Background
Acute kidney injury (AKI) is a major complication in sepsis, and is associated with a high mortality rate. Nearly half of the patients in the intensive care unit (ICU) develop AKI, and the mortality rate among these patients ranges from 30% to 50% [
1,
2]. Early recognition of AKI is therefore important as it allows for early treatment initiation and better prognostication of the clinical course in patients with sepsis.
The definition of AKI is based on absolute or relative changes in serum creatinine levels and the weight-adjusted hourly urine output [
3]. The weight-adjusted hourly urine output is closely associated with early onset of AKI and high mortality rates [
4‐
6]. To date, however, the precise body weight definition that should be used for establishing a urinary diagnosis of AKI remains unclear. For example, in patients with obesity or weight loss, there is a substantial difference between the actual body weight (ABW) and ideal body weight (IBW), which can lead to under- or over-diagnosis of AKI.
Only one study [
7] has evaluated the influence of body weight on the urinary diagnosis of AKI thus far; they reported that ABW was more sensitive but less specific than IBW. In contrast, in acute respiratory distress syndrome (ARDS) [
8] and obese patients [
9], IBW is recommended over ABW because the sizes of the vital organs are more closely related to IBW than to ABW. In this regard, we hypothesized that IBW is more useful in terms of evaluating renal function and establishing a urinary diagnosis of AKI than ABW in heterogeneous patient populations.
Therefore, in this study, we investigated the influence of body weight definitions on the urinary diagnosis of AKI in septic patients who were at risk of AKI. In addition, we evaluated the severity of illness and 90-day mortality for each body weight type determined according to each patients’ body mass index (BMI).
Discussion
Body weight must be taken into consideration in various clinical situations, such as in the management of ARDS and administration of drugs. For example, the low tidal ventilation strategy as a management approach to ARDS is selected based on the IBW, because the lung volume is more closely related to the IBW than the ABW [
17,
18]. In contrast, when calculating the dosage of medications for morbidly obese patients, there is no marked difference in the utility between ABW and IBW [
9]. Furthermore, fluid resuscitation is crucial in the management of patients with sepsis, and can increase the body weight by up to 10% after initial resuscitation [
19]. In such cases, it is unclear whether we should determine the baseline body weight at ICU admission or after the patient’s condition has stabilized a few hours later. In contrast, IBW can be estimated based on the sex and height, which are not affected by fluid balance. Furthermore, renal function is not affected by changes in temporary variables such as daily body weight. As such, the use of IBW seems logically more suitable for evaluating renal function and establishing a urinary diagnosis of AKI than ABW.
In this retrospective study, we investigated the most appropriate body weight definition required to accurately make a urinary diagnosis of AKI. We found a discrepancy rate of 7.6% in terms of the urinary diagnosis of AKI between AKI [ABW] and AKI [IBW]. The number cases of AKI [ABW] was higher than AKI [IBW], which meant a higher sensitivity for detecting AKI. In the AKI [ABW] group, the mortality rate was significantly different among the BMI subgroups, while in the AKI [IBW] group, there were no significant differences in the mortality rates among the BMI subgroups. However, there was no difference in the severity of illness among patients diagnosed with AKI based on ABW or IBW. In this regard, the type of body weight might not have clinical significance in terms of the early recognition of urinary AKI, although AKI [ABW] presented higher sensitivity than AKI [IBW].
To date, there is no consensus about what type of body weight should be used to calculate the weight-adjusted hourly urine output for the urinary diagnosis of AKI according to the KDIGO criteria. Only one study has examined this issue [
7]; that study found that ABW was more sensitive but less specific than IBW in terms of diagnosing and staging AKI using the urine output criterion. However, the population in that study had a higher mean BMI than our studied population (28.0 vs. 22.5), and only 7.8% of patients had a BMI ≤ 20. Therefore, especially for underweight patients, the utility of ABW to diagnose AKI with regards to its superior sensitivity when compared to IBW remains unclear; our findings suggest that AKI [ABW] might yield more heterogeneity in terms of mortality rate prediction and timing of recognizing AKI than AKI [IBW]. In this study, however, there were no significant differences between the two groups in severity of illness. Previous studies suggested that overweight and obese patients presented lower mortality than underweight patients irrespective of the severity of illness [
20,
21]. From this perspective, increased mortality in underweight patients with AKI [ABW] seems more of an “obesity paradox” rather than an underdiagnosis. In this regard, the types of body weight used for urinary AKI might have no clinical significance.
For the early recognition of AKI, 6-h urine output of < 0.5 mL/kg/h and elevated serum creatinine level (≥ 0.3 mg/dL) have been used [
3]. Moreover, AKI could be more sensitively detected using both the urine output and creatinine criteria, than using the creatinine criteria alone [
4‐
6,
22]. However, creatinine production is highly heterogeneous across individuals, differs according to muscle mass, physical activity, and dietary meat consumption, and tends to overestimate the prevalence of AKI in obese patients and underestimate the prevalence in underweight patients. In addition, the urinary diagnosis of AKI depends on the type of body weight used. In this context, the present AKI definition might not be ideal for patients with abnormal body weight such as morbidly obese patients. However, serum creatinine levels would easily be elevated in this population because of their high muscle mass, and this phenomenon could help to make an early diagnosis of AKI. Our study supported this speculation: serum creatinine levels increased in line with the BMI. Creatinine shows small variations in underweight patients because of their lower muscle mass than in obese patients, and this might lead to the under-recognition of AKI despite using two different definitions of AKI, creatinine, and urine output criteria.
Measurement of urine output is not only more sensitive and quicker than measuring serum creatinine once a day in detecting AKI, but it is also important to realize that patients only fulfilling AKI definitions based on urine output criteria differ from patients fulfilling AKI definitions based on serum creatinine with or without urine output measurements. In this study, 15.7% of AKI [ABW] patients and 12.9% of AKI [IBW] patients were not diagnosed with AKI based on the serum creatinine definition. In this regard, serum creatinine and urine output for diagnosing AKI do not always act complementarily, but may show independent pathophysiologies. Further studies are needed to evaluate this concern in these populations.
To evaluate renal function, serum creatinine was commonly used. However, its value was highly affected by body types. Recently, cystatin C has alternatively been recommended for the diagnosis of AKI instead of creatinine [
23]. Cystatin C is a serum protein filtered freely at the glomerulus as is creatinine, but unlike creatinine, it is produced by all nucleated cells and its level is not determined by muscle mass; therefore, its generation appears to be more uniform across populations [
24]. Generally, cystatin C is not recommended to evaluate renal function, and KDIGO guidelines still use serum creatinine. On the other hand, there are several studies in which cystatin C appears to be a better biomarker in the prediction of AKI, especially in the early phase [
25‐
28]. The concentration of cystatin C peaks earlier than serum creatinine in patients with AKI, and may enable the earlier detection of kidney dysfunction than creatinine [
29]. In this study, in line with previous studies, we used cystatin C to evaluate renal function along with serum creatinine in more detail. As a result, both underweight and overweight patients in the AKI [ABW] group showed highly heterogeneous serum cystatin C levels. In this regard, we should recognize that the use of ABW to establish a urinary diagnosis of AKI would result in delayed recognition of AKI in the underweight group, compared to the findings obtained using IBW, irrespective of their severity of illness. To confirm this finding, further studies are needed to evaluate the relationship between BMI and cystatin C concentration in septic AKI patients.
Limitations
Several limitations associated with the present study should be mentioned. First, this was a single-center, retrospective study. The sample size was relatively small, particularly when divided into BMI subgroups. Further studies are needed to confirm our findings, especially for the underweight patients. Second, we did not evaluate fluid balance before admission to the ICU; therefore, the baseline body weight might differ from that in the pre-morbid state. In addition, the timing of body weight measurement was not always just after ICU admission. However, we tried to select the most reliable body weight value after ICU admission in an effort to minimize any errors. Third, we did not measure other AKI biomarkers, such as urine neutrophil gelatinase-associated lipocalin (NGAL), to evaluate the accuracy of urinary AKI. Finally, whether or not the patients’ underweight statuses were due to malignant disease was unclear. The presence of such disease, for example, cachexia, might be associated with the relatively higher mortality rate observed in this subgroup than that in the other BMI subgroups.
Despite these limitations, our study has several strengths. All of our patients were evaluated using the Sepsis-3 criteria as being at risk for AKI. In addition, to the best of our knowledge, our study is the first to focus on various body weight types in order to evaluate the homogeneity of the timing of establishing a urinary diagnosis of AKI.