The association between acute kidney injury and Polymyxin B treatment: A retrospective cohort study

Abstract

Purpose

This retrospective study aimed to analyse the impact of polymyxin B (PMB) on nephrotoxicity parameters and identify associated variables.

Patients and methods

The study, which was conducted at a tertiary general hospital in China, included 84 patients over the age of 18 who had received PMB for a period of more than 48 h. Patients were divided into two groups based on the presence or absence of acute kidney injury (AKI) according to KDIGO standards. The identification of risk factors for PMB–associated AKI was facilitated by data collection and multivariate logistic regression analysis.

Results

The majority of patients were male, with a median age of 80 years (interquartile range (IQR): 68.5, 87.0) and a median weight of 60.0 kg (IQR: 50.0, 65.0). PMB was administered with a median loading dose of 1.73 mg/kg (IQR: 1.67, 1.82) and a median daily maintenance dose of 1.82 mg/kg (IQR: 1.67, 2.22) over a median treatment duration of 7.75 days (IQR: 5.00, 10.38). The development of AKI was observed in 36 patients (42.9%), with a median time to onset of 5 days (IQR: 3, 6). In the cohort of patients who developed AKI, 11 (30.6%) patients discontinued PMB therapy, while 8 (16.7%) patients required renal replacement therapy (RRT). The study revealed that concurrent chronic kidney disease (CKD) (odds ratio (OR) = 5.47, 95% confidence interval (CI) 1.52–19.64, P = 0.01) and the daily maintenance dose (OR = 12.57, 95% CI 2.84–55.59, P = 0.00) were independently associated with AKI onset following PMB therapy.

Conclusions

The potential association between PMB therapy and AKI raises clinical concern. Concurrent CKD and higher PMB maintenance doses were identified as independent risk factors for AKI associated with PMB therapy. Consequently, rigorous monitoring of renal function indices and therapeutic drug concentrations is recommended to facilitate early detection of nephrotoxic risks, thereby minimizing renal injury and ensuring the safe administration of PMB.

Keywords

Polymyxin B acute kidney injury logistic regression model drug safety risk factor

Introduction

In the late 1950s, polymyxin antibiotics were employed for the treatment of gram–negative bacterial (GNB) infections on a clinical basis.¹ However, due to their high incidence of adverse reactions, they were gradually phased out in favour of safer antibiotic alternatives. In recent years, there has been a notable increase in the prevalence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) gram-negative bacterial infections, particularly among Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter species.² Polymyxin B (PMB), reintroduced for clinical use in China in 2018 and regarded as the ultimate defence against infections caused by XDR-GNB, poses a significant challenge for clinical physicians due to its risk of nephrotoxicity, particularly when treating critically ill patients with complex conditions and multiple risk factors, which may further elevate the risk of nephrotoxicity and severely impact patient prognosis.^3,4 A retrospective analysis of US Food and Drug Administration Adverse Event Reporting System (FAERS) data (2004–2020) demonstrated that PMB-associated acute kidney injury (AKI) occurred at a rate of 2.88%, which was lower than the 3.80% observed with polymyxin E.⁵ On the one hand, the instructions for PMB state that therapeutic doses of PMB sulfate may lead to nephrotoxicity and mild renal tubular damage,⁶ yet they fail to provide a specific dose adjustment strategy. Conversely, the International Consensus Guidelines for Optimal Polymyxin Use assert that clinical pharmacokinetic (PK) studies have demonstrated that decreasing doses in patients with reduced creatinine clearance (Clcr) results in lower plasma concentrations of PMB.¹ Consequently, there is no PK rationale to support dose adjustments based on renal function. Data from four retrospective studies indicated that PMB–associated nephrotoxicity was linked to various factors, including high daily dosages,^3,7 pre-existing chronic renal insufficiency,⁸ septic shock,⁹ concurrent use of nephrotoxic agents (e.g. vancomycin or aminoglycosides),⁷ loop diuretics,⁸ and vasopressors.⁹ The association between PMB and the development of nephrotoxicity remains a subject of ongoing debate. It is a well–established fact that the majority of patients receiving PMB are critically ill individuals, forming a heterogeneous patient population predisposed to acute kidney injury (AKI) induced by multiple etiological factors, including sepsis, hypovolemia, and concurrent nephrotoxic medications.^1,3,7–9 It is imperative for clinicians to comprehend the impact of both disease-related factors and drug-specific parameters on the development of AKI during PMB therapy. In light of this, we conducted a retrospective study to evaluate the likelihood of AKI associated with PMB and to identify the clinical factors that could predict a high risk of this adverse event during treatment.

Material and methods

Study design

This retrospective study was conducted to observe the occurrence of nephrotoxicity and identify risk factors associated with PMB administration at the First Hospital of Changsha (a tertiary general hospital in China) between January 2021 and December 2022.

Inclusion criteria: (1) Patients over 18 years old; (2) Patients diagnosed with either hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP) caused by carbapenem-resistant Acinetobacter baumannii (CRAB), carbapenem-resistant Enterobacteriaceae, or multidrug-resistant Pseudomonas aeruginosa (MDRPA), who have received PMB for more than 48 h. Exclusion criteria: (1) Patients with AKI at the time of HAP diagnosis; (2) Patients who died within 48 h of PMB use; (3) Patients with chronic kidney disease (CKD) and an estimated glomerular filtration rate (eGFR) of less than 15 mL·min⁻¹·1.73 m⁻² (calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation), or who had undergone renal replacement therapy at baseline; (4) Patients for whom clinical data were incomplete. Refer to Figure 1 for the flowchart outlining the case collection process.

Figure 1.

Case collection process diagram.

This study was conducted in accordance with all relevant tenets of the 1975 Helsinki Declaration as revised in 2024. The study adhered to the STROBE guidelines for reporting observational studies.¹⁰ Approval for this study was granted by the Medical Ethics Committee (an Independent Ethics Committee, IEC) of the First Hospital of Changsha (China) (Approval Number: 2023-241). Given the retrospective nature of the study and the use of anonymized clinical data (with no personally identifiable information), the IEC explicitly waived the requirement for written informed consent. Data were extracted from routine clinical records and transferred to an anonymised, password-protected database which was securely maintained and did not contain any personally identifiable information.

Physicians strictly adhered to the manufacturer's approved prescribing information for PMB administration or internationally recognised clinical practice guidelines.^1,6 The following clinical information was collected through the hospital information system: patient demographic characteristics including age and gender; comorbidity data encompassing the age-adjusted Charlson Comorbidity Index (aCCI), specific comorbid conditions, and ICU admission status; infection-related parameters such as infection site and type, along with volume management status; medication details comprising daily PMB dose, treatment duration, and adverse reactions observed during PMB therapy; and concomitant medications categorized as vasopressors (e.g. epinephrine, noradrenaline, metaraminol), diuretics (e.g. furosemide, torsemide), paracetamol, non-steroidal anti-inflammatory drugs (e.g. compound aminopyrine antipyrine barbitone, indomethacin), antibiotics (e.g. vancomycin, amikacin, voriconazole for injection), and mannitol. Clinical laboratory test results were systematically gathered at three key time points: prior to PMB initiation (baseline), every two days during the treatment course, and following treatment discontinuation.

Variables and definitions

Baseline serum creatinine was measured on the day that PMB was initiated. According to the KDIGO criteria,¹¹ AKI was diagnosed when either the serum creatinine (Scr) level increased by at least 1.5 times compared to the baseline level, or the urine output remained below 0.5 ml·kg⁻¹·h⁻¹ for six hours. The severity of nephrotoxicity during PMB therapy was assessed using the RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease) classification system, which categorises renal dysfunction based on peak Scr values during therapy relative to individual baseline levels.¹¹ Creatinine clearance (CLCR) was calculated for each patient using the Cockcroft–Gault equation based on Scr levels, age, body weight and sex.

Diagnoses of MDR or XDR HAP and VAP were confirmed by two respiratory physicians in accordance with the 2018 Chinese guidelines for diagnosing and treating HAP and VAP.¹² The patient's comorbidities were assessed using the age-adjusted Charlson comorbidity index (aCCI) score.¹³ The PMB loading dose was defined as the first dose exceeding the maintenance dose. We defined high-dose PMB as exceeding 150 mg per day, compared with the authorised dose of 50 mg twice daily (referred to as ‘low-dose’ in our study).

The case report form (CRF) was jointly designed by respiratory physicians and clinical pharmacists. Two clinical pharmacists independently reviewed the CRF data and assessed the causality of adverse drug reactions based on the World Health Organization–Uppsala Monitoring Centre (WHO–UMC) system.¹⁴

Outcome definition

The outcome of the current study was defined as the occurrence of AKI, length of hospital stay (LOS) and 30-day mortality. The latter was defined as all-cause death within 30 days of the initiation of PMB treatment.

Statistical methods

The patients were divided into AKI group and non-AKI groups based on the presence or absence of AKI. This study aimed to identify potential risk factors linked to AKI related to PMB through multivariate analysis by comparing the differences in demographics, characteristics, clinical and laboratory parameters, and PMB treatment status between the two groups.

The data were initially recorded in Microsoft Word and then summarised in Microsoft Excel to create a database. After auditing, the data were imported into the SPSS 25.0 statistical package for verification, collation, and analysis. Categorical data were presented as frequencies (%), and continuous data were presented as means ± standard deviations (SD) or medians (interquartile range, IQR). Data with a normal distribution and homogeneous variance were tested using an independent samples t-test; data with uneven variance were tested using a corrected t-test; data with a non-normal distribution were tested using a Mann Whitney U-test; and categorical data were tested using a Chi-square test or a Fisher's exact test. Multivariable logistic regression analyses were performed to incorporate the risk factors identified in the univariate analysis into the multivariate models. The variables considered to be clinically relevant and statistically significant (P value < 0.05) were used as the covariates. All P values were two-sided, with P < 0.05 being considered statistically significant.

Results

Demographics and clinical characteristics

A total of 84 patients who received PMB at the First Hospital of Changsha between January 2021 and December 2022 were identified as eligible for inclusion in the study (see Figure 1). During this period, a total of 122 patients received PMB therapy. Of these patients, 38 were excluded from the final analysis due to violations of the predefined eligibility criteria, including: PMB duration of less than 48 h (n = 22), baseline renal replacement therapy (n = 14), and incomplete clinical documentation (n = 2). Consequently, the final cohort comprised 84 patients who both received PMB therapy and met all inclusion criteria, forming the basis for subsequent analysis. The demographics and clinical characteristics of all participators were summarized in Table 1. Most patients were male (70/84, 83.3%), with a median age of 80 years (IQR 68.5, 87.0) and a median weight of 60.0 kg (IQR 50.0, 65.0). The aCCI score for this group ranged from 2 to 13. Most patients presented with comorbidities, including chronic pulmonary disease, coronary heart disease, cerebrovascular disease, diabetes mellitus, and renal disease. Septic shock occurred in 83.3% of cases, while 63.1% required vasoactive agents prior to PMB initiation. The administration of PMB was conducted with a median loading dose of 1.73 mg·kg⁻¹ (IQR: 1.67, 1.82), followed by a median daily maintenance dose of 1.82 mg·kg⁻¹ (IQR: 1.67, 2.22) over a median duration of 7.75 days (IQR: 5.00, 10.38). It was observed that three subjects did not receive the loading dose, while 19 individuals received a high-dose PMB.

Table 1.

Demographic and clinical data for all patients included in the study [( $\bar{x}$ ± s) / N (%)].

Variables	N = 84
Age (years)	80 (68.50, 87.00)
Men [N (%)]	70 (83.33)
Weight (kg)	60.00 (50.00, 65.00)
Comorbidities
aCCI score	7 (5, 8)
Chronic pulmonary disease [N (%)]	35 (41.67)
Chronic heart failure [N (%)]	22 (26.19)
Cerebral vascular disease [N (%)]	27 (32.14)
Malignant disease [N (%)]	7 (8.33)
Diabetes [N (%)]	25 (29.76)
Chronic kidney disease [N (%)]	18 (21.43)
Septic shock^a [N (%)]	70 (83.33)
White blood cell count^a (×10⁹·L⁻¹)	9.49 (7.20, 13.38)
Hemoglobin^a (g·L⁻¹)	85 (72.00, 99.00)
Serum albumin^a (g·L⁻¹)	28.55 (26.13, 31.30)
Alanine aminotransferase^a (UI·L⁻¹)	24.25 (11.63, 55.78)
Total bilirubin^a (umol·L⁻¹)	10.30 (7.30, 14.38)
Creatinine clearance^a (ml·min-1)	49.76 (29.85, 76.32)
Procalcitonin^a (ng·ml⁻¹)	1.35 (0.40, 4.71)
PMB dose regimen
Loading dose(mg·kg⁻¹)	1.73 (1.67, 1.82)
Daily maintenance dose (mg·kg⁻¹)	1.82 (1.67, 2.22)
Total therapeutic dose (mg)	850.0 (500.0, 1200.0)
Daily dose ≥ 150 mg [N (%)]	19 (22.62)
Therapy duration (days)	7.75 (5.00, 10.38)
The median time until the occurrence of AKI (days)	5 (3, 6)
Concomitant drugs	0～4
Vancomycin [N (%)]	5 (5.95)
Aminoglycoside [N (%)]	4 (4.76)
Norepinephrine [N (%)]	53 (63.10)
Loop diuretic [N (%)]	48 (57.14)
Outcomes
AKI [N (%)]	36 (42.86)
Length of hospital stay (days)	32 (20.0, 44.8)
30-day all-cause mortality [N (%)]	39 (46.43)

Notes: ^aAt time of PMB treatment initiation.

Abbreviations: aCCI, age-adjusted Charlson Comorbidity Index; PMB, Polymyxin B; AKI, acute kidney injury.

Analysis of the risk factors of PMB therapy on AKI

Among the 84 patients receiving PMB therapy, 36 (42.8%) of them developed AKI. Of these, 20 (55.5%) were categorised as ‘Risk’, 9 (25.0%) as ‘Injury’, and 7 (19.4%) as ‘Failure’, according to the RIFLE classification system. The median time to onset of AKI was five days (IQR: 3, 6). In the cohort of patients who developed AKI, 11 (30.6%) patients discontinued PMB therapy, while 8 (16.7%) patients required renal replacement therapy (RRT). As shown in Table 2, baseline characteristics including age, gender, body weight, aCCI, sepsis status, number of concurrent medications, hospital length of stay, and relevant laboratory parameters demonstrated no statistically significant differences between the groups (p > 0.05 for all comparisons). With the exception of concurrent CKD (P = 0.01), underlying diseases were found to be similar between the groups. A statistically significant difference was identified between the AKI and non-AKI groups with respect to baseline creatinine clearance (P = 0.02). During the administration of PMB, a discrepancy was observed in the daily maintenance dose administered to patients with and without AKI (P = 0.00). The median time for the onset of AKI was 5 days (IQR: 3, 6). Within the AKI cohort, seven cases exhibited a return to normalcy following drug withdrawal, while eight cases underwent renal replacement therapy. The 30-day all-cause mortality rate was recorded as 47.2%. No significant differences in the level of concomitant medications were observed between the groups. In the multivariate analysis, concurrent CKD (OR = 5.47, 95% confidence interval (CI) 1.52–19.64, P = 0.01) and the daily maintenance dose (OR = 12.57, 95% CI 2.84–55.59, P = 0.00) were independently associated with AKI onset following PMB therapy. A significant difference was observed in creatinine clearance levels and 30-day all-cause mortality rates between the AKI and non-AKI groups following PMB therapy, as demonstrated in Table 3.

Table 2.

Multivariate analysis of AKI related with PMB [( $\bar{x}$ ± s) / N(%)].

Variables	Non-AKI (n = 48)	AKI (n = 36)	OR (95%CI)	P value	OR (95%CI)	P value
Age (years)	79.00 (68.00, 86.75)	81.50 (72.25, 87.00)	1.02 (0.99–1.06)	0.23
Male (N(%))	39 (81.25)	31 (86.11)	1.43 (0.44–4.71)	0.56
Weight (kg)	60.00 (53.50, 65.00)	60.00 (50.00, 60.00)	0.95 (0.90–1.00)	0.06
Comorbidities
aCCI score	6.00 (5.00, 8.00)	7.00 (6.00, 8.75)	1.17 (0.96–1.43)	0.12
Chronic kidney disease (N(%))	5 (10.42)	13 (36.11)	4.86 (1.54–15.33)	0.01*	5.47 (1.52–19.64)	0.01*
Chronic pulmonary disease (N(%))	18 (37.50)	17 (47.22)	1.49 (0.62–3.59)	0.37
Coronary heart disease (N(%))	25 (52.08)	22 (61.11)	1.45 (0.60–3.48)	0.41
Cerebral vascular disease (N(%))	15 (31.25)	12 (33.33)	1.1 (0.44–2.77)	0.84
Diabetes (N(%))	14 (29.17)	11 (30.55)	1.07 (0.42–2.75)	0.89
Baseline condition
White blood cell count (×10⁹·L⁻¹)	9.05 (7.20, 12.91)	10.45 (6.90, 14.44)	1 (0.93–1.09)	0.84
Hemoglobin (g·L⁻¹)	83.50 (69.75, 92.75)	89.00 (73.00, 107.25)	1.02 (1.00–1.04)	0.08
Serum albumin (g·L⁻¹)	29.1 (26.63, 31.88)	28.15 (26.10, 30.13)	0.93 (0.84–1.03)	0.14
Alanine aminotransferase (UI·L⁻¹)	24 (12.20, 56.23)	26.7 (9.85, 55.65)	1 (0.99–1.01)	0.64
Total bilirubin (umol·L⁻¹)	10.15 (6.48, 14.38)	10.9 (7.40, 14.70)	1 (0.98–1.01)	0.58
Creatinine clearance (ml·min⁻¹)	57.92 (29.85, 90.03)	45.1 (28.09, 61.49)	0.98 (0.97–0.997)	0.02*
Procalcitonin (ng/ml)	1.07 (0.30, 4.12)	2.41 (0.60, 5.03)	0.98 (0.94–1.01)	0.21
Septic shock (N(%))	41 (85.42)	29 (80.56)	0.71 (0.22–2.24)	0.56
PMB dose regimen
Loading dose(mg·kg⁻¹)	1.67 (1.54, 2.0)	1.82 (1.67, 2.22)	2.59 (0.84–8.05)	0.10
Daily maintenance dose (mg·kg⁻¹)	1.82 (1.54, 2.00)	2.00 (1.67, 2.50)	5.84 (1.73–19.68)	0.00*	12.57 (2.84–55.59)	0.00*
Daily dose ≥ 150 mg (N(%))	9 (18.75)	10 (27.78)	1.67 (0.60–4.66)	0.33
Total therapeutic dose (mg)	875.00 (625.00, 1187.50)	800.00 (500, 1312.50)	1.0 (1.00–1.00)	0.96
Therapy duration (days)	5.75 (8.00, 10.00)	7 (4.00, 12.38)	1.0 (0.89–1.12)	0.96
Concomitant drugs
Vancomycin (N(%))	4 (8.3)	1 (2.78)	0.31 (0.03–2.94)	0.31
Aminoglycoside (N(%))	3 (6.25)	1 (2.78)	0.429 (0.04–4.30)	0.47
Norepinephrine (N(%))	27 (56.25)	26 (72.22)	2.02 (0.80–5.10)	0.14
Loop diuretic (N(%))	24 (50.00)	24 (66.67)	2 (0.82–4.89)	0.13

Notes: Categorical data were presented as frequencies (%), and continuous data were presented as means ± standard deviations (SD) or medians (interquartile range, IQR). *p value <0.05 was considered statistically significant.

Abbreviations: AKI, acute kidney injury; PMB, Polymyxin B; OR, odds ratio; CI, confidence interval; aCCI, age-adjusted Charlson Comorbidity Index.

Table 3.

Comparisons of outcomes following PMB therapy: with vs. without AKI.

Variables	Non-AKI (n = 48)	AKI (n = 36)	P value
Creatinine clearance (ml·min⁻¹)	62.23 (40.28, 82.97)	26.55 (16.09, 36.78)	0.00*
Length of hospital stay	35.50 (24.25, 45.5)	24.00 (19.00, 44.00)	0.13
30-day all-cause mortality	22 (45.83)	17 (47.22)	0.90

Notes: *p value <0.05 was considered statistically significant.

Abbreviations: PMB, Polymyxin B; AKI, acute kidney injury.

Discussion

In light of the escalating prevalence of multidrug resistance in Gram-negative bacteria, PMB is poised to become increasingly utilized as a crucial therapeutic option.^1,4 In our study, a total of 42.8% of patients exhibited the development of AKI subsequent to PMB-based therapy. Among these patients, 13.1% had to discontinue the medication due to nephrotoxicity. A meta-analysis of 11 studies involving 262 patients indicated that the pooled incidence of nephrotoxicity associated with PMB was 26.8% (95% CI: 17.1%–36.4%).¹⁵ Moreover, a further meta-analysis concentrating on all-cause nephrotoxicity among 2994 patients (from 28 studies) treated with intravenous PMB revealed an incidence of 40.7% (95% CI: 35.0%–46.6%).¹⁶ Our findings demonstrate consistency with those reported in the latter meta-analysis. Kubin et al. posit that nephrotoxicity is a dose-dependent limiting factor for PMB use.¹⁷ Consistent with prior research, our study identified concurrent CKD⁸ and daily maintenance dose^3,7 as risk factors for AKI following PMB therapy.

In our study, concurrent CKD was identified as an independent risk factor for PMB-related AKI. In order to eliminate potential sources of interference, patients with an eGFR of less than 15 mL·min⁻¹·1.73 m⁻², as well as those with end-stage renal disease or who had undergone renal replacement therapy at baseline, were excluded from the study. Our study included patients with a documented history of CKD stages I-IV. Notwithstanding the restoration of complete renal function, patients who have experienced AKI exhibit an increased risk of progression to CKD. In certain instances, this may even progress to end stage renal disease (ESRD).¹⁸ Furthermore, earlier studies have shown that patients with a lower creatinine clearance rate (Clcr), such as below 60 ml·min⁻¹, demonstrate a significantly elevated risk of developing AKI.^8,19 Our study emphasises that patients with underlying renal impairment may be more prone to further renal injury, highlighting the crucial importance of prompt monitoring of renal function to detect the onset of AKI.

In our study, the daily maintenance dose was also found to be independently associated with an elevated risk of AKI following PMB therapy. In view of the poor correlation between the PMB PK and CLCR,¹ the daily maintenance dose was not adjusted according to the patient's renal function. It is noteworthy that Rigatto et al. found that a PMB total dose exceeding 150 mg·day⁻¹ was strongly correlated with AKI risk.¹⁹ The results of specific in vitro studies suggest that PMB exhibits a concentration-dependent nephrotoxicity mechanism. Animal studies have revealed the potential mechanism of nephrotoxicity induced by PMB. This mechanism is related to the reabsorption and subsequent accumulation of the drug in renal proximal convoluted tubule cells,²⁰ where the reabsorption process in renal tubules occurs through a saturable, non-passive manner.²¹ The daily maintenance dosage in our study remained consistently below the recommended 2.5–3 mg·kg⁻¹ established by consensus guidelines,¹ potentially attributable to multiple contributing factors. Firstly, while Gram-negative bacteria in HAP/VAP in China exhibited good sensitivity to PMB,²² it is crucial to recognise that only drug instructions and pharmacopoeias hold legal authority in mainland China, with guidelines and consensus statements serving merely as clinical references. Consequently, in our study, 82.1% of patients adhered to the recommended dosage as stipulated in the drug instructions, which involved an initial dose of 100 mg followed by 50 mg administered every 12 h.⁶ Secondly, the availability of clinical pharmacokinetic/pharmacodynamic (PK/PD) data for PMB in Chinese patients was limited, a fact that necessitated further research to optimise the balance between efficacy and safety. Notably, studies conducted in Chinese populations have demonstrated that a loading dose of 2.5 mg·kg⁻¹ is optimal, irrespective of renal status. For empirical treatment, a fixed 60 mg every 12 h maintenance dose is recommended for patients with renal-impaired infected with Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii, whereas a 1.25 mg·kg⁻¹ weight-based maintenance dose is suggested for those with normal renal function.²³ In our study, the median age of participants exceeds 80 years, with a baseline creatinine clearance rate of 49.76 ml·min⁻¹. In light of the patient's compromised renal function, the dosage administered is aligned with the findings from the aforementioned research. Moreover, medication costs during the study period limited the utilization of higher PMB doses, introducing an additional dimension of complexity to dosing decisions.

Research has indicated that the concurrent administration of vasopressors, diuretics, and the presence of septic shock each constitute independent risk factors for PMB-associated AKI.^14,24,25 The intrarenal perfusion redistribution that results from sepsis, in conjunction with its deleterious effects on renal function, renders the renal tubules more vulnerable to the toxic effects of polymyxin.²⁶ Furthermore, a number of concomitant pharmaceutical agents, including aminoglycosides, vancomycin, and amphotericin B, have been identified in several studies as risk factors for PMB-induced AKI.²⁷ However, these results were not replicated in our analysis.

Limitations

This study is subject to several limitations that should be given due consideration. Firstly, the relatively small sample size may hinder our ability to test all potential factors influencing PMB-associated AKI. Secondly, patients with pre-existing renal dysfunction that had worsened prior to the initiation of PMB therapy were excluded from the study. Dedicated pharmacokinetic (PK) studies are required to elucidate the dose-toxicity relationship of PMB. Thirdly, while no significant differences in concomitant nephrotoxic medication use were observed, residual confounding from unmeasured variables cannot be entirely excluded. In order to enhance our comprehension of PMB-associated AKI, it is imperative to undertake longitudinal follow-up in order to assess long-term renal outcomes. Furthermore, multi-centre and prospective studies with large samples spanning various regions must be conducted.

Conclusions

The precise mechanism of PMB-associated AKI remains to be elucidated, underscoring the imperative for identifying risk factors to ensure its safe clinical application. This study identified concurrent CKD and elevated maintenance doses as potential risk factors for PMB-associated AKI. Therefore, it is crucial to closely monitor renal function parameters. This enables the early detection of nephrotoxic risks and minimises renal injury, ensuring the safe administration of PMB. Multi-centre, prospective studies involving large sample sizes from different regions are essential for advancing our understanding of PMB-associated AKI.

Footnotes

Acknowledgments

We would like to express our gratitude to Wenxin Yiyan (ERNIE Bot version 3.5) for its valuable assistance in enhancing the readability and fluency of the language in this article. The AI tool's contributions have been instrumental in improving the overall quality of our manuscript. We maintain full responsibility for the content and accuracy of the work presented under our names.

ORCID iDs

Long Wen

Xiaohui Liu

Lihua Liu

Jiheng Liu

Authors’ contributions

Long Wen wrote the manuscript. Xiaohui Liu and Jiheng Liu designed the research, Long Wen, Dixuan Jiang, Xiaohui Liu and Lihua Liu performed the research. Xuefeng Yuan analyzed the data.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study received financial support from the Project of Hunan Provincial Health Commission (No.202103020580), the Science and Health Joint Project of the Natural Science Foundation of Hunan Province (No.2021JJ70056) and Natural Science Foundation of Hunan Province (NO.2023JJ60067).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

The data sets analyzed during the present study are available from the corresponding author (gcys2021@126.com) upon reasonable request.

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