The impact of initiation timing of continuous renal replacement therapy on outcomes in critically ill patients with acute kidney injury: a retrospective study from the MIMIC-IV database

doi:10.21203/rs.3.rs-5177507/v1

Download PDF

Article

The impact of initiation timing of continuous renal replacement therapy on outcomes in critically ill patients with acute kidney injury: a retrospective study from the MIMIC-IV database

https://doi.org/10.21203/rs.3.rs-5177507/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Background

Acute kidney injury (AKI) is common in critically ill patients, optimal timing for initiation of renal replacement therapy (RRT) for AKI but without life-threatening indications is unclear.

Methods

A retrospective study was performed using the Medical Information Mart for Intensive Care (MIMIC-IV), including AKI patients identified based on Kidney Disease Improving Global Outcomes (KDIGO) definition, The time to initiate CRRT was defined as the interval from first diagnosis of AKI to the initiation of CRRT, analyzed as a continuous variable. The primary outcome was 28-day mortality, restricted cubic splines (RCS) to assess the relationship between CRRT initiation timing intervals and clinical outcomes.

Results

The study included 673 patients, with a 28-day mortality rate of 38.78%. RCS analysis revealed no significant association between variations in CRRT timing intervals and 28-day mortality (P > 0.05). In the subgroup of patients with non-renal SOFA scores < 8, observed an increase in 28-day mortality (OR, 1.011 [95% CI, 1.001-1.021], P < 0.05), along with a greater likelihood of reduced 28-day CRRT, mechanical ventilation (MV), and ICU-free days for each 1-hour delay in CRRT initiation (OR, -0.037 [95% CI, -0.064 to -0.010], P < 0.05; OR, -0.051 [95% CI, -0.078 to -0.024], P < 0.05; OR, -0.056 [95% CI, -0.082 to -0.003], P < 0.05).

Conclusion

The findings indicate that while no significant relationship exists between mortality and the timing of CRRT initiation, patients with lower non-renal SOFA scores who initiate RRT promptly may experience improved clinical outcomes. Further exploration and validation require the adoption of novel research methodologies and more pertinent clinical studies.

Health sciences/Diseases

Health sciences/Diseases/Kidney diseases

Health sciences/Nephrology

Health sciences/Nephrology/Kidney

Health sciences/Nephrology/Kidney diseases

Health sciences/Nephrology/Renal replacement therapy

Acute kidney injury

Renal-replacement therapy

Continuous renal replacement therapy initiation time

Acute kidney injury (AKI) is common among critically ill patients and at risk for increased morbidity and mortality[1]. Continuous renal replacement therapy (CRRT) is indicated when medical management is insufficient to maintain fluid balance or when complications of acute kidney injury (AKI) occur[2–5]. Determining the optimal timing of CRRT initiation remains a top research priority in the most recent Kidney Disease Improving Global Outcomes (KDIGO) Conference on Controversies in AKI[6, 7]. In the past decade, considerable attention has been directed toward identifying the optimal timing for the initiation of CRRT. Several randomized controlled trials involving adult populations have examined the influence of initiation timing on CRRT outcomes, yet the findings remain inconclusive[2, 3, 8–11].

This cohort study presents a quantitative analysis focused on the timing of CRRT initiation and its endpoints, aiming to assess the effect of CRRT initiation timing on 28-day mortality in patients with acute kidney injury (AKI) utilizing data from the MIMIC-IV database.

2.1 Study design and setting

We performed a retrospective observational cohort study at a single institution, utilizing data from the Medical Information Mart for Intensive Care IV version 2.2 (MIMIC-IV v2.2)[12], a comprehensive publicly accessible database developed and maintained by the Computational Physiology Lab at the Massachusetts Institute of Technology (MIT). The database, sourced from Beth Israel Deaconess Medical Center in Boston, Massachusetts, USA, encompasses extensive, anonymized clinical data from over 380,000 patients admitted between 2008 and 2019. All data were obtained from PhysioNet (https://physionet.org/) following the completion of data permission applications and the signing of the necessary agreements. The institutional review board waived the necessity for written informed consent and ethical review, as the study utilized de-identified patient data and was conducted retrospectively. After finishing the online training for the Collaborative Institutional Training Initiative program (record ID: 55632299), one author of this study (MN) received access to the database. This study was conducted in compliance with the 2014 revision of the Declaration of Helsinki[13, 14]. This study adheres to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline[15].

2.2 Participants

The study population included 17,385 adult patients diagnosed with AKI as defined by the KDIGO criteria, identified within the MIMIC-IV version 2.2 database. For patients with multiple admissions, only the first hospitalization was taken into account. This analysis excluded individuals who did not receive CRRT, as well as those with a history of end-stage kidney disease (ESKD), peritoneal dialysis, or emergency CRRT necessitated by hyperkalemia (serum potassium level > 6.5 mmol/L), metabolic acidosis (pH < 7.15), or fluid overload unresponsive to diuretics with pulmonary edema prior to the diagnosis of AKI. Furthermore, patients who were pregnant, had malignancies, or had undergone kidney transplantation were also excluded, along with those with missing data exceeding 30% or lacking follow-up information. Ultimately, the final study cohort comprised 673 patients, who were categorized into two groups based on the primary outcome. (Fig. 1).

2.3 Data collection

Data collection was conducted utilizing Structured Query Language (SQL) with PostgreSQL (version 16.1) to extract baseline characteristics, clinical interventions, and outcomes of patients from the MIMIC-IV version 2.2 database. The dataset included demographic information (age, gender, body mass index [BMI]), timing of admission, initiation of CRRT, diagnosis of AKI, source of intensive care unit (ICU) admission, comorbidities, Sequential Organ Failure Assessment (SOFA) score, non-renal SOFA score, severity of AKI, organ support interventions (vasoactive support, mechanical ventilation [MV], CRRT), and clinical outcomes (mortality, length of hospital stay, length of ICU stay). The calculation for 28-day MV, CRRT, and ICU-free days involves subtracting the duration of MV or CRRT utilization, as well as the length of ICU stay, from a total of 28 days. Patients who die within the 28-day period are assigned a value of 0 for this outcome measure, reflecting the competitive nature of this endpoint. Comorbidities were identified using codes from the International Classification of Diseases, 10th Revision (ICD-10) and ICD-9. The minimum serum creatinine (SCr) value recorded prior to ICU admission was utilized as the baseline SCr, while the peak SCr value within 24 hours of AKI diagnosis was recorded as the SCr at the time of diagnosis. The follow-up period commenced upon admission and concluded upon reaching the predefined endpoints of interest.

2.4 Main exposure

The variable of interest was the time to CRRT initiation, anchored to the first diagnosis of AKI. This was defined as the duration (in hours) from the initial diagnosis of AKI to the commencement of CRRT. The diagnosis of AKI was established in accordance with the KDIGO criteria, which encompass any of the following: an increase in SCr of ≥ 0.3 mg/dL (26.5 µmol/L) within 48 hours; an increase in SCr to ≥ 1.5 times the baseline value within the preceding 7 days; or a urine output of < 0.5 mL/kg/hour for a duration of 6 hours[16].

2.5 Primary and secondary outcomes

The primary outcome of the study was 28-day mortality. Secondary outcomes included 90-day mortality, 1-year mortality, the number of 28-day MV-free days, 28-day CRRT-free days, and 28-day ICU-free days. The 28-day mortality was defined as death occurring within 28 days following the diagnosis of AKI. Definitions for 90-day mortality and 1-year mortality were derived from the 28-day mortality. Data on patient deaths in the MIMIC-IV database were obtained from death records during hospitalization or from the Massachusetts Department of Public Health database for deaths recorded post-discharge[12]. The calculation for 28-day MV, CRRT, and ICU-free days involves subtracting the duration of MV or CRRT utilization, as well as the length of ICU stay, from a total of 28 days. Patients who die within the 28-day period are assigned a value of 0 for this outcome measure, reflecting the competitive nature of this endpoint.

2.6 Subgroup Analysis

Subgroup analyses were performed using the same statistical modeling methods applied to the primary outcome, stratified by gender, age, non-renal SOFA score, and history of pre-existing chronic kidney disease (CKD). The subgroup analyses included: (1) male versus female patients; (2) patients aged > 65 years compared to those aged ≤ 65 years; (3) patients with non-renal SOFA scores of < 8 versus ≥ 8; and (4) patients with and without a history of CKD prior to admission. The age subgroup was established based on classifications used in previous studies[2, 4, 8, 10, 17]. For the non-renal SOFA subgroup, participants were stratified according to the median (IQR) of the population. In constructing the baseline table for the non-renal SOFA subgroup, early and late initiation times of CRRT were treated as categorical variables for statistical analysis, with the median CRRT initiation time serving as the categorical cutoff.

2.7 Statistical analysis

Continuous variables were summarized as mean (standard deviation) or median (interquartile range), and group comparisons were performed using the Mann–Whitney U test, depending on the nature of the data. Categorical variables were presented as frequencies and percentages, and comparisons between groups were made using Fisher’s exact test or the Pearson chi-square test. Logistic regression and linear regression analyses were conducted to evaluate the odds ratios (OR) for primary and secondary outcomes, along with the corresponding 95% confidence intervals (CI). This study performed a restricted cubic spline (RCS) analysis to investigate the relationship between CRRT initiation timing intervals and the odds ratio for 28-day mortality. In this analysis, CRRT initiation timing intervals were treated as the independent variable, while the primary outcome was designated as the dependent variable. This approach elucidates the trends in the OR and the 95% CI for 28-day mortality in relation to variations in CRRT initiation timing intervals.

Ordinal regression models were used to explore the trend relationships between 28-day CRRT-free days, MV-free days, ICU-free days, and CRRT initiation time[18]. The outcomes for 28-day CRRT-free days, MV-free days, and ICU-free days were estimated using the ordinal regression model, with a common OR and 95% CI calculated. Subgroup analyses were performed to assess correlations between each subgroup and the primary outcome, with results presented in the form of a forest plot. Kaplan-Meier curves were utilized to illustrate the relationship between the primary outcome and CRRT initiation time across subgroups. The Wald χ² test was applied to evaluate the significance of the interaction term. A two-sided P-value of < 0.05 was considered statistically significant. All statistical analyses were performed using R software, version 4.4.0, IBM SPSS 25.0, Microsoft Excel, and Stata MP18 (64-bit).

3.1 Patient Characteristics

A total of 17385 adults with acute kidney injury (AKI), as defined by KDIGO criteria, were reviewed from the MIMIC-IV database. Ultimately, 673 patients were identified in the final cohort who met the specified inclusion and exclusion criteria (Fig. 1). Among the reviewed patients, 412 (61.22%) were classified into the 28-day survival group, while 261 (38.78%) were categorized as the 28-day non-survival group. The cohort comprised 401 males (59.60%), with a median age of 61.0 years (interquartile range [IQR] 50.0–70.0). The baseline characteristics of the cohort are summarized in Table 1.

Table 1

Demographics and Clinical Characteristics of Patients with and without 28-day survivals
Variables	Total	28-day survival	28-day non-survival	P-value
Variables	N = 673	N = 412	N = 261	P-value
Age, years, median (IQR)	61.00 (50.00–70.00)	60.00 (48.00–69.00)	62.00 (52.00–73.00)	0.012
Male, n (%)	401 (59.60%)	250 (60.70%)	151 (57.90%)	0.467
BMI, Kg/m², median (IQR)	29.98 (25.60–35.07)	29.86 (25.52–35.15)	30.22 (25.60–34.95)	0.662
Time to RRT^a, h, median (IQR)	39.93 (14.23–80.23)	38.96 (13.58–83.13)	40.22 (17.44–73.06)	0.875
Time to AKI^b, h, median (IQR)	6.87 (1.51–10.69)	6.87 (0.99–10.70)	6.85 (2.82–10.83)	0.320
Admission type, n (%)
Elective	150 (22.30%)	92 (22.30%)	58 (22.20%)	0.439
Emergency	327 (48.60%)	120 (46.00%)	207 (50.70%)
Urgent	196 (29.10%)	113 (27.40%)	83 (31.80%)
Comorbidity, n (%)
Hypertension	223 (33.10%)	127 (30.80%)	96 (36.80%)	0.11
Diabetes	206 (30.60%)	110 (26.70%)	96 (36.80%)	0.006
Heart failure	233 (34.60%)	147 (35.70%)	86 (33.00%)	0.468
Myocardial infarction	68 (10.10%)	34 (8.30%)	34 (13.00%)	0.045
Chronic liver disease	196 (29.10%)	105 (25.50%)	91 (34.90%)	0.009
Chronic pulmonary disease	310 (46.10%)	192 (46.60%)	118 (45.20%)	0.724
Chronic kidney disease	406 (60.30%)	231 (56.10%)	175 (67.00%)	0.005
Stroke	40 (5.90%)	27 (6.60%)	13 (5.00%)	0.401
AKI KDIGO stage, n (%)
I stage	80 (11.90%)	50 (12.10%)	30 (11.50%)	0.822
II stage	206 (30.60%)	129 (31.30%)	77 (29.50%)
III stage	387 (57.50%)	233 (56.60%)	154 (59.00%)
Sepsis at ICU admission, n (%)	571 (84.80%)	337 (81.80%)	234 (89.70%)	0.006
MV, n (%)	662 (98.40%)	402 (97.60%)	260 (99.60%)	0.058
Vasoactive support, n (%)	576 (85.60%)	326 (79.10%)	250 (95.80%)	<0.001
Surgery, n (%)	210 (31.20%)	112 (27.20%)	98 (37.50%)	0.005
Baseline SCr, mg/dL	1.20 (0.67–2.10)	1.11 (0.66–2.20)	1.30 (0.68–2.10)	0.251
AKI first SCr, mg/dL	4.40 (4.10–4.80)	4.30 (3.50–4.80)	4.50 (4.20–4.70)	<0.001
SOFA, median (IQR)	11.00 (8.00–14.00)	10.50 (8.00–13.00)	12.00 (8.00–14.00)	0.001
Non renal SOFA, median (IQR)	8.00 (5.00–11.00)	7.00 (5.00–10.00)	9.00 (5.50–11.00)	<0.001
Hospital stay, day, median (IQR)	17.10 (8.19–29.87)	25.18 (15.92–39.67)	7.94 (3.89–13.18)	<0.001
Abbreviation: AKI, acute kidney injury; BMI, Body mass index; IQR, interquartile range; ICU, intensive care unit; GCS, glasgow coma scale; KDIGO, kidney disease improving global outcomes; MV, mechanical ventilation; RRT, renal replacement therapy; SOFA, sequential organ failure assessment; SCr, serum creatinine; ^a time from diagnose of AKI to initiation CRRT therapy; ^b time from admitted ICU to diagnose of AKI;

3.2 Timing of CRRT Initiation

The median time to initiation of CRRT was 39.93 hours (IQR 14.23–80.23 hours). The median time to diagnosis of AKI was 6.87 hours (IQR 1.51–10.69 hours). Upon comparison of CRRT initiation timing with primary and secondary outcomes, no significant associations were identified (refer to supplementary material eFig. 1). Regression analysis examining the correlation between outcomes and CRRT initiation timing indicated that, although mortality rates and the number of 28-day free days did not demonstrate statistically significant differences, each one-hour delay in CRRT initiation was associated with an 8.0% increase in the likelihood of prolonged hospital stay (hospital stay: OR, 0.08 [95% CI, 0.044–0.118]; P < 0.05) (refer to supplementary material eTable 2, eFig. 2).

3.3 Primary and Secondary Outcomes

The primary outcome of the study was 28-day mortality, with 261 patients (38.78%) dying during this period. Secondary outcomes are summarised in Table 1. Among the 673 patients who received CRRT, restricted cubic spline (RCS) analysis indicated that 28-day mortality was not significantly associated with the timing of CRRT initiation (P > 0.05, Fig. 2A). Furthermore, linear regression analyses examining the relationship between CRRT initiation timing and both primary and secondary outcomes revealed no statistically significant differences in 28-day mortality, 90-day mortality, 1-year mortality, 28-day CRRT-free days, 28-day MV-free days, or 28-day ICU-free days (P > 0.05, Fig. 2B, C, D) (refer to supplementary material eTable. 2).

3.4 Subgroup Analysis

The timing of CRRT initiation was not statistically associated with primary or secondary outcomes. Consequently, subgroup analyses were conducted to explore the relationships between primary and secondary outcomes and CRRT initiation timing within specific populations. These analyses were performed based on gender, age, non-renal SOFA score, and history of pre-existing CKD (Fig. 3).

In the subgroup with non-renal SOFA scores < 8, each 1-hour delay in CRRT initiation was associated with a 1.1% increase in the odds of 28-day mortality (OR, 1.011 [95% CI, 1.001–1.021], P < 0.05, Fig. 3). Kaplan-Meier curves for 28-day mortality in relation to CRRT initiation timing demonstrated that the survival rate in the non-renal SOFA < 8 group was significantly higher compared to the non-renal SOFA ≥ 8 subgroup (P < 0.05, Fig. 4). Notably, the slope of the Kaplan-Meier curve for the non-renal SOFA < 8 group was relatively shallow at the initiation of CRRT, becoming steeper with further delays in initiation (Fig. 4). This observation indicates that the slope of the Kaplan-Meier curve reflects the rate of increase in 28-day mortality as the time to CRRT initiation lengthens. Furthermore, the RCS analysis comparing the non-renal SOFA < 8 group and time to CRRT initiation revealed that the odds ratio for 28-day mortality during the immediate CRRT initiation phase increased with delays in initiation, with statistically significant findings (non-renal SOFA < 8: P < 0.05 vs non-renal SOFA ≥ 8: P > 0.05, eFig. 3).

In the non-renal SOFA < 8 group, secondary outcomes such as 90-day mortality and 1-year mortality also increased with longer time to CRRT initiation (P < 0.05, Fig. 5). Conversely, the number of 28-day CRRT-free days, MV-free days, and ICU-free days decreased with increasing time to CRRT initiation (P < 0.05, Fig. 5). In the non-renal SOFA ≥ 8 group, the correlations between secondary outcomes and time to CRRT initiation were not statistically significant (P > 0.05, Fig. 5). Each 1-hour delay in CRRT initiation was associated with a decrease in 28-day CRRT-free days, MV-free days, and ICU-free days, with the following odds ratios: 28-day non-CRRT days: OR, -0.037 [95% CI, -0.064 to -0.010], P < 0.05; 28-day non-MV days: OR, -0.051 [95% CI, -0.078 to -0.024], P < 0.05; and 28-day non-ICU days: OR, -0.056 [95% CI, -0.082 to -0.003], P < 0.05 (refer to supplementary material eTable. 3).

This cohort study examined the timing of CRRT initiation in patients with acute kidney injury using data from the MIMIC-IV database[12]. Unlike previous studies that imposed strict definitions for early and delayed initiation, this study did not specify exact hour thresholds for CRRT initiation[4, 10, 11, 19, 20]. The primary outcome was 28-day mortality, with no significant difference in CRRT initiation timing between the survival and non-survival groups. Secondary outcomes did not demonstrate any association with CRRT initiation timing.

Recent randomized controlled trials[10, 11, 19, 20] have investigated the timing of renal replacement therapy (RRT), but their findings have yielded conflicting results. Most knowledge regarding the relationship between RRT timing and clinical outcomes has emerged from observational studies and their meta-analyses, which have suggested potential benefits of early RRT[21, 22]. However, these studies often contain substantial biases. A common limitation across both observational and randomized trials is the grouping of participants at fixed time points for CRRT initiation or severity, leading to inconsistencies. For instance, Gaudry et al[23], in a study involving over 600 patients, found no significant difference in 60-day mortality when comparing early versus delayed RRT strategies[24]. Another referenced study reported that patients received RRT at a median of 2 hours following randomization in the early strategy and at 57 hours in the delayed strategy; contrary to their hypothesis, no survival benefit was observed for the delayed group.

In the current study, conventional group categorizations were discarded in favour of observing CRRT initiation time as a continuous variable. This approach aimed to determine the optimal time point for CRRT initiation by analysing its effect on the primary outcome (28-day mortality). The methodology employed restricted cubic spline (RCS) curves to represent the relationship between CRRT initiation time and outcome metrics, a technique not previously applied in studies of CRRT timing but observed in other domains. For instance, a recent study identified an optimal body mass index (BMI) interval using RCS curves, revealing a J-shaped association between BMI and all-cause mortality, with the lowest mortality at 25 kg/m²[25]. In this study, the median CRRT initiation time for all patients was 39.93 hours (IQR 14.23–80.23). Despite utilising 28-day mortality as the primary outcome and defining CRRT initiation time as the duration from AKI diagnosis to CRRT commencement, the analysis revealed that while the odds ratio (OR) for 28-day mortality fluctuated during the observation period, this trend did not reach statistical significance, as it included 1 within the 95% CI (P > 0.05, Fig. 2). Consistent with previous research[2, 11, 23, 26], this study found no correlation between 28-day mortality and the timing of CRRT initiation.

Secondary outcomes, including 90-day mortality, 1-year mortality, 28-day CRRT-free days, MV-free days, and ICU-free days, were also analysed to assess the optimal timing for CRRT initiation. In these analyses, 90-day mortality was shown to differ from 28-day mortality, as the OR decreased progressively with delays in CRRT initiation, although the 95% CI still crossed 1, indicating no statistical significance (P > 0.05). The trend for 1-year mortality mirrored a flatter upward curve correlating with CRRT initiation time but remained statistically insignificant (Fig. 2). Previous studies noted a lower 90-day mortality associated with early RRT initiation[2], however, there were no significant differences concerning non-MV days or overall hospital days. Notably, while no statistical differences were found in primary or secondary outcomes, an increase in the length of hospital stay was observed with prolonged time to CRRT initiation, likely due to the study’s exclusive focus on patients receiving CRRT.

Further analysis was performed on several subgroups based on baseline characteristics and disease severity. Subgroup analyses for the primary outcome were conducted according to gender, age, non-renal SOFA score, and history of CKD. In the subgroup with non-renal SOFA < 8, earlier CRRT initiation yielded a lower OR for mortality, with 28-day mortality increasing with delays in CRRT initiation, particularly sustained up to the 50-hour mark (Fig. 3). Similarly, this subgroup exhibited statistically significant reductions in 90-day and 1-year mortality, as well as increases in 28-day CRRT-free days, MV-free days, and ICU-free days (P < 0.05, Fig. 4). While some studies have suggested that early CRRT initiation might extend ICU and MV days[23], the findings of this study contradict this, possibly because all participants in this study underwent CRRT. A comparable trend was observed in patients with a history of comorbid CKD, although subgroup comparisons were limited due to the small number of patients without prior CKD.

The subgroup with non-renal SOFA < 8 was further analysed, and the baseline characteristics of the two subgroups are detailed in the Supplementary Material (see Supplementary Material eTable 3). Analysis of these baseline characteristics revealed that the median age of the non-renal SOFA < 8 group was 68.00 years (IQR 52.00–73.00), compared to a median age of 59.00 years (IQR 48.00–69.00) in the other group, indicating a significant age difference. In terms of comorbidities, the non-renal SOFA < 8 subgroup exhibited a higher prevalence of a history of diabetes and heart failure, suggesting that this subset of older patients with multiple chronic conditions may benefit from the early initiation of CRRT. A recent post hoc analysis of the AKIKI trial[27], however, presented conclusions that contrast with those of the current study. The authors stratified the original AKIKI cohort into septic and ARDS phenotypes, concluding that early initiation of renal replacement therapy (RRT) in this vulnerable subset of patients with concurrent ARDS or sepsis was associated with an increased 60-day mortality rate. However, a thorough examination of the results section of this study indicates that the mean SOFA score was 11, with no statistically significant difference in average scores between the two phenotypes. Importantly, this mean SOFA score is higher than that observed in our study. The authors additionally stratified the subjects according to their SOFA scores into three subgroups: 3–10, 10–13, and 13–20. The forest plot presented illustrates that the hazard ratio (HR) for the SOFA (3–10) subgroup is consistently below 1, indicating that more refined stratification of SOFA scores may yield further insights. Alternatively, employing a scoring methodology similar to the non-renal SOFA scoring utilized in this study could prove advantageous. Furthermore, a subset of patients in the late-stage cohort of the AKIKI trial did not receive CRRT, with all non-CRRT patients classified within this late-stage group. This allocation might artificially lower the mortality rates in the late-stage cohort, potentially leading to an overestimation of mortality rates in the early-stage group. Given various confounding factors (as discussed at the conclusion of this study), we chose to exclude patients who did not receive CRRT from our analysis. Consequently, this study specifically targets the subgroup of patients who received CRRT, aiming to assess whether they derive any benefits from the earlier initiation of this therapeutic intervention. Previous observational studies[17] have indicated that early initiation of CRRT can reduce mortality among patients receiving RRT. Potential explanations for this include improved management of extracellular fluid volume, acid-base balance, and electrolyte abnormalities with earlier RRT initiation. Additionally, the prompt removal of toxins that accumulate due to impaired kidney function may facilitate faster clinical recovery. Although patients in this study with lower non-renal SOFA scores had a more fragile renal function due to their advanced age and multiple comorbidities, early initiation of CRRT was more likely to preserve renal function and mitigate other factors contributing to poor outcomes. In contrast, patients with higher non-renal SOFA scores faced multiple confounding risk factors associated with multi-organ dysfunction, which overall elevated mortality rates, suggesting that early CRRT initiation may not significantly alter final outcomes in this group.

While this study did not demonstrate any clinical outcome benefits associated with variations in RRT initiation timing in the absence of emergency criteria, subgroup analyses indicated that among patients with low non-renal SOFA scores, those who initiated RRT as early as possible experienced improved clinical outcomes, primarily reflected in reduced mortality and increased 28-day CRRT-free days, mechanical ventilation-free days, and ICU-free days. Furthermore, this study represents the first attempt to utilize restricted cubic spline (RCS) curves to treat CRRT initiation time as a continuous variable, aiming to identify the optimal initiation time in conjunction with outcome metrics amidst variations in CRRT initiation timing. Although a definitive optimal CRRT initiation time could not be established in this study, the effects of variations in outcomes with changes in CRRT initiation time were detectable in subgroup analyses, providing a foundation for future exploration of optimal CRRT initiation timing in more specific patient populations.

This study has several limitations. First, we included only patients who received continuous renal replacement therapy among the eligible cohort. During the screening process within the MIMIC-IV database, it proved challenging to identify patients who did not undergo CRRT following the diagnosis of acute kidney injury after excluding those with indications for urgent CRRT initiation. To mitigate bias, we deliberately excluded all patients who met the inclusion criteria but did not receive CRRT, and we aim to explore improved database screening methodologies in future research. The second limitation is inherent to the MIMIC database, which is a single-center, retrospective observational study; thus, the potential for selection bias is unavoidable. To address this concern, we implemented rigorous screening criteria based on nadir values and conducted subgroup analyses to compare differences between the unused subgroups and primary outcomes. Lastly, the inability to extract the latest biomarkers associated with acute renal insufficiency, as well as certain specialized laboratory indicators, poses a limitation due to the constraints of the database. Consequently, we could not assess prognosis in conjunction with these contemporary biomarkers. Future research will seek to supplement our findings by exploring additional databases to enhance the robustness of our results.

In conclusion, this study showed no significant relation of mortality between the variation of initiation time of RRT in patients with severe acute kidney injury but with no immediate, life-threatening complications linked to acute kidney injury, but patients with low non-renal SOFA, those who initiated RRT as early as possible benefited in clinical outcomes. Further exploration and validation require the adoption of novel research methodologies and more pertinent clinical studies.

Ethics and consent statement

The Medical Information Mart for Intensive Care-IV database was supported by grants from the National Institute of Biomedical Imaging and Bioengineering (NIBIB) of the National Institutes of Health (NIH) under award numbers R01-EB001659 (2003–2013) and R01-EB017205 (2014–2018). In these databases, the true identity information about the patient is hidden. Thus, obtaining the patient’s informed consent was not needed. The author of this study (MN) completed the relevant course training and obtained the certificate to access these databases (record ID: 55632299).

Consent for publication

All authors were aware of and approved the publication.

Data availability statement

The MIMIC-IV database is available from https://mimic.physionet.org. The raw data were extracted using structure query language (SQL) and PostgreSQL, as well as using Excel 2019, R software, version 4.4.0, IBM SPSS 25.0 and Stata MP18 (64-bit) for data entry and analysis, respectively.

Funding

This work was supported by the Beijing Municipal Natural Science Foundation (No. 7224335).

CRediT authorship contribution statement

Mangsuer Nuermaimaiti and Ran Lou: created the study protocol, Mangsuer Nuermaimaiti and Meiping Wang: performed the statistical analyses, and wrote the first manuscript draft. Li Jiang and Meiping Wang assisted the analysis and explained statistical methods, Mangsuer Nuermaimaiti and Nan Wang collaborated on writing the code for data extraction from the database and data extraction. Tingting Wang and Quan Si assisted in screening and verifying the accuracy of the extracted data. Quan Si assisted in funding acquisition. Li Jiang assisted with manuscript revision and data confirmation. Li Jiang and Mangsuer Nuermaimaiti contributed to data interpretation and manuscript revision. All authors read and approved the final manuscript.

Declaration of competing interest

The authors declare that they have no competing interests.

Kellum JA, Romagnani P, Ashuntantang G, Ronco C, Zarbock A & Anders HJ. Acute kidney injury. Nature Reviews Disease Primers 2021; 7:52.
Zarbock A, Kellum JA, Schmidt C, Van Aken H, Wempe C, Pavenstadt H, Boanta A, Gerss J & Meersch M. Effect of Early vs Delayed Initiation of Renal Replacement Therapy on Mortality in Critically Ill Patients With Acute Kidney Injury: The ELAIN Randomized Clinical Trial. JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION 2016; 315:2190-2199.
Wald R, Kirkham B, DaCosta BR, Ghamarian E, Adhikari N, Beaubien-Souligny W, Bellomo R, Gallagher MP, Goldstein S, Hoste E, Liu KD, Neyra JA, Ostermann M, Palevsky PM, Schneider A, Vaara ST & Bagshaw SM. Fluid balance and renal replacement therapy initiation strategy: a secondary analysis of the STARRT-AKI trial. CRITICAL CARE 2022; 26:360.
Wald R, Gaudry S, Da CB, Adhikari N, Bellomo R, Du B, Gallagher MP, Hoste EA, Lamontagne F, Joannidis M, Liu KD, McAuley DF, McGuinness SP, Nichol AD, Ostermann M, Palevsky PM, Qiu H, Pettila V, Schneider AG, Smith OM, Vaara ST, Weir M, Dreyfuss D & Bagshaw SM. Initiation of continuous renal replacement therapy versus intermittent hemodialysis in critically ill patients with severe acute kidney injury: a secondary analysis of STARRT-AKI trial. INTENSIVE CARE MEDICINE 2023; 49:1305-1316.
Wald R & Bagshaw SM. Integration of Equipoise into Eligibility Criteria in the STARRT-AKI Trial. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 2021; 204:234-237.
Ostermann M, Bellomo R, Burdmann EA, Doi K, Endre ZH, Goldstein SL, Kane-Gill SL, Liu KD, Prowle JR, Shaw AD, Srisawat N, Cheung M, Jadoul M, Winkelmayer WC & Kellum JA. Controversies in acute kidney injury: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference. KIDNEY INTERNATIONAL 2020; 98:294-309.
Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. NEPHRON 2012; 120:c179-c184.
Pan HC, Chen YY, Tsai IJ, Shiao CC, Huang TM, Chan CK, Liao HW, Lai TS, Chueh Y, Wu VC & Chen YM. Accelerated versus standard initiation of renal replacement therapy for critically ill patients with acute kidney injury: a systematic review and meta-analysis of RCT studies. CRITICAL CARE 2021; 25:5.
Zampieri FG, Da CB, Vaara ST, Lamontagne F, Rochwerg B, Nichol AD, McGuinness S, McAuley DF, Ostermann M, Wald R & Bagshaw SM. A Bayesian reanalysis of the Standard versus Accelerated Initiation of Renal-Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial. CRITICAL CARE 2022; 26:255.
Chen WY, Cai LH, Zhang ZH, Tao LL, Wen YC, Li ZB, Li L, Ling Y, Li JW, Xing R, Liu XY, Lin ZD, Deng ZT, Wang SH, Lin QH, Zhou DR, He ZJ & Xiong XM. The timing of continuous renal replacement therapy initiation in sepsis-associated acute kidney injury in the intensive care unit: the CRTSAKI Study (Continuous RRT Timing in Sepsis-associated AKI in ICU): study protocol for a multicentre, randomised controlled trial. BMJ Open 2021; 11:e40718.
Fayad AI, Buamscha DG & Ciapponi A. Timing of kidney replacement therapy initiation for acute kidney injury. Cochrane Database of Systematic Reviews 2022; 11:D10612.
Johnson A, Bulgarelli L, Shen L, Gayles A, Shammout A, Horng S, Pollard TJ, Hao S, Moody B, Gow B, Lehman LH, Celi LA & Mark RG. MIMIC-IV, a freely accessible electronic health record dataset. Scientific Data 2023; 10:1.
Czarkowski M. [Helsinki Declaration--next version]. Pol Merkur Lekarski 2014; 36:295-297.
Snaedal J. [The Helsinki Declaration]. Laeknabladid 2014; 100:135.
Vandenbroucke JP, von Elm E, Altman DG, Gotzsche PC, Mulrow CD, Pocock SJ, Poole C, Schlesselman JJ & Egger M. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration. PLOS MEDICINE 2007; 4:e297.
Lameire NH, Bagga A, Cruz D, De Maeseneer J, Endre Z, Kellum JA, Liu KD, Mehta RL, Pannu N, Van Biesen W & Vanholder R. Acute kidney injury: an increasing global concern. LANCET 2013; 382:170-179.
Wald R & Bagshaw SM. The timing of renal replacement therapy initiation in acute kidney injury: is earlier truly better?*. CRITICAL CARE MEDICINE 2014; 42:1933-1934.
Liu Q, Shepherd BE, Li C & Harrell FJ. Modeling continuous response variables using ordinal regression. STATISTICS IN MEDICINE 2017; 36:4316-4335.
Gist KM, Menon S, Anton-Martin P, Bigelow AM, Cortina G, Deep A, De la Mata-Navazo S, Gelbart B, Gorga S, Guzzo I, Mah KE, Ollberding NJ, Shin HS, Thadani S, Uber A, Zang H, Zappitelli M & Selewski DT. Time to Continuous Renal Replacement Therapy Initiation and 90-Day Major Adverse Kidney Events in Children and Young Adults. JAMA Network Open 2024; 7:e2349871.
Jeong R, Wald R & Bagshaw SM. Timing of renal-replacement therapy in intensive care unit-related acute kidney injury. Current Opinion in Critical Care 2021; 27:573-581.
Schneider AG, Uchino S & Bellomo R. Severe acute kidney injury not treated with renal replacement therapy: characteristics and outcome. NEPHROLOGY DIALYSIS TRANSPLANTATION 2012; 27:947-952.
Gaudry S, Ricard JD, Leclaire C, Rafat C, Messika J, Bedet A, Regard L, Hajage D & Dreyfuss D. Acute kidney injury in critical care: experience of a conservative strategy. JOURNAL OF CRITICAL CARE 2014; 29:1022-1027.
Gaudry S, Hajage D, Schortgen F, Martin-Lefevre L, Pons B, Boulet E, Boyer A, Chevrel G, Lerolle N, Carpentier D, de Prost N, Lautrette A, Bretagnol A, Mayaux J, Nseir S, Megarbane B, Thirion M, Forel JM, Maizel J, Yonis H, Markowicz P, Thiery G, Tubach F, Ricard JD & Dreyfuss D. Initiation Strategies for Renal-Replacement Therapy in the Intensive Care Unit. NEW ENGLAND JOURNAL OF MEDICINE 2016; 375:122-133.
Bellomo R, Cass A, Cole L, Finfer S, Gallagher M, Lo S, McArthur C, McGuinness S, Myburgh J, Norton R, Scheinkestel C & Su S. Intensity of continuous renal-replacement therapy in critically ill patients. NEW ENGLAND JOURNAL OF MEDICINE 2009; 361:1627-1638.
Bhaskaran K, Dos-Santos-Silva I, Leon DA, Douglas IJ & Smeeth L. Association of BMI with overall and cause-specific mortality: a population-based cohort study of 3.6 million adults in the UK. Lancet Diabetes & Endocrinology 2018; 6:944-953.
Barbar SD, Dargent A & Quenot JP. Timing of Renal-Replacement Therapy in Acute Kidney Injury and Sepsis. NEW ENGLAND JOURNAL OF MEDICINE 2019; 380:399.
Gaudry S, Hajage D, Schortgen F, Martin-Lefevre L, Verney C, Pons B, Boulet E, Boyer A, Chevrel G, Lerolle N, Carpentier D, de Prost N, Lautrette A, Bretagnol A, Mayaux J, Nseir S, Megarbane B, Thirion M, Forel JM, Maizel J, Yonis H, Markowicz P, Thiery G, Tubach F, Ricard JD & Dreyfuss D. Timing of Renal Support and Outcome of Septic Shock and Acute Respiratory Distress Syndrome. A Post Hoc Analysis of the AKIKI Randomized Clinical Trial. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 2018; 198:58-66.

No competing interests reported.

SupplementContent.docx

Download PDF

Reviews received at journal
10 Nov, 2024
Reviewers agreed at journal
01 Nov, 2024
Reviewers agreed at journal
30 Oct, 2024
Reviewers invited by journal
30 Oct, 2024
Editor assigned by journal
30 Oct, 2024
Editor invited by journal
20 Oct, 2024
Submission checks completed at journal
16 Oct, 2024
First submitted to journal
29 Sep, 2024

You are reading this latest preprint version

The impact of initiation timing of continuous renal replacement therapy on outcomes in critically ill patients with acute kidney injury: a retrospective study from the MIMIC-IV database

Status:

Version 1

Abstract

Figures

1 Introduction

2 Methods

2.1 Study design and setting

2.2 Participants

2.3 Data collection

2.4 Main exposure

2.5 Primary and secondary outcomes

2.6 Subgroup Analysis

2.7 Statistical analysis

3 Results

3.1 Patient Characteristics

3.2 Timing of CRRT Initiation

3.3 Primary and Secondary Outcomes

3.4 Subgroup Analysis

4 Discussion

5 Conclusions

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1