Urinary Exosomes Identify Inflammatory Pathways in Vancomycin Associated Acute Kidney Injury.

Background: Vancomycin is commonly used as a first line therapy for gram positive organisms such as methicillin resistant . Vancomycin-induced acute kidney injury (V-AKI) has been reported in up to 43% of patients, especially in those with higher targeted trough concentrations. The precise mechanism of injury in humans remains elusive, with recent evidence directed towards proximal tubule cell apoptosis.

Augmentation of Urinary Lactoferrin Enhances Host Innate Immune Clearance of Uropathogenic Escherichia coli.

Urinary tract infection (UTI) is a prominent global health care burden. Although UTI is readily treated with antibiotics in healthy adults, complicated cases in immune-compromised individuals and the emerging antibiotic resistance of several uropathogens have accelerated the need for new treatment strategies. Here, we surveyed the composition of urinary exosomes in a mouse model of uropathgenic Escherichia coli (UPEC) UTI to identify specific urinary tract defense constituents for therapeutic development.

Biomarkers of Renal Injury in Cirrhosis: Association with Acute Kidney Injury and Recovery after Liver Transplantation.

Background: To define urine or serum biomarkers in predicting renal function recovery after liver transplantation (LT).

Methods: Adults listed for LT (February 2011-July 2014) and with modified diet for renal disease-6 (MDRD-6) <60 mL/min provided urine/blood samples at baseline and serially until LT for biomarkers in serum (pg/mL) and urine (pg/mg creatinine).

Results: Of 271 LT listed patients (mean age 57 years, 63% males, median listing MELD 17.

Tamm-Horsfall glycoprotein engages human Siglec-9 to modulate neutrophil activation in the urinary tract.

Urinary tract infections are a major problem in human medicine for which better understanding of native immune defenses may reveal new pathways for therapeutic intervention. Tamm-Horsfall glycoprotein (THP), the most abundant urinary protein, interacts with bacteria including uropathogenic Escherichia coli (UPEC) as well host immune cells. In addition to its well-studied functions to antagonize bacterial colonization, we hypothesize that THP serves a critical host defense function through innate immune modulation.

Rationale and Design of the Genetic Contribution to Drug Induced Renal Injury (DIRECT) Study.

Introduction: Nephrotoxicity from drugs accounts for 18% to 27% of cases of acute kidney injury. Determining a genetic predisposition may potentially be important in minimizing risk. The aims of this study are as follows: to determine whether a genetic predisposition exists for the development of drug-induced kidney disease (DIKD), using genome-wide association and whole-genome sequencing studies; to describe the frequency, course, risk factors, resolution and outcomes of DIKD cases; to investigate the role of ethnic/racial variability in the genetics of DIKD; and to explore the use of different tools establishing causality of DIKD.

Clinical Significance of Persistent Global and Focal Computed Tomography Nephrograms After Cardiac Catheterization and Their Relationships to Urinary Biomarkers of Kidney Damage and Procedural Factors: Pilot Study.

Objectives: We evaluate the relationships between persistent computed tomography (CT) nephrograms and acute kidney injury after cardiac catheterization (CC). We compare changes in urinary biomarkers kidney injury molecule 1 (KIM-1), cystatin C, and serum creatinine to procedural factors.

Materials And Methods: From 159 eligible patients without renal insufficiency (estimated glomerular filtration rate >60 mL/min), 40 random patients (age range, 42-81 years; mean age, 64 years; 25 men, 15 women) gave written informed consent to undergo unenhanced CT limited to their kidneys 24 hours after CC.

Proteomic analysis of urine exosomes reveals renal tubule response to leptospiral colonization in experimentally infected rats.

Background: Infectious Leptospira colonize the kidneys of reservoir (e.g. rats) and accidental hosts such as humans.

Mannan-binding lectin in diabetic kidney disease: the impact of mouse genetics in a type 1 diabetes model.

Unlabelled: BACKGROUND. Mannan-binding lectin (MBL) is involved in the development of diabetic nephropathy. MBL is a part of the innate immune system where it can activate the complement system.

Role of reactive oxygen species in hyperadrenergic hypertension: biochemical, physiological, and pharmacological evidence from targeted ablation of the chromogranin a (Chga) gene.

Background: Oxidative stress, an excessive production of reactive oxygen species (ROS) outstripping antioxidant defense mechanisms, occurs in cardiovascular pathologies, including hypertension. In the present study, we used biochemical, physiological, and pharmacological approaches to explore the role of derangements of catecholamines, ROS, and the endothelium-derived relaxing factor nitric oxide (NO(•)) in the development of a hyperadrenergic model of hereditary hypertension: targeted ablation (knockout [KO]) of chromogranin A (Chga) in the mouse.

Methods And Results: Homozygous ⁻(/)⁻ Chga gene knockout (KO) mice were compared with wild-type (WT, +/+) control mice.

Novel systems biology insights using antifibrotic approaches for diabetic kidney disease.

Although several interventions slow the progression of diabetic nephropathy, current therapies do not halt progression completely. Recent preclinical studies suggested that pirfenidone (PFD) prevents fibrosis in various diseases, but the mechanisms underlying its antifibrotic action are incompletely understood. To explore the therapeutic potential of PFD, we studied the PFD-treated db/db diabetic mouse kidney by liquid chromatography-tandem mass spectrometry proteomics.

Pirfenidone is renoprotective in diabetic kidney disease.

Although several interventions slow the progression of diabetic nephropathy, current therapies do not halt progression completely. Recent preclinical studies suggested that pirfenidone (PFD) prevents fibrosis in various diseases, but the mechanisms underlying its antifibrotic action are incompletely understood. Here, we evaluated the role of PFD in regulation of the extracellular matrix.

Profiling of human mesangial cell subproteomes reveals a role for calmodulin in glucose uptake.

Proteomics combined with cell fractionation was used to identify proteins regulated by high glucose (HG) in human mesangial cells (HMC). Total membrane and cytosolic fraction proteins derived from HMC after 7 days of HG exposure were resolved by a two-dimensional gel electrophoresis approach. DeCyder software was used to analyze the HG-induced protein spot dysregulation.

Nitrative inactivation of thioredoxin-1 and its role in postischemic myocardial apoptosis.

Background: Intracellular proteins involved in oxidative stress and apoptosis are nitrated in diseased tissues but not in normal tissues; definitive evidence to support a causative link between a specific protein that is nitratively modified with tissue injury in a specific disease is limited, however. The aims of the present study were to determine whether thioredoxin (Trx), a novel antioxidant and antiapoptotic molecule, is susceptible to nitrative inactivation and to establish a causative link between Trx nitration and postischemic myocardial apoptosis.

Methods And Results: In vitro exposure of human Trx-1 to 3-morpholinosydnonimine resulted in significant Trx-1 nitration and almost abolished Trx-1 activity.

Two-dimensional fluorescence difference gel electrophoresis analysis of the urine proteome in human diabetic nephropathy.

Urinary proteins may provide clues regarding pathogenesis of kidney disease as well as providing markers of disease activity. We employed two-dimensional differential in-gel electrophoretic analysis (2-D DIGE) to assess multiple urine samples in patients with diabetic nephropathy. Patient samples were collected as timed overnight collections.

Triclosan: a shot in the arm for antimalarial chemotherapy.

In order that malaria be successfully contained, it is important that one has a clear understanding of the normal physiology and biochemistry of the parasite essential to its survival in its human host. Until very recently, the conventional approaches to antimalarial chemotherapy have consistently been plagued with the uncanny ability of the parasite to evolve resistance to drugs. The recently discovered plasmodial fatty acid biosynthetic pathway as well as its inhibition by triclosan that classifies it as belonging to type II, provide with a very crucial breakthrough to the crusade against malaria.

Paradigm shifts in malaria parasite biochemistry and anti-malarial chemotherapy.

A fatty acid synthesis (FAS) pathway was recently discovered and established in the obligate human parasite Plasmodium falciparum. Its inhibition by triclosan (2,4,4'-trichloro-2'-hydroxydiphenyl ether) leads to its classification as a type II FAS. Humans, the vertebrate host for the malarial parasite utilize type I FAS, which is not inhibited by triclosan.