Introduction

Acute kidney injury (AKI) is a common complication in critically ill patients, and the incidence of AKI patients requiring dialysis has also increased recently1,2,3. The development of AKI can be associated with increased morbidity, mortality and health-care costs1,4,5. Renal replacement therapy (RRT) remains the primary supportive strategy in the management of critically ill patients with severe AKI. However, in spite of improvements in RRT technology, such as the advent of continuous renal replacement therapy (CRRT) for patients with unstable hemodynamics, the mortality of patients with AKI requiring RRT remains high6,7,8. Several issues need to be addressed to improve the outcomes of these critically ill patients, such as the appropriate time to initiate RRT, the optimal intensity, and the choice of modality for RRT.

In common practice, RRT is usually initiated for acute management of life-threatening complications of AKI such as severe hyperkalemia, pulmonary edema, refractory metabolic acidosis, uremic pericarditis, and uremic encephalopathy9. Beyond these indications however, the appropriate timing for initiating RRT in critically ill patients is unknown. Early initiation of RRT is supposed to achieve better fluid and electrolyte balance, superior acid-base homeostasis, and more efficient removal of uremia toxins than standard therapy. Through these mechanisms, early RRT may help prevent AKI -associated kidney-specific or other vital organ injuries10,11,12,13. However, early RRT carries risks of several adverse events including vascular access placement-associated complications, catheter-related infections, bleeding due to the use of anticoagulants, too rapid changes in electrolytes, unnecessary clearance of important medications, delayed recovery of renal function and increased costs13,14. Several randomized controlled trials15,16,17,18,19,20,21,22,23 (RCTs) were conducted to find the optimal timing of RRT for critically ill AKI patients, but no consistent results were found. In 2018, one large RCT24 focused on patients with septic shock and severe AKI in the IDEAL-ICU trial found no significant difference in 90-day mortality between patients with early and delayed initiation of RRT. Their findings were consistent with those in another multicenter RCT by the AKIKI study group22, but were contrary to the findings of a recent single-center RCT in the ELAIN trial23. All of these findings indicate uncertainty about the usefulness of early RRT in critically ill patients. Although this issue had been discussed in one meta-analyses25 recently, we aimed to conduct an updated systematic review and meta-analysis of RCTs to assess the efficacy of early initiation of RRT in critically ill AKI patients.

Materials and Methods

Study search and selection

This systematic review and meta-analysis were conducted according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement (Supplemental Table 1). All clinical studies were identified by a systematic review of the literature in the PubMed, Embase, and Cochrane databases until August 13, 2019 using the following Mesh terms – “earl*”, “accelerat*”, “acute kidney”, “acute renal”, “anuria”, “oliguria”, “acute renal failure”, “anuria”, “oliguria”, “organ failure”, “dialy*”, “renal replacement”, “hemodialysis”, “hemofiltration”, “hemodiafiltration”, “RCT*” and “random*”. We excluded observation studies, case reports or case series, studies enrolling pediatric patients, and conference abstracts, and therefore, only RCTs that compared the clinical efficacy of early RRT and late RRT for critically ill adult patients with AKI were included. In addition, we searched all references in the relevant articles and reviews for additional eligible studies. Two reviewers (Chang & Wang) searched and examined publications independently to avoid bias. When they disagreed, another author (Lai) resolved the issue. The data included authors, year of publication, study design and duration, study population, sites of study, disease severity, indications for early RRT, and outcomes. Ethics board approval and patient consent were not required due to the nature of a systematic review. This meta-analysis was performed according the guidelines of Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA).

Definitions and outcome

The primary outcome was 28-day mortality and secondary outcomes included recovery of renal function, RRT dependence among survivors and adverse events.

Data analysis

We used the Cochrane Risk of Bias tool to evaluate the quality of enrolled studies and the risk of bias26. The statistical analysis was conducted using the software Review Manager, version 5.3. The degree of heterogeneity was evaluated with the Q statistic generated from the χ2 test. The proportion of statistical heterogeneity was assessed by the I2 measure. Heterogeneity was considered significant when the p-value was less than 0.10 or the I2 more than 50%. The fixed effects model and the random effects model were applied when the data was homogenous and heterogeneous, respectively. Pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated for outcome analyses. Funnel plot was used to probe for publication bias. A p-value <0.05 was set as the threshold of statistical significance. Sensitivity analyses were conducted by excluding or subgrouping studies to reduce the potential confounding effects of patient population, RRT modality, study design, and study sample size.

Results

Study selection and characteristics

The search program yielded 807 references, including 207 from Pubmed, 325 from Embase, and 274 from the Cochrane database. Then, 425 articles were screened for title and abstract after excluding 382 duplicated articles. Finally, a total of eleven RCTs15,16,17,18,19,20,21,22,23,24,27 fulfilling the inclusion criteria were included in this meta-analysis (Fig. 1, Supplemental Table 2). All the studies15,16,17,18,19,20,21,22,23,24 were designed to compare the clinical efficacy of early and late RRT for critically ill patients with AKI (Table 1). During the initial enrollment, early and late RRT was applied for 1131 and 1111 patients, respectively. Four studies17,18,20,23 were conducted in a single center, and other seven were multicenter studies15,16,19,21,22,24,27. Six studies were performed in Europe15,16,19,22,23,24, four studies were conducted in Asia17,18,20,27, and one study21 was done in North America. The modalities of RRT varied, including mixed intermittent hemodialysis (IHD)/CRRT in three studies21,22,24, CRRT only in six studies15,16,19,20,23,27, and IHD only in two studies17,18. Two studies19,24 only enrolled patients with sepsis, and more than half of enrolled patients had sepsis in another three studies21,22,27. Figure 2 show the analyses of risk of bias. The risk of allocation concealment, the risk of blinding of participants and personnel, and the risk of blinding of outcome assessment were classified as high or unclear.

Figure 1
figure 1

Flowchart of the study selection for the meta-analysis.

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Table 1 Characteristics of enrolled studies.
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Figure 2
figure 2

Risk of bias in each study and domain.

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Primary outcomes

In the eleven enrolled trials, the pooled 28-day mortality was 38.1% (431/1131) and 40.7% (453/1111) in the groups of patients assigned to early and late RRT, respectively, with no significant difference between groups (RR, 0.95; 95% CI, 0.78–1.15, I2 = 63%, Fig. 3). Sensitivity analysis after deleting an individual study each time to reflect the influence of the single dataset on the pooled RR showed similar findings. The publication bias was shown in funnel plot (Fig. 4). We found no differences between early and late RRT in terms of 60-day mortality RR, 0.96; 95% CI, 0.75–1.23, I2 = 31%) in four studies16,22,23,24, and 90-day mortality (RR, 0.97 95% CI, 0.64–1.45, I2 = 0%) in four studies16,21,23,24. Four studies reported the ICU mortality15,16,21,24 and five studies15,16,17,18,21 showed in-hospital mortality. The pooled ICU mortality (RR, 1.16; 95% CI, 0.88–1.52, I2 = 0%) and in hospital-mortality (RR, 1.25; 95% CI, 0.74–2.11, I2 = 49%) were similar between groups.

Figure 3
figure 3

Forest plot for 28-day mortality.

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Figure 4
figure 4

Funnel plot for 28-day mortality.

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In the four studies16,17,20,23 that only enrolled surgical patients, the early RRT group had a lower risk of mortality than the late RRT group (RR, 0.52; 95% CI, 0.27–0.99, I2 = 77%). There were no significant differences in terms of mortality between groups in the analysis of other subgroups, including mixed study populations, study sites, study designs, portion of patients with sepsis and RRT modality (Table 2).

Table 2 Subgroup analysis.
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Secondary outcomes

Six studies15,20,22,23,24,27 reported the rate of RRT dependence in survivors on day 28, and no significant difference was found between early and late RRT groups (RR, 0.90; 95% CI, 0.67–1.25, I2 = 0%, Fig. 5). The five studies16,18,21,23,24 that reported the rate of RRT dependence on day 90, showed similar rates in the two groups (RR, 0.76; 95% CI, 0.30–1.90, I2 = 0%). The recovery of renal function was reported in eight studies15,16,18,20,21,22,23,27, with similar rates in the two groups (RR, 1.03; 95% CI, 0.89–1.19, I2 = 56%, Fig. 6).

Figure 5
figure 5

Forest plot for dialysis-dependence among survivors on day 28.

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Figure 6
figure 6

Forest plot for renal function recovery.

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Adverse events

We assessed the rates of several common adverse events during RRT including hemorrhage, hypotension, arrhythmia, catheter-related infection, hypokalemia, hyperkalemia, metabolic acidosis and hypophosphatemia. A pooled analysis of five studies15,18,21,22,27 reporting the risk of catheter-related infections showed the early RRT group had a higher risk of this infection than late RRT group (RR, 1.7, 95% CI, 1.01–2.97, I2 = 0%) The early RRT group had a higher risk of hypophosphatemia than the late RRT group in a pooled analysis of 3 studies16,22,27 (RR, 2.5, 95% CI, 1.25–4.99, I2 = 77%). There were no significant differences between early and late groups in terms of hemorrhage (RR, 0.88, 95% CI, 0.68–1.14, I2 = 0%) in seven studies15,16,18,21,22,23,24, hypotension (RR, 1.11, 95% CI, 0.96–1.29, I2 = 0%) in six studies16,18,21,23,24,27, arrhythmia (RR, 1.21, 95% CI, 0.83–1.77, I2 = 36%) in six studies17,21,22,23,24,27, hypokalemia (RR, 1.11, 95% CI, 0.83–1.47, I2 = 24%) in three studies16,22,27, and hyperkalemia (RR, 0.52, 95% CI, 0.17–1.61, I2 = 57%) in three studies16,22,24. Pooled analysis of two studies16,24 showed that the early RRT group had a lower risk of metabolic acidosis than the late RRT group (RR, 0.60, 95% CI, 0.39–0.90, I2 = 0%).

Discussion

This meta-analysis of eleven RCTs with 1131 and 1111 AKI patients receiving early and late RRT, respectively, provided several significant findings. Most importantly, early RRT was not associated with a better outcome for these patients than late RRT. Overall, there was no significant difference in 28-day mortality between groups. There were no differences with different study sites (Europe, Asia or North America), study designs (single or multi-center), portion of patients with sepsis (50–<100%, or 100%) or RRT modality (IHD, CRRT, mixed). The early and late RRT groups had similar ICU-, hospital-, 60 day- and 90 day- mortality rates. All these findings are consistent with previous meta-analyses25,28,29,30, and indicate that early RRT does not provide additional survival benefits for AKI patients compared with late RRT. In addition to mortality, Pasin et al.25 ever showed that early RRT was associated with a significant reduction in length of hospital stay. However, the positive impact of early RRT on the length of hospital stay still need further confirmation in the high-quality studies.

Subgroup analysis of four studies16,17,20,23 that only enrolled surgical patients showed that the early RRT group had a lower risk of mortality than the late RRT group (RR, 0.52; 95% CI, 0.27–0.99, I2 = 77%). This finding is consistent with the result of a previous meta-anlaysis31 of nine retrospective cohort studies and two RCTs showing a lower 28-day mortality rate the early RRT group (OR = 0.29, 95% CI, 0.16–0.52, p < 0.0001) than the late RRT group among critically ill patients with AKI after cardiac surgery. However, both that meta-analysis31 and our findings in surgical patients were based on studies with very high heterogeneity. Further research with a larger number of studies and consistent results is still needed to confirm this finding in surgical patients.

We also found no differences in the recovery of renal function or RRT dependency in the early and late RRT groups. In Karvellas et al.’s meta-analysis32 of 15 studies, early RRT was associated with greater renal recovery than late RRT. However, only two RCTs were enrolled in that meta-analysis32, and the quality of those heterogeneous studies varied. In contrast, the present analysis only enrolled large-scale RCTs, and our findings were consistent with other meta-analyses29,30,33 of RCTs. These results should be more convincing than Karvellas et al.'s meta-analysis32. Therefore, based on current evidence, early RRT was not associated with greater renal recovery and lower dialysis dependence than late RRT for critically ill patients with AKI.

We cannot omit another important issue of RRT – safety. We evaluated the risks of several common complications during RRT. Although the incidence of most adverse events such as hemorrhage, hypotension, arrhythmia, hypokalemia and hyperkalemia were similar between groups, the early RRT group had higher risks of catheter-related infections, and hypophosphatemia than the late RRT group. Overall, our findings should remind clinicians to keep alert concerning the high risks of these two complications in early RRT for patients with AKI.

Although this meta-analysis enrolled several large-scale RCTs with a reasonable quality to enhance the level of evidence, there was one major limitation. There was relatively high heterogeneity with an I2 value of more than 50% in the outcome analysis. These heterogeneities could be caused by significant variations in the study design, population characteristics, disease severity, timing of initiating RRT, modality of RRT, and duration of follow-up in the studies.

Conclusion

This meta-analysis suggested that early RRT does not improve the survival, RRT dependence, or renal function recovery of critically ill patients with AKI in comparison with late RRT. Early RRT was associated with a lower 28-day mortality than late RRT in surgical patients with AKI. However, clinicians should be vigilant as early RRT can carry higher risks of catheter-related infection and hypophosphatemia during dialysis than late RRT.