Impact Of Renal Replacement Therapy On Mortality And Renal Outcomes in Critically Ill Patients With Acute Kidney Injury: A Population-Based Cohort Study in Korea Between 2008 And 2015V Ⅱ

3. Results 

A total of 124,182 ICU patients who were diagnosed with AKI were analyzed: 56.5%, 12.2%, and 31.3% in the control, dialysis, and CRRT groups, respectively (Table 1). The average proportion of AKI patients who received CRRT was 31.1% during the study period, which increased steadily from 24.1% in 2008 to 36.7% in 2014. During the same period, the in-hospital mortality rate of patients who received CRRT increased by 1% (58.9–59.7%) (Figure 2). 

Table 1. Patient characteristics. 

Values are numbers and proportions, except for age, Charlson index (mean and standard deviation), and total cost (median and interquartile range). CRRT, continuous renal replacement therapy; ECMO, extracorporeal membrane oxygenation. Dialysis was defifined as intermittent hemodialysis and peritoneal dialysis. * USD 1 = KRW 1158 (exchange rate as of 1 December 2015)

The mean patient age (SD) was 67.1 ± 15.2 years, and 59.2% of the patients were men. The dialysis and CRRT groups included younger patients (control vs. dialysis and CRRT: 69.4% vs. 64.5% and 64.0%, p < 0.001), were more likely to include males (57.4% vs. 60.1% and 62.0%, p < 0.001), had a higher proportion of pre-existing kidney diseases (11.0% vs. 39.3% and 19.2%, p < 0.001), and showed more frequent admission in tertiary hospitals (28.8% vs. 40.6% and 57.5%, p < 0.001) than the control group. Among the three groups, MV (80.3%), ECMO (5.1%), and vasopressor drugs (49.5%) were most frequently used in the CRRT group. 

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The in-hospital mortality rate was significantly higher in the CRRT group than in the control and dialysis groups (control vs. dialysis vs. CRRT; 30.8% vs. 24.4% vs. 59.0%; p < 0.001) (Table 2). Even after adjustment for several confounders, the CRRT group had a significantly higher in-hospital mortality than the control and dialysis groups (fully adjusted or compared with the control group 2.04 (95% CI, 1.98–2.11, p < 0.001)). When the association between RRT and in-hospital mortality was evaluated depending on the pre-existing kidney disease, the CRRT group showed a significantly higher risk of in-hospital mortality in both subgroups (fully adjusted or compared with the control group; 2.10 (95% CI, 2.03–2.17) in the subgroup without pre-existing kidney disease vs. 1.70 (95% CI, 1.56–1.84) in the subgroup with pre-existing kidney disease). In the dialysis group, the in-hospital mortality of the subgroup without pre-existing kidney disease was comparable with that of the control group (fully adjusted or compared with the control group 0.98 (95% CI, 0.93–1.03)). However, the dialysis subgroup with pre-existing kidney disease showed lower in-hospital mortality (fully adjusted OR compared with the control group 0.67 (95% CI, 0.61–0.74)).

The median hospital LOS among survivors (n = 77,185) was 17 days (IQR, 9–31), 25 days (IQR, 14–43), and 29 days (IQR, 16–53) in the control, dialysis, and CRRT groups, respectively (Table 3). The dialysis group was more likely to have a longer hospital and ICU LOS than the control group. ICU LOS in the CRRT group was 43% longer than that in the control group. The association between RRT and LOS was consistent regardless of pre-existing kidney diseases. 

In all patients who were discharged, the median follow-up of AKI patients was 365 days (IQR 128–365 days). During the 47,141.1 person-years of the follow-up period, 3433 (4.45%) patients progressed to ESKD (incidence rate 72.8/1000 person-years). The incidence rate of ESKD was higher in the dialysis and CRRT groups than in the control group (control vs. dialysis vs. CRRT groups; 16.2 vs. 463.8 vs. 126.5 per 1000 person-years). In the Kaplan–Meier survival analyses, the cumulative incidence of ESKD was significantly higher in the dialysis group than in the control and CRRT groups (log-rank test, p < 0.001) (Figure 3).

Figure 2. Yearly trends of acute kidney injury and in-hospital mortality according to renal replacement therapy modality: (a) Bars and lines represent the absolute numbers and the proportion of critically ill patients with AKl among all intensive care unit patients, respectively. The proportion of patients who received CRRT increased steadily from 24.1% in 2008 to 36.7% in 2014.; (b) Bars and lines represent the absolute number of deaths and the mortality of critically ill patients with AKl, the mortality rate of patients who received CRRT increased by 1% for 7 years (58.9% in 2008 and 59.7% in 2014)

Compared with the control group, the age- and gender-adjusted HRs for ESKD were 25.48 (95% CI, 21.30–30.48) and 7.74 (95% CI, 6.59–9.10) in the dialysis and CRRT groups, respectively. This association remained signifificant after further adjustment for multiple confounders (fully adjusted HR compared with the control group: 17.67 (95% CI, 15.06–20.72) in the dialysis group and 7.28 (95% CI, 6.29–8.41) in the CRRT group) (Table 4). In patients with pre-existing kidney disease, the risk of ESKD in the dialysis and CRRT groups was higher than that in the control group (fully adjusted HR compared with the control group; dialysis vs. CRRT groups, 15.15 (95% CI, 12.88–17.83) vs. 5.83 (95% CI, 4.89–6.96); p < 0.001). In patients without pre-existing kidney disease, the risk of ESKD was even higher in both dialysis and CRRT groups than in the control group (fully adjusted HR; dialysis vs. CRRT groups, 20.06 (95% CI, 16.06–25.05) vs. 8.86 (95% CI, 7.30–10.76); p < 0.001). 

Table 2. Risk of hospital mortality according to RRT modalities and pre-existing kidney disease.

Values are numbers and proportions, except for age, Charlson index (mean and standard deviation), and total cost (median and interquartile range). CRRT, continuous renal replacement therapy; ECMO, extracorporeal membrane oxygenation. Dialysis was defined as intermittent hemodialysis and peritoneal dialysis. * USD 1= KRW 1158 (exchange rate as of 1 December 2015).

Figure 3. Cumulative incidence of end-stage kidney disease (ESKD) according to the modality of renal replacement therapy: All patients (a); patients with pre-existing kidney disease (b); and patients without pre-existing kidney disease (c); the risk of ESKD was the highest in the dialysis group with pre-existing kidney disease. 

Table 3. Hospital and ICU length of stay according to RRT modalities and pre-existing kidney disease. 

ICU, intensive care unit; RRT, renal replacement therapy; CRRT, continuous renal replacement therapy; IQR, interquartile range; CI, confidence interval. an Adjusted for differences in the type of hospital, history of comorbidity (myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, rheumatologic disease, liver disease, diabetes, kidney disease (adjusted only overall group), cancer, AIDS/HIV), mechanical ventilator, vasopressor drugs, and extracorporeal membrane oxygenation. b Ratios and 95% CI were estimated from linear regression with a log-transformed variable as the outcome.

Table 4. Risk of end-stage kidney disease (ESKD) according to RRT modalities and pre-existing kidney disease.

RRT, renal replacement therapy; CRRT, continuous renal replacement therapy. Model 1 was adjusted for age and gender. Model 2 was further adjusted for type of hospital, history of comorbidity (myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, rheumatologic disease, liver disease, diabetes, kidney disease (adjusted only overall group), cancer, AIDS/HIV), mechanical ventilator, vasopressor drugs, and extracorporeal membrane oxygenation. 

4. Discussion

This study investigated the overall outcomes of AKI depending on the type of RRT and pre-existing kidney disease in critically ill adult patients using a nationwide population-based cohort in Korea during a 7-year period. The CRRT group had a signifificantly higher risk of in-hospital mortality, whereas the dialysis group showed lower in-hospital mortality than the control group. Specifically, among the patients without pre-existing kidney disease, in-hospital mortality was higher in the CRRT group, and the incidence of ESKD was also higher in both dialysis and CRRT groups than in the control group. These results suggest that severe AKI that develops as a consequence of multiorgan failure may exert a critically adverse impact on patient survival and renal outcomes. Further, the lower in-hospital mortality in the dialysis group may indicate the importance of appropriate RRT in the treatment of AKI in critically ill patients. 

Previous prospective randomized studies comparing the effects of dialysis and CRRT showed no difference in mortality between the two treatment modalities [19–21]. One meta-analysis of 30 randomized controlled trials and eight prospective cohort studies found no difference in all-cause mortality between patients treated with intermittent hemodialysis and those treated with CRRT [22]. In a recent meta-analysis of 21 studies, the modality of RRT was not associated with in-hospital and ICU mortality [23]. According to a retrospective population-based matched cohort study comparing outcomes according to CRRT and hemodialysis (propensity-matched patients with no difference in mechanical ventilation, number of days between hospitalization and initiation of RRT, and baseline characteristics), there was no difference in mortality between the two groups [24]. In contrast to these reports, our results showed that the CRRT group had signifificantly higher mortality than both the control and dialysis groups. In clinical practice, CRRT has been preferentially used in AKI patients with unstable vital signs or poor overall medical conditions; thus, these patients are expected to show a higher mortality rate. Further, in an 8-year observational cohort study by De Corte et al., non-survivors had worse profiles of disease severity, and CRRT as the initial RRT modality was associated with long-term mortality [25]. In our study, although it was not possible to obtain severity scores directly from our database, ECMO, mechanical ventilation, and vasopressor were used more frequently in the CRRT group than in the dialysis or the control groups, suggesting that patients with higher severity scores were included in the CRRT group. Unlike other previous studies with no difference in mortality between the dialysis group and the CRRT group, the CRRT group in our study had a higher mortality. We believe that our result was more representative of real-world practice reflflecting the overall severity of patients.

Few studies have investigated the impact of pre-existing kidney disease and RRT modality on AKI outcomes among critically ill patients. In our study, the dialysis group with pre-existing kidney disease showed lower in-hospital mortality than the control group. A prospective cohort study of AKI in critically ill patients reported that patients with pre-existing kidney disease had a lower mortality rate but were more likely to be dialysis-dependent at hospital discharge [26]. CKD is known to increase susceptibility to AKI, and AKI on CKD is associated with a worse renal outcome [27]. Patients with pre-existing kidney disease may take a relatively shorter time to reach the indications for RRT during the course of AKI, or early RRT can be considered based on their medical history of kidney disease. Our hypothesis is that multiorgan failure might be more frequent in AKI patients without pre-existing kidney disease, and RRT might be performed relatively earlier in patients with pre-existing kidney disease, resulting in reduced in-hospital mortality in our study population. Moreover, the mortality at day 60 was signifificantly higher in patients who received late RRT (61.8%) than in those who received early RRT (48.5%) in the Artificial Kidney Initiation in Kidney Injury (AKIKI) trial [28], which supports our hypothesis. The Early versus Late Initiation of Renal Replacement Therapy in Critically Ill Patients with AKI (ELAIN) trial also demonstrated that early initiation of RRT signifificantly reduced 90-day and 1-year all-cause mortality compared to delayed initiation of RRT [29,30].

Furthermore, intrarenal alterations at a molecular, cellular, and tissue level related to pre-existing kidney diseases seem to affect not only the severity of AKI but also the degree of the renal repair process, including fibrosis [6]. Previous studies reported that AKI contributes to the deterioration of renal function in CKD patients [31,32]. In a retrospective cohort study including patients older than 67 years, those with AKI on CKD showed a signifificantly higher risk of ESKD than those with AKI or CKD alone [26]. Further, in a cohort study of 9425 patients with postoperative AKI, patients with pre-existing kidney disease had higher risks of long-term mortality and dialysis dependency than those without pre-existing kidney disease [32]. Additionally, in several studies, the CRRT group showed better renal recovery and a lower rate of dialysis dependency than the dialysis group [24,33–36]. Similarly, our results showed that the cumulative incidence of ESKD was higher in the dialysis group than in the CRRT group, especially in the subgroup with pre-existing kidney disease. The incidence rate of ESKD was signifificantly higher in patients with pre-existing kidney disease, regardless of the RRT modality received. However, the dialysis group showed lower in-hospital mortality than the control group. These results support the clinical importance of timely RRT to improve the survival of critically ill patients with AKI, although maintenance dialysis reduces the quality of life and increases the burden of medical costs [37]. Our results also suggest the necessity of further study focusing on overall outcomes of AKI in critically ill patients stratified by the presence of pre-existing kidney disease. 

This study has several limitations. First, detailed clinical data, such as the etiology of AKI, serum creatinine, and urine volume could not be analyzed because of the inherent limitations of the national registry database used in our study. However, the main purpose of this study was to compare hard outcomes such as in-hospital mortality and the risk of ESKD development depending on the application of RRT or RRT modalities. Although a contemporary consensus-based definition of AKI could not be used, we believe that our large database was sufficient to investigate the primary aim of our study. Second, the overall severity scores of critically ill patients, such as sequential organ failure assessment (SOFA) and acute physiology and chronic health evaluation (APACHE) scores, were not measured. However, considering that MV, ECMO, and vasopressor drugs were used more frequently in the CRRT group than in the dialysis group, the CRRT group seemed to include patients with hemodynamic instability and worse medical conditions. Unlike previous studies showing similar mortality in both CRRT and dialysis groups, our study showed higher mortality in the CRRT group after adjusting for confounding variables. We believe that our study reveals a difference in mortality among critically ill patients with AKI according to the modality of RRT in the real world. Third, the definition of ‘kidney disease’ was based on diagnostic codes. The NHIS department regularly audits claims in the Korean health insurance system, and the government provides special insurance coverage by evaluating the procedures and treatment under disease codes. Therefore, our HIRA database is considered reliable and has been widely used for research purposes [10].

Despite these limitations, our study has clinically important strengths including the study’s design and statistical methods based on the analysis of a large population-based cohort. This enables a meaningful report of mortality and progression to ESKD considering both available RRT modalities and the presence of pre-existing kidney disease. Additionally, medical treatments associated with relevant critically ill patient conditions such as MV, ECMO, and vasopressor drugs were comprehensively analyzed. 

5. Conclusions 

Among critically ill patients with AKI in Korea, patients with pre-existing kidney disease in the dialysis group had relatively lower in-hospital mortality and a greater risk of progression to ESKD than those with pre-existing kidney disease in both the control and CRRT groups. In-hospital mortality was the highest in the CRRT group without pre-existing kidney disease, while the risk of ESKD was higher in the subgroup without pre-existing kidney disease. Our findings may support the critical impact of severe AKI requiring RRT on both mortality and long-term renal outcomes in critically ill patients, including those without pre-existing kidney disease. Further prospective studies considering pre-existing kidney disease are required to elucidate the clinical impact of RRT modality on overall and renal outcomes in clinically ill patients with AKI. 

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