Optimal timing of initiating continuous renal replacement therapy in septic shock patients with acute kidney injury

Acute kidney injury (AKI) in patients with septic shock is associated with high mortality, but the appropriate timing for initiating continuous renal replacement therapy (CRRT) is controversial. We retrospectively enrolled 158 septic shock patients with AKI in the medical intensive care unit (ICU) from July 2016 to April 2018. The time from AKI onset to CRRT initiation was compared according to ICU mortality using Cox proportional hazard, receiver operating characteristic, and Kaplan-Meier survival analyses. At the time of ICU discharge, the mortality rate was 50.6% (n = 80). It took longer to initiate CRRT in non-survivors than in survivors (hazard ratio 1.009; 95% confidence interval [CI] 1.003–1.014; P = 0.002). The cut-off time from AKI onset to CRRT initiation for ICU mortality was 16.5 hours (area under the curve 0.786; 95% CI 0.716–0.856; P < 0.001). The cumulative mortality rate was significantly higher in patients in whom CRRT was initiated beyond 16.5 hours after AKI onset than in those in whom CCRT was initiated within 16.5 hours (log-rank test, P < 0.001). Several clinical situations must be considered to determine the optimal timing of CRRT initiation in these patients. Close observation and CRRT initiation within 16.5 hours after AKI onset may help improve survival.

We began our research with the following practical and basic questions. How do the time from AKI onset to CRRT initiation influence on the survival of septic shock patients? When is the optimal timing to initiate CRRT in septic shock patients with AKI? Therefore, in this study, we analysed the relationship between the period from AKI onset to CRRT initiation and ICU mortality and attempted to suggest an appropriate timing of CRRT to increase the survival rate in septic shock patients with AKI.
comparison of renal function. A comparison of the renal function parameters at the time of AKI occurrence, ICU admission, and initiation of CRRT is shown in A comparison of the time from AKI to CRRT initiation showed that survivors received CRRT earlier than non-survivors (9 hours vs. 26 hours, P < 0.001). However, there was no statistically significant difference in the duration of CRRT between the survivors and non-survivors (78 hours and 67 hours, respectively; P = 0.607).
Mortality rate of patients who initiated cRRt early and late. The area under the receiver operating characteristic (AUROC) curve of the interval time from AKI to CRRT initiation for ICU mortality was 0.786 (95% CI, 0.716-0.856; P < 0.001). The cut-off value of the optimal interval time was within 16.5 hours (sensitivity 0.638, specificity 0.821), as shown in Fig. 1.

Discussion
Renal failure is associated with high mortality in critically ill patients, especially patients with septic shock. Several trials have determined ways to predict decreased renal function and to improve clinical outcomes [16][17][18] . Recently, a new method, using machine leaning, is being studied to develop a prediction algorithm for AKI 19 . However, various clinical situations must be considered, and in some cases, renal dysfunction progresses rapidly, so it is still not easy to predict decreased renal function early. Thus, appropriate interventions at the right time are more important factors for improving hospital outcomes of septic shock patients with renal failure.
In critically ill patients, organ failures are associated with mortality, and the RRT in patients with AKI is known to improve the clinical course 20 . Especially, in patients with septic shock, RRT plays an additional role in modulating immune responses and influencing circulating levels of inflammatory mediators, unlike with other patients primarily requiring replacement of renal function 5,7 . And it is known to be more effective and hemodynamically stable in CRRT than IHD 6 .
However, in the KDIGO guideline, the initiation time of RRT is described to as 'when life-threatening changes' , and it is more ambiguous when trying to initiate the CRRT clinically, because physicians are required to consider various situations 9 . Therefore, many researches on the timing and variables associated with the initiation of CRRT have been performed. In the prospective study, time limits for early and late initiation of CRRT were set up previously, and various outcomes including the survival rate were observed in the two randomized groups. However,  because of the ethical concern associated with the time limit of the intervention, life threatening patients were excluded and time limits for initiation of CRRT was not enough long. Since patients with septic shock are at high severity and intervention within a time has an impact on survival rate, it is not an appropriate way 12,21 .
In this study, we retrospectively reviewed medical records and determined the time of AKI occurrence according to the KDIGO definition. Focused on the mortality, clinically most important outcome, we compared the interval time from AKI to CRRT initiation to find optimal time points without setting the time limit first. Even if patients were admitted to the ICU, the cases who had applied CRRT not for the septic shock were excluded from the study. 895 patients were admitted to the medical ICU about 2 years, 158 of whom were enrolled to our research. Our study population included severe septic shock patients who did not simply occurred AKI but also required CRRT. Their severity was demonstrated in Table 1 as SOFA, APACHE II and SAPS II score. Unexpectedly, the renal function at the time of AKI occurrence, WBC count, and procalcitonin level, which indicates the severity of infections, were higher in survivors, but the HR for ICU mortality did not increase statistically. However, the interval time from AKI to CRRT initiation and mechanical ventilator use were different between the groups. It took a longer time to initiate CRRT after AKI in non-survivors than in survivors, and non-survivors used mechanical ventilator more frequently than survivors. The HR was also proven to increase ICU mortality significantly, suggesting that the interval time from the onset of AKI to CRRT initiation is an independent risk factor for ICU mortality. Only the patients who did not agree with the do not resuscitate (DNR) order and who were assertive in treatment were enrolled; the duration of CRRT was long enough in both groups, and the patients had no significant risk factors.
The causes of infection were slightly different between the groups according to outcomes. Urinary tract infection was more frequent in survivors than in non-survivors, while respiratory infection was more common in non-survivors than survivor, although there was no statistical difference. We cautiously suggest that clinician's follow-up and estimate the decrease in renal function more carefully in septic shock patients with urinary tract infection, and initiate CRRT earlier in these patients. CKD stage 5, which is an indication of RRT, was an exclusion criterion when selecting the study population, and there was no statistically difference in a history of CKD as a comorbid disease according to survival (Table 1).
In patients with septic shock, RRT is thought to improve the survival rate by correcting acidosis and inflammatory mediators 3,4 . However, there is still controversy regarding the modality of dialysis and optimal timing of initiating interventions for survival benefit 13,15,22 . On the basis of our study's results, we think that CRRT initiation within 16.5 hours increases the survival rate in patients with septic shock. However, many of the previous prospective studies on ICU patients found that early CRRT did not increase the survival rate in these patients 10,11,[23][24][25][26] . The conclusion that early CRRT is related with an increased survival rate was mostly proven by a retrospective study 13,14,27 . Perhaps, in the prospective study, the interval time for early versus late CRRT could not be long enough to make a difference in ICU mortality.
Most studies have shown that the appropriate initiation time of CRRT for survival benefit is usually within 24 hours form AKI, but the range varied from 8 hours to 18 days 10,12,28 . Herein, we analysed the interval time to predict ICU mortality using the receiver operating characteristic curve. The optimal timing for initiating CRRT was within 16.5 hours from AKI occurrence. There was also significant survival benefit in the group that initiated CRRT within 16.5 hours from AKI onset when comparing overall mortalities at 28, 60, and 90 days.
The severity of patients enrolled in this study was high because they were septic shock, and this is one of the strengths of this study compared with previous prospective studies 11,25 . This 16.5 hours is located in the gray zone, which is not included in the protocols of early vs. late application in recent two prospective studies [Artificial Kidney Initiation in Kidney Injury (AKIKI) trial 11   www.nature.com/scientificreports www.nature.com/scientificreports/ studies have evaluated patients with septic shock; however, most of them included all patients admitted to the ICU, so the severity of patients was not high. Thus, it was difficult to apply these results directly to septic shock patients with a relatively high severity in clinical practice.
According to the KDIGO Clinical Practice Guideline for AKI, unlike the definition of AKI, the initiation time of RRT was not clearly defined; thus, it was based on clinical judgment. Therefore, the concept of distinguishing between early and late CRRT was defined arbitrarily depending on the authors, and time intervals from AKI to RRT was not long enough because of the ethical issue in prospective studies. Consequently, although early initiation of CRRT may affect the survival rate positively, it was difficult to suggest the appropriate timing for initiating CRRT. In the present retrospective study, we did not specify the concept of distinguishing early from late CRRT before the comparison, and the interval time of AKI to CRRT initiation was compared without the ethical concern associated with the time limit of the intervention. Therefore, we are convinced that the optimal timing of CRRT initiation suggested by our research findings is in accordance with the definition of early CRRT and could be generally applied in various clinical situations of septic shock patients. Furthermore, practical cut-off time from AKI to CRRT initiation is needed for the prospective validation study. In this regard, we presented the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for each cut-off time for ICU mortality in Supplementary Table 1. The Kaplan-Meier curve also showed a difference between the two groups even after 24 hours of cut-off. (Supplementary Fig. 1) Therefore, we expect future researchers to proceed with the prospective validation using cut-off time from 16 hours to 24 hours. But finally, practical cut-off time should be decided by each researcher in the future.
Nevertheless, this study has several limitations. First, RRT is known to improve the survival rate in septic shock patients with AKI, but it is necessary to compare whether CRRT or IHD is better. Because this study included septic shock patients with high severity who required ICU management, it is difficult to compare the detailed parameters of RRT, such as the dialysis interval, period of dialysis, and choice of CRRT or IHD. However, in patients who have suspected infections more frequently than septic shock, it is also necessary to determine which modality would be better considering the risks and benefits, clinically. Second, this study was conducted with a small sample size from a single institution, and it is not yet possible to generalise our findings to various patient groups. Future validation studies of other types of ICUs and multicentre studies are needed. Third, we could not analyse the specific reasons for CRRT initiation in septic shock patients with AKI. Subgroup analysis according to the reasons for CRRT initiation may have an impact on the prognosis of septic shock patients with AKI.
The timing of initiating CRRT cannot be determined based on only a few variables; thus, it is necessary to consider various clinical situations. Herein, we tried to determine the appropriate timing that could be applied to various clinical conditions, especially septic shock. We recommend careful observation when treating septic shock patients with AKI, and CRRT should be initiated within 16.5 hours of AKI onset, if possible, to help increase survival rates.

Methods
Study design and patient population. This study was a single-centre, retrospective cohort study, and the study protocol was approved by the institutional review board (IRB) of Severance Hospital (IRB number: 4-2018-0769) and performed in accordance to the Helsinki declaration. Individual patient data were stored as encrypted file and only authorized investigators were able to access the personal medical records to protect the privacy of patients. Informed consent was waived because the study was retrospective in design. determine the change of SCr and urine output measured before CRRT initiation. AKI was diagnosed based on the KDIGO Clinical Practice Guideline for AKI definitions. AKI was defined as any of the following: an increase in the SCr level by ≥0.3 mg/dL (≥26.5 µmol/L) within 48 hours; an increase in the SCr level to ≥1.5 times the baseline, which is known or presumed to have occurred within the last 7 days; or a decrease in the urine volume <0.5 mL/kg/h for 6 hours. If a patient presented with AKI without a baseline SCr level, it could be estimated using the Modification of Diet in Renal Disease (MDRD) Study equation, assuming that the baseline eGFR is 75 mL/ min per 1.73 m 2 = 186 × (SCr)-1.154 × (age)-0.203 × (0.742 for women) × (1.210 for black patients) 9 . As the renal function parameters, SCr and eGFR were calculated using the MDRD equation, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation, and CKD-EPI Cystatin C equation at the initiation of CRRT; additionally, the neutrophil gelatinase-associated lipocalin and cystatin C levels were recorded.
When the urine output was recorded hourly, the time point of decreased urine volume <0.5 mL/kg/h for 6 hours was defined as the time of AKI occurrence. Otherwise, the time point assumed that the increased SCr level was ≥0.3 mg/dL or ≥1.5 times the baseline based on the laboratory findings. The values of other parameters were measured within 24 hours at the time of CRRT initiation and ICU admission.
Septic shock was defined based on The Third International Consensus Definitions for Sepsis and Septic Shock. Sepsis was diagnosed when the acute change of at least 2 points in the Sequential Organ Failure Assessment (SOFA) score was associated with suspected infection. Septic shock was a subset of sepsis, and the following criteria were required for diagnosis: a sepsis status and the requirement of vasopressor therapy to increase the mean arterial pressure (MAP) ≥65 mmHg and increase the lactate level >2 mmol/L (18 mg/dL) despite adequate fluid resuscitation 29 . clinical outcomes. We performed the study by setting the study population and goals close to the aforementioned definitions and criteria as possible. First, based on the KDIGO guideline, which is accepted undisputedly, we determined the time of AKI occurrence, and then we calculated the time to initiation of CRRT.
As the primary outcome, the optimal interval time was analysed according to ICU mortality using the AUROC curve. After determining the cut-off time by the AUROC curve, we divided patients into the two groups who initiated CRRT within and after 16.5 hours without previously specify the point to distinguish between early versus late CRRT. The secondary outcome was a comparison of the overall mortalities at 28, 60, and 90 days between the two groups.