Hypoxia-inducible factor activators: a novel class of oral drugs for the treatment of anemia of chronic kidney disease.

Anemia is a hallmark of chronic kidney disease (CKD), worsens with disease progression, and profoundly affects a patient's well-being. Major pathogenic factors are inadequate kidney erythropoietin (EPO) production and absolute and functional iron deficiency. The 2 mainstays of current anemia treatment are a) replacement therapy with recombinant EPO or 1 of its glycosylated derivatives, administered subcutaneously or intravenously, and b) intravenous (IV) iron injections.

Disruption of mitochondrial electron transport impairs urinary concentration via AMPK-dependent suppression of aquaporin 2.

Urinary concentration is an energy-dependent process that minimizes body water loss by increasing aquaporin 2 (AQP2) expression in collecting duct (CD) principal cells. To investigate the role of mitochondrial (mt) ATP production in renal water clearance, we disrupted mt electron transport in CD cells by targeting ubiquinone (Q) binding protein QPC (UQCRQ), a subunit of mt complex III essential for oxidative phosphorylation. QPC-deficient mice produced less concentrated urine than controls, both at baseline and after type 2 vasopressin receptor stimulation with desmopressin.

Intraoperative Oxygen Treatment, Oxidative Stress, and Organ Injury Following Cardiac Surgery: A Randomized Clinical Trial.

Importance: Liberal oxygen (hyperoxia) is commonly administered to patients during surgery, and oxygenation is known to impact mechanisms of perioperative organ injury.

Objective: To evaluate the effect of intraoperative hyperoxia compared to maintaining normoxia on oxidative stress, kidney injury, and other organ dysfunctions after cardiac surgery.

Design, Setting, And Participants: This was a participant- and assessor-blinded, randomized clinical trial conducted from April 2016 to October 2020 with 1 year of follow-up at a single tertiary care medical center.

Clinical Risk Assessment and Prediction in Congenital Heart Disease Across the Lifespan: JACC Scientific Statement.

Congenital heart disease (CHD) comprises a range of structural anomalies, each with a unique natural history, evolving treatment strategies, and distinct long-term consequences. Current prediction models are challenged by generalizability, limited validation, and questionable application to extended follow-up periods. In this JACC Scientific Statement, we tackle the difficulty of risk measurement across the lifespan.

Updates on Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors in the Treatment of Renal Anemia.

Background: Anemia is a common complication of chronic kidney disease. The hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) is a new class of oral drugs for the treatment of renal anemia.

Summary: Clinical trials have consistently shown that HIF-PHIs can effectively increase hemoglobin in both the dialysis population and the nondialysis population.

Empathy across cultures - one size does not fit all: from the ego-logical to the eco-logical of relational empathy.

Empathy is extolled in Western healthcare and medical education as an exemplary quality to cultivate in trainees and providers. Yet it remains an elusive and inadequately understood attribute. It posits a "one size fits all" unidimensional attribute applicable across contexts with scant attention given to its multifaceted dimensions in intercultural contexts.

Detecting Drug-Drug Interactions in COVID-19 Patients.

COVID-19 patients with multiple comorbid illnesses are more likely to be using polypharmacy to treat their COVID-19 disease and comorbid conditions. Previous literature identified several DDIs in COVID-19 patients; however, various DDIs are unrecognized. This study aims to discover novel DDIs by conducting comprehensive research on the FDA Adverse Event Reporting System (FAERS) data from January 2020 to March 2021.

EPO synthesis induced by HIF-PHD inhibition is dependent on myofibroblast transdifferentiation and colocalizes with non-injured nephron segments in murine kidney fibrosis.

Aim: Erythropoietin (EPO) is regulated by hypoxia-inducible factor (HIF)-2. In the kidney, it is produced by cortico-medullary perivascular interstitial cells, which transdifferentiate into collagen-producing myofibroblasts in response to injury. Inhibitors of prolyl hydroxylase domain (PHD) dioxygenases (HIF-PHIs) activate HIF-2 and stimulate kidney and liver EPO synthesis in patients with anemia of chronic kidney disease (CKD).

Disruption of mitochondrial complex III in cap mesenchyme but not in ureteric progenitors results in defective nephrogenesis associated with amino acid deficiency.

Oxidative metabolism in mitochondria regulates cellular differentiation and gene expression through intermediary metabolites and reactive oxygen species. Its role in kidney development and pathogenesis is not completely understood. Here we inactivated ubiquinone-binding protein QPC, a subunit of mitochondrial complex III, in two types of kidney progenitor cells to investigate the role of mitochondrial electron transport in kidney homeostasis.

The effect of diabetes on abdominal aortic aneurysm growth over 2 years.

Objective: Abdominal aortic aneurysm (AAA) is a common progressive disease and a significant cause of morbidity and mortality. Prior investigations have shown that diabetes mellitus (DM) may be relatively protective of AAA incidence and growth. The Non-invasive Treatment of Aortic Aneurysm Clinical Trial (N-TACT) is a contemporary study of small AAA growth that provides a unique opportunity to validate and explore the effect of DM on AAA.

Pharmacological HIF-PHD inhibition reduces renovascular resistance and increases glomerular filtration by stimulating nitric oxide generation.

Aim: Hypoxia-inducible factors (HIFs) are O -sensitive transcription factors that regulate multiple biological processes which are essential for cellular adaptation to hypoxia. Small molecule inhibitors of HIF-prolyl hydroxylase domain (PHD) dioxygenases (HIF-PHIs) activate HIF-dependent transcriptional programs and have broad clinical potential. HIF-PHIs are currently in global late-stage clinical development for the treatment of anaemia associated with chronic kidney disease.

Human reconstructed kidney models.

The human kidney, which consists of up to 2 million nephrons, is critical for blood filtration, electrolyte balance, pH regulation, and fluid balance in the body. Animal experiments, particularly mice and rats, combined with advances in genetically modified technology have been the primary mechanism to study kidney injury in recent years. Mouse or rat kidneys, however, differ substantially from human kidneys at the anatomical, histological, and molecular levels.

Kidney epithelial targeted mitochondrial transcription factor A deficiency results in progressive mitochondrial depletion associated with severe cystic disease.

Abnormal mitochondrial function is a well-recognized feature of acute and chronic kidney diseases. To gain insight into the role of mitochondria in kidney homeostasis and pathogenesis, we targeted mitochondrial transcription factor A (TFAM), a protein required for mitochondrial DNA replication and transcription that plays a critical part in the maintenance of mitochondrial mass and function. To examine the consequences of disrupted mitochondrial function in kidney epithelial cells, we inactivated TFAM in sine oculis-related homeobox 2-expressing kidney progenitor cells.

Pleiotropy in the Genetic Predisposition to Rheumatoid Arthritis: A Phenome-Wide Association Study and Inverse Variance-Weighted Meta-Analysis.

Objective: This study was undertaken to investigate the hypothesis that a genetic predisposition toward rheumatoid arthritis (RA) increases the risk of 10 cardiometabolic and autoimmune disorders previously associated with RA in epidemiologic studies, and to define new genetic pleiotropy present in RA.

Methods: Two approaches were used to test our hypothesis. First, we constructed a weighted genetic risk score (wGRS) and then examined its association with 10 prespecified disorders.

Got glycogen? An energy resource in HIF-mediated prevention of ischemic kidney injury.

Hypoxia-inducible factor activation reprograms glucose metabolism and leads to glycogen accumulation in multiple cell types. In this issue of Kidney International, Ito and colleagues demonstrate that pharmacologic inhibition of hypoxia-inducible factor-prolyl hydroxylase domain oxygen sensors in renal epithelial cells enhances glycogen synthesis and protects from subsequent hypoxia and glucose deprivation. In vivo studies advance the concept that renal glycogen metabolism contributes to cytoprotection afforded by pre-ischemic hypoxia-inducible factor-prolyl hydroxylase domain inhibition.

Conceptualizing Medical Humanities Programs in Low-Resource Settings in Africa.

The role of the humanities in medical education remains a topic of dynamic debate in medical schools of high-income countries. However, in most low- and middle-income countries, the medical humanities are less topical and rarely even have a place in the curriculum. Reasons for this dearth include inadequate resources to support such programs coupled with misapprehension of the role and significance of the humanities in medical education.

Evaluation of a Novel System to Enhance Clinicians' Recognition of Preadmission Adverse Drug Reactions.

Background: Often unrecognized by providers, adverse drug reactions (ADRs) diminish patients' quality of life, cause preventable admissions and emergency department visits, and increase health care costs.

Objective: This article evaluates whether an automated system, the Adverse Drug Effect Recognizer (ADER), could assist clinicians in detecting and addressing inpatients' ongoing preadmission ADRs.

Methods: ADER uses natural language processing to extract patients' medications, findings, and past diagnoses from admission notes.

Improving neonatal intubation safety: A journey of a thousand miles.

Neonatal intubation is one of the most common procedures performed by neonatologists, however, the procedure is difficult and high risk. Neonates who endure the procedure often experience adverse events, including bradycardia and severe oxygen desaturations. Because of low first attempt success rates, neonates are often subjected to multiple intubation attempts before the endotracheal tube is successfully placed.

Occasional staining for p63 in malignant vascular tumors: a potential diagnostic pitfall.

Expression of p63, a putative marker for epithelial or myoepithelial differentiation, has been used to distinguish spindle cell carcinoma from sarcoma. The specificity of p63 for epithelial differentiation has not been thoroughly evaluated however, since p63 expression has been explored in only a handful of mesenchymal tumors. After observing unexpected immunohistochemical staining for p63 in an angiosarcoma of the breast, we evaluated a series of benign and malignant vascular tumors to determine the frequency of such a finding.

Markers of epithelial-mesenchymal transition and epithelial differentiation in sarcomatoid carcinoma: utility in the differential diagnosis with sarcoma.

The distinction between sarcomatoid carcinoma (SC) and bona fide sarcoma can be difficult using conventional immunohistochemical markers. Epithelial-mesenchymal transition (EMT) has been proposed as a histogenetic mechanism for the development of SC. Expression of selected markers of EMT (Twist and Slug) was compared with other markers of epithelial differentiation in SC and spindle cell sarcoma to determine the utility of these antigens in this differential diagnosis.

Inflammatory myofibroblastic tumor of the urinary bladder in a 27-year-old woman with systemic lupus erythematosus.

Spindle cell lesions of the urinary bladder are uncommon tumors, and are most often spindle cell (sarcomatoid) carcinomas, non-neoplastic reactive mesenchymal proliferations, or soft tissue sarcomas. Inflammatory myofibroblastic tumors (IMTs) may also occur in this location. Herein, we report an unusual case of an IMT arising in a previously uninstrumented bladder of a 27-year-old African American female with systemic lupus erythematosus.

Steroid hormone receptor and COX-2 expression in chordoma.

Reports of sex steroid receptor expression in chordoma suggest that these tumors may be responsive to hormone manipulation therapy. Immunohistochemical stains for estrogen receptor (ER)-alpha, ER-beta, progesterone receptor (PR), androgen receptor (AR), and cyclooxygenase 2 (COX-2), were performed on a tissue microarray containing 21 samples of chordoma. Most chordomas expressed COX-2, ER-beta, and AR, whereas ER-alpha and PR stains were negative in all cases.

Impacts of weight change on prehypertension in middle-aged and elderly women.

Background: Individuals with prehypertension, a new blood pressure category defined as systolic blood pressure of 120-139 mm Hg and/or diastolic blood pressure of 80-89 mm Hg, are at an increased risk for heart diseases and are strongly recommended to practice lifestyle changes, including weight control. Data on impacts of long-term weight change on prehypertension are sparse.

Objective: To evaluate the association between weight change since age 20 and prehypertension risk.