Serum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden

Trimethlyamine-N-oxide (TMAO) was recently identified as a promoter of atherosclerosis. Patients with CKD exhibit accelerated development of atherosclerosis; however, no studies have explored the relationship between TMAO and atherosclerosis formation in this group. This study measured serum concentrations and urinary excretion of TMAO in a CKD cohort (n=104), identified the effect of renal transplant on serum TMAO concentration in a subset of these patients (n=6), and explored the cross-sectional relationship between serum TMAO and coronary atherosclerosis burden in a separate CKD cohort (n=220) undergoing coronary angiography. Additional exploratory analyses examined the relationship between baseline serum TMAO and long-term survival after coronary angiography. Serum TMAO concentrations demonstrated a strong inverse association with eGFR (r²=0.31, P<0.001). TMAO concentrations were markedly higher in patients receiving dialysis (median [interquartile range], 94.4 μM [54.8–133.0 μM] for dialysis-dependent patients versus 3.3 μM [3.1–6.0 μM] for healthy controls; P<0.001); whereas renal transplantation resulted in substantial reductions in TMAO concentrations (median [min–max] 71.2 μM [29.2–189.7 μM] pretransplant versus 11.4 μM [8.9–20.2 μM] post-transplant; P=0.03). TMAO concentration was an independent predictor for coronary atherosclerosis burden (P=0.02) and predicted long-term mortality independent of traditional cardiac risk factors (hazard ratio, 1.26 per 10 μM increment in TMAO concentration; 95% confidence interval, 1.13 to 1.40; P<0.001). In conclusion, serum TMAO concentrations substantially increase with decrements in kidney function, and this effect is reversed by renal transplantation. Increased TMAO concentrations correlate with coronary atherosclerosis burden and may associate with long-term mortality in patients with CKD undergoing coronary angiography.     

Correlation of Radiologic with Surgical Peritoneal Cancer Index Scores in Patients with Pseudomyxoma Peritonei and Peritoneal Carcinomatosis: How Well Can We Predict Resectability?

Introduction

Pseudomyxoma peritonei (PMP) and peritoneal carcinomatosis (PC) arises from primary or secondary peritoneal cancer and can be treated with complete surgical removal of disease. Suitability for surgery is based on a peritoneal cancer index (PCI), with a PCI?≥?20 representing unresectable disease.

Aims

Compare preoperative imaging with surgical findings based on PCI.

Methods

All cases of patients with PMP and PC undergoing cytoreductive surgery ± hyperthermic intraperitoneal chemotherapy (HIPEC) between 2010 and 2014 were included. Two staff radiologists blinded to surgical PCI scores retrospectively reviewed imaging studies to calculate corresponding radiologic PCI scores for each patient. Correlation between radiologic PCI and surgical PCI, as obtained from operative reports, was assessed using Spearman’s rho correlation coefficients. Preoperative assessment of a PCI cutoff of 20 on imaging was compared with actual surgical PCI using sensitivity, specificity, and positive and negative predictive values.

Results

Forty-two patients had a mean surgical PCI?±?SEM score of 15.1?±?1.3 and mean radiologic PCI of 15.5?±?1.5. The most common tumor histologies were appendiceal (60 %) and colon (33 %) adenocarcinoma and were of low tumor grade (67 %). Correlation between individual radiologists and surgical PCI was 0.59 and 0.62, respectively (all p?<?0.001). When mean radiologic PCI was used, this correlation with surgical PCI improved to 0.64 and to 0.65 when good quality studies only were considered (all p?<?0.001). Radiologic PCI score had a sensitivity of 76 %, a specificity of 69 %, positive predictive value of 85 %, and a negative predictive value of 56 % when compared with the surgical PCI. In patients with a radiologic PCI score?≥?20, 6/13 (46 %) still achieved adequate cytoreduction.

Conclusions

Good quality cross-sectional imaging, combined with overreading and formal assessment of all components of the PCI score yields the best correlation with actual surgical findings. Although preoperative assessment of PCI?≥?20 was reasonably accurate, using this cutoff to assess resectability is problematic as almost half of these patients were still able to undergo adequate cytoreduction. Better assessment of resectability is needed preop, either by refinement of the PCI criteria or routine staging laparoscopy.

     

Voluntary Running-Wheel Activity,Arterial Blood Gases,and Thermal Antinociception in Rats after 3 Buprenorphine Formulations

Buprenorphine HCl (BUP) is a μ-opioid agonist used in laboratory rodents. New formulations of buprenorphine (for example, sustained-released buprenorphine [BUP SR], extended-release buprenorphine [BUP ER]) have been developed to extend the analgesic duration. In a crossover design, 8 adult rats were injected subcutaneously with either BUP, BUP SR, BUP ER, or saline, after which voluntary running-wheel activity, arterial blood gases, and thermal withdrawal latency were assessed. Wheel running was decreased at 24 h compared with baseline in all treatment groups but returned to baseline by 48 h. Arterial pH, HCO₃^–, and CO₂ were not changed between groups or over time. However, arterial oxygen was lower than baseline in the BUP (–8 ± 2 mm Hg), BUP SR (–7 ± 1 mm Hg), and BUP ER (–17 ± 2 mm Hg) groups compared with saline controls (3 ± 2 mm Hg); the BUP ER group showed the greatest decrease when all time points were combined. BUP increased the withdrawal latency at 1 h (15% ± 3%), whereas BUP ER increased latencies at 4, 8, 12, and 48 h (35% ± 11%, 21% ± 7%, 26% ± 7%, and 22% ± 9%, respectively) and BUP SR prolonged latencies at 24, 48, and 72 h (15% ± 6%, 18% ± 5%, and 20% ± 8%, respectively). The duration of thermal analgesia varied between buprenorphine formulations, but all 3 formulations reduced voluntary-running activity at 24 h after injection and might cause hypoxemia in normal adult rats.Abbreviations: BUP, buprenorphine hydrochloride; BUP SR, sustained-release buprenorphine; BUP ER, extended-release buprenorphineBuprenorphine HCl (BUP), a synthetic opiate first synthesized in the late 1960s, has been used extensively in laboratory rodents for many years.⁸ The antinociceptive effects of BUP are mediated via actions at the μ-opioid receptor, although the drug has been classified as both a full- and a partial μ-opiate receptor agonist.²⁶ BUP administration is associated with minimal toxicity in rodents because its therapeutic index is at least 3 times greater than that of morphine in animals.⁷ BUP produces minimal to modest respiratory depression, quantified by using arterial blood gas evaluation, even at excessive intravenous doses (3 to 90 mg/kg).^9,16 The analgesic efficacy of BUP has been assessed in several models of acute and chronic pain in rodents.^4,15 Although efficacious in some models, BUP''s duration of action frequently requires repeated postoperative dosing,²⁴ which can reduce body weight and food consumption and affect ambient locomotor activity, thus complicating the ability to use these parameters as signs of postoperative pain.² In addition, the repeated postoperative handling of rats necessary to redose BUP itself may increase animal stress and further contribute to decreases in postoperative weight gain and food intake.^6,14,28 In addition, repeated postoperative dosing of BUP is associated with hyperalgesia, which may limit its usefulness in chronically painful animals.⁶To reduce the negative side effects associated with repeated dosing of BUP, new formulations of BUP (for example, sustained-released buprenorphine [BUP SR], extended-release buprenorphine [BUP ER]) have become available recently with the potential to produce long-lasting analgesia. For example, a single dose of BUP SR has shown analgesic efficacy for as long as 72 h in thermal, incisional, and orthopedic pain models in rats.^5,11 In addition, BUP ER can achieve thermal analgesia in rats for 5 d; however, data are limited on this formulation due to its novelty (commercially released for rats in 2014).¹ These long-lasting formulations may reduce the amount of postoperative animal handling required for multiple injections as well as the associated negative effects. However, no studies have directly evaluated the consequences of these new formulations on important postoperative factors, such as voluntary activity.²Respiratory depression, manifest as arterial hypercapnia, is commonly associated with pure mu-opioid agonists in rats.⁹ However, BUP administration appears to have a “ceiling” effect on ventilation, where a maximum effect is seen despite increases in dose.⁹ Although respiratory rate has been used to estimate opioid-induced respiratory impairment in some models,¹⁰ other studies confirm respiratory rate is not an accurate assessment of ventilation due to subsequent changes in tidal volume and dead space ventilation;²⁹ arterial blood gas analysis is the gold standard to detect hypoventilation using arterial carbon dioxide levels.¹⁹ To the author''s knowledge, no studies have investigated blood gases following either long-acting buprenorphine preparation.The objective of the current study was to use a crossover design to evaluate the effects of a clinically applicable, single dose of subcutaneous BUP, BUP SR, or BUP ER on voluntary running-wheel activity, resting arterial blood gases, and antinociception according to a thermal withdrawal model in healthy adult rats. Administration of all formulations was hypothesized to produce quantifiable thermal analgesia, reduce voluntary running activity, and result in mild hypoventilation and arterial hypoxemia after injection in healthy adult rats. In addition, the effects were predicted to be of similar magnitude among BUP, BUP SR, and BUP ER but of shorter duration in the BUP group compared with the BUP SR and BUP ER groups.     

Indoxyl sulphate and kidney disease: Causes,consequences and interventions

In the last decade, chronic kidney disease (CKD), defined as reduced renal function (glomerular filtration rate (GFR) < 60 mL/min per 1.73 m²) and/or evidence of kidney damage (typically manifested as albuminuria) for at least 3 months, has become one of the fastest‐growing public health concerns worldwide. CKD is characterized by reduced clearance and increased serum accumulation of metabolic waste products (uremic retention solutes). At least 152 uremic retention solutes have been reported. This review focuses on indoxyl sulphate (IS), a protein‐bound, tryptophan‐derived metabolite that is generated by intestinal micro‐organisms (microbiota). Animal studies have demonstrated an association between IS accumulation and increased fibrosis, and oxidative stress. This has been mirrored by in vitro studies, many of which report cytotoxic effects in kidney proximal tubular cells following IS exposure. Clinical studies have associated IS accumulation with deleterious effects, such as kidney functional decline and adverse cardiovascular events, although causality has not been conclusively established. The aims of this review are to: (i) establish factors associated with increased serum accumulation of IS; (ii) report effects of IS accumulation in clinical studies; (iii) critique the reported effects of IS in the kidney, when administered both in vivo and in vitro; and (iv) summarize both established and hypothetical therapeutic options for reducing serum IS or antagonizing its reported downstream effects in the kidney.     

Recombinant bactericidal/permeability-increasing protein rBPI21 protects against pneumococcal disease

Bactericidal/permeability-increasing (BPI) protein has been shown to play an important role in innate immunity to gram-negative bacteria, by direct microbicidal as well as endotoxin-neutralizing action. Here we examined potential interactions between a recombinant 21-kDa bioactive fragment of BPI, rBPI21, and the gram-positive pathogen Streptococcus pneumoniae. rBPI21 bound to pneumococci and pneumolysin (Ply) in a direct and specific fashion. We observed an enhanced inflammatory response in mouse macrophages when rBPI21 was combined with killed pneumococci or supernatant from overnight growth of pneumococci. In addition, rBPI21 augmented the proapoptotic activity of Ply+ (but not Ply-) pneumococci in TLR4-defective murine macrophages (known to be defective also in their apoptotic response to pneumolysin) in a tumor necrosis factor alpha-dependent manner. rBPI21 also enhanced the association of pneumococci with murine macrophages. In a model of invasive pneumococcal disease in TLR4-defective mice, the intranasal administration of rBPI21 following intranasal inoculation of Ply+ pneumococci both enhanced upper respiratory tract cell apoptosis and prolonged survival. We have thus discovered a novel interaction between pneumococcus and rBPI21, a potent antimicrobial peptide previously considered to target only gram-negative bacteria.