salicylates and Acute-Kidney-Injury

Non-steroidal anti-inflammatory agents ( NSAIA ) are increasingly used in clinical practice. They exert the majority of their therapeutic and adverse effects by inhibiting prostaglandin synthesis. A variety of clinically important side effects have been described following their administration. We review the renal complications, which include sodium retention, interference with the effectiveness of diuretics, impairment of water excretion, development of hyperkalemia, interference with the therapy of hypertension, and induction of at least four different forms of renal failure. The hemodynamic variety of renal failure and the side effects affecting fluid and electrolyte homeostasis are most likely to become manifest in the context of conditions leading to decreased renal perfusion. Guidelines for use of NSAIA , detection of patients at risk, and therapeutic approaches are provided.

Topics: Acute Kidney Injury; Adult; Aged; Anti-Inflammatory Agents; Blood Pressure; Female; Glomerulonephritis; Hemodynamics; Humans; Hyperkalemia; Hyponatremia; Kidney Diseases; Kidney Papillary Necrosis; Male; Middle Aged; Nephritis, Interstitial; Prostaglandin Antagonists; Prostaglandins; Risk; Salicylates; Water-Electrolyte Balance

This article attempts to help in the understanding of the mechanisms responsible for a modified drug pharmacokinetic profile in disease states. The main factors influencing the fate of the drug as it moves from the site of administration to the sites of elimination are depicted. Changes in absorption kinetics can be due to altered gastrointestinal peristalsis and secretions as well as modifications of splanchnic blood flow. Pathological states may affect the binding of drugs to plasma proteins, mainly human serum albumin and alpha 1 acid glycoprotein. The resulting modifications in the free fraction of the drug can cause a change in the volume of distribution. The distribution can also be influenced by circulatory disorders modifying local blood flows and thus impeding drug entry into the tissues. Many diseases can alter hepatic and/or renal clearance. This is not surprising since the elimination mechanisms are dependent upon many factors such the enzymatic status of the liver, plasma protein binding, and blood flow to both the liver and the kidney. Some examples such as the modification of furosemide pharmacokinetics in acute renal failure, the impaired metabolism of opiate analgesics in hepatic insufficiency, the alterations of the usual disposition process in salicylic acid intoxication, and the influence of cardiac failure upon some drugs pharmacokinetics, have been chosen to illustrate some of the aspects discussed. Some simple rules for making a rational selection of drugs in pathological states are also outlined.

Topics: Acute Kidney Injury; Blood Proteins; Disease; Furosemide; Glomerular Filtration Rate; Heart Failure; Humans; Intestinal Absorption; Kidney; Kinetics; Liver Diseases; Narcotics; Pharmaceutical Preparations; Protein Binding; Salicylates; Tissue Distribution

Topics: Acute Kidney Injury; Barbiturates; Blood Volume; Child; Child, Preschool; Costs and Cost Analysis; Heart Failure; Humans; Hyperkalemia; Hypocalcemia; Hypotension; Intestinal Obstruction; Intestinal Perforation; Kidney Failure, Chronic; Metabolic Diseases; Methods; Nutrition Disorders; Peritoneal Dialysis; Poisoning; Renal Dialysis; Salicylates; Time Factors

Topics: Acute Kidney Injury; Barbiturates; Brain Edema; Humans; Hyperkalemia; Methanol; Methods; Osmolar Concentration; Osmotic Pressure; Peritoneal Dialysis; Poisoning; Pulmonary Edema; Salicylates; Time Factors; Uremia

Topics: Acetaminophen; Acid-Base Equilibrium; Acidosis; Acute Kidney Injury; Alkalosis, Respiratory; Aspirin; Calcium; Coma; Dehydration; Fever; Gastric Lavage; Hemorrhage; Humans; Hydrogen-Ion Concentration; Infusions, Parenteral; Poisoning; Salicylamides; Salicylates; Seizures; Tetany; Vomiting

Topics: Acute Kidney Injury; Ascites; Dialysis; Ethanol; Methanol; Nephritis; Peritoneal Cavity; Peritoneal Dialysis; Poisoning; Renal Dialysis; Renal Insufficiency; Salicylates; Toxicology

Topics: Acute Kidney Injury; Aged; Anemia; Anti-Inflammatory Agents, Non-Steroidal; Female; Geriatric Assessment; Humans; Kidney Function Tests; Male; Risk Factors; Salicylates

This study aimed to evaluate the risk factors and the association of acute kidney injury (AKI) with outcomes, and resource utilisation in patients hospitalised because of salicylate intoxication in the United States.. Hospitalised patients with a primary diagnosis of salicylate intoxication from 2003 to 2014 were identified in the National Inpatient Sample (NIS) database. End-stage kidney disease patients were excluded. The occurrence of AKI was identified using hospital diagnosis code. Clinical characteristics, in-hospital treatment, outcomes and resource utilisation were compared between patients with and without AKI.. A total of 13 787 eligible hospital admissions were included in the analysis. AKI occurred in 1279 (9.3%) admissions. Older age, male sex, more recent year of hospitalisation, anaemia, hypertension, congestive heart failure, chronic kidney disease, volume depletion, sepsis and ventricular arrhythmia/cardiac arrest were significantly associated with increased risk of AKI, whereas Hispanic race was associated with decreased risk. AKI was significantly associated with increased risk of organ failure, and in-hospital mortality. In addition, the need for ventilation support, blood component transfusion, renal replacement therapy, length of hospital stay and hospitalisation cost were higher in AKI patients.. Approximately one tenth of salicylate intoxication patients developed AKI during hospitalisation. AKI was associated with higher morbidity, mortality and resource utilisations.

Topics: Acute Kidney Injury; Aged; Hospital Mortality; Hospitalization; Humans; Male; Renal Replacement Therapy; Retrospective Studies; Risk Factors; Salicylates; United States

A host of pathogenic factors induce acute kidney injury (AKI) leading to insufficiencies of renal function. In the present study we evaluated the role of myocardin-related transcription factor A (MRTF-A) in the pathogenesis of AKI. We report that systemic deletion of MRTF-A or inhibition of MRTF-A activity with CCG-1423 significantly attenuated AKI in mice induced by either ischemia-reperfusion or LPS injection. Of note, MRTF-A deficiency or suppression resulted in diminished renal ROS production in AKI models with down-regulation of NAPDH oxdiase 1 (NOX1) and NOX4 expression. In cultured macrophages, MRTF-A promoted NOX1 transcription in response to either hypoxia-reoxygenation or LPS treatment. Interestingly, macrophage-specific MRTF-A deletion ameliorated AKI in mice. Mechanistic analyses revealed that MRTF-A played a role in regulating histone H4K16 acetylation surrounding the NOX gene promoters by interacting with the acetyltransferase MYST1. MYST1 depletion repressed NOX transcription in macrophages. Finally, administration of a MYST1 inhibitor MG149 alleviated AKI in mice. Therefore, we data illustrate a novel epigenetic pathway that controls ROS production in macrophages contributing to AKI. Targeting the MRTF-A-MYST1-NOX axis may yield novel therapeutic strategies to combat AKI.

Topics: Acetylation; Acute Kidney Injury; Anilides; Animals; Benzamides; Cells, Cultured; Disease Models, Animal; Gene Deletion; Histone Acetyltransferases; Histones; Lipopolysaccharides; Macrophages; Mice; NADPH Oxidase 1; NADPH Oxidase 4; Promoter Regions, Genetic; Reactive Oxygen Species; Salicylates; Trans-Activators

Topics: Acid-Base Equilibrium; Acidosis; Acute Kidney Injury; Humans; Salicylates

SUMOylation is a form of post-translational modification where small ubiquitin-like modifiers (SUMO) are covalently attached to target proteins to regulate their properties. SUMOylation has been demonstrated during cell stress and implicated in cellular stress response. However, it is largely unclear if SUMOylation contributes to the pathogenesis of kidney diseases, such as acute kidney injury (AKI). Here we have demonstrated a dynamic change of protein SUMOylation in ischemic and cisplatin nephrotoxic AKI in mice. In rat kidney proximal tubular cells (RPTC), cisplatin-induced SUMOylation was diminished by two antioxidants (N-acetylcysteine and dimethylurea), supporting a role of oxidative stress in the activation of SUMOylation. In addition, SUMOylation by SUMO-2/3, but not SUMO-1, was partially suppressed by pifithrin-alpha (a pharmacological inhibitor of p53), supporting a role of p53 in SUMOylation by SUMO-2/3. We further examined the role of SUMOylation during cisplatin treatment of RPTC by using ginkgolic acid (GA), a pharmacological inhibitor of SUMOylation. Pretreatment with GA suppressed SUMOylation and importantly, GA enhanced apoptosis during cisplatin incubation. Taken together, the results demonstrate the first evidence of SUMOylation in AKI and suggest that SUMOylation may play a cytoprotective role in kidney tubular cells.

Topics: Acetylcysteine; Acute Kidney Injury; Animals; Antineoplastic Agents; Apoptosis; Cisplatin; Free Radical Scavengers; HEK293 Cells; Humans; Kidney Tubules, Proximal; Mice; Oxidative Stress; Rats; Salicylates; SUMO-1 Protein; Sumoylation; Tumor Suppressor Protein p53

Topics: Acute Kidney Injury; Adult; Anti-Inflammatory Agents, Non-Steroidal; Humans; Male; Renal Dialysis; Salicylates; Treatment Outcome

A 44-year-old woman with scleroderma and Sjögren's syndrome developed altered consciousness, acute renal failure, and rhabdomyolysis. She had no history of trauma, seizures, alcohol abuse, hyperthermia, or other possible causative factors for rhabdomyolysis. A high serum salicylate level indicated a diagnosis of salicylate intoxication. Medical history after recovery revealed chronic salicylate ingestion for severe headaches. This is possibly the first reported case of rhabdomyolysis caused by chronic salicylate intoxication. Continuous hemodiafiltration early in hospitalization was an effective treatment.

Topics: Acute Kidney Injury; Adult; Female; Hemodiafiltration; Humans; Rhabdomyolysis; Salicylates; Salicylic Acid; Scleroderma, Systemic; Sjogren's Syndrome; Unconsciousness

Intracellular iron reportedly mediates many forms of tissue injury, including ischemic and myohemoglobinuric acute renal failure. This action may be explained by the ability of iron to catalyze the formation of the highly toxic hydroxyl radical (.OH) from H2O2 via the Fenton/Haber-Weiss reactions. To assess whether renal tubular myoglobin/iron loading, induced by a physiological mechanism (endocytosis), alters its susceptibility to O2 deprivation/reoxygenation- and H2O2-mediated injury, rats were infused with myoglobin or its vehicle (5% dextrose, control rats), and after 2 hours, proximal tubular segments (PTSs) were isolated for study. This infusion caused substantial myoglobin endocytic uptake (approximately 25 micrograms/mg PTS protein), and it doubled PTS catalytic iron content (assessed by bleomycin assay). Nevertheless, PTS viability (percent lactate dehydrogenase release) was minimally affected (4% to 6% increase), and an increased .OH burden (assessed by the salicylate trap method) did not appear to result. Deferoxamine addition, reported to protect against in vivo acute renal failure, paradoxically increased .OH levels (approximately 25%) in myoglobin-loaded, but not control, PTSs. Conversely, dimethylthiourea (an .OH scavenger) depressed .OH (by approximately 80%) in all PTSs. Myoglobin/iron loading modestly increased PTS vulnerability to exogenous H2O2 addition (P < .001). However, tubular susceptibility to hypoxia (15 and 30 minutes)/reoxygenation injury was not affected. .OH levels appeared to fall in response to both forms of injury, suggesting decreased .OH production and/or .OH scavenging. To assess whether myoglobin decreases .OH levels in the presence of Fenton reactants, myoglobin and six other test proteins were incubated with Fe2+/H2O2. Myoglobin decreased .OH levels by approximately 70%, a significantly greater decrement than was observed with the other proteins tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Kidney Injury; Animals; Hydrogen Peroxide; Hydroxybenzoates; Hydroxyl Radical; Hypoxia; In Vitro Techniques; Iron; Kidney Tubules, Proximal; L-Lactate Dehydrogenase; Male; Myoglobin; Rats; Rats, Sprague-Dawley; Salicylates

Recent in vivo studies suggest that heme Fe causes proximal tubular lipid peroxidation and cytotoxicity, thereby contributing to the pathogenesis of myoglobinuric (Mgb) acute renal failure. Because hydroxyl radical (.OH) scavengers [dimethylthiourea (DMTU), benzoate, mannitol] can mitigate this injury, it is postulated that .OH is a mediator of Mgb-induced renal damage. The present study has tested these hypotheses using an isolated rat proximal tubular segment (PTS) system. An equal mixture of Fe2+/Fe3+ (4 mM total), when added to PTS, caused marked cytotoxicity [as defined by lactate dehydrogenase (LDH) release] and lipid peroxidation [assessed by malondialdehyde (MDA) increments]. Fe2+ or Fe3+ alone each induced massive MDA elevations, but only Fe2+ caused cytotoxicity. Although both DMTU and benzoate decreased LDH release during the Fe2+/Fe3+ challenge, mannitol and GSH did not, despite equivalent reductions in .OH (gauged by the salicylate trap method). GSH and catalase (but not DMTU, benzoate, or mannitol) decreased MDA concentrations, suggesting the Fe-driven lipid peroxidation was more H2O2 than .OH dependent. Deferoxamine totally blocked Fe-induced LDH release, even under conditions in which it caused an apparent increase in .OH generation. Mgb paradoxically protected against Fe-mediated PTS injury, an effect largely reproduced by albumin. In conclusion, these data suggest that: (a) Fe can cause PTS lipid peroxidation and cytotoxicity by a non-.OH-dependent mechanism; (b) Fe-mediated cytotoxicity and lipid peroxidation are not necessarily linked; and (c) Mgb paradoxically protects PTS against Fe-mediated injury, suggesting that: (i) Mgb Fe may require liberation from its porphyrin ring before exerting toxicity; and (ii) the protein residue may blunt the resulting injury.

Topics: Acute Kidney Injury; Animals; Benzoates; Benzoic Acid; Deferoxamine; Hydroxides; Hydroxyl Radical; In Vitro Techniques; Iron; Kidney Tubules, Proximal; L-Lactate Dehydrogenase; Lipid Peroxidation; Male; Myoglobin; Perfusion; Rats; Rats, Inbred Strains; Salicylates; Superoxide Dismutase; Thiourea

Nonacetylated salicylates have not been reported to cause the hemodynamically mediated acute renal failure associated with nonsteroidal anti-inflammatory drug therapy. A 73-year-old woman with a creatinine clearance of 0.33 mL/s (20 mL/min), hypertension, and arteriosclerotic cardiovascular disease developed reversible renal insufficiency when her dose of salsalate was increased to 4.5 g/d (serum salicylate concentration, 2.22 mmol/L [30.7 mg/dL]). Under close observation the patient was re-treated with lower doses of salsalate while renal function and the urinary excretions of prostaglandins were monitored. The excretion of prostaglandin E2 decreased abruptly while the excretion of 6-keto-prostaglandin F1 alpha decreased more gradually as the dose of salsalate was increased. Renal function appeared to decline in parallel with the decrease in 6-keto-prostaglandin F1 alpha and recovered rapidly after discontinuation of salsalate therapy. Nonacetylated salicylates can cause a hemodynamically mediated acute renal failure in patients at risk for this nephropathy.

Topics: Acute Kidney Injury; Aged; Arthritis; Dinoprostone; Disease Susceptibility; Dose-Response Relationship, Drug; Female; Humans; Prostaglandins; Prostaglandins E; Prostaglandins F; Salicylates

A case of kidney failure in a patient with cirrhosis of the liver in the ascitic stage after treatment of a non-steroid anti-inflammatory drug, diflunisal, is reported. The pathogenesis of the kidney impairment, quickly reversed by withdrawal of the drug, is attributed to pharmacological inhibition of cyclo-oxygenase and prostaglandin synthesis with consequent alterations of intrarenal haemodynamics and renal blood flow.

Topics: Acute Kidney Injury; Diflunisal; Female; Humans; Kidney; Liver Cirrhosis, Alcoholic; Middle Aged; Renal Circulation; Salicylates

Topics: Acute Kidney Injury; Adult; Diflunisal; Humans; Male; Nephritis, Interstitial; Salicylates

Topics: Acute Kidney Injury; Aspirin; Child, Preschool; Female; Humans; Infant; Male; Pulmonary Edema; Renal Dialysis; Salicylates

1 The decreased binding of drugs and dyes to plasma proteins from male and female rats with acute renal failure has been investigated using equilibrium dialysis at 37 degrees C. 2 Acute renal failure induced by bilateral ligation of the ureters produced a greater than threefold increase in the unbound fraction of o-methyl red relative to normal rat plasma. Unbound dye concentration in plasma from sham-operated control rats was also significantly increased but to a lesser extent. 3 Glycerol-induced acute renal failure produced a significant increase in the unbound fractions of o-methyl red, methyl orange, bromocresol green (BCG), 2-(4'-hydroxybenzeneazo) benzoic acid (HABA), phenytoin and salicylic acid. A marginally significant increase in unbound warfarin concentration was observed. 4 Glycerol-induced renal failure had no effect on total plasma protein concentration and experiments with o-methyl red and salicylic acid indicated that a direct effect of glycerol was not responsible for the diminution of binding. 5 Glycerol-induced acute renal failure, which produced decreases in drug and dye binding similar to those reported for human uraemic plasma, provides a convenient non-surgical animal model for the investigation of this phenomenon.

Topics: Acute Kidney Injury; Animals; Blood Proteins; Coloring Agents; Creatinine; Disease Models, Animal; Female; Glycerol; Male; Phenytoin; Rats; Salicylates; Sex Factors; Urea; Ureter; Warfarin

Topics: 1-Propanol; Acute Kidney Injury; Aged; Albumins; Antidepressive Agents; Antihypertensive Agents; Benzyl Compounds; Cephaloridine; Coumarins; Digitoxin; Diuretics; Drug Interactions; Ethacrynic Acid; Guanethidine; Guanidines; Heart; Heart Block; Heart Conduction System; Humans; Hypoglycemia; Hypotension; Kidney; Pancreas; Phenylbutazone; Salicylates; Sympathetic Nervous System; Tolbutamide; Warfarin

Topics: Acute Kidney Injury; Aged; Aspirin; Blood Proteins; Female; Humans; In Vitro Techniques; Male; Middle Aged; Phenylbutazone; Phenytoin; Protein Binding; Salicylates; Serum Albumin; Sulfadiazine; Thiopental

Topics: Acidosis; Acute Kidney Injury; Adrenal Insufficiency; Alkalosis; Alkalosis, Respiratory; Carbohydrates; Dehydration; Diabetic Ketoacidosis; Electrolytes; Heat Exhaustion; Humans; Hyperkalemia; Hypernatremia; Hypokalemia; Hyponatremia; Nutritional Requirements; Parenteral Nutrition; Potassium Deficiency; Proteins; Pyloric Stenosis; Salicylates; Shock; Sodium; Vitamins; Water Intoxication

Topics: Acute Kidney Injury; Adolescent; Adult; Aged; Barbiturates; Child; Female; Glutethimide; Humans; Kidney Function Tests; Male; Methods; Middle Aged; Norway; Poisoning; Renal Dialysis; Salicylates; Statistics as Topic; Time Factors

Topics: Acute Disease; Acute Kidney Injury; Humans; Poisoning; Renal Dialysis; Salicylates; Suicide

Topics: Acute Kidney Injury; Adult; Benzoates; Burns, Electric; Humans; Malates; Male; Necrosis; Ointments; Paralysis; Peripheral Nervous System Diseases; Radial Nerve; Salicylates

Topics: Acidosis; Acute Kidney Injury; Alcoholism; Anuria; Child; Diabetes Mellitus; Dialysis; Humans; Hypertension; Hypertension, Malignant; Hyponatremia; Malaria; Peritoneal Dialysis; Poisoning; Renal Dialysis; Renal Insufficiency; Salicylates; Uremia

Topics: Acute Kidney Injury; Barbiturates; Dialysis; Kidneys, Artificial; Peritoneal Dialysis; Peritoneum; Poisoning; Renal Dialysis; Renal Insufficiency; Salicylates; Toxicology

Topics: Acute Kidney Injury; Aspirin; Blood Chemical Analysis; Bronchopneumonia; Coma; Diagnosis, Differential; Diuresis; Gastric Lavage; Heart Arrest; Heart Failure; Humans; Infusions, Parenteral; Kidney; Kidneys, Artificial; Phenacetin; Poisoning; Pulmonary Edema; Renal Insufficiency; Salicylates; Statistics as Topic; Toxicology

Topics: Acute Kidney Injury; Humans; Kidney; Kidneys, Artificial; Salicylates

Topics: Acute Kidney Injury; Humans; Kidney; Salicylates

Topics: Acute Kidney Injury; Aspirin; Humans; Salicylates