Mechanisms of antimicrobial-induced nephrotoxicity in children.

2019

2019 Aug 01

1460-2091

<p>Drug-induced nephrotoxicity is responsible for 20% to 60% of cases of acute kidney injury in hospitalized patients and is associated with increased morbidity and mortality in both children and adults. Antimicrobials are one of the most common classes of medications prescribed globally and also among the most common causes of nephrotoxicity. A broad range of antimicrobial agents have been associated with nephrotoxicity, but the features of kidney injury vary based on the agent, its mechanism of injury and the site of toxicity within the kidney. Distinguishing nephrotoxicity caused by an antimicrobial agent from other potential inciting factors is important to facilitate both early recognition of drug toxicity and prompt cessation of an offending drug, as well as to avoid unnecessary discontinuation of an innocuous therapy. This review will detail the different types of antimicrobial-induced nephrotoxicity: acute tubular necrosis, acute interstitial nephritis and obstructive nephropathy. It will also describe the mechanism of injury caused by specific antimicrobial agents and classes (vancomycin, aminoglycosides, polymyxins, antivirals, amphotericin B), highlight the toxicodynamics of these drugs and provide guidance on administration or monitoring practices that can mitigate toxicity, when known. Particular attention will be paid to paediatric patients, when applicable, in whom nephrotoxin exposure is an often-underappreciated cause of kidney injury.</p>

10.1093/jac/dkz325

J. Antimicrob. Chemother.

31369087

Association of Acute Kidney Injury With Concomitant Vancomycin and Piperacillin/Tazobactam Treatment Among Hospitalized Children.

2017

e173219

2017 Oct 02

2168-6211

<p><strong>Importance: </strong>β-Lactam antibiotics are often coadministered with intravenous (IV) vancomycin hydrochloride for children with suspected serious infections. For adults, the combination of IV vancomycin plus piperacillin sodium/tazobactam sodium is associated with a higher risk of acute kidney injury (AKI) compared with vancomycin plus 1 other β-lactam antibiotic. However, few studies have evaluated the safety of this combination for children.</p>

<p><strong>Objective: </strong>To assess the risk of AKI in children during concomitant therapy with vancomycin and 1 antipseudomonal β-lactam antibiotic throughout the first week of hospitalization.</p>

<p><strong>Design, Setting, and Participants: </strong>This retrospective cohort study focused on children hospitalized for 3 or more days who received IV vancomycin plus 1 other antipseudomonal β-lactam combination therapy at 1 of 6 large children's hospitals from January 1, 2007, through December 31, 2012. The study used the Pediatric Health Information System Plus database, which contains administrative and laboratory data from 6 pediatric hospitals in the United States. Patients with underlying kidney disease or abnormal serum creatinine levels on hospital days 0 to 2 were among those excluded. Patients 6 months to 18 years of age who were admitted through the emergency department of the hospital were included. Data were collected from July 2015 to March 2016. Data analysis took place from April 2016 through July 2017. (Exact dates are not available because the data collection and analysis processes were iterative.).</p>

<p><strong>Main Outcomes and Measures: </strong>The primary outcome was AKI on hospital days 3 to 7 and within 2 days of receiving combination therapy. Acute kidney injury was defined using KDIGO criteria and was based on changes in serum creatinine level from hospital days 0 to 2 through hospital days 3 to 7. Multiple logistic regression was performed using a discrete-time failure model to test the association between AKI and receipt of IV vancomycin plus piperacillin/tazobactam or vancomycin plus 1 other antipseudomonal β-lactam antibiotic.</p>

<p><strong>Results: </strong>A total of 1915 hospitalized children who received combination therapy were identified. Of the 1915 patients, a total of 866 (45.2%) were female and 1049 (54.8%) were male, 1049 (54.8%) were identified as white in race/ethnicity, and the median (interquartile range) age was 56 (2.1-12.7) years. Among the cohort who received IV vancomycin plus 1 other antipseudomonal β-lactam antibiotic, 157 patients (8.2%) had antibiotic-associated AKI. This number included 117 of 1009 patients (11.7%) who received IV vancomycin plus piperacillin/tazobactam combination therapy. After adjustment for age, intensive care unit level of care, receipt of nephrotoxins, and hospital, IV vancomycin plus piperacillin/tazobactam combination therapy was associated with higher odds of AKI each hospital day compared with vancomycin plus 1 other antipseudomonal β-lactam antibiotic combination (adjusted odds ratio, 3.40; 95% CI, 2.26-5.14).</p>

<p><strong>Conclusions and Relevance: </strong>Coadministration of IV vancomycin and piperacillin/tazobactam may increase the risk of AKI in hospitalized children. Pediatricians must be cognizant of the potential added risk of this combination therapy when making empirical antibiotic choices.</p>

10.1001/jamapediatrics.2017.3219

JAMA Pediatr

28973124

Urinary kidney injury biomarkers and tobramycin clearance among children and young adults with cystic fibrosis: a population pharmacokinetic analysis.

2017

254-60

2017 Jan

1460-2091

<p><strong>BACKGROUND: </strong>Tobramycin is frequently used for treatment of bronchopneumonia in patients with cystic fibrosis (CF). Variability in tobramycin clearance (CL) is high in this population with few reliable approaches to guide dosing.</p>

<p><strong>OBJECTIVES: </strong>We sought to evaluate the pharmacokinetics of once-daily intravenous tobramycin in patients with CF and test the influence of covariates on tobramycin CL, including serum creatinine (SCr) and urinary biomarkers: neutrophil gelatinase-associated lipocalin (NGAL), retinol-binding protein (RBP) and kidney injury molecule-1 (KIM-1).</p>

<p><strong>METHODS: </strong>This was a prospective, observational cohort study of children/young adults with CF receiving once-daily intravenous tobramycin from October 2012 to May 2014 at Cincinnati Children's Hospital Medical Center. Therapeutic drug monitoring data were prospectively obtained. Population pharmacokinetic analyses were performed using non-linear mixed-effects modelling.</p>

<p><strong>RESULTS: </strong>Thirty-seven patients (median age 15.3 years, IQR 12.7-19.5) received 62 tobramycin courses. A one-compartment model with allometrically scaled weight for tobramycin CL and volume of distribution (V) best described the data. Urinary NGAL was associated with tobramycin CL (P &lt; 0.001), as was urinary RBP (P &lt; 0.001). SCr, estimated glomerular filtration rate and urinary KIM-1 were not significant covariates. The population pharmacokinetic parameter estimates were CL = 8.60 L/h/70 kg (relative standard error 4.3%) and V = 31.3 L/70 kg (relative standard error 4.7%).</p>

<p><strong>CONCLUSIONS: </strong>We describe urinary biomarkers as predictors of tobramycin CL using a population pharmacokinetic modelling approach. Our findings suggest that patient weight and urinary NGAL or RBP could be used to individualize tobramycin therapy in patients with CF.</p>

10.1093/jac/dkw351

J. Antimicrob. Chemother.

27585963

Prevalence, predictors, and outcomes of cardiorenal syndrome in children with dilated cardiomyopathy: a report from the Pediatric Cardiomyopathy Registry.

2015

2177-88

2015 Dec

1432-198X

<p><strong>BACKGROUND: </strong>The association of cardiorenal syndrome (CRS) with mortality in children with dilated cardiomyopathy (DCM) is unknown.</p>

<p><strong>METHODS: </strong>With a modified Schwartz formula, we estimated glomerular filtration rates (eGFR) for children ≥1 year of age with DCM enrolled in the Pediatric Cardiomyopathy Registry at the time of DCM diagnosis and annually thereafter. CRS was defined as an eGFR of &lt;90 mL/min/1.73 m(2). Children with and without CRS were compared on survival and serum creatinine concentrations (SCr). The association between eGFR and echocardiographic measures was assessed with linear mixed-effects regression models.</p>

<p><strong>RESULTS: </strong>Of 285 eligible children with DCM diagnosed at ≥1 year of age, 93 were evaluable. CRS was identified in 57 of these 93 children (61.3%). Mean (standard deviation) eGFR was 62.0 (22.6) mL/min/1.73 m(2) for children with CRS and 108.0 (14.0) for those without (P &lt; 0.001); median SCr concentrations were 0.9 and 0.5 mg/dL, respectively (P &lt; 0.001). The mortality hazard ratio of children with CRS versus those with no CRS was 2.4 (95% confidence interval 0.8-7.4). eGFR was positively correlated with measures of left ventricular function and negatively correlated with age.</p>

<p><strong>CONCLUSIONS: </strong>CRS in children newly diagnosed with DCM may be associated with higher 5-year mortality. Children with DCM, especially those with impaired left ventricular function, should be monitored for renal disease.</p>

10.1007/s00467-015-3165-8

Pediatr. Nephrol.

26210985

Risk factors for acute kidney injury during aminoglycoside therapy in patients with cystic fibrosis.

2015

1879-88

2015 Oct

1432-198X

<p><strong>BACKGROUND: </strong>Aminoglycoside (AG) therapy is a common cause of acute kidney injury (AKI) in cystic fibrosis (CF) patients. The aim of this study was to identify factors associated with AKI during intravenous AG courses in this population.</p>

<p><strong>METHODS: </strong>This was a matched case-control study utilizing two independent cohorts of hospitalized CF patients receiving ≥ 3 days of intravenous AG at Cincinnati Children's Hospital Medical Center and Children's of Alabama. All admissions with AKI (cases, N = 82) were matched to two randomly selected admissions without AKI (controls, N = 164) by center, gender, and age ±3 years of the case. AKI was defined as a 1.5-fold increase in the baseline serum creatinine (SCr) level or by an increase in SCr level of 0.3 mg/dL within 48 h. Admissions with AKI before day 4 or without at least weekly SCr monitoring were excluded from the analysis. Factors were compared between cases and controls using simple and multiple conditional logistic regression.</p>

<p><strong>RESULTS: </strong>Multivariable analysis identified receipt of an AG within 90 days prior to admission, longer duration of AG therapy, low serum albumin, and receipt of trimethoprim/sulfamethoxazole as independent risk factors for developing AKI. Infection with Staphylococcus aureus diminished the odds of developing AKI.</p>

<p><strong>CONCLUSIONS: </strong>This study identifies risk factors contributing to AG-associated AKI in CF patients. These findings can be used to anticipate high-risk scenarios and limit AKI in CF patients under clinical care.</p>

10.1007/s00467-015-3097-3

Pediatr. Nephrol.

25912993

Daily serum creatinine monitoring promotes earlier detection of acute kidney injury in children and adolescents with cystic fibrosis.

2014

435-41

2014 Jul

1873-5010

<p><strong>BACKGROUND: </strong>The epidemiology of aminoglycoside-associated acute kidney injury (AG-AKI) has not been well described in pediatric patients with cystic fibrosis (CF). We aimed to assess the impact of daily serum creatinine (SCr) measurement on detection of AG-AKI at our institution.</p>

<p><strong>METHODS: </strong>We examined a cohort of hospitalized patients with CF who received an intravenous (IV) aminoglycoside for ≥ 3 days. We compared the rate, timing, and medical management surrounding detection of AG-AKI during 2 periods: January 2010-May 2011 (Era 1, SCr measured at the discretion of the medical team, N=124) and June 2011-June 2012 (Era 2, SCr measured daily, N=103). Our primary outcome was detection of AG-AKI defined as ≥ 50% increase in SCr from baseline (lowest value in prior 6 months), or ≥ 0.3mg/dL rise within 48 h, occurring after day 2.</p>

<p><strong>RESULTS: </strong>The use of once daily tobramycin (p=0.02) and IV fluids (p&lt;0.001) was higher during Era 2, while AG courses were shorter (p=0.04), and fewer concomitant nephrotoxins (p=0.04) were given; higher daily tobramycin doses (p&lt;0.001) were administered. Although the rate of AG-AKI was not significantly different (12% during Era 1 vs. 20% during Era 2, p=0.09), the number of AG-AKI days detected increased (5.5 vs. 2.9 per 100 AG days, p=0.003), and detection occurred earlier (median 6 vs. 9 days, log rank test p=0.02) during the daily SCr period.</p>

<p><strong>CONCLUSIONS: </strong>Daily SCr measurement promoted earlier and increased detection of AG-AKI in patients with CF at our institution. We suggest systematic evaluation for AKI during aminoglycoside administration in patients with CF.</p>

10.1016/j.jcf.2014.03.005

J. Cyst. Fibros.

24718099

Increased Vancomycin Exposure and Nephrotoxicity in Children: Therapeutic Does Not Mean Safe.

2016

65-7

2016 Mar

2048-7207

10.1093/jpids/piu122

J Pediatric Infect Dis Soc

26908492