Stroke from A Large Left Atrial Myxoma

A 36-year-old male involved in a car accident was found to have an embolic stroke due to a left atrial myxoma. Open heart surgery was delayed 4 weeks to decrease the risk of neurologic complications from the anticoagulation required for cardiopulmonary bypass. After resection of the myxoma, intraoperative transesophageal echocardiography found severe mitral regurgitation, which was repaired

Complement C5a induces renal injury in diabetic kidney disease by disrupting mitochondrial metabolic agility

The sequelae of diabetes include microvascular complications such as diabetic kidney disease (DKD), which involves glucose-mediated renal injury associated with a disruption in mitochondrial metabolic agility, inflammation, and fibrosis. We explored the role of the innate immune complement component C5a, a potent mediator of inflammation, in the pathogenesis of DKD in clinical and experimental diabetes. Marked systemic elevation in C5a activity was demonstrated in patients with diabetes; conventional renoprotective agents did not therapeutically target this elevation. C5a and its receptor (C5aR1) were upregulated early in the disease process and prior to manifest kidney injury in several diverse rodent models of diabetes. Genetic deletion of C5aR1 in mice conferred protection against diabetes-induced renal injury. Transcriptomic profiling of kidney revealed diabetes-induced downregulation of pathways involved in mitochondrial fatty acid metabolism. Interrogation of the lipidomics signature revealed abnormal cardiolipin remodeling in diabetic kidneys, a cardinal sign of disrupted mitochondrial architecture and bioenergetics. In vivo delivery of an orally active inhibitor of C5aR1 (PMX53) reversed the phenotypic changes and normalized the renal mitochondrial fatty acid profile, cardiolipin remodeling, and citric acid cycle intermediates. In vitro exposure of human renal proximal tubular epithelial cells to C5a led to altered mitochondrial respiratory function and reactive oxygen species generation. These experiments provide evidence for a pivotal role of the C5a/C5aR1 axis in propagating renal injury in the development of DKD by disrupting mitochondrial agility, thereby establishing a new immunometabolic signaling pathway in DKD

Effects of glycaemic management on diabetic kidney disease

Hyperglycaemia contributes to the onset and progression of diabetic kidney disease (DKD). Observational studies have not consistently demonstrated a glucose threshold, in terms of HbA1c levels, for the onset of DKD. Tight glucose control has clearly been shown to reduce the incidence of micro- or macroalbuminuria. However, evidence is now also emerging to suggest that intensive glucose control can slow glomerular filtration rate loss and possibly progression to end stage kidney disease. Achieving tight glucose control needs to be balanced against the increasing appreciation that glucose targets for the prevention of diabetes related complications need be individualised for each patient. Recently, empagliflozin which is an oral glucose lowering agent of the sodium glucose cotransporter-2 inhibitor class has been shown to have renal protective effects. However, the magnitude of empagliflozin's reno-protective properties are over and above that expected from its glucose lowering effects and most likely largely result from mechanisms involving alterations in intra-renal haemodynamics. Liraglutide and semaglutide, both injectable glucose lowering agents which are analogues of human glucagon like peptide-1 have also been shown to reduce progression to macroalbuminuria through mechanisms that remain to be fully elucidated. Here we review the evidence from observational and interventional studies that link good glucose control with improved renal outcomes. We also briefly review the potential reno-protective effects of newer glucose lowering agents

Cardio-renal protection with empagliflozin

Cardiovascular (CV) and kidney disease are common and significant complications in people with type 2 diabetes (T2DM). CV disease is the leading cause of death, morbidly and hospitalisations for people with T2DM. Furthermore, diabetic kidney disease is a major risk factor for CV disease and is the main reason why patients need renal replacement therapy. In this perspective, we highlight the results of the recent landmark EMPA-REG OUTCOME trial which has shown that empagliflozin, a member of the sodium-glucose co-transporter 2 (SGLT-2) inhibitor class of glucose lowering medications, reduces death from CV causes, hospitalisation for heart failure and progression to end stage kidney disease in patients with T2DM and established CV disease. The SGLT2 receptor mediates high-capacity glucose uptake in the early proximal tubule, and SGLT2 inhibitors, via their ability to promote glycosuria, have been developed as glucose lowering medications. As well as having a glucose lowering effect, SGLT-2 inhibitors also reduce blood pressure, promote weight loss and reduce uric acid levels. Potential side-effects or concerns related to the use of SGLT-2 inhibitors include increased rates of urinary tract infections, genital tract infections, postural hypotension, diabetic ketoacidosis, acute kidney injury and possible increased rates of fractures. The exact mechanisms that result in empagliflozin’s dramatic CV and renal protective effects, with a very favourable safety/tolerability profile, in the EMPA-REG study remain to be fully defined. However, they are most likely distinct from the glucose lowering effects of empagliflozin. CV safety trials involving dapagliflozin and canagliflozin, members of the SGLT-2 class, are under way and the results from these studies will help to answer the question as to whether the cardio-renal benefits of empagliflozin are a class-effect or not. Without doubt, trials to investigate whether SGLT-2 inhibitors have cardio-renal protective effects in patients without diabetes will start soon

Systematic review and meta-analysis of prevalence of sarcopenia in post acute inpatient rehabilitation

Summary: Sarcopenia is associated with poor function and increased risk of falls and disability. This work reports a systematic review and meta-analysis of prevalence of sarcopenia in post acute inpatient rehabilitation. Sarcopenia is found to be present in approximately 50% of rehabilitation patients and its prevalence may vary with admission diagnosis. Purpose: To conduct a systematic review and meta-analysis of reported prevalence of sarcopenia in post acute inpatient rehabilitation. Methods: Systematic review conducted according to PRISMA guidelines (PROSPERO registration number CRD42016054135). Databases searched MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Methodology Register, and CINAHL. Studies considered the following: published January 1988–February 2017. Key terms are as follows: “sarcopenia” AND “inpatient rehabilitation” OR “rehabilitation” AND/OR “prevalence”. Abstracts and subsequently full studies reporting sarcopenia prevalence in adults admitted to rehabilitation reviewed irrespective of design, provided sarcopenia diagnosis included at least assessment of muscle mass. Random effect meta-analysis was conducted. Methodological quality assessment: Agency for Healthcare Research and Quality, US Department of Health and Human Services tool (MORE tool); Joanna Briggs Institute Prevalence Critical Appraisal Tool. Results: Four hundred twenty-six studies identified during initial search, 399 excluded after reviewing titles and abstracts, 21 full text articles reviewed, and six studies met inclusion criteria. Patient populations: after hip fracture (five studies), general deconditioning (one study). Identified sarcopenia prevalence ranged from 0.28 to 0.69. Pooled sarcopenia prevalence obtained with random effect meta-analysis: 0.56 (95% CI 0.46–0.65), heterogeneity I2 = 92.9%. Main quality shortcomings: lack of reporting of inter- and intra-rater reliability, lack of generalizability to other rehabilitation populations. Conclusions: Original research examining sarcopenia prevalence in inpatient rehabilitation is scarce. Patient populations studied to date are not representative of general rehabilitation population with regard to both age and admission diagnoses. Sarcopenia may be present in approximately half of rehabilitation patients and its prevalence may vary with admission diagnosis

Exploration of the shared pathophysiological mechanisms of gestational diabetes and large for gestational age offspring

Gestational diabetes mellitus (GDM) and large for gestational age (LGA) offspring are two common pregnancy complications. Connections also exist between the two conditions, including mutual maternal risk factors for the conditions and an increased prevalence of LGA offspring amongst pregnancies affected by GDM. Thus, it is important to elucidate potential shared underlying mechanisms of both LGA and GDM. One potential mechanistic link relates to macronutrient metabolism. Indeed, derangement of carbohydrate and lipid metabolism is present in GDM, and maternal biomarkers of glucose and lipid control are associated with LGA neonates in such pregnancies. The aim of this paper is therefore to reflect on the existing nutritional guidelines for GDM in light of our understanding of the pathophysiological mechanisms of GDM and LGA offspring. Lifestyle modification is first line treatment for GDM, and while there is some promise that nutritional interventions may favourably impact outcomes, there is a lack of definitive evidence that changing the macronutrient composition of the diet reduces the incidence of either GDM or LGA offspring. The quality of the available evidence is a major issue, and rigorous trials are needed to inform evidence-based treatment guidelines