Association of all-cause mortality with pre-dialysis systolic blood pressure and its peridialytic change in chronic hemodialysis patients.

BACKGROUND: Pre-dialysis systolic blood pressure (pre-HD SBP) and peridialytic SBP change have been associated with morbidity and mortality among hemodialysis (HD) patients in previous studies, but the nature of their interaction is not well understood. METHODS: We analyzed pre-HD SBP and peridialytic SBP change (calculated as post-HD SBP minus pre-HD SBP) between January 2001 and December 2012 in HD patients treated in US Fresenius Medical Care facilities. The baseline period was defined as Months 4-6 after HD initiation, and all-cause mortality was noted during follow-up. Only patients who survived baseline and had no missing covariates were included. Censoring events were renal transplantation, modality change or study end. We fitted a Cox proportional hazard model with a bivariate spline functions for the primary predictors (pre-HD SBP and peridialytic SBP change) with adjustment for age, gender, race, diabetes, access-type, relative interdialytic weight gain, body mass index, albumin, equilibrated normalized protein catabolic rate and ultrafiltration rate. RESULTS: A total of 172 199 patients were included. Mean age was 62.1 years, 61.6% were white and 55% were male. During a median follow-up of 25.0 months, 73 529 patients (42.7%) died. We found that a peridialytic SBP rise combined with high pre-HD SBP was associated with higher mortality. In contrast, when concurrent with low pre-HD SBP, a peridialytic SBP rise was associated with better survival. CONCLUSION: The association of pre-HD and peridialytic SBP change with mortality is complex. Our findings call for a joint, not isolated, interpretation of pre-HD SBP and peridialytic SBP change.

Association of Central Venous Oxygen Saturation Variability and Mortality in Hemodialysis Patients.

BACKGROUND: Central venous oxygen saturation (ScvO2) is correlated with cardiac output. In most patients, ScvO2 declines during hemodialysis (HD) due to factors such as reduced preload, myocardial stunning, and intermittent arrhythmias. Previous research has shown that low ScvO2 is associated with higher mortality in chronic HD patients. In this research, we tested the hypothesis that ScvO2 variability is associated with all-cause mortality. METHODS: We conducted a retrospective study in 232 chronic HD patients with central venous catheter as vascular access. ScvO2 was recorded 1× per minute during dialysis using the Crit-Line monitor. A 6-month baseline comprising at least 10 dialysis treatments with ScvO2 recordings preceded a follow-up period of up to 3 years. The coefficient of variation (CV) of ScvO2 (100 times the ratio of the standard deviation and mean of ScvO2) served as a measure of ScvO2 stability during baseline. Patients were stratified by median population CV of ScvO2 during baseline, and survival during follow-up was compared between the 2 groups by Kaplan Meier and multivariate Cox analysis. The association between CV of ScvO2 and all-cause mortality during follow-up was further assessed by Cox analysis with a spline term for CV of ScvO2. RESULTS: The mean CV ± standard deviation of ScvO2 in our population was 6.1 ± 2.7% and the median was 5.3%. Univariate Kaplan-Meier analysis (p = 0.043) and multivariate Cox analysis (hazard ratio [HR] 1.16; p = 0.0005) indicated that a CV of ScvO2 > 5.3% was significantly associated with increased mortality. In Cox analysis with spline term, a CV of ScvO2 >  11% was associated with a significantly increased HR for all-cause mortality. CONCLUSION: High ScvO2 variability during dialysis is associated with increased all-cause mortality.

Reliability and agreement of sodium (23Na) MRI in calf muscle and skin of healthy subjects from the US.

PURPOSE: To quantify the reliability and agreement of sodium (23Na) MRI in calf muscle and skin of healthy subjects and to measure the smallest real difference (SRD) in each. SUBJECTS AND METHODS: Thirty healthy subjects underwent 23Na MRI studies of the calf. A scan-rescan protocol was performed the same day and 1 week later. Relative sodium concentration was measured in the calf muscle and skin and compared between studies. RESULTS: A high degree of reliability was confirmed between the scan and rescan tests using linear regression analysis. The Bland-Altman plots indicated high agreement between runs in all regions. The SRD was measured between scans taken the same day and one week later. Correlations were also reported with age, gender and race. CONCLUSIONS: Reliability and agreement of 23Na MRI in the calf muscle and skin show promise for accurately assessing serial changes in patients.

Association between intradialytic central venous oxygen saturation and ultrafiltration volume in chronic hemodialysis patients.

Background: Cardiac disease is highly prevalent in hemodialysis (HD) patients. Decreased tissue perfusion, including cardiac, due to high ultrafiltration volumes (UFVs) is considered to be one of the drivers of cardiac dysfunction. While central venous oxygen saturation (ScvO2) is frequently used as an indicator of cardiac output in non-uremic populations, the relationship of ScvO2 and UFV in HD patients remains unclear. Our aim was to determine how intradialytic ScvO2 changes associate with UFV. Methods: We conducted a 6-month retrospective cohort study in maintenance HD patients with central venous catheters as vascular access. Intradialytic ScvO2 was measured with the Critline monitor. We computed treatment-level slopes of intradialytic ScvO2 over time (ScvO2 trend) and applied linear mixed effects models to assess the association between patient-level ScvO2 trends and UFV corrected for body weight (cUFV). Results: We studied 6042 dialysis sessions in 232 patients. In about 62.4% of treatments, ScvO2 decreased. We observed in nearly 80% of patients an inverse relationship between cUFV and ScvO2 trend, indicating that higher cUFV is associated with steeper decline in ScvO2 during dialysis. Conclusions: In most patients, higher cUFV volumes are associated with steeper intradialytic ScvO2 drops. We hypothesize that in a majority of patients the intradialytic cardiac function is fluid dependent, so that in the face of high ultrafiltration rates or volume, cardiac pre-load and consequently cardiac output decreases. Direct measurements of cardiac hemodynamics are warranted to further test this hypothesis.

Intradialytic hypertension is associated with low intradialytic arterial oxygen saturation.

Background: The pathophysiology of a paradoxical systolic blood pressure (SBP) rise during hemodialysis (HD) is not yet fully understood. Recent research indicated that 10% of chronic HD patients suffer from prolonged intradialytic hypoxemia. Since hypoxemia induces a sympathetic response we entertained the hypothesis that peridialytic SBP change is associated with arterial oxygen saturation (SaO2). Methods: We retrospectively analyzed intradialytic SaO2 and peridialytic SBP change in chronic HD patients with arteriovenous vascular access. Patients were followed for 6 months. We defined persistent intradialytic hypertension (piHTN) as average peridialytic SBP increase ≥10 mmHg over 6 months. Linear mixed effects (LME) models were used to explore associations between peridialytic SBP change and intradialytic SaO2 in univariate and adjusted analyses. Results: We assessed 982 patients (29 872 HD treatments; 59% males; 53% whites). Pre-dialysis SBP was 146.7 ± 26.5 mmHg and decreased on average by 10.1 ± 24.5 mmHg. Fifty-three (5.7%) patients had piHTN. piHTN patients had lower intradialytic SaO2, body weight and interdialytic weight gain. LME models revealed that with every percentage point lower mean SaO2, the peridialytic SBP change increased by 0.46 mmHg (P < 0.001). This finding was corroborated in multivariate analyses. Conclusion: We observed an inverse relationship between intradialytic SaO2 and the blood pressure response to HD. These findings support the notion that hypoxemia activates mechanisms that partially blunt the intradialytic blood pressure decline, possibly by sympathetic activation and endothelin-1 secretion. To further explore that hypothesis, specifically designed prospective studies are required.

Intradialytic Central Venous Oxygen Saturation is Associated with Clinical Outcomes in Hemodialysis Patients.

Central venous oxygen saturation (ScvO2) in the superior vena cava is predominantly determined by cardiac output, arterial oxygen content, and oxygen consumption by the upper body. While abnormal ScvO2 levels are associated with morbidity and mortality in non-uremic populations, ScvO2 has received little attention in hemodialysis patients. From 1/2012 to 8/2015, 232 chronic hemodialysis patients with central venous catheters as vascular access had their ScvO2 monitored during a 6-month baseline period and followed for up to 36 months. Patients were stratified into upper and lower two tertiles by a ScvO2 of 61.1%. Survival analysis employed Kaplan-Meier curves and adjusted Cox proportional hazards models. Patients in the lower tertiles of ScvO2 were older, had longer hemodialysis vintage, lower systolic blood pressure, lower ultrafiltration rates, higher leukocyte counts and neutrophil-to-lymphocyte ratios. Kaplan-Meier analysis indicated a shorter survival time in the lower tertiles of ScvO2 (P = 0.005, log-rank test). In adjusted Cox analysis, a 1 percent point decrease in mean ScvO2 was associated with a 4% increase in mortality (HR 1.04 [95% CI 1.01-1.08], P = 0.044), indicating that low ScvO2 is associated with poor outcomes. Research on the relative contributions of cardiac output and other factors is warranted to further elucidate the pathophysiology underlying this novel finding.

Erythrocyte Sodium Sensitivity and Eryptosis in Chronic Hemodialysis Patients.

BACKGROUND/AIMS: In hemodialysis (HD) patients the endothelial and erythrocyte glycocalyx is impaired which in turn correlates with elevated erythrocyte sodium sensitivity (ESS). Additionally, apoptotic erythrocyte death (eryptosis), characterized by phosphatidylserine (PS) exposure on the cell surface, is increased in this population. We aimed to explore the relationship of ESS and eryptosis. METHODS: Blood samples were collected from 11 healthy controls and 20 chronic HD patients before and after midweek HD. ESS was quantified by the salt blood test. PS-exposure, intracellular reactive oxygen species (ROS) of erythrocytes and reticulocytes were assessed by flow cytometry. RESULTS: Compared to controls ESS was significantly higher in HD patients preHD and did not change during treatment. The percentage of eryptotic cells did not differ between controls and patients preHD. However, eryptosis decreased during HD. ESS and eryptosis were uncorrelated, while eryptosis was positively correlated with intracellular ROS and percent reticulocytes. CONCLUSIONS: Higher ESS levels in HD patients indicate a pathologic glycocalyx. ESS and eryptosis were not correlated. The decreased eryptosis postHD may possibly be related to dialytic uremic toxin removal, but is likely multifactorial. The relationship between eryptosis and intracellular ROS warrants further research.

Physical Activity and Sleep Patterns in Hemodialysis Patients in a Suburban Environment.

BACKGROUND/AIMS: Hemodialysis (HD) patients are less active than their healthy counterparts. They are often plagued with sleep disorders that affect the quality of their sleep. Our aim was to objectively quantify activity and sleep quality among HD patients in a suburban HD population. METHODS: Activity and sleep parameters were measured using a commercially available activity tracker in 29 HD patients from Baton Rouge, LA, USA. Patients in the feedback group received their activity and sleep data at each dialysis treatment. In addition, questionnaires were administered at the beginning and end of the study period. Patients were stratified based on activity levels and sleep quality. RESULTS: Patients walked an average of 5,281 steps/day and slept 370.5 min/night. Informing patients about their daily number of steps taken, did not increase activity. Only 3% of the population followed were active, defined as walking more than 10,000 steps per day. Patients walked significantly less on dialysis days compared to the other days of the week. Many of the patients experienced poor sleep quality, with patients in the first shift experiencing the greatest disturbance to their sleep/wake cycle. CONCLUSION: Patients in a suburban environment walked much less than those in a previously studied urban population. They rarely met the recommended goal of 10,000 steps/day, even on non-dialysis days. Interventions to increase physical activity may target any day of the week, particularly HD days. Prospective, long-term studies are needed to evaluate the use of activity trackers in dialysis patients and their impact on physical activity.

Intradialytic Hypoxemia and Clinical Outcomes in Patients on Hemodialysis.

BACKGROUND AND OBJECTIVES: Intradialytic hypoxemia has been recognized for decades, but its associations with outcomes have not yet been assessed in a large patient cohort. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Our retrospective cohort study was conducted between January of 2012 and January of 2015. We recorded blood oxygen saturation every minute during hemodialysis in patients with arteriovenous access. A 6-month baseline period with at least 10 treatments with oxygen saturation measurements preceded a 12-month follow-up. Patients were stratified by the presence or absence of prolonged intradialytic hypoxemia defined as oxygen saturation <90% for at least one third of the treatment time. Demographic, laboratory, and treatment data and hospitalization and mortality rates were compared between the groups. Multivariate Cox regression analysis was used to assess baseline predictors of all-cause mortality during follow-up. RESULTS: In total, 100 (10%) of 983 patients had prolonged intradialytic hypoxemia. These patients were older (+3.6 years; 95% confidence interval, 0.8 to 6.3), had longer dialysis vintage (+1.2 years; 95% confidence interval, 0.3 to 2.1), and had higher prevalence of congestive heart failure (+10.8%; 95% confidence interval, 1.6 to 20.7) and chronic obstructive pulmonary disease (+13%; 95% confidence interval, 5 to 21.2). They also resembled an inflammatory phenotype, with lower serum albumin levels (-0.1 g/dl; 95% confidence interval, -0.2 to 0) and higher neutrophil-to-lymphocyte ratios (+1; 95% confidence interval, 0.5 to 1.6). They had lower hemoglobin levels (-0.2 g/dl; 95% confidence interval, -0.4 to 0) and required more erythropoietin (+1374 U per hemodialysis treatment; 95% confidence interval, 343 to 2405). During follow-up, all-cause hospitalization (1113 hospitalizations; univariate hazard ratio, 1.46; 95% confidence interval, 1.22 to 1.73) and mortality (89 deaths; adjusted hazard ratio, 1.98; 95% confidence interval, 1.14 to 3.43) were higher in patients with prolonged intradialytic hypoxemia. CONCLUSIONS: Prolonged intradialytic hypoxemia was associated with laboratory indicators of inflammation, higher erythropoietin requirements, and higher all-cause hospitalization and mortality.

Quantifying Physical Activity Levels and Sleep in Hemodialysis Patients Using a Commercially Available Activity Tracker.

BACKGROUND/AIMS: Hemodialysis (HD) patients are less active than their healthy counterparts and frequently experience poor sleep. Our aims were to objectively quantify activity and sleep quality in HD patients of an urban population and to determine the effect of providing feedback on activity. METHODS: Activity parameters and sleep parameters were collected by a commercially available activity tracker in 29 chronic HD patients. Patients in the feedback group were provided with their activity and sleep data during each HD treatment. Questionnaires were administered at the beginning and at the end of the study. RESULTS: On average, patients walked 8,454 steps/day and slept 349 min/night. Only 28% of the patients were sedentary, defined as walking <5,000 steps/day. Providing feedback did not increase the activity in this urban population. Patients walked significantly less on Sundays compared to other days of the week: 7,024 steps on Sundays vs. 8,633 steps on HD days and 8,732 on non-HD days. It was also found that patients experienced poor sleep quality. HD treatments during shift 1 (6 a.m. to 10 a.m.) interfered with sleep patterns. Most patients reported that physical activity became more important to them after the 5-week period. The tracking device was very well accepted. CONCLUSION: Interventions to increase physical activity on Sundays could improve physical activity levels overall. Prospective studies are necessary to further explore the use of tracking devices to identify patients at risk and to implement targeted interventions.

Intradialytic Hypoxemia in Chronic Hemodialysis Patients.

When kidney failure occurs, patients are at risk for fluid overload states, which can cause pulmonary edema, pleural effusions, and upper airway obstruction. Kidney disease is also associated with impaired respiratory function, as in central sleep apnea or chronic obstructive pulmonary disease. Hence, respiratory and renal diseases are frequently coexisting. Hypoxemia is the terminal pathway of a multitude of respiratory pathologies. The measurement of oxygen saturation (SO2) is a basic and commonly used tool in clinical practice. Both arterial oxygen saturation (SaO2) and central venous oxygen saturation (ScvO2) can be easily obtained in hemodialysis (HD) patients, SaO2 from an arteriovenous access and ScvO2 from a central catheter. Here, we give a brief overview of the anatomy and physiology of the respiratory system, and the different technologies that are currently available to measure oxygen status in dialysis patients. We then focus on literature regarding intradialytic SaO2 and ScvO2. Lastly, we present clinical vignettes of intradialytic drops in SaO2 and ScvO2 in association with different symptoms and clinical scenarios with an emphasis on the pathophysiology of these cases. Given the fact that in the general population hypoxemia is associated with adverse outcomes, including increased mortality, cardiac arrhythmias and cardiovascular events, we posit that intradialytic SO2 may serve as a potential marker to identify HD patients at increased risk for morbidity and mortality.

A physiologically based model of vascular refilling during ultrafiltration in hemodialysis.

An assessment of fluid status can be obtained by monitoring relative blood volume (RBV) during hemodialysis (HD) treatment. The dynamics of RBV is determined by fluid removal from the intravascular compartment by ultrafiltration (UF) and vascular refill from the interstitium. To characterize this dynamics, a two-compartment model describing the short-term dynamics of vascular refilling and UF is developed. Fluid movement between the compartments is governed by lymphatic and microvascular fluid shifts. Further, protein flux is described by convection, diffusion and the lymphatic protein flux. Patient specific parameters are identified based on hematocrit (Hct) measurements by the Crit-Line monitor (CLM). Different measurement frequencies and UF profiles are compared to determine data fidelity and influence on the quality of parameter estimates. This relevant information can be used to assess the (patho)physiological status of hemodialysis patients and could aid in individualizing therapy.

It's a non-dialysis day Do you know how your patient is doing? A case for research into interdialytic activity.

Hemodialysis (HD) patients are less active than their healthy counterparts; this is associated with higher mortality. Healthcare workers observe their patients only during HD, which accounts for about 7% of the week. Knowing more about what occurs in between sessions, particularly with respect to physical activity, may improve patient care and prognosis. Yet without a standard method to measure interdialytic activity, it is difficult to compare the effect of interventions. However, it is unclear how interdialytic activity can be accurately measured. Since activity associated with quality of life is multi-dimensional, objective and subjective tools should be used in conjunction. While commercially available tracking devices can be seamlessly incorporated into everyday life and can increase awareness of user's activity, their validation is needed in the HD population. Fertile topics for research should include the relationship between objective and subjective measures in HD patients, and the investigation of physical activity in non-ambulatory HD patients.

Nano-visualization of viral DNA breaching the nucleocytoplasmic barrier.

Nuclear pore complexes (NPCs) mediate all transport between the cytosol and the nucleus highly selectively. Their selectivity can become an insurmountable hurdle for exogenously applied therapeutic macromolecules. Many viruses naturally overcome the NPC barrier. Therefore, gene therapy often utilizes viral particles as nano-carriers for exogenous therapeutic macromolecules. Viral gene therapy, however, frequently leads to severe adverse effects. We intend to elucidate the mechanisms underlying controlled release of viral DNA at the NPC in order to design new non-viral approach for intranuclear DNA delivery. For this purpose, we developed a comprehensive experimental strategy combining nano-imaging and biochemical methods. Here, we apply Herpes simplex virus type 1 (HSV-1) as an ideal example. HSV-1 contains its long 145kbp DNA in a capsid which is merely 125nm in size. The capsid shields and targets the DNA specifically to the NPC. Only at the NPC, the capsid releases the DNA for nuclear delivery. The underlying mechanisms of this multi-step process remain unresolved. In this work we follow the fate of HSV-1 DNA in the process of transit across the NPC. Our results indicate an involvement of hydrophobicity for capsid opening. Furthermore, the DNA is presumably released as a single thread. We assume that it penetrates the NPC in this conformation. It is compacted by the host intranuclear proteins once it reaches the interior of the nucleus. Our proposed experimental strategy can be extended to other viruses. Moreover, our observations may help design potent non-viral based nano-carriers for gene therapy.