Multiple studies have shown the detrimental impact of AKI on ICU patients. Unfortunately, the etiology and mechanism of AKI remain unclear. Various reasons such as infection, trauma and other problems that prompt the patient to be admitted into ICU could induce AKI or worsen any pre-existing condition of AKI.(1) Therefore, it is important to have AKI epidemiology data, including the risk factors that may cause AKI, so the country can appropriately manage the health care for these kinds of patients, especially for Indonesia which has limited resources. AKI has been reported to occur in 20-50% of the patients in ICUs around the world [10]. In Indonesia, at the Central Army Hospital of Gatot Soebroto, almost half of the ICU patients (43%) had AKI. This indicated that AKI was a common problem in Indonesian’s ICU (Figure 1). This high incidence of AKI showed that there were problems within the public health system and socioeconomic factors may also affect the epidemiology of AKI in low resource setting [11].
In this study, 373 participants in ICU had AKI of which 181 participants (48.5%) had AKI stage 3 as per the KDIGO criteria. Early diagnosis of AKI in ICU patients is challenging and may explain why our center had many AKI stage 3 participants (Figure 1). Likewise, our findings are similar to those reported from less developed countries. A recent study conducted by Srisawat, et al., reported that the incidence of AKI stage 3 among patients in ICU was 28.9%; 16.4% of the patients at ICU had AKI stage 2 and 7.5% had AKI stage 1.(11) Aside from that, they also showed that when the patients were admitted to ICU, most of the AKI patients progressed to AKI stage 3. This can be explained that AKI was not recognized in time so was not treated appropriately by the time the patients were admitted to the ICU. Hence, the prevalence of AKI patients in developing countries are higher than those in developed country. For example, a recent study conducted in Australia reported that 37.1% of their patients in ICU developed AKI; 18.1% had AKI stage 1, 10.1% had AKI stage 2 and 8.9% had AKI stage 3.(10) The prevalence of AKI in Australia was lower than our study because the doctors there were more vigilant in managing patients with AKI so that their patients did not progress to AKI stage 3. Aside from early diagnosis and treatment, the doctors in Australia have access to many resources and data so have an advantage compared to the developing countries.
Currently, there is limited epidemiology data on AKI in Indonesia. As a result of this, we conducted this study to fill in the gaps so that other organizations in the country can use our data as the reference. In our center, based on the multivariate analysis using logistic regression, the significant factors that were associated with severe AKI were male, CKD and malignancy, high APACHE II score, and use of a vasopressor (Table 3). Even though age was not significantly associated with severe AKI, however, we noticed that the older the participant was, the more severe the AKI was. For our study, the mean age of our participants with AKI was 58 years (± 15 years old). Our findings corroborated the results from a study conducted in Malaysia which showed that the mean age of the AKI patients was 53 years (± 16 years old) and that 56% of the patients had AKI stage 3, 25% had AKI stage 2 and 18% had AKI stage 1 [12]. At the moment, we do not know why age was associated with the severity of AKI. It is possible that age among different ethnicities and countries could have an affect on the severity of AKI. It is also possible that our sample size was not large enough to detect age as one of the risk factors associated with AKI. Another explanation could be that as people age, the more comorbidities they will have, and the kidney, similarly also undergoes age-dependent structural and functional alterations over time [13]. One experimental study using rats showed that aged rats exhibited reduced antioxidant potential and increased oxidative stress after ischemia-reperfusion compared to young rats [14]. The authors showed that the total plasma antioxidant potential (AOP) of aged rats was lower than that of the young rats regardless whether they underwent ischemia-reperfusion or not. Besides this, the renal tissue 8-OHdG levels, which contributes to the destruction of the kidney, were increased in aged rats after reperfusion injury. Thus, this may explain why elderly patients have an increased risk for non-recovery of the renal function after acute ischemia and heightened susceptibility to AKI [15].
Aside from age, our study showed that comorbidities were associated with the severity of AKI. The two most common comorbidities of AKI in our study were diabetes mellitus (N=145) and hypertension (N=147). A previous study showed that having diabetes had a 2.8 fold of increased risk for developing AKI [16]. The mechanism by which diabetes increases the severity of AKI has not yet been well established, but a great deal of research supports the connection between obesity, inflammation, and insulin resistance [17]. Inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) are produced by adipocytes and have been shown to cause insulin resistance [18].
As for hypertension, it too has been shown to increase the risk of developing AKI (OR, 1.13; 95% Cl, 1.02-1.05). Hypertension is commonly found in patients with AKI and vice versa due to several mechanisms with inter-related complications, such as balance disorders of the vascular active substances, renin-angiotensin system activation, changes in the inflammatory factors, and increases in the active oxygen species [19]. Inflammation causes changes in the endothelial function and further increases in the arterial stiffness, oxidative stress and increased circulating angiotensin II levels. Not only that, but it can also reduce the availability of nitric oxide (NO) and worsen the vascular damage. Hence, the combination of hypertension, increased angiotensin II levels and oxidative stress can initiate events that can result in the damage of the renal system [20].
Another comorbidity detected in our study to be associated with AKI was CKD. In this study, our participants were 9.47 times more likely to have CKD as one of their comorbidities. In recent years, studies from different regions reported that CKD is a strong risk factor for the development of AKI, mainly in septic patients. Currently, CKD is found in 30% of the patients who develop AKI in ICU [21]. It is noteworthy that CKD has the highest percentage of association with AKI and is a strong predictor of developing AKI in critically ill patients.
Beside this, almost half of the AKI participants (49.6%) used mechanical ventilation while less than a fifth (17.3%) of non-AKI participants used mechanical ventilation. When we compared the ventilated non-AKI participants to the ventilated AKI participants, the ventilated AKI participants had a higher APACHE score and three days SOFA score. This finding confirmed that AKI in ICU is a prominent risk factor that can worsen the patients’ health conditions, more specifically in low-risk AKI-RRT patients [22]. In addition, Vieira, et al., showed that renal dysfunction had a serious consequence during the use of mechanical ventilation and weaning from mechanical ventilation. The median duration of mechanical ventilation use in AKI patients was 3 days longer than non-AKI patients (10 vs 7 days) [23]. The underlying mechanism that may contribute to the use of mechanical ventilation in AKI patients is severe acute respiratory insufficiency. In order to reach the acceptable gas exchange level, therefore mechanical ventilation is needed to increase the intrathoracic pressure to compensate for these negative changes. If mechanical ventilation is not used, then the AKI patients can progress to renal dysfunction such as renal tubular apoptosis [22].
Apart from the need of mechanical ventilators, RRT is another item that is needed for our AKI participants. In our study, 92 (24.6%) AKI participants required RRT (AKI-RRT). Thus, this finding indicated that RRT in ICU settings is important [24]. It is crucial that AKI patients have access to RRT because the mortality rates among AKI patients are high, especially in critically ill patients in ICU setting [25]. Because of this, facilities should try to overcome challenges of not having various modalities of RRT and hire, at least, one nephrologist.
One of the most common RRT modality used in this study was IHD. Like most hospitals in developing countries, IHD is also the most commonly used method (66 procedures, 71.7%). On the other hand, an online questionnaire study that targeted members from the European Society of Intensive Care Medicine from 50 countries showed that half of the intensivists preferred to use CRRT compared to IHD. The reason why they preferred to use CRRT was because they perceived that this modality had a better hemodynamic stability, had a better therapeutic effect since it can remove the cytokines and can easily control the balance of the fluid [26].
In regards to mortality among patients with AKI, it was shown that the hospital mortality and ICU mortality rates were both worse in patients with AKI at any given stage compared to the in-hospital mortality rate of non-AKI patients. This data was obtained from a cohort study conducted by Mandelbaum, et al., which assessed the hospital mortality and ICU mortality rates in critically ill patients with AKI. The mortality rate in non-AKI patients was 6.25%, in AKI stage 1 patients it was 13.87%, in AKI stage 2 patients it was 16.42%, and in AKI stage 3 patients it was 33.76%. The ICU mortality rate was also higher in AKI patients as follows: 4.54% for non-AKI patients, 10.06% for AKI stage 1 patients, 13.15% for AKI stage 2 patients, and 30.48% for AKI stage 3 patients [27].
Next, we looked at the Kaplan-Meier survival curves according to the presence of AKI and we saw that there was a significant survival difference between AKI participants and non-AKI participants. The survival curve for AKI participants were steeper than the non-AKI participants. This finding showed that the survival rate in AKI participants was worse compared to non-AKI participants. Previous studies clearly showed that AKI patients had worser outcomes compared to non-AKI patients. Hence, it is important to prevent AKI from happening or manage AKI at an earlier stage. This will be beneficial to both the country and the patients. This will help decrease the healthcare burden and increase the patients’ overall survival rates [28].
This study has several strengths. First, we were able to identify the risk factors for developing AKI which can be used to develop a predictability score to prevent AKI and ultimately improve AKI outcome. Also, these risk factors can be utilized in the hospitals so that we can prevent the occurrence of AKI and help the AKI patients have a better prognosis. Another key strength of this study was the availability of the data for mild (AKI stage 1/2) and severe AKI (AKI stage 3). These data made it possible for us to identify the risk factors associated with the development of AKI in ICU participants. The other strength was that our AKI criteria was based on the KDIGO criteria which employed both the creatinine level and urine output data. Because of this, the finding from this study can be used as a reference for other AKI studies conducted in ICU in other hospitals, especially in Indonesia. Last, our findings were able to fill in the gap by providing the country its AKI epidemiological data.
Our study did have some limitations. We collected data from only one site, at the Gatot Soebroto Hospital. Therefore, our data may not truly represent the incidence of AKI in all hospitalized ICU patients across Indonesia. Second, we only collected the data from ICU. Hence, it is possible that our participants could have developed AKI before ICU admission. Third, we only had baseline creatinine level from 9.9% of the participants. However, we were able to determine the baseline creatinine by choosing the reference creatinine from the lower value between the first serum creatinine on the day of admission and the creatinine from the MDRD formula which assumed that the GFR was at least 75mL/min/1.73m2. We demonstrated that it was feasible to exclusively use the MDRD-derived values to generate the baseline serum creatinine levels for our participants [29-31]. We also know that the limitation of MDRD back calculation is based on the assumption that the participant did not have CKD. This was not a problem for our study. For us, our database has the CKD status of the participant before ICU admission. If the participant had a history of CKD, then we used the first available serum creatinine as the baseline serum creatinine level, not the MDRD back calculation. Last, we did not collect data on the drugs used by the participants which could affect the level of the serum creatinine.