A comparison of early versus late initiation of renal replacement therapy for acute kidney injury in critically ill patients: an updated systematic review and meta-analysis of randomized controlled trials

We screened PubMed, EMBASE and Cochrane databases between January 1, 1985, and June 30, 2016, to identify randomized trials that assessed the timing of initiation of RRT in patients with AKI. The search strategies were restricted to human RCTs and English language. Studies published before 1985 were excluded because there has been great progress in RRT technology and critical care practices in recent years.

The following keywords or medical subject headings were used: “acute kidney injury”, “acute kidney”, “acute renal”, “renal replacement therapy”, “renal replacement”, “hemodialysis”, “hemofiltration”, “dialysis”, “dialyzed”, “dialyzing”, “time to treatment”, “time”, “timing”, “initiation”, “start”, “accelerate”, “accelerated”, “accelerating”, “acceleration”, “early”, “earlier”, “late”. The search was slightly adjusted according to the requirements of the different databases. The authors’ personal files and reference lists of relevant review articles were also reviewed. The flow chart of the search strategies is summarized in Fig. 1.

Studies reporting the timing of RRT initiation in patients with AKI were selected for further review. The inclusion criteria were as follows: (1) randomized controlled trials; (2) adult critically ill population; and (3) clearly comparing early versus late RRT initiation with effect on mortality and/or clinically relevant secondary outcomes. We excluded studies without clear comparisons of the outcomes. A cursory review of titles and abstracts was independently performed by two reviewers (Xiao-mei Yang and Guo-wei Tu). Disagreement on the inclusion/exclusion of RCTs was resolved through consensus and, if necessary, consultation with a senior investigator (Zhe Luo). Retained RCTs were reviewed in detail.

Data extracted included basic characteristics (author’s name, publication year, country of study, study period, study design, patient population, duration of follow-up, total number of patients, mean age, percentage of male), definition of “early” and “late” RRT, main characteristics at the time of RRT initiation (modality, creatinine, urine output, acute physiology and chronic health evaluation [APACHE II] score, sequential organ failure assessment [SOFA] score). The primary outcome was mortality, including 14-day mortality, 28-day mortality, 30-day mortality, 60-day mortality, 90-day mortality, ICU mortality, and in-hospital mortality. The longest follow-up mortality reported in the individual studies was extracted for the pooling analysis. Secondary outcomes included the ICU length of stay (LOS), hospital LOS, recovery of renal function, RRT dependence, duration of RRT, renal recovery time and mechanical ventilation time.

The quality of evidence of each study was assessed (Xiao-mei Yang and Jian Gao) according to the guidelines of the GRADE Working Group (http://​www.​gradeworkinggrou​p.​org/​index.​html), using the GRADE profiler (version 3.6.1, http://​ims.​cochrane.​org/​revman/​gradepro) and GRADE handbook to determine the quality of evidence and strength of recommendation.

Meta-analysis was performed using the relative risks (RRs) for binary outcome and weighted mean difference (WMD) for continuous outcome measures. Alternatively, when there was no event in either groups during the follow-up, we used relative difference (RD), defined as the difference in the incidence rate of the early RRT group from that in the late RRT group. Data were pooled using a random effects model based on the inverse variance approach to give a more conservative estimate of the effect, allowing for any heterogeneity between studies. Statistical heterogeneity among studies was assessed by using the Q statistic and I² statistics [14]. Meta-analyses were performed using RevMan 5.3 (Cochrane IMS, Oxford, UK, http://​ims.​cochrane.​org/​revman/​download). All additional analyses were performed by using Stata/MP 12.1 (Stata Corp, College Station, TX, USA). A P-value < 0.05 was set as the threshold of statistical significance. Neither ethics board approval nor patient consent was required due to the nature of a systematic review.

Risk of bias was assessed independently by 2 reviewers (Xiao-mei Yang and Guo-wei Tu) as recommended in the Cochrane Handbook, which includes 6 domains: selection bias, performance bias, detection bias, attrition bias, reporting bias, and other potential sources of bias. When there was insufficient information to allocate a high or low score, an “unclear” risk score was allocated. Disagreements in score allocations were resolved through group discussion. Publication bias was assessed using funnel plots, Begg’s test and Egger’s test [15], with P < 0.1 indicative of reporting biases.

A total of 1020 potentially relevant citations were identified and screened from databases. We retrieved 23 articles for full-text review, and 14 were excluded based on eligibility criteria. Nine RCTs fulfilled all criteria for the final meta-analysis (Fig. 1). All studies were written in English.

The basic characteristics of the studies selected are shown in Table 1. A total of 1636 patients were enrolled. Of these studies, four of the studies were multi-center studies [12, 16‐18], four were single-center studies [13, 19‐21], and one was a two-center study [22]. Three studies examined only patients following cardiac surgery [17, 19, 20], whereas the remaining six studies were mixed with medical or surgical patients [12, 13, 16, 18, 21, 22]. The follow-up time reported in these studies ranged from 14 to 90 days.

The definition of early and late initiation of RRT for each specific study is outlined in Table 2. Five studies used urine output and/or serum creatinine or serum urea nitrogen or creatinine clearance for defining early and late RRT [18‐22], two studies started early RRT when with diagnosis of severe sepsis or post-cardiac surgery shock [16, 17], and the latest two studies in 2016 used Kidney Disease: Improving Global Outcomes (KIDGO) stage 2 or stage 3 to define early RRT [12, 13]. In most of the studies, late RRT was defined as a classic indication, including azotemia, oliguria, pulmonary edema, hyperkalemia and metabolic acidosis. The individual studies defined early and late RRT by using variable cutoff values in serum creatinine or urine output.

The modality of RRT varied significantly among the individual studies (Table 3). The modality of continuous vena-venous hemofiltration (CVVH) was used in five studies [13, 16, 17, 20, 22] and intermittent hemodialysis (IHD) was used in two studies [19, 21]. In the remaining two studies, some of the patients received CVVH modality, and the others received IHD or sustained low-efficiency dialysis (SLED) modality [12, 18]. At the time of initiation of RRT, the early group had serum creatinine ranging from 1.7 to 7.4 mg/dL and urine output from 400 to 1543 ml/day while the late group had serum creatinine ranging from 1.8 to 10.4 mg/dL and urine output ranging from 150 to 1491 ml/day (Table 3). Several studies reported illness severity measured by APACHE II score and SOFA score before RRT initiation. The APACHE II score ranged from 19 to 30.6 in the early group and 18 to 32.7 in the late group, whereas the SOFA score ranged from 7.6 to 15.6 in the early group and 8.2 to 16 in the late group (Table 3).

The definition of mortality reported in these studies differed considerably, including 14-day mortality [20], 28-day mortality [12, 13, 16, 22], 30-day mortality [17], 60-day mortality [12, 13, 17], 90-day mortality [13, 17, 18], ICU mortality [17, 18, 22], and in-hospital mortality [17‐19, 21, 22]. We selected the longest follow-up mortality of each study as the primary end point. Figure 2 showed the mortalities of individual studies and pooled analysis. The total number of participants was 827 in the early group, with 338 deaths, and 809 in the late group, with 344 deaths. Pooled analysis of the studies indicated no mortality benefit with “early” RRT, with an RR of 0.98 (95% CI 0.78 to 1.23, P = 0.84). However, there was relatively high statistical heterogeneity with an I² value of 60% (P = 0.01).

To explore the factors that may result in heterogeneity, several subgroup analyses were performed. Analyses grouped by patient population (post cardiac surgery versus multisystem), by RRT modality (CVVH versus IHD or IHD/CVVH), by study design (single center versus multicenter), by study sample size (≥100 versus <100), by duration of follow-up (≥100 days versus <100 days), by urine output (significant difference versus no significant difference between early and late RRT group), by creatinine (significant difference versus no significant difference between early and late RRT group), or by KDIGO classification of early RRT group (stage 1–2 versus stage 3) demonstrated no significant difference in the overall effect estimates. Meta-regression analyses showed no statistically significant association between RR and patient population, RRT modality, study design, study sample size, duration of follow-up, urine output, creatinine, and KDIGO classification (Table 4, Figs. 3 and 4).

The analysis of secondary outcomes included the ICU LOS, hospital LOS, recovery of renal function, RRT dependence, duration of RRT, renal recovery time and mechanical ventilation time. Due to the variability in the reporting of ICU LOS and hospital LOS, we performed a pooled analysis for subgroups, including ICU LOS/hospital LOS in survivors and nonsurvivors. There was no significant difference in ICU LOS and heterogeneity between early and late RRT group for survivors or nonsurvivors (Fig. 5). A similar subgroup analysis performed on hospital LOS also showed no significant difference (Fig. 6). Seven of the nine studies reported recovery of renal function and RRT dependence. Pooled analysis also demonstrated no significant change in renal function recovery (RR 1.02, 95% CI 0.88 to 1.19, I² = 59%; Fig. 7) or RRT dependence (RR 0.76, 95% CI 0.42 to 1.37, I² = 0%; Fig. 8) between the early and late RRT groups. Three studies reported the duration of RRT [13, 17, 21], two studies reported renal recovery time [21, 22] and three studies reported mechanical ventilation time [13, 17, 22]. Pooled analysis of these studies showed no significant increase in duration of RRT in early RRT (Mean difference 1.43, 95% CI -1.75 to 4.61, I² = 78%; Fig. 9), renal recovery time (Mean difference 0.73, 95% CI -2.09 to 3.56, I² = 70%; Fig. 10) or mechanical ventilation time (Mean difference − 0.95, 95% CI -3.54 to 1.64, I² = 64%; Fig. 11).

One critical outcome (the overall mortality of patients) and 7 important outcomes, including ICU LOS of survivors, hospital LOS of survivors, renal function recovery, renal recovery time, duration of RRT, RRT dependence and mechanical ventilation time, were evaluated using the GRADE system. The level of evidence quality was moderate for overall mortality and low for other secondary outcomes (Table 5).

Several RRT-related complications were reported in the studies, including hemorrhage, thrombocytopenia, thrombosis, hypokalemia, hypophosphatemia, hyperkalemia, RRT-associated arrhythmia, RRT-associated seizure, hypothermia, catheter infection and hypotension during RRT (Table 6). We found no significant differences in complications between the early and late RRT groups, with no heterogeneity between trials, except for hypophosphatemia (I² = 92%; P < 0.0001).

Risk of bias is shown in Fig. 12. Of the nine studies, two studies did not report random sequence generation, and three studies did not report allocation concealment and were thus considered to have an unclear risk of bias. Overall, the included RCTs had a low risk of bias. The funnel plot was symmetrical (Fig. 13), which indicated the absence of publication bias between the trials included in our meta-analysis (P = 0.832, Egger’s test; P = 0.917, Begg’s test).