Renal Osteodystrophy or Kidney-Induced Osteoporosis?

PURPOSE OF REVIEW: Chronic kidney disease (CKD) affects nearly 10% of the population. The incidence of fractures in population studies demonstrate an increase with worsening stages of kidney disease suggesting specific CKD related causes of fracture. RECENT FINDINGS: The increase in fractures with CKD most likely represents disordered bone quality due to the abnormal bone remodeling from renal osteodystrophy. There is also an increase in fractures with age in patients with CKD, suggesting that patients with CKD also have many fracture risk factors common to patients without known CKD. Osteoporosis is defined by the National Institutes of Health as "A skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. Bone strength reflects the integration of two main features: bone quantity and bone quality." Thus, CKD-related fractures can be considered a type of osteoporosis-where the bone quality is additionally impaired above that of age/hormonal-related osteoporosis. Perhaps using the term CKD-induced osteoporosis, similar to steroid-induced osteoporosis, will allow patients with CKD to be studied in trials investigating therapeutic agents. In this series, we will examine how CKD-induced osteoporosis may be diagnosed and treated

Calcium as a cardiovascular toxin in CKD-MBD

Disordered calcium balance and homeostasis are common in patients with chronic kidney disease. Such alterations are commonly associated with abnormal bone remodeling, directly and indirectly. Similarly, positive calcium balance may also be a factor in the pathogenesis of extra skeletal soft tissue and arterial calcification. Calcium may directly affect cardiac structure and function through direct effects to alter cell signaling due to abnormal intracellular calcium homeostasis 2) extra-skeletal deposition of calcium and phosphate in the myocardium and small cardiac arterioles, 3) inducing cardiomyocyte hypertrophy through calcium and hormone activation of NFAT signaling mechanisms, and 4) increased aorta calcification resulting in chronic increased afterload leading to hypertrophy. Similarly, calcium may alter vascular smooth muscle cell function and affect cell signaling which may predispose to a proliferative phenotype important in arteriosclerosis and arterial calcification. Thus, disorders of calcium balance and homeostasis due to CKD-MBD may play a role in the high cardiovascular burden observed in patients with CKD

Helgenomsekvensering av ESBL-produserende bakterieisolater fra norsk vannmiljøprøver

Beta-lactams are among the most used antibiotics in Norway and have several associated resistance mechanisms. Among the most concerning is the production of extended-spectrum beta-lactamases (ESBLs) and carbapenemases. Antibiotic resistance is intricate, complexed by evolution and dissemination of resistance genes and mechanisms. Research prospects include studying antibiotics and how they work (modes of actions) and studying bacteria´s ability to fight back (resistance mechanisms). Surveillance gives insight into resistance mechanisms, bacteria that harbour them and their dissemination. While Norwegian surveillance provides insight into ESBL prevalence in clinical settings and agriculture, environmental studies are not as vast. The aim here was to investigate ESBL-containing and carbapenem-resistant strains from Norwegian aquatic environmental samples, applying micro- and molecular biological methods including selective screening, 16S rRNA Sanger sequencing, MIC tests and multiplex PCR. ESBL, carbapenem and other resistance genes were characterized utilizing Illumina and Nanopore whole genome sequencing. Complete hybrid assemblies were obtained for isolates KA0, KA5 and KB3 which were characterized as non-identical but very similar Rahnella variigena strains (100%) and Herbasprillium huttiense (82%), respectively. Nanopore assemblies were obtained for isolates KA4, KA7 and KB8 which were characterized as R. variigena (100%), Pseudomonas laurentiana (100%) and Herbsapirillum aquaticum (70%), respectively. Class A beta-lactamase genes were found in all isolates except Pseudomonas isolate KA7. blaRAHN was plasmid harboured in all Rahnella isolates, which may be further environmentally disseminated. This study indicated that ESBL-encoding genes are prevalent in the Norwegian aquatic environment and pose the risk of spreading.B-laktamer er blant de mest brukte antibiotikaene i Norge og har flere tilknyttede resistensmekanismer. Blant de mest bekymringsfulle er produksjonen av utvidet spektrum Elaktamaser (ESBLS) og karbapenemaser. Antibiotika resistens er innviklet og blir mer komplisert ved evolusjon og spredning av resistensgener og mekanismer. Forskningsmuligheter inkluderer studier av antibiotika og hvordan de virker (modus for handlinger), i tillegg til bakteriens evne til å bekjempe de (resistensmekanismer). Overvåkning gir innsikt i resistensmekanismer, bakterier som bærer dem og hvordan de sprer seg. Norsk overvåkning gir innsikt i ESBL-prevalens klinisk og i landbruk, men der er færre miljøtestudier. Målet her var å undersøke ESBL-inneholdende og karbapenemresistente stammer fra norske akvatiske miljøprøver ved bruk av mikro- og molekylærbiologiske metoder inkludert selektiv screening, 16S rRNA Sanger-sekvensering, MIC prøver og Multiplex PCR. ESBL, karbapenem og andre resistensgener ble karakterisert ved å benytte Illumina og Nanopore helgenomsekvensering. Komplett hybrid assemblies ble oppnådd for isolater KA0, KA5 og KB3 som ble karakterisert som to ikke-identiske men svært liknende Rahnella variigena stammer (100%) og Herbasprillium huttiense (82%), respektivt. Nanopore-assemblies ble oppnådd for isolater KA4, KA7 og KB8 som ble karakterisert som R. Variigena (100%), Pseudomonas Laurentiana (100%) og Herbasprillium aquaticum (70%), respektivt. Klasse A E-laktamasegener ble funnet i alle isolater unntatt Pseudomonas isolat KA7. blaRAHN var plasmid lokalisert i alle Rahnella isolater, som kan være ytterligere spredd i miljøet. Denne studie viser at ESBL-kodingsgener er utbredt i det norske akvatiske miljøet og kan spre seg.M-K

Indiana CTSI Preclinical Innovation Think Tank Program

The skills and knowledge required for successful commercialization of new technologies (intellectual property protection, SBIR/STTR funding, and startup creation) are very different than those for traditional academic research (scientific publication and R01-style grant funding). The Indiana CTSI Think Tank Program is designed to provide early guidance to academic and clinical investigators interested in advancing their discoveries to the market. The program is open to investigators from Indiana University (IU), Purdue University, or the University of Notre Dame; and includes a pool of advisors across these universities and industry around the state to provide investigators with a wide range of expertise and perspectives.N/

How Good Are Provider Annotations?: A Machine Learning Approach

Introduction: CMS-2728 form (Medical Evidence Report) assesses 23 comorbidities chosen to reflect poor outcomes and increased mortality risk. Previous studies questioned the validity of physician reporting on forms CMS-2728. We hypothesize that reporting of comorbidities by computer algorithms identifies more comorbidities than physician completion, and, therefore, is more reflective of underlying disease burden. Methods: We collected data from CMS-2728 forms for all 296 patients who had incident ESRD diagnosis and received chronic dialysis from 2005 through 2014 at Indiana University outpatient dialysis centers. We analyzed patients' data from electronic medical records systems that collated information from multiple health care sources. Previously utilized algorithms or natural language processing was used to extract data on 10 comorbidities for a period of up to 10 years prior to ESRD incidence. These algorithms incorporate billing codes, prescriptions, and other relevant elements. We compared the presence or unchecked status of these comorbidities on the forms to the presence or absence according to the algorithms. Findings: Computer algorithms had higher reporting of comorbidities compared to forms completion by physicians. This remained true when decreasing data span to one year and using only a single health center source. The algorithms determination was well accepted by a physician panel. Importantly, algorithms use significantly increased the expected deaths and lowered the standardized mortality ratios. Discussion: Using computer algorithms showed superior identification of comorbidities for form CMS-2728 and altered standardized mortality ratios. Adapting similar algorithms in available EMR systems may offer more thorough evaluation of comorbidities and improve quality reporting

Skeletal and cardiovascular consequences of a positive calcium balance during hemodialysis

Patients on hemodialysis are exposed to calcium via the dialysate at least three times a week. Changes in serum calcium vary according to calcium mass transfer during dialysis, which is dependent on the gradient between serum and dialysate calcium concentration (d[Ca]) and the skeleton turnover status that alters the ability of bone to incorporate calcium. Although underappreciated, the d[Ca] can potentially cause positive calcium balance that leads to systemic organ damage, including associations with mortality, myocardial dysfunction, hemodynamic tolerability, vascular calcification, and arrhythmias. The pathophysiology of these adverse effects includes serum calcium changes, parathyroid hormone suppression, and vascular calcification through indirect and direct effects. Some organs are more susceptible to alterations in calcium homeostasis. In this review, we discuss the existing data and potential mechanisms linking the d[Ca] to calcium balance with consequent dysfunction of the skeleton, myocardium, and arteries

Matrix vesicles induce calcification of recipient vascular smooth muscle cells through multiple signaling pathways

In patients with chronic kidney and end-stage renal diseases, the major risk factor for progression of arterial calcification is the presence of existing (baseline) calcification. Here, we tested whether calcification of arteries is extended from calcified vascular smooth muscle cells (VSMCs) to adjacent normal cells by matrix vesicle–induced alteration of cell signaling. Matrix vesicles isolated from VSMC of rats with chronic kidney disease were co-cultured with VSMCs from normal littermates. Endocytosis of vesicles by recipient cells was confirmed by confocal microscopy. The addition of cellular matrix vesicles with characteristics of exosomes and low fetuin-A content enhanced the calcification of recipient VSMC. Further, only cellular-derived matrix vesicles induced an increase in intracellular calcium ion concentration, NOX1 (NADPH oxidase) and the anti-oxidant superoxide dismutase-2 in recipient normal VSMC. The increase in intracellular calcium ion concentration was due to release from endoplasmic reticulum and partially attributed to the activation of both NOX1 and mitogen-activated protein kinase (MEK1 and Erk1/2) signaling, since inhibiting both pathways blocked the increase in intracellular calcium ion in recipient VSMC. In contrast, matrix vesicles isolated from the media had no effect on the intracellular calcium ion concentration or MEK1 signaling, and did not induce calcification. However, media matrix vesicles did increase Erk1/2, although not to the level of cellular matrix vesicles, and NOX1 expression. Blockade of NOX activity further inhibited the cellular matrix vesicle–induced accelerated calcification of recipient VSMC, suggesting a potential therapeutic role of such inhibition. Thus, addition of cellular-derived matrix vesicles from calcifying VSMC can accelerate calcification by inducing cell signaling changes and phenotypic alteration of recipient VSMC

Health Equity Starts with Us: Recommendations from the IN-CTSI Racial Justice and Health Equity Task Force

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