Impact of metabolic disorders on the structural, functional, and immunological integrity of the blood-brain barrier: Therapeutic avenues.

Mounting evidence has linked the metabolic disease to neurovascular disorders and cognitive decline. Using a murine model of a high-fat high-sugar diet mimicking obesity-induced type 2 diabetes mellitus (T2DM) in humans, we show that pro-inflammatory mediators and altered immune responses damage the blood-brain barrier (BBB) structure, triggering a proinflammatory metabolic phenotype. We find that disruption to tight junctions and basal lamina due to loss of control in the production of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) causes BBB impairment. Together the disruption to the structural and functional integrity of the BBB results in enhanced transmigration of leukocytes across the BBB that could contribute to an initiation of a neuroinflammatory response through activation of microglia. Using a humanized in vitro model of the BBB and T2DM patient post-mortem brains, we show the translatable applicability of our results. We find a leaky BBB phenotype in T2DM patients can be attributed to a loss of junctional proteins through changes in inflammatory mediators and MMP/TIMP levels, resulting in increased leukocyte extravasation into the brain parenchyma. We further investigated therapeutic avenues to reduce and restore the BBB damage caused by HFHS-feeding. Pharmacological treatment with recombinant annexin A1 (hrANXA1) or reversion from a high-fat high-sugar diet to a control chow diet (dietary intervention), attenuated T2DM development, reduced inflammation, and restored BBB integrity in the animals. Given the rising incidence of diabetes worldwide, understanding metabolic-disease-associated brain microvessel damage is vital and the proposed therapeutic avenues could help alleviate the burden of these diseases.

Experience of SARS-CoV-2 infection in two kidney transplant recipients living with HIV-1 infection.

There is still no consensus on the optimal management of COVID-19 within the general population due to the emerging evidence base. High-risk groups, including kidney transplant recipients living with HIV present unique additional challenges. Here we discuss two kidney transplant recipients living with HIV with SARS-CoV-2 infection and their clinical course, and review the existing literature for this subset of challenging patients.

Kidney Transplantation in a Patient Lacking Cytosolic Phospholipase A2 Proves Renal Origins of Urinary PGI-M and TX-M.

RATIONALE: The balance between vascular prostacyclin, which is antithrombotic, and platelet thromboxane A2, which is prothrombotic, is fundamental to cardiovascular health. Prostacyclin and thromboxane A2 are formed after the concerted actions of cPLA2α (cytosolic phospholipase A2) and COX (cyclooxygenase). Urinary 2,3-dinor-6-keto-PGF1α (PGI-M) and 11-dehydro-TXB2 (TX-M) have been taken as biomarkers of prostacyclin and thromboxane A2 formation within the circulation and used to explain COX biology and patient phenotypes, despite concerns that urinary PGI-M and TX-M originate in the kidney. OBJECTIVE: We report data from a remarkable patient carrying an extremely rare genetic mutation in cPLA2α, causing almost complete loss of prostacyclin and thromboxane A2, who was transplanted with a normal kidney resulting in an experimental scenario of whole-body cPLA2α knockout, kidney-specific knockin. By studying this patient, we can determine definitively the contribution of the kidney to the productions of PGI-M and TX-M and test their validity as markers of prostacyclin and thromboxane A2 in the circulation. METHODS AND RESULTS: Metabolites were measured using liquid chromatography-tandem mass spectrometry. Endothelial cells were grown from blood progenitors. Before kidney transplantation, the patient's endothelial cells and platelets released negligible levels of prostacyclin (measured as 6-keto-prostaglandin F1α) and thromboxane A2 (measured as TXB2), respectively. Likewise, the urinary levels of PGI-M and TX-M were very low. After transplantation and the establishment of normal renal function, the levels of PGI-M and TX-M in the patient's urine rose to within normal ranges, whereas endothelial production of prostacyclin and platelet production of thromboxane A2 remained negligible. CONCLUSIONS: These data show that PGI-M and TX-M can be derived exclusively from the kidney without contribution from prostacyclin made by endothelial cells or thromboxane A2 by platelets in the general circulation. Previous work relying on urinary metabolites of prostacyclin and thromboxane A2 as markers of whole-body endothelial and platelet function now requires reevaluation.

Healthcare use, costs and quality of life in patients with end-stage kidney disease receiving conservative management: results from a multi-centre observational study (PACKS).

BACKGROUND: Previous research has explored the cost of providing renal replacement therapies in patients with end-stage kidney disease and their quality of life. This is the first study to examine the healthcare costs of patients receiving conservative care without dialysis for end-stage kidney disease. This alternative to dialysis is an option for patients who prefer a supportive and palliative care approach. AIM: Descriptive cost and quality of life analyses alongside a UK-based multi-centre observational study in patients receiving conservative management for end-stage kidney disease. DESIGN: Health service use was recorded up to 12 months after making the decision to receive conservative management. Mean costs were calculated for each 3-month time period. The annual cost was calculated in two ways: by using only patients with complete cost data and by using all available data weighted by the number of patients at each time point. SETTING: In total, 42 patients who opted for conservative management over dialysis were recruited. RESULTS: Mean costs were £1622 (0-3 months), £1008 (3-6 months), £554 (6-9 months) and £2626 (9-12 months). Mean annual cost based on complete data ( n = 8) was £5511, and the weighted mean annual cost was £5620. CONCLUSION: The importance of this study is twofold. First, it provides substantive new information for health and social care planning of conservative management by demonstrating where demand exists for services, in both the United Kingdom and other countries with a comparable health service structure. Second, methodologically, it indicates that it is feasible to collect service use data directly from this patient population.

Nephrotic syndrome in adults.

Nephrotic syndrome is an important presentation of glomerular disease characterised by heavy proteinuria, hypoalbuminaemia and oedema. The differential diagnosis of the underlying condition is wide including primary renal disorders and secondary diseases such as malignancy, infection, diabetes and amyloid. Presentations to acute medicine may be with hypervolaemia, complications of the nephrotic state (such as venous thromboembolism), or complications of therapy (such as infection). Early recognition of nephrotic syndrome is possible through simple urinalysis for protein and testing serum albumin, although a high index of suspicion is sometimes required in patients with comorbidities including potentially distracting cardiac or hepatic diseases.

Clinician views of patient decisional conflict when deciding between dialysis and conservative management: Qualitative findings from the PAlliative Care in chronic Kidney diSease (PACKS) study.

BACKGROUND: Only a paucity of studies have addressed clinician perspectives on patient decisional conflict, in making complex decisions between dialysis and conservative management (renal supportive and palliative care). AIM: To explore clinician views on decisional conflict in patients with end-stage kidney disease. DESIGN: Interpretive, qualitative study. SETTING AND PARTICIPANTS: As part of the wider National Institute for Health Research, PAlliative Care in chronic Kidney diSease study, semi-structured interviews were conducted with clinicians (nephrologists n = 12; 7 female and clinical nurse specialists n = 15; 15 female) across 10 renal centres in the United Kingdom. Interviews took place between April 2015 and October 2016 and a thematic analysis of the interview data was undertaken. RESULTS: Three major themes with associated subthemes were identified. The first, 'Frequent changing of mind regarding treatment options', revealed how patients frequently altered their treatment decisions, some refusing to make a decision until deterioration occurred. The second theme, 'Obligatory beneficence', included clinicians helping patients to make informed decisions where outcomes were uncertain. In weighing up risks and benefits, and the impact on patients, clinicians sometimes withheld information they thought might cause concern. Finally, 'Intricacy of the decision' uncovered clinicians' views on the momentous and brave decision to be made. They also acknowledged the risks associated with this complex decision in giving prognostic information which might be inaccurate. LIMITATIONS: Relies on interpretative description which uncovers constructed truths and does not include interviews with patients. CONCLUSION: Findings identify decisional conflict in patient decision-making and a tension between the prerequisite for shared decision-making and current clinical practice. Clinicians also face conflict when discussing treatment options due to uncertainty in equipoise between treatments and how much information should be shared. The findings are likely to resonate across countries outside the United Kingdom.

Membranous nephropathy: a retrospective observational study of membranous nephropathy in north east and central London.

BACKGROUND: Membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults. MN is a clinically heterogeneous disease and it is difficult to accurately predict outcomes (including end stage renal failure) at presentation and whom to treat with potentially toxic therapies. We aimed to identify factors predicting outcome in MN in our cohort from two large tertiary London units by undertaking a retrospective data analysis of 148 biopsy-proven MN patients from North East and Central London between 1995 and 2015. METHODS: Review of clinical and biochemistry databases. RESULTS: Surprisingly, patients that reached end stage renal failure (ESRF) had a less severe nephrosis compared to those that did not develop ESRF; serum albumin 33 g/L (3.3 g/dL) versus 24 g/L (2.4 g/dL), p = 0.002 and urinary protein creatinine ratio (uPCR) 550 mg/mmol (5500 mg/g) versus 902 mg/mmol (9020 mg/g), p = 0.0124. The correlation with ESRF was strongest with the presenting creatinine; 215 µmol/L (2.43 mg/dL) compared to 81 µmol/L (0.92 mg/dL), p < 0.0001. Patients presenting with creatinine of >120 µmol/L (1.36 mg/dL; corresponding to an eGFR of ≤60 ml/min in non-Black males) had an increased rate of ESRF and a faster decline. Other traditional risk factors for progression were not significantly associated with ESRF. Black patients presented with higher serum creatinine but no statistically significant difference in the estimated glomerular filtration rate, a higher rate of progression to ESRF and had a poorer response to treatment. CONCLUSIONS: This ethnically diverse cohort does not demonstrate the traditional risk profile associated with development of ESRF. Thus, careful consideration of therapeutic options is crucial, as current risk modelling cannot accurately predict the risk of ESRF. Further studies are required to elucidate the role of antibodies and risk genes.

Characteristics and outcomes of dialysis patients with infective endocarditis.

BACKGROUND: The incidence of infective endocarditis (IE) in dialysis patients is higher than the general population. Dialysis patients who develop endocarditis are thought to have a poorer prognosis than other patients with IE. AIM: To examine the risk profiles, clinical features, and outcomes of patients on dialysis who developed IE in a large cohort. DESIGN AND METHODS: A retrospective analysis of all patients developing IE on dialysis (using the modified Duke criteria) was undertaken between 1998 and 2011. Patients were identified from a prospectively collected clinical database. RESULTS: 42 patients developed IE out of a total incident dialysis population of 1,500 over 13 years. 95% of the patients (40/42) were on long-term haemodialysis (HD) and 5% (2/42) on peritoneal dialysis. Mean patient age was 55.2 years (IQR: 43-69), and mean duration of HD prior to IE was 57.4 months. Primary HD access at the time of diagnosis was an arteriovenous fistula in 35% (14/40), a dual-lumen tunnelled catheter in 55% (22/40), and a dual-lumen non-tunnelled catheter in 10% (4/40). Staphylococcus aureus (including methicillin-resistant S. aureus) was present in 57.1% (24/42). The aortic valve was affected in 42.8% of the patients (18/42), the mitral valve in 30.9% (13/42), and both valves in 9.5% (4/42). 33.3% of the patients had an abnormal valve before the episode of IE. In 21.4% (9/42), valve surgery was performed and mortality was lower in the surgical group compared to the group managed medically during hospitalisation (11.1 vs. 15.2%, p = 0.892), at 3 months (13.1 vs. 19.6%, p = 0.501), and during follow-up (p = 0.207), but this difference did not reach statistical significance. Age >60 years, septic emboli, and methicillin-resistant S. aureus were all adverse prognostic factors. Patients receiving surgery were younger (mean 47.1 ± 14.4 years vs. 57.4 ± 14.3, p = 0.049) and less likely to be infected with S. aureus (surgery 33.3% vs. antibiotics 63.6%, p = 0.046). CONCLUSION: This is one of the largest reported series of IE in dialysis patients. The incidence of IE remains high and the prognosis poor in dialysis patients, although patients selected for early valve surgery have good 1-year survival.

The use of culturally adapted and translated depression screening questionnaires with South Asian haemodialysis patients in England.

BACKGROUND: Depression is common amongst patients receiving haemodialysis (HD). Assessment and intervention when faced with language and cultural barriers is challenging. To support clinician decisions, we conducted a cross-sectional study to assess the use of culturally adapted and translated versions of commonly-used depression screening questionnaires with South Asian patients receiving HD in England. METHODS: Patients completed adapted versions of the Patient Health Questionnaire (PHQ-9), the Centre for Epidemiological Studies Depression Scale Revised (CESD-R), and the Beck Depression Inventory II (BDI-II). All questionnaires were available in Gujarati, Punjabi, Urdu, and Bengali. A comparative sample of white-Europeans completed the questionnaires in English. The research was based across 9 National Health Service (NHS) Trusts in England. Structural validity of translated questionnaires was assessed using confirmatory factor analysis. Diagnostic accuracy was explored in a subgroup of South Asians against ICD-10 categories using the Clinical Interview Schedule Revised (CIS-R) with receiver operating curve (ROC) analysis. RESULTS: 229 South Asian and 120 white-European HD patients participated. A single latent depression factor largely accounted for the correlations between items of the PHQ-9, CESD-R and BDI-II. Issues with measurement equivalence implied that scores on the translations may not be comparable with the English language versions. Against CIS-R based ICD-10 diagnosis of depression, sensitivity was modest across scales (50-66.7%). Specificity was higher (81.3-93.8%). Alternative screening cut-offs did not improve positive predictive values. CONCLUSIONS: Culturally adapted translations of depression screening questionnaires are useful to explore symptom endorsement amongst South Asian patients. However, data indicate that standard cut-off scores may not be appropriate to classify symptom severity. Use of the CIS-R algorithms for optimal case identification requires further exploration in this setting. Strategies to encourage recruitment of under-represented groups in renal research are also warranted, especially for in-depth discussions related to psychological care needs.

Renal Function Underpins the Cyclooxygenase-2: Asymmetric Dimethylarginine Axis in Mouse and Man.

Introduction: Through the production of prostacyclin, cyclooxygenase (COX)-2 protects the cardiorenal system. Asymmetric dimethylarginine (ADMA), is a biomarker of cardiovascular and renal disease. Here we determined the relationship between COX-2/prostacyclin, ADMA, and renal function in mouse and human models. Methods: We used plasma from COX-2 or prostacyclin synthase knockout mice and from a unique individual lacking COX-derived prostaglandins (PGs) because of a loss of function mutation in cytosolic phospholipase A2 (cPLA2), before and after receiving a cPLA2-replete transplanted donor kidney. ADMA, arginine, and citrulline were measured using ultra-high performance liquid-chromatography tandem mass spectrometry. ADMA and arginine were also measured by enzyme-linked immunosorbent assay (ELISA). Renal function was assessed by measuring cystatin C by ELISA. ADMA and prostacyclin release from organotypic kidney slices were also measured by ELISA. Results: Loss of COX-2 or prostacyclin synthase in mice increased plasma levels of ADMA, citrulline, arginine, and cystatin C. ADMA, citrulline, and arginine positively correlated with cystatin C. Plasma ADMA, citrulline, and cystatin C, but not arginine, were elevated in samples from the patient lacking COX/prostacyclin capacity compared to levels in healthy volunteers. Renal function, ADMA, and citrulline were returned toward normal range when the patient received a genetically normal kidney, capable of COX/prostacyclin activity; and cystatin C positively correlated with ADMA and citrulline. Levels of ADMA and prostacyclin in conditioned media of kidney slices were not altered in tissue from COX-2 knockout mice compared to wildtype controls. Conclusion: In human and mouse models, where renal function is compromised because of loss of COX-2/PGI2 signaling, ADMA levels are increased.

A survey to determine the views of renal transplant patients on generic substitution in the UK.

Rising healthcare costs promote the generic substitution among patients because it is identifiable costs. A key concern is that patients should be involved in the decision of switching. The aim of this study was to examine renal transplant patients' views on generic substitution in the UK. A total of 163 renal patients were surveyed using 36 multiple-choice questions at Barts and The London Renal Transplant Clinic, in the UK. Transplant recipients over 18 years, able to read and write English and willing to fill in the questionnaire were targeted; 84% of patients were conscious of the availability of generic medicines, 70% understood the terms "generic" and "branded" in relation to medicines and 54% were aware of generic substitution practice. However, 75% did not know if they were taking generics and 84% felt that generics are not equivalent or only equivalent sometimes and they were uncertain that generics had the same quality as branded medicines. Moreover, many patients admitted that they would not accept the generic substitution of ciclosporin when become available in the UK. A number of factors such as patients' education, knowledge, severity of the disease, efficacy of generic medicines and patients' involvement in decisions regarding their health appear to drive patients' attitudes towards generic substitution.

Accelerated decline of GFR in diabetic nephropathy predicted by interferon release assay to tuberculosis antigens.

BACKGROUND: The QuantiFERON® test (QFT) is a diagnostic tool for active and latent tuberculosis (TB) infections. High rates of positivity to QuantiFERON® have been demonstrated in patients with chronic kidney disease (CKD) and diabetic patients. We performed a pilot study to investigate if QFT positivity in diabetic CKD patients predicted the rate of renal function decline. METHODS: QFT was performed in 38 diabetic patients with CKD 4-5 not on dialysis. The rate of decline in estimated glomerular filtration rate (eGFR) was calculated. RESULTS: 18/38 patients had a positive QFT. Patients with a positive QFT had a steeper decline in eGFR, compared with patients with a negative QFT. Ethnicity (a marker of risk of previous TB exposure), urine protein/creatinine ratio, use of ACE inhibitors/angiotensin II receptor blockers and statins, serum C-reactive protein, vitamin D levels, HbA1c concentration and presenting GFR did not differ significantly. CONCLUSIONS: The finding in this small cohort needs to be replicated in a larger study because our study is susceptible to both type I and type II statistical error. We found that QFT positivity was associated with a more rapid rate of decline in GFR, but this association may be coincidental (with the difference in decline attributed to differences in the blood pressure or proteinuria of the two groups). Moreover, an association does not necessarily mean causality, although it would be interesting to speculate if we are identifying patients with latent TB who have an active interstitial nephritis. Another intriguing possibility is that this assay identifies patients with an immunological phenotype that predisposes to eGFR loss.

Prevalence and management of anaemia in renal transplant recipients: data from ten European centres.

BACKGROUND: Although it is a known predictor of mortality, there is a relative lack of recent information about anaemia in kidney transplant recipients. Thus, we now report data about the prevalence and management of post-transplant anaemia (PTA) in Europe 5 years after the TRansplant European Survey on Anemia Management (TRESAM) study. METHODS: In a cross-sectional study enrolling the largest number of patients to date, data were obtained from 5,834 patients followed at 10 outpatient transplant clinics in four European countries using the American Society of Transplantation anaemia guideline. RESULTS: More than one third (42%) of the patients were anaemic. The haemoglobin (Hb) concentration was significantly correlated with the estimated glomerular filtration rate (eGFR) (r = 0.4, p < 0.001). In multivariate analysis, eGFR, serum ferritin, age, gender, time since transplantation and centres were independently and significantly associated with Hb. Only 24% of the patients who had a Hb concentration <110 g/l were treated with an erythropoiesis-stimulating agent. The prevalence of anaemia and also the use of erythropoiesis-stimulating agents were significantly different across the different centres, suggesting substantial practice variations. CONCLUSIONS: PTA is still common and under-treated. The prevalence and management of PTA have not changed substantially since the TRESAM survey.

Do oral aluminium phosphate binders cause accumulation of aluminium to toxic levels?

BACKGROUND: Aluminium (Al) toxicity was frequent in the 1980s in patients ingesting Al containing phosphate binders (Alucaps) whilst having HD using water potentially contaminated with Al. The aim of this study was to determine the risk of Al toxicity in HD patients receiving Alucaps but never exposed to contaminated dialysate water. METHODS: HD patients only treated with Reverse Osmosis(RO) treated dialysis water with either current or past exposure to Alucaps were given standardised DFO tests. Post-DFO serum Al level > 3.0 µmol/L was defined to indicate toxic loads based on previous bone biopsy studies. RESULTS: 39 patients (34 anuric) were studied. Mean dose of Alucap was 3.5 capsules/d over 23.0 months. Pre-DFO Al levels were > 1.0 µmol/L in only 2 patients and none were > 3.0 µmol/L. No patients had a post DFO Al levels > 3.0 µmol/L. There were no correlations between the serum Al concentrations (pre-, post- or the incremental rise after DFO administration) and the total amount of Al ingested.No patients had unexplained EPO resistance or biochemical evidence of adynamic bone. CONCLUSIONS: Although this is a small study, oral aluminium exposure was considerable. Yet no patients undergoing HD with RO treated water had evidence of Al toxicity despite doses equivalent to 3.5 capsules of Alucap for 2 years. The relationship between the DFO-Al results and the total amount of Al ingested was weak (R² = 0.07) and not statistically significant. In an era of financial prudence, and in view of the recognised risk of excess calcium loading in dialysis patients, perhaps we should re-evaluate the risk of using Al-based phosphate binders in HD patients who remain uric.

Exploration of Caregiver Experiences of Conservatively Managed End-Stage Kidney Disease to Inform Development of a Psychosocial Intervention: The ACORN Study Protocol.

BACKGROUND: End-stage kidney disease (ESKD) is an overwhelming illness that impacts not just patients, but also their informal carers. Patients who opt for conservative management rather than dialysis experience difficult symptoms and the psychosocial consequences of their condition. Informal carers of patients who choose conservative management can also experience high levels of psychosocial burden, yet there is little guidance on how best to support informal carers, and no evidence on psychosocial interventions to address unmet needs. AIM: The aim of this study is to explore the experiences and unmet needs of informal carers of patients with ESKD receiving conservative management in order to inform the development of a psychosocial intervention. METHODS: This qualitative study will consist of three stages: (I) semi-structured interviews with informal carers in England and Northern Ireland, (II) focus groups with healthcare professionals and informal carers, and (III) national workshops to refine the components of a psychosocial intervention. DISCUSSION: Informal carers of patients with ESKD who are receiving conservative management experience a high psychosocial burden, but there is limited evidence on how best to provide support, particularly as the patient nears the end of life. To our knowledge this study will be the first to address this gap by exploring the experiences and unmet needs of informal carers, with the aim of informing the development of a psychosocial intervention to support the health and wellbeing of informal carers.

Exercise programme to improve quality of life for patients with end-stage kidney disease receiving haemodialysis: the PEDAL RCT.

BACKGROUND: Whether or not clinically implementable exercise interventions in haemodialysis patients improve quality of life remains unknown. OBJECTIVES: The PEDAL (PrEscription of intraDialytic exercise to improve quAlity of Life in patients with chronic kidney disease) trial evaluated the clinical effectiveness and cost-effectiveness of a 6-month intradialytic exercise programme on quality of life compared with usual care for haemodialysis patients. DESIGN: We conducted a prospective, multicentre randomised controlled trial of haemodialysis patients from five haemodialysis centres in the UK and randomly assigned them (1 : 1) using a web-based system to (1) intradialytic exercise training plus usual-care maintenance haemodialysis or (2) usual-care maintenance haemodialysis. SETTING: The setting was five dialysis units across the UK from 2015 to 2019. PARTICIPANTS: The participants were adult patients with end-stage kidney disease who had been receiving haemodialysis therapy for > 1 year. INTERVENTIONS: Participants were randomised to receive usual-care maintenance haemodialysis or usual-care maintenance haemodialysis plus intradialytic exercise training. MAIN OUTCOME MEASURES: The primary outcome of the study was change in Kidney Disease Quality of Life Short Form, version 1.3, physical component summary score (from baseline to 6 months). Cost-effectiveness was determined using health economic analysis and the EuroQol-5 Dimensions, five-level version. Additional secondary outcomes included quality of life (Kidney Disease Quality of Life Short Form, version 1.3, generic multi-item and burden of kidney disease scales), functional capacity (sit-to-stand 60 and 10-metre Timed Up and Go tests), physiological measures (peak oxygen uptake and arterial stiffness), habitual physical activity levels (measured by the International Physical Activity Questionnaire and Duke Activity Status Index), fear of falling (measured by the Tinetti Falls Efficacy Scale), anthropometric measures (body mass index and waist circumference), clinical measures (including medication use, resting blood pressure, routine biochemistry, hospitalisations) and harms associated with intervention. A nested qualitative study was conducted. RESULTS: We randomised 379 participants; 335 patients completed baseline assessments and 243 patients (intervention, n = 127; control, n = 116) completed 6-month assessments. The mean difference in change in physical component summary score from baseline to 6 months between the intervention group and control group was 2.4 arbitrary units (95% confidence interval -0.1 to 4.8 arbitrary units; p = 0.055). Participants in the intervention group had poor compliance (49%) and very poor adherence (18%) to the exercise prescription. The cost of delivering the intervention ranged from £463 to £848 per participant per year. The number of participants with harms was similar in the intervention (n = 69) and control (n = 56) groups. LIMITATIONS: Participants could not be blinded to the intervention; however, outcome assessors were blinded to group allocation. CONCLUSIONS: On trial completion the primary outcome (Kidney Disease Quality of Life Short Form, version 1.3, physical component summary score) was not statistically improved compared with usual care. The findings suggest that implementation of an intradialytic cycling programme is not an effective intervention to enhance health-related quality of life, as delivered to this cohort of deconditioned patients receiving haemodialysis. FUTURE WORK: The benefits of longer interventions, including progressive resistance training, should be confirmed even if extradialytic delivery is required. Future studies also need to evaluate whether or not there are subgroups of patients who may benefit from this type of intervention, and whether or not there is scope to optimise the exercise intervention to improve compliance and clinical effectiveness. TRIAL REGISTRATION: Current Controlled Trials ISRCTN83508514. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 40. See the NIHR Journals Library website for further project information.

Although the benefits of exercise in the general population are well recognised, we do not know if offering cycling exercise during haemodialysis is an effective way to improve quality of life, and if this would be a cost-effective way to provide exercise training for this patient population. To determine whether or not this type of exercise training is effective, and provides value for money, this study compared cycling during haemodialysis treatment, three times per week for 6 months, with usual care that does not include routine delivery of any exercise training. Five regions of the UK were included in the study. We compared the results from the two groups at the start of the study and at 6 months, after correcting for age and diabetes status. We also assessed the economic impact of delivering the cycling during haemodialysis programme and interviewed people from different regions of the UK in both groups. The baseline assessments revealed a deconditioned population in the study. There was no difference in quality of life or any physical function measures between the group that performed cycling during haemodialysis and the usual-care group. Compliance with the exercise intervention was very poor. Interviews with patients showed that patient engagement with the exercise training was linked to the presence of an exercise culture, and leadership to provide this, in the renal unit. An economic evaluation showed that delivering cycling during haemodialysis would not be value for money when delivered to a deconditioned haemodialysis population. Ways to engage patients with exercise training during their haemodialysis treatment should be explored further.

Randomized Trial-PrEscription of intraDialytic exercise to improve quAlity of Life in Patients Receiving Hemodialysis.

INTRODUCTION: Whether clinically implementable exercise interventions in people receiving hemodialysis (HD) therapy improve health-related quality of life (HRQoL) remains unknown. The PrEscription of intraDialytic exercise to improve quAlity of Life (PEDAL) study evaluated the clinical benefit and cost-effectiveness of a 6-month intradialytic exercise program. METHODS: In a multicenter, single-blinded, randomized, controlled trial, people receiving HD were randomly assigned to (i) intradialytic exercise training (exercise intervention group [EX]) and (ii) usual care (control group [CON]). Primary outcome was change in Kidney Disease Quality of Life Short-Form Physical Component Summary (KDQOL-SF 1.3 PCS) from baseline to 6 months. Cost-effectiveness was determined using health economic analysis; physiological impairment was evaluated by peak oxygen uptake; and harms were recorded. RESULTS: We randomized 379 participants; 335 and 243 patients (EX n = 127; CON n = 116) completed baseline and 6-month assessments, respectively. Mean difference in change PCS from baseline to 6 months between EX and CON was 2.4 (95% confidence interval [CI]: -0.1 to 4.8) arbitrary units (P = 0.055); no improvements were observed in peak oxygen uptake or secondary outcome measures. Participants in the intervention group had poor compliance (47%) and poor adherence (18%) to the exercise prescription. Cost of delivering intervention ranged from US$598 to US$1092 per participant per year. The number of participants with harms was similar between EX (n = 69) and CON (n = 56). A primary limitation was the lack of an attention CON. Many patients also withdrew from the study or were too unwell to complete all physiological outcome assessments. CONCLUSIONS: A 6-month intradialytic aerobic exercise program was not clinically beneficial in improving HRQoL as delivered to this cohort of deconditioned patients on HD.

The PrEscription of intraDialytic exercise to improve quAlity of Life in patients with chronic kidney disease trial: study design and baseline data for a multicentre randomized controlled trial.

BACKGROUND: Exercise interventions designed to improve physical function and reduce sedentary behaviour in haemodialysis (HD) patients might improve exercise capacity, reduce fatigue and lead to improved quality of life (QOL). The PrEscription of intraDialytic exercise to improve quAlity of Life study aimed to evaluate the effectiveness of a 6-month intradialytic exercise programme on QOL and physical function, compared with usual care for patients on HD in the UK. METHODS: We conducted a prospective, pragmatic multicentre randomized controlled trial in 335 HD patients and randomly (1:1) assigned them to either (i) intradialytic exercise training plus usual care maintenance HD or (ii) usual care maintenance HD. The primary outcome of the study was the change in Kidney Disease Quality of Life Short Form (KDQOL-SF 1.3) Physical Component Score between baseline and 6 months. Additional secondary outcomes included changes in peak aerobic capacity, physical fitness, habitual physical activity levels and falls (International Physical Activity Questionnaire, Duke's Activity Status Index and Tinetti Falls Efficacy Scale), QOL and symptom burden assessments (EQ5D), arterial stiffness (pulse wave velocity), anthropometric measures, resting blood pressure, clinical chemistry, safety and harms associated with the intervention, hospitalizations and cost-effectiveness. A nested qualitative study investigated the experience and acceptability of the intervention for both participants and members of the renal health care team. RESULTS: At baseline assessment, 62.4% of the randomized cohort were male, the median age was 59.3 years and 50.4% were white. Prior cerebrovascular events and myocardial infarction were present in 8 and 12% of the cohort, respectively, 77.9% of patients had hypertension and 39.4% had diabetes. Baseline clinical characteristics and laboratory data for the randomized cohort were generally concordant with data from the UK Renal Registry. CONCLUSION: The results from this study will address a significant knowledge gap in the prescription of exercise interventions for patients receiving maintenance HD therapy and inform the development of intradialytic exercise programmes both nationally and internationally. TRIAL REGISTRATION: ISRCTN N83508514; registered on 17 December 2014.

Baricitinib counteracts metaflammation, thus protecting against diet-induced metabolic abnormalities in mice.

OBJECTIVE: Recent evidence suggests the substantial pathogenic role of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway in the development of low-grade chronic inflammatory response, known as "metaflammation," which contributes to obesity and type 2 diabetes. In this study, we investigated the effects of the JAK1/2 inhibitor baricitinib, recently approved for the treatment of rheumatoid arthritis, in a murine high-fat-high sugar diet model. METHODS: Male C57BL/6 mice were fed with a control normal diet (ND) or a high-fat-high sugar diet (HD) for 22 weeks. A sub-group of HD fed mice was treated with baricitinib (10 mg/kg die, p.o.) for the last 16 weeks (HD + Bar). RESULTS: HD feeding resulted in obesity, insulin-resistance, hypercholesterolemia and alterations in gut microbial composition. The metabolic abnormalities were dramatically reduced by chronic baricitinib administration. Treatment of HD mice with baricitinib did not change the diet-induced alterations in the gut, but restored insulin signaling in the liver and skeletal muscle, resulting in improvements of diet-induced myosteatosis, mesangial expansion and associated proteinuria. The skeletal muscle and renal protection were due to inhibition of the local JAK2-STAT2 pathway by baricitinib. We also demonstrated that restored tissue levels of JAK2-STAT2 activity were associated with a significant reduction in cytokine levels in the blood. CONCLUSIONS: In summary, our data suggest that the JAK2-STAT2 pathway may represent a novel candidate for the treatment of diet-related metabolic derangements, with the potential for EMA- and FDA-approved JAK inhibitors to be repurposed for the treatment of type 2 diabetes and/or its complications.