Translation of immunomodulatory therapy to treat chronic heart failure: Preclinical studies to first in human

BACKGROUND: Inflammation has been associated with progression and complications of chronic heart failure (HF) but no effective therapy has yet been identified to treat this dysregulated immunologic state. The selective cytopheretic device (SCD) provides extracorporeal autologous cell processing to lessen the burden of inflammatory activity of circulating leukocytes of the innate immunologic system. AIM: The objective of this study was to evaluate the effects of the SCD as an extracorporeal immunomodulatory device on the immune dysregulated state of HF. HF. METHODS AND RESULTS: SCD treatment in a canine model of systolic HF or HF with reduced ejection fraction (HFrEF) diminished leukocyte inflammatory activity and enhanced cardiac performance as measured by left ventricular (LV) ejection fraction and stroke volume (SV) up to 4 weeks after treatment initiation. Translation of these observations in first in human, proof of concept clinical study was evaluated in a patient with severe HFrEFHFrEF ineligible for cardiac transplantation or LV LV assist device (LVAD) due to renal insufficiency and right ventricular dysfunction. Six hour SCD treatments over 6 consecutive days resulted in selective removal of inflammatory neutrophils and monocytes and reduction in key plasma cytokines, including tumor necrosis factor-alpha (TNF-α),), interleukin (IL)-6, IL-8, and monocyte chemoattractant protein (MCP)-1. These immunologic changes were associated with significant improvements in cardiac power output, right ventricular stroke work index, cardiac index and LVSV index…. Stabilization of renal function with progressive volume removal permitted successful LVAD implantation. CONCLUSION: This translational research study demonstrates a promising immunomodulatory approach to improve cardiac performance in HFrEFHFrEF and supports the important role of inflammation in the progression of HFHF

Management of dysnatremias with continuous renal replacement therapy

Disorders of serum sodium concentration are common in critically ill patients who may have concomitant acute kidney injury, chronic kidney disease, or end‐stage kidney disease. Many of these patients may require customized serum sodium level management with dialysis which, if not strictly controlled, can lead to significant complications. Thus, controlled correction of the serum sodium level is necessary to avoid the development of osmotic demyelination syndrome in hyponatremic patients and dialysis disequilibrium syndrome in hypernatremic patients. Continuous renal replacement therapy offers unique benefits through the ability to slowly and safely correct dysnatremias that can be tailored to specific patient needs and should be considered in select patients.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/170939/1/sdi12983.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/170939/2/sdi12983_am.pd

Association of Systolic Blood Pressure Variability With Mortality, Coronary Heart Disease, Stroke, and Renal Disease.

BackgroundIntraindividual blood pressure (BP) fluctuates dynamically over time. Previous studies suggested an adverse link between greater visit-to-visit variability in systolic blood pressure (SBP) and various outcomes. However, these studies have significant limitations, such as a small size, inclusion of selected populations, and restricted outcomes.ObjectivesThis study investigated the association of increased visit-to-visit variability and all-cause mortality, cardiovascular events, and end-stage renal disease (ESRD) in a large cohort of U.S. veterans.MethodsFrom among 3,285,684 U.S. veterans with and without hypertension and normal estimated glomerular filtration rates (eGFR) during 2005 and 2006, we identified 2,865,157 patients who had 8 or more outpatient BP measurements. Systolic blood pressure variability (SBPV) was measured using the SD of all SBP values (normally distributed) in 1 individual. Associations of SD quartiles (<10.3, 10.3 to 12.7, 12.7 to 15.6, and ≥15.6 mm Hg) with all-cause mortality, incident coronary heart disease (CHD), stroke, and ESRD was examined using Cox models adjusted for sociodemographic characteristics, baseline eGFR, comorbidities, body mass index, SBP, diastolic BP, and antihypertensive medication use.ResultsSeveral sociodemographic variables (older age, male sex, African-American race, divorced or widowed status) and clinical characteristics (lower baseline eGFR, higher SBP and diastolic BP), and comorbidities (presence of diabetes, hypertension, cardiovascular disease, and lung disease) were all associated with higher intraindividual SBPV. The multivariable adjusted hazard ratios and 95% confidence intervals for SD quartiles 2 through 4 (compared with the first quartile) associated with all-cause mortality, CHD, stroke, and ESRD were incrementally higher.ConclusionsHigher SBPV in individuals with and without hypertension was associated with increased risks of all-cause mortality, CHD, stroke, and ESRD. Further studies are needed to determine interventions that can lower SBPV and their impact on adverse health outcomes

Long-term decline in renal function is more significant after endovascular repair of infrarenal abdominal aortic aneurysms

OBJECTIVE: It is not clear whether endovascular aneurysm repair (EVAR) of abdominal aortic aneurysms (AAAs) results in an increase in renal insufficiency during the long term compared with open repair (OR). We reviewed our experience with AAA repair to determine whether there was a significant difference in postoperative and long-term renal outcomes between OR and EVAR. METHODS: A retrospective cohort study was conducted of all patients who underwent AAA repair between January 1993 and July 2013 at a tertiary referral hospital. Demographics, comorbidities, preoperative and postoperative laboratory values, morbidity, and mortality were collected. Patients with ruptured AAAs, preoperative hemodialysis, juxtarenal or suprarenal aneurysm origin, and no follow-up laboratory values were excluded. Preoperative, postoperative, 6-month, and yearly serum creatinine values were collected. Glomerular filtration rate (GFR) was calculated on the basis of the Chronic Kidney Disease Epidemiology Collaboration equation. Acute kidney injury (AKI) was classified using the Kidney Disease: Improving Global Outcomes guidelines. Change in GFR was defined as preoperative GFR minus the GFR at each follow-up interval. Comparison was made between EVAR and OR groups using multivariate logistics for categorical data and linear regression for continuous variables. RESULTS: During the study period, 763 infrarenal AAA repairs were performed at our institution; 675 repairs fit the inclusion criteria (317 ORs and 358 EVARs). Mean age was 73.9 years. Seventy-nine percent were male, 78% were hypertensive, 18% were diabetic, and 31% had preoperative renal dysfunction defined as GFR below 60 mL/min. Using a multivariate logistic model to control for all variables, OR was found to have a 1.6 times greater chance for development of immediate postoperative AKI compared with EVAR (P = .038). Hypertension and aneurysm size were independent risk factors for development of AKI (P = .012 and .022, respectively). Using a linear regression model to look at GFR decline during several years, there was a greater decline in GFR in the EVAR group. This became significant starting at postoperative year 4. AKI and preoperative renal dysfunction were independent risk factors for long-term decline in renal function. CONCLUSIONS: Although AKI is less likely to occur after EVAR, patients undergoing EVAR experience a significant but delayed decline in GFR over time compared with OR. This became apparent after postoperative year 4. Studies comparing EVAR and OR may need longer follow-up to detect clinically significant differences in renal function

Long-term decline in renal function is more significant after endovascular repair of infrarenal abdominal aortic aneurysms

OBJECTIVE: It is not clear whether endovascular aneurysm repair (EVAR) of abdominal aortic aneurysms (AAAs) results in an increase in renal insufficiency during the long term compared with open repair (OR). We reviewed our experience with AAA repair to determine whether there was a significant difference in postoperative and long-term renal outcomes between OR and EVAR. METHODS: A retrospective cohort study was conducted of all patients who underwent AAA repair between January 1993 and July 2013 at a tertiary referral hospital. Demographics, comorbidities, preoperative and postoperative laboratory values, morbidity, and mortality were collected. Patients with ruptured AAAs, preoperative hemodialysis, juxtarenal or suprarenal aneurysm origin, and no follow-up laboratory values were excluded. Preoperative, postoperative, 6-month, and yearly serum creatinine values were collected. Glomerular filtration rate (GFR) was calculated on the basis of the Chronic Kidney Disease Epidemiology Collaboration equation. Acute kidney injury (AKI) was classified using the Kidney Disease: Improving Global Outcomes guidelines. Change in GFR was defined as preoperative GFR minus the GFR at each follow-up interval. Comparison was made between EVAR and OR groups using multivariate logistics for categorical data and linear regression for continuous variables. RESULTS: During the study period, 763 infrarenal AAA repairs were performed at our institution; 675 repairs fit the inclusion criteria (317 ORs and 358 EVARs). Mean age was 73.9 years. Seventy-nine percent were male, 78% were hypertensive, 18% were diabetic, and 31% had preoperative renal dysfunction defined as GFR below 60 mL/min. Using a multivariate logistic model to control for all variables, OR was found to have a 1.6 times greater chance for development of immediate postoperative AKI compared with EVAR (P = .038). Hypertension and aneurysm size were independent risk factors for development of AKI (P = .012 and .022, respectively). Using a linear regression model to look at GFR decline during several years, there was a greater decline in GFR in the EVAR group. This became significant starting at postoperative year 4. AKI and preoperative renal dysfunction were independent risk factors for long-term decline in renal function. CONCLUSIONS: Although AKI is less likely to occur after EVAR, patients undergoing EVAR experience a significant but delayed decline in GFR over time compared with OR. This became apparent after postoperative year 4. Studies comparing EVAR and OR may need longer follow-up to detect clinically significant differences in renal function

Translation of immunomodulatory therapy to treat chronic heart failure: Preclinical studies to first in human

Background Inflammation has been associated with progression and complications of chronic heart failure (HF) but no effective therapy has yet been identified to treat this dysregulated immunologic state. The selective cytopheretic device (SCD) provides extracorporeal autologous cell processing to lessen the burden of inflammatory activity of circulating leukocytes of the innate immunologic system. Aim The objective of this study was to evaluate the effects of the SCD as an extracorporeal immunomodulatory device on the immune dysregulated state of HF. HF. Methods and results SCD treatment in a canine model of systolic HF or HF with reduced ejection fraction (HFrEF) diminished leukocyte inflammatory activity and enhanced cardiac performance as measured by left ventricular (LV) ejection fraction and stroke volume (SV) up to 4 weeks after treatment initiation. Translation of these observations in first in human, proof of concept clinical study was evaluated in a patient with severe HFrEFHFrEF ineligible for cardiac transplantation or LV LV assist device (LVAD) due to renal insufficiency and right ventricular dysfunction. Six hour SCD treatments over 6 consecutive days resulted in selective removal of inflammatory neutrophils and monocytes and reduction in key plasma cytokines, including tumor necrosis factor-alpha (TNF-α),), interleukin (IL)-6, IL-8, and monocyte chemoattractant protein (MCP)-1. These immunologic changes were associated with significant improvements in cardiac power output, right ventricular stroke work index, cardiac index and LVSV index…. Stabilization of renal function with progressive volume removal permitted successful LVAD implantation. Conclusion This translational research study demonstrates a promising immunomodulatory approach to improve cardiac performance in HFrEFHFrEF and supports the important role of inflammation in the progression of HFHF

Translation of immunomodulatory therapy to treat chronic heart failure: Preclinical studies to first in human.

BackgroundInflammation has been associated with progression and complications of chronic heart failure (HF) but no effective therapy has yet been identified to treat this dysregulated immunologic state. The selective cytopheretic device (SCD) provides extracorporeal autologous cell processing to lessen the burden of inflammatory activity of circulating leukocytes of the innate immunologic system.AimThe objective of this study was to evaluate the effects of the SCD as an extracorporeal immunomodulatory device on the immune dysregulated state of HF. HF.Methods and resultsSCD treatment in a canine model of systolic HF or HF with reduced ejection fraction (HFrEF) diminished leukocyte inflammatory activity and enhanced cardiac performance as measured by left ventricular (LV) ejection fraction and stroke volume (SV) up to 4 weeks after treatment initiation. Translation of these observations in first in human, proof of concept clinical study was evaluated in a patient with severe HFrEFHFrEF ineligible for cardiac transplantation or LV LV assist device (LVAD) due to renal insufficiency and right ventricular dysfunction. Six hour SCD treatments over 6 consecutive days resulted in selective removal of inflammatory neutrophils and monocytes and reduction in key plasma cytokines, including tumor necrosis factor-alpha (TNF-α),), interleukin (IL)-6, IL-8, and monocyte chemoattractant protein (MCP)-1. These immunologic changes were associated with significant improvements in cardiac power output, right ventricular stroke work index, cardiac index and LVSV index…. Stabilization of renal function with progressive volume removal permitted successful LVAD implantation.ConclusionThis translational research study demonstrates a promising immunomodulatory approach to improve cardiac performance in HFrEFHFrEF and supports the important role of inflammation in the progression of HFHF

Safety Summary of the Selective Cytopheretic Device: A Review of Safety Data Across Multiple Clinical Trials in ICU Patients With Acute Kidney Injury and Multiple Organ Failure

OBJECTIVES:. Acute kidney injury (AKI) requiring continuous kidney replacement therapy is a significant complication in ICU patients with mortality rates exceeding 50%. A dysregulated immune response can lead to systemic inflammation caused by hyperactivity of pro-inflammatory neutrophils and monocytes leading to tissue damage. The selective cytopheretic device (SCD) is an investigational medical device in a new class of cell-directed extracorporeal therapies distinct from cytokine adsorbers or filters, as it targets activated leukocytes. These leukocytes are the cellular sources driving this hyperinflammatory process. The objective of this report is to summarize the safety experience from clinical studies of the SCD in ICU patients with AKI or acute respiratory distress syndrome (ARDS) and multiple organ dysfunction (MOD). DATA SOURCES AND STUDY SELECTION:. The studies included in this report represent all relevant trials of the SCD conducted in patients with AKI or ARDS and MOD. Adverse event data, clinical laboratory data and mortality rates were described and summarized in this report. DATA EXTRACTION AND DATA SYNTHESIS:. Five clinical studies were included in this report, including four adult studies of AKI and/or ARDS and one pediatric AKI study, which involved 151 patients treated with the SCD in an ICU setting. Over 800 SCD sessions were deployed with an estimated 19,000 exposure hours with no device-related infections or attributable serious adverse events. Furthermore, there were no safety signals of leukopenia, thrombocytopenia, or other indications of immunodepletion or immunosuppression. CONCLUSIONS:. The SCD has shown to be a promising extracorporeal therapy with promising clinical results and a favorable safety profile. These studies support that the SCD can be added as a therapeutic intervention in critically ill AKI patient populations with multiple organ failure without adding additional safety risks

Change in Lactate Levels After Hemodialysis in Patients With End-Stage Renal Disease

STUDY OBJECTIVE: Patients with end-stage renal disease commonly visit the emergency department (ED). The purpose of this investigation is to examine the prevalence of baseline abnormal lactate levels and to evaluate the effects of hemodialysis on serum lactate levels. METHODS: This was a prospective observational cohort study performed at an outpatient dialysis facility at an urban tertiary care hospital. The study consisted of 226 patients with end-stage renal disease who were receiving long-term hemodialysis and were enrolled during a 2-day period at the beginning of December 2015. Blood drawn for lactate levels was immediately analyzed before and after hemodialysis sessions. All patients completed their hemodialysis sessions. RESULTS: The prevalence of an abnormal lactate level (greater than 1.8 mmol/L) before hemodialysis was 17.7% (n=40). Overall, lactate levels decreased by 27% (SD 35%) after hemodialysis, with a decrease of 37% (SD 31%) for subgroups with a lactate level of 1.9 to 2.4 mmol/L, and 62% (SD 14%) with a lactate of 2.5 to 3.9 mmol/L. CONCLUSION: The data presented help providers understand the prevalence of abnormal lactate values in an outpatient end-stage renal disease population. After hemodialysis, lactate levels decreased significantly. This information may help medical providers interpret lactate values when patients with end-stage renal disease present to the ED