUSION: Due to the modularised software architecture and the status-based calculation process, different technologies could be applied. This facilitates the installation of the software at multiple health care providers, for which adjustments need to be carried out at one part of the software only.

Effluent microscopy is a useful adjuvant diagnostic tool in peritoneal dialysis-associated peritonitis.

BACKGROUND: Infectious complications are the leading cause of technical failure in peritoneal dialysis (PD); however, targeted anti-infective therapy is not feasible at the onset, as effluent cultures take days and may be inconclusive. Although recommended by the guidelines, divergent positivity rates of Gram-stained effluent microscopy question the value of its usefulness. This study aimed to evaluate if microscopy of cell types serves as an additional and timely diagnostic approach. MATERIALS AND METHODS: This single-center retrospective analysis included prevalent PD patients (n = 250) between 2007 and 2017. Automated quantitative cell count, cytological analysis of Hemacolor and Gram-stained effluent sediment, and effluent cultures were conducted during peritonitis episodes. We calculated the rate of peritonitis, positivity rate of effluent cultures, and effluent microscopy. RESULTS: There were 155 at-risk cases of peritonitis in 662.7 years during the observation period. The culture positivity rate was 73.5%. In neutrophilic culture-negative peritonitis (CNP), effluent Gram staining yielded the identification of the microbial species in 51.6% cases. In 24.4% of CNP, effluent microscopy showed eosinophilic peritonitis, which occurred with less initial effluent leucocytes and showed better PD survival. CONCLUSION: In PD-associated peritonitis, Gram-stained dialysate with effluent microscopy supplements culture results in CNP. Hemacolor staining is crucial for differentiating eosinophilic peritonitis, showing a divergent clinical course and outcome.

Supine equilibration of extracellular fluid in peritoneal dialysis varies with intra-abdominal pressure.

BACKGROUND: Increased intra-abdominal pressure (PIA) leads to venous congestion in splanchnic and adjoining circulations. The aim is to examine whether PIA in peritoneal dialysis (PD) affects the mobilization of extracellular fluid from the lower body in supine body position. METHODS: Patients were studied during a regular peritoneal equilibration test (PET) in supine body position using multifrequency bioimpedance analysis to determine extracellular resistance and absolute volume overload (AVO) in wrist-to-ankle (W2A) as well as in ankle-to-ankle (A2A) configurations. Measurements were taken at baseline (T0) after draining the peritoneal cavity, at T1 shortly after filling with 2 L of standard dialysate, and at T2 before taking the 2 h PET samples. PIA was measured from the column height in the PD catheter. Extracellular resistance in the lower extremities (RL) was taken as half of the A2A resistance. RESULTS: Eighteen patients (56 ± 15 years, 76 ± 21 kg, body mass index (BMI) 26.4 ± 7 kg/m2, 13 men) were studied. After having assumed a supine body position for the duration of 17, 77, and 155 min, AVO continuously decreased from 1.6 ± 1.3 (T0) to 1.2 ± 1.5 (T1) and 1.0 ± 1.4 L (T2). RL significantly increased from 238 ± 57 (T0) to 254 ± 62 (T1) and 264 ± 67 Ohm (T2). This increase was negatively correlated to BMI and PIA measured at any time point, but not to net ultrafiltration volume. CONCLUSIONS: Orthostatic fluid shifts from the lower limbs may take up to 2 h in supine PD patients, especially with high BMI and PIA because of venous congestion in splanchnic and adjoining circulations.

Contrast Induced Acute Kidney Injury and its Impact on Mid-Term Kidney Function, Cardiovascular Events and Mortality.

The existence and clinical relevance of contrast induced acute kidney injury (CI-AKI) is still heavily debated and angiographic procedures are often withheld in fear of CI-AKI, especially in CKD-patients. We investigated the incidence of CI-AKI in cardiovascular high risk patients undergoing intra-arterial angiography and its impact on mid-term kidney function, cardiovascular events and mortality. We conducted a prospective observational trial on patients undergoing planned intra-arterial angiographic procedures. All subjects received standardized intravenous hydration prior to contrast application. CI-AKI was defined according to a ≥25% increase of creatinine from baseline to either 24hrs or 48hrs after angiography. Plasma creatinine and eGFR were recorded from the institutional medical record system one and three months after hospital discharge. Patients were followed up for two years to investigate the long term effects of CI-AKI on cardiovascular events and mortality. We studied 706 (317 female) patients with a mean eGFR of 52.0 ± 15 ml·min-1·1.73 m-2. The incidence of CI-AKI was 10.2% (72 patients). In 94 (13.3%) patients serum creatinine decreased ≥25% either 24 or 48 hours after angiography. Patients with CI-AKI had a lower creatinine and a higher eGFR at baseline, but no other independent predictors of CI-AKI could be identified. Kidney function was not different between both groups one and three months after discharge. After a two year follow up the overall incidence of cardiovascular events was 56.5% in the CI-AKI group and 58.8% in the Non CI-AKI group (p = 0.8), the incidence of myocardial infarctions, however, was higher in CI-AKI-patients. Overall survival was also not different between patients with CI-AKI (88.6%) and without CI-AKI (84.7%, p = 0.48). The occurrence of CI-AKI did not have any negative impact on mid-term kidney function, the incidence of cardiovascular events and mortality. Considerable fluctuations of serum creatinine interfere with the presumed diagnosis of CI-AKI. Necessary angiographic procedures should not be withheld in fear of CI-AKI.

Author Correction: Structural and functional differences in gut microbiome composition in patients undergoing haemodialysis or peritoneal dialysis.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

A randomized controlled trial of alanyl-glutamine supplementation in peritoneal dialysis fluid to assess impact on biomarkers of peritoneal health.

In early clinical testing, acute addition of alanyl-glutamine (AlaGln) to glucose-based peritoneal dialysis (PD) fluids restored peritoneal cellular stress responses and leukocyte function. This study was designed to test the effect of extended treatment with AlaGln-supplemented PD fluid on biomarkers of peritoneal health. In a double-blinded, randomized crossover design, stable PD patients were treated with AlaGln (8 mM) or placebo added to PD fluid for eight weeks. As primary outcome measures, dialysate cancer-antigen 125 (CA-125) appearance rate and ex vivo stimulated interleukin-6 (IL-6) release were assessed in peritoneal equilibration tests. In 8 Austrian centers, 54 patients were screened, 50 randomized, and 41 included in the full analysis set. AlaGln supplementation significantly increased CA-125 appearance rate and ex vivo stimulated IL-6 release. AlaGln supplementation also reduced peritoneal protein loss, increased ex vivo stimulated tumor necrosis factor (TNF)-α release, and reduced systemic IL-8 levels. No adverse safety signals were observed. All 4 peritonitis episodes occurred during standard PD fluid treatment. A novel AlaGln-supplemented PD fluid improves biomarkers of peritoneal membrane integrity, immune competence, and systemic inflammation compared to unsupplemented PD fluid with neutral pH and low-glucose degradation. A phase 3 trial is needed to determine the impact of AlaGln supplementation on hard clinical outcomes.

Structural and functional differences in gut microbiome composition in patients undergoing haemodialysis or peritoneal dialysis.

Complications of end-stage renal disease (ESRD) are critically related to inflammation. The gut microbiome is a key driver of inflammation. Since dialysis modalities may differently influence the gut microbiome, we aimed to compare the effects of haemodialysis (HD) and peritoneal dialysis (PD) on patients' gut microbiome composition and function. We therefore studied faecal microbiome composition and function as well as inflammation and gut permeability in 30 patients with ESRD (15 HD, 15 PD) and compared to 21 healthy controls. We found an increase in potentially pathogenic species and a decrease in beneficial species in patients on HD and to a lesser extend in patients on PD when compared to controls. These changes in taxonomic composition also resulted in differences in predicted metagenome functions of the faecal microbiome. In HD but not in PD, changes in microbiome composition were associated with an increase in c-reactive protein (CRP) but not with intestinal inflammation or gut permeability. In conclusion microbiome composition in ESRD differs from healthy controls but also between modes of dialysis. These differences are associated with systemic inflammation and cannot completely be explained by dialysis vintage. The mode of renal replacement therapy seems to be an important driver of dysbiosis in ESRD.

Neutrophil gelatinase-associated lipocalin (NGAL) fails as an early predictor of contrast induced nephropathy in chronic kidney disease (ANTI-CI-AKI study).

The aim of the study was to evaluate the diagnostic accuracy of urinary neutrophil gelatinase- associated lipocalin (uNGAL) in patients with chronic kidney disease (CKD) as an early biomarker for contrast induced acute kidney injury (CI-AKI) and to investigate whether patients with an uNGAL increase might benefit from an additional intravenous volume expansion with regard to CI-AKI-incidence. We performed a prospective randomized controlled trial in 617 CKD-patients undergoing intra-arterial angiography. Urinary NGAL was measured the day before and 4-6hrs after angiography. In the event of a significant rise of uNGAL patients were randomized either into Group A, who received intravenous saline post procedure or Group B, who did not receive post-procedural i.v. fluids. Ten patients (1.62%) exhibited a significant rise of uNGAL after angiography and were randomized of whom one developed a CI-AKI. In the entire cohort the incidence of CI-AKI was 9.4% (58 patients) resulting in a specificity of 98.4% (95% CI: 97.0-99.3%) and a sensitivity of 1.72% (95% CI: 0.044-9.2%) of uNGAL for the diagnosis of CI-AKI. In this study uNGAL failed to predict CI-AKI and was an inadequate triage tool to guide an early intervention strategy to prevent CI-AKI. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01292317.

Mode of renal replacement therapy determines endotoxemia and neutrophil dysfunction in chronic kidney disease.

Bacterial infection and sepsis are common complications of chronic kidney disease (CKD). A vicious cycle of increased gut permeability, endotoxemia, inadequate activation of the innate immune system and resulting innate immune dysfunction is hypothesized. We assessed endotoxemia, neutrophil function and its relation to oxidative stress, inflammation and gut permeability in patients with CKD grade 3-5 without renal replacement therapy (CKD group, n = 57), patients with CKD stage 5 undergoing haemodialysis (HD, n = 32) or peritoneal dialysis (PD, n = 28) and patients after kidney transplantation (KT, n = 67) in a cross-sectional observational study. In HD patients, endotoxin serum levels were elevated and neutrophil phagocytic capacity was decreased compared to all other groups. Patients on HD had a significantly higher mortality, due to infections during follow up, compared to PD (p = 0.022). Oxidative stress, neutrophil energy charge, systemic inflammation and gut permeability could not completely explain these differences. Our findings suggest that dialysis modality and not renal function per se determine the development of neutrophil dysfunction and endotoxemia in CKD-patients. HD patients are particularly prone to neutrophil dysfunction and endotoxemia whereas neutrophil function seems to improve after KT. Multi-target approaches are therefore warranted to improve neutrophil function and potentially reduce the rate of infections with patients undergoing haemodialysis.

Concordance of absolute and relative plasma volume changes and stability of Fcells in routine hemodialysis.

Central hematocrit (H) measurements are currently used to track the degree of ultrafiltration-induced hemoconcentration with the aim to detect and prevent excessive intravascular fluid depletion during hemodialysis (HD). Failure to maintain hemodynamic stability is commonly attributed to the misinterpretation of H caused by an unaccountable increase in Fcells , the ratio of whole-body hematocrit to H. It was the aim to examine Fcells under everyday conditions in a group of stable HD patients. Absolute plasma volume (Vp ) and H were concomitantly measured during routine HD in the extracorporeal system in hourly intervals by noninvasive and continuous technology (CritLine-Instrument-III) and indocyanine green dye dilution to derive relative plasma volumes from Vp and H (RPVp , RPVH ), respectively, and to calculate Fcells . Thirteen patients were studied during two midweek treatments (n = 26). Both absolute Vp (P < 0.05) and relative plasma volumes RPVH (P < 0.001) decreased during HD. Vp at any time point was positively correlated to RPVH (r = 0.52). Moreover, relative plasma volumes RPVH and RPVp determined by independent techniques were identical and showed negligible bias (-0.2%) but considerable limits of agreement (-15.6% to +15.3%). Fcells was stable and in the range of 0.9 ± 0.05 throughout HD and not different from the value assumed at the beginning of HD. Although Fcells remains constant in patients on routine dialysis and relative plasma volumes (RPVH and RPVp ) determined by independent techniques are therefore comparable, the variability of experimental conditions during dialysis and the limited accuracy of absolute volume measurements using available technology continues to complicate the ultrafiltration control problem.

Increased Hepato-Splanchnic Vasoconstriction in Diabetics during Regular Hemodialysis.

BACKGROUND AND OBJECTIVES: Ultrafiltration (UF) of excess fluid activates numerous compensatory mechanisms during hemodialysis (HD). The increase of both total peripheral and splanchnic vascular resistance is considered essential in maintaining hemodynamic stability. The aim of this study was to evaluate the extent of UF-induced changes in hepato-splanchnic blood flow and resistance in a group of maintenance HD patients during regular dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Hepato-splanchnic flow resistance index (RI) and hepato-splanchnic perfusion index (QI) were measured in 12 chronic HD patients using a modified, non-invasive Indocyaningreen (ICG) dilution method. During a midweek dialysis session we determined RI, QI, ICG disappearance rate (kICG), plasma volume (Vp), hematocrit (Hct), mean arterial blood pressure (MAP) and heart rate (HR) at four times in hourly intervals (t1 to t4). Dialysis settings were standardized and all patient studies were done in duplicate. RESULTS: In the whole study group mean UF volume was 1.86 ± 0.46 L, Vp dropped from 3.65 ± 0.77L at t1 to 3.40 ± 0.78L at t4, and all patients remained hemodynamically stable. In all patients RI significantly increased from 12.40 ± 4.21 mmHg∙s∙m2/mL at t1 to 14.94 ± 6.36 mmHg∙s∙m2/mL at t4 while QI significantly decreased from 0.61 ± 0.22 at t1 to 0.52 ± 0.20 L/min/m2 at t4, indicating active vasoconstriction. In diabetic subjects, however, RI was significantly larger than in non-diabetics at all time points. QI was lower in diabetic subjects. CONCLUSIONS: In chronic HD-patients hepato-splanchnic blood flow substantially decreases during moderate UF as a result of an active splanchnic vasoconstriction. Our data indicate that diabetic HD-patients are particularly prone to splanchnic ischemia and might therefore have an increased risk for bacterial translocation, endotoxemia and systemic inflammation.

Sensitivity of Hematocrit to Osmotic Effects Induced by Changes in Dialysate Conductivity: Implications for Relative Blood Volume Measurement and Control.

Hemodialysis is accompanied by osmotic perturbations with distinct effects on red blood cell, plasma, and blood volumes. A series of in vitro studies was done to analyze the separate effect on cell volume. Whole porcine blood was circulated through an extracorporeal circulation maintaining a constant blood volume. Hemoconcentration was continuously measured by established optical and ultrasonic online techniques. Osmotic perturbation was performed by variation of dialysate conductivity within the clinical range of 13-15 mS/cm. Blood samples were analyzed using a microcentrifuge and a standard cell counter. As dialysate conductivity increased, centrifuge hematocrit (in %) decreased with a slope of -1.91% per unit of conductivity in mS/cm (r2 = 0.98). At the same time, Coulter-Counter hematocrit slightly decreased only by -0.18% (r2 = 0.53), while optical and ultrasonic hematocrit showed a small increase by 0.44% (r2 = 0.97) and 0.69% (r2 = 0.94) per unit of conductivity in mS/cm. The sensitivity to osmotic perturbation is consistent with theory and with specific characteristics of measuring techniques used in this study. The differences, however, need to be considered when comparing measurements obtained by different techniques. Finally, devices used for relative blood volume measurement in hemodialysis should be insensitive to osmosis-induced changes in red blood cell volume.

On-line dialysate infusion to estimate absolute blood volume in dialysis patients.

It was the aim to measure the distribution volume and the elimination of ultra-pure dialysate in stable hemodialysis patients during on-line hemodiafiltration (HDF). Dialysate was automatically infused as a volume indicator using standard on-line HDF equipment. Indicator concentration was noninvasively measured in the arterial blood-line (using the blood volume monitor, Fresenius Medical Care, Bad Homburg vor der Höhe, Germany), and its time course was analyzed to obtain the elimination rate and the distribution volume V(t) at the time of dilution. Blood volume at treatment start (V0) was calculated accounting for the degree of intradialytic hemoconcentration. Five patients (two females) were studied during 15 treatments. Two to six measurements using indicator volumes ranging from 60 to 210 ml were done in each treatment. V0 was 4.59 ± 1.15 L and larger than the volume of 4.08 ± 0.48 L estimated from anthropometric relationships. The mean half-life of infused volume was 17.2 ± 29.7 min. Given predialysis volume expansion V0 was consistent with blood volume determined from anthropometric measurements. Information on blood volume could substantially improve volume management in hemodialysis patients and fluid therapy in intensive care patients undergoing extracorporeal blood treatment. The system has the potential for complete automation using proper control inputs for BVM and HDF modules of the dialysis machine.

Absolute blood volume and hepatosplanchnic blood flow measured by indocyanine green kinetics during hemodialysis.

A technique to measure absolute blood volume and hepatosplanchnic blood flow (Q(h)) during hemodialysis (HD) is explored. The dispersion and elimination of indocyanine green (ICG) were measured using a noninvasive optical device attached to the extracorporeal system and compared with transcutaneous measurements. Distribution volume (V) and elimination rate constant (k) were determined from arterial indicator concentrations assuming standard single-pool behavior. Cardiac output (Q(c)) and access flow (Q(a)) were measured by saline dilution technique. Duplicate dilutions were available in seven subjects (two female subjects, 78.0 ± 9.66 kg dry weight). k was not different between measuring techniques (0.246 ± 0.07 vs. 0.249 ± 0.064 min⁻¹, p = n.s.). V was 4.71 ± 0.75 L (60.86 ± 10.21 ml/kg dry body weight) as anticipated for anthropometric blood volume (p = n.s). Indocyanine green half-life was 3.05 ± 0.89 min and in the range of normal liver function. Therefore, ICG clearance (K = kV, 1.14 ± 0.32 L/min) was assumed to correspond to Q(h). Systemic blood flow (Q(s)) calculated as difference between Q(c) (7.11 ± 1.47 L/min) and Q(a) (1.56 ± 0.88 L/min) was 5.55 ± 1.33 L/min. Thus, during HD 21 ± 5% of Q(s) were consumed by the hepatosplanchnic circulation. The analysis of ICG distribution and elimination using available online technology for routine HD provides plausible point-of-care information, which could be of clinical interests in extracorporeal applications.

Loss of antimicrobial effect of trisodium citrate due to 'lock' spillage from haemodialysis catheters.

BACKGROUND: Due to its reported antimicrobial effects, hypertonic citrate (46.7%) is a widely used catheter lock solution, but following instillation, citrate inevitably spills into the systemic circulation. This process is mainly driven by hydraulic effects during instillation and density differences between blood and lock solution. Hence, in haemodialysis catheters, intra-luminal citrate concentration ranges from 0% (at the tip in catheters with side holes), 3% (between the side holes and the highest point of the catheter) to 46.7% (at the Luer end) with possible differences in antimicrobial effects. We investigated in vitro the antimicrobial effect of pure citrate 46.7%, citrate 46.7% diluted with saline and blood to a net concentration of 3% (=citrate 3%), and of citrate-free blood, simulating in vivo conditions in different catheter sections. METHODS: Time-kill studies measuring the antimicrobial effect of citrate 46.7%, citrate 3% and citrate-free blood were performed with overnight cultures of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). RESULTS: Citrate 46.7% reduced the number of E. coli by 2 log units but after 24 h, 10(6) CFU/mL were still present. Citrate 3% and citrate-free blood had no antimicrobial effect on E. coli. Citrate 46.7%, citrate 3% and citrate-free blood had scarce antimicrobial effect on S. aureus within 24 h. CONCLUSIONS: Spillage of catheter lock solution leading to reduced intra-luminal citrate concentrations considerably reduces the antimicrobial effect of citrate 46.7% on E. coli. As none of the solutions tested had relevant antimicrobial effect on S. aureus, the antimicrobial effect of 46.7% citrate lock solution in vivo has to be seriously questioned.