Translational and mechanistic studies of protection of human kidney cells from injury

Acute kidney injury (AKI) is a common syndrome, affecting up to 14% of patients in hospital and with no specific treatment. It is associated with significant morbidity and mortality and affects patients under the care of all specialities. Patients who have cardiac surgery are particularly vulnerable to AKI in that they often have multiple risk factors for AKI such as older age, hypertension, and type II diabetes. Planned cardiac bypass surgery gives an opportunity to study ischaemia reperfusion injury (IRI) to the kidney, and allows the testing of potential protective agents and therefore translation from preclinical studies. The drug Heme Arginate (HA) has been in clinical use for more than 20 years for the treatment of acute porphyria and has a good safety profile. Interestingly, HA treatment induces upregulation of the anti-inflammatory enzyme heme oxygenase-1 (HO-1) and preclinical studies have indicated that HA protects aged mice from renal IRI with macrophage HO-1 expression being critical. Despite encouraging data from Phase I studies in healthy volunteers, HA has not been used in an elderly and comorbid patient population of patients with cardiac disease. There is a known association between iron and inflammation. Therefore, the Heme Arginate in patients planned for Cardiac Surgery (HACS) clinical trial was designed to investigate if HA effectively induces HO-1 expression and if it is safe in this patient group. The HACS trial demonstrated that HO-1 gene expression in peripheral blood mononuclear cells was significantly increased, but that HO-1 protein was not upregulated. There was however a significant increase in HO-1 protein in serum. A recent study of HO-1 expression in the human heart following HA dosing has provided comparable results for peripheral blood mononuclear cells in a similar aged and comorbid patient group. Results will inform future Phase II and Phase III clinical trials. Continuing the theme of repurposing drugs licensed for human use, dimethyl fumarate (DMF) is a fumaric acid ester which is licensed for the treatment of multiple sclerosis (MS) and psoriasis. Its exact mechanisms of action are unknown but likely involves activation of the strongly anti-inflammatory nuclear factor erythroid 2–related factor 2 (Nrf2) pathway (of which HO-1 is downstream) and inhibition of the nuclear localisation of the transcription factor NF-B. Preclinical studies have suggested that macrophages are key to both the development of AKI and subsequent kidney repair. A treatment which could alter macrophage phenotype from pro-inflammatory (classically activated/M1) to anti-inflammatory reparative (alternatively activated/M2) would be of interest in AKI. Experimental work in vitro and in vivo was carried out to examine the effect of DMF on the Nrf2 pathway and to explore the effect of DMF on both murine and human macrophages. Interestingly, DMF reduced phagocytosis of apoptotic cells by murine bone marrow derived macrophages (BMDMs) at high dose, but pilot data suggested that DMF treatment ameliorated the classically activated M1 phenotype of BMDMs as measured by nitrite production. In addition, DMF administration to mice upregulated Nrf2 dependent genes including HO-1 in kidney tissue. Preliminary studies of the effect of DMF upon murine renal IRI did not show protection from AKI although the severity if the injury may have precluded this and further work is required. It is hoped that HA may offer therapeutic potential in the prevention and treatment of IRI and further clinical trials are ongoing. DMF offers potential as an attractive oral anti-inflammatory therapy and merits further study

Antioxidant effectiveness of vegetable powders on the lipid and protein oxidative stability of cooked Turkey meat patties : implications for health

Peer reviewedPublisher PD

Beetroot improves oxidative stability and functional properties of processed foods : singular and combined effects with chocolate

The authors are grateful to the Rural and Environment Science and Analytical Services (RESAS) Division of the Scottish government for funding the study. None of the authors declare any conflicts of interest.Peer reviewedPostprin

Healthy snacks in hospitals : testing the potential effects of changes in availability

Acknowledgements: The authors would like to thank the food retail staff and managers in each location and the food retailers who provided access to their sales data. Funding: Study 1 was funded by the Scottish Government Chief Scientist Office [CGA/16/17]. Study 2 was conducted while JA was a Royal Society of Edinburgh Sabbatical Grant Holder. Open access via Sage agreementPeer reviewedPostprin

Breads Fortified with Freeze-Dried Vegetables : Quality and Nutritional Attributes. Part 1: Breads Containing Oil as an Ingredient

Acknowledgments: Funds for the study were provided by the Scottish Government’s Rural and Environment Science and Analytical Services Division and conducted as part of the Scottish Government Strategic Research programme (Diet and Health Theme of the Food Land & People Programme). The authors are grateful to Phillip Morrice, Vivian Buchan and Donna Henderson for helping with the nutritional analysis of the breads. The authors declare no conflicts of interest.Peer reviewedPublisher PD

Breads Fortified with Freeze-Dried Vegetables : Quality and Nutritional Attributes. Part II: Breads Not Containing Oil as an Ingredient

Acknowledgments: Funds for the study were provided by the Scottish Government's Rural and Environment Science and Analytical Services Division and conducted as part of the Scottish Government Strategic Research programme (Diet and Health Theme of the Food Land & People Programme). The authors are grateful to Phillip Morrice, Vivian Buchan, and Donna Henderson for helping with the nutritional analysis of the breads. The authors declare no conflicts of interest.Peer reviewedPublisher PD

Cognition in chronic kidney disease: a systematic review and meta-analysis

Background Cognitive impairment is common in people with chronic kidney disease (CKD) and associated with increased morbidity and mortality. Subtle changes can impact engagement with healthcare, comprehension, decision-making, and medication adherence. We aimed to systematically summarise evidence of cognitive changes in CKD. Methods We searched MEDLINE (March 2016) for cross-sectional, cohort or randomised studies that measured cognitive function in people with CKD (PROSPERO, registration number CRD42014015226). The CKD population included people with eGFR < 60 mL/min/1.73 m2, not receiving renal replacement therapy, in any research setting. We conducted a meta-analysis using random effects, expressed as standardised mean differences (SMD) with 95% confidence intervals (CI). Outcomes were performance in eight cognitive domains. Bias was assessed with the Newcastle-Ottawa Scale (NOS). Results We identified 44 studies reporting sufficient data for synthesis (51,575 participants). Mean NOS score for cohort studies was 5.8/9 and for cross-sectional 5.4/10. Studies were deficient in NOS outcome and selection due to poor methods reporting and in comparison group validity of demographics and chronic disease status. CKD patients (eGFR < 60 mL/min/1.73 m2) performed worse than control groups (eGFR ≥ 60 mL/min/1.73 m2) on Orientation & Attention (SMD –0.79, 95% CI, –1.44 to –0.13), Language (SMD –0.63, 95% CI, –0.85 to –0.41), Concept Formation & Reasoning (SMD –0.63, 95% CI, –1.07 to –0.18), Executive Function (SMD –0.53, 95% CI, –0.85 to –0.21), Memory (SMD –0.48, 95% CI, –0.79 to –0.18), and Global Cognition (SMD –0.48, 95% CI, –0.72 to –0.24). Construction & Motor Praxis and Perception were unaffected (SMD –0.29, 95% CI, –0.90 to 0.32; SMD –1.12, 95% CI, –4.35 to 2.12). Language scores dropped with eGFR (<45 mL/min/1.73 m2 SMD –0.86, 95% CI, –1.25 to –46; 30 mL/min/1.73 m2 SMD –1.56, 95% CI, –2.27 to –0.84). Differences in Orientation & Attention were greatest at eGFR < 45 mL/min/1.73 m2 (SMD –4.62, 95% CI, –4.68 to –4.55). Concept Formation & Reasoning differences were greatest at eGFR < 45 mL/min/1.73 m2 (SMD –4.27, 95% CI, –4.23 to –4.27). Differences in Executive Functions were greatest at eGFR < 30 mL/min/1.73 m2 (SMD –0.54, 95% CI, –1.00 to –0.08). Conclusions Cognitive changes occur early in CKD, and skills decline at different rates. Orientation & Attention and Language are particularly affected. The cognitive impact of CKD is likely to diminish patients’ capacity to engage with healthcare decisions. An individual’s cognitive trajectory may deviate from average