Impaired Delivery of Cholesterol Effluxed From Macrophages to Hepatocytes by Serum From CKD Patients May Underlie Increased Cardiovascular Disease Risk.

INTRODUCTION: Although chronic kidney disease (CKD) is associated with increased risk for coronary artery disease (CAD), the underlying mechanisms are not completely defined. In the present study, we tested the hypothesis that flux of cholesterol from macrophage foam cells to liver is impaired in subjects with CKD. METHODS: Consecutive healthy patients, patients with at least 1 CAD risk factor, patients with established CAD, and patients with CKD stages G3 to G5 (n ≥ 15/group) were recruited prospectively. The ability of total patient serum without any modifications to (i) facilitate efflux of cholesterol from human THP1-macrophage foam cells under physiological conditions (cholesterol efflux capacity [CEC]) and (ii) to deliver this effluxed cholesterol to primary hepatocytes with physiological expression of high-density lipoprotein (HDL) receptor SR-BI (capacity to deliver cholesterol to hepatocytes [CDCH]) was evaluated. RESULTS: Although healthy patients, patients with at least 1 CAD risk factor, and patients with established CAD all showed similar CEC, patients with CKD showed significantly higher CEC. CDCH was significantly lower in all groups compared with the healthy patients; however, when corrected for higher CEC, CDCH in patients with CKD was significantly lower than in patients with CAD. CDCH correlated with age, body mass index, metabolic parameters, inflammatory markers, and kidney function markers (estimated glomerular filtration rate [eGFR], serum creatinine, and serum cystatin C). CONCLUSIONS: These results suggest that aberrations in delivery of cholesterol effluxed from macrophage foam cells to liver for final elimination or the last step of reverse cholesterol transport, may underlie the increased risk of CAD in patients with CKD.

Unsupervised analysis of combined lipid and coagulation data reveals coagulopathy subtypes among dialysis patients.

Hemodialysis (HD) and peritoneal dialysis (PD) are the primary means of managing end stage renal disease (ESRD). However, these treatment modalities are associated with the onset of coagulation abnormalities. Effective management of coagulation risk among these patients requires the identification of surrogate markers that provide an early indication of the coagulation abnormalities. The role of sphingolipids in the manifestation and prediction of coagulation abnormalities among dialysis patients have never been investigated. Herein, we report the first instance of an in depth investigation into the sphingolipid changes among ESRD patients undergoing HD and PD. The results reveal distinct differences in terms of perturbations to specific sphingolipid biosynthetic pathways that are highly dependent on the treatment modality. Our studies also demonstrated strong correlation between specific sphingolipids and coagulation parameters, such as HexCer(d18:1/26:0) and maximal amplitude (MA), SM(d18:1/24:1) and tissue factor pathway inhibitor, and sphingosine 1-phosphate d18:1 and FX (Spearman ρ of 0.93, 0.89, and -0.89, respectively). Furthermore, our study revealed the potential for using HexCer(d18:1/22:0), HexCer(d18:1/24:0), and HexCer(d18:1/26:0) (r2 = 0.71, 0.82, and 0.63, respectively) and coagulation parameter MA (r2 = 0.7) for successful diagnosis of differential coagulopathies among ESRD patients undergoing HD, providing an opportunity toward personalized disease management.

Effectiveness of a Pharmacist-Physician Team-Based Collaboration to Improve Long-Term Blood Pressure Control at an Inner-City Safety-Net Clinic.

PURPOSE: To evaluate the effectiveness of a pharmacist-physician collaborative practice model (PPCPM) to improve long-term blood pressure (BP) control rates in a primarily African-American underserved urban population. PRACTICE INNOVATION: Volunteer physicians established initial diagnoses, whereas pharmacists provided most (more than 70%) of the medication management. During each scheduled visit, the pharmacist reconciled the medication list, completed a clinical interview, conducted a focused physical examination, developed and implemented a treatment plan, and provided documentation in a shared medical record. EVALUATION: A retrospective chart review was performed to collect data for a longitudinal cohort of patients managed by the PPCPM from 2010-2013. RESULTS: Of 385 patients with at least two pharmacist visits during 2009, 172 patients received continuous care over the study period. At baseline, the mean age of the cohort was 51.3 years, 62% were female, and 76% were African-American. Approximately 65% were obese (body mass index 30 kg/m(2) or higher), and 39% were cigarette smokers. Mean baseline BP was 156/98 mm Hg, with only 17% of the cohort at their BP goal of lower than 140/90 mm Hg. The BP control rate improved to 66% during the first year and persisted throughout the study period, with 68% of patients at goal in 2013 (p<0.05 compared with baseline). CONCLUSION: The PPCPM BP control rate ranks in the 90th percentile of National Committee for Quality Assurance benchmarks and was superior even to the 2013 reported mean for commercial insurers. The PPCPM effectively improved hypertension control in an uninsured, primarily African-American, urban population despite significant health barriers. Key elements of this asynchronous care model included access to a common medical record, optimization of distinct interprofessional roles, frequent follow-up with evaluation, and collaborative practice agreement with sufficient scope of practice to implement medication changes at the time of the visit.

A model of acute kidney injury in mice with cirrhosis and infection.

BACKGROUND & AIMS: Infectious acute kidney injury (AKI) is a life threatening complication of cirrhosis with limited therapeutic options. The aim of this study was to develop a model of infectious AKI in cirrhotic mice. METHODS: Cirrhosis was established by intragastric administration of carbon tetrachloride (CCl4 ). Systemic haemodynamics was assessed invasively while cardiac function was assessed by echocardiography. AKI was induced using varying doses of lipopolysaccharide (LPS) titrated to produce 50% lethality. Renal function was assessed from serum creatinine and urine output (UOP). Renal injury was evaluated by urinalysis (proteinuria and casts) and renal histology. These mice were compared to: (i) normal mice, (ii) normal mice + LPS, and (iii) mice treated with CCl4 alone. RESULTS: Cirrhosis with increased cardiac output, decreased systemic vascular resistance, activation of renin-angiotensin-aldosterone axis developed after 12 weeks of CCl4 administration. LPS injection produced a dose-dependent increase in mortality (33% at 2 mg/kg vs. 80% at 6 mg/kg) without urine (casts or proteinuria) or histological evidence of tubular injury. 2 mg/kg LPS injection produced a rise in creatinine (0.79 ± 0.27 mg/dl in CCl4 +LPS compared to 0.45 ± 0.14 in CCl4 alone, P < 0.05) and a decrease in UOP (0.86 ± 0.4 ml/16 h in CCl4 + LPS compared to 1.70 ± 0.7 ml/16 h in CCl4 mice, P < 0.05). UOP remained low in mice that died while it recovered over 48-72 h in those that recovered. Control mice treated with 2 mg/kg LPS did not experience AKI. CONCLUSIONS: Cirrhotic CCl4 treated mice develop functional AKI and mimic most of the features of infectious AKI following LPS injection.

Differences in coagulation between hemodialysis and peritoneal dialysis.

BACKGROUND: End-stage renal disease patients have significant cardiovascular morbidity and mortality, but little is known about differences in coagulation profiles between patients on hemodialysis (HD) and on peritoneal dialysis (PD). Given their long-term exposure to glucose-based dialysate, patients on PD can experience metabolic derangements. Theoretically, that exposure should create a more prothrombotic environment than occurs in HD patients. The objective of the present study was to quantify potential differences in baseline coagulation between PD and HD patients. ♢ METHODS: Our single-center cross-sectional study at a large academic health science center enrolled 50 age-, race-, and sex-matched subjects (10 control subjects, 20 HD patients, and 20 PD patients). Measurements included platelet function, platelet receptor distribution, and coagulation dynamics by thromboelastography and Hemodyne hemostasis assay (Hemodyne, Richmond, VA, USA). ♢ RESULTS: Compared with healthy control subjects, patients on both forms of dialysis showed prothrombotic coagulation protein profiles. The tissue-factor pathway was markedly elevated in both groups, but PD was associated with significantly greater concentrations of tissue factor (p = 0.0056) and tissue-factor pathway inhibitor (p = 0.0138). Similarly, compared with patients receiving HD, patients on PD had greater concentrations of fibrinogen (p = 0.0325), which corresponded with platelet hyperfunction as measured by platelet contractile force and clot elastic modulus (p = 0.003 and 0.017 respectively, compared with values in HD patients). Platelet receptor distribution was similar between the groups. ♢ CONCLUSIONS: Compared with patients on HD, patients on PD appear to have a more prothrombotic profile. The clinical relevance of these findings needs to be studied in a prospective manner.

Post-paracentesis circulatory derangements are related to monocyte activation.

BACKGROUND & AIMS: Post-paracentesis circulatory dysfunction is associated with development of hepatorenal syndrome and increased mortality. The impact of large volume paracentesis (LVP) on the 24-h blood pressure (BP) profile is unknown, and the relationship to Na+-retentive and pro-inflammatory cytokines also remains unknown. The aims of this study were to (i) define the effects of LVP with albumin administration on 24-h BP profiles, and (ii) relate changes in BP over time to changes in Na+-retentive hormones, clinical factors and inflammatory cytokines. METHODS: Ten patients undergoing LVP had 24-h ambulatory BP monitoring performed pre- and post-paracentesis. Markers of the innate immune system, bacterial translocation and Na+-retentive hormones were drawn pre- and post-LVP. RESULTS: Mean arterial pressure (MAP) dropped in nine of the 10 patients in the 24 h following a paracentesis compared to 24 h preceding the procedure (mean drop of 5.5 mmHg, P<0.005). A mixed effects model was used to define time-covariate interactions in predicting changes in BP profile. Monocyte chemotactic protein-1 (MCP1) was associated with Δsystolic BP (ß=-0.011, P<0.05), Δdiastolic BP (ß=-0.012, P<0.05) and ΔMAP (ß=-0.012, P<0.05). Plasma renin activity was also significantly associated with Δsystolic BP (ß=-0.21, P<0.05). Renal function was also significantly reduced following LVP. CONCLUSIONS: Systolic, diastolic and MAP decreased over 24 h after LVP compared to the 24 h pre-LVP. This drop is related to increases in MCP-1 after LVP. Increased MCP-1, a marker of monocyte activation, was strongly related to changes in BP.

An Epidemiological Study of Anemia and Renal Dysfunction in Patients Admitted to ICUs across the United States.

The aims of this study were to determine the associations between anemia of critical illness, erythropoietin stimulating agents (ESA), packed red blood cell transfusions and varying degrees of renal dysfunction with mortality, and ICU- and hospital length of stay (LOS). This was a cross-sectional retrospective study of 5,314 ICU patients from USA hospitals. Hospital, patient demographics, and clinical characteristics were collected. Predictors of mortality and hospital and ICU LOS were evaluated using multivariate logistic regression models. The mean ICU admission hemoglobin in this study was 9.4 g/dL. The prevalence of ESA use was 13% and was associated with declining renal function; 26% of the ICU patients in this study received transfusion. ESA utilization was associated with 28% longer hospital LOS (P < 0.001). ICU LOS was increased by up to 18% in patients with eGFR rates of <30 and 30-59 mL/min/1.73 m(2), respectively (P < 0.05) but not in those receiving dialysis. Mortality was significantly associated with renal dysfunction and dialysis with odds ratios of 1.94, 2.66 and 1.40 for the dialysis, and eGFR rates of <30 and 30-59 and mL/min/1.73 m(2), respectively (P < 0.05). These data provide a snapshot of anemia treatment practices and outcomes in USA ICU patients with varying degrees of renal dysfunction.

Medical management of the liver transplant recipient.

Long-term survival of liver transplant recipients has become the rule rather than the exception. As a result, the medical complications of long-term survival, including atherosclerotic cardiovascular disease, metabolic bone disease, and de novo malignancy, have accounted for an increasing proportion of late morbidity and mortality. Risk factors for these complications begin before transplant and are potentially modifiable but are exacerbated by the requirement for immunosuppressive medications after transplantation. Surveillance and early intervention programs administered by transplant hepatologists and other medical subspecialists may improve long-term outcomes in liver transplant recipients by ameliorating risk factors for atherosclerosis, bone fractures, and cancer.

Effect of timing of dialysis on mortality in critically ill, septic patients with acute renal failure.

Acute renal failure with concomitant sepsis in the intensive care unit is associated with significant mortality. The purpose of this study was to determine if the timing of initiation of renal replacement therapy (RRT) in septic patients had an effect on the 28-day mortality. Retrospective data on medical intensive care unit patients with sepsis and acute renal failure requiring RRT were included. Renal replacement therapy started with a blood urea nitrogen (BUN) of <100 mg/dL was defined as "early" initiation, and initiation with a BUN >or=100 mg/dL was defined as "late." Multivariate logistic regression analysis with the primary outcome of death at 14, 28, and 365 days following the initiation of RRT was performed. One hundred thirty patients were studied. The early dialysis (mean BUN 66 mg/dL) group had 85 patients; the late group (mean BUN 137 mg/dL) had 62 patients. The mean acute physiology and chronic health evaluation II score was 24.5 in both groups. The overall 14, 28, and 365-day survival rates were 58.1%, 41.9%, and 23.6%. Survival rates for the early group were 67%, 47.7%, and 30.7% at 14, 28, and 365 days. Survival rates for the late group were 46.7%, 31.7%, and 13.3% at 14, 28, and 365 days. Upon logistic regression analysis, initiating dialysis with a BUN >100 mg/dL predicted death at 14 days (odds ratio [OR] 3.6, 95% confidence interval [CI] 1.7-7.6, P=0.001), 28 days (OR 2.6, 95% CI 1.2-5.7, P=0.01), and 365 days (OR 3.5, 95% CI 1.2-10, P=0.02). Septic patients who started dialysis with a BUN <100 mg/dL had improved mortality rates up to 1 year after initiation of dialysis in this single-center, retrospective analysis.

An in vivo-in vitro study of cefepime and cefazolin dialytic clearance during high-flux hemodialysis.

STUDY OBJECTIVES: To assess the influence of in vitro and in vivo hemodialysis with a new high-flux dialyzer on the clearance of cefazolin and cefepime; to assess the correlation of in vivo dialytic clearance of these antibiotics with blood flow rate; and to assess the correlation between in vitro and in vivo dialytic clearances of these antibiotics. DESIGN: Prospective, open-label, dialysis clearance study. SETTING: A tertiary-care, university health science center. PATIENTS: Five adults who received high-flux hemodialysis 3 times/week. Intervention. For the in vivo experiment, patients received a single intravenous infusion of cefazolin 1 g and cefepime 1 g before dialysis and then underwent a modified hemodialysis session. For the in vitro experiment, a buffered simulated plasma water (SPW) solution containing cefazolin and cefepime was used. Hemodialysis for both experiments was performed with use of a new high-flux polysulfone dialyzer. MEASUREMENTS AND MAIN RESULTS: Cefazolin and cefepime dialytic clearances were determined at blood and/or SPW flow rates of 100, 200, 300, and 400 ml/minute after a 15-minute equilibration period. The degree of correlation of in vitro and in vivo clearances with blood flow rate was determined. Cefepime dialytic clearance increased proportionally with blood flow rate (p<0.01), reaching a maximum mean +/- SD value of 178.9 +/- 24.3 ml/minute at a blood flow rate of 400 ml/minute. Cefazolin dialytic clearance ranged from a mean +/- SD of 42.3 +/- 7.7 to 52.7 +/- 16 ml/minute; no significant correlation was noted between blood flow rate and dialytic clearance. In vitro cefazolin and cefepime dialytic clearances increased proportionally with SPW flow rate (p<0.05). After adjusting the in vitro cefazolin and cefepime dialytic clearances based on their degrees of protein binding, the correlation between the in vitro and in vivo cefepime dialytic clearances was significant (r(2)=0.91, p=0.04), but no significant correlation was noted between the in vitro and in vivo cefazolin clearances (r(2)=0.61, p=0.22). CONCLUSION: The in vivo hemodialysis clearances of cefepime and cefazolin with the new high-flux polysulfone dialyzer used in this study are markedly higher than values reported with conventional dialyzers but similar to values observed with other high-flux hemodialyzers. The in vivo dialytic clearance of cefazolin was significantly lower than the in vitro values, most likely due to cefazolin's high degree of protein binding. These results highlight the limitation of directly applying in vitro data to clinical situations.

Estimating dialysis adequacy using ionic dialysance.

The aim of this study was to determine the efficacy and feasibility of estimating dialysis adequacy using ionic dialysance (ID). We retrospectively reviewed the medical records of patients receiving thrice weekly dialysis for an eight-month period at a single-center Veterans Affairs hospital. Dialysis adequacy was determined monthly using pre- and post-treatment BUN measurements to calculate the single pool Kt/V (spKt/V) with the formula set forth by Daugirdas. On the same treatment day, K(ID)t was determined by multiplying the average ID times the time (t) of the treatment. A surrogate volume, V(ID), was estimated by dividing K(ID)t by spKt/V using data from the first six months. During the subsequent two months, we compared dialysis adequacy estimated by urea-based spKt/V to ionic dialysance based K(ID)t/V(ID) utilizing V(ID). In the first month, K(ID)t/V(ID) estimations and the simultaneous spKt/V determinations averaged 1.55 +/- 0.36 and 1.59 +/- 0.42, respectively. In the second month, K(ID)t/V(ID) and spKt/V averaged 1.52 +/- 0.33 and 1.54 +/- 0.35, respectively. K(ID)t/V(ID) correlated well with spKt/V, as the slope was 0.85 (r = 0.95, p < 0.001). There was considerable intra-patient variability of K(ID), time, and K(ID)t/V(ID) with coefficient of variations (CV) of 8.4 +/- 4.3, 9.0 +/- 5.3, and 15.8 +/- 9.2, respectively. However, the CV for K(ID)t/V(ID) was similar to the CV for spKt/V (15.3 +/- 7.4). These results suggest that it is possible to estimate dialysis adequacy during every treatment using K(ID)t/V(ID). Furthermore, there is considerable variability in the delivered dialysis adequacy, suggesting that many sessions result in sub-optimal dialysis.