Exploring metabolic dysfunction in chronic kidney disease

Abstract Impaired kidney function and chronic kidney disease (CKD) leading to kidney failure and end-stage renal disease (ESRD) is a serious medical condition associated with increased morbidity, mortality, and in particular cardiovascular disease (CVD) risk. CKD is associated with multiple physiological and metabolic disturbances, including hypertension, dyslipidemia and the anorexia-cachexia syndrome which are linked to poor outcomes. Specific hormonal, inflammatory, and nutritional-metabolic factors may play key roles in CKD development and pathogenesis. These include raised proinflammatory cytokines, such as interleukin-1 and −6, tumor necrosis factor, altered hepatic acute phase proteins, including reduced albumin, increased C-reactive protein, and perturbations in normal anabolic hormone responses with reduced growth hormone-insulin-like growth factor-1 axis activity. Others include hyperactivation of the renin-angiotensin aldosterone system (RAAS), with angiotensin II and aldosterone implicated in hypertension and the promotion of insulin resistance, and subsequent pharmacological blockade shown to improve blood pressure, metabolic control and offer reno-protective effects. Abnormal adipocytokine levels including leptin and adiponectin may further promote the insulin resistant, and proinflammatory state in CKD. Ghrelin may be also implicated and controversial studies suggest activities may be reduced in human CKD, and may provide a rationale for administration of acyl-ghrelin. Poor vitamin D status has also been associated with patient outcome and CVD risk and may indicate a role for supplementation. Glucocorticoid activities traditionally known for their involvement in the pathogenesis of a number of disease states are increased and may be implicated in CKD-associated hypertension, insulin resistance, diabetes risk and cachexia, both directly and indirectly through effects on other systems including activation of the mineralcorticoid receptor. Insight into the multiple factors altered in CKD may provide useful information on disease pathogenesis, clinical assessment and treatment rationale such as potential pharmacological, nutritional and exercise therapies

A comparison of the malnutrition screening tools, MUST, MNA and bioelectrical impedance assessment in frail older hospital patients

Summary Background & aims This cohort study aimed to investigate and compare the ability to predict malnutrition in a group of frail older hospital patients in the United Kingdom using the nutritional risk screening tools, MUST (malnutrition universal screening tool), MNA-SF® (mini nutritional assessment-short form) and bioelectrical impedance assessment (BIA) of body composition. Methods MUST and MNA-SF was performed on 78 patients (49 males and 29 females, age: 82 y ± 7.9, body mass index (BMI): 25.5 kg/m2 ± 5.4), categorised by nutritional risk, and statistical comparison and test reliability performed. BIA was performed in 66 patients and fat free mass (FFM), fat mass (FM) and body cell mass (BCM) and index values (kg/m2) calculated and compared against reference values. Results MUST scored 77% patients ‘low risk’, 9% ‘medium risk’ and 14% ‘high risk’, compared to MNA-SF categorisation: 9%, 46% and 45%, respectively (P < 0.000001). Reliability assessment found poor reliability between the screening tools (coefficient, r = 0.4). Significant positive correlations were found between most variables (P < 0.05–<0.001); although females exhibited greater variation. FFM index analysis found 40% of males low/depleted, 21% borderline/at risk with 96% categorised by MNA-SF as either malnourished or at risk (MUST-35%). 29% males had low FM index and all appropriately classified by MNA-SF. 30% females had low FFM index or borderline, MNA-SF screening appropriately categorised 86% (compared to MUST-29%). Conclusions This preliminary data may have significant clinical implications and highlights the potential ability of the MNA-SF and BIA to accurately assess malnutrition risk over MUST in frail older hospital patients

A Patient and Public Involvement (PPI) Review Exploring Patient Reported Outcome Measures in Adult CAR T-cell therapy Patients

Background & Aims: Chimeric Antigen Receptor (CAR) T-cell therapy is a novel anti-cancer treatment option for patients with refractory or relapsed haematological malignancies. Preliminary research shows a significant proportion of patients receiving CAR T-cell therapy develop malnutrition and cachexia during treatment, with these nutritional issues associated with adverse patient outcomes. There is a lack of literature and no specific validated measures on patient experience and burden of symptoms for CAR T-cell therapy patients as well as the importance of clinical outcomes for these patients. Patient and public involvement (PPI) is a fundamental feature of proper research execution as it informs issues in the research that are most important in patients. The aim of this review was to identify priority patient-reported outcome measures in CAR T-cell therapy patients using PPI, in addition to exploring patient experiences, burden of symptoms, priorities, and knowledge of nutritional priorities in cancer. The PPI outcomes will also aid to inform the design and development of a future novel cohort study. Methods: Using participatory research (PPI), six adults aged 26e70 years who have received CAR T-cell therapy in the past two years, participated in one-to-one interviews. The interview questions were focused on the aims of identifying patient recommendations regarding clinical outcome measures of interest, their relevance to patient's experience of CAR T-cell therapy, and optimal design of the future cohort research protocol

Resistance exercise and nutritional interventions for augmenting sarcopenia outcomes in chronic kidney disease: a narrative review

Sarcopenia is an age-related progressive muscle disease characterized by loss of muscle mass, muscle strength and physical performance with high prevalence in chronic kidney disease (CKD). CKD is associated with decreased muscle protein synthesis and muscle breakdown due to a number of factors including, the uremic inflammatory environment of the disease. CKD patients are highly sedentary and at risk of malnutrition which may exacerbate sarcopenia outcomes even further. Short and long-term exercise and nutritional interventions have been studied and found to have some positive effects on sarcopenia measures in CKD. This narrative review summarized evidence between 2010 and 2020 of resistance exercise (RE) alone or combined with nutritional interventions for improving sarcopenia outcomes in CKD. Due to lack of CKD-specific sarcopenia measures, the second European Working Group on Sarcopenia in Older People (EWGSOP2) definition has been used to guide the selection of the studies. The literature search identified 14 resistance exercise-based studies and 5 nutrition plus RE interventional studies. Muscle strength outcomes were increased with longer intervention duration, intervention supervision, and high participant adherence. Data also suggested that CKD patients may require increased RE intensity and progressive loading to obtain detectable results in muscle mass. Unlike muscle strength and muscle mass, physical performance was readily improved by all types of exercise in long or short-term interventions. Four studies used RE with high-protein nutritional supplementation. These showed significant benefits on muscle strength and physical performance in dialysis patients while non-significant results were found in muscle mass. More research is needed to confirm if a combination of RE and vitamin D supplementation could act synergistically to improve muscle strength in CKD. The current evidence on progressive RE for sarcopenia in CKD is encouraging; however, real-life applications in clinical settings are still very limited. A multidisciplinary patient-centred approach with regular follow-up may be most beneficial due to the complexity of sarcopenia in CKD. Long-term randomized control trials are needed to verify optimal RE prescription and explore safety and efficacy of other nutritional interventions in CKD

Regulation of skeletal muscle proteolysis

Proteolysis is a component of protein turnover, controlled by multiple proteolytic systems. Alterations in system components within skeletal muscle has been associated with hypertrophy, remodelling, atrophy, apoptosis and metabolic dysregulation. Key components may have novel regulatory roles, e. g. calpain-3 and cathepsin-L. Experiments described within this thesis investigated the hypothesis that the gene expression of specific proteolytic system components within skeletal muscle may be co-ordinately regulated and altered during nutritional and pharmacological states known to modify protein turnover and induce muscle growth. Gene expression for multiple components of the calpain system was analysed in calf LD (Longissmus dorsi) by Quantitative Real-Time PCR in a plane of nutrition trial. There were three groups: low (LOW), high (HIGH) plane of nutrition and LOW to HIGH (REFED). Half of each group were slaughtered 48 hrs after refeeding, whilst the remainder were slaughtered 13 days later. Total RNA yield/g LD increased (P < 0.05) across all groups between slaughter dates. Calpain-3 expression increased in LOW and REFED and calpastatin in all groups between slaughter dates, with a trend towards significance (P = 0.073, P=0.085, respectively). In the 1St slaughter, calpain-3 expression had a trend to be lower in the LOW group and values for REFED were similar to HIGH value level. cDNA probes for unique and novel proteolytic system components were generated by RT-PCR and used to investigate the effects of acute and chronic Q-adrenergic stimulation, on the gene expression of those specific components in pig LD, by northern blotting. The ß2-adrenergic agonist clenbuterol (5 ppm) decreased glycogen levels (mg/g LD) (P < 0.001), increased cathepsin-L expression (P < 0.001) and increased E2G 1 values numerically within 24 hrs of treatment. Cathepsin-L was unchanged by adrenaline administration. Calpain-3 was unchanged with either clenbuterol or adrenaline treatment. The significance and implications of the data are discussed

The prevalence of malnutrition (MUST and MNA-SF), frailty and physical disability and relationship with mortality in older care home residents

Background & Aims: Currently, there is lack of universal consensus on the use of effective malnutrition screening tools. Although malnutrition, frailty and physical disability are interrelated and associated with mortality in older people, there is a paucity of research in care home settings. With a high co-prevalence of these conditions, understanding their interconnectedness can provide a holistic view of an older person's health condition. The purpose of this study was to examine the prevalence of malnutrition (and risk) frailty and physical disability among care home residents using different methods, as well as the associations between markers of malnutrition (MUST and MNA-SF), physical function (Barthel Index, BI), frailty (Edmonton Frailty Scale, EFS), and all-cause mortality in care home residents.// Methods: In Lincoln, UK, 508 residents from care homes underwent screening for malnutrition (MNA-SF and MUST), frailty (EFS), and physical function (BI) as part of standard comprehensive geriatric assessment (CGA) between November 2015 and January 2018. Prevalence of conditions were assessed and MNA-SF, MUST, EFS, and BI-specific survival in each category were compared using Kaplan-Meier survival analysis (KMSA) with log-rank test. Multivariable analyses were conducted using the Cox proportional hazard model to identify prognostic factors that were statistically significant in care home residents.// Results: There was significant discordance between malnutrition risk measured by MUST and MNA-SF. The percentage of patients ‘at risk’/‘medium risk’ and ‘malnourished’/‘high risk’ was 25.3%/49.9% for MNA and for 19.6%/31.57% for MUST. The prevalence of frailty measured by EFS was high with the percentage of residents with severe frailty being 70.9%. Only 8.6% of patients were functionally independent. The association between malnutrition risk (MUST) and mortality was not significant. MNA-SF appeared to be a better tool at predicting mortality in older care home residents (p < 0.001). Furthermore, the association between frailty (EFS) and mortality was significant (p < 0.01).// Conclusions: This study found high levels of malnutrition, frailty, and disability among UK care home residents, and a discordance between MUST and MNA-SF scoring patterns. The MNA-SF and EFS were better predictors of mortality than MUST and BI, highlighting the need for sensitive tools in assessing malnutrition and frailty risks in this population

Non‐steroidal anti‐inflammatory drugs for treatment of cancer cachexia: A systematic review

Cancer cachexia (CC) is a multifactorial syndrome driven by inflammation, defined by ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support. CC leads to progressive functional impairment, with its clinical management complicated and limited therapeutic options available. The objective of this review was to assess the efficacy and safety of non‐steroidal anti‐inflammatory drugs (NSAIDs) on patient‐centred outcomes in patients with CC. In 2013, two systematic reviews concluded that there was insufficient evidence to recommend NSAIDs for clinical management of CC outside of clinical trials. However, clinical trials of multi‐component CC interventions have included NSAIDs as an intervention component, so an up‐to‐date assessment of the evidence for NSAIDs in the treatment of CC is warranted. Four databases (MEDLINE, EMBASE, CENTRAL and CINAHL) and three trial registers (clinicaltrials.gov, WHO ICTRP and ISRCTN) were searched on 16 December 2022. Randomized controlled trials (RCTs) comparing any NSAID (any dose or duration) with a control arm, in adult patients with CC, reporting measures of body weight, body composition, nutrition impact symptoms, inflammation, physical function or fatigue, were eligible for inclusion. Primary outcomes (determined with patient involvement) were survival, changes in muscle strength, body composition, body weight and quality of life. Included studies were assessed for risk of bias using the Revised Cochrane risk‐of‐bias tool for randomized trials. Five studies were included, which investigated Indomethacin (n = 1), Ibuprofen (n = 1) and Celecoxib (n = 3). Four studies were judged to be at high risk of bias for all outcomes, with one study raising concerns for most outcomes. Considerable clinical and methodological heterogeneity amongst the studies meant that meta‐analysis was not appropriate. There was insufficient evidence to determine whether Indomethacin or Ibuprofen is effective or safe for use in patients with CC; RCTs with lower risk of bias are needed. Celecoxib studies indicated it was safe for use in this population at the doses tested (200–400 mg/day) but found contrasting results regarding efficacy, potentially reflecting heterogeneity amongst the studies. There is inadequate evidence to recommend any NSAID for CC. While current clinical trials for CC treatments are shifting towards multi‐component interventions, further research to determine the efficacy and safety of NSAIDs alone is necessary if they are to be included in such multi‐component interventions. Furthermore, the lack of data on patient‐determined primary outcomes in this review highlights the need for patient involvement in clinical trials for C

"Wasting in Chronic Kidney Disease – a Complex Issue".

Chronic kidney disease (CKD) has become a global health burden and is associated with increased morbidity and mortality. In particular, wasting is highly prevalent in later stages of the illness with muscle loss being a common problem. The aetiology and progression of this wasting is complex and multiple states have been identified linked to wasting in CKD. These include: ‘malnutrition’, ‘disease‐related malnutrition’, ‘protein‐energy wasting’, ‘cachexia’, ‘sarcopenia’, ‘frailty’ and ‘muscle wasting‘. The purpose of this paper is to review these terms in the context of CKD. Common features include weight loss, loss of muscle mass and muscle function principally driven by CKD disease specific factors and inflammatory mediators. Disease‐related malnutrition would appear to be a more appropriate term for CKD than malnutrition as it take in to consideration disease specific factors such as inflammation for example. Frailty is commonly associated with age‐related decline in physiological function. Development of novel screening tools measuring across multiple domains of nutritional status, muscle and physical function may be useful in CKD. Research into potential treatments are currently underway with focus on multi‐modal therapies including nutrition, resistance training and anabolic drugs such as myostatin blockade and selective androgen receptor modulators. A better understanding of different states and terms may help guide assessment and treatment opportunities for patients

Using ³⁶Cl exposure dating to date mass movement and assess land stability on the Nicholas Range, Tasmania

Detailed mapping of dolerite slope deposits overlying sedimentary Triassic rocks on the northern slopes of the Nicholas Range in northeastern Tasmania has revealed an extensive mass movement complex. Landforms north of the summit plateau of the Nicholas Range include the following: (1) a cliff of dolerite columns with associated scree slopes at its base; (2) a topple landscape consisting of several topples that have fallen in a north-easterly direction; (3) a ripple landscape consisting of a series of long boulder ridges aligned approximately east-west. Exposure dates were obtained for three large boulders (collapsed dolerite columns) from a ridge within the ripple landscape. The two youngest dates gave a mean age of 52.1 ± 1.9 ka using36Cl. This is the estimated age for collapse of the dated columns from the cliff face c. 750 m to the south. Boulder ages and landscape morphology indicate that the ripple landscape developed by physical and chemical degradation and concurrent northern displacement of topples over a slip plane formed at the contact between dolerite colluvium and underlying Triassic sedimentary rocks. There is no evidence of movement today, other than localised debris flows associated with knickpoints in streams, and it is deduced that movement on the slip plane occurred under a cooler climate than that prevailing today, possibly under the influence of melting of winter snow during the last glacial cycle. As there is no evidence of significant recent mass movement and forests in the area are likely to have experienced many stand-destroying forest fires in the Holocene, forest harvest is not considered to pose a risk to landscape stability