Epicardial Fat Volume as a Good Predictor for Multivessel Coronary Artery Disease.

INTRODUCTION: Epicardial adipose tissue may have an important role in the pathogenesis of coronary artery disease (CAD). AIM: We aimed to study the association between epicardial fat volume (EFV) and presence of obstructive as well as multivessel CAD. METHODS: A total of 87 adult subjects with suspected CAD who underwent both quantified by multidetector computerized tomography (MDCT) and Invasive Coronary Angiography (ICA) were enrolled in this observational study. EVF was measured by MDCT by calculating the sum of cross- sectional areas of fat multiplied by slice thickness. EFV measurement and its association with the presence of obstructive CAD (defined as coronary artery stenosis > 70%) was evaluated. RESULTS: Overall, 89.6% patients had obstructive CAD with higher EFV as compared to 10.3% patients with non-obstructive CAD (57 ± 20.14 cm3 vs. 44 ± 7.4 cm3; P < 0.001). Furthermore, EFV was significantly increased in group II as compared with group I (74 ± 24.3 ml vs. 53 ± 16.2 ml; P < 0.003). On the hand, the coronary calcium score (CAC) was insignificantly increased in group II as compared with group I (486.1 vs. 211.2; P = 0.10). Multivariate analysis revealed that, EFV might be an independent risk factor for not only the presence of obstructive CAD (odds ratio [OR], 1.062; 95% CI 1.018- 1.108; P < 0.005) but also in predicting multivessel disease affection. CONCLUSIONS: Our results demonstrated that, EFV was significantly increased not only with obstructive CAD, independent of other traditional risk factors and CAC score, but also it can be considered a good predictor of multivessel disease occurrence.

Roxadustat Versus Epoetin Alfa for Treating Anemia in Patients with Chronic Kidney Disease on Dialysis: Results from the Randomized Phase 3 ROCKIES Study.

BACKGROUND: Concerns regarding cardiovascular safety with current treatments for anemia in patients with dialysis-dependent (DD)-CKD have encouraged the development of alternatives. Roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, stimulates erythropoiesis by increasing endogenous erythropoietin and iron availability. METHODS: In this open-label phase 3 study, patients with DD-CKD and anemia were randomized 1:1 to oral roxadustat three times weekly or parenteral epoetin alfa per local clinic practice. Initial roxadustat dose depended on erythropoiesis-stimulating agent dose at screening for patients already on them and was weight-based for those not on them. The primary efficacy end point was mean hemoglobin change from baseline averaged over weeks 28‒52 for roxadustat versus epoetin alfa, regardless of rescue therapy use, tested for noninferiority (margin, -0.75 g/dl). Adverse events (AEs) were assessed. RESULTS: Among 2133 patients randomized (n=1068 roxadustat, n=1065 epoetin alfa), mean age was 54.0 years, and 89.1% and 10.8% were on hemodialysis and peritoneal dialysis, respectively. Mean (95% confidence interval) hemoglobin change from baseline was 0.77 (0.69 to 0.85) g/dl with roxadustat and 0.68 (0.60 to 0.76) g/dl with epoetin alfa, demonstrating noninferiority (least squares mean difference [95% CI], 0.09 [0.01 to 0.18]; P<0.001). The proportion of patients experiencing ≥1 AE and ≥1 serious AE was 85.0% and 57.6% with roxadustat and 84.5% and 57.5% with epoetin alfa, respectively. CONCLUSIONS: Roxadustat effectively increased hemoglobin in patients with DD-CKD, with an AE profile comparable to epoetin alfa. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With Chronic Kidney Disease, on Dialysis. CLINICALTRIALS: gov Identifier: NCT02174731.

Towards a Rational Balanced Pancreatic and Islet Allocation Schema.

Allocation of donated organs for transplantation is a complex process that considers numerous factors such as donor, organ and candidate characteristics and practical issues such as geography. Whole pancreas and isolated islet transplantation are lifesaving for certain individuals with diabetes. Herein, we suggest a revised allocation schema that matches donor characteristics with candidate medical condition while allowing for geographic considerations. It is hoped that adoption of this schema will shorten allocation time, decrease organ waste and optimize the parity between organ donor characteristics and candidate state of health.

Influence of adding vitamin D3 to standard clarithromycin-based triple therapy on the eradication rates of Helicobacter pylori infection.

BACKGROUND AND STUDY AIMS: The successful eradication rates with standard clarithromycin-based triple therapy are declining concerning the high antibiotic resistance rate and adverse drug reactions. This study aims to evaluate the effect of adding 1,25-hydroxyvitamin D3 on the eradication rates of the standard clarithromycin-based triple therapy for Helicobacter pylori infection. PATIENTS AND METHODS: This is a randomized prospective comparative study of 150 patients diagnosed with H. pylori gastritis using magnifying narrow-band imaging endoscopy and supported by a stool antigen test. Patients were divided into two groups: group A (n = 75) treated with amoxicillin, clarithromycin, and esomeprazole for 2 weeks; group B (n = 75) treated with 1,25-hydroxyvitamin D3 for 1 month plus amoxicillin, clarithromycin, and esomeprazole for 2 weeks. The H. pylori eradication rates were assessed using stool antigen test conducted 4 weeks after the end of therapy. Furthermore, the H. pylori eradication rates were assessed with per-protocol (PP) and intention-to-treat (ITT) analyses. RESULTS: The current results showed that H. pylori eradication was achieved in 46 of 62 (74.19%) and 46 of 75 (61.33%) patients via PP and ITT analyses, respectively, in group A. However, eradication was achieved in 60 of 68 (88.23%) and 60 of 75 (80%) patients via PP and ITT analyses, respectively, in group B. Therefore, the H. pylori eradication rates in the group where vitamin D3 was added to the clarithromycin-based triple therapy were significantly higher than in the other groups (p = 0.012 and p = 0.029 in ITT and PP analyses, respectively). CONCLUSIONS: Adding vitamin D3 to the standard clarithromycin-based triple therapy could provide an additional advantage to achieve significantly higher eradication rates for H. pylori infection.

Roxadustat for Treating Anemia in Patients with CKD Not on Dialysis: Results from a Randomized Phase 3 Study.

BACKGROUND: Current anemia therapies for patients with non-dialysis-dependent CKD may require injection and medical visits. Roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, stimulates erythropoiesis and improves iron homeostasis. METHODS: In this double-blind phase 3 study, we randomized patients with non-dialysis-dependent CKD stages 3-5 and hemoglobin <10.0 g/dl (1:1) to thrice-weekly 70-mg oral roxadustat or placebo. Doses were titrated throughout the study based on hemoglobin levels. The primary efficacy end point was mean change from baseline in hemoglobin averaged over weeks 28-52 versus placebo, irrespective of rescue therapy use. We assessed patients for adverse events. RESULTS: The study included 2781 patients, 1393 who received roxadustat and 1388 who received placebo. Mean baseline hemoglobin was 9.1 g/dl for both groups. The mean change in hemoglobin from baseline was 1.75 g/dl (95% confidence interval [95% CI], 1.68 to 1.81) with roxadustat versus 0.40 g/dl (95% CI, 0.33 to 0.47) with placebo, (P<0.001). Among 411 patients with baseline elevated high-sensitivity C-reactive protein, mean change in hemoglobin from baseline was 1.75 g/dl (95% CI, 1.58 to 1.92) with roxadustat versus 0.62 g/dl (95% CI, 0.44 to 0.80) with placebo, (P<0.001). Roxadustat reduced the risk of red blood cell transfusion by 63% (hazard ratio, 0.37; 95% CI, 0.30 to 0.44). The most common adverse events with roxadustat and placebo, respectively, were ESKD (21.0% versus 20.5%), urinary tract infection (12.8% versus 8.0%), pneumonia (11.9% versus 9.4%), and hypertension (11.5% versus 9.1%). CONCLUSIONS: Roxadustat effectively increased hemoglobin in patients with non-dialysis-dependent CKD and reduced the need for red blood cell transfusion, with an adverse event profile comparable to that of placebo. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With CKD, Not on Dialysis, NCT02174627.

The Efficacy of Argon Plasma Coagulation versus Carvedilol for Treatment of Portal Hypertensive Gastropathy.

BACKGROUND/AIM: Several treatment options have been developed for portal hypertensive gastropathy (PHG); medications and endoscopic management. The aim of this study was to evaluate the efficacy and safety of argon plasma coagulation (APC) versus Carvedilol in treatment of a cohort of Egyptian patients with severe PHG. METHODS: A total of 130 patients with severe PHG were enrolled; 10 patients were excluded due to death and failure to complete the treatment sessions accordingly, 120 patients were included. Patients were divided into 2 groups: Group A (n = 52) treated with APC; Group B (n = 68) treated with oral Carvedilol. Success was defined as stabilization of hemoglobin (Hb) over 100 g/dL or Hb increase >10% from pretreatment level and reduction of blood transfusion requirements over the following 3 months after the start of therapy. Upper gastrointestinal endoscopy was performed to assess the degree and site of PHG. APC was conducted to areas with mucosal ectatic vascular lesions. RESULTS: PHG was mostly fundic (36.35%) in APC group and (36.76%) in Carvedilol group (p = 0.56). Throughout follow-up period, there was significant increase in Hb level, serum iron, and serum ferritin with a significant decrease in total iron-binding capacity (TIBC) in APC group as compared to Carvedilol group (p < 0.001). Additionally, there was gradual increase in the mean Hb, serum iron, and serum ferritin and gradual decrease of TIBC in Carvedilol group. Accordingly, there was an overall improvement of iron deficiency anemia (IDA) in both groups; however, it was significantly better in APC group than in Carvedilol group. No major adverse events were detected in both the groups. CONCLUSION: APC significantly improves IDA and decreases transfusion requirements in patients with severe PHG as compared to oral Carvedilol with small risk of adverse events. Furthermore, the combination of APC and Carvedilol unless contraindicated could have a synergistic effect in controlling severe PHG.

The Influence of Adding Diphenhydramine Before Initiation of Moderate Sedation with Midazolam and Pethidine for Improving Quality of Colonoscopy.

BACKGROUND: Combination of Intravenous benzodiazepines with opiates appears to be essential in order to guarantee high quality of moderate sedation during colonoscopy. Diphenhydramine is recommended for endoscopic procedures in difficult-to-sedate patients However, the studies supporting its use have yielded conflicting results. OBJECTIVE: To assess the value of adding diphenhydramine hydrochloride before initiation of moderate sedation with midazolam and pethidine for Improving Quality of Sedation during colonoscopy. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled study of 150 Patients undergoing diagnostic colonoscopy. Of 150 patients, data were analyzed for 100 patients randomized into two groups: Diphenhydramine group (n = 53) received 50 mg of diphenhydramine intravenously before initiation of moderate sedation with pethidine and midazolam while in placebo group (n = 47) received placebo in addition to pethidine and midazolam. Amount of pethidine and midazolam used and Quality of sedation were assessed. RESULTS: The mean doses of pethidine was significantly higher in placebo group as compared to diphenhydramine group (69.9 ± 35.4 mg vs 61.2 ± 21.0 mg, p < 0.01) However, no significant difference between the two groups regarding midazolam mean dose (4.9.±2.1 mg vs 4.8 ± 2.0 mg,p = 0.786). More patients in diphenhydramine group were being very satisfied with the procedure as compared to those in placebo group (88.67% vs 59.57%,p < 0.001).Furthermore more endoscopist in diphenhydramine group were being very satisfied with the procedure as compared to those in placebo group (77.35% vs 51.06%,p < 0.001). CONCLUSIONS: Intravenous diphenhydramine hydrochloride given before initiation of midazolam and pethidine offers a significant Improvement of Quality of moderate Sedation during colonoscopy without increasing the number of sedation related complications.

Adiponectin level changes among Egyptians with gastroesophageal reflux disease.

BACKGROUND AND AIM: Visceral fat is an important endocrine organ that secretes different bioactive substances such as adipocytokines. The aim of this study was to investigate the adiponectin level changes among patients with erosive gastroesophageal reflux disease (GERD)and its consequence on pathogenesis. METHODS: In this study, 150 subjects were selected and divided into four groups: Group І (n = 40) were healthy individuals with an average body mass index and had no gastrointestinal tract symptoms; Group ІІ (n = 50) were patients with mild to moderate erosive esophagitis; Group ІІІ (n = 40) were patients with severe erosive esophagitis; and finally, Group ІV (n = 20) were patients with Barrett's esophagus. Upper gastrointestinal endoscopy was performed for Groups II, III, and IV only, and histopathological assessment was conducted for the suspicious cases of Barrett's esophagus. The measurement of serum adiponectin was performed for all groups using the ELISA test. RESULTS: Our results revealed that the serum level of adiponectin was significantly lower in patients with different grades of GERD as well Barrett's esophagus as compared to healthy controls (P-value < 0.001). Additionally, the serum level of adiponectin was correlated with different grades of GERD as the highest level of the adiponectin was found in the control group (11.05 ± 2.58) followed by mild to moderate GERD (6.39 ± 1.64) and then severe GERD (2.42 ± 1.00); finally, the lowest level was detected in the Barrett's esophagus group (1.99 ± 0.47). Our study showed significant correlation between body mass index, waist circumference, and waist-hip ratio on one hand and serum adiponectin level on the other hand, with a statistically significant difference (P-value < 0.001). The best cut-off value for serum adiponectin was 7.7 (µg/mL), with a sensitivity of 91.8% and specificity of 97.5%. CONCLUSIONS: Low serum adiponectin level appears to be associated with an increased risk of erosive esophagitis, and visceral fat accumulation is related to the impaired secretion of adiponectin, which may have an influence on the pathogenesis of GERD.

Urinary neutrophil gelatinase-associated lipocalin as a marker for disease activity in lupus nephritis.

The neutrophil gelatinase-associated lipocalin (NGAL) has been emerging as a novel biomarker of acute kidney injury while its value in lupus nephritis is uncertain. The aim of this study was to assess urinary NGAL levels as a marker for disease activity in patients with lupus nephritis.This study included 70 systemic lupus erythematosus (SLE) patients; 50 with active lupus nephritis (LN) and 20 without as well as 20 matched controls. The neutrophil gelatinase-associated lipocalin (NGAL) in both serum and urine samples was measured by enzyme-linked immunosorbent assay (ELISA). Patients with active LN received standard treatment then assessed for response as well as the value of urinary NGAL (uNGAL). Our results revealed that, The SLE patients with or without LN had an elevated urinary NGAL as compared to controls (p < 0.000) and the mean of uNGAL was (20.67 ± 5.34),(10.63 ± 3.53),(5.65 ± 2.49) respectively. Furthermore,Urinary NGAL levels in LN patients were significantly higher than those in non-LN patients (P < 0.0001). In the ROC curve analysis , the diagnostic performance of uNGAL for discriminating patients with nephritis from those without nephritis showed that the best cutoff value was 13.66 ng/ml ,sensitivity 92%,specificity 75%,area undercurve (0.959) and (P < 0.0001). Measurement of urinary NGAL levels showed an excellent diagnostic performance for discriminating patients with LN from SLE without nephritis.

Exocytosis Protein DOC2B as a Biomarker of Type 1 Diabetes.

Context: Efforts to preserve ß-cell mass in the preclinical stages of type 1 diabetes (T1D) are limited by few blood-derived biomarkers of ß-cell destruction. Objective: Platelets are proposed sources of blood-derived biomarkers for a variety of diseases, and they show distinct proteomic changes in T1D. Thus, we investigated changes in the exocytosis protein, double C2 domain protein-ß (DOC2B) in platelets and islets from T1D humans, and prediabetic nonobese diabetic (NOD) mice. Design, Patients, and Main Outcome Measure: Protein levels of DOC2B were assessed in platelets and islets from prediabetic NOD mice and humans, with and without T1D. Seventeen new-onset T1D human subjects (10.3 ± 3.8 years) were recruited immediately following diagnosis, and platelet DOC2B levels were compared with 14 matched nondiabetic subjects (11.4 ± 2.9 years). Furthermore, DOC2B levels were assessed in T1D human pancreatic tissue samples, cytokine-stimulated human islets ex vivo, and platelets from T1D subjects before and after islet transplantation. Results: DOC2B protein abundance was substantially reduced in prediabetic NOD mouse platelets, and these changes were mirrored in the pancreatic islets from the same mice. Likewise, human DOC2B levels were reduced over twofold in platelets from new-onset T1D human subjects, and this reduction was mirrored in T1D human islets. Cytokine stimulation of normal islets reduced DOC2B expression ex vivo. Remarkably, platelet DOC2B levels increased after islet transplantation in patients with T1D. Conclusions: Reduction of DOC2B is an early feature of T1D, and DOC2B abundance may serve as a valuable in vivo indicator of ß-cell mass and an early biomarker of T1D.

The effect of vitamin D deficiency on eradication rates of Helicobacter pylori infection.

BACKGROUND/AIM: Many studies have investigated risk factors other than antibiotic resistance linked to Helicobacter pylori (H. pylori) eradication failure. The aim of this study was to study the effect of serum levels of 25-hydroxy-vitamin D (25[OH]D) on eradication rates of H. pylori infection. METHODS: This study included 150 patients diagnosed with H. pylori gastritis using magnifying narrow-band imaging endoscopy supported by stool antigen test. Serum 25-OH vitamin D levels were measured via the Enzyme-Linked Immune Sorbent assay (ELISA) method before starting eradication therapy of H. pylori infection. All patients were treated with clarithromycin-based triple therapy for 14 days. H. pylori eradication was determined via a stool antigen test performed 4 weeks after the end of therapy. According to the serum level of 25-OH vitamin D levels, the patients were divided into two groups: group I (sufficient) had a vitamin D level of ≥20 ng/mL, while group II (deficient) had a vitamin D level of <20 ng/mL. RESULTS: Our results revealed that eradication was successful in 105 (70%) patients and failed in 45 (30%) patients. The mean 25[OH]D level was significantly lower in the eradication failure group compared to the successful treatment group (14.7 ± 4.5 vs 27.41 ± 7.1; P < 0.001). Furthermore, there were significantly more patients with deficient 25[OH]D levels in the failed treatment group, 30 (66.6%), compared to the successful group, 10 (9.5%) (P < 0.001). CONCLUSIONS: Our results demonstrated that 25-OH vitamin D deficiency may be considered a risk factor related to eradication failure of H. pylori infection. In addition, a further randomized trial to evaluate the effect of vitamin D supplementation in H. pylori eradication is mandatory.

Quantifying Insulin Therapy Requirements to Preserve Islet Graft Function Following Islet Transplantation.

A mathematical nonlinear regression model of several parameters (baseline insulin intake, posttransplant 2-h postprandial blood glucose, and stimulated C-peptide) from type 1 diabetics with HbA1c <6.5% who do not require insulin therapy and have no hypoglycemic instances was developed for accurately predicting supplemental insulin requirements in the posttransplant period. An insulin deficit threshold of 0.018 U/kg/day was defined as the average first-year calculated insulin deficit (CID), above which HbA1c rose to >6.5% during year 2 of the posttransplant period. When insulin-untreated subjects were divided into two groups based on whether the average CID was smaller (group I) or greater (group II) than the insulin deficit threshold, HbA1c was found to be similar in the two groups in year 1, but increased significantly in group II to above 6.5% (with mean glucose of 121.9 mg/dl) but remained below 6.5% in group I subjects (with mean glucose of 108.7 mg/dl) in year 2 of the follow-up period. The greater insulin deficit in group II was also associated with a higher susceptibility to hyperglycemia during periods of low serum Rapamune and Prograf levels (combined levels below 11.2 and 4.7 ng/ml, respectively). Although the differences between predicted insulin requirement (PIR) and actual empirical insulin intake in the insulin-treated subjects were generally small, they were nonetheless sufficient to identify over- and underinsulinization at each follow-up visit for all subjects (n = 14 subjects, 135 observations). The newly developed model can effectively identify underinsulinized islet transplant recipients at risk for graft dysfunction due to inadequate supplemental insulin intake or those potentially susceptible to graft function loss due to inadequate immunosuppression. While less common following islet cell therapy, the model can also identify overinsulinized subjects who may be at risk for hypoglycemia.

The Choice of Enzyme for Human Pancreas Digestion is a Critical Factor for Increasing the Success of Islet Isolation.

BACKGROUND: We evaluated three commercially available enzymes for pancreatic digestion by comparing key parameters during the islet isolation process, as well as islet quality post-isolation. METHODS: Retrospectively compared and analyzed islet isolations from pancreata using three different enzyme groups: Liberase HI (n=63), Collagenase NB1/Neutral Protease (NP) (n=43), and Liberase Mammalian Tissue Free Collagenase/Thermolysin (MTF C/T) (n=115). A standardized islet isolation and purification method was used. Islet quality assessment was carried out using islet count, viability, in vitro glucose-stimulated insulin secretion (GSIS), glucose-stimulated oxygen consumption rate (ΔOCR), and in vivo transplantation model in mice. RESULTS: Donor characteristics were not significantly different among the three enzyme groups used in terms of age, sex, hospital stay duration, cause of death, body mass index (BMI), hemoglobin A1c (HbA1c), cold ischemia time (CIT), and pancreas weight. Digestion efficacy (percentage of digested tissue by weight) was significantly higher in the Liberase MTF C/T group (73.5 ± 1.5 %) when compared to the Liberase HI group (63.6 ± 2.3 %) (p<0.001) and the Collagenase NB1/NP group (61.7 ± 2.9%) (p<0.001). The stimulation index for GSIS was significantly higher in the Liberase MTF C/T group (5.3 ± 0.5) as compared to the Liberase HI (2.9 ± 0.2) (p<0.0001) and the Collagenase NB1/NP (3.6 ± 2.9) (p=0.012) groups. Furthermore, the Liberase MTF C/T enzymes showed the highest success rate of transplantation in diabetic NOD Scid mice (65%), which was significantly higher than the Liberase HI (42%, p=0.001) and the Collagenase NB1/NP enzymes (41%, p<0.001). CONCLUSIONS: Liberase MTF C/T is superior to Liberase HI and Collagenase NB1/NP in terms of digestion efficacy and glucose-stimulated insulin secretion in vitro. Moreover, Liberase MTF C/T had a significantly higher success rate of transplantation in diabetic NOD Scid mice compared to Liberase HI and Collagenase NB1/NP enzymes.

Sodium zirconium cyclosilicate in hyperkalemia.

BACKGROUND: Hyperkalemia (serum potassium level, >5.0 mmol per liter) is associated with increased mortality among patients with heart failure, chronic kidney disease, or diabetes. We investigated whether sodium zirconium cyclosilicate (ZS-9), a novel selective cation exchanger, could lower serum potassium levels in patients with hyperkalemia. METHODS: In this multicenter, two-stage, double-blind, phase 3 trial, we randomly assigned 753 patients with hyperkalemia to receive either ZS-9 (at a dose of 1.25 g, 2.5 g, 5 g, or 10 g) or placebo three times daily for 48 hours. Patients with normokalemia (serum potassium level, 3.5 to 4.9 mmol per liter) at 48 hours were randomly assigned to receive either ZS-9 or placebo once daily on days 3 to 14 (maintenance phase). The primary end point was the exponential rate of change in the mean serum potassium level at 48 hours. RESULTS: At 48 hours, the mean serum potassium level had decreased from 5.3 mmol per liter at baseline to 4.9 mmol per liter in the group of patients who received 2.5 g of ZS-9, 4.8 mmol per liter in the 5-g group, and 4.6 mmol per liter in the 10-g group, for mean reductions of 0.5, 0.5, and 0.7 mmol per liter, respectively (P<0.001 for all comparisons) and to 5.1 mmol per liter in the 1.25-g group and the placebo group (mean reduction, 0.3 mmol per liter). In patients who received 5 g of ZS-9 and those who received 10 g of ZS-9, serum potassium levels were maintained at 4.7 mmol per liter and 4.5 mmol per liter, respectively, during the maintenance phase, as compared with a level of more than 5.0 mmol per liter in the placebo group (P<0.01 for all comparisons). Rates of adverse events were similar in the ZS-9 group and the placebo group (12.9% and 10.8%, respectively, in the initial phase; 25.1% and 24.5%, respectively, in the maintenance phase). Diarrhea was the most common complication in the two study groups. CONCLUSIONS: Patients with hyperkalemia who received ZS-9, as compared with those who received placebo, had a significant reduction in potassium levels at 48 hours, with normokalemia maintained during 12 days of maintenance therapy. (Funded by ZS Pharma; ClinicalTrials.gov number, NCT01737697.).

Peginesatide to Manage Anemia in Chronic Kidney Disease Patients on Peritoneal Dialysis.

UNLABELLED: ♦ BACKGROUND: Peginesatide is a novel, synthetic, peptide-based pegylated erythropoiesis-stimulating agent that is designed specifically to stimulate the erythropoietin receptor. The purpose of the present study was to assess, for the first time, the efficacy and safety of peginesatide in chronic kidney disease (CKD) patients receiving peritoneal dialysis (PD) and previously on epoetin treatment. ♦ METHODS: In this open-label multicenter study, 59 PD patients with CKD were converted from epoetin (alfa or beta) to once-monthly peginesatide. Doses were titrated to maintain hemoglobin levels between 10 g/dL and 12 g/dL during the 25 weeks of the study. The primary endpoint was change from baseline in mean hemoglobin values during the evaluation period (weeks 20 - 25). ♦ RESULTS: The mean hemoglobin value during the evaluation period was 11.3 ± 1.07 g/dL, and the mean change from baseline was 0.10 ± 1.15 g/dL (95% confidence limits: -0.24, 0.44 g/dL). During the evaluation period, most patients maintained hemoglobin levels between 10 g/dL and 12 g/dL (63.0%) and within ±1.0 g/dL of baseline (60.9%). The median weekly epoetin dose at baseline was 96.0 U/kg, and the median starting peginesatide dose was 0.047 mg/kg. Forty-three patients (72.9%) completed the study. Six patients (10.2%) received red blood cell transfusions. The observed adverse event profile was consistent with underlying conditions in the PD patient population. The most common adverse event was peritonitis (20.3%), a complication commonly associated with PD. Four deaths occurred during the study (2 related to septic shock, and 1 each to myocardial ischemia and myasthenia gravis). ♦ CONCLUSIONS: In this study, once-monthly peginesatide maintained hemoglobin levels in PD patients after conversion from epoetin.

Sodium levels of human pancreatic donors are a critical factor for determination of islet efficacy and survival.

Organs from hypernatremia (elevated Na+) donors when used for transplantation have had dismal outcomes. However, islet isolation from hypernatremic donors for both transplantation and research applications has not yet been investigated. A retrospective analysis of in vivo and in vitro islet function studies was performed on islets isolated from hypernatremic (serum sodium levels≥160 meq/l) and normal control (serum sodium levels≤155 meq/l) donors. Twelve isolations from 32 hypernatremic and 53 isolations from 222 normal donors were randomly transplanted into diabetic NOD Scid mice. Sodium levels upon pancreas procurement were significantly elevated in the hypernatremia group (163.5±0.6 meq/l) compared with the normal control group (145.9±0.4 meq/l) (P<0.001). The postculture islet recovery rate was significantly lower in the hypernatremia (59.1±3.8%) group compared with the normal (73.6±1.8%) group (P=0.005). The duration of hypernatremia was inversely correlated with the recovery rate (r2=0.370, P<0.001). Furthermore, the percentage of successful graft function when transplanted into diabetic NOD Scid mice was significantly lower in the hypernatremia (42%) group compared with the normal control (85%) group (P<0.001). The ability to predict islet graft function posttransplantation using donor sodium levels and duration of hypernatremia was significant (ROC analysis, P=0.022 and 0.042, respectively). In conclusion, duration of donor hypernatremia is associated with reduced islet recovery postculture. The efficacy of islets from hypernatremia donors diminished when transplanted into diabetic recipients.

Effects of local low-dose rocuronium on the quality of peribulbar anesthesia for cataract surgery.

OBJECTIVES: Peribulbar anesthesia is associated with delayed and/or incomplete orbital akinesia compared with retrobulbar anesthesia. This study examined the effects of adding rocuronium 5 mg to two different concentrations of lidocaine-bupivacaine mixture on onset time of orbital and eyelid akinesia in patients undergoing cataract surgery. METHODS: In a double-blind study, 90 patients were equally randomized to receive a mixture of 0.5 ml normal saline, 4 ml lidocaine 2%, and 4 ml bupivacaine 0.5% (group I), a mixture of rocuronium 0.5 ml (5 mg), 4 ml lidocaine 2%, and 4 ml bupivacaine 0.5% (group II), or a mixture of rocuronium 0.5 ml (5 mg), 4 ml lidocaine 1%, and 4 ml bupivacaine 0.25% (group III). Orbital akinesia was assessed on a 0-8 score (0 = no movement, 8 = normal) at 2 min intervals for 10 min. Time to adequate anesthesia was also recorded. Results are presented as mean±SD. RESULTS: Ocular movement score decreased during the assessment period in all groups. However, at 2 min after block administration, the score decreased to 4±2 (95% CI 3,5) in groups II and III compared with 5±2 (95% CI 4,6) in group I (P<0.01). Time to adequate condition to begin surgery was 9.8±2.9 vs. 6.9±4.1 vs. 7.9±3.9 min for groups I, II, and III, respectively (P=0.01). CONCLUSION: The addition of rocuronium 5 mg to a mixture of lidocaine 2% and bupivacaine 0.5% shortened the onset time of peribulbar anesthesia in patients undergoing cataract surgery without causing adverse effects.

Increased platelet expression of FcGammaRIIa and its potential impact on platelet reactivity in patients with end stage renal disease.

BACKGROUND: Increased platelet reactivity has been implicated in cardiovascular disease - the major cause of death in patients with end stage renal disease (ESRD). FcGammaRIIA is a component of glycoprotein VI and Ib-IX-V that mediate activation of platelets by collagen and von Willebrand factor. To determine whether expression of FcGammaRIIA impacts platelet reactivity we quantified its expression and platelet reactivity in 33 patients with ESRD who were undergoing hemodialysis. METHODS: Blood samples were obtained from patients immediately before hemodialysis and before administration of heparin. Platelet expression of FcGammaRIIA and the activation of platelets in response to low concentrations of convulxin (1 ng/ml, selected to mimic effects of collagen), thrombin (1 nM), adenosine diphosphate (ADP, 0.2 microM), or platelet activating factor (PAF, 1 nM) were determined with the use of flow cytometry in samples of whole blood anticoagulated with corn trypsin inhibitor (a specific inhibitor of Factor XIIa). RESULTS: Patients were stratified with respect to the median expression of FcGammaRIIA. Patients with high platelet expression of FcGammaRIIA exhibited 3-fold greater platelet reactivity compared with that in those with low expression in response to convulxin (p < 0.01) and 2-fold greater activation in response to thrombin, ADP, and PAF (p < 0.05 for each). For each agonist, expression of FcGammaRIIA correlated modestly but positively with platelet reactivity. The strongest correlation was with thrombin-induced activation (r = 0.6, p < 0.001). CONCLUSION: Increased platelet reactivity in response to low concentrations of diverse agonists is associated with high expression of FcGammaRIIA and may contribute to an increased risk of thrombosis in patients with ESRD.

Platelet FcgammaRIIA receptor surface expression is increased in patients with ESRD and is associated with atherosclerotic cardiovascular events.

BACKGROUND: Accelerated atherogenesis is a prominent feature of end-stage renal disease (ESRD). METHODS: Expression of platelet FcgammaRIIA immunoglobulin G receptor (FcgammaR) was measured in 2 populations: (1) 48 patients with ESRD with a mean age of 50.7 +/- 2.3 (SEM) years and (2) 48 healthy age- and sex-matched controls aged 53.6 +/- 1.6 years. RESULTS: Platelet FcgammaR expression was enhanced significantly in patients with ESRD (mean fluorescence intensity [MFI], 7.88 +/- 0.42 [SEM]; 95% confidence interval [CI], 7.03 to 8.72 versus 5.07 +/- 0.21; 95% CI, 4.64 to 5.49; P < 0.0001). In patients with ESRD, multivariate analysis showed that hemoglobin level and diastolic blood pressure were related inversely to FCgammaR expression (P = 0.01 and P = 0.03, respectively). Atherosclerotic cardiovascular events (ACVEs) were recorded prospectively for the ESRD cohort. A total of 22 ACVEs, defined as the occurrence of myocardial infarction (10 events), cerebrovascular accident (7 events), and/or a peripheral vascular event (5 events), were observed. In the group with greater receptor expression (MFI > 7.785; n = 24), 13 of 17 patients (76.5%) experienced at least 1 ACVE, whereas only 4 of 17 patients (23.5%) with low FcgammaR expression (MFI < 7.785; n = 24) experienced an event (P = 0.007). CONCLUSION: (1) Uremia is associated with enhanced platelet FcgammaR expression, and (2) patients with greater platelet FcgammaR expression are significantly more likely to experience ACVEs; however, (3) the small sample size is a limitation and our work therefore is a hypothesis-generating pilot study that remains to be confirmed.