Advance Publication by J-STAGE Japanese Journal of Infectious Diseases

Risk factors for colistin-associated acute kidney injury: a multicenter study from Turkey    

Serdar Gul, Ferit Kuscu, Hande Aydemir, Dogan Baris Ozturk, Ozcan Deveci, Fazilet Duygu, Birgul Kacmaz, Ferda Yaman, and Emel Aslan          

Received: November 5, 2014. Accepted: April 15, 2015  Published online: July 10, 2015 DOI: 10.7883/yoken.JJID.2014.501                         

Advance Publication articles have been accepted by JJID but have not been copyedited or formatted for publication.

 

Tittle page Risk factors for colistin-associated acute kidney injury: a multicenter study from Turkey Serdar Gul, Department of Infectious Diseases and Clinical Microbiology, Kirikkale University,Kirikkale,

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Turkey. [email protected] Ferit Kuscu

Department of Infectious Diseases and Clinical Microbiology, Numune Educational and

Hande Aydemir

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Research Hospital, Adana, Turkey.

Department of Infectious Diseases and Clinical Microbiology, Bulent Ecevit University,Zonguldak, Turkey.

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Dogan Baris Ozturk

Department of Infectious Diseases and Clinical Microbiology, Ulucanlar Eye Educational and

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Research Hospital, Ankara, Turkey.

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Ozcan Deveci

Department of Infectious Diseases and Clinical Microbiology, Dicle University, Diyarbakir, Turkey.

Fazilet Duygu Department of Infectious Diseases and Clinical Microbiology, Gaziosmanpasa University, Tokat, Turkey.

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Birgul Kacmaz Department of Infectious Diseases and Clinical Microbiology, Kirikkale University,Kirikkale, Turkey. Ferda Yaman

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Department of Anesthesiology and Reanimation, Kirikkale University,Kirikkale, Turkey. Emel Aslan

Department of Infectious Diseases and Clinical Microbiology, Dicle University, Diyarbakir,

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Turkey.

Corresponding author: Serdar Gul, Kirikkale University. Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology, Yahsihan, Kirikkale/Turkey. Email adres:

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[email protected] Phone number: +90 505 925 51 44 Postal adres: Kirikkale University. Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology, Yahsihan, Kirikkale/Turkey.

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Key words: colistin; acute kidney injury; risk factors

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Running title: Colistin-associated AKI

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Abstract The aim of this study was to investigate the incidence of acute kidney injury (AKI) and its risk factors due to colistin use in patients infected with multi-drug resistant pathogens. This multicenter, retrospective, observational study was conducted in Turkey at five different

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research and university hospitals. Cox-regression analyses were performed, to determine

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independent predictors of acute kidney injury. From April 2012 to July 2014, a total of 216 patients aged between 18-94 years, treated with colistimethate sodium (CMS) were included in the study. The mean age of the patients was 60.3±20.1, ranging between 18-94 years. The overall incidence of AKI was 34.3% (74/216) at any time during treatment. Results of the Cox

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regression analysis indicated that concomitant use of loop diuretics, baseline creatinin level and CMS dosage were independently associated with AKI. According to our results, patients with higher baseline creatinin levels or patients who have to use concomitant loop diuretics may be monitored more closely and dose adjustment should be done promptly. Additionally,

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more comprehensive studies are needed into the efficacy of low dose colistin since the higher doses increase the risk of AKI.

Key words: colistin, acute kidney injury, risk factor

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Introduction

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Colistin, which belongs to polymyxin class of cationic polypeptide antibiotics, is an old antibiotic that was used until the early 1980s. Because of its toxicity, colistin has not been used to treat infections caused by Gram-negative bacilli for many years. Because of the emergence of multi-drug resistant isolates of Gram negative- bacilli such as Acinetobacter baumannii or Pseudomonas aeruginosa, this old drug gained new interest for its activity against these multi-drug resistant pathogens (1). Renal toxicity is the most common adverse effect of this agent. The mechanism of renal toxicity is not exactly clear but proximal 3   

tubulopathy and toxicity to mammalian uroepithelium were observed in some studies. It has been reported that the nephrotoxicity of colistin is generally mild and reversible (2-3).

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Little is known about the incidence of renal toxicity and the risk factors of nephrotoxicity due

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to colistin. We have therefore investigated the incidence of acute kidney injury (AKI) and its risk factors due to colistin usage in patients infected with multi-drug resistant pathogens. Materials and Methods

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This multicenter, retrospective, observational study was conducted in Turkey at five different research and/or university hospitals:

1- Kirikkale University Hospital (KUH), 200 beds tertiary care hospital located in Middle

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Anatolia region.

2- Tokat Gaziosmanpasa University Hospital (GOPUH), 400 beds tertiary care hospital located in Middle-Black Sea region.

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3- Diyarbakir Dicle University Hospital (DUH), 1150 beds tertiary care hospital located in South-East Anatolia region.

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4- Zonguldak Bulent Ecevit University Hospital (BEUH), 527 beds tertiary care hospital located in West-Black Sea region

5- Adana Numune Educational and Research Hospital (NERH), 910 beds tertiary care hospital located in Mediterranean region.

From April 2012 to July 2014, patients who were aged ≥18 and who were treated with colistimethate sodium (CMS) were included in the study. Exclusion criteria were: Being 4   

50 percent developing over seven days or urine output of six hours (8). The patients were treated with CMS (Colimycin®, Kocak Farma, Turkey each vial

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contained 150 mg colistin base activity, which is approximately equivalent to 360 mg, or five million IU of CMS), which is the only available form of colistin in Turkey (9-11). Although the prospectus recommendation of IV CMS dosage for this drug is 2.5-5

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mg/kg/day (base activity), divided into two-four doses for normal renal function, it is

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usually used as a fixed doses of 300 mg or 450 mg/day divided into two/three doses according to the manufacturers recommendations in Turkey. Our patients received dosage in line with this recommendation. Manufacturers who had not recommended a loading dose for the drug have recently started to do so. Since some of the patients were included in this study before this recommendation, some of our patients were not given a loading dose for this reason.

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Types of infections were assessed according to the US Centers for Disease Control and Prevention (CDC) criteria (12). Statistical analysis was performed using the SPSS software version 15.0 (SPSS Inc., Chicago, IL). Age, gender, baseline creatinine level, intensive care unit admission, comorbidities, usage

The univariate analysis to identify variables associated with acute

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as univariate predictors.

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of concomitant nephrotoxic drugs, daily dose of base colistin and infusion time were screened

kidney injury due to colistin therapy was performed with Chi-square, Fisher's exact, Student's t and Mann-Whitney U tests. The tests were selected on the basis of Kolmogorov–Smirnov normality testing with Lilliefors' correction. The possible factors (p