• Impact of Dietetic Intervention on Skin Autofluorescence and Nutritional Status in Persons Receiving Dialysis: A Proof of Principle Study

      Willingham, Fiona; Selby, Nicholas; Taal, Maarten (2020-02)
      OBJECTIVE: Advanced glycation end-products (AGEs) are uremic toxins that result from oxidative stress and food consumption. It has been reported that markers of malnutrition are more important determinants of increased skin autofluorescence (SAF), a measure of AGE accumulation and risk factor for mortality, than high dietary AGE intake in a hemodialysis (HD) population, suggesting that correcting malnutrition may decrease SAF. DESIGN AND METHODS: We investigated this hypothesis in a single-center, nonrandomized proof-of-principle study. We enrolled 27 patients on HD and one on peritoneal dialysis with malnutrition who received individualized nutritional advice and support over 6 months. SAF was measured at baseline, 3 months, and 6 months. Dietary intake and nutritional status were assessed at baseline and 6 months. Results were compared with a control group of malnourished patients on dialysis (n = 41 HD and 8 peritoneal dialysis) from a previous observational study. RESULTS: The intervention group showed a significant increase in dietary intake, including AGEs, Subjective Global Assessment score, and serum albumin, while SAF levels remained stable for over 6 months (3.8 ± 0.7 arbitrary units [AU] vs. 3.7 ± 0.7 AU; P = .3). Conversely, in the control group, SAF increased significantly during the observation period (3.5 ± 0.9 AU vs. 3.8 ± 1.2 AU; P = .03) during which there was no improvement in nutritional intake and other markers of nutrition, although dietary AGE intake and Subjective Global Assessment score did increase. CONCLUSION: Dietetic support was associated with stable SAF levels in this proof-of-principal study despite an increase in dietary AGE intake, suggesting that interventions to improve nutrition may be important in preventing the rise in SAF observed in malnourished dialysis populations. Further long-term studies are needed to test this hypothesis and evaluate the impact on survival.
    • Impact of gut hormone FGF-19 on type-2 diabetes and mitochondrial recovery in a prospective study of obese diabetic women undergoing bariatric surgery

      Piya, Milan (2017-02)
      BACKGROUND: The ileal-derived hormone, fibroblast growth factor 19 (FGF-19), may promote weight loss and facilitate type-2 diabetes mellitus remission in bariatric surgical patients. We investigated the effect of different bariatric procedures on circulating FGF-19 levels and the resulting impact on mitochondrial health in white adipose tissue (AT). METHODS: Obese and type-2 diabetic women (n = 39, BMI > 35 kg/m(2)) undergoing either biliopancreatic diversion (BPD), laparoscopic greater curvature plication (LGCP), or laparoscopic adjustable gastric banding (LAGB) participated in this ethics approved study. Anthropometry, biochemical, clinical data, serum, and AT biopsies were collected before and 6 months after surgery. Mitochondrial gene expression in adipose biopsies and serum FGF-19 levels were then assessed. RESULTS: All surgeries led to metabolic improvements with BPD producing the greatest benefits on weight loss (↓30%), HbA1c (↓28%), and cholesterol (↓25%) reduction, whilst LGCP resulted in similar HbA1c improvements (adjusted for BMI). Circulating FGF-19 increased in both BPD and LGCP (χ(2)(2) = 8.088; P = 0.018), whilst, in LAGB, FGF-19 serum levels decreased (P = 0.028). Interestingly, circulating FGF-19 was inversely correlated with mitochondrial number in AT across all surgeries (n = 39). In contrast to LGCP and LAGB, mitochondrial number in BPD patients corresponded directly with changes in 12 of 14 mitochondrial genes assayed (P < 0.01). CONCLUSIONS: Elevated serum FGF-19 levels post-surgery were associated with improved mitochondrial health in AT and overall diabetic remission. Changes in circulating FGF-19 levels were surgery-specific, with BPD producing the best metabolic outcomes among the study procedures (BPD > LGCP > LAGB), and highlighting mitochondria in AT as a potential target of FGF-19 during diabetes remission.
    • Impact of malnutrition on health-related quality of life in persons receiving dialysis: a prospective study.

      Pittman, Zoe; Selby, Nicholas; Taal, Maarten
      Health-related quality of life (HRQoL) is severely impaired in persons receiving dialysis. Malnutrition has been associated with some measures of poor HRQoL in cross-sectional analyses in dialysis populations, but no studies have assessed the impact of malnutrition and dietary intake on change in multiple measures of HRQoL over time. We investigated the most important determinants of poor HRQoL and the predictors of change in HRQoL over time using several measures of HRQoL. We enrolled 119 haemodialysis and 31 peritoneal dialysis patients in this prospective study. Nutritional assessments (Subjective Global Assessment [SGA], anthropometry and 24-hour dietary recalls) and HRQoL questionnaires (Short Form-36 [SF-36] mental [MCS] and physical component scores [PCS] and European QoL-5 Dimensions [EQ5D] health state [HSS] and visual analogue scores [VAS]) were performed at baseline, 6 and 12 months. Mean age was 64(14) years. Malnutrition was present in 37% of the population. At baseline, malnutrition assessed by SGA was the only factor independently (and negatively) associated with all four measures of HRQoL. No single factor was independently associated with decrease in all measures of HRQoL over 1 year. However, prevalence/development of malnutrition over one year was an independent predictor of 1-year decrease in EQ5D HSS and 1-year decrease in fat intake independently predicted the 1-year decline in SF-36 MCS and PCS, and EQ5D VAS. These findings strengthen the importance of monitoring for malnutrition and providing nutritional advice to all persons on dialysis. Future studies are needed to evaluate the impact of nutritional interventions on HRQoL and other long-term outcomes.
    • Improving Clinical Prediction Rules In Acute Kidney Injury With The Use of Biomarkers of Cell Cycle Arrest: A Pilot Study.

      Selby, Nicholas (2018-06)
      INTRODUCTION: Early recognition of patients developing acute kidney injury is of considerable interest, we report the first use of a combination of a clinical prediction rule with a biomarker in emergent adult medical patients to improve AKI recognition. METHODS: Single-centre prospective pilot study of medical admissions without AKI identified as high risk by a clinical prediction rule. Urine samples were obtained and tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) - biomarkers associated with cell cycle arrest, were measured. OUTCOME: Creatinine based KDIGO hospital-acquired AKI (HA-AKI). RESULTS: Of 69 patients recruited, HA-AKI developed in 13% (n = 9), in whom biomarker values were higher (median 0.43 [interquartile range 0.21-1.25] vs. 0.07 [0.03-0.16] in cases without (P = 0.008). Peak rise in creatinine was higher in biomarker positive cases (median 30 μmol/l (7-72) vs 1 μmol/l (0-16), P = 0.002). AUROC was 0.78 (95% CI 0.57-0.98). At the suggested cut-off (0.3) sensitivity for predicting AKI was 78% (95% CI 40-97%), specificity 89% (78-95%), positive predictive value 50% (31-69%) and negative predictive value 96% (89-99%). DISCUSSION: Addition of a urinary biomarker allows exclusion of a significant number of patients identified to be at higher risk of AKI by a clinical prediction rule.
    • Improving readiness for recruitment through simulated trial activation: the Adjuvant Steroids in Adults with Pandemic influenza (ASAP) trial.

      Bewick, Tom (2017-11)
      BACKGROUND: Research in public health emergencies requires trials to be set up in readiness for activation at short notice and in anticipation of limited timelines for patient recruitment. We conducted a simulated activation of a hibernating pandemic influenza clinical trial in order to test trial processes and to determine the value of such simulation in maintaining trial readiness. METHODS: The simulation involved the Nottingham Clinical Trials Unit, one participating hospital, one manufacturing unit and the Investigational Medicinal Product (IMP) supplier. During the exercise, from 15 September 2015 to 2 December 2015, clinical staff at the participating site completed the trial training package, a volunteer acting as a patient was recruited to the study, 'dummy' IMP was prescribed and follow-up completed. RESULTS: Successful activation of the hibernating trial with patient recruitment within 4 weeks of 'arousal' as planned was demonstrated. A need for greater resilience in anticipation of staff absenteeism was identified, particularly in relation to key trial procedures where the potential for delay is high. A specific issue relating to the IMP Stock Control System was highlighted as a potential source of error that could compromise the randomisation sequence. The simulation exercise was well received by site investigators and increased their confidence in being able to meet the likely demands of the trial when activated. The estimated cost of the exercise was £1995; 90% of this being staff costs. CONCLUSIONS: Simulated activation is useful as a means to test, and prepare for, the rapid activation of 'hibernating' research studies. Whether simulation exercises can also help reduce waste in complex clinical trial research deserves further exploration. TRIAL REGISTRATION: EudraCT Number 2013-001051-12, ISRCTN72331452 . Registered on 6 March 2013.
    • In Patients With Severe Alcoholic Hepatitis, Prednisolone Increases Susceptibility to Infection and Infection-Related Mortality, and Is Associated With High Circulating Levels of Bacterial DNA.

      Austin, Andrew (2017-04)
      BACKGROUND & AIMS: Infections are common in patients with severe alcoholic hepatitis (SAH), but little information is available on how to predict their development or their effects on patients. Prednisolone is advocated for treatment of SAH, but can increase susceptibility to infection. We compared the effects of infection on clinical outcomes of patients treated with and without prednisolone, and identified risk factors for development of infection in SAH. METHODS: We analyzed data from 1092 patients enrolled in a double-blind placebo-controlled trial to evaluate the efficacy of treatment with prednisolone (40 mg daily) or pentoxifylline (400 mg 3 times each day) in patients with SAH. The 2 × 2 factorial design led to 547 patients receiving prednisolone; 546 were treated with pentoxifylline. The trial was conducted in the United Kingdom from January 2011 through February 2014. Data on development of infection were collected at evaluations performed at screening, baseline, weekly during admission, on discharge, and after 90 days. Patients were diagnosed with infection based on published clinical and microbiologic criteria. Risk factors for development of infection and effects on 90-day mortality were evaluated separately in patients treated with prednisolone (n = 547) and patients not treated with prednisolone (n = 545) using logistic regression. Pre treatment blood levels of bacterial DNA (bDNA) were measured in 731 patients. RESULTS: Of the 1092 patients in the study, 135 had an infection at baseline, 251developed infections during treatment, and 89 patients developed an infection after treatment. There was no association between pentoxifylline therapy and the risk of serious infection (P = .084), infection during treatment (P = .20), or infection after treatment (P = .27). Infections classified as serious were more frequent in patients treated with prednisolone (odds ratio [OR], 1.27; 95% confidence interval [CI], 1.27-2.92; P = .002). There was no association between prednisolone therapy and infection during treatment (OR, 1.04; 95% CI, 0.78-1.37; P = .80). However, a higher proportion (10%) of patients receiving prednisolone developed an infection after treatment than of patients not given prednisolone (6%) (OR, 1.70; 95% CI, 1.07-2.69; P = .024). Development of infection was associated with increased 90-day mortality in patients with SAH treated with prednisolone, independent of model for end-stage liver disease or Lille score (OR, 2.46; 95% CI, 1.41-4.30; P = .002). High circulating bDNA predicted infection that developed within 7 days of prednisolone therapy, independent of Model for End-Stage Liver Disease and white blood cell count (OR, 4.68; 95% CI, 1.80-12.17; P = .001). In patients who did not receive prednisolone, infection was not independently associated with 90-day mortality (OR, 0.94; 95% CI, 0.54-1.62; P = .82) or levels of bDNA (OR, 0.83; 95% CI, 0.39-1.75; P = .62). CONCLUSIONS: Patients with SAH given prednisolone are at greater risk for developing serious infections and infections after treatment than patients not given prednisolone, which may offset its therapeutic benefit. Level of circulating bDNA before treatment could identify patients at high risk of infection if given prednisolone; these data could be used to select therapies for patients with SAH. EudraCT no: 2009-013897-42; Current Controlled Trials no: ISRCTN88782125.
    • Incidence of metachronous visible lesions in patients referred for radiofrequency ablation (RFA) therapy for early Barrett's neoplasia: a single-centre experience.

      Cole, Andrew (2016-01)
      OBJECTIVE: Evaluate the incidence of metachronous visible lesions (VLs) in patients referred for radiofrequency ablation (RFA) for early Barrett's neoplasia. DESIGN: This study was conducted as part of the service evaluation audit. SETTING: Tertiary referral centre. PATIENTS: All patients with dysplastic Barrett's oesophagus referred for RFA were included for analysis. White light high-resolution endoscopy (HRE), autofluorescence imaging and narrow band imaging were sequentially performed. Endoscopic mucosal resection (EMR) was performed for all VL. Three to six months after EMR, all patients underwent initial RFA and then repeat RFA procedures at three monthly intervals. INTERVENTIONS: All endoscopy reports and final staging by EMR/surgery were evaluated and included for analysis. RESULTS: Fifty patients were analysed; median age 73 years, 84% men. 38/50 patients (76%) had a previous EMR due to the presence of VL before referred for ablation; twelve patients had no previous treatment. In total, 151 ablation procedures were performed, median per patient 2.68. Twenty metachronous VL were identified in 14 patients before the first ablation or during the RFA protocol; incidence was 28%. All metachronous lesions were successfully resected by EMR. Upstaging after rescue EMR compared with the initial histology was observed in four patients (28%). CONCLUSIONS: In total, 28% of patients enrolled in the RFA programme were diagnosed to have metachronous lesions. This high-incidence rate highlights the importance of a meticulous examination to identify and resect any VL before every ablation session. RFA treatment for early Barrett's neoplasia should be performed in tertiary referral centres with HRE and EMR facilities and expertise.
    • Increased incidence of adult pneumococcal pneumonia during school holiday periods.

      Bewick, Tom (2017-03)
      Child contact is a recognised risk factor for adult pneumococcal disease. Peaks in invasive pneumococcal disease incidence observed during winter holidays may be related to changes in social dynamics. This analysis was conducted to examine adult pneumococcal community-acquired pneumonia (CAP) incidence during school holiday periods. Between September 2008 and 2013, consecutive adults admitted to hospitals covering the Greater Nottingham area with a diagnosis of CAP were studied. Pneumococcal pneumonia was detected using culture and antigen detection methods. Of 2221 adults studied, 575 (25.9%) were admitted during school holidays and 643 (29.0%) had pneumococcal CAP. CAP of pneumococcal aetiology was significantly more likely in adults admitted during school holidays compared to term time (35.3% versus 26.7%; adjusted OR 1.38, 95% CI 1.11-1.72, p=0.004). Over the 5-year period, the age-adjusted incidence of hospitalised pneumococcal CAP was higher during school holidays compared to term time (incident rate ratio 1.35, 95% CI 1.14-1.60, p<0.001); there was no difference in rates of all-cause CAP or non pneumococcal CAP. Reported child contact was higher in individuals with pneumococcal CAP admitted during school holidays compared to term time (42.0% versus 33.7%, OR 1.43, 95% CI 1.00-2.03, p=0.046). Further study of transmission dynamics in relation to these findings and to identify appropriate intervention strategies is warranted.
    • Individualised dialysate temperature improves intradialytic haemodynamics and abrogates haemodialysis-induced myocardial stunning, without compromising tolerability.

      Jefferies, Helen; Burton, James; McIntyre, Christopher (2011-01)
      BACKGROUND/AIMS: Haemodialysis-induced myocardial stunning is associated with intradialytic hypotension, increased likelihood of cardiovascular events and death. Dialysis at 35°C reduces stunning, but adverse thermal symptoms limit technique adoption. This study investigated whether individualised body temperature dialysis improves haemodynamic stability and abrogates stunning. METHODS: Randomised crossover study of 11 patients compared LV regional wall motion abnormalities (RWMAs) at 37°C (HD(37)) and body temperature ('individualised', HD(ind)). Regional systolic function was quantitatively assessed by echocardiography. Haemodynamics were assessed using continuous pulse wave analysis. Thermal symptoms were scored by questionnaire. RESULTS: Mean predialysis body temperature was 36.0 ± 0.1°C. Mean number of peak stress RWMAs per patient was lower with HD(ind) (3.9 ± 1.4 vs. 5.3 ± 1.5, p = 0.03). Intradialytic systolic BP was higher during HD(ind) versus HD(37) (p < 0.001). Individualised body temperature dialysis demonstrated symptomatic tolerability comparable to HD(37). CONCLUSIONS: Individualised-temperature haemodialysis abrogates stunning, providing effective haemodynamic stabilisation at no additional therapy cost.
    • Infarct size following complete revascularization in patients presenting with STEMI: a comparison of immediate and staged in-hospital non-infarct related artery PCI subgroups in the CvLPRIT study.

      Kelly, Damian (2016-11)
      BACKGROUND: The CvLPRIT study showed a trend for improved clinical outcomes in the complete revascularisation (CR) group in those treated with an immediate, as opposed to staged in-hospital approach in patients with multivessel coronary disease undergoing primary percutaneous intervention (PPCI). We aimed to assess infarct size and left ventricular function in patients undergoing immediate compared with staged CR for multivessel disease at PPCI. METHODS: The Cardiovascular Magnetic Resonance (CMR) substudy of CvLPRIT was a multicentre, prospective, randomized, open label, blinded endpoint trial in PPCI patients with multivessel disease. These data refer to a post-hoc analysis in 93 patients randomized to the CR arm (63 immediate, 30 staged) who completed a pre-discharge CMR scan (median 2 and 4 days respectively) after PPCI. The decision to stage non-IRA revascularization was at the discretion of the treating interventional cardiologist. RESULTS: Patients treated with a staged approach had more visible thrombus (26/30 vs. 31/62, p = 0.001), higher SYNTAX score in the IRA (9.5, 8-16 vs. 8.0, 5.5-11, p = 0.04) and a greater incidence of no-reflow (23.3 % vs. 1.6 % p < 0.001) than those treated with immediate CR. After adjustment for confounders, staged patients had larger infarct size (19.7 % [11.7-37.6] vs. 11.6 % [6.8-18.2] of LV Mass, p = 0.012) and lower ejection fraction (42.2 ± 10 % vs. 47.4 ± 9 %, p = 0.019) compared with immediate CR. CONCLUSIONS: Of patients randomized to CR in the CMR substudy of CvLPRIT, those in whom the operator chose to stage revascularization had larger infarct size and lower ejection fraction, which persisted after adjusting for important covariates than those who underwent immediate CR. Prospective randomized trials are needed to assess whether immediate CR results in better clinical outcomes than staged CR. TRIAL REGISTRATION: ISRCTN70913605 , Registered 24th February 2011. DOI: 10.1186/s12968-016-0298-2 PMID: 27842548 [PubMed - in process] 2. Mol Med Rep. 2016 Nov 8. doi: 10.3892/mmr.2016.5933. [Epub ahead of print] Selection of suitable reference genes for gene expression studies in normal human ovarian tissues, borderline ovarian tumours and ovarian cancer. Ofinran O(1), Bose U(1), Hay D(1), Abdul S(2), Tufatelli C(1), Khan R(1). Author information: (1)Division of Medical Sciences and Graduate Entry Medicine, School of Medicine, The University of Nottingham, Royal Derby Hospital, Derby DE22 3DT, UK. (2)Department of Gynaecological Oncology, Royal Derby Hospital, Derby DE22 3NE, UK. The use of reference genes is the most common method of controlling the variation in mRNA expression during quantitative polymerase chain reaction, although the use of traditional reference genes, such as β actin, glyceraldehyde 3 phosphate dehydrogenase or 18S ribosomal RNA, without validation occasionally leads to unreliable results. Therefore, the present study aimed to evaluate a set of five commonly used reference genes to determine the most suitable for gene expression studies in normal ovarian tissues, borderline ovarian and ovarian cancer tissues. The expression stabilities of these genes were ranked using two gene stability algorithms, geNorm and NormFinder. Using geNorm, the two best reference genes in ovarian cancer were β glucuronidase and β actin. Hypoxanthine phosphoribosyltransferase 1 and β glucuronidase were the most stable in ovarian borderline tumours, and hypoxanthine phosphoribosyltransferase 1 and glyceraldehyde 3 phosphate dehydrogenase were the most stable in normal ovarian tissues. NormFinder ranked β actin the most stable in ovarian cancer, and the best combination of two genes was β glucuronidase and β actin. In borderline tumours, hypoxanthine phosphoribosyltransferase 1 was identified as the most stable, and the best combination was hypoxanthine phosphoribosyltransferase 1 and β glucuronidase. In normal ovarian tissues, β glucuronidase was recommended as the optimum reference gene, and the most optimum pair of reference genes was hypoxanthine phosphoribosyltransferase 1 and β actin. To the best of our knowledge, this is the first study to investigate the selection of a set of reference genes for normalisation in quantitative polymerase chain reactions in different ovarian tissues, and therefore it is recommended that β glucuronidase, β actin and hypoxanthine phosphoribosyltransferase 1 are the most suitable reference genes for such analyses.
    • Infarct Size Following Treatment With Second- Versus Third-Generation P2Y12 Antagonists in Patients With Multivessel Coronary Disease at ST-Segment Elevation Myocardial Infarction in the CvLPRIT Study.

      Kelly, Damian (2016-05)
      BACKGROUND: Third-generation P2Y12 antagonists (prasugrel and ticagrelor) are recommended in guidelines on ST-segment elevation myocardial infarction. Mechanisms translating their more potent antiplatelet activity into improved clinical outcomes versus the second-generation P2Y12 antagonist clopidogrel are unclear. The aim of this post hoc analysis of the Complete Versus Lesion-Only PRImary PCI Trial-CMR (CvLPRIT-CMR) substudy was to assess whether prasugrel and ticagrelor were associated with reduced infarct size compared with clopidogrel in patients undergoing primary percutaneous coronary intervention. METHODS AND RESULTS: CvLPRIT-CMR was a multicenter, prospective, randomized, open-label, blinded end point trial in 203 ST-segment elevation myocardial infarction patients with multivessel disease undergoing primary percutaneous coronary intervention with either infarct-related artery-only or complete revascularization. P2Y12 inhibitors were administered according to local guidelines. The primary end point of infarct size on cardiovascular magnetic resonance was not significantly different between the randomized groups. P2Y12 antagonist administration was not randomized. Patients receiving clopidogrel (n=70) compared with those treated with either prasugrel or ticagrelor (n=133) were older (67.8±12 versus 61.5±10 years, P<0.001), more frequently had hypertension (49% versus 29%, P=0.007), and tended to have longer symptom-to-revascularization time (234 versus 177 minutes, P=0.05). Infarct size (median 16.1% [quartiles 1-3, 10.5-27.7%] versus 12.1% [quartiles 1-3, 4.8-20.7%] of left ventricular mass, P=0.013) and microvascular obstruction incidence (65.7% versus 48.9%, P=0.022) were significantly greater in patients receiving clopidogrel. Infarct size remained significantly different after adjustment for important covariates using both generalized linear models (P=0.048) and propensity score matching (P=0.025). CONCLUSIONS: In this analysis of CvLPRIT-CMR, third-generation P2Y12 antagonists were associated with smaller infarct size and lower microvascular obstruction incidence versus the second-generation P2Y12 antagonist clopidogrel for ST-segment elevation myocardial infarction. CLINICAL TRIAL REGISTRATION: URL: http://www.isrctn.com/ISRCTN70913605.
    • Infections in relapsed myeloma patients treated with isatuximab plus pomalidomide and dexamethasone during the COVID-19 pandemic: Initial results of a UK-wide real-world study.

      Firas, AK
      OBJECTIVES: There are no real-world data describing infection morbidity in relapsed/refractory myeloma (RRMM) patients treated with anti-CD38 isatuximab in combination with pomalidomide and dexamethasone (IsaPomDex). In this UK-wide retrospective study, we set out to evaluate infections experienced by routine care patients who received this novel therapy across 24 cancer centres during the COVID-19 pandemic. METHODS: The primary endpoint was infection morbidity (incidence, grading, hospitalization) as well as infection-related deaths. Secondary outcomes were clinical predictors of increased incidence of any grade (G2-5) and high grade (≥G3) infections. RESULTS: In a total cohort of 107 patients who received a median (IQR) of 4 cycles (2-8), 23.4% of patients experienced ≥1 any grade (G2-5) infections (total of 31 episodes) and 18.7% of patients experienced ≥1 high grade (≥G3) infections (total of 22 episodes). Median time (IQR) from start of therapy to first episode was 29 days (16-75). Six patients experienced COVID-19 infection, of whom 5 were not vaccinated and 1 was fully vaccinated. The cumulative duration of infection-related hospitalizations was 159 days. The multivariate (MVA) Poisson Regression analysis demonstrated that a higher co-morbidity burden with Charlson Co-morbidity Index (CCI) score ≥4 (incidence rate ratio (IRR) = 3, p = 0.012) and sub-optimal myeloma response less than a partial response.
    • Influence of dialysis therapies in the development of cardiac disease in CKD.

      Odudu, Aghogho; McIntyre, Christopher (2012-05)
      It is well recognised that dialysis patients suffer excess morbidity and mortality and that this is mainly due to cardiac failure and sudden cardiac death rather than conventional risk factors. Dialysis patients are primed by a number of structural, functional and microcirculatory abnormalities to experience demand myocardial ischaemia. We have shown that haemodialysis induces repetitive myocardial ischaemia in the majority of patients. In this way, haemodialysis itself may contribute to the development of heart failure and the risk of sudden death. There is recent appreciation that peritoneal dialysis is also capable of exerting short-term effects on cardiovascular performance through mechanisms both mutual and exclusive to haemodialysis. The aim of this paper is to give an appreciation of the possibility that modification of the dialysis procedure is capable of improving treatment tolerability and has the potential to reduce the excessive rates of cardiovascular morbidity and mortality.
    • Inhaled corticosteroids and bone health.

      Sellahewa, Luckni (2014-01)
      Inhaled corticosteroids (ICS) are the cornerstones in the management of bronchial asthma and some cases of chronic obstructive pulmonary disease. Although ICS are claimed to have low side effect profiles, at high doses they can cause systemic adverse effects including bone diseases such as osteopenia, osteoporosis and osteonecrosis. Corticosteroids have detrimental effects on function and survival of osteoblasts and osteocytes, and with the prolongation of osteoclast survival, induce metabolic bone disease. Glucocorticoid-induced osteoporosis (GIO) can be associated with major complications such as vertebral and neck of femur fractures. The American College of Rheumatology (ACR) published criteria in 2010 for the management of GIO. ACR recommends bisphosphonates along with calcium and vitamin D supplements as the first-line agents for GIO management. ACR recommendations can be applied to manage patients on ICS with a high risk of developing metabolic bone disease. This review outlines the mechanisms and management of ICS-induced bone disease.
    • Injectable semaglutide and reductions in HbA1c and weight in the real-world in people switched from alternative glucagon-like peptide 1 receptor agonists.

      Crabtree, Thomas; Idris, Iskandar
      The ABCD semaglutide audit was designed to capture the routine clinical outcomes of people commenced on semaglutide in the UK. Previous work demonstrated differential reductions in HbA1c and weight dependent on previous GLPRA exposure. The analysis, in this research letter, demonstrates decreases in HbA1c and weight associated with semaglutide occur irrespective of previous GLP1RA use. However, HbA1c reductions were less if switched from dulaglutide or liraglutide and weight changes were attenuated if switched from dulaglutide or exenatide - potentially suggesting differing potencies between GLP1RAs. Dedicated studies with head-to-head comparisons are needed to confirm these findings. This article is protected by copyright. All rights reserved.
    • Integrating peritoneal and home haemodialysis: a nurse's perspective from a single centre.

      Rhodes, Carol; Beech, Nicola; Chesterton, Lindsay; Fluck, Richard (2011-12)
      Home based dialytic therapy is underutilized in most renal centres. This article describes a nurse led and delivered approach to problem solving from a patient perspective, resulting in an increase in prevalent and incident patient numbers on home HD and peritoneal dialysis. Overall, between 2004 and 2010 home-based therapies have risen from 61 to 119 prevalent patients, with a fall in in-centre patient numbers.
    • Intensive Hemodialysis and Health-Related Quality of Life.

      Fluck, Richard (2016-11)
      Diminished health-related quality of life (HRQoL) is common in dialysis patients and associated with increased risks for morbidity and mortality. Patients may present limitations in both physical and mental HRQoL. Poor physical HRQoL may be defined by limited physical function, role limitations due to physical health, dissatisfaction with physical ability, and impaired mobility. Sleep disorders such as obstructive sleep apnea, restless legs, and fatigue are typical manifestations of poor physical HRQoL in dialysis patients. Poor mental HRQoL may be defined by depressive thinking, lack of positive affect, anxiety, and feelings of social isolation. The prevalence of depression is high in dialysis patients. Intensive hemodialysis (HD) can positively address HRQoL. In 3 randomized clinical trials, relative to conventional HD, intensive HD increased physical and mental component summary scores from the 36-Item Short-Form Health Survey (SF-36), although individual treatment effects of daily nocturnal HD were not statistically significant. In another large prospective study, initiation of short daily HD therapy was followed after 12 months by improvements in all SF-36 domains, sleep quality, and restless legs symptoms. In a small study of nocturnal HD, apnea and hypopnea episodes per hour decreased by almost 70% after conversion from conventional HD. Intensive HD is also associated with a large reduction in postdialysis recovery time. In contrast, 2 randomized clinical trials failed to demonstrate statistically significant effects of intensive HD on the Beck Depression Inventory score despite a significant decrease in Beck Depression Inventory score in the prospective study of short daily HD. Furthermore, intensive HD may not improve objective physical performance and can increase burden on caregivers in the home setting. In conclusion, intensive HD potentially can address both physical and mental aspects of poor HRQoL relative to conventional HD. However, more studies are needed to understand the effects of intensive HD, including specific schedules, on HRQoL.
    • Intensive Hemodialysis and Potential Risks With Increasing Treatment.

      Fluck, Richard (2016-11)
      Although intensive hemodialysis (HD) can address important clinical problems, increasing treatment also introduces risks. In this review, we assess risks pertaining to 6 domains: vascular access complications, infection, mortality, loss of residual kidney function, solute balance, and patient and care partner burden. In the Frequent Hemodialysis Network (FHN) trials, short da ily and nocturnal schedules increased the incidence of access complications, although the incidence of access loss was not statistically higher. Observational studies indicate that infection-related hospitalization is an ongoing challenge with short daily HD. Excess risk may be catalyzed by poor infection control practices in the home setting in which intensive HD is typically delivered, but with fixed probability of bacterial contamination per cannulation, greater treatment frequency necessarily increases the risk for infectious complications. Buttonhole cannulation may increase the risk for metastatic infections. However, intensive HD in the home setting is associated with lower risk for infection than peritoneal dialysis. Data regarding mortality are equivocal. With extended follow-up of individuals in the FHN trials, short daily HD was associated with lower risk relative to the usual schedule, whereas nocturnal HD was associated with higher risk. In many, but not all, observational studies, short daily HD has been associated with lower risk than both in-center HD and peritoneal dialysis; however, observational studies are subject to unmeasured confounding. Intensive HD can accelerate the loss of residual kidney function in new dialysis patients with substantial urine output and can deplete solutes (eg, phosphorus) to the extent that supplementation is necessary. Finally, intensive HD may increase burden on patients and caregivers, possibly leading to technique failure. Some of these problems might be addressed with careful monitoring, so that relevant interventions (eg, antibiotics, retraining, and respite care) can be delivered. Ultimately, intensive HD is not a panacea for end-stage renal disease. Potential benefits and risks of treatment should be jointly considered.
    • Intensive Hemodialysis and Treatment Complications and Tolerability

      Fluck, Richard (2016-11)
      Hemodialysis (HD) treatment can be difficult to tolerate. Common complications are intradialytic hypotension (IDH) and long time to recovery after an HD session. IDH, as defined by nadir systolic blood pressure < 90mmHg and intradialytic decline > 30mmHg, occurs in almost 8% of HD sessions. IDH may be caused by aggressive ultrafiltration in response to interdialytic weight gain, can lead to myocardial stunning and cardiac arrhythmias, and is associated with increased risk for death. Long recovery time after a treatment session is also common. In DOPPS (Dialysis Outcomes and Practice Patterns Study), recovery time was 2 to 6 hours for 41% of HD patients and longer than 6 hours for 27%; recovery time was linearly associated with increased risks for death and hospitalization. Importantly, both decreases in blood pressure and feeling washed out or drained have been identified by patients as more important outcomes than death or hospitalization. Intensive HD likely reduces the likelihood of IDH. In the Frequent Hemodialysis Network trial, short daily and nocturnal schedules reduced the per-session probability of IDH by 20% and 68%, respectively, relative to 3 sessions per week. Due to lower ultrafiltration volume and/or rate, intensive HD may reduce intradialytic blood pressure variability. In a cross-sectional study, short daily and nocturnal schedules were associated with slower ultrafiltration and less dialysis-induced myocardial stunning than 3 sessions per week. In FREEDOM (Following Rehabilitation, Economics, and Everyday-Dialysis Outcome Measurements), a prospective cohort study of short daily HD, recovery time was reduced after 12 months from 8 hours to 1 hour, according to per-protocol analysis. Recovery time after nocturnal HD may be minutes. In conclusion, intensive HD can improve the tolerability of HD treatment by reducing the risk for IDH and decreasing recovery time after HD. These changes may improve the patient centeredness of end-stage renal disease care.
    • International Criteria for Acute Kidney Injury: Advantages and Remaining Challenges.

      Selby, Nicholas; Fluck, Richard; Kolhe, Nitin; Taal, Maarten (2016-09)
      Nicholas Selby and colleagues describe how the definition of acute kidney injury brings opportunities and challenges in identifying patients at higher risk of adverse outcomes.