Clinical Predictors of Mortality of Patients With Acute Kidney Injury Requiring Renal Replacement Therapy

Background: Acute kidney injury (AKI) is frequently encountered around 40% in critically ill patients and associate with a high mortality particularly in AKI patients requiring renal replacement therapy (RRT). The objective of this study was to assess the clinical predictors for 28-day mortality in AKI patients requiring RRT. Methods: This is a retrospective cohort study from prospectively collected data over a year (2014-2015). AKI patients requiring RRT were included. We collected demographic and laboratory data of AKI patients requiring RRT within 24 hours before initiation of RRT. We excluded patients with pre-existing chronic kidney disease stage 5 and AKI patients requiring peritoneal dialysis. We compared clinical characteristics and analyzed the predictors of mortality of survivors and non-survivors according to 28-day mortality. Results: We included 122 AKI patients requiring RRT. Mortality rate at day 28 and 90 after AKI diagnosis were 59% (95% con�dence interval [CI] 49.7-67.8) and 72.1% (95%CI 63.3-79.9). On multivariable analysis, clinical predictors for 28-day mortality were baseline serum creatinine (hazard ratio [HR] 0.57, 95% CI 0.36-0.90), SOFA score before initiation of RRT (HR 1.08, 95%CI 1.01-1.15), presence of vasopressors before initiation of RRT (HR 3.04, 95%CI 1.12-8.25), serum lactate > 4 mmol/L before initiation of RRT effect <10 days of survival time (HR 2.49, 95%CI 1.17-5.26), and serum lactate > 4 mmol/L before initiation of RRT effect ≥ 10 days of survival time (HR 1.31, 95%CI 0.47-3.60). Conclusion: A lower baseline serum creatinine was associated with the mortality in AKI patients requiring RRT. SOFA score, presence of vasopressors, and a higher serum lactate before initiation of RRT are useful clinical predictors for the 28-day mortality.


Introduction
Acute kidney injury (AKI) is a syndrome characterized by an abrupt deterioration of renal function resulting in a sharp increase in serum creatinine (SCr) and/or decrease in urine output [1].Advanced severity of AKI leads to the accumulation of nitrogenous metabolites and water electrolyte imbalances, which harmfully affects distant organ functions such as lungs, heart, and brain [2].Incidence of AKI is up to 20% of hospitalized patients [3] and 30-60% of critically ill patients [4][5][6].
Patients with AKI has a high mortality rate ranging 25-60% [3,4,6] and there is a stepwise increase of mortality with increase of AKI severity, particularly stage II and III AKI [7,8].These rates remained virtually unchanged despite the optimization of care [9].In the literature, risk factors associated with death of critically ill patients with AKI include old age, prolonged hospitalization, a higher severity of illness, presence of comorbidities, oliguria, hypovolemia, metabolic acidosis, sepsis, multiple trauma, use of vasoactive drugs and respiratory failure [10].Timing and intensity of renal replacement therapy (RRT) do not have a bene cial effect on mortality [11][12][13][14].
Although various modalities of RRT are generally safe, there are some potential adverse events associated with RRT such as hypotension, bleeding, allergic reactions, and complications of vascular access [15].Because RRT is costly and consumes healthcare resources [16], patient selection for RRT is a crucial step.Predictive factors and a model for death should be investigated.However, clinical predictors for death in AKI patients requiring RRT are not fully elucidated.The aim of this study is to determine clinical predictors associated with mortality in AKI patients requiring RRT in intensive care units.

Materials And Methods
We conducted a retrospective study from prospectively collected data submitted to the epidemiological study of organ failure and support in the intensive care unit of Srinagarind Hospital, Khon Kaen University, Thailand.from June 1, 2014 to May 31, 2015.Our hospital is a tertiary academic referral center.We included all adult (> 18 years old) patients admitted to the medical intensive care unit (ICU) or a cardiac ICU with diagnosis of AKI requiring RRT.We excluded patients with pre-existing chronic kidney disease stage 5 (de ned as an estimated glomerular ltration rate [GFR] < 15 mL/min/1.73m 2 or on chronic dialysis) [17] and AKI patients requiring peritoneal dialysis.We compared clinical characteristics and analyzed the predictors of mortality of survivors and non-survivors based on 28-day mortality.
This study was approved by the Khon Kaen University Ethics Committee for Human Research (Approval Number: HE581457).Informed consent was waived by the Institutional Review Board because this study is the retrospective study of the data analysis using information contained in medical charts and records, which were completely anonymized.
Data collection and de nition AKI was de ned according to the Kidney Disease Improving Global Outcomes 2012 guidelines, using SCr and urine output criteria [18].Demographic data were recorded including; age, sex, body mass index, ICU diagnosis, Acute Physiology and Chronic Health Evaluation II (APACHEII) score at ICU admission, Sequential Organ Failure Assessment (SOFA) score at ICU admission, Charlson comorbidity index and baseline SCr.Modes of RRT including intermittent hemodialysis and continuous renal replacement therapy (CRRT) were collected.Timing of RRT initiation since hospital admission, ICU admission and AKI diagnosis were also recorded.Clinical characteristics within 24 hours before initiation of RRT were recorded including presence of acute respiratory failure, shock requiring vasopressor, pulmonary edema, acute coronary syndrome, SOFA score, urine volume and cumulative uid balance.The worst laboratory parameters were collected within 24 hours before initiation of RRT including blood urea nitrogen (BUN), SCr, serum bicarbonate, arterial blood gas, base excess, serum albumin and serum lactate.
Acute respiratory failure is de ned as a patient who requires invasive mechanical ventilation or noninvasive ventilation for ≥ 24 hours [19,20].Shock is de ned as a patient having mean arterial pressure < 65 mmHg along with tissue hypoperfusion including cold clammy skin, mottled skin, altered mental status or decrease of urine output [21].Sepsis and septic shock are de ned according to the 2012 surviving sepsis campaign [22].The primary outcome of interest is the mortality at day 28 after diagnosis of AKI.

Statistical analysis
Continuous variables were expressed as mean (standard deviation) or median (interquartile range [IQR]) as appropriate.Categorical variables were expressed as counts and percentages (%).Study population was divided into two groups (survivors and non-survivors at day 28 after diagnosis of AKI).Two sample ttest and Wilcoxon rank-sum were used to compare continuous variables as appropriate between survivors and non-survivors.Chi-square test and Fischer's exact test were used to compare categorical variables as appropriate between two groups.

Multiple imputation
There were ve predictors that had missing values more than 10%, which could produce biased estimates and lead to invalid conclusions if the complete case analysis were performed.Therefore, missing data was handled using multiple imputation by chained equations and analyzed 50 imputed data sets in order to complete Cox proportional hazard regression models [23,24].The imputation processes included variables that were incorporated into both regression models and also included outcomes variables [25].The number of imputed datasets was based on a quadratic function of the fraction of missing information [26].Calculations of missing values were done in R version 4.0.0 using automatic predictor selection tool of the mice 3.8.0package.

Derivation of the survival model
A Cox proportional hazards (PH) model and an extended Cox model were used to examine the association between clinical predictors and survival time at day 28 after diagnosis of AKI.The PH assumption was tested using Schoenfeld residuals.The lactate variable violated the PH assumption; hence, the extended Cox model with Heaviside functions were applied.To build multivariable regression model, univariable regression was rst performed.The variables signi cant at P < 0.2 by univariable analysis were identi ed as potential predictor variables and entered into a multivariable regression model.
Variable selection techniques included two steps.The rst step involved performing backward and forward stepwise model selection based on the Akaike information criterion separately on each imputed dataset, followed by the construction of a new supermodel that contained all variables that were present in at least a half of the initial models.Second, a special procedure for backward elimination was applied to all variables present in the supermodel.The pooled likelihood ratio p-value was calculated.If the largest p-value is > 0.05, the corresponding variable was removed, and the procedure was repeated on the smaller model.The procedure stops if all P ≤ 0.05.The model estimates and standard errors were combined into a single set of results using Rubin's rules.The model performance was evaluated using Harrell's discrimination index (or C-statistics).All the statistical analyses were performed using R software version 4.0.0The level of statistical signi cance was set at p < 0.05 (two tailed).
The percentages of missing data across 15 variables that were put in the full regression model varied from 0 to 46.7%.The percentages of baseline SCr and serum lactate before RRT were the two most common missing variables, 46.7% and 32.8%, respectively (Table 1 and Table 2 3 and Fig. 1. On multivariable analysis, non-survivors at day 28 showed signi cant association with a lower baseline SCr (hazard ratio [HR] 0.57, 95%CI 0.36-0.90,P = 0.02), a higher SOFA score before RRT (HR 1.08, 95%CI 1.01-1.15,P = 0.03), a higher rate of shock requiring vasopressor (HR 3.04, 95%CI 1.12-8.25,P = 0.03), and serum lactate > 4 mmol/L for survival time < 10 days (HR 2.49, 95%CI 1.17-5.26,P = 0.02).For the measure of discrimination, the Harrell C-statistics for the reduced model was 0.76 (95%CI 0.70-0.82).Patients with lower baseline SCr before hospitalization was strongly associated with mortality.Moreover, a higher severity of illness score (SOFA score) before initiation of RRT was also associated with mortality.Cardiovascular failure requiring vasopressors was more important than other organ failure to predict mortality.Higher degree of tissue hypoperfusion indicated by a higher serum lactate level was a strong independent factor for mortality among AKI patients requiring RRT.
Death rates of dialysis patients with severe AKI and multiple organ failure is at around 50-80% [8, 12,27,28].Similar to those data in the literatures, our study showed mortality of 59% among AKI patients requiring RRT.A wide range of mortality in AKI could be explained by the heterogeneity of patients.
The multinational AKI-EPI study showed that older age, a higher severity of illness, a higher severity of AKI, presence of liver failure, emergency surgery and a lower SCr at ICU admission were associated with death [4].Regarding the predictors of mortality, our study focused on AKI patients requiring RRT population because some factors may be modi ed to improve survival.This study showed inverse correlation between baseline SCr before admission and mortality.This result was in line with the AKI-EPI study in that the higher the SCr at time of ICU admission, the lower the likelihood ratio of death [4].
Moreover, a lower SCr was associated with death of not only AKI patients but also of general hospitalized patients [29].SCr is one of the surrogates for muscle mass; hence, low Scr re ects poor nutritional status [30].Cr is distributed in the total body water.Thus, positive uid balance can increase total body water, which confer the diluting effect on SCr concentration resulting a falsely lowered SCr in the ICU [31].SCr at the time of RRT can also predict mortality [32], possibly re ecting hemodilution due to uid overload.
Our results showed that a higher severity of organ failure before initiation of RRT, which was indicated by SOFA score, was signi cantly associated with death.This result was in accordance with the study of Chertow et al. in that extrarenal organ failures, presence of sepsis or septic shock, and older age at the day of dialysis were associated with high mortality [32].
In addition, model for predicting mortality at the day of dialysis had more predictive power than the day of AKI diagnosis [32].We also found that vasopressor requirement and a higher serum lactate, especially more than 4 mmol/L, are associated with higher likelihood of death.These ndings were in line with several studies [33][34][35].Moreover, indicators of hemodynamic failure were retained in the nal multivariable model.Renal replacement therapy may lead to intradialytic hypotension [36-38] that aggravated hemodynamic disturbances.
Several kidney-speci c severity scores were developed using demographic data, comorbidity, organ failure, laboratory data, and treatments.However, they were developed for a decade.Although predictive risk model for 60-day mortality of Demirjian et al. is high accuracy [39], external validation is low [40].
Hence, implication of clinical predictive models need to be developed in a larger population.
We acknowledge a number of limitations of the current study, which are in part due to the retrospective cohort study.Since half of the study population did not have a baseline SCr, we addressed this problem using multiple imputation instead of complete case analysis.However, a large epidemiological study of AKI had missing baseline SCr of one-third [4].We explored both of baseline characteristics and laboratory data before initiation of RRT to build an exhaustive model.A future study needs to be conducted in a larger population.

Conclusions
In conclusion, the mortality rate among the AKI patients requiring RRT is high.Based on our ndings, a higher SOFA score, requirement of vasopressors, a higher serum lactate before initiation of RRT and baseline SCr should be considered for the clinical predictors of the mortality of AKI patients requiring RRT.

Figures Figure 1 Forest
Figures ).Baseline clinical characteristics between survivors and non-survivors at day 28 after diagnosis of AKI were shown in Table1.The non-survivors had a signi cantly higher severity of illness at the day of ICU admission (mean SOFA score 13.7 vs 10.3, P < 0.001; mean APACHE II score 33.1 vs 25.8, P < 0.001) and lower baseline SCr (0.90 [0.65-1.30]vs1.38 [0.90-2.18],P=0.01).The non-survivors had a higher prevalence of septic AKI (66 [91.7%] vs 31 [62%], P < 0.001) but had a lower prevalence of renal AKI (14[19.4%]vs18 [35%], P = 0.04).In addition, the number of patients requiring CRRT was higher among non- AKI = acute kidney injury; APACHE = acute physiology, age, chronic health evaluation; CKD = chronic kidney disease; CRRT = continuous renal replacement therapy; eGFR = estimated glomerular ltration rate; ICU = intensive care unit; IQR = interquartile range; RRT = renal replacement therapy; SCr = serum creatinine; SD = standard deviation; SOFA = sequential organ failure assessment.* P < 0.05 when compared with survivors AKI = acute kidney injury; APACHE = acute physiology, age, chronic health evaluation; CKD = chronic kidney disease; CRRT = continuous renal replacement therapy; eGFR = estimated glomerular ltration rate; ICU = intensive care unit; IQR = interquartile range; RRT = renal replacement therapy; SCr = serum creatinine; SD = standard deviation; SOFA = sequential organ failure assessment.* P < 0.05 when compared with survivors BUN = blood urea nitrogen; IQR = interquartile range; SD = standard deviation; SOFA = sequential organ failure assessment.* P < 0.05 when compared with survivors Predictors of mortality at day 28 Fifteen variables were studied by multivariable extended Cox model.Because serum lactate was a timevarying covariate; hence, the extended Cox model with Heaviside functions was used to estimate effect of time varying covariate.Predictors associated with mortality at day 28 were shown in Table

Table 3
Factors associated with non-survivors in patients with renal replacement therapy is a common condition in medical ICU settings and remains a major cause of death.Despite therapeutic and diagnostic advances, the mortality of AKI patients has remained high in recent decades.Regarding of our results, 60% of AKI patients requiring RRT did not survive at day 28 after development of AKI and the mortality rate increased up to 75% at day 90 after development of AKI.
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