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Impact of Continuous Renal Replacement Therapy Intensity on Septic Acute Kidney Injury

Mayumi, Kengo; Yamashita, Tetsushi; Hamasaki, Yoshifumi; Noiri, Eisei; Nangaku, Masaomi; Yahagi, Naoki; Doi, Kent

doi: 10.1097/SHK.0000000000000496
Clinical Aspects
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ABSTRACT The intensity of continuous renal replacement therapy (CRRT) for acute kidney injury (AKI) has been evaluated, but recent randomized clinical trials have failed to demonstrate a beneficial impact of high intensity on the outcomes. High intensity might cause some detrimental results recognized recently as CRRT trauma. This study was undertaken to evaluate the association of CRRT intensity with mortality in a population of AKI patients treated with lower-intensity CRRT in Japan. A retrospective single-center cohort study enrolled 125 AKI patients treated with CRRT in mixed intensive care units of a university hospital in Japan. Subanalysis was conducted for septic and postsurgical AKI. The median value of the prescribed total effluent rate was 20.1 (interquartile range 15.3–27.1) mL/kg/h. Overall, univariate Cox regression analysis indicated no association of the CRRT intensity with the 60-day in-hospital mortality rate (hazard ratio 1.006, 95% confidence interval [CI] 0.991–1.018, P = 0.343). In subanalysis with the septic AKI patients, multivariate analysis revealed two factors associated independently with the 60-day mortality rate: the Sequential Organ Failure Assessment score at initiation of CRRT (hazard ratio 1.152, 95% CI 1.025–1.301, P = 0.0171) and the CRRT intensity (hazard ratio 1.024, 95% CI 1.004–1.042, P = 0.0195). The CRRT intensity was associated significantly with higher 60-day in-hospital mortality in septic AKI, suggesting that unknown detrimental effects of CRRT with high-intensity CRRT might worsen the outcomes in septic AKI patients.

*Department of Nephrology and Endocrinology

22nd Century Medical and Research Center

Department of Emergency and Critical Care Medicine, The University of Tokyo, Tokyo, Japan

Address reprint requests to Dr Kent Doi, Department of Emergency and Critical Care Medicine, University Hospital, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-8655, Japan. E-mail: kdoi-tky@umin.ac.jp.

Received 4 August, 2015

Revised 17 August, 2015

Accepted 16 September, 2015

Funding: This study was partly supported by grants from the Tokyo Society of Medical Sciences (to K.D.). Asahi Kasei Corporation (Tokyo, Japan) partly supported this study, but did not contribute to the study design, data analysis, or manuscript preparation.

The authors have no conflicts of interest to declare.

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INTRODUCTION

For critically ill patients with severe acute kidney injury (AKI) —a well recognized complication of critical illness—continuous renal replacement therapy (CRRT) has become a common treatment in the past several decades. The Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Study—an international observational study for AKI in critically ill patients—revealed that the mortality of patients requiring renal replacement therapy (RRT) is unacceptably high (1). Numerous clinical studies including several randomized controlled trials (RCTs) have been conducted to ascertain the optimal CRRT intensity for severe AKI. A single-center RCT found that patients treated with 35 mL/kg/h of CRRT had better outcomes than those treated with 20 mL/kg/h (2). However, more recently, two large RCTs have found that increasing CRRT intensity to 35 or 40 mL/kg/h did not improve the outcomes of patients with severe AKI (3, 4). On the basis of these findings, current AKI guidelines recommend the delivery of an effluent volume of 20 to 25 mL/kg/h for CRRT in AKI (5). Nevertheless, AKI patients in Japan are typically treated with approximately 10 to 16 mL/kg/h of CRRT because of the limitations of the Japanese medical insurance system. Although the lower limit of sufficient dose has been studied inadequately, one study from Japan has suggested that this dose (10–16 mL/kg/h) is sufficient to avoid any decline in the survival rate of AKI patients treated by CRRT (6). This study was conducted to evaluate the lower-threshold CRRT intensity sufficient to provide similar outcomes to those of the higher intensity for severe AKI. In addition, many clinical conditions are associated with mortality in critically ill patients with severe AKI. Among them, sepsis is the strongest contributing factor of to hospital death (7). Postsurgical conditions are another factor. Therefore, for this study, we conducted subgroup analysis related to sepsis complications and postsurgical intensive care unit (ICU) admission.

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METHODS

Study population and data collection

All patients aged 18 years or older hospitalized in the ICU of a single center (The University of Tokyo Hospital), from June 2011 to April 2014, were screened retrospectively to ascertain whether they had been treated with CRRT during their ICU stay. Patients with pre-existing end-stage renal disease on chronic hemodialysis were excluded from this study. For patients admitted to the ICU more than once before discharge, we collected data only for the first admission. Data of trough concentrations of vancomycin (VCM) and teicoplanin (TEIC) were collected from the patients who were determined as sepsis described below and treated by CRRT from June 2011 to April 2015 in the same ICU. If multiple measurements of trough concentration were conducted in one patient, the first three results were used. The study protocol was approved by The University of Tokyo Institutional Review Board. Informed consent was waived because of the noninterventional, retrospective design of the study.

All data were collected retrospectively on standardized data forms: Acute Physiology and Chronic Health Evaluation (APACHE II) score during the first 24 h of admission (8), blood tests at the initiation of CRRT, and data elements on CRRT (modality, blood flow rate, dialysate and replacement fluid rate, and type of dialysis membrane). Patient outcomes were also obtained. Because all patients were treated with postdilution hemodiafiltration, the CRRT intensity was calculated using a total effluent rate (the sum of the dialysate and replacement fluid rates and ultrafiltration rate) and expressed in units of mL/kg/h. The body weight used for this calculation was obtained at the initiation of CRRT. The CRRT intensity was calculated from a total effluent rate and body weight at initiation of CRRT. Patients were categorized into two groups by dose: higher intensity (above the median) and lower intensity (below the median). The presence or absence of sepsis and surgical operations was also assessed. Sepsis was defined as systemic inflammatory response syndrome (SIRS) caused by a suspected or proven bacterial or fungal infection according to the American College of Chest Physicians and the Society of Critical Care Medicine Consensus Conference Committee guidelines (9).

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Statistical analysis

Statistical analyses were conducted using software (JMP ver. Pro 11; SAS Institute Inc., Cary, NC). Continuous variables were expressed as mean ± standard deviation or median with an interquartile range (IQR). They were compared between two groups using Student t tests. Categorical variables were expressed as the number and percentage, with comparisons by Pearson chi-square analysis or Fisher exact test. All probability values were two-sided; P valueless than 0.05 was inferred as significant.

Cumulative mortality rates for 60 days were calculated according to the Kaplan-Meier method. Prespecified subgroup analyses were performed according to the presence or absence of sepsis. Cox regression analysis was used to evaluate the independent association of CRRT intensity with the 60-day in-hospital mortality rate. The variables showing P less than 0.05 in the univariate Cox regression analysis were entered into the multivariate analysis followed by stepwise variable selection.

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RESULTS

A total of 175 patients treated with CRRT were screened. Finally, 125 patients were enrolled into this study, excluding 2 patients younger than 18 years and 48 end-stage renal disease patients who had been treated using chronic hemodialysis. Patient information and clinical characteristics are presented in Table 1. The median value of the prescribed total effluent rate was 20.1 mL/kg/h (IQR 15.3–27.1). The enrolled patients were divided into two groups by prescribed CRRT intensity (Table 1): 63 patients received lower CRRT intensity (equal to the median or less, ≤20.1 mL/kg/h), although 62 received higher CRRT intensity (above the median, >20.1 mL/kg/h). Although patients treated with a higher intensity were diagnosed predominantly with sepsis and although they had a lower Sequential Organ Failure Assessment (SOFA) score at CRRT initiation, no other clinical factor, except for body weight and platelet count, including age, sex, the APACHE II score, the blood urea nitrogen (BUN), or serum creatinine levels, differed significantly between the groups.

Table 1

Table 1

Within 60 days after CRRT initiation, in-hospital death occurred in 26 (41.9%) of 62 patients in the higher-intensity group and in 25 (39.6%) of 63 patients in the lower-intensity group (odds ratio [OR] in the higher-intensity group 1.09, 95% confidence interval [CI] 0.53–2.24, P = 0.79). Kaplan-Meier analysis estimated the probability of 60-day in-hospital mortality as similar between the two treatment groups (Fig. 1). Univariate Cox regression analysis showed that the CRRT intensity was not significantly associated with 60-day in-hospital mortality (hazard ratio 1.006, 95% CI 0.991–1.018, P = 0.343) (Table 2).

Fig. 1

Fig. 1

Table 2

Table 2

In subgroup analysis, high CRRT intensity was associated significantly with the 60-day in-hospital mortality rate in patients with sepsis, but not in patients without sepsis. Table 3 presents the sites and microbiology of infections in the present cohort. Postsurgical admission had no effect on the association of CRRT intensity with mortality (Table 4). Therefore, we further evaluated the effect of CRRT intensity on the 60-day in-hospital mortality rate in CRRT-treated AKI patients who had sepsis as a complication.

Table 3

Table 3

Table 4

Table 4

The sepsis patients were divided into two groups by prescribed CRRT intensity (Table 5): 28 patients received lower CRRT intensity (equal to the median or less, ≤21.5 mL/kg/h), although 28 received higher CRRT intensity (above the median, >21.5 mL/kg/h). Univariate analysis indicated six prognostic factors that were significantly associated with 60-day in-hospital mortality rate: the CRRT intensity, APACHE II at ICU admission, platelet count, vasopressor use, and SOFA score at ICU admission and at the initiation of CRRT (Table 6). Multivariate analysis revealed two factors to be independently associated with 60-day in-hospital mortality: SOFA score at initiation of CRRT (hazard ratio 1.270, 95% CI 1.094–1.483, P = 0.0017) and CRRT intensity (hazard ratio 1.029, 95% CI 1.008–1.048, P = 0.0091) (Table 7). Data of trough concentrations of VCM (n = 28) and TEIC (n = 31) in septic AKI patients treated by CRRT were analyzed. Trough concentrations were lower in the higher-intensity group than in the lower-intensity group (Table 8).

Table 5

Table 5

Table 6

Table 6

Table 7

Table 7

Table 8

Table 8

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DISCUSSION

We conducted a single-center retrospective observational study to investigate the association of the CRRT intensity with the 60-day in-hospital mortality rate in critically ill patients treated in an adult mixed ICU. Although the overall analysis showed no association of the CRRT intensity with the 60-day in-hospital mortality rate, higher CRRT intensity was associated significantly with higher 60-day in-hospital mortality, even after adjusting for confounding factors in the group of septic patients. Previous clinical studies have evaluated the beneficial effects of high CRRT intensity on AKI patients, but they failed to demonstrate its effectiveness (3, 4). Of note, these two multicenter RCTs did not show the disadvantage of higher-intensity CRRT. Although this study was conducted in an observational manner, the results suggest that higher CRRT intensity provides harmful effects rather than beneficial effects to AKI patients, especially those complicated with sepsis, who were expected to have been affected by overwhelming cytokine storm and therefore were assumed to be good responders of high-intensity CRRT. Another retrospective observational study conducted by Fujii et al. reported no significant difference in in-hospital mortality between the lower-intensity CRRT group (median 14.2 mL/kg/h) and the higher-intensity CRRT group (median 20.0 mL/kg/h) (10). However, multiple logistic regression analysis revealed that higher CRRT intensity is significantly associated with increased in-hospital mortality rate in accordance with our present study. It is noteworthy that the proportions of sepsis complications in these studies are similar (38% in this study; 55% in Fujii et al.'s study).

Why is higher CRRT intensity shown to increase mortality of septic AKI patients in these two studies? One possible explanation is that these two observational studies were conducted in Japan. The overall CRRT intensities were lower than others reported in the relevant literature (median 16 mL/kg/h in Fujii et al.'s study; 20 mL/kg/h in our present study). The Japanese health insurance system recommends CRRT dose as 15 L/day (e.g., 10 mL/kg/h for 60 kg body weight). On the basis of two large multicenter RCTs, which found no benefit of the higher intensity of 40 to 45 mL/kg/h compared with the lower intensity of 20 to 25 mL/kg/h (3, 4), the current AKI guideline recommends delivering an effluent volume of 20 to 25 mL/kg/h for CRRT in AKI (5). It should be addressed that higher intensity in the Japanese studies is as much as lower intensity in these RCTs (20–25 mL/kg/h). No RCT has compared two lower intensities such as 10 to 15 mL/kg/h vs. 20 to 25 mL/kg/h. For comparison of CRRT intensities in this lower range, higher-intensity CRRT might provide harmful effects rather than benefits to septic AKI patients. Further investigation, ideally by RCT, must be undertaken to confirm our speculation.

What is the potential mechanism by which higher CRRT intensity increased the mortality of septic AKI patients? Recently, shortcomings deriving from CRRT have been suggested as CRRT trauma (11). Complications associated with high CRRT intensity include electrolyte abnormality, nutrition loss, and inadequate antibiotics administration. Among electrolyte complications, hypophosphatemia is the most frequently observed in patients undergoing CRRT, but subanalysis of one recent RCT (the Randomized Evaluation of Normal versus Augmented Level [RENAL] Replacement Therapy Study) using multivariable logistic regression analysis revealed that hypophosphatemia is not an independent predictor of mortality (12). Regarding the loss of nutrition during CRRT, micronutrients such as water-soluble vitamins, trace elements, and amino acids are easily eliminated during CRRT therapy. Especially, the amino acid loss is not negligible. It must be counterbalanced by increasing the amino acid supply by approximately 0.2 g/kg/day (13). Immune system function is known to be modified through altered supply of some amino acids such as arginine and glutamine. Because the Surviving Sepsis Campaign Guideline (SSCG) recommends administration of oral or external feedings within the first 48 h after the diagnosis of sepsis (14), nutrition loss by higher CRRT intensity might negatively affect septic AKI patients. Finally, the elimination of antibiotics is increasingly common among patients receiving high-intensity CRRT. Lower trough concentrations of VCM and TEIC in the higher-intensity group were observed in this study (Table 8). In general, renal elimination of drugs is decreased in patients with AKI, but residual renal function, in conjunction with RRTs, enhances drug clearance. Maintenance doses must reflect these circumstances. In addition, the volume of hydrophilic agent distribution can increase as a result of fluid overload and decreased binding of the drug to serum proteins; antibiotic loading doses must be increased to account for these changes (15). Nevertheless, at clinical sites, antibiotics tend to be prescribed in small doses to septic patients with RRTs. Timely and appropriate antibiotic therapy for the treatment of sepsis is known to influence in-hospital mortality rates significantly (16, 17). Maintaining reliably sufficient concentrations of antibiotic drugs is extremely important.

Our study entails several limitations which might have affected the results. First, this study was conducted at a single center. The number of patients analyzed was insufficiently large. One previous retrospective study conducted in a single center showed the different results from the present study; a lower delivered intensity contributed to predict higher mortality in a septic AKI cohort (18). Evaluations in multicenter ICUs with larger cohorts should be conducted to verify our findings. Second, this is a retrospective observational study that incorporates biases inherent in this study design. Because the CRRT intensity was judged by the attending physicians (intensivists and nephrologists), a higher intensity might have actually been prescribed for more severely ill patients. Third, patients receiving a lower CRRT intensity had a significantly greater body weight (Table 1). Inverse correlation between obesity and mortality of patients with heart failure, pneumonia, and severe sepsis has been reported recently (19–22). Creatine is converted into creatinine by a nonenzymatic cyclization throughout the body, but especially in skeletal muscle, and creatinine production can fall because of reductions in lean body mass. Reportedly, a higher serum creatinine is paradoxically associated with better patient survival (23, 24). Although the body weight at CRRT initiation and baseline serum creatinine concentration are not associated significantly with 60-day in-hospital mortality in the Cox proportional analysis of the present study, this inverse correlation between obesity or muscle mass and mortality might affect the association between CRRT intensity and mortality. Finally, the Japanese health insurance system for ICU patients, which is not fee-for-service, but episode-of-care payment system, might have a significant impact on CRRT intensity in this study. The prescribed dose in this study was mostly larger than the recommended dose (15 L/day) by the health insurance system because ICU physicians did not have to strictly follow this limit.

In conclusion, although overall analyses showed no association of the CRRT intensity with the 60-day in-hospital mortality rate, higher CRRT intensity was associated significantly with higher 60-day in-hospital mortality, even after adjusting for confounding factors in the group of septic patients. These results indicate that the shortcomings of high-intensity CRRT (electrolyte abnormality, nutrition loss, and elimination of antibiotics) tend to affect mortality, especially in septic patients.

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Keywords:

Acute kidney injury; continuous renal replacement therapy; CRRT intensity; intensity; intensive care; mortality; sepsis

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