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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2020  |  Volume : 31  |  Issue : 5  |  Page : 1057-1061
Colistin-induced Nephrotoxicity in a Tertiary Teaching Hospital


1 Pharmaceutical Care Service, Ministry of the National Guard - Health Affairs; King Abdullah International Medical Research Center; King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
2 King Saud bin Abdulaziz University for Health Sciences; Department of Biostatistics and Bioinformatics, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia

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Date of Web Publication21-Nov-2020
 

   Abstract 


Colistin-induced nephrotoxicity is a well-known major adverse event, which may occur within seven days [early acute kidney injury (AKI)] with a high mortality rate of 70% or after seven days (late AKI). The main objective of this retrospective study is to assess the severity and associated risk factors for the development of colistin-related nephrotoxicity. An observational retrospective cohort study was conducted over 12 months (January–December 2017). All patients with a baseline normal renal function, who received intravenous colistin for >72 h, were included. Nephrotoxicity was defined using the RIFLE criteria (Risk, Injury, Failure, Loss, and End-stage renal disease). The demographic and clinical variables were retrieved from the hospital's electronic medical record system and compiled in an electronic database. All the statistical analysis was carried out by SAS JMP from SAS Institute Inc., Cary, NC. Seventy patients met the inclusion criteria. Colistin-induced nephrotoxicity occurred in 45.71% of the patients, of whom 40.6% were at Risk, 21.9% at Injury, and 37.5% at Failure according to RIFLE criteria. In patients who developed AKI, the average total colistin dose received before AKI was 4.4 mg/kg/day. More than half of the AKI group (53.13%) received an inappropriate total dose of colistin. Age, 65 years and older, was significantly associated with a high risk of nephrotoxicity (P <0.05), which developed within 6.8 ± 0.44 days from receiving a colistin dose. Clinical pharmacy services were consulted in 28.13% of the cases, and the dose was adjusted in 37.5% of the patients. Colistin nephrotoxicity is common and is associated more with older age group and inappropriate dosing.

How to cite this article:
Al-Abdulkarim DA, Alzuwayed OA, Al Ammari M, Al Halwan S, Al Maklafi N, Thomas A. Colistin-induced Nephrotoxicity in a Tertiary Teaching Hospital. Saudi J Kidney Dis Transpl 2020;31:1057-61

How to cite this URL:
Al-Abdulkarim DA, Alzuwayed OA, Al Ammari M, Al Halwan S, Al Maklafi N, Thomas A. Colistin-induced Nephrotoxicity in a Tertiary Teaching Hospital. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2020 Dec 2];31:1057-61. Available from: https://www.sjkdt.org/text.asp?2020/31/5/1057/301171



   Introduction Top


Acute kidney injury (AKI) is a potentially life-threatening condition, often complicating the course of treatment, and identified by rapid deterioration of related biomarkers. Approximately 7% of all hospitalized patients develop AKI, with a higher prevalence (up to 20%) in an intensive care unit (ICU) setting.[1] Mortality, secondary to AKI, has been reported in up to 50% of critically ill patients and in 15% of patients in general wards.[2]

Colistin is a bactericidal glycopeptide antibiotic, with broad-spectrum activity against multidrug-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae.[3] Its kinetic activity is concentration dependent with a postantibiotic effect. Nephrotoxicity is a known major adverse event of colistin due to an increase in tubular permeability, resulting in anionic, cationic, and water influx causing cell swelling and lysis. The result is acute tubular necrosis.[4] Early AKI, due to colistin, occurs within seven days and has a higher risk of mortality (70%); late AKI occurs after seven days.[5] In a study done by Pogue et al, colistin-induced nephrotoxicity was dose dependent. AKI developed in 30% of patients who received colistin at a dose of 3–4.9 mg/kg, and it exceeded 69% in patients who received more than 5 mg/kg colistin.[6]

Other risk factors may contribute to nephrotoxicity secondary to colistin, including, but not limited to, advanced age and concomitant use of other nephrotoxic medication such as aminoglycoside, vancomycin, and diuretics.[7],[8]

The RIFLE criteria [Risk, Injury, Failure, Loss, and End-stage kidney disease (ESRD)] [Table 1] is a validated tool used in literature to evaluate drug-induced AKI, providing a definition and categorization of various degrees of AKI from mild renal impairment to the need for renal replacement therapy (RRT).[9],[10]
Table 1: Definition of the Risk, Injury, Failure, Loss, and end-stage renal disease criteria.

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The aim of the study was to assess the characteristics of colistin-induced AKI, the associated risk factors as well as the severity of colistin-induced nephrotoxicity.


   Subjects and Methods Top


The design for the study was an observational retrospective cohort study, which was approved by the Institutional Review Board (IRB) of King Abdullah International Medical Research Center (KAIMRC), Riyadh, in December 2018. The study was conducted from January to December 2017. All patients, 18 years and older, with normal renal function at baseline, and who received intravenous colistin for more than 72 h, were included. Patients were excluded if they received colistin in 14 days before study enrollment or admitted to an ICU. Colistin total daily dose was recorded in milligrams/kilogram of ideal body weight. The study was conducted at King Abdulaziz Medical City, Central Region, which is a Joint Commission International standard accredited 1501-bed tertiary care academic medical center.

Variables and definition

Nephrotoxicity was defined according to the RIFLE criteria. Both demographic information (age, gender, and actual and ideal body weight) and clinical variables (comorbidities, type of organism, indication for colistin, base line serum creatinine level, colistin total daily dose over 14 days, total colistin daily dose just before AKI, and concomitant nephrotoxic medications) were retrieved from the institution's electronic medical records.


   Statistical Analysis Top


Data were entered in a Microsoft Excel spreadsheet using best practices and analyzed using SAS JMP from SAS Institute Inc., Cary, NC. Categorical variables were summarized as frequency and percentage, and quantitative variables were summarized as mean and standard deviation. Chi-square or Fisher's exact tests were used to investigate the association between categorical variables and AKI, and the Student's t-test was used to assess the difference in average values of continuous variables in AKI and non-AKI groups. P <0.05 was considered as statistically significant for rejecting the hypothesis.


   Results Top


The sample size realized as 70 in the final analysis. The majority of the screened patients were excluded according to the protocol's exclusion criteria. The average age for the sample was 64.1 ± 20.3, with males constituting 62.86% of the sample. Colistin was prescribed for different indications including treatment of urinary tract infection (31.4%), bacteremia (25.7%), pneumonia (20%), and osteomyelitis (11.43%). The most prevalent microorganisms isolated were multidrug-resistant including A. baumannii (28.75%), P. aeruginosa (28.75%), K. pneumoniae (27.14%), and Escherichia coli (8.57%). Colistin was prescribed at an average total dose of 4.1 mg/kg/day for all patients, and 45.71% developed AKI within 6.8 ± 0.44 days. None of the patients required RRT, and AKI needed to recover within 13.8 ± 23.8 days. The patients’ demographics and clinical characteristics are listed in [Table 2].
Table 2: Demographic and clinical characteristics of patients used colistin.

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Of the AKI group, 40.6% were at Risk, 21.9% at Injury, and 37.5% at Failure as per RIFLE criteria [Table 3]. More than half (56.2%) of the AKI-group were prescribed an inappropriate colistin dose, and neither nephrology nor clinical pharmacy services (56.25%) were consulted to adjust the dose after AKI occurred.
Table 3: Distribution of patients with nephrotoxicity according to Risk, Injury, Failure, Loss, and end-stage renal disease criteria except loss and end-stage renal disease.

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Advance age (65 years and above) was significantly associated with the risk of nephrotoxicity (P <0.05), and no statistically significant association was found with the use of other nephrotoxic medications (aminoglycoside, P = 0.15, or diuretics, P = 0.21) or any other comorbidities of the patients.


   Discussion Top


Colistin is a broad-spectrum antibiotic with activity against different multidrug-resistant Gram-negative bacteria. It had been re-introduced in the market after being withdrawn due to its nephrotoxicity.[11] The primary aim of this retrospective study was to use the RIFLE criteria as a tool to assess the incidence of colistin-induced nephrotoxicity. Nephrotoxicity developed in 45.71% of the patients treated with colistin for different indications within 6.8 ± 0.44 days from initiating the therapy. These results are consistent with the study of Hartzell et al reporting AKI of various degrees in 45% of the sample.[12] A higher incidence (48%) had been reported by Temocin et al.[7] Ko et al in their study divided their patients in early- and late-onset AKI, and 70% of the patients who developed early-onset AKI had a higher in hospital mortality rate compared to the late-onset AKI.[5] Pogue et al analyzed 54 patients treated with colistin retrospectively and found that 45% developed nephrotoxicity within the first seven days of therapy.[6]

As reported in previous studies, our study confirmed that advance age (older than 65 years) is a significant risk factor for developing colistin-induced nephrotoxicity.[7] The use of potentially nephrotoxic drugs such as vancomycin, aminoglycosides, Angiotensin-converting enzyme (ACE) inhibitors, diuretics, and nonsteroidal anti-inflammatory drugs, were analyzed, but none had a significant association with nephrotoxicity. The reason is possibly due to the limited use of these agents in the sample; this result contradicts former studies, indicating that concomitant use of nephrotoxic agents may be a serious risk factor for developing AKI while receiving colistin therapy. Temocin reported that aminoglycosides had a significant association with developing nephrotoxicity.[7],[13]

As reported in the literature, the incidence of colistin-induced nephrotoxicity was presumed to increase with comorbidities such as diabetes and hypertension. The current study did not find a significant association between the different comorbidities including diabetes and hypertension and developing of colistin-induced nephrotoxicity. Kim et al reported a similar result.[14] However, Neha and Kari report that AKI is more likely to occur in patients with hypertension in acute illness settings (P = 0.037.[8]


   Limitations Top


First, our study had a retrospective design and some data were missing when retrieved from the medical records. Second, the sample size may have been too limited to identify possible significant associations. A large prospective study is recommended to investigate the true rate of colistin-induced nephrotoxicity.


   Conclusion Top


Colistin is a known nephrotoxic antibiotic that should be used carefully with close renal function monitoring, especially in the elderly population. It is recommended that colistin should be initiated with the lowest possible dose.

Conflict of interest: None declared.



 
   References Top

1.
Yong K, Dogra G, Boudville N, Pinder M, Lim W. Acute kidney injury: Controversies revisited. Int J Nephrol 2011;2011:762634.  Back to cited text no. 1
    
2.
Ympa YP, Sakr Y, Reinhart K, Vincent JL. Has mortality from acute renal failure decreased? A systematic review of the literature. Am J Med 2005;118:827-32.  Back to cited text no. 2
    
3.
Ordooei Javan A, Shokouhi S, Sahraei Z. A review on colistin nephrotoxicity. Eur J Clin Pharmacol 2015;71:801-10.  Back to cited text no. 3
    
4.
Knotek M. Drug-Induced Kidney Injury. EJIFCC 2009;20:54-8.  Back to cited text no. 4
    
5.
Ko Hj, Jeon Mh, Choo Ej, et al. Early acute kidney injury is a risk factor that predicts mortality in patients treated with colistin. Nephron Clin Pract 2011;117:c284-8.  Back to cited text no. 5
    
6.
Pogue JM, Lee J, Marchaim D, et al. Incidence of and risk factors for colistin-associated nephrotoxicity in a large academic health system. Clin Infect Dis 2011;53:879-84.  Back to cited text no. 6
    
7.
Temocin F, Erdinc S, Tulek N, Demirelli M, Bulut C, Ertem G. Incidence and Risk Factors for Colistin-Associated Nephrotoxicity. Jpn J Infect Dis 2015;68:318-20.  Back to cited text no. 7
    
8.
Neha M, Kari L. Nephrotoxicity associated with intravenous colistin in critically ill patients. Pharmacotherapy 2011;31:1257-64.  Back to cited text no. 8
    
9.
Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P, Acute Dialysis Quality Initiative workgroup. Acute renal failure - Definition, outcome measures, animal models, fluid therapy and information technology needs: The Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004;8:R204-12.  Back to cited text no. 9
    
10.
Kellum JA, Bellomo R, Ronco C. Definition and classification of acute kidney injury. Nephron Clin Pract 2008;109:c182-7.  Back to cited text no. 10
    
11.
Gurjar M. Colistin for lung infection: An update. J Intensive Care 2015;3:3.  Back to cited text no. 11
    
12.
Hartzell JD, Neff R, Ake J, et al. Nephrotoxicity associated with intravenous colistin (colistimethate sodium) treatment at a tertiary care medical center. Clin Infect Dis 2009;48:1724-8.  Back to cited text no. 12
    
13.
Falagas ME, Kasiakou SK. Toxicity of polymyxins: A systematic review of the evidence from old and recent studies. Crit Care 2006;10:R27.  Back to cited text no. 13
    
14.
Kim J, Lee KH, Yoo S, Pai H. Clinical characteristics and risk factors of colistin-induced nephrotoxicity. Int J Antimicrob Agents 2009;34:434-8.  Back to cited text no. 14
    

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Correspondence Address:
Dalal A Al-Abdulkarim
Pharmaceutical Care Service, Ministry of the National Guard - Health Affairs, Riyadh
Saudi Arabia
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DOI: 10.4103/1319-2442.301171

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    Abstract
   Introduction
   Subjects and Methods
   Statistical Analysis
   Results
   Discussion
   Limitations
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