DOCSLIB.ORG

Drug-Induced Nephrotoxicity

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Drug-Induced Nephrotoxicity Drug-induced nephrotoxicity Gabriel Teixeira Montezuma Sales1 Renato Demarchi Foresto² 1. Universidade Federal de São Paulo, São Paulo, SP, Brasil 2. Hospital do Rim, São Paulo, SP, Brasil http://dx.doi.org/10.1590/1806-9282.66.S1.82 SUMMARY Acute kidney injury is a very common diagnosis, present in up to 60% of critical patients, and its third main cause is drug toxicity. Nephrotoxicity can be defined as any renal injury caused directly or indirectly by medications, with acute renal failure, tubulopathies, and glomerulopathies as common clinical presentations. Some examples of drugs commonly associated with the acute reduction of glomerular filtration rate are anti-inflammatories, antibiotics, such as vancomycin and aminoglycosides, and chemotherapeutic agents, such as cisplatin and methotrexate. Cases of tubulopathy are very common with amphotericin B, polymyxins, and tenofovir, and cases of glomerulopathies are common with VEGF inhibitors, bisphosphonates, and immunotherapy, and it is also common to have more than one clinical presentation related to a single agent. Early diagnosis is essential for the good evolution of the patient, with a reduction of renal exposure to the toxic agent, which requires knowing the risk factors and biomarkers. General measures such as correcting hydro- electrolytic disorders and hypovolemia, monitoring the serum level, avoiding combinations with the synergy of renal injury, and looking for similar options that are less toxic are the foundations for the treatment of complications that are still common and often preventable. KEYWORDS: Drug-related side effects and adverse reactions. Acute kidney injury. Kidney tubules. INTRODUCTION Acute kidney injury (AKI) is a very common diag- scale. The reason for such high rates of drug-induced nosis in both hospital and pre-hospital environments kidney injury is the function of drug and metabolite and may reach 60% of patients hospitalized in an inten- excretion performed by the kidneys, with the conse- sive therapy unit. There has been a growth in its inci- quent exposure of its structures with high energy need dence in recent decades, which can be explained by an (glomeruli and tubules) to the high concentration of increase in risk factors such as advanced age, chronic exogenous substances2.3. kidney disease (CKD), and diabetes mellitus. Epidemi- Drug-induced nephrotoxicity is defined by the pres- ological studies show that nephrotoxicity is the third ence of any kidney injury caused directly or indirectly most common cause of AKD (Acute Kidney Disease), by medication. The presentation varies from an acute which has become worst in recent decades due to the or chronic reduced glomerular filtration rate (GFR) to more frequent use of drugs with the potential to cause nephrotic syndrome and hydroelectrolytic disorders kidney damage, with studies showing a frequency up (HED) related, respectively, to glomerular and tubular to 20% of nephrotoxic drug use in critical patients1. damage. For epidemiological purposes, most studies Although safety studies are necessary for the only consider an increase in creatinine, hindering a release of new drugs, side effects are often detected precise analysis of the true magnitude of the problem1. only after they are put into the market, when they The loss of GFR is a late marker of kidney injury, start being used by different populations on a global and other biomarkers are being researched to allow CORRESPONDING AUTHOR: Gabriel Teixeira Montezuma Sales Email: [email protected] REV ASSOC MED BRAS 2020; 66(SUPPL 1):S:82-S90 82 SALES, G. T. M. AND FORESTO, R. D. for an earlier intervention, which could improve the A common problem when investigating the main prognosis of these patients. Although there is no ben- etiology of AKI is the absence of tests to define the efit proven by high-quality studies, there are some predominant mechanism of the injury. In clinical promising candidates: practice, it is common to have patients that are sep- • KIM - 1 (Kidney Injury Molecule - V1), adhesion tic, hypotensive, with signs of dehydration, and on molecule produced in the proximal convoluted tubule medication that is possibly toxic, all common causes (PCT), which is increased in urinary concentration in of kidney injury. situations of ischemia and drug toxicity, with accu- To suggest causality, some criteria are proposed6: racy demonstrated for cisplatin, gentamicin, and • Exposure to the agent for at least 24 hours. cyclosporine, in some cases with increase 48 hours • Injury mechanism related to a drug compatible after the introduction of the toxic agent and before with the condition presented. the GFR reduction. • Investigation of other causes of nephropathy with • Beta-2 microglobulin is a protein produced mainly evolution or clinical manifestations that are not com- by lymphocytes that increases its urine concentration pletely compatible. in inflammatory diseases, including infections, and Knowing the risk populations is essential for the autoimmune diseases. It is filtered at the glomeru- prevention and early diagnosis of nephrotoxicity. lus, reabsorbed in the TCP, and considered a marker The main risk factors are related to the reduction of of tubular injury. A study on kidney transplantation the renal functional reserve (glomeruli without the showed an increase before the worsening of kidney ability to increase the filtration rate), a larger con- function in patients with toxicity by calcineurin inhibi- centration of drugs on the tubules, and synergistic tor (CNi), with high accuracy to differentiate rejection. injury mechanisms. Some examples are drugs with • Clusterin, a protein involved in the process of vasoconstrictor effect associated with diuretics and apoptosis and antiapoptosis found in various organs, drugs that compete for the transporter responsible including the kidney. It is not filtered and, in the for tubular secretion, increasing the cytoplasm con- tubules, is produced in stress situations to prevent cell centration, such as in the combination of cisplatin death. Its greater accuracy in the diagnosis of tubu- and aminoglycoside7. lar damage has been demonstrated, when compared to creatinine, with the use of cisplatin, vancomycin, TABLE 1. RISK FACTORS RELATED TO NEPHROTOXICITY tacrolimus, and gentamicin. It presents as much early BY DRUGS increase as KIM-1 and does not increase in patients Advanced age Hypovolemia Chronic kidney disease with glomerular damage. >1 nephrotoxic Hypoalbuminemia Cardiopathy • Cystatin C, a protein produced by all nucleated Genetic polymor- Diabetes Obesity cells and filtered freely. It is completely reabsorbed in phisms the proximal tubule and classically used as a way of High doses Hypotension estimating the GFR in conditions under stable kidney function conditions, in which the creatinine clearance Renal toxicity can be divided into dose-dependent is less reliable, such as in cirrhotic patients. Studies on and idiosyncratic. In the first type, both the prevention amphotericin B, polymyxin, vancomycin, and cisplatin and the treatment involve minimizing the duration have shown a better correlation with renal toxicity and concentration of the drug, especially in situations when compared to creatinine4. associated with higher risk, such as the concomitant use of other nephrotoxic substances, renal ischemia, and patients with CKD. In the second type, there are EPIDEMIOLOGY few measures associated with the prevention and, in The AKI epidemiology varies according to the cri- general, the treatment involves completely avoiding teria used and the profile of the hospitals included in the drug. Examples of the first type are vancomycin, each study, but the proportion related to drug toxicity aminoglycosides, cisplatin, methotrexate, nonsteroi- reaches 25% of the cases. Approximately 20% of the dal anti-inflammatories, while the second are causes cases require renal replacement therapy, which is of acute interstitial nephritis, like proton pump inhib- related to increased mortality, with rates of over 60% itors, beta-lactams, and some causes of thrombotic in developing countries1.5. microangiopathy (TMA), such as CNi. 83 REV ASSOC MED BRAS 2020; 66(SUPPL 1):S:82-S90 DRUG-INDUCED NEPHROTOXICITY TABLE 2. COMBINATIONS OF DRUGS WITH SYNERGISTIC NEPHROTOXICITY choosing other options for analgesia in patients with Cyclosporine/NSAIDS + Diuretic/ACEI/ARB increased risk of AKI, maintaining it for the minimum Aminoglycoside + Cisplatin/Cephalothin time possible, and correcting hypovolemia when Vancomycin + Piperacillin-tazobactam present8.9. Cyclosporine + Simvastatin Methotrexate + Penicillins/Salicylate/Sulfas VANCOMYCIN To facilitate the diagnostic approach, it is important A widely used antibiotics against gram-positive to know the clinical manifestations that are charac- hospital bacteria, it is a cause of AKI in 5 to 15% of the teristic of each nephrotoxic drug; some of the most patients, depending on different specific risk factors, common are acute and chronic reduction of GFR, such as daily dose > 4g, treatment time > 14 days, tubulopathies, and glomerulopathies, which will be and high serum concentration, although there are illustrated below. To make matters more complicated, cases even at therapeutic level (15 to 20 mg/L). Oral several agents present mixed characteristics, and it is vancomycin, due to its low absorption, is not a cause common to have non-oliguric AKI with signs of PCT of toxicity. injury. We will not include drugs whose mechanisms The injury mechanism is
Load more

Recommended publications
  • Activity of Cefepime-Zidebactam Against Multidrug-Resistant (MDR) Gram-Negative Pathogens
    antibiotics Article Activity of Cefepime-Zidebactam against Multidrug-Resistant (MDR) Gram-Negative Pathogens Kenneth S. Thomson 1,* , Sameh AbdelGhani 1,2, James W. Snyder 1 and Gina K. Thomson 1,3 1 Department of Pathology and Laboratory Medicine, School of Medicine, University of Louisville, Louisville, KY 40202, USA; [email protected] (S.A.); [email protected] (J.W.S.); [email protected] (G.K.T.) 2 Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62511, Egypt 3 Microbiology Department, University of Louisville Hospital, Louisville, KY 40202, USA * Correspondence: [email protected] Received: 18 February 2019; Accepted: 19 March 2019; Published: 23 March 2019 Abstract: This study compared the activity of cefepime + zidebactam (FEP-ZID) and selected currently available antibacterial agents against a panel of multidrug-resistant (MDR) clinical isolates chosen to provide an extreme challenge for antibacterial activity. FEP–ZID had a very broad and potent in vitro spectrum of activity, and was highly active against many MDR isolates of Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii. Notably, it inhibited isolates producing carbapenemases of Ambler classes A, B, and D, and P. aeruginosa isolates with multiple resistance mechanisms including combinations of upregulated efflux, diminished or non-functional OprD porins, and AmpC overproduction. Its clinical role will be determined initially by the breakpoints assigned to it, comparison studies with other investigational β-lactamase inhibitor combinations, and ultimately by the developing body of therapeutic outcome data. Keywords: carbapenemase-producing organism; carbapenemase; zidebactam; therapy 1. Introduction Gram-negative multidrug-resistant (MDR) pathogens, particularly carbapenemase-producing organisms (CPOs), cause infections of high mortality that are typically treated with antibiotic combinations that include toxic drugs such as polymyxins and aminoglycosides [1].
    [Show full text]
  • Inherited Renal Tubulopathies—Challenges and Controversies
    G C A T T A C G G C A T genes Review Inherited Renal Tubulopathies—Challenges and Controversies Daniela Iancu 1,* and Emma Ashton 2 1 UCL-Centre for Nephrology, Royal Free Campus, University College London, Rowland Hill Street, London NW3 2PF, UK 2 Rare & Inherited Disease Laboratory, London North Genomic Laboratory Hub, Great Ormond Street Hospital for Children National Health Service Foundation Trust, Levels 4-6 Barclay House 37, Queen Square, London WC1N 3BH, UK; [email protected] * Correspondence: [email protected]; Tel.: +44-2381204172; Fax: +44-020-74726476 Received: 11 February 2020; Accepted: 29 February 2020; Published: 5 March 2020 Abstract: Electrolyte homeostasis is maintained by the kidney through a complex transport function mostly performed by specialized proteins distributed along the renal tubules. Pathogenic variants in the genes encoding these proteins impair this function and have consequences on the whole organism. Establishing a genetic diagnosis in patients with renal tubular dysfunction is a challenging task given the genetic and phenotypic heterogeneity, functional characteristics of the genes involved and the number of yet unknown causes. Part of these difficulties can be overcome by gathering large patient cohorts and applying high-throughput sequencing techniques combined with experimental work to prove functional impact. This approach has led to the identification of a number of genes but also generated controversies about proper interpretation of variants. In this article, we will highlight these challenges and controversies. Keywords: inherited tubulopathies; next generation sequencing; genetic heterogeneity; variant classification. 1. Introduction Mutations in genes that encode transporter proteins in the renal tubule alter kidney capacity to maintain homeostasis and cause diseases recognized under the generic name of inherited tubulopathies.
    [Show full text]
  • Neomycin and Polymyxin B Sulfates and Gramicidin
    NEOMYCIN AND POLYMYXIN B SULFATES AND GRAMICIDIN- neomycin sulfate, polymyxin b sulfate and gramicidin solution/ drops A-S Medication Solutions ---------- Neomycin and Polymyxin B Sulfates and Gramicidin Ophthalmic Solution, USP (Sterile) Rx only DESCRIPTION: Neomycin and Polymyxin B Sulfates and Gramicidin Ophthalmic Solution, USP is a sterile antimicrobial solution for ophthalmic use. Each mL contains: ACTIVES: Neomycin Sulfate, (equivalent to 1.75 mg neomycin base), Polymyxin B Sulfate equal to 10,000 Polymyxin B units, Gramicidin, 0.025 mg; INACTIVES: Sodium Chloride, Alcohol (0.5%), Poloxamer 188, Propylene Glycol, Purified Water. Hydrochloric Acid and/ or Ammonium Hydroxide may be added to adjust pH (4.7-6.0). PRESERVATIVE ADDED: Thimerosal 0.001%. Neomycin Sulfate is the sulfate salt of neomycin B and C, which are produced by the growth of Streptomyces fradiae Waksman (Fam. Streptomycetaceae). It has a potency equivalent of not less than 600 micrograms of neomycin base per milligram, calculated on an anhydrous basis. The structural formulae are: Polymyxin B Sulfate is the sulfate salt of polymyxin B1 and B2 which are produced by the growth of Bacillus polymyxa (Prazmowski) Migula (Fam. Bacillaceae). It has a potency of not less than 6,000 polymyxin B units per milligram, calculated on an anhydrous basis. The structural formulae are: Gramicidin (also called gramicidin D) is a mixture of three pairs of antibacterial substances (Gramicidin A, B and C) produced by the growth of Bacillus brevis Dubos (Fam. Bacillaceae). It has a potency of not less than 900 mcg of standard gramicidin per mg. The structural formulae are: CLINICAL PHARMACOLOGY: A wide range of antibacterial action is provided by the overlapping spectra of neomycin, polymyxin B sulfate, and gramicidin.
    [Show full text]
  • Effect of Renin-Angiotensin System Inhibitors on the Comparative Nephrotoxicity of Nsaids and Opioids During Hospitalization
    Kidney360 Publish Ahead of Print, published on April 27, 2020 as doi:10.34067/KID.0001432020 Effect of renin-angiotensin system inhibitors on the comparative nephrotoxicity of NSAIDs and opioids during hospitalization Todd A. Miano1,2,3; Michael G. S. Shashaty2,4; Wei Yang1,2,3; Jeremiah R. Brown5,6,7; Athena Zuppa8; Sean Hennessy1,2,3 Affiliations: 1. Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine at the University of Pennsylvania 2. Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania 3. Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania 4. Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine at the University of Pennsylvania 5. The Dartmouth Institute for Health Policy and Clinical Practice, Lebanon, New Hampshire 6. Department of Epidemiology, Geisel School of Medicine, Hanover, New Hampshire 7. Department of Biomedical Data Science, Geisel School of Medicine, Hanover, New Hampshire 8. Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA Corresponding author: Todd A. Miano, PharmD, PhD; Address: 423 Guardian Drive, 725 Blockley Hall, Philadelphia, PA 19104; E-mail: [email protected] ; twitter: @Miano81 Copyright 2020 by American Society of Nephrology. Abstract Background: Nonsteroidal anti-inflammatory drugs (NSAIDS) are increasingly important alternatives to opioids for analgesia during hospitalization, as health systems implement opioid minimization initiatives. Increasing NSAID use may increase acute kidney injury (AKI) rates, particularly in patients with predisposing risk factors. Inconclusive data in outpatient populations suggests that NSAID nephrotoxicity is magnified by renin-angiotensin system inhibitors (RAS-I).
    [Show full text]
  • Farrukh Javaid Malik
    I Farrukh Javaid Malik THESIS PRESENTED TO OBTAIN THE GRADE OF DOCTOR OF THE UNIVERSITY OF BORDEAUX Doctoral School, SP2: Society, Politic, Public Health Specialization Pharmacoepidemiology and Pharmacovigilance By Farrukh Javaid Malik “Analysis of the medicines panorama in Pakistan – The case of antimicrobials: market offer width and consumption.” Under the direction of Prof. Dr. Albert FIGUERAS Defense Date: 28th November 2019 Members of Jury M. Francesco SALVO, Maître de conférences des universités – praticien hospitalier, President Université de Bordeaux M. Albert FIGUERAS, Professeur des universités – praticien hospitalier, Director Université Autonome de Barcelone Mme Antonia AGUSTI, Professeure, Vall dʹHebron University Hospital Referee Mme Montserrat BOSCH, Praticienne hospitalière, Vall dʹHebron University Hospital Referee II Abstract A country’s medicines market is an indicator of its healthcare system, the epidemiological profile, and the prevalent practices therein. It is not only the first logical step to study the characteristics of medicines authorized for marketing, but also a requisite to set up a pharmacovigilance system, thus promoting rational drug utilization. The three medicines market studies presented in the present document were conducted in Pakistan with the aim of describing the characteristics of the pharmaceutical products available in the country as well as their consumption at a national level, with a special focus on antimicrobials. The most important cause of antimicrobial resistance is the inappropriate consumption of antimicrobials. The results of the researches conducted in Pakistan showed some market deficiencies which could be addressed as part of the national antimicrobial stewardship programmes. III Résumé Le marché du médicament d’un pays est un indicateur de son système de santé, de son profil épidémiologique et des pratiques [de prescription] qui y règnent.
    [Show full text]
  • Effects of Ramipril in Nondiabetic Nephropathy: Improved Parameters of Oxidatives Stress and Potential Modulation of Advanced Glycation End Products
    Journal of Human Hypertension (2003) 17, 265–270 & 2003 Nature Publishing Group All rights reserved 0950-9240/03 $25.00 www.nature.com/jhh ORIGINAL ARITICLE Effects of ramipril in nondiabetic nephropathy: improved parameters of oxidatives stress and potential modulation of advanced glycation end products KSˇ ebekova´1, K Gazdı´kova´1, D Syrova´2, P Blazˇı´cˇek2, R Schinzel3, A Heidland3, V Spustova´1 and R Dzu´ rik 1Institute of Preventive and Clinical Medicine, Bratislava, Slovakia; 2Military Hospital, Bratislava, Slovakia; 3University Wuerzburg, Germany Enhanced oxidative stress is involved in the progres- patients on conventional therapy did not differ signifi- sion of renal disease. Since angiotensin converting cantly from the ramipril group, except for higher Hcy enzyme inhibitors (ACEI) have been shown to improve levels in the latter. Administration of ramipril resulted in the antioxidative defence, we investigated, in patients a drop in blood pressure and proteinuria, while creati- with nondiabetic nephropathy, the short-term effect of nine clearance remained the same. The fluorescent the ACEI ramipril on parameters of oxidative stress, AGEs exhibited a mild but significant decline, yet CML such as advanced glycation end products (AGEs), concentration was unchanged. The AOPP and malon- advanced oxidation protein products (AOPPs), homo- dialdehyde concentrations decreased, while a small rise cysteine (Hcy), and lipid peroxidation products. Ramipril in neopterin levels was evident after treatment. The (2.5–5.0 mg/day) was administered to 12 newly diag- mentioned parameters were not affected significantly in nosed patients for 2 months and data compared with a the conventionally treated patients. Evidence that rami- patient group under conventional therapy (diuretic/ pril administration results in a mild decline of fluores- b-blockers) and with age- and sex-matched healthy cent AGEs is herein presented for the first time.
    [Show full text]
  • Non-Steroidal Anti-Inflammatory Nephrotoxicity* RICHARD MANIGLIA, B.A.T ALLAN B
    ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 18, No. 3 Copyright © 1988, Institute for Clinical Science, Inc. Non-Steroidal Anti-Inflammatory Nephrotoxicity* RICHARD MANIGLIA, B.A.t ALLAN B. SCHWARTZ, M.D.,$ and SHEILA MORIBER-KATZ, M.D.f§ f Department of Pathology and Laboratory Medicine, tDepartment of Medicine, §Division of Renal Pathology and Electron Microscopy, Hahnemann University School of Medicine, Philadelphia, PA 19102 ABSTRACT Non-steroidal anti-inflammatory drugs have a wide range of use in clini­ cal practice because of their analgesic and anti-inflammatory properties. However, their potential nephrotoxicity has been noted. The case histo­ ries were studied, retrospectively, in 13 patients who were taking non-ste- roidal anti-inflammatory drugs as follows: four on fenoprofen (Nalfon®), three on naproxen (Naprosyn®), two on ibuprofen (Motrin®), two on sulin- dac (Clinoril®), one on tolmetin (Tolectin®), and one on indomethacin (Indocin®) and who exhibited abnormal urinalysis or a deterioration in renal function. Nine of the patients underwent renal biopsies, and eight of these biopsies were positive for interstitial nephritis. In addition to the presentation of additional cases of non-steroidal anti-inflammatory drug nephrotoxicity, a brief review of the current theories of the nephrotoxic mechanism is presented. Introduction this paper will be the non-aspirin, non­ steroidal anti-inflammatory drugs Numerous reports exist that document (NSAID). Since these drugs have a wide the nephrotoxicity of drugs such as the spectrum of use in clinical practice, their synthetic penicillin (methacillin, carben- deleterious actions are of more than just icillin, ampicillin), other antibiotics academic interest. It is hoped that by (aminoglycosides, amphotericin B), understanding the nephrotoxic patho­ thiazide and loop diuretics, and anti­ physiologic mechanisms of non-steroidal neoplastic agents.
    [Show full text]
  • Rational Design and Synthesis of Modified Teixobactin Analogues: Ng, Vivian; Kuehne, Sarah A; Chan, Weng
    University of Birmingham Rational design and synthesis of modified teixobactin analogues: Ng, Vivian; Kuehne, Sarah A; Chan, Weng DOI: 10.1002/chem.201801423 License: Other (please specify with Rights Statement) Document Version Peer reviewed version Citation for published version (Harvard): Ng, V, Kuehne, SA & Chan, W 2018, 'Rational design and synthesis of modified teixobactin analogues: in vitro antibacterial activity against Staphylococcus aureus, Propionibacterium acnes and Pseudomonas aeruginosa', Chemistry: A European Journal. https://doi.org/10.1002/chem.201801423 Link to publication on Research at Birmingham portal Publisher Rights Statement: This is the peer reviewed version of the following article: Ng, V. , Kuehne, S. and Chan, W. (2018), Rational design and synthesis of modified teixobactin analogues: in vitro antibacterial activity against Staphylococcus aureus, Propionibacterium acnes and Pseudomonas aeruginosa. Chem. Eur. J.. Accepted Author Manuscript. doi:10.1002/chem.201801423, which has been published in final form at 10.1002/chem.201801423. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self- Archiving. General rights Unless a licence is specified above, all rights (including copyright and moral rights) in this document are retained by the authors and/or the copyright holders. The express permission of the copyright holder must be obtained for any use of this material other than for purposes permitted by law. •Users may freely distribute the URL that is used to identify this publication. •Users may download and/or print one copy of the publication from the University of Birmingham research portal for the purpose of private study or non-commercial research.
    [Show full text]
  • Pathophysiologic Mechanisms of Selected Types of Nephrotoxicity 3/12/14, 10:45 AM
    Pathophysiologic Mechanisms of Selected Types of Nephrotoxicity 3/12/14, 10:45 AM Today News Reference Education Log In Register Pathophysiologic Mechanisms of Selected Types of Nephrotoxicity Author: Piper Julie Hughes, MD, MS; Chief Editor: Vecihi Batuman, MD, FACP, FASN more... Updated: Dec 18, 2013 Aminoglycoside Nephrotoxicity Aminoglycosides preferentially affect the proximal tubular cells. These agents are freely filtered by the glomeruli and quickly taken up by the proximal tubular epithelial cells, where they are incorporated into lysosomes after first interacting with phospholipids on the brush border membranes. They exert their main toxic effect within the tubular cell by altering phospholipid metabolism. In addition to their direct effect on cells, aminoglycosides cause renal vasoconstriction. The 2 critical factors in the development of acute kidney injury (AKI) secondary to aminoglycoside nephrotoxicity are dosing and duration of therapy. Aminoglycoside uptake by the tubules is a saturable phenomenon, so uptake is limited after a single dose. Thus, a single daily large dose is preferable to 3 doses per day. One dose per day presumably causes less accumulation in the tubular cells once the saturation point is reached.[1, 2] For further information, go to Acute Renal Failure and Acute Tubular Necrosis. Amphotericin B Nephrotoxicity Amphotericin B binds to sterols in cell membranes, thereby creating pores that compromise membrane integrity and increase membrane permeability. It binds not only to ergosterol in fungal cell walls but also to cholesterol in human cell membranes; this is what accounts for its nephrotoxicity. Characteristic electrolyte abnormalities include wasting of potassium and magnesium secondary to increased permeability of the cell membranes.
    [Show full text]
  • April 2020 Radar Diagnoses and Cohorts the Following Table Shows
    RaDaR Diagnoses and Cohorts The following table shows which cohort to enter each patient into on RaDaR Diagnosis RaDaR Cohort Adenine Phosphoribosyltransferase Deficiency (APRT-D) APRT Deficiency AH amyloidosis MGRS AHL amyloidosis MGRS AL amyloidosis MGRS Alport Syndrome Carrier - Female heterozygote for X-linked Alport Alport Syndrome (COL4A5) Alport Syndrome Carrier - Heterozygote for autosomal Alport Alport Syndrome (COL4A3, COL4A4) Alport Syndrome Alport Anti-Glomerular Basement Membrane Disease (Goodpastures) Vasculitis Atypical Haemolytic Uraemic Syndrome (aHUS) aHUS Autoimmune distal renal tubular acidosis Tubulopathy Autosomal recessive distal renal tubular acidosis Tubulopathy Autosomal recessive proximal renal tubular acidosis Tubulopathy Autosomal Dominant Polycystic Kidney Disease (ARPKD) ADPKD Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) ADTKD Autosomal Recessive Polycystic Kidney Disease (ARPKD) ARPKD/NPHP Bartters Syndrome Tubulopathy BK Nephropathy BK Nephropathy C3 Glomerulopathy MPGN C3 glomerulonephritis with monoclonal gammopathy MGRS Calciphylaxis Calciphylaxis Crystalglobulinaemia MGRS Crystal-storing histiocytosis MGRS Cystinosis Cystinosis Cystinuria Cystinuria Dense Deposit Disease (DDD) MPGN Dent Disease Dent & Lowe Denys-Drash Syndrome INS Dominant hypophosphatemia with nephrolithiasis or osteoporosis Tubulopathy Drug induced Fanconi syndrome Tubulopathy Drug induced hypomagnesemia Tubulopathy Drug induced Nephrogenic Diabetes Insipidus Tubulopathy Epilepsy, Ataxia, Sensorineural deafness, Tubulopathy
    [Show full text]
  • Polymyxin B April 2019 Background Polymyxin B Injection Is Available
    Polymyxin B April 2019 Background . Polymyxin B injection is available for inpatient use. This product is being used by the irrigation mode of administration. The proposal is to implement the intravenous route of administration with restrictions for use. Several changes were made to the FDA drug approval process in the 1960s which is after the time (1951) when polymyxin B was originally approved by the FDA.1,2 The approval process for polymyxin B was different than medications that are approved today. Thus, there is a lack of robust clinical trials on polymyxin B’s efficacy, safety and pharmacokinetics. Efficacy Polymyxin B was FDA approved for acute infections caused by susceptible strains of Pseudomonas aeruginosa and for serious infections caused by the following organisms (if susceptible) when other less toxic drugs are ineffective or contraindicated: H. influenzae (meningeal, IT route), Escherichia coli (UTI), Aerobacter (Klebsiella) aerogenes (bacteremia), Klebsiella pneumoniae (bacteremia).3 It should be noted that this drug did not go through the modern drug development process and thus, pharmacokinetic evidence since its approval has indicated that it is not appropriate for UTIs. Guidelines indicate that polymyxin B is the preferred polymyxin therapy for systemic use in invasive infections other than UTIs.5 Safety Polymyxin B has several black box warnings (BBW): administration by the IM and IT routes should only be done in hospitalized patients, nephrotoxicity and neurotoxicity can occur, safe use in pregnancy has not been established,
    [Show full text]
  • Synthesis and Structure−Activity Relationships of Teixobactin
    Ann. N.Y. Acad. Sci. ISSN 0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Special Issue: Antimicrobial Therapeutics Reviews REVIEW Synthesis and structure−activity relationships of teixobactin John A. Karas,1 Fan Chen,1 Elena K. Schneider-Futschik,1,2 Zhisen Kang,1 Maytham Hussein,1 James Swarbrick,1 Daniel Hoyer,1,3,4 Andrew M. Giltrap,5 Richard J. Payne,5 Jian Li,6 and Tony Velkov1 1Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, the University of Melbourne, Parkville, Victoria, Australia. 2Lung Health Research Centre, Department of Pharmacology & Therapeutics, the University of Melbourne, Parkville, Victoria, Australia. 3The Florey Institute of Neuroscience and Mental Health, the University of Melbourne, Parkville, Victoria, Australia. 4Department of Molecular Medicine, the Scripps Research Institute, La Jolla, California. 5School of Chemistry, the University of Sydney, Sydney, New South Wales, Australia. 6Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, Victoria, Australia Address for correspondence: Tony Velkov and John A. Karas, Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, the University of Melbourne, Parkville, VIC 3010, Australia. [email protected] OR [email protected] The discovery of antibiotics has led to the effective treatment of bacterial infections that were otherwise fatal and has had a transformative effect on modern medicine. Teixobactin is an unusual depsipeptide natural product that was recently discovered from a previously unculturable soil bacterium and found to possess potent antibacterial activity against several Gram positive pathogens, including methicillin-resistant Staphylococcus aureus and vancomycin- resistant Enterococci.
    [Show full text]