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.