Enriching the Evidence Base for Icodextrin Davies, Simon J.
American journal of kidney diseases,
June 2020, 2020-Jun, 2020-06-00, 20200601, Volume:
75, Issue:
6
Journal Article
The speed with which small solutes cross the peritoneal membrane, termed peritoneal solute transport rate (PSTR), is a key measure of individual membrane performance. PSTR can be quantified easily by ...using the 4-hour dialysate to plasma creatinine ratio, which, although only an approximation to the diffusive characteristics of the membrane, has been well validated clinically in terms of its relationship to patient survival and changes in longitudinal membrane function. This has led to changes in peritoneal dialysis modality use and dialysis prescription. An important determinant of PSTR is intraperitoneal inflammation, as exemplified by local interleukin 6 production, which is largely independent of systemic inflammation and its relationship to comorbid conditions and increased mortality. There is no strong evidence to support the contention that the peritoneal membrane in some individuals with high PSTR is qualitatively different at the start of treatment; rather, it represents a spectrum that is determined in part by genetic factors. Both clinical and experimental evidence support the view that persistent intraperitoneal inflammation, detected as a continuously high or increasing PSTR, may predispose the membrane to progressive fibrosis.
The Standardized Outcomes in Nephrology (SONG) initiative is designed to improve research productivity by building consensus. Stakeholders involved with peritoneal dialysis (PD) have put life ...participation on top of their list, along with treatment-related infection, cardiovascular complications, and patient and technique survival. This should lead to improved reporting of these outcomes and their prioritization in future research.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Continuous glucose exposure contributes to severe ultrafiltration failure in peritoneal dialysis. In their study, Wang et al. describe a mechanistic pathway involving direct activation by glucose of ...mesothelial cell protein kinase C α that, when blocked, or absent in a mouse knockout model, prevents fibrosis and the associated reduction in ultrafiltration. Interestingly, this pathway involves the 3 main mechanisms of membrane injury (inflammation, neoangiogenesis, and fibrogenesis), offering a potential target for therapeutic intervention.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective
To investigate whether rituximab, an anti–B cell therapy, improves symptoms of fatigue and oral dryness in patients with primary Sjögren's syndrome (SS).
Methods
We conducted a multicenter, ...randomized, double‐blind, placebo‐controlled, parallel‐group trial that included health economic analysis. Anti‐Ro–positive patients with primary SS, symptomatic fatigue, and oral dryness were recruited from 25 UK rheumatology clinics from August 2011 to January 2014. Patients were centrally randomized to receive either intravenous (IV) placebo (250 ml saline) or IV rituximab (1,000 mg in 250 ml saline) in 2 courses at weeks 0, 2, 24, and 26, with pre‐ and postinfusion medication including corticosteroids. The primary end point was the proportion of patients achieving a 30% reduction in either fatigue or oral dryness at 48 weeks, as measured by visual analog scale. Other outcome measures included salivary and lacrimal flow rates, quality of life, scores on the European League Against Rheumatism (EULAR) Sjögren's Syndrome Patient Reported Index and EULAR Sjögren's Syndrome Disease Activity Index, symptoms of ocular and overall dryness, pain, globally assessed disease activity, and cost‐effectiveness.
Results
All 133 patients who were randomized to receive placebo (n = 66) or rituximab (n = 67) were included in the primary analysis. Among patients with complete data, 21 of 56 placebo‐treated patients and 24 of 61 rituximab‐treated patients achieved the primary end point. After multiple imputation of missing outcomes, response rates in the placebo and rituximab groups were 36.8% and 39.8%, respectively (adjusted odds ratio 1.13 95% confidence interval 0.50, 2.55). There were no significant improvements in any outcome measure except for unstimulated salivary flow. The mean ± SD costs per patient for rituximab and placebo were £10,752 ± 264.75 and £2,672 ± 241.71, respectively. There were slightly more adverse events (AEs) reported in total for rituximab, but there was no difference in serious AEs (10 in each group).
Conclusion
The results of this study indicate that rituximab is neither clinically effective nor cost‐effective in this patient population.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Intraoperative hypotension is a common event, and a recent study suggests that maintenance of blood pressure may reduce complications. The splanchnic circulation provides a reservoir of blood that ...can be mobilized during hemorrhage; hence, intestinal microcirculation is sensitive to volume changes. The aim of this study was to assess the impact of hemorrhage on intestinal microcirculation and hemodynamics, and the effects of phenylephrine on these parameters.
Eight anesthetized, mechanically ventilated Yorkshire/Landrace crossbreed pigs were studied. Graded hemorrhage was performed with the removal of 20% of blood volume in 5% increments. Hemodynamic and intestinal microcirculatory measurements were performed at each stage with side-stream dark field microscopy, following which mean arterial pressure (MAP) was corrected with phenylephrine to baseline values and measurements repeated. A repeated measurement 1-way analysis of variance (ANOVA) was used to compared changes from baseline measurements.
The mean baseline microcirculation score was 42 (standard deviation SD = 5). A 5% hemorrhage decreased the microcirculation score by a mean difference of 19 (95% confidence interval CI, 12-27; P < .0001), and an additional 5% hemorrhage further reduced the microcirculation score by a mean difference of 12 (95% CI, 4-19; P = .0001). Subsequent hemorrhage or administration of phenylephrine did not significantly change the microcirculation scores except when phenylephrine was administered at the 15% hemorrhage stage, which increased the microcirculation score by a mean difference of 7 (95% CI, 1-13; P = .003). All hemodynamic variables were returned to baseline values following hemorrhage by the phenylephrine infusion.
Intestinal microcirculatory flow is reduced early in hemorrhage and is uncorrected by phenylephrine infusion. Hemodynamic changes associated with hemorrhage are corrected by phenylephrine and do not reflect microcirculatory flow status.
Both overhydration and comorbidity predict mortality in end-stage kidney failure (ESKF) but it is not clear whether these are independent of one another. We undertook a systematic review of studies ...reporting outcomes in adult dialysis patients in which comorbidity and overhydration, quantified by whole body bioimpedance (BI), were reported. PubMed, EMBASE, PsychInfo and the Cochrane trial database were searched (1990-2017). Independent reviewers appraised studies including methodological quality (assessed using QUIPS). Primary outcome was mortality, with secondary outcomes including hospitalisation and cardiovascular events. Of 4028 citations identified, 46 matched inclusion criteria (42 cohorts; 60790 patients; 8187 deaths; 95% haemodialysis/5% peritoneal dialysis). BI measures included phase angle/BI vector (41%), overhydration index (39%) and extra:intracellular water ratio (20%). 38 of 42 cohorts had multivariable survival analyses (MVSA) adjusting for age (92%), gender (66%), diabetes (63%), albumin (58%), inflammation (CRP/IL6-37%), non-BI nutritional markers (24%) and echocardiographic data (8%). BI-defined overhydration (BI-OH) independently predicted mortality in 32 observational cohorts. Meta-analysis revealed overhydration >15% (HR 2.28, 95% CI 1.56-3.34, P < 0.001) and a 1-degree decrease in phase angle (HR 1.74, 95% CI 1.37-2.21, P < 0.001) predicted mortality. BI-OH predicts mortality in dialysis patients independent of the influence of comorbidity.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Diabetic nephropathy is highly correlated with the occurrence of other complications of type 1 diabetes (T1D) and type 2 diabetes (T2D) mellitus; for example, hypertension with cardiovascular disease ...(CVD) being the most frequent cause of death in patients with end-stage renal disease and undergoing renal dialysis. Hyperglycemia and insulin resistance (IR) are responsible for the micro- and macrovascular complications of diabetes through different mechanisms. In particular, IR plays a key role in the etiology of atherosclerosis in both diabetic and non-diabetic patients. IR – exacerbated by organ-level selectivity – is more important than glycemic control per se in determining cardiovascular outcomes. This may be exacerbated by the fact that IR is organ and pathway specific due to the only selective loss of sensitivity to insulin action of specific pathways/processes. Therefore, it is counterintuitive that the use of peritoneal dialysis (PD) in (frequently) diabetic renal disease patients should involve their exposure to high daily doses of glucose peritoneally. In view of the controversy about the causal association between glucose load and CVD in PD patients, we discuss the role that selective IR may play in the progression of CVD in diabetic renal end-stage patients. In discussing these associations, we propose that reducing glucose exposure in PD solutions may be beneficial especially if coupled with strategies that address IR directly, and the avoidance of excessive use of insulin treatment in T2D.
Diabetic patients undergoing peritoneal dialysis (PD) are exposed to high dose of glucose throughout the day.Insulin resistance (IR) exacerbates the effects of the insulin secretagogue effects of high glucose exposure.Selective IR between tissues and pathways amplifies the effects of selected pathways of insulin signaling remaining active under conditions of increased hyperglycemia and hyperinsulinemia.Selective insulinemia in the endothelium and nephrons may increase the cardiometabolic risk.PD solutions that substitute glucose partly for other osmolytes such as xylitol and L-carnitine may offer a strategy to minimize the risks of induction of selective IR.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Heterogeneous palladium catalysts modified by N-heterocyclic carbenes (NHCs) are shown to be highly effective toward the direct synthesis of hydrogen peroxide (H2O2), in the absence of the promoters ...which are typically required to enhance both activity and selectivity. Catalytic evaluation in a batch regime demonstrated that through careful selection of the N-substituent of the NHC it is possible to greatly enhance catalytic performance when compared to the unmodified analogue and reach concentrations of H2O2 rivaling that obtained by state-of-the-art catalysts. The enhanced performance of the modified catalyst, which is retained upon reuse, is attributed to the ability of the NHC to electronically modify Pd speciation.
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IJS, KILJ, NUK, PNG, UL, UM
Summary Background Intensive treatment of multiple cardiovascular risk factors can halve mortality among people with established type 2 diabetes. We investigated the effect of early multifactorial ...treatment after diagnosis by screening. Methods In a pragmatic, cluster-randomised, parallel-group trial done in Denmark, the Netherlands, and the UK, 343 general practices were randomly assigned screening of registered patients aged 40–69 years without known diabetes followed by routine care of diabetes or screening followed by intensive treatment of multiple risk factors. The primary endpoint was first cardiovascular event, including cardiovascular mortality and morbidity, revascularisation, and non-traumatic amputation within 5 years. Patients and staff assessing outcomes were unaware of the practice's study group assignment. Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00237549. Findings Primary endpoint data were available for 3055 (99·9%) of 3057 screen-detected patients. The mean age was 60·3 (SD 6·9) years and the mean duration of follow-up was 5·3 (SD 1·6) years. Improvements in cardiovascular risk factors (HbA1c and cholesterol concentrations and blood pressure) were slightly but significantly better in the intensive treatment group. The incidence of first cardiovascular event was 7·2% (13·5 per 1000 person-years) in the intensive treatment group and 8·5% (15·9 per 1000 person-years) in the routine care group (hazard ratio 0·83, 95% CI 0·65–1·05), and of all-cause mortality 6·2% (11·6 per 1000 person-years) and 6·7% (12·5 per 1000 person-years; 0·91, 0·69–1·21), respectively. Interpretation An intervention to promote early intensive management of patients with type 2 diabetes was associated with a small, non-significant reduction in the incidence of cardiovascular events and death. Funding National Health Service Denmark, Danish Council for Strategic Research, Danish Research Foundation for General Practice, Danish Centre for Evaluation and Health Technology Assessment, Danish National Board of Health, Danish Medical Research Council, Aarhus University Research Foundation, Wellcome Trust, UK Medical Research Council, UK NIHR Health Technology Assessment Programme, UK National Health Service R&D, UK National Institute for Health Research, Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, Novo Nordisk, Astra, Pfizer, GlaxoSmithKline, Servier, HemoCue, Merck.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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