Evaluation of the timing of initiating continuous renal replacement therapy in community-acquired septic patients with acute kidney injury

Min Xiao; Bingqi Liu; Mao Zhou; Daqing Wang; Li Chen

doi:10.4103/cjp.cjp_16_21

ORIGINAL ARTICLE

Year : 2021 | Volume : 64 | Issue : 3 | Page : 135-141

Evaluation of the timing of initiating continuous renal replacement therapy in community-acquired septic patients with acute kidney injury

Min Xiao, Bingqi Liu, Mao Zhou, Daqing Wang, Li Chen
Department of Intensive Care Unit, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China

Date of Submission	26-Feb-2021
Date of Decision	27-Apr-2021
Date of Acceptance	04-May-2021
Date of Web Publication	24-Jun-2021

Correspondence Address:
Dr. Li Chen
Department of Intensive Care Unit, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, 637000
China

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/cjp.cjp_16_21

Abstract

Acute kidney injury (AKI) in community-acquired septic patients is often associated with relatively high mortality rate. However, the appropriate timing for continuous renal replacement therapy (CRRT) initiation remains controversial. In the present study, we retrospectively analyzed 123 community-acquired septic patients with AKI admitted to the medical intensive care unit (ICU). The baseline patient characteristics and renal function parameters were compared between survivors and non-survivors. Then, we used the Cox proportional hazard analysis to identify the risk factors for ICU mortality. Moreover, we employed the area under the receiver operating characteristic curve analysis to determine the cutoff time for CRRT initiation. Finally, we used the cutoff time to separate the patients into early (treatment initiated earlier than the cutoff time) and late (treatment initiated later than the cutoff time) CRRT groups and performed the Kaplan–Meier survival analysis to assess the overall mortalities. At the time of ICU release, the mortality rate of the 123 patients was 48.8% (n = 60). We identified several baseline characteristics and renal function parameters that were significantly different between the survivors and the non-survivors. All of them were also identified as the risk factors for community-acquired sepsis. Importantly, the cutoff time point to distinguish the early and late CRRT initiation groups was determined to be 16 h after AKI onset. Based on such grouping, the mortality rate was significantly lower in the early CRRT initiation group at 30, 60 and 90 days. Our data suggest that initiating CRRT within 16 h may help improve the mortality rate of community-acquired septic patients.

Keywords: Renal replacement, sepsis, timing

How to cite this article:
Xiao M, Liu B, Zhou M, Wang D, Chen L. Evaluation of the timing of initiating continuous renal replacement therapy in community-acquired septic patients with acute kidney injury. Chin J Physiol 2021;64:135-41

How to cite this URL:
Xiao M, Liu B, Zhou M, Wang D, Chen L. Evaluation of the timing of initiating continuous renal replacement therapy in community-acquired septic patients with acute kidney injury. Chin J Physiol [serial online] 2021 [cited 2023 May 29];64:135-41. Available from: https://www.cjphysiology.org/text.asp?2021/64/3/135/319285

Introduction

Sepsis and septic shock are the most common cause of acute kidney injury (AKI), accounting for approximately 50% of the total AKI cases in intensive care units (ICU).^[1] Importantly, septic AKI has a higher mortality rate than non-septic AKI.^[2],[3] Around 70% of patients with AKI require renal replacement therapy (RRT).^[1] RRT is known to improve the survival of ICU patients thanks to its correction on metabolic acidosis.^[4] Continuous RRT (CRRT) is employed to treat sepsis-associated renal failure and the outcome is stabilized by enhanced circulation and eliminated inflammatory mediators.^[5] There is evidence suggesting that early diagnosis of sepsis and treatment with antimicrobials can decrease patient mortality.^[6],[7],[8] Despite the fact that RRT may reduce mortality,^{[9],[10],[11]} limited knowledge is obtained on the effectiveness of CRRT on sepsis.^{[12],[13],[14]} Most of the current studies focus on the effect of CRRT on nosocomial sepsis, whereas very few studies have been reported on community-acquired septic patients who require CRRT. In addition, many of the previous trials were performed on general, non-ICU patients; however, septic shock is a life-threatening disease that often requires ICU caring.

Based on the guideline suggested by the Kidney Disease Improving Global Outcomes (KDIGO), the initiation time of CRRT for AKI depends on the severity of changes in fluid, electrolyte, and acid-base balance.^[15] In clinical practice, it is recommended that CRRT should be initiated when the overall condition can be improved, rather than single improvement in single index.^[15] Therefore, no clear consensus has been reached on the optimal timing of CRRT initiation.

In the present study, we analyzed the association between the period from AKI onset to CRRT initiation and ICU mortality to seek the optimal timing of CRRT for community-acquired sepsis.

Materials and Methods

Study design

This was a single-center retrospective study. The study was approved by the review board of North Sichuan Medical College (2019C05251) and performed according to the guidelines from the Helsinki Declaration. Willingness of sharing their medical record for potential research studies was confirmed by all participated patients at the time of admission.

Patients

Patients above the age of 18 years who had primary infections in different internal organs and received CRRT in ICU between 2016 and 2019 were screened for the eligibility of the present study. A total of 312 patients were screened. The exclusion criteria included chronic dialysis (n = 70), previous renal transplantation (n = 10), cardiopulmonary arrest on admission (n = 2), accident-related injuries (n = 2), drug poisoning (n = 3), organ transplantation (n = 1), and pregnancy (n = 7). Patients were also excluded because of non-infectious diseases and secondary infections, e.g. nosocomial infections after surgery. Eventually, we included 123 patients with primary infectious diseases who received CRRT within 72 h after admission for the present study. Detailed flow of patient selection is illustrated in [Figure 1]. Patients' mean arterial pressure was maintained above 65 mmHg using vasopressor therapy, such as norepinephrine.

Figure 1: Patient recruitment flow chart. CRRT: Continuous renal replacement therapy, ICU: Intensive care unit.

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Indications for the initiation of CRRT were followed according to previous description.^[16] Specifically, indications include volume overload that compromises organ function, metabolic acidosis with a pH less than 7.1 to 7.2 or serum bicarbonate level less than 12 to 15 mmol/L, hyperkalemia greater than 6.5 mmol/L after medical management, and onset of uremia and azotemia.

Analyzed variables

AKI onset time was determined based on the change of serum creatinine (SCr) level and urine output measured prior to CRRT initiation. It was defined as the time when the hourly measured urine volume decreased by 0.5 mL/kg/h for 6 h and increased SCr by 0.3 mg/dL or 1.5 times of the baseline values.

AKI was diagnosed based on the KDIGO Clinical Practice Guideline. AKI was confirmed if any of the following criteria were met: an increase in SCr level by more than 0.3 mg/dL (≥26.5 μmol/L) within 48 h after admission, an increase in SCr level by more than 1.5 times presumably within the past 7 days, or a decrease in urine volume by 0.5 mL/kg/h for 6 h. It is worth noting that due to the initiation of CRRT, all patients were classified as stage 3 AKI regardless of the SCr level. Other parameters were measured within 24 h after the initiation of CRRT and ICU admission.

Sepsis was diagnosed when the acute change of at least 2 points in the Sequential Organ Failure Assessment (SOFA) score was identified as a result of the suspected infection.

Clinical outcome definition

The cutoff value of the optimal interval time was determined based on the area under the receiver operating characteristic (AUROC) curve. Once the cutoff was determined, the patients were further divided into two groups who received CRRT within (early) and after (late) 16.5 h. The secondary outcome was conducted by comparing the overall mortalities at 30, 60, and 90 days between the two groups.

Statistics

Patients' demographic characteristics were compared with descriptive statistics. Categorical variables were presented as total number and percentage, whereas continuous variables were presented as medians and interquartile ranges; both of which were analyzed with the Mann–Whitney test. Cox proportional hazard analysis was employed to identify the variables that are related to ICU mortality. Overall mortalities at 30, 60, and 90 days in patients received either early or late CRRT were compared by Kaplan–Meier analysis.

P < 0.05 was considered statistically significant and a two-tailed 95% confidence interval (CI) was used. All statistical analyses were performed with the SPSS 17.0 (IBM, Armonk, NY, USA) software.

Results

Patient characteristics

Data of 123 qualified patients were included in this study and the ICU mortality rate was 48.8% (60 patients). The analyzed patient characteristics are listed in [Table 1]. In general, the SOFA, the acute physiology and chronic health evaluation score II (APACHE II), the simplified acute physiology score II (SAPS II), mechanical ventilation used, respiratory and urinary tract source of infection, and serum bilirubin, sodium, lactate, and procalcitonin were all significantly different between the survivor and non-survivors [Table 1]. Specifically, all the above-mentioned parameters were lower in the survivor group, except for urinary tract infection and procalcitonin level [Table 1]. The significantly higher SOFA, APACHE II, and SAPS II scores in the non-survivor group indicate that these patients suffered more severe organ failure and disease compared to the survivors. In addition, the mechanical ventilator was used significantly more often in the non-survivors, indicating more severe respiratory failure in these patients.

Table 1: Comparison of baseline characteristics of community-acquired septic patients admitted to intensive care unit for continuous renal replacement therapy between survivors and non-survivors

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Evaluation of renal function

A comparison of the renal function parameters between the survivors and non-survivors at the time of AKI occurrence, ICU admission, and CRRT initiation was performed, and the detailed analysis is shown in [Table 2]. At the time of AKI onset, serum lactate, blood urea nitrogen (BUN), creatinine levels, and the amount of urine daily output were all significantly different between the two groups. Specifically, all the measured values for these parameters were higher in the survivors, except for the serum lactate level [Table 2]. Similar outcome was observed at the time of ICU admission, whereas no difference was observed for the BUN level between the two groups and the SCr was higher in the non-survivors [Table 2]. The same outcome was observed at the time of CRRT initiation [Table 2]. Importantly, the time from AKI to CRRT initiation was significantly shorter in the survivors, with a similar CRRT duration [Table 2].

Table 2: Comparison of renal function related parameters of community-acquired septic patients admitted to intensive care unit for continuous renal replacement therapy between survivors and non-survivors

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Evaluation of risk factors for septic patients

Next, we performed Cox proportional hazard analysis for ICU mortality. Besides patients' age and gender, all analyzed parameters that demonstrated significant difference between the survivor and non-survivors, including the interval time from AKI to CRRT initiation, were all identified as risk factors for community-acquired sepsis using univariate analysis [Table 3]. We also applied multivariate analysis on these parameters, but only SOFA, APACHE II, SAPS II scores, mechanical ventilator used, and interval time from AKI to CRRT initiation remained significant [Table 3].

Table 3: Cox proportional hazard analysis for intensive care unit mortality

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Mortality rate comparison between early and late continuous renal replacement therapy initiation

The AUROC curve of the interval time from AKI to CRRT initiation for ICU mortality was 0.823 (95% CI, 0.756–0.904; P < 0.001) [Figure 2]. In addition, the cutoff value of the optimal interval time was 16 h (sensitivity 0.625, specificity 0.804) [Figure 2].

Figure 2: Area under the receiver operating characteristic curve analysis of optimal CRRT initiation time for ICU mortality. AUC: Area under curve, CI: Confidential interval, CRRT: Continuous renal replacement therapy.

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Then, we adopted the cutoff value to compare the overall mortalities at 30, 60, and 90 days using the Kaplan–Meier curve. There were 72 patients in the group that initiated CRRT before 16 h and 51 patients in the group that initiated after. The 30-day mortality rates were 13.9% (10 out of 72) and 39.2% (20 out of 51), respectively (log-rank test, P < 0.0001; HR 2.638; 95% CI, 1.731–4.002) [Figure 3]a. The 60-day mortality rates were 26.4% (19 out of 72) and 54.9% (28 out of 51), respectively (log-rank test, P < 0.0001; HR 2.349; 95% CI, 1.884–2.929) [Figure 3]b. The 90-day mortality rates were 37.5% (27 out of 72) and 70.6% (36 out of 51), respectively (log-rank test, P < 0.0001; HR 2.175; 95% CI, 1.862–2.54) [Figure 3]c. The cumulative mortality rates were significantly different at all three time points between the two groups. Detailed distribution of the cumulative survivors is shown in [Figure 3]d.

Figure 3: 30 days (a), 60 days (b) and 90 days (c) mortality of community-acquired septic patients in the early (within 16 h) and late (more than 16 h) CRRT initiation groups. (d) Cumulative survival data presented in (a-c). CRRT: Continuous renal replacement therapy

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Discussion

The present study evaluated the impact of the timing of CRRT initiation on the mortality of community-acquired septic patients. We first compared the baseline characteristics and renal function parameters between the survivors and the non-survivors and identified a number of factors that were significantly different between the two groups. In addition, all of these factors were also identified as the risk factors for community-acquired sepsis, including the interval time between AKI onset and CRRT initiation. Using the AUROC analysis, we determined the cutoff time point to be 16 h to distinguish the early and late CRRT initiation groups. Subsequent analysis of mortality rate between the two groups verified that the interval time between AKI onset and CRRT initiation was indeed an important aspect that affects the final outcome of sepsis treatment. Nevertheless, given that the SOFA, APACHE II, and SAPS II scores, as well as the frequency of mechanical ventilator usage were also found to be significantly higher in the non-survivors, it is likely that the timing to initiate CRRT might only play a partial role in predicting ICU mortality.

One of the strengths of our study is that we included high severity ICU patients that were specifically suffered from community-acquired sepsis. Data of all 123 patients included in the present study were carefully selected. They not only suffered from community-acquired sepsis-induced AKI, but also received CRRT at certain point during the course of treatment. Their severity can be deduced from the SOFA, APACHE II, and SAPS II scores listed in [Table 1]. We noticed that the patients' SOFA and APACHE II scores may implicate higher expected mortality rates than what was actually observed in the present study. This might be due to the limited follow-up duration of the study and/or the relatively wide distribution range of the scores.

The cause of infection was a bit different between the survivors and non-survivors, although gastrointestinal infection appeared to be the major cause for both groups. Significantly more urinary tract infections and significantly less respiratory infections were found in the survivors, which might provide some indications on the impact of infection origin on survival status of septic patients.

CRRT has been known to improve the survival rate of septic patients by regulating acidosis and inflammatory mediators.^[4],[17] Nonetheless, controversies still exist on the optimal timing of initiating CRRT for survival benefit.^[18] Our results show that CRRT initiation within 16 h of AKI onset is significantly helpful for reducing the mortality rate in community-acquired septic patients, which is consistent with a recent study performed on septic shock patients.^[19] Our cutoff time also falls within the previously suggested range of CRRT initiation time for survival benefit.^{[11],[20],[21]} Intriguingly, many of the previous prospective studies on ICU admitted patients reveal no correlation between the timing of CRRT initiation and patient survival.^{[9],[21],[22],[23]} Recent randomized, controlled trial,^[24] and systematic review and individual patient data meta-analysis^[25] also showed that the timing of RRT initiation did not affect survival in critically ill patients with AKI. On the other hand, several retrospective studies conclude that early CRRT initiation has an impact on the survival rate for sepsis.^{[26],[27],[28]} This discrepancy between the two types of study might be due to the difference in the cutoff time point that separates early and late CRRT initiation.

In the KDIGO Clinical Practice Guideline, the initiation time of CRRT is not clearly defined, and therefore when to start CRRT in practical circumstances is entirely dependent on the doctor's own judgment. Hence, the concept of distinguishing between early and late CRRT initiation does not fall into the concern of most of the prospective studies, resulting in not long enough time intervals between AKI onset and CRRT initiation. The present retrospective study compared the interval time without any ethical limitation, and therefore, our findings are in line with the definition of early CRRT initiation and could be potentially applied to clinical situations concerning community-acquired sepsis. For future research, this kind of practically applicable cutoff time point definition requires validation from further clinical prospective studies.

The present study has a few limitations. First, since it is a single-centered retrospective study, a relatively small patient population with community-acquired sepsis was analyzed. Therefore, generalization of our results to a wider patient population still requires further validation studies on ICU patients with other types of sepsis, as well as multicenter studies. Second, we did not assess any cytokines and biomarkers in relation to the sepsis cases and, therefore, could not provide any indications on the underlying biological mechanisms. Third, we could not follow the specific reasons that decided the initiation of CRRT or individual patients, which might have an impact on the prognosis of community-acquired sepsis.

Conclusion

In summary, we attempt to evaluate the impact of timing of CRRT initiation on community-acquired septic patients. We propose that CRRT should be initiated within 16 h of AKI onset for these patients, with a possibility of reducing their mortality rates.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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