xlr-11 and Acute-Kidney-Injury

Synthetic cannabinoids (SCBs)-related intoxications and deaths have been increasingly reported, turning its widespread recreational use into a major public health concern. Specifically, a direct link between SCBs and acute kidney injury (AKI) has been established. XLR-11 is an SCB commonly found in the toxicological analysis of patients with SCB-associated AKI. However, the pathophysiology of AKI among SCB consumers remains unknown. This work thus represents the first in vitro assessment of SCB nephrotoxicity, as a first approach to identify its cellular targets. We demonstrate that XLR-11, at biologically relevant concentrations (in the nanomolar range), primarily targets mitochondrial function in human proximal tubule (HK-2) cells, inducing a transient hyperpolarization of the mitochondrial membrane and increasing ATP production, accompanied by Bax translocation from cytosol into mitochondria. These phenomena further triggered energy-dependent apoptotic cell death pathways, indicated by increased caspase-3 activity and chromatin condensation. Experiments using SR141716A and SR144258, specific antagonists for CB1 and CB2 receptors, respectively, as well as HEK293T cells (which do not express CBRs) highlighted these processes' dependence on CBR activation. Nevertheless, ATP formation seemed to follow a CBR-independent pathway. Our findings using specific inhibitors of endogenous cannabinoids biosynthesis (i.e. MAFP and THL) further evidenced the involvement of the endocannabinoid system in the regulation of these processes, as XLR-11 binding to CBRs seemed to compromise endocannabinoid-mediated preservation of mitochondrial function. Nevertheless, the exact mechanisms involved require further clarification.

Topics: Acute Kidney Injury; Adenosine Triphosphate; Apoptosis; bcl-2-Associated X Protein; Cannabinoids; Caspase 3; Chromatin Assembly and Disassembly; Dose-Response Relationship, Drug; Endocannabinoids; Energy Metabolism; HEK293 Cells; Humans; Kidney Tubules, Proximal; Membrane Potential, Mitochondrial; Mitochondria; Psychotropic Drugs; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Signal Transduction

Synthetic cannabinoids are illegal drugs of abuse known to cause adverse neurologic and sympathomimetic effects. They are an emerging health risk: 11% of high school seniors reported smoking them during the previous 12 months. We describe the epidemiology of a toxicologic syndrome of acute kidney injury associated with synthetic cannabinoids, review the toxicologic and public health investigation of the cluster, and describe clinical implications of the cluster investigation.. Case series of nine patients affected by the toxicologic syndrome in Oregon and southwestern Washington during May-October 2012. Cases were defined as acute kidney injury (creatinine > 1.3 mg/dL) among persons aged 13-40 years without known renal disease who reported smoking synthetic cannabinoids. Toxicology laboratories used liquid chromatography and time-of-flight mass spectrometry to test clinical and product specimens for synthetic cannabinoids, their metabolites, and known nephrotoxins. Public health alerts informed clinicians, law enforcement, and the community about the cluster and the need to be alert for toxidromes associated with emerging drugs of abuse.. Patients were males aged 15-27 years (median, 18 years), with intense nausea and flank or abdominal pain, and included two sets of siblings. Peak creatinine levels were 2.6-17.7 mg/dL (median, 6.6 mg/dL). All patients were hospitalized; one required dialysis; none died. No alternate causes of acute kidney injury or nephrotoxins were identified. Patients reported easily purchasing synthetic cannabinoids at convenience, tobacco, and adult bookstores. One clinical and 2 product samples contained evidence of a novel synthetic cannabinoid, XLR-11 ([1-(5-fluoropentyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone).. Whether caused by direct toxicity, genetic predisposition, or an as-yet unidentified nephrotoxin, this association between synthetic cannabinoid exposure and acute kidney injury reinforces the need for vigilance to detect new toxicologic syndromes associated with emerging drugs of abuse. Liquid chromatography and time-of-flight mass spectrometry are useful tools in determining the active ingredients in these evolving products and evaluating them for toxic contaminants.

Topics: Acute Kidney Injury; Adolescent; Adult; Cannabinoids; Designer Drugs; Drug Combinations; Humans; Illicit Drugs; Kidney; Male; Oregon; Poison Control Centers; Poisoning; Psychotropic Drugs; Smoke; Treatment Outcome; Washington; Young Adult