Exploration of zileuton protective mechanisms against vancomycin-associated nephrotoxicity.

Vancomycin is one of the most commonly used parenteral antibiotics for treating drug-resistant bacterial infections, however, it is hindered by nephrotoxicity. We previously demonstrated that zileuton could delay the onset of vancomycin-associated nephrotoxicity in rats. Here, we sought to understand the mechanism(s) of zileuton renal protection.

Dual-function polyester nanoparticles for amplified anti-inflammatory effects.

This study investigates a dual-acting drug delivery system using naringenin (NAR) as a folate receptor ligand to enhance intestinal uptake and encapsulated NAR for combating inflammation. The dual-acting systems were tested in vitro on cisplatin-induced human kidney-2 cells and in vivo in a mouse model of cisplatin-induced acute kidney injury (AKI). NAR-loaded passive nanoparticles [P2Ns(NAR)] and dual-acting systems [P2Ns-NAR(NAR)] showed notable advantages over unformulated NAR, reducing the required dose by up to 57 and 79%, respectively.

Drug development studies supporting zileuton as a parenteral adjuvant to attenuate antibiotic-associated nephrotoxicity.

Glycopeptide, polymyxin, and aminoglycoside antibiotics are among the most commonly used agents to treat drug-resistant bacterial infections; however, their clinical use is hindered by nephrotoxicity. We previously reported that zileuton has the potential to attenuate antibiotic-associated nephrotoxicity in an animal model. Here, we further report the development of a parenteral formulation and exploration of dosing strategies for zileuton.

Interplay between Skeletal Muscle Catabolism and Remodeling of Arteriovenous Fistula by Yes-Associated Protein 1 (YAP1) Signaling.

Key Points: Atrophied muscle–derived myostatin stimulated mesenchymal stem cell differentiation and adverse arteriovenous (AV) fistula remodeling through yes-associated protein 1 (YAP1) activation. Treatment with myostatin peptibody inhibited muscle wasting and blocked mesenchymal stem cell activation and AV fistula fibrosis. A light-sensitive drug-release strategy was engineered for the periadventitial delivery of verteporfin to improve AV fistula patency.

Early Versus Late Initiation of Dialysis in CKD Stage 5: Time for a Consensus.

Chronic kidney disease (CKD), a major global public health problem, emerged as one of the leading causes of death, affecting over 800 million individuals worldwide, with significant burden to patients and their caregivers, and may lead to end-stage kidney disease (ESKD). The decision on optimal initiation of chronic dialysis is a common problem faced by nephrologists, patients, and caregivers due to lack of adequate data. Determining the ideal time to initiate maintenance dialysis for individuals struggling with ESKD has remained a puzzle.

Mechanisms of gelofusine protection in an in vitro model of polymyxin B-associated renal injury.

Polymyxins are a last-resort treatment option for multidrug-resistant gram-negative bacterial infections, but they are associated with nephrotoxicity. Gelofusine was previously shown to reduce polymyxin-associated kidney injury in an animal model. However, the mechanism(s) of renal protection has not been fully elucidated.

Chronic Interstitial Nephritis in Agricultural Communities: Observational and Mechanistic Evidence Supporting the Role of Nephrotoxic Agrochemicals.

Chronic interstitial nephritis in agricultural communities (CINAC) is an epidemic of kidney disease affecting specific tropical and subtropical regions worldwide and is characterized by progressive CKD in the absence of traditional risk factors, such as hypertension and diabetes. CINAC prevalence is higher among young, male agricultural workers, but it also affects women, children, and nonagricultural workers in affected areas. Biopsies from patients with CINAC across regions commonly demonstrate tubular injury with lysosomal aggregates, tubulointerstitial inflammation, and fibrosis and variable glomerular changes.

Nanocurcumin combined with insulin alleviates diabetic kidney disease through P38/P53 signaling axis.

Treatments for diabetic kidney disease (DKD) mainly focus on managing hyperglycemia and hypertension, but emerging evidence suggests that inflammation also plays a role in the pathogenesis of DKD. This 10-week study evaluated the efficacy of daily oral nanoparticulate-curcumin (nCUR) together with long-acting insulin (INS) to treat DKD in a rodent model. Diabetic rats were dosed with unformulated CUR alone, nCUR alone or together with INS, or INS alone.

Potential Mechanisms Involved in Chronic Kidney Disease of Unclear Etiology.

Background And Objectives: The etiology of chronic kidney disease of unclear etiology, also known as Mesoamerican nephropathy, remains unclear. We investigated potential etiologies for Mesoamerican nephropathy in an immigrant dialysis population.

Design, Setting, Participants, & Measurements: Migrants with Mesoamerican nephropathy kidney failure (=52) were identified by exclusion of known causes of kidney disease and compared using a cross-sectional survey with demographically similar patients with kidney failure from other causes (=63) and age/sex/place of origin-matched healthy participants (=16).

Megalin-Mediated Trafficking of Mitochondrial Intracrines: Relevance to Signaling and Metabolism.

The multi-ligand binding protein megalin (LRP2) is ubiquitously expressed and facilitates cell uptake of hormones, nutrients and vitamins. We have recently shown megalin is present in the mitochondria of cultured epithelial and mesenchymal cells, as well as many organs and tissues. Mitochondrial megalin associates with stanniocalcin-1 and SIRT3; two proteins that promote anti-oxidant defenses.

Interactions between leucines within the signal peptides of megalin and stanniocalcin-1 are crucial for regulation of mitochondrial metabolism.

The mitochondrial intracrine Stanniocalcin 1 (STC1) activates mitochondrial anti-oxidant defenses. LRP2 (megalin) shuttles STC1 to the mitochondria through retrograde early endosome-to-Golgi- and Rab32-mediated pathway, and LRP2 KO impairs mitochondrial respiration and glycolysis. We determined STC1-LRP2 interaction domains using HA- and FLAG-tagged fragments of STC1 and LRP2, respectively, co-expressed in HEK293T cells.

Mesangial IgM deposition predicts renal outcome in patients with IgA nephropathy: a multicenter, observational study.

Mesangial IgM deposition is found in patients with immunoglobulin A nephropathy (IgAN). This study aims to investigate the relationships between mesangial IgM deposition and disease progression in IgAN patients. A total of 1239 patients with biopsy-proven primary IgAN were enrolled in this multicenter, observational study between January 2013 and August 2017.

Sirtuin-3 mediates sex differences in kidney ischemia-reperfusion injury.

Studies suggest that biological sex influences susceptibility to kidney diseases with males demonstrating greater risk for developing ischemic acute kidney injury (AKI). Sex-related differences in mitochondrial function and homeostasis exist, likely contributing to sexual dimorphism in kidney injury, but the mechanisms are not well characterized. Our observations reveal lower baseline expression of Sirtuin-3 (Sirt3, a major mitochondrial acetyltransferase) in the kidneys of male mice versus females.

A multicenter, prospective, observational study to determine association of mesangial C1q deposition with renal outcomes in IgA nephropathy.

It was reported that histopathologic lesions are risk factors for the progression of IgA Nephropathy (IgAN). The aim of this study was to investigate the relationships between mesangial deposition of C1q and renal outcomes in IgAN. 1071 patients with primary IgAN diagnosed by renal biopsy were enrolled in multiple study centers form January 2013 to January 2017.

Iso-osmolar hyponatremia from polyethylene glycol.

Understanding and applying pathophysiological concepts to patient care is an important skill for physicians in the clinical setting. Here, we present a case that demonstrates how the application of common physiological concepts relating to the widely accepted hyponatremia algorithm led to an accurate diagnosis of hyponatremia. This case documents iso-osmolar hyponatremia caused by orally administered polyethylene glycol absorption in the gastrointestinal tract.

Soluble Urokinase Receptor and Acute Kidney Injury.

Background: Acute kidney injury is common, with a major effect on morbidity and health care utilization. Soluble urokinase plasminogen activator receptor (suPAR) is a signaling glycoprotein thought to be involved in the pathogenesis of kidney disease. We investigated whether a high level of suPAR predisposed patients to acute kidney injury in multiple clinical contexts, and we used experimental models to identify mechanisms by which suPAR acts and to assess it as a therapeutic target.

Oral delivery of nanoparticle urolithin A normalizes cellular stress and improves survival in mouse model of cisplatin-induced AKI.

The popular anticancer drug cisplatin causes many adverse side effects, the most serious of which is acute kidney injury (AKI). Emerging evidence from laboratory and clinical studies suggests that the AKI pathogenesis involves oxidative stress pathways; therefore, regulating such pathways may offer protection. Urolithin A (UA), a gut metabolite of the dietary tannin ellagic acid, possesses antioxidant properties and has shown promise in mouse models of AKI.

Stanniocalcin-1 is a Modifier of Oxygen-Induced Retinopathy Severity.

: Abnormal activation of signaling pathways related to angiogenesis, inflammation, and oxidative stress has been implicated in the pathophysiology of retinopathy of prematurity (ROP), a leading cause of blindness in pre-term infants. Therapies for ROP include laser and anti-vascular endothelial growth factor agents. However, these therapies have side effects, and even with adequate treatment, visual acuity can be impaired.

Mitochondrial dysfunction in acute kidney injury and sex-specific implications.

The kidney is one of the most energy-demanding organs in the human body, and the maintenance of mitochondrial homeostasis is central to kidney function. Recent advances have led to a greater appreciation of how mitochondrial dysfunction contributes to the pathogenesis of AKI, from decreased ATP production, to enhanced mitochondrial oxidative stress, cell necrosis and apoptosis. Accumulating evidence suggests sexual dimorphism in the response to AKI with males demonstrating greater risk for developing ischemia-reperfusion and sepsis-induced kidney injury.

Can physicians detect hyperkalemia based on the electrocardiogram?

Objective: Although there is no consensus on how to use an electrocardiogram (ECG) in patients with hyperkalemia, physicians often obtain it in the acute setting when diagnosing and treating hyperkalemia. The objective of this study is to evaluate if physicians are able to detect hyperkalemia based on the ECG.

Methods: The study was conducted at a large county hospital with a population of end stage renal disease (ESRD) patients who received hemodialysis (HD) solely on an emergent basis.

aP2-Cre Mediated Ablation of GHS-R Attenuates Adiposity and Improves Insulin Sensitivity during Aging.

Ghrelin via its receptor, the growth hormone secretagogue receptor (GHS-R), increases food intake and adiposity. The tissue-specific functions of GHS-R in peripheral tissues are mostly unknown. We previously reported that while GHS-R expression is very low in white and brown fat of young mice, expression increases during aging.

Megalin mediates plasma membrane to mitochondria cross-talk and regulates mitochondrial metabolism.

Mitochondrial intracrines are extracellular signaling proteins, targeted to the mitochondria. The pathway for mitochondrial targeting of mitochondrial intracrines and actions in the mitochondria remains unknown. Megalin/LRP2 mediates the uptake of vitamins and proteins, and is critical for clearance of amyloid-β protein from the brain.