Biochemical and clinical impact of organic uremic retention solutes : a comprehensive update

In this narrative review, the biological/biochemical impact (toxicity) of a large array of known individual uremic retention solutes and groups of solutes is summarized. We classified these compounds along their physico-chemical characteristics as small water-soluble compounds or groups, protein bound compounds and middle molecules. All but one solute (glomerulopressin) affected at least one mechanism with the potential to contribute to the uremic syndrome. In general, several mechanisms were influenced for each individual solute or group of solutes, with some impacting up to 7 different biological systems of the 11 considered. The inflammatory, cardio-vascular and fibrogenic systems were those most frequently affected and they are one by one major actors in the high morbidity and mortality of CKD but also the mechanisms that have most frequently been studied. A scoring system was built with the intention to classify the reviewed compounds according to the experimental evidence of their toxicity (number of systems affected) and overall experimental and clinical evidence. Among the highest globally scoring solutes were 3 small water-soluble compounds [asymmetric dimethylarginine (ADMA); trimethylamine-N-oxide (TMAO); uric acid], 6 protein bound compounds or groups of protein bound compounds [advanced glycation end products (AGEs); p-cresyl sulfate; indoxyl sulfate; indole acetic acid; the kynurenines; phenyl acetic acid;] and 3 middle molecules [(2)-microglobulin; ghrelin; parathyroid hormone). In general, more experimental data were provided for the protein bound molecules but for almost half of them clinical evidence was missing in spite of robust experimental data. The picture emanating is one of a complex disorder, where multiple factors contribute to a multisystem complication profile, so that it seems of not much use to pursue a decrease of concentration of a single compound

Neuroinflammatory targets and treatments for epilepsy validated in experimental models

A large body of evidence that has accumulated over the past decade strongly supports the role of inflammation in the pathophysiology of human epilepsy. Specific inflammatory molecules and pathways have been identified that influence various pathologic outcomes in different experimental models of epilepsy. Most importantly, the same inflammatory pathways have also been found in surgically resected brain tissue from patients with treatment-resistant epilepsy. New antiseizure therapies may be derived from these novel potential targets. An essential and crucial question is whether targeting these molecules and pathways may result in anti-ictogenesis, antiepileptogenesis, and/or disease-modification effects. Therefore, preclinical testing in models mimicking relevant aspects of epileptogenesis is needed to guide integrated experimental and clinical trial designs. We discuss the most recent preclinical proof-of-concept studies validating a number of therapeutic approaches against inflammatory mechanisms in animal models that could represent novel avenues for drug development in epilepsy. Finally, we suggest future directions to accelerate preclinical to clinical translation of these recent discoveries

Clinical Research on Diabetic Complications

Refrigeration, air conditioning, and heat pumps (RACHP) have an important impact on the final energy uses of many sectors of modern society, such as residential, commercial, industrial, transport, and automotive. Moreover, RACHP also have an important environmental impact due to the working fluids that deplete the stratospheric ozone layer, which are being phased out according to the Montreal Protocol (1989). Last, but not least, high global working potential (GWP), working fluids (directly), and energy consumption (indirectly) are responsible for a non-negligible quota of greenhouse gas (GHG) emissions in the atmosphere, thus impacting climate change

Multidisciplinary Experiences in Renal Replacement Therapy

Renal replacement therapy (RRT) is used to replace the capacity of blood filtration, which is completely lost in end-stage renal disease (ESRD). This book examines RRT from a multidisciplinary perspective. In nine comprehensive chapters over three sections, the book shows how clinical routines, especially RRT, are increasingly focused on the translational scenario of the health sciences. Chapters discuss health and wellness, hemodialysis, and clinical biomarkers of renal disease

Fatigue in Patients on Chronic Hemodialysis: The Role of Indoleamine 2,3-Dioxygenase (IDO) Activity, Interleukin-6, and Muscularity

Fatigue is a frequent symptom in hemodialysis (HD), and the indolamine-2,3-dioxygenase (IDO) metabolic trap has been hypothesized in the pathogenesis of fatigue. The association between IDO activity according to fatigue and its relationship with muscle mass and function in HD patients was verified. Chronic HD patients were considered, and fatigue was assessed. The plasma kynurenines and tryptophan ratio (Kyn/Trp), as surrogate of IDO activity, and interleukin (IL)-6 were measured. Muscularity was assessed by BIA and muscle strength by hand-grip dynamometer. 50 HD patients were enrolled, and fatigue was present in 24% of the cohort. Patients with fatigue showed higher Kyn/Trp (p = 0.005), were older (p = 0.007), and IL-6 levels resulted higher than in non-fatigue patients (p < 0.001). HD patients with fatigue showed lower intracellular water (surrogate of muscle mass) (p < 0.001), as well as lower hand grip strength (p = 0.02). The Kyn/Trp ratio positively correlated with IL-6 and ECW/ICW (p = 0.004 and p = 0.014). By logistic regression analysis, higher ICW/h(2) was associated with lower odds of fatigue (OR, 0.10; 95% CI, 0.01 to 0.73). In conclusion, our cohort fatigue was associated with a higher Kyn/Trp ratio, indicating a modulation of IDO activity. The Kyn/Trp ratio correlated with IL-6, suggesting a potential role of IDO and inflammation in inducing fatigue and changes in muscularity

Aspirin: A review of its neurobiological properties and therapeutic potential for mental illness

There is compelling evidence to support an aetiological role for inflammation, oxidative and nitrosative stress (O&NS), and mitochondrial dysfunction in the pathophysiology of major neuropsychiatric disorders, including depression, schizophrenia, bipolar disorder, and Alzheimer's disease (AD). These may represent new pathways for therapy. Aspirin is a non-steroidal anti-inflammatory drug that is an irreversible inhibitor of both cyclooxygenase (COX)-1 and COX-2, It stimulates endogenous production of anti-inflammatory regulatory 'braking signals', including lipoxins, which dampen the inflammatory response and reduce levels of inflammatory biomarkers, including C-reactive protein, tumor necrosis factor-α and interleukin (IL)--6, but not negative immunoregulatory cytokines, such as IL-4 and IL-10. Aspirin can reduce oxidative stress and protect against oxidative damage. Early evidence suggests there are beneficial effects of aspirin in preclinical and clinical studies in mood disorders and schizophrenia, and epidemiological data suggests that high-dose aspirin is associated with a reduced risk of AD. Aspirin, one of the oldest agents in medicine, is a potential new therapy for a range of neuropsychiatric disorders, and may provide proof-of-principle support for the role of inflammation and O&NS in the pathophysiology of this diverse group of disorders

Cardiopulmonary and metabolic physiology during hemodialysis and inter-/intra-dialytic exercise

Hemodialysis is associated with numerous symptoms and side effects that, in part, may be due to subclinical hypoxia. However, acute cardiopulmonary and metabolic physiology during hemodialysis is not well defined. Intradialytic and interdialytic exercise appear to be beneficial and may alleviate these side effects. To better understand these potential benefits, the acute physiological response to exercise should be evaluated. The aim of this study was to compare and characterize the acute physiological response during hemodialysis, intradialytic exercise, and interdialytic exercise. Cardiopulmonary physiology was evaluated during three conditions: 1) hemodialysis without exercise (HD), 2) intradialytic exercise (IDEx), and 3) interdialytic exercise (Ex). Exercise consisted of 30-min constant load cycle ergometry at 90% V̇O2AT (anaerobic threshold). Central hemodynamics (via noninvasive bioreactance) and ventilatory gas exchange were recorded during each experimental condition. Twenty participants (59 ± 12 yr, 16/20 male) completed the protocol. Cardiac output (Δ = -0.7 L/min), O2 uptake (Δ = -1.4 mL/kg/min), and arterial-venous O2 difference (Δ = -2.0 mL/O2/100 mL) decreased significantly during HD. Respiratory exchange ratio exceeded 1.0 throughout HD and IDEx. Minute ventilation was lower (P = 0.001) during IDEx (16.5 ± 1.1 L/min) compared with Ex (19.8 ± 1.0 L/min). Arterial-venous O2 difference was partially restored further to IDEx (4.6 ± 1.9 mL/O2/100 mL) compared with HD (3.5 ± 1.2 mL/O2/100 mL). Hemodialysis altered cardiopulmonary and metabolic physiology, suggestive of hypoxia. This dysregulated physiology contributed to a greater physiological demand during intradialytic exercise compared with interdialytic exercise. Despite this, intradialytic exercise partly normalized cardiopulmonary physiology during treatment, which may translate to a reduction in the symptoms and side effects of hemodialysis.NEW &amp; NOTEWORTHY This study is the first, to our knowledge, to directly compare cardiopulmonary and metabolic physiology during hemodialysis, intradialytic exercise, and interdialytic exercise. Hemodialysis was associated with increased respiratory exchange ratio, blunted minute ventilation, and impaired O2 uptake and extraction. We also identified a reduced ventilatory response during intradialytic exercise compared with interdialytic exercise. Impaired arterial-venous O2 difference during hemodialysis was partly restored by intradialytic exercise. Despite dysregulated cardiopulmonary and metabolic physiology during hemodialysis, intradialytic exercise was well tolerated.</p